MODULATORS OF CYSTEINE PROTEASE

Abstract: The present invention concerns novel mediators of the activity of picornavirus 3C protease and the modulation of the activity of other similar proteins. The modulators may be used in pharmaceutical compositions either for inhibition of 3C protease (for example in viral infections) or for the enhancement of the activity of proteins similar to the 3C protease such as Apopain (for induction of apoptosis).

Description: MODULATORS OF CYSTEINE PROTEASE FIELD OF THE INVENTION The present invention concerns novel pharamaceutical compositions. In particular, the pharmaceutical compositions of the invention comprise cysteine protease modulators. The pharmaceutical compositions of the invention are preferably used for the treatment of viral infections, and diseases resulting from inappropriate apoptosis. BACKGROUND OF THE INVENTION Cysteine proteases are a major family of peptide-bond-cleaving hydrolases, defined as proteases in which the thiol group of a cysteinee residue serves as nucleophile in catalysis. All known cysteinee peptidases require a second residue - an adjacent histidine - for catalysis. While the role of the histidine has been postulated to be a general base in analogy to well-understood serine proteases, it has been clearly demonstrated in theoretical studies that the catalytic histidine cannot act as a base, rather that it acts by donating a proton to the substrate. Cysteinee proteases have been found in the previous literature in viruses, bacterial protozoa, plants, mammals and fungi. There are currently known 38 families of cysteinee proteases (C1-C38), most of which are divided into 5 separately evolved clans (CA-CE). Clan CB enzymes are chymotrypsin-like cysteine proteases containing a His/Cys diad (catalytic histidine preceding catalytic cysteinee in the linear sequence), and responsible for proteolytic cleavage of pol polyproteins (containing the RNA polymerase). These enzymes, commonly hydrolyse glutaminyl bonds, and act on crucial cell proteins as additional substrates. Peptidases of Clan CA - include vital mammalian enzymes (papain, cathepsins) are peptides which normal activitiy is essential and therefor these anzymes should not be inhibited in any type of pharmaceutical compositions. Clan CC includes 16 families of papin-like viral peptidases (C6-C9,C16,C21,C23,C27-29,C31-C36), comprising a cys/his diad. Despite Sequence similarity to Clan CA enzymes, these viral proteins are functionally similar to Clan CB enzymes, cleaving viral polyproteins. Clan CD is represented by a single family (C14), comprising cytosolic endopeptidases known only from animals, which are involved in the process of apoptosis (programmed cell death). There is no structural data regarding peptidases of Clan CE (family C5 adenovirus endopeptidase), as well as untyped enzymes. One untyped family, however, C13, containing medically important proteases, such as Schistosoma mansoni haemoglobinase, is similar to Clan CB enzymes substrate specificity (asparaginyl compared to glutaminyl bonds), as well as in low sensitivity to E64. The latter property may indicate a fold similar to Clan CB chy motry psin- like-enzymes . Picornaviruses are single-stranded positive RNA viruses that are encapsulated in a protein capsid. These viruses cause a wide range of diseases in man and animal mcluding common cold, poliomyelitis, hepatitis A, encephalitis, meningitis and foot-and-mouth disease, as well as diseases in plants such as the potty disease in potatoes. After inclusion into the host cell, the picomaviral RNA is translated into a 247-kDa protein that is co-and post-translationally cleaved, yielding 11 mature proteins. Cysteine proteases, denoted 2 A and 3C, which are part of the picomaviral self polyprotein are responsible for these cleavages. The 2A protease cleaves co-translationally between the structural and non-structural proteins and the 3C protease cleaves post-translationally the remaining cleavage sites except one. Having been recognized as important proteins in the picomaviral life cycle, by virtue of being responsible for its maturation, the 3C and 2 A proteases have been a prime target for extensive structural and mechanistic investigations during the last few years and their mechanism and structural features have been determined (Kreisberg et al, Organic Reactivity: Physical and Biological Aspects, 110-122 (1995)). Site-directed mutagenesis studies (Cheah K.C. et al, J. Biol Chem., 265 (13):7187-7189 (1990)) confirmed by X-ray studies (Matthews et al, Cell, 77:761-771, (1994)) led to the finding that the catalytic site of 3C is composed of the following amino acids: Cys in position 146, Glu/ Asp in position 71 and His in position 40. These three amino acids in the catalytic site of the 3C enzyme constitute a hybrid between the amino acids at the catalytic site of cyteine proteases and serine proteases. Having been recognized as important proteins in the picomaviral life cycle, by virtue of being responsible for its maturation, the 3C (and to a lesser extent the 2A) proteases have been prime targets for extensive structural and mechanistic investigations during the last few years. Aspects such as substrate-specificity, mechanism and structural features have been determined. The 3C protease has been shown by mutagenesis and crystallography to depend on a his/cys diad (His40, Cys 146 - rhinovirus numbering). A third conserved residue in the 3C protease, Asp 71, was initially considered analogous to Asnl75 (the third member in the catalytic triad of papain), however crystallography has shown this residue to be of minor catalytic importance. Due to the involvement of various cysteine proteases in many disorders and diseases ranging from microorganism infection (viral and bacterial) to inflammatory and tumor processes, there have been recently many attempts to find inhibitors for cysteine proteases (Otto and Schimeister, Chem. Rev., 97:133-171, 1997). There have also been attempts to find suitable inhibitors of the picomavims 3C and 2 A proteases in order to treat viral infections. Due to the fact that inhibiting these proteases will avoid production of new virions since there are no native cellular proteases which can replace the cleavage activity of the viral proteases. Therefore, finding an efficient inhibitor against 3C and/or 2 A picomavims proteases will lead to the production of an anti-viral pharmaceutical composition against a large number of viral diseases, both in man and in animal. The first agent found as an inhibitor of the 3 C protease is Thysanone, an antibiotic compound obtained from Thysanophora peniciloides (Singh et al, Tetrahedron Lett, 32:5279-82 (1991)). However, this compound was not developed into a pharmaceutical composition, since it was found to be an efficient inhibitor of the enzyme elastase present in erythrocytes. Two additional antibiotic compounds, of fungal origin, termed citrinin hydrate and radicinin were obtained by screening microbial extracts (Kadam et al, J. Antibiotics 7:836-839 (1994)). These novel two compounds showed a lower level of inhibition than thysanone. The same year a new compound termed kalafungin, which is also an antibiotic compound, was discovered by structural comparison to radicinin, and was found to be a better inhibitor, by three orders of magnitude, than radicinin and citrinin hydrate (McCall et al, Biotechology, 12: 1012-1016 (1994)). Another group of inhibitors, substituted isatins, has also been examined (S.E. Webber, et al., Med. Chem., 39:5072-5082, 1996). Certain members of this group show significant inhibition of 3C proteases with concentrations in the nmolar range, but are highly toxic. Other members of the group are relatively non-toxic, but have poor antiviral activity. It has recently been shown that peptidyl Michael acceptors inhibit rhinovims replication at low micromolar concentrations with a therapeutic index exceeding 10 (Kong et al, J. Med. Chem., 4*1:2579-2587 (1998) or at nanomolar concentrations (Dragovich et al., J. Med. Chem., 41:2819-2834 (1998)). Thus, none of the above inhibitors has been demonstrated to be clinically useful possessing a sufficiently high therapeutic index with favorable toxicology and bioavailability profiles. Transition-state analogs are well established as enzyme and protease inhibitors (Barrett, AJ. and Salvesen, G., Proteinase Inhibitors, Elsevier, 1986). Functional groups such as _ketone, aldehyde, chloromethyl-ketone (REVS) and recently isatin are widely used for the inhibition of serine and cysteine proteases. Class-specificity is achieved by utilization of phosphine or boron geometries (serine proteases) or groups such as epoxide, (Albeck, M., Fluss, S. and Persky, R., J. Am. Chem. Soc, 118:3591-3596, 1996), cyclopropenone (Ando, R. and Morinaka, Y., J. Am. Chem. Soc, lj_5: 1174-1175, 1993) and vinyl-sulfones (Bromme, D., et al., Biochem. J., 315:85-89, 1996). This approach, protease inhibition through transition-state mimicry, yields highly potent inhibitors when combined with target-specific amino-acid residues or their peptidomimetic equivalent. The high molecular weight and complexity of potent TS-analogs frequently cause transport problems, resulting in diminished in vivo efficacy. In other diseases it is desired to activate cysteine proteases. These diseases are characterized by deficient apoptosis, i.e. by insufficient programmed cell death. These diseases include certain types of cancer, viral diseases and certain autoimmune diseases. One of the key apoptotic elements identified is Apopain (caspase 3) (Nicholson, Nature Biotech., 14:297-301 (1996)). Modulators of this protein are sought for the modulation of apoptosis and the provision of novel therapeutics. Inhibitors of Apopain are useful for the treatment of diseases in which excessive apoptosis occurs, including neurodegenerative diseases such as Alzheimer, Parkinson and Huntington and cardiovascular diseases such as ischemic cardiac damage. Enhancers of this protein are useful for the treatment of diseases in which insufficient apoptosis occurs, such as cancer, viral infections and certain autoimmune diseases. It would have been highly desirable to constmct cysteine protease modulators, which could be administered to a subject for various pharmaceutical and medicinal purposes. SUMMARY OF THE INVENTION The present invention concerns modulators of cysteine proteases and more specifically modulators of picomavirus 3C-cysteine protease and of similar proteins. The present invention is based on the finding that several chemical compounds are capable of inhibiting the picomavims 3C-cysteine protease. Thus, according to the first aspect of the invention termed "the inhibiting aspect" there are provided inhibitors of picomavims 3C proteases and inhibitors of proteins having similar activity. The present invention is based on a further finding discovered by x-ray analysis that there exists a structural similarity between Apopain and the rhinovirus 3C protease. Similarity in active site and catalytic machinery between the two enzymes has suggested similar mechanism and activity. Thus compounds which enhance or inhibit 3C protease are assumed to have activity also towards Apopain. Thus by a second aspect termed "the enhancing aspect", the present invention concerns enhancers of 3C-like proteases such as Apopain. According to the present invention there are provided pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one, as an active ingredient, compound selected of the formula. wherein Z is selected from the group consisting of C, Si, P and S; Xi, X 2 are independently O, S, NR^; Ri is selected from the group consisting of: (i) hydrogen, hydroxyl, phenyl (optionally substituted with 1-4 R u ), a straight saturated or unsaturated hydrocarbon chain of from about 1 to about 10 carbon atoms, optionally substituted with one or more R 11 , wherein R 11 and R 6 are each independently selected from the group consisting of: (ia) C- . -Q alkyl (optionally substituted with R 111 ), C 2 -C alkenyl (optionally substituted with R 111 ), C -C 3 alkylyl (optionally substituted with R 111 ), C C 3 alkoxy (optionally substituted with R 111 ), C 3 -C 8 cycloalkyi (optionally substituted with R 111 ); (ib) halogen, cyano, nitro, amino, oxo, hydroxy, adamantyl, carbamyl, carbamyloxy or acetyl; (ic) an oligopeptide of 1-4 amino acid residues and (id) NR 13 R 14 , C0 2 R 13 , 0(C=OR 13 ), S0 2 R 13 , SOR 13 R 14 , (C=0)NR 1: R 14 , or R 14 (C=0)R 13; wherein: R J is hydrogen, phenyl, benzyl, C C 6 alkyl and C 3 -C 6 cycloalkyi; and R 14 is hydrogen, hydroxyl, Cι-C alkyl or benzyl; (ii) an oligopeptide of 1 to 5 amino acids (iii) C 3 -C 7 cycloalkyi (optionally containing 1-3 unsaturations), C 6 -Cι 0 bicycloalkyl (optionally containing 1-4 unsaturations), (C 3 -C 7 cycloalkyl)methyl (optionally containing 1-3 unsaturations), C 7 -C 10 aralkyl (optionally containing 1 unsaturations on alkyl), methylnaphthyl (α or β), adamantane, C 5 -C 8 heterocyclic ring system including at least one nitrogen, oxygen or sulfur atoms (optionally containing 1-3 unsaturations), or a (C 5 -C 9 heterocyclic ring system) alkyl (optionally containing 1-3 unsaturations), a C 3 -C 6 heterocyclic ring system fused to an aromatic ring (optionally containing 1-2 nonbenzenoid unsaturations) or a (C 3 -C- 5 heterocyclic ring system) fused to an aromatic ring (0-2 nonbenzenoid unsaturations)methyl; (iv) Cι-C 5 alkoxy (optionally substituted with. 1-3 R 11 ), NH-W whrein W is the substituents as defined in (i) to (iii) above, or N connected to 2 W independently selected from (i) to (iii) as defined above; A, A' are independently selected from the group consisting of: (i) hydrogen, hydroxyl, phenyl ( optionally substituted with 1-4 R u ), acetyl, allyl. a straight saturated or unsaturated hydrocarbon chain of from about 1 to about 8 carbon atoms, optionally substituted with one or more R 11 , wherein R 11 is as defined above; (ii) CONR 13 R 14 , SONR 13 R 14 (sulfamyl) S0 2 NR 13 R 14 , R 13 , R 14 as defined above; (iii) A, A' may form an aromatic ring optionally containing 1-3 heteroatoms and fully substituted with Y, R 3 , Y', Z', wherein: Y is hydrogen, OH, CH 2 OH, CH 2 SH, halogen, CF 3 , CN, CONR 12 R 13 , S0 2 NR 12 R 13 , SONR 12 R 13 , C r C 3 alkoxy (optionally substituted with 1-3 R 11 ), C r C 3 alkyl (optionally substituted with 1-3 R 11 ); Z' is hydrogen, OH, Cι-C 4 alkoxy (optionally containing 1-2 unsaturations and substituted with 1-3 R 15 ), or C 5 -C 7 carbocyclic or heterocyclic ring system connected to Rj (optionally containing 1-2 unsaturations); R 15 is selected from phenyl (optionally substituted with 1-3 R 14 ), naphthyl (optionally substituted with 1-3 R 14 ), or a C 3 -C 6 heterocyclic ring system fused to an aromatic ring (optionally containing 1-2 nonbenzenoid unsaturations and optionally substituted with 1-3 R 14) ; Y' is hydrogen, OH, halogen, nitro, CN, CF 3 , CONR 12 R 13 , S0 2 NR 12 R 13 , SONR 12 R I3 , C r C 3 alkyl (optionally substituted with. 1-3 R u ); R 3 is H, OH, methyl, C r C 3 alkoxy, allyl, amino; alternatively, Z' and Y' may be joined to form a phenyl ring, resulting in a naphthalene system; or Z' and Y' may be joined to form a 9-11 member bicyclic ring (1-3 heteroatoms, 1-2 unsaturations, optionally substituted with 1-4 R ). alternatively, Z' and Ri may combine to form a C 5 -C 7 carbocyclic ring (containing 1-3 unsaturations, substituted with 1-5 R 1 1 ) ; or Z' and R j may jointly form a C 5 -C 7 heterocyclic ring (1-3 heteroatoms, 1-3 unsaturations, substituted with 1-5 R u ). or (iv) A, A' may form a C 5 -C 7 carbocyclic ring coupled (optionally containing 1-3 unsaturations and optionally substituted with 1-2 R 11 ); R 111 is hydrogen, halogen, hydroxy, methyl, ethyl, acetyl, carboxamide, N0 2 , sulfamide, phenyl or sulfamyl. The pharmaceutical composition of the invention may be used for the modulation of protease activity such as the picomavirus 3C-protease and 3C protease-like proteins, i.e. proteins having similar structure and activity. The term "modulation " in the context of the present invention includes both inhibitors and enhancers of this protease. The term "3C protease-like protein " refers to cysteine proteases with active site structure similar to that of picomavims 3C protease, as discovered by homology or by x-ray analysis. An example of such a protease is Apopain. The active ingredient in the pharmaceutical composition of the invention is preferably one of the following formulae (II)-(VI): wherein A and A' are as defined in (i) or (ii) above wherein R 6 is defined above or R 6 and R 1 may form together a C 5 .C 7 carbocyclic or heterocyclic ring, optionally containing 1-2 unsaturations, optionally substituted with 1-2 R n . R 6 and R 1 may altematively form a C 8 -Cι 0 bicyclic ring containing 0-3 heteroatoms and 0-4 unsaturations. Preferred active ingredients of the pharmaceutical composites of the invention where the compound is of formula III, are compounds selected from the following formulae III(i)-III(xii): which have the activity of inhibition of the 3C protease. IΙI(ix) III(x) Where the compound is of formula IΙI(i), the substituents are preferably as follows: Z is OH; Ri is CH 3; Z' is H, O-methyl, OH, or OCH 2 CONH 2 ; Y' is Cl, H, F, Br, OH, CN, methyl or OCH 3 : R 3 is H, O-methyl, methyl or OH; and Y is H, Cl, N0 2 , Br, CN or COO ethyl Y' and Z' may form a 9-member bicyclic ring containing 0-2 unsaturations and 1-2 heteroatoms and substituted with 4 R π (selected from methyl, oxo, acetyl, hydroxyl). Where the compound is of formula IΙI(ii) the substituents are preferably ws: Z is OH R- is CH 2 CH 3 ; Z' is H; Y ' is OH; R 3 and y are each Hi Where the compound is of formula IΙI(iii) the substituents are preferably ws: Z is OH R, is (CH 2 ) 4 (CH 3 ) Z' is H, OCH 2 CONH 2 , OH or O-methyl; Y ' is Cl or H; R 3 is OH or O-methyl; Y is H or Cl; Where the compound is of formula IΙI(iv) the substituents are preferably ws: Z is OH; Z' is H or OH; Y' is H, Cl, N0 2 or I; R 3 is H or OH; and Y is H, Cl or I Where the compound is of formula III(v) the substituents are as follows: Z is OH; R, is NHW; Y and Y' are N0 2 ; Z' is H; R 3 is H; and W is CH 2 pheny 1, CH 2 CH 2 phenyl or (CH 2 ) 7 CH 3 Where the compound is of formula IΙI(vi) the substituents are preferably: Z is OH; Y',Z' are a benzofused system; R. is CH 3 Y is H; and R 3 is H. Where the compound is of the formula IΙI(vii) the substituents are preferably: Z is OH; Ri is o-phenol; Z' is H; Y' is H; R Ri 3 is O-methyl; and Y is H. Where the compound is of formula IΙI(viii) the substituents are preferably: Z is OH; Rj is CH 2 CO phenyl; Z' is H; Y ' is CL Br or H; R 3 is H or methyl; and Y is H. Where the formula is of IΙI(ix) the substituents are preferably: Z is OH; R r Z' form together C=C-C=0; Y,Y',R 3 are each H. Where the compound is of formula III(x) the substituents are preferably: R. - OMe Z =OH Z' =H,OH Y' = H, Cl Y = H,C1 R 3 = H,Me Where the compound is of formula IΙI(xi) the substituents are preferably: R CH 2 ) 2 Ph Z = OH Z' = H, OH Y' = H, Cl Y = H, Cl R 3 = H,OH R„=H,OH Where the compound is of formula IΙI(xii) the substituents are preferably: R,(Z') = C=C(0-Z')-Phenyl Z = OH Y'=H,C1 Y = H, Cl R 3 -H,OH R π =H,OH R1 2 = H, OH Preferred active ingredients of the invention, where the compounds are of formula II, have the following substitutes: X) and X 2 are O, R- is CH 3 , phenyl (optionally substituted with 1-3 R 11 ) A is CH 3 or phenyl; and A' is COCH 3 or H. Preferred active ingredients of the invention, where the compounds are of the formula IV the substituents are preferably as follows: X 2 is OH; Y, R 3 , Y' are H; and R 11 is OH or H; Preferred active ingredients of the pharmaceutical compositions of the invention where the compound is of formula V are compounds selected from V(i) and V(ii) which serve as inhibitors. Where the compound is of formula V(i) the substituents are preferably: R ! (R 6 ) = 0-(o-R 6 )Phenyl Z = OH Z' = H Y' = H, Cl Y = H, Cl R 3 - H Where the compound is of formula V(ii) the substituents are preferably: Z = OH Z' = H Y' = H, C1 Y = H, Cl R 3 - Me, H VI Where the compound is of formula VI the substituents are preferably: Rι= H Z = OH Z' = H Y' = H, Cl Y = H The term "amino acid" used above is understood to include the 20 naturally occurring amino acids; those amino acids often modified post-translationally in vivo, including for example hydroxyproline, phosphoserine and phosphothreonine; and other unusual amino acids including, but not limited to, 2-aminoadipic acid, hydroxylysine, isodesmosine, nor-valine, nor-leucine and omithine. Furthermore, the term "amino acid" includes both D- and L-amino acids. The term "oligopeptide " refers to a series of amino acids linked by peptide bonds. Suitable sequences of amino acids may be chosen according to the teachings of Cordingley et al, J. Biol Chem., 265(16) -.9062-9066 (1990) various amino acids may be screened as follows: a desirable protease, such as the 3C picomavirus protease is immobilized to a solid support. Candidate sequences are brought into contact with the immobilized protease. Those residues which bind to the immobilized proteases are chosen as candidate sequences. The pharmaceutical compositions of the present invention are suitable for the treatment of diseases the manifestations of which involve cysteine proteases of the CB Clan (families C3,C4,C24,C30,C37 and C38) of the CD Clan (family C14), of the CE clan and of family C13. The term "diseases which manifestation is dependent on cysteine proteases ", refers to a disease which can be treated, prevented, alleviated or cured by inhibition of cysteinee proteases of the of the CB Clan, the CD Clan, the CE clan and the C 13 family. Preferably the inhibition is of "picomavirus 3C-like cysteine proteases ", which are cysteine protease having an active site similar to the active site of the 3C protease having a catalytic dyad of Histidine and Cysteine and most preferably of 3C-cysteine proteases. Thus, most preferably the pharmaceutical compositions of the invention according to the inhibition aspect of the invention are for the treatment of viral infections and of diseases wherein excessive apoptosis is implicated and wherein apoptosis should be reduced and most preferably of picomaviral infection, neurodegenerative disease and certain cardiovascular diseases. The pharmaceutical compositions of the invention according to the inhibition aspect of the invention are suitable for the treatment of: common colds, allergic rhinitis, poliomyelitis, hepatitis-A, encephalitis, meningitis, hand foot-and-mouth disease, encephalomyocarditis, summer flu (enteroviral upper respiratory infection), asthma, various allergies, myocarditis, acute hemorrhagic conjunctivitis, disseminated neonatal infection and Borhnolm's disease. All the above are diseases the manifestation of which is dependent on the activity of a cysteine protease of the CB clan. The inhibitors of the pharmaceutical compositions of the present invention selectively bind to the picomaviral proteases, essentially in a similar manner as the viral coded natural substrate of the proteases, and compete with the substrates for proteases. This competition serves to inhibit viral maturation and thus to inhibit disease progression in vivo. The pharmaceutical compositions of the present invention are suitable also for treatment of diseases manifested by the activity of the cysteine proteases of the CD clan, i.e. apoptosis-involved diseases, which includes activation, as in cancer, as well as inhibition (as in neurodegenerative diseases) of apoptosis. The pharmaceutical compositions of the present invention are also suitable for the treatment of adenovims-involved diseases. Thus the present invention according to the inhibition aspect further provides a method for treatment of viral infection, in particular a picomaviral infection, by administrating to a subject, in need of such treatment, a pharmaceutically acceptable amount of a compound of formulae (I) to (VI), which has protease inhibitor activity optionally together with a pharmaceutically acceptable carrier. The present invention further concerns according to the inhibition aspect a method for the treatment of cardiovascular diseases such as ischemic cardiac damage by administrating to a subject, in need of such treatment, a pharmaceutically acceptable amount of a compound of formulae (I) to (VI), which has protease inhibitor activity optionally together with a pharmaceutically acceptable carrier. The present invention according to the inhibition aspect thereof further provides a method for the treatment of neurodegenerative diseases such as Alzheimer, Parkinson and Huntington, a pharmaceutically acceptable amount of a compound of formulae (I) to (VT), which has protease inhibitor activity optionally together with a pharmaceutically acceptable carrier. As will be no doubt appreciated by the person versed in the art, the Formulae I-VI above cover a large number of possible compounds, some of which are inhibitors and some are enhancers, and from those which are inhibitors some are more effective inhibitors of cysteine proteases of the above types than others. In order to determine which of the compounds are suitable as 3C protease inhibitors according to the inhibition aspect, compounds may be screened for inhibitory activities according to one of the following assays: Assays for screening picomaviral protease inhibitors I. Birch et al. {Protein Expression and Purification, 6:609-618 (1995)) have developed a continuous fluorescence assay to determine kinetic parameters and to screen potential HRV14 3C protease inhibitors. The assay consists of a consensus peptide for rhinoviruses connected to a fluorescence donor group (anthranilic acid; Anc) at the N terminal and to an acceptor group (p-N0 2 -Phe; Pnp) at the P4 position, both groups flanking the scissile bond (Gln/Gly). The substrate peptide consists on the following sequence: Anc-Thr-Leu-Phe-Gln-Gly-Pro-Val-Pnp-Lys. There is a linear time dependent increase in fluorescence intensity as the substrate is cleaved, which allows continuous monitoring of the reaction. Multiwell plates containing one inhibitor per well allow rapid screening by measuring the fluorescence intensity in each well. II. Heinz et al. {Antimicrobial Agents and Chemotherapy, 267-270 (1996)) developed an assay method for measuring 3C protease activity and inhibition using the substrate biotin-Arg-Ala-Glu-Leu-Gln-Gly- Pro-Tyr-Asp-Glu-Lys-fluorescein-isothiocyanate.. Cleavage mixtures containing inhibitors are allowed to bind to avidin beads and are PC17IL98/00602 - 21 - subsequently washed.. The resultant fluorescence of the bead is proportional to the degree of inhibition. III. Another assay developed by McCall et al. {Bio/Technology, _ , 1012-1016 (1994)) measures on top of inhibitory effects of the candidate inhibitors, also their capability to enter into cells, so that a high capacity screen for compounds that inhibit the 3C protease of HRV-1B was developed. The assay uses a recombinant strain of E-coli expressing both the protease and a tetracycline resistance gene modified to contain the minimal 3C protease cleavage sequence. Cultures growing in microtiter plates containing tetracycline are treated with potential inhibitors. Culture with no inhibition of the 3C protease, show reduced growth due to cleavage of the essential gene product. Normal growth is seen only in cultures that contains an effective 3C protease inhibitor. IV. An assay was developed in the lab, based on a protein consisting of the 3 C protease fused to DHFR. The cleavage of the fusion protem by external 3C protease (type 1A) is monitored by gel-electrophoresis. The degree of cleavage is proportional to the ratio of low molecular weight proteins (3C and DHFR) to intact fusion protein, as observed on the gel. V. Other assays developed for inhibition of other cysteine proteases are well known in the art. The pharmaceutical compositions of the invention according to the "enhancement aspect" are suitable for diseases manifested by deficient apoptosis, i.e. inappropriate activity of Apopain and of other "3C protease-like proteins". The term "3C protease-like proteins " refers to cysteine proteases with active site stmcture similar to that of a picomavims 3C protease, as discovered by homology or by x-ray analysis. An example of such a protease is Apopain. In particular, the diseases are characterized by insufficient apoptosis and include among others autoimmune diseases, viral- caused infectious diseases and certain types of cancer. The diseases may be treated, prevented, alleviated or cured by compositions of the invention having Apopain enhancing activity. Diseases in which insufficient apoptosis is implicated will be cured by Apopain enhancement leading to normal or excessive levels of apoptosis - thus, for example, certain cancers originating from subnormal levels of programmed cell death, will be eliminated following the restoration of normal levels of apoptosis or the establishment of higher than normal levels of apoptosis. The present invention further concerns a method for treatment of autoimmune diseases, viral-caused infectious diseases and certain types of cancer as well as cardiovascular diseases such as ischemic cardiac damage by administering to a subject in need of such treatment a pharmaceutically acceptable array of a compound of formulae I -VI, which has protease enhancing activity, together with a pharmaceutically acceptable carrier. As will be no doubt appreciated by a person versed in the art, formulae I-VI above cover a large number of possible compounds, some of which are inhibitors and some are enhancers, from those which are enhancers some are more effective than others. In order to determine compounds that are most suitable as enhancers, compounds may be screened by the following additional assay (VI): VI: Apopain (Caspase-3) Regulation Assay The FluorAce™ Apopain Assay Kit (Bio-rad) was employed in multiwell format. Compounds assayed were diluted 5-fold in distilled water (from stock solutions in ethanol or DMSO) and centrifuged (5', 14K rpm). 10 μL of the supernatant was further diluted in wells containing 100 μL distilled water and 40 μL 6xBuffer (41.7mM PIPES, pH 7.4, 8.3 mM EDTA, 0.42% CHAPS, 20.8 mM DTT). This process was carried out twice to yield duplicate wells for each compound. Control wells were prepared by addition of EtOH and DMSO (5 -fold diluted in distilled water) into wells containing 6xBuffer and distilled water (40 μL and 100 μL, respectively), to form 8 wells with each solvent. Enzyme (stock solution 10-fold diluted in distilled water, see Bio-rad booklet 4100119) was added to one set of compound-containing cells and to 8 control wells (4 with ethanol and 4 with DMSO). The plate was preincubated for -80' at 27°-28°C. Substrate (Z-DEVD-AFC, 490 μM, 40 μL) was then added to all wells. The plate was left at room temperature and fluorescence (360/4θt530/2θl) was measured at several time points (FL500 fluorimetric reader, Bio-tek instruments). Fluorescence at enzyme-containing wells was background-subtracted at each time point and initial rates were determined by linear regression (typically R 2 >0.97). Percentage inhibition and activation was determined by relating the slope with compound to the control slope (with appropriate solvent). IC50 values are extrapolated. Pharmaceutically acceptable carriers are well known in the art and are disclosed, for instance, in Sprowl's American Pharmacy, Dittert, L. (ed.), J.B. Lippincott Co., Philadelphia, 1974, and Remington's Pharmaceutical Sciences, Gennaro, A. (ed.), Mack Publishing Co., Easton, Pennsylvania, 1985. Pharmaceutical compositions of the compounds of the present invention, or of pharmaceutically acceptable salts thereof, may be formulated as solutions or lyophilized powders for parenteral admmistration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use, The liquid formulation is generally a buffered, isotonic, aqueous solution, but a lipophilic carrier, such as propylene glycol optionally with an alcohol, may be more appropriate for compounds of this invention. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water of buffered sodium or ammonium acetate solution. Such a formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler of nebulizer for insufflation. It may be desirable to add excipients such as ethanol, polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternately, the compounds of the invention may be encapsulated, tableted or prepared in an emulsion or symp for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include symp, soy bean oil, peanut oil, olive oil, glycerin, saline, ethanol, and water. Solubizing agents, such as dimethylsulfoxide, ethanol or formamide, may also be added. Carriers, such as oils, optionally with solubizing excipients, are especially suitable. Oils include any natural or synthetic non-ionic water-immiscible liquid, or low melting solid, which is capable of dissolving lipophilic compounds. Natural oils, such as triglycerides are representative, In fact, another aspect of this invention is a pharmaceutical composition comprising a compound of formula (I) and an oil. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Solubilizing agents, such as dimethylsulfoxide or formamide, may also be added. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a symp, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule. For rectal administration, a pulverized powder of the compounds of this invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository. The pulverized posers may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch. Nasal administration of the compounds of the invention may also be desired especially for the treatment of common cold and allergic rhinivity. The present invention also concerns a method for the detection of picor- naviral infection. According to the method of the invention a compound of the invention bearing a detectable label (for example attached to one of its substituents), is incubated with a sample, suspected of containing picomavimses, under conditions enabling binding of the compound to proteases. Preferably the sample should be treated with a lysing agent in order to release the picomavims proteins from inclusion bodies. Then it is determined whether the labeled compounds of the invention are bound to any proteins in assay. A positive answer (beyond a predetermined control level) is indicative of the presence of a picomavims in the assayed sample. The present invention further concerns several novel chemical compounds denoted in the examples as follows: SA#121, SA#132, SA#116, SA#118, SA#134, SA#135, SA#120, SA#127, SA#128, SA#15*, SA#16*, SA#107*, SA#108*, SA#110**, SA#43, SA#109*, SA#139, SA#51. * previously described ** commercially available The invention will now be described in reference to some non-limiting examples. DETAILED DESCRIPTION OF THE INVENTION Syntheses The numbers in the following examples refers to the number of the compound as appears in the tables preceded by SA#. Example 116 202 mg (0.97 mmol) of 2,4-dihydroxyhexanophenone (Aldrich, 96%) was completely dissolved in methylene chloride (anhydrous, 8 mL), containing 2 equivalents of methanol (81 μL, 1.98 mmol, added by pipette). To the light brown solution were added at room temperature (24°C) with stirring 2 mL of a freshly prepared 1M solution of sulfuryl chloride in anhydrous dichloromethane. The color of the solution turned slightly yellow immediately, and the yellowness deepened 15 minutes later. At this stage the starting material was completely consumed, as shown by reverse-phase HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm). The reaction was continued for 45 minutes further, after which the solvents were flash-evaporated to give beige powder (269 mg; -100% yield), which was dried under high vacuum overnight. An analytical sample was purified by crystallization from CDC1 3 (~10 mg/mL with active charcoal, white needles). M.P. (Corr.): 102°-103°C. IR (KBr disk) v 1629.7 cm '1 (strong). HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm): R t =1.9' (100%). Η NMR (CDC1 3 ) : δ 13.31 (s, 1H), 7.69 (s, 3H), 7.04-5.44 (broad s, 1H), 2.88 (t, 2H, J=7 Hz), 1.84-1.54 (m, 2H, J=7 Hz), 1.54-1.14 (m, 4H), 0.88 (t, 3H). 13 C NMR (CDC1 3 , 60 MHz, adjacent hydrogens by parallel DEPT): 205.6 (q), 159.4 (q), 154.5 (q), 129.3 (t), 114.4 (q), 111.9 (q), 109.6 (q), 38.6 (s), 31.7 (s), 24.6 (s), 23.0 (s), 14.5 (p). MS (Ef): 276.0 (M + , 19%), 205.0 (M + -C 5 H U, 2 chlorine atoms, 100%). Example 120 A solution of 3,5-dinitrosalicylic acid (1140 mg, 5.0 mmol) in dichloromethane (-10 mL) was treated with excess PC1 5 at room temperature for 40 minutes. The methylene chloride was removed by rotary evaporation and the resultant oil was washed with hexanes (3 times), dissolved in methylene chloride (10 mL) and cooled to 0°C. 1.1 Equivalents of triethylamine (780 μL, 5,5 mmol) and benzylamine (600 μL, 5.5 mmol) were introduced by pipette and the reaction mixture was gradually warmed to room temperature in the course of 40 minutes. The solution was neutralized by addition of 5% aqueous HCl and extracted twice with ethyl acetate. The organic phases were combined and evaporated, and the residue was washed with petrol ether and cooled, resulting in a viscous brown oil. The cmde oil was purified by flash chromatography (0-10% EtAc petrol ether 60-80). Fraction 5 (4% EtAc) contained pure material (TLC, reverse phase HPLC) and was evaporated and left overnight in-vacuo (on an oil pump). The orange oil obtained was taken up in methylene chloride and washed with aqueous K 2 C0 3 . A fine yellow-orange sediment appeared (540 mg, -30% yield), which was pure by reverse phase HPLC (30% acetonitrile in H 2 0, 1 mL/min, 256 nm, Η NMR (CD 3 OD, 200 MHz) : δ 8.99 (d, 1H, J=3.2 Hz), 8,82 (d, 1H, J=3.2 Hz) 7.35-7.05 (m, 5H), 3.64 (t, 2H, J=7.4 Hz), 2.92 (t, 2H, J=7.4 Hz). MS (FAB + ): 318.1 (MH + , 76%). Example 121 Williamson ether synthesis was carried out in accordance with the procedure of Burgstahler & Worden {Organic Synthesis, Coll. Vol. V, 1973, pp. 251-4). To a 25 mL round-bottomed flask, equipped with a magnetic stirrer and a water-jacketed reflux condenser, were added 2,6-dihydroxyacetophenone (Sigma, 1.52g. 10.0 mmol), chloroacetamide (Aldrich, 953 mg, 10.2 mmol) and distilled water (5.5 mL). The turbid suspension was heated rapidly on an oil bath set at 110°C and 2 mL of an aqueous 5N NaOH solution were added (pipette). A clear dark orange solution formed immediately and the reaction mixture was left overnight with tap-water cooling under light reflux (oil-bath temperature between 110° and 114°C). The dark red solution was cooled to room temperature and a red oil separated beneath an orange solution. 5N NaOH was added (1 mL) and the solution was decanted. The oil was dried under high vacuum, dissolved in ethyl acetate and 438 mg were purified by column chromatography (Si0 2 , ethyl acetate, 197x21 mm, 24 g, 1.5 drops/minute). Fractions 10-12 (bright yellow-orange) were pooled and yielded on evaporation orange solid (106 mg). M.P. (Corr.): 151°-152°C. HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm): R t =2.4' (100%). 1H NMR (DMSO-d 6 ) : δ 11.78 (broad s, 1H), 7.44 (broad s, 2H), 7.30 (t, 1H, J=8.3 Hz), 6.53 (d, 1H, J=8.3 Hz), 6.44 (d, 1H, J=8.3 Hz), 4.53 (s, 2H), 2.60 (s, 3H). MS (EI + ): 209.1 (MT, 55%), 137.0 (M + -(CH 2 ) 2 CONH 2 , 100%). Example 127 A solution of 3,5-dinitrosalicylic acid (839 mg, 3.68 mmol) in dichloromethane (10 mL) was treated with excess PC1 5 at room temperature for 30 minutes. The mixture was filtered through cotton wool, the methylene chloride evaporated and the resultant oil washed 3 times with hexanes, dissolved in methylene chloride (10 mL) and cooled to 0°C. 1.1 Equivalents of triethylamine (575 μL, 4.05 mmol) and of n-octylamine (510 μL, 4.06 mmol) were introduced by pipette and the reaction mixture was brought to room temperature in the course of 30 minutes. The solution was neutralized by addition of 5% aqueous HCl and the methylene chloride layer was separated, dried with MgS0 4 and filtered through cotton wool. The clear filtrate mixed with silica gel 60H, evaporated, loaded on a column and separated by flash chromatography with a petrol ether (b.p. 60-80) forerun (200 mL) followed by a smooth gradient of 5-20% EtAc in petrol ether. Fractions containing product were pooled, dried by flash-evaporation and washed with aqueous sodium carbonate. The solvent was decanted and the sedimented orange particles were filtered with a glass sinter, washed with ice-cold water, powdered with a glass rod, washed with methylene chloride and grounded once more, yielding 360 mg of bright orange powder (30% yield), pure by HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm, R t =1.28'). Η NMR (CD 3 OD, 200 MHz) : δ 8.99 (d, 1H, J=3.2 Hz), 8,82 (d, 1H, J=3.2 Hz) 7.35-7.05 (m, 5H), 3.64 (t, 2H, J=7.4 Hz), 2.92 (t, 2H, J=7.4 Hz). MS (FAB + ): 332.1 (MF , 100%), Example 128 A solution of 3,5-dinitrosalicylic acid (1040 mg, 4.56 mmol) in dichloromethane (15 mL) was treated with excess PC1 5 at room temperature for 45 minutes. The mixture was filtered through cotton wool and the solvent was evaporated. The resultant viscous red oil cooled to 0°C on an ice-water bath and washed twice with scrubbing with hexanes. The washed acid chloride was resuspended in methylene chloride at 0°C, and 1.1 Equivalents of triethylamine (830 μL, 5.00 mmol) and of n-octylamine (712 μL, 5.03 mmol) were introduced by pipette. The reaction mixture was brought to room temperature in the course of 4 hours, at the end of which 20 mL 5% aqueous HCl were added. The methylene chloride phase was separated, mixed with silica gel 60H, evaporated, loaded on a column and separated by flash chromatography with 2% EtAc in petrol ether 60-80. Fractions containing product were pooled, dried by flash-evaporation and washed with aqueous sodium carbonate. The sediment was filtered in-vacuo and washed with methylene chloride. The orange sediment thus obtained was pure by reverse phase HPLC (30% acetonitrile in H 2 0, 1 mL/min, 256 nm, R t =1.37'). 1H NMR (CD 3 OD, 200 MHz) : δ 9.02 (d, 1H, J=4 Hz), 8,80 (d, 1H, J=4Hz) 3.46 (t, 2H, J=8 Hz), 1.80-1.60 (m, 2H), 1.60-1.12 (m, 10H), 0.91 (t, 3H, J=8 Hz). MS (FAB + ): 340.2 (MH + , 100%), 362.2 (MNa + , 24%), 378.1 (MK + , 32%). Example 132 To a three-necked flask equipped with a reflux condenser, a calcium chloride trap and a rubber septum were added 2,4,6-trihydroxybenzoic acid (2.00 g, 10 mmol) and CaCl 2 -distilled ethanol (15.5 mL). To the bright-colored solution was added by syringe boron-trifluoride-etherate (1.5 mL), and scant white fumes were observed. The solution was refluxed overnight with stirring at room temperature. The yellow-orange solution was decomposed by addition of water (50 mL) and was extracted with ether (3 x 50 mL) and ethyl acetate (2 x 50 mL). Evaporation of the ethyl acetate extract yielded an orange pasty solid, containing the desired ethyl trihydroxybenzoate, contaminated with phloroglucinol, and other minor side-products (1.2 g). Isolation of the ester was achieved by column chromatography (silica gel 60 ; 15%-50% ethyl acetate/petroleum ether 60-80). Fractions 12-13 (50% ethyl acetate) were pooled and evaporated to yield 341 mg of 85% pure (reverse-phase HPLC, 70% acetonitrile in H 2 0, 1 mL/min, 256 nm, R t =2.25') ethyl trihydroxybenzoate (NMR). This material was dried in-vacuo and to a hoesch condensation (procedure by Whalley, J.Chem. Soc, 1951, 3229). 340 mg (-1.5 mmol) were placed in a flame-dried air-jacketed 2-necked flask equipped with an in-situ HCl gas-generating system (H 2 S0 4 equal pressure funnel, Kipp apparatus with NH 4 C1, connected in tandem to H 2 S0 and air traps) was dissolved in 50 mL sodium dried ether. To the clear solution were added oven-dried ZnCl 2 (0.8 g) and A1C1 3 (anhydrous, under argon). Upon addition of A1C1 3 a vigorous reaction ensued and the solution turned immediately turbid yellow. Acetonitrile (HPLC grade; 2mL, 38 mmol) was added and a dry stream of dry hydrogen chloride gas was passed through the mixture. The solution became clear within a few minute, was turbid again after one hour and was left overnight at room temperature. The ethereal solution was filtered in-vacuo and the white solid (ketimine hydrochloride) was dissolved in water (25 mL) and hydrolysed by heating on a hot plate. The aqueous solution was concentrated to 5 mL and cooled. Upon cooling, needles appeared which were kept overnight at 4°C. Cold filtration yielded sweet-odored yellow needles which were dried intensively in a flash evaporator (12 mg). The material was 72% pure by reverse-phase HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm, R t =3.50'). Η NMR (CD 3 OD, 200 MHz) : δ 5.97 (s, 1H), 4.13 (q, 2H, J-7.0 Hz), 2.63 (s, 3H), 1.51 (t, 3H, J=7.0 Hz). Examples 134, 135 14 mg of 2,4-dihydroxy-6-methoxy-hexanophenone (Example 108 in PCT; 0.06 mmol) was dissolved in methylene chloride (anhyd., 1 mL) containing 20 μL of methanol. To the stirred opaque solution was added via hamilton syringe 120 μL of a IM solution of sulfuryl chloride in anhydrous dichloromethane. A faint yellow color appeared and the solution was left in open air with stirring overnight. Yellow needles resided on the sides of the flask (16 mg, -100% yield) and were purified by column chromatography (Si0 2 , 20% ethyl acetate in petrol ether 60-80, 50x5 mm, 1 g, 0.5 mL fractions). Evaporation of fraction 5 yielded -2 mg yellow flakes corresponding to example 134. HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm, R t =5.45'). 1H NMR (CDC1 3 , 200 MHz) : δ 13.23 (s, 1H), 6,43 (s, 1H), 6.2-6.0 (broad s, 1H), 3.91 (s, 3H), 3.06 (t, 2H, J=7.4 Hz), 1.8-1.6 (m, 2H), 1.4-1.2 (m, 4H), 0.91 (t, 3H, J=6.4 Hz). MS (EI + ): 272.1 (MH + , 15.5%), 201.0 (M + -C 5 H n, 1 chlorine atom, 100%). Fraction 7 yielded upon evaporation -3 mg of pure example 135 as yellowish flakes. HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm, R t =5.78'). 1H NMR (CDC1 3 , 200 MHz) : δ 14.63 (s, 1H), 6,14 (s, 1H), 3.88 (s, 3H), 3.00 (t, 2H, 3=7.4 Hz), 1.8-1.5 (m, 2H), 1.5-1.3 (m, 4H), 0.91 (t, 3H). Example 139 Synthesis was carried out essentially as described above in example 121, The main difference residing in the temperature at which the base is added (room temperature vs. 100°C). 131 mg (0.86 mmol) 2,5-dihydroxy- acetophenone (Sigma) was placed in a 5 mL glass trap equipped with a magnetic stirrer and connected to a water-cooled reflux condenser. To the reaction vessel are added 82 mg chloroacetamide (0.88 mmol), 0.17 mL NaOH (5N) and 1.2 mL H 2 0. The orange solution was heated rapidly on an oil bath (oil temperature of 106°-110°C) and mild reflux ensued. The reaction was left overnight (24 h) in reflux and cooled to room temperature, resulting in a dark brown solution with sediments on the vessel walls. The pH was found to be neutral, and the solution was dried in high vacuum. Pure material (HPLC, TLC) was obtained by column chromatography (Si0 2 , 40%- 100% ethyl acetate in petrol ether 60-80, 128x12 mm, 5 g). Fractions 12-15 (EtAc) were pooled and evaporated to yield 7 mg of a yellow solid. HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm, R t =2.5\ 96%). 1H NMR (DMSO-d 6 , 200 MHz) : δ 12.2-10.8 (broad s, 1H), 7,54 (broad s, 1H), 7.39 (d, 1H, J=3.2 Hz), 7.22 (dd, 1H, Jj =9.5 Hz, J 2 =3.2 Hz), 6.92 (d, 1H, J=9.5 Hz), 4.42 (s, 2H), 2.62 (s, 3H). Example 43 256 mg (1.13 mmol) of 2'-hydroxy-3-phenylpropiophenone (Aldrich) were dissolved in methylene chloride (8 mL) containing 2 equivalents of methanol (91 μL), in a 25 mL round bottom flask equipped with a magnetic stirrer and an 8" reflux condenser. To the clear solution was added (by glass pipette) 2.26 mL sulfuryl chloride (lM/methylene chloride, freshly prepared), and the color was observed to intensify. The mixture was left at room temperature (21°C) for 4 hours with stirring. At this time a major product was observed by reverse-phase HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm), amounting to 55% of the total mixture. An additional amount of sulfuryl chloride IM solution was added (0.56 mL, 0.5 eq.) and the mixture was left for 2.5 hours at room temperature with stirring, after which HPLC showed an increase in major product (72%). Solvents were evaporated (water bath at 67°C), resulting in a yellow oil (384 mg, -100% yield), Upon cooling a milky solid formed, with orange droplets. The cmde mixture was dissolved in 2% ethyl acetate/petrol ether 40-60,with a few drops of methylene chloride. The pale yellow solution (with few orange droplets) was purified by column chromatography (~8g Si0 2 , 2% ethyl acetate in petrol ether 40-60, 185x12 mm, -3 mL fractions). Fractions 6 and 7 were evaporated to yield 22 mg of pure product (HPLC), as a colorless oil with strong scent. HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm): R t =12.9'. 1H NMR (DMSO-d 6 , trace CDC1 3 , 200 MHz): δ 11.63 (s, 1H, sharp), 7.85 (d, 1H, J=2.3 Hz), 7.52 (dd, 1H, 1^8.5 Hz, J 2 =2.3 Hz), 7.38-7.05 (m, 5H), 7.00 (d, 1H, J=8.7 Hz), 3.43 (t, 2H, J=7.4 Hz), 2.92 (t, 2H, J=7.5 Hz). MS (EI + ): 260.1 (M + , 62%, 1 chlorine atom), 155.1 (M + -(CH 2 ) 2 Ph, 100%, 1 chlorine atom). Example 109 To 2,6-dihydroxyacetophenone (152mg, 1 mmol) in a 25 mL round bottom flask equipped with a magnetic stirrer were added absolute methanol (325 μl, 2 eq.) and dichloromethane (8 ml) to provide an almost clear orange solution. Sulfuryl chloride was added at room temperature (0.65 mL) and a yellow solid appeared. Dichloromethane was added (10 mL) to form a solid suspension. Filtration in-vacuo provided pale yellow and brown airy chunks (622 mg). The filtrate provided an additional amount (139 mg). The total yield was -87%). Recrystallization of the major fraction from ethanol provided clumps of small yellow needles (187 mg). Recrystallization of the filtrate from EtOH-water provided off-yellowish sheaths (91 mg). HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm): R t =4.6'. 1H NMR (CDC1 3 , 200 MHz): δ 10.05 (sharp s, IH), 7.54 (s, IH), 2.79 (s, 4H), MS (EI + ): 220.0 (M + , 44%), 205.0 (M^-CHs, 97%). Example 15 A stirred solution of 2,6-dihydroxy-4-methoxyhexanophenone (cf. example 107; 28 mg, 0.12 mmol) in absolute methanol (0.25 ml), was diluted in anhydrous dichloromethane (10 ml) at room temperature. A IM solution of sulfuryl chloride in anhydrous dichloromethane was added dropwise (0.26 ml, 2.2 eq.), and the color of the resultant mixture was observed to change from faint yellow to bright vivid yellow within seconds. 20 minutes later, the solvents were evaporated and residual sulfuryl chloride was removed in vacuo, resulting in yellow crystals (34 mg, quantitative). M.P. 101°C. ! H NMR (CDCI 3 , 200 MHz): δ 10.32 (s, 2H), 3.98 (s, 3H), 3.13 (t, 2H), 1.71 (t, 2H), 1.35 (m, 4H), 0.91 (t, 3H) [identical to spectrum described by Masento et al, 1988, Biochem. J. 256: 23-28], MS (EI + ): 306.0 (M + , 21%), 235.0 (M + -C 5 H„ , 100%). Example 16 2,4-dihydroxy-6-methoxyhexanophenone (cf. example 108; 10 mg, 0.04 mmol) was reacted with sulfuryl chloride in a manner analogous to that described in example 15 above. The product was vaccuum-dried, resulting in orange crystals (12 mg). 1H NMR (CDC1 3 , 200 MHz): δ 14.02 (s, IH), 6.51 (s, IH), 3.91 (s, 3H), 3.05 (t, 2H), 1.69 (t, 2H), 1.32 (m, 4H), 0.89 (t, 3H). Examples 107 and 108 Dihydroxyanisole (1.113g, 7.9 mmol), hexanonitrile (1.60 ml, 13.2 mmol) and zinc chloride (700 mg) were dissolved in 50 ml of sodium-dried ether. The stirred solution was saturated with a steady stream of dry hydrogen chloride gas and after 5 minutes turned milky. 10 minutes later, a viscous orange oil separated, and the mixture was left overnight. The colorless solution was decanted and the oil was taken in 50 ml of ice-cold water. The resultant clear orange-red solution was extracted with ether (2 x 50 ml) and the aqueous phase was boiled on a hot-plate and concentrated to half the original volume (ca. 30 ml). At this point, the solution became turbid, and upon cooling a brown-orange solid separated (810 mg). 750 mg (3.15 mmol) of this isomeric methoxy-hexanoresorcinones mixture was loaded on a silica gel column equilibriated with dichloromethane. Fractions 6-7 contained pure (TLC) of the minor isomer. Evaporation of the solvent yielded 78 mg of white solid, corresponding to example 107, M.P. 121°C. TLC (dichloromethane), R f =0.33. 1H NMR (CD 3 OD, 200 MHz): δ 5.90 (s, 2H), 3.76 (s, 3H), 3.03 (t, 2H), 1.65 (t, 2H), 1.35 (m, 4H), 0.91 (t, 3H). MS (EI + ): 167.1 (M'-CsH, *, 100%), 238.2 ( 1" , 15%o). Fractions 10-12 12 (4:1 dichloromethane: ether was added at fraction 12) contained pure (TLC) major isomer. Removal of the solvents yielded 384 mg of grayish solid, corresponding to example 108, M.P. 109°C. TLC (dichloromethane), R =0.10. 1H NMR (CD 3 OD, 200 MHz): δ 5.94 (d, IH), 5.87 (d,lH), 3.84 (s, 3H), 2.93 (t, 2H), 1.62 (t, 2H), 1.34 (m, 4H), 0.92 (m , 3H). MS (EI + ): 238.2 (M + , 39%), 167.1 ( '-CsHu, 100%). Example 107 was altematively prepared by esterification of 5-methoxy resorcinol with hexanoyl chloride and fries rearrangement of the resultant mixture (procedure by Kay et al, USP #5,037,854). Example 110 Procedure by Phloroglucinol (1.2 g, 9.5 mmol) was dissolved in anhydrous ether (60 mL) at room temperature (26°C) and to the clear solution were added ZnCl 2 (resulting in some sediment) and acetonitrile (1.4 mL). Through the solution was passed a dry stream of freshly generated hydrogen chloride gas (1 mole total amount) and the solution became cloudy. 5 minutes later an orange oil formed and the solution brightened. After 2 further minutes the solution became orange and the oil darkened. About 50 minutes later, when gas passage was complete, the system was closed and the oil solidified. Cold water (60 mL) was added to the orange crystals and solubility was achieved by vigorous stirring. The solution was extracted with ether (2x120 mL) and evaporated (to -30 mL). Upon cooling airy woolly colorless crystals appeared (1.157g, 73% yield). MS (EI + ): 168.1 (M " , 46%), 153.1 (M + -CH 3 , 100%). Example 51 To a clear yellow solution of cyanophenol (491 mg, 4.12 mmol) in Pyridine (5 mL) was added acetyl chloride (PCl 5 -refluxed, quinoline-distilled, 290 μL, 4.08 mmol). Heating and sedimentation were observed and the solution was left overnight with stirring. Reverse phase HPLC showed complete conversion to a hydrophobic product (70% acetonitrile in H 2 0, 1 mL/min, 256 nm). The reaction contents were poured onto 5% HCl (50 mL) with stirring and to this mixture was added a methylene chloride wash of the reaction flask (20 mL). After phase separation, the organic phase was washed with sodium bicarbonate (50 mL) and aq. NaCl(sat.; 50 mL), dried (Na 2 S0 ), filtered and evaporated to yield an orange oil. 405 mg of this oil (2.5 mmol) were heated on an oil bath (137°C) and flushed with argon. A1C1 3 was added rapidly in a few portions while flushing. The solid brown-purple mass was cooled to room temperature, put on ice and 5% HCl was added (10 mL) under ice. Ether was added (25 mL), the phases were separated and the ethereal phase was extracted with 5% sodium bicarbonate (25 mL). The orange aqueous phase contained some suspension and was acidified by addition of 5% HCl (15 mL, until foaming ceased). An orange solid sedimented. Filtration and refiltration yielded 9 mg. HPLC (70% acetonitrile in H 2 0, 1 mL/min, 256 nm): R t =3.6' (95-98%). 1H NMR (CDCI 3 , trace DMSO-d 6 , 200 MHz): δ 13.00 (s, IH, sharp), 8.01 (dd, IH, Hz), 7.04 (t, IH, J=7.9 Hz), 2.70 (s, 3H). MS (EI + ): 161.1 (M * . 10%), 44.0 (COH, 100%). II. Antiviral Assay - XTT Method Antirhinoviral activity and cytotoxicity were determined by an XTT assay, as described previously for HIV-1 (Weislow et al, J. Nat. Cane. Inst., 81(8):577-586, 1989) and for HRV-14 (Webber et al, J. Med. Chem. 5072-5082, 1996). Specifically, each compound was assayed by the following procedure: 24 hours-old Hl-Hela cells [ATCC] are plated in a 96-well plate (~ 30,000 cells/well, ~ 60% confluence), washed with PBS (100 μL) and aspirated. Four 10-fold dilutions of vims (HRV 1A, IB, 14 or 16, obtained from ATCC) are prepared (in PBS A - 0.1% BSA in PBS) and immediately added (1 dilution per row, 20 μL per well) to the top half of the plate (layout). The lower half of the plate is mock-infected by addition of 20 μL PBS A per well. The cells are incubated 1 hour at room temperature (ca. 25°C), and medium is introduced (DMEM+10% FCS: 30 μL and Leibovitch medium (Biological Industries, Bet Haemek, Israel): 50 μL. A working solution of the assayed compound is prepared by dilution of an appropriate stock solution (in DMSO or ethanol) 40-fold in Leibovitch medium, and 9 further dilutions are made in Leibovitch medium (no toxic or inhibitory effect observed in DMSO or ethanol controls). To each of the first ten columns is added a decreasing dilution of compound (50 μL per cell), followed by DMEM+10% FCS (30 μL per cell), followed by DMEM+10% FCS (30 μL per well). To each of the last two columns (untreated vims-infected and mock-infected cells) is added 50 μL Leibovitch medium and 30 μL DMEM+10% FCS. A final volume of 100 μL per well (- 3% FCS) is thus obtained. The Assay was conducted in 2 formats, as described below: Format 1 -1, -2, -3, -4: log 10 viral doses (-1, -2, -3, -4, respectively). .0, .1 , .2, ... wells treated with compound at 0, 1, 2, ... 2-fold dilutions, respectively. T: Cytotoxicity (treated, mock infected). VC (dark-shaded area): vims control (vims- infected, untreated). C (light-shaded area): cell control (untreated mock-infected). The plate is then incubated 2-3 days at 34°C (5% C0 2 ), a mixture of XTT (1 mg/mL in EMEM) and N-methylphenasonium methosulfate (PMS) is added (50 μL). The plate is measured immediately (0-hour measurement) and following 3-5 hours of incubation at 37°C (t-hour measurement) by a microplate reader (SLT - Lab instruments - Austria, Model EAR-400) at a wavelength of 450 nm (reference wavelength 620 nm). Corrected absorbance values (t-hour - 0-hour measurements) are converted to % cell-viability by arbitrary assignment of 100% viability to the average cell control absorbance (see layout). TC 50 values - defined as the concentration of compound which retards cell growth by 50% - are obtained by interpolation of or extrapolation from appropriate quadruple determinations (layout). IC 50 was defined as the concentration of compound which restores 50% of the viral-caused decrease in cell viability (relative to treated uninfected control). The decrease in viability resultant from vims action was determined at each concentration of compound, in relation to the corresponding cytotoxicity. IC 50 values were determined by linear interpolation (in some cases extrapolation). Format 2 The plate layout was as follows: A/B - compound A or B Aι, 2 „3 - 1 st , 2 nd , 3 rd 2-fold dilution of compound A CC - Cell control (uninfected cells only, no compound added) VC - Virus control (infected cells, no compound added) A single vims dilution was used per plate. Procedures prior to XTT addition were either identical to format 1 or as follows: Compounds were titrated 2-fold in EMEM (in 50 μL) and about 30,000 cells per well were added (in 30 μL EMEM with 10% FCS). Appropriate dilution of vims was then added (20 μL in EMEM). The final concentration of FCS was -3%. XTT addition was similar to format 1. The incubation time was 3-12 hours (usually 3-5 hours). The wavelength employed for plate reading was generally as in format 1. In some cases, however, the measuring wavelength was 490 nm (reference wavelength 620 nm). Results were obtained by 2-point linear interpolation (in 0 some cases extrapolation), as in format 1. Results described herein correspond to VC viabilities of 0-25% (75-100%) loss of viability with vims relative to cell control). Results 5 A) Results obtained by the XTT Assay in both foπnats are listed in the following Tables (Compounds are from Aldrich Chem. Comp. unless otherwise indicated). IC 50 and TC 50 values are in micromolar. Formula II 0 Format 1 Format 2 Formula III Formula IΙI(i) Format 1 Compounds 121 and 132 synthesized in the Lab. Compound #14 by Sigma Chemical Format 2 Formula IΙI(ii) Format 1 SA# Z' Y' R 3 Y TCso IC50 HRV 36 H OH H H 1720 ± 660 27 14 Format 2 Formula IΙI(iii) Format 1 Syntheses of compounds by the Lab. Format 2 All compounds synthesized by Lab except SA-114 Formula IΙI(iv) Format 1 SA# Z' Y' R 3 Y TCso ICso HRV 34 OH H OH H 410±30 94 14 Format 2: SA# Z' Y' R 3 Y ICso HRV μM 33 H Cl H Cl 9±1 1A 4±1 IB 14 ±3 14 6±1 16 46 H NO 2 H H 170 ±100 14 47 H I H I 12 ±2 14 Formula III(v) Format 1 Format 2 Synthesis of compounds by the Lab. Formula IΙI(vi) Format 1 Format 2 Formula IΙI(vii) Format 1 Format 2 Formula IΙI(viii) Format 1 SA# Z' Y' R 3 Y TCso ICso HRV 137 H Cl H H 47 ± 10 6.2 1A 131 H H H H 5 ± 1 0.6 14 Format 2 Formula IΙI(ix) Format 1 SA# Y' R 3 Y TCso ICso HRV 3 H H H 10 + 0.4 9 14 Format 2 SA# Y' Rs Y ICso HRV 3 H H H 4±2 14 72 + 34 16 Formu laIII(x) Formula IΙI(xi) Format 2 #43 Synthesized in lab #91 Sigma Chem. Formula IΙI(xii) Format 2 Sigma Chem. Comp., #100 Synthesis Formula IV Format 1 SA# χ 2 Y R 3 Y' R 11 R 11 R il R J1 TCso ICso HRV 122 OH H H H OH OH H H 330 ± 30 104 1A (R 11 is used both for OH and for H clockwise from ketone) Format 2 Formula V Formula V(i) Format 2 Formu la V(ii) Formal t 2 Foπnula VI Format 2 B) Results relating to Apopain modulation (inhibition and activation) were obtained by application of assay VI and are listed in the tables below (compounds are from Aldrich Chem. Comp. unless otherwise indicated). Formula III Formula III(i) 51, 109, 110 synthesis Formula IΙI(iii) Formula IΙI(ix) SA# Y' R 3 Y ICso Activity 3 H H H < 1 Inhibitor Formula xi (Z=OH, Rι=CH 2 CH 2 Ph) Sigma Chem.

Claims: CLAIMS: 1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as an active ingredient, a compound of formula (I): wherein Z is selected from the group consisting of C, Si, P and S; X], X 2 are independently O, S, N O ; R I is selected from the group consisting of: (i) hydrogen, hydroxyl, phenyl (optionally substituted with 1-4 R 11 ), a straight saturated or unsaturated hydrocarbon chain of from about 1 to about 10 carbon atoms, optionally substituted with one or more R 11 , wherein R π and R 6 are each independently selected from the group consisting of: (ia) C r C 4 alkyl (optionally substituted with R 111 ), C 2 -C 4 alkenyl (optionally substituted with R ), C 2 -C 3 alkylyl (optionally substituted with R 111 ), C]-C 3 alkoxy (optionally substituted with R 1 u ), C 3 -C 8 cycloalkyi (optionally substituted with R u ι ); (ib) halogen, cyano, nitro, amino, oxo, hydroxy, adamantyl, carbamyl, carbamyloxy or acetyl; (ic) an oligopeptide of 1-4 amino acid residues and (id) NR 13 R 14 , C0 2 R 13 , 0(C=OR 13 ), S0 2 R 13 , SOR l3 R 14 , (CO)NR 13 R 14 , or NR 14 (C=0)R 13; wherein: R 13 is hydrogen, phenyl, benzyl, C C 6 alkyl and C 3 -C 6 cycloalkyi; and R 14 is hydrogen, hydroxyl, C C 4 alkyl or benzyl; (ii) an oligopeptide of 1 to 5 amino acids (iii) C 3 -C 7 cycloalkyi (optionally containing 1-3 unsaturations), C 6 -Cι 0 bicycloalkyl (optionally containing 1-4 unsaturations), (C 3 -C 7 cycloalkyl)methyl (optionally containing 1-3 unsaturations), C 7 -Cι 0 aralkyl (optionally containing 1 unsaturations on alkyl), methylnaphthyl (α or β), adamantane, C 5 -C 8 heterocyclic ring system including at least one nitrogen, oxygen or sulfur atoms (optionally containing 1-3 unsaturations), or a (C 5 -C 9 heterocyclic ring system) alkyl (optionally containing 1-3 unsaturations), a C 3 -C 6 heterocyclic ring system fused to an aromatic ring (optionally containing 1-2 nonbenzenoid unsaturations) or a (C 3 -C 6 heterocyclic ring system) fused to an aromatic ring (0-2 nonbenzenoid unsaturations)methyl; (iv) C r C 5 alkoxy (optionally substituted with. 1-3 R 11 ), NH-W whrein W is the substituents as defined in (i) to (iii) above, or N connected to 2 W independently selected from (i) to (iii) as defined above; A, A' are independently selected from the group consisting of: (i) hydrogen, hydroxyl, phenyl ( optionally substituted with 1-4 R 11 ), acetyl, allyl. a straight saturated or unsaturated hydrocarbon chain of from about 1 to about 8 carbon atoms, optionally substituted with one or more R n , wherein R 1 x is as defined above; (ii) CONR 13 R 14 , SONR 13 R 14 (sulfamyl) S0 2 NR 13 R 14 , R 13 , R 14 as defined above; (iii) A, A' may form an aromatic ring optionally containing 1-3 heteroatoms and fully substituted with Y, R 3 , Y', Z', wherein: Y is hydrogen, OH, CH 2 OH, CH 2 SH, halogen, CF 3 , CN, CONR 12 R 13 , S0 2 NR 12 R 13 , SONR 12 R 13 , C r C 3 alkoxy (optionally substituted with 1-3 R 11 ), C C 3 alkyl (optionally substituted with 1-3 R 11 ); Z' is hydrogen, OH, C C 4 alkoxy (optionally containing 1-2 unsaturations and substituted with 1-3 R 15 ), or C 5 .C 7 carbocyclic or heterocyclic ring system connected to Ri (optionally containing 1-2 unsaturations); R 15 is selected from phenyl (optionally substituted with 1-3 R 14 ), naphthyl (optionally substituted with 1-3 R 14 ), or a C 3 -C 6 heterocyclic ring system fused to an aromatic ring (optionally containing 1-2 nonbenzenoid unsaturations and optionally substituted with 1-3 R 14) ; Y' is hydrogen, OH, halogen, mtro, CN, CF 3 , CONR 12 R 13 , S0 2 NR 12 R 13 , SONR I2 R ,3 , C r C 3 alkyl (optionally substituted with. 1-3 R 11 ); R 3 is H, OH, methyl, C C 3 alkoxy, allyl, amino; altematively, Z' and Y' may be joined to form a phenyl ring, resulting in a naphthalene system; or Z' and Y' may be joined to form a 9-11 member bicyclic ring (1-3 heteroatoms, 1-2 unsaturations, optionally substituted with 1-4 R 11 ). altematively, Z' and R \ may combine to form a C 5 -C 7 carbocyclic ring (containing 1-3 unsaturations, substituted with 1-5 R 11 ) ; or Z' and R] may jointly form a C 5 -C 7 heterocyclic ring (1-3 heteroatoms, 1-3 unsaturations, substituted with 1-5 Rn). or (iv) A, A' may form a C 5 -C 7 carbocyclic ring coupled (optionally containing 1-3 unsaturations and optionally substituted with 1-2 R 11 ); R 111 is hydrogen, halogen, hydroxy, methyl, ethyl, acetyl, carboxamide, N0 2 , sulfamide, phenyl or sulfamyl. 2. A pharmaceutical composition according to Claim 1 wherein the active ingredient is of formula II. wherein A and A' are as defined in (i) or (ii) above 3. A pharmaceutical composition according to Claim 1 wherein the active ingredient is of formula III: 4. A pharmaceutical composition according to Claim 1 wherein the active ingredient is of formula IV: 5. A pharmaceutical composition according to Claim 1 wherein the active ingredient is of formula V: wherein R 6 is defined in Claim 1 or R 6 and R 1 may form together a C 5 .C 7 carbocyclic or heterocyclic ring, optionally containing 1-2 unsaturations, optionally substituted with 1-2 R 11 . 6. A pharmaceutical composition according to Claim 2, wherein Ri is CH 3 , phenyl, 2-hydroxy benzene or 5-chloro-2-hydroxy benzene; A is CH 3 or phenyl; and A' is CO CH 3 or H. 7. A pharmaceutical composition according to Claim 1, wherein the active ingredient is of formula VI: 8. A pharmaceutical composition according to Claim 3 wherein the active ingredient is selected from the group consisting of: IΙI(ix) III(x) 9. A pharmaceutical composition according to Claim 8 formula IΙI(i) wherein Z is OH; R, is CH 3; Z' is H, O-methyl, OH, or OCH 2 CONH 2 ; Y' is Cl, H, F, Br, CN, methyl or OCH 3 ; R 3 is H, O-methyl, methyl or OH; and Y is H, Cl, N0 2 Br, CN or COOethyl Y' and Z' may form a 9-member bicyclic ring containing 0-2 unsaturations and 1-2 heteroatoms and substituted with 4 Rn (selected from methyl, oxo, acetyl, hydroxyl). 10. A pharmaceutical composition according to Claim 8, formula IΙI(ii), wherein Z is OH R is CH 2 CH 3 ; Z' is H; Y ' is OH; R 3 and y are each H; 11. A pharmaceutical composition according to Claim 8 Formula IΙI(iii), wherein Z is OH Z ' is H, OCH 2 CONH 2 , OH or O-methyl; Y ' is Cl or H; R R 33 is OH or O-methyl; Y is H or Cl; 12. A pharmaceutical composition according to Claim 8 formula IΙI(iv), wherein Z' is H or OH; Y' is H, Cl, N0 2 or I; R 3 is H or OH; and Y is H, Cl or I 13. A pharmaceutical composition according to Claim 8 formula III(v), wherein Z is OH; Y and Y' are N0 2 ; Z ' is H; R 3 is H; and W is CH 2 pheny 1, CH 2 CH 2 phenyl or (CH 2 ) 7 -CH 3 14. A pharmaceutical composition according to Claim 8 formula IΙI(vi), wherein Z is OH; Y',Z' are a benzofused system; Y is H; and R, is H. 15. A pharmaceutical composition according to Claim 8 formula IΙI(vii), wherein is OH; is o-phenol; is H; is H; is O-methyl; and Y is H. 16. A pharmaceutical composition according to Claim 8 formula III(viii), wherein Z is OH; Ri is CH 2 CO phenyl; TJ is H; Y r is Cl, Br or H; R 3 is H, or methyl; and Y isH. 17. A pharmaceutical composition according to Claim 8 formula IΙI(ix), wherein Z is OH; R Z' form together C=C-C=0 Y,Y',R 3 are each H. 18. A pharmaceutical composition according to Claim 8 formula III(x), wherein Z =OH Z' = H, OH Y' = H, Cl Y = H, Cl R 3 = H,Me 19. A pharmaceutical composition according to Claim 8 formula IΙI(xi), wherein R,=(CH 2 ) 2 Ph Z = OH Z'=H,OH Y' = H, Cl Y = H,C1 R 3 = H,OH R,,=H,OH 20. A pharmaceutical composition according to Claim 8 formula IΙI(xii), wherein R,(Z') - C*=C(0-Z')-Phenyl Z = OH Y' = H, Cl Y - H, Cl R 3 = H, OH R, ι = H, OH Rι 2 = H, OH 21. A pharmaceutical composition according to Claim 4 wherein X 2 is OH, OR, O-methyl Y, R 3; Y' are H and; R 11 is OH or H 22. A pharmaceutical composition according to Claim 5, wherein the active ingredient is selected from the group of compounds V(i) and V(ii) consisting of: 23. A pharmaceutical composition according to Claim 22 formula V(i), wherein R 1 (R 6 ) = 0-(o-R 6 )Phenyl Z = OH Z' = H Y' = H, Cl Y = H, Cl R 3 = H 24. A pharmaceutical composition according to Claim 22 formula V(ii), wherein R,(R 6 ) = C^C- H-R^ Z = OH Z' = H Y' - H, Cl Y = H, Cl R 3 = Me, H 25. A pharmaceutical composition according to Claim 1 , wherein the active ingredient is of formula VI, wherein Rι= H Z = OH Z' = H Y' = H, Cl Y = H 26. A pharmaceutical composition according to Claims 1 to 25 for the modulation of the activity of 3C protease, or of 3C protease-like proteins. 27. A pharmaceutical composition according to Claim 26, wherein the modulation is an inhibition. 28. A pharmaceutical composition according to Claim 27, for the treatment of a disease whose manifestation is dependent on the activity of cysteine proteases of the clans (CB,CD,CE and a family CE). 29. A pharmaceutical composition according to Claim 28 for the treatment of a disease whose manifestations are dependent on the activity of 3C-like cysteine proteases. 30. A pharmaceutical composition according to Claim 29 for the treatment of picomaviral infections. 31. A pharmaceutical composition according to Claim 30 for the treatment of common colds, allergic rhinitis, poliomyelitis, hepatitis- A, encephalitis, meningitis, hand foot-and-mouth disease, encephlomyocarditis, summer flu, (enteroviral upper respiratory infection,) asthma, various allergies, myocarditis, acute haemorrhagic conjunctivitis, disseminated neonatal infection and Borhnolm's disease. 32. A pharmaceutical composition according to Claim 26, wherein the 3C-protease-like protein is Apopain. 33. A pharmaceutical composition according to Claim 32, wherein the modulation is enhancement. 34. A pharmaceutical composition according to Claim 27, wherein the modulator is inhibition. 35. A pharmaceutical composition according to Claim 34, for the treatment of a disease selected from the group consisting of autoimmune diseases, infectious diseases caused by bacteria, viruses and fungi, and cancers manifested by insufficient apoptosis. 36. A pharmaceutical composition according to Claim 34, wherein the disease is selected from the group consisting of: neurodegenerative diseases and cardiovascular diseases. 37. A method for the detection of picomavims presence in a sequence, comprising: (i) contacting the sample with at least one of compounds (I) to (VI); (ii) determining whether binding occurred between the compounds and components in the sample, a positive determination indicates picomavims presence in the sample. 38. A method for the modulation of the activity of 3C protease or the modulation of the activity of 3C protease-like protein comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I): wherein Z is selected from the group consisting of C, Si, P and S; Xi, X 2 are independently O, S, NR^; R ! is selected from the group consisting of: (i) hydrogen, hydroxyl, phenyl (optionally substituted with 1-4 R 11 ), a straight saturated or unsaturated hydrocarbon chain of from about 1 to about 10 carbon atoms, optionally substituted with one or more R 11 , wherein R 11 and R 6 are each independently selected from the group consisting of: (ia) C r C 4 alkyl (optionally substituted with R 111 ), C 2 -C 4 alkenyl (optionally substituted with R 111 ), C 2 -C 3 alkylyl (optionally substituted with R 111 ), C r C 3 alkoxy (optionally substituted with R 1 U ), C 3 -C 8 cycloalkyi (optionally substituted with R 111 ); (ib) halogen, cyano, nitro, amino, oxo, hydroxy, adamantyl, carbamyl, carbamyloxy or acetyl; (ic) an oligopeptide of 1-4 amino acid residues and (id) NR 13 R 14 , C0 2 R 13 , 0(C=OR 13 ), S0 2 R 13 , SOR 13 R 14 , (C=0)NR 13 R 14 , or NR 14 (C=0)R 13; wherein: R 13 is hydrogen, phenyl, benzyl, C C 6 alkyl and C 3 -C 6 cycloalkyi; and R 14 is hydrogen, hydroxyl, C C 4 alkyl or benzyl; (ii) an oligopeptide of 1 to 5 amino acids (iii) C 3 -C 7 cycloalkyi (optionally containing 1-3 unsaturations), C 6 -Cι 0 bicycloalkyl (optionally containing 1-4 unsaturations), (C 3 -C 7 cycloalkyl)methyl (optionally containing 1-3 unsaturations), C 7 -C 10 aralkyl (optionally containing 1 unsaturations on alkyl), methylnaphthyl (α or β), adamantane, C 5 -C 8 heterocyclic ring system including at least one nitrogen, oxygen or sulfur atoms (optionally containing 1-3 unsaturations), or a (C 5 -C 9 heterocyclic ring system) alkyl (optionally containing 1-3 unsaturations), a C 3 -C 6 heterocyclic ring system fused to an aromatic ring (optionally containing 1-2 nonbenzenoid unsaturations) or a (C 3 -C 6 heterocyclic ring system) fused to an aromatic ring (0-2 nonbenzenoid unsaturations)methyl; (iv) Cι-C 5 alkoxy (optionally substituted with. 1-3 R 11 ), NH-W whrein W is the substituents as defined in (i) to (iii) above, or N connected to 2 W independently selected from (i) to (iii) as defined above; A, A' are independently selected from the group consisting of: (i) hydrogen, hydroxyl, phenyl ( optionally substituted with 1-4 R 11 ), acetyl, ally 1. a straight saturated or unsaturated hydrocarbon chain of from about 1 to about 8 carbon atoms, optionally substituted with one or more R u , wherein R 11 is as defined above; (ii) CONR 13 R 14 , SONR 13 R 14 (sulfamyl) S0 2 NR 13 R 14 , R 13 , R 14 as defined above; (iii) A, A' may form an aromatic ring optionally containing 1-3 heteroatoms and fully substituted with Y, R 3 , Y\ Z', wherein: Y is hydrogen, OH, CH 2 OH, CH 2 SH, halogen, CF 3 , CN, CONR 12 R 13 , S0 2 NR 12 R 13 , SONR 12 R 13 , C r C 3 alkoxy (optionally substituted with 1-3 R 11 ), C r C 3 alkyl (optionally substituted with 1-3 R 11 ); Z' is hydrogen, OH, Cι-C 4 alkoxy (optionally containing 1-2 unsaturations and substituted with 1-3 R 15 ), or C 5 .C 7 carbocyclic or heterocyclic ring system connected to Ri (optionally containing 1-2 unsaturations); R 15 is selected from phenyl (optionally substituted with 1-3 R 14 ), naphthyl (optionally substituted with 1-3 R 14 ), or a C -C 6 heterocyclic ring system fused to an aromatic ring (optionally containing 1-2 nonbenzenoid unsaturations and optionally substituted with 1-3 R , Y' is hydrogen, OH, halogen, nitro, CN, CF 3 , CONR 12 R 13 , S0 2 NR 12 R 13 , SONR 12 R 13 , C C 3 alkyl (optionally substituted with. 1-3 R 11 ); R 3 is H, OH, methyl, C C 3 alkoxy, allyl, amino; alternatively, Z' and Y' may be joined to form a phenyl ring, resulting in a naphthalene system; or Z' and Y' may be joined to form a 9-11 member bicyclic ring (1-3 heteroatoms, 1-2 unsaturations, optionally substituted with 1-4 R 1 1 ). altematively, Z' and R ! may combine to form a C 5 -C 7 carbocyclic ring (containing 1-3 unsaturations, substituted wi-h 1-5 R 11 ) ; or Z' and Ri may jointly form a C 5 -C 7 heterocyclic ring (1-3 heteroatoms, 1-3 unsaturations, substituted with 1-5 R π ). or (iv) A, A' may form a C 5 -C 7 carbocyclic ring coupled (optionally containing 1-3 unsaturations and optionally substituted with 1-2 R 11 ); R m is hydrogen, halogen, hydroxy, methyl, ethyl, acetyl, carboxamide, N0 2 , sulfamide, phenyl or sulfamyl. 39. Use of a compound of the formula (I) wherein Z is selected from the group consisting of C, Si, P and S; Xi, X 2 are independently O, S, NR^; Ri is selected from the group consisting of: (i) hydrogen, hydroxyl, phenyl (optionally substituted with 1-4 R 11 ), a straight saturated or unsaturated hydrocarbon chain of from about 1 to about 10 carbon atoms, optionally substituted with one or more R 11 , wherein R 11 and R 6 are each independently selected from the group consisting of: (ia) C,-C 4 alkyl (optionally substituted with R 111 ), C 2 -C 4 alkenyl (optionally substituted with R 111 ), C 2 -C 3 alky by 1 (optionally substituted with R 111 ), C r C 3 alkoxy (optionally substituted with R U 1 ), C 3 -C 8 cycloalkyi (optionally substituted with R 111 ); (ib) halogen, cyano, nitro, amino, oxo; hydroxy, adamantyl, carbamyl, carbamyloxy or acetyl; (ic) an oligopeptide of 1-4 amino acid residues and (id) NR 13 R 14 , C0 2 R 13 , 0(C=OR 13 ), S0 2 R 13 , SOR 13 R 14 , (C=0)NR 13 R 14 , or NR 14 (C=0)R 13; wherein: R lj is hydrogen, phenyl, benzyl, C r C 6 alkyl and C 3 -C 6 cycloalkyi; and R 14 is hydrogen, hydroxyl, Cι-C 4 alkyl or benzyl; (ii) an oligopeptide of 1 to 5 amino acids (iii) C 3 -C 7 cycloalkyi (optionally containing 1-3 unsaturations), C 6 -Cι 0 bicycloalkyl (optionally containing 1-4 unsaturations), (C 3 -C 7 cycloalkyl)methyl (optionally containing 1-3 unsaturations), C 7 -Cι 0 aralkyl (optionally containing 1 unsaturations on alkyl), methylnaphthyl (α or β), adamantane, C 5 -C 8 heterocyclic ring system including at least one nitrogen, oxygen or sulfur atoms (optionally containing 1-3 unsaturations), or a (C 5 -C 9 heterocyclic ring system) alkyl (optionally containing 1-3 unsaturations), a C 3 -C 6 heterocyclic ring system fused to an aromatic ring (optionally containing 1-2 nonbenzenoid unsaturations) or a (C 3 -C 6 heterocyclic ring system) fused to an aromatic ring (0-2 nonbenzenoid unsaturations)methy 1 ; (iv) C-ι-C- 5 alkoxy (optionally substituted with. 1-3 R 11 ), NH-W whrein W is the substituents as defined in (i) to (iii) above, or N connected to 2 W independently selected from (i) to (iii) as defined above; A, A' are independently selected from the group consisting of: (i) hydrogen, hydroxyl, phenyl ( optionally substituted with 1-4 R 11 ), acetyl, allyl. a straight saturated or unsaturated hydrocarbon chain of from about 1 to about 8 carbon atoms, optionally substituted with one or more R 11 , wherein R 11 is as defined above; (ii) CONR ,3 R 14 , SONR 13 R 14 (sulfamyl) S0 2 NR 13 R 14 , R 13 , R 14 as defined above; (iii) A, A' may form an aromatic ring optionally containing 1-3 heteroatoms and fully substituted with Y, R 3 , Y\ Z\ wherein: Y is hydrogen, OH, CH 2 OH, CH 2 SH, halogen, CF 3 , CN, CONR 12 R 13 , S0 2 NR 12 R 13 , SONR 12 R 13 , C r C 3 alkoxy (optionally substituted with 1-3 R 11 ), C,-C 3 alkyl (optionally substituted with 1-3 R 11 ); Z' is hydrogen, OH, C r C 4 alkoxy (optionally containing 1-2 unsaturations and substituted with 1-3 R 15 ), or C 5 -C 7 carbocyclic or heterocyclic ring system connected to R ! (optionally containing 1-2 unsaturations); R 15 is selected from phenyl (optionally substituted with 1-3 R 14 ), naphthyl (optionally substituted with 1-3 R 14 ), or a C 3 -C 6 heterocyclic ring system fused to an aromatic ring (optionally containing 1-2 nonbenzenoid unsaturations and optionally substituted with 1-3 R 14) ; Y' is hydrogen, OH, halogen, nitro, CN, CF 3 , CONR 12 R 13 , S0 2 NR 12 R 13 , SONR 12 R 13 , C r C 3 alkyl (optionally substituted with. 1-3 R 11 ); R 3 is H, OH, methyl, C C 3 alkoxy, allyl, amino; altematively, Z' and Y' may be joined to form a phenyl ring, resulting in a naphthalene system; or TJ and Y' may be joined to form a 9-11 member bicyclic ring (1-3 heteroatoms, 1-2 unsaturations, optionally substituted with 1-4 R 11 ). altematively, Z' and Ri may combine to form a C 5 -C 7 carbocyclic ring (containing 1-3 unsaturations, substituted with 1-5 R 11 ) ; or Z' and Ri may jointly form a C 5 -C 7 heterocyclic ring (1-3 heteroatoms, 1-3 unsaturations, substituted with 1-5 Rπ). or (iv) A, A' may form a C 5 -C 7 carbocyclic ring coupled (optionally containing 1-3 unsaturations and optionally substituted with 1-2 R 11 ); R 111 is hydrogen, halogen, hydroxy, methyl, ethyl, acetyl, carboxamide, N0 2 , sulfamide, phenyl or sulfamyl. for the preparation of a medicament for the modulation of the activity of 3C protease or the modulation of the activity of 3C-protease-like protein.

Inventors: ARAD DORIT, ELIAS YUVAL, ARAD, DORIT, ELIAS, YUVAL
Applicants: ARAD DORIT, ELIAS YUVAL, ARAD, DORIT, ELIAS, YUVAL
Application year: 1998
Main classification: A61K31
IPC codes: A61K31, A61K38, A61P9, A61P25, A61P31, A61P37, A61P43, C07D213, C07D231, C07D263, C07D311, G01N33