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Title:
NEW ANTICANCER COMPOUNDS
Document Type and Number:
WIPO Patent Application WO/2009/065926
Kind Code:
A2
Abstract:
The present invention relates to new polysulf urated compounds containing 2 or more sulphur atoms belonging to the class of organic thiosulf onates, or dithiole-thione derivatives cyclic or linear, or trithiocarbonates for the use alone or in combination with other anticancer treatments for the treatment and/or prevention of cancer and inflammatory diseases.

Inventors:
SPARATORE ANNA (IT)
DEL SOLDATO PIERO (IT)
SANTUS GIANCARLO (IT)
Application Number:
PCT/EP2008/065985
Publication Date:
May 28, 2009
Filing Date:
November 21, 2008
Export Citation:
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Assignee:
SULFIDRIS S R L (IT)
SPARATORE ANNA (IT)
DEL SOLDATO PIERO (IT)
SANTUS GIANCARLO (IT)
International Classes:
A61K31/5025; C07C301/00; C07D339/02; C07D339/06
Foreign References:
US4760078A1988-07-26
US3943176A1976-03-09
US20030220524A12003-11-27
US6277617B12001-08-21
US3931235A1976-01-06
US4197311A1980-04-08
US3976769A1976-08-24
EP0966304B12005-05-25
US20020151570A12002-10-17
DE874447C1953-04-23
US20060270635A12006-11-30
Other References:
REDDY ET AL: "Chemoprevention of Colon Cancer by Thiol and other Organosulfur Compounds" ACS SYMPOSIUM SERIES, vol. 546, 1994, pages 164-172, XP009116458
R.LUBET ET AL: "Chemopreventive efficacy of Anethole Trithione" INT.J.CANCER, vol. 72, 1997, pages 95-101, XP002237061
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002527079 Database accession no. BRN 1740837 & BOLDYREW: DOKLADY AKADEMII NAUK SSSR, vol. 94, 1954, page 877,
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002527080 Database accession no. BRN 1912441 & WEIDNER ET AL: JOURNAL OF MEDICINAL CHEMISTRY, vol. 7, 1964, pages 671-673,
E.PERRINO ET AL: "New sulfurated derivatives of valproic acid with enhanced histone deacetylase inhibitory activity1-23" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, 2008, pages 1893-1897, XP002527078
DATABASE BEILSTEIN BEILSTEIN INSTITUTE FOR ORGANIC CHEMISTRY, FRANKFURT-MAIN, DE; XP002527081 Database accession no. BRN 153879 & SCHMITT ET AL: COMPTES RENDUS HEBDOMADAIRES DES SEANCES DE L'ACADEMIE DES SCIENCES, vol. 230, 1950, page 1774,
L.LI ET AL: "Anti-inflammatory and gastrointestinal effects of a novel diclofenac derivative" FREE RADICAL BIOLOGY & MEDICINE, vol. 42, 2007, pages 706-719, XP005878077
Attorney, Agent or Firm:
POSTIGLIONE, Ferruccio (Ing. C. Gregorj S.p.A.Via L. Murator, 13/b Milan, IT)
Download PDF:
Claims:

CLAIMS

1. Compounds of general formula:

A-X-Y-B (I) wherein

A is a polysulfurated group containing 2 or more atoms of sulphur, selected from the group comprising an organic thiosulfonate moiety or a dithiole-thione derivative cyclic or linear or trithiocarbonates; X is zero or a group capable to link to ~Y or ~B, selected from a group comprising -COO-; -0~ ; -CONH-; -0C0-; -0C00-; -CO-; -NH-CO-;

Y is zero; - (C n - ) alkyl-, - (C n - ) alkyl-CO- , ~0- (C n' )alkyl-O-, -00C- (C n - ) alkyl-COO- ; -0- (C n O alkyl- , -HN- (C n -) alkyl-, -HNCO- (C n' ) alkyl- ; -00C- (C n - ) alkyl- ; -(C n O alkyl-0-C0- (C n . - ) alkyl- ; -(C n O alkyl-CO-0- (C n -O alkyl-; wherein (C n O alkyl and (C n -O alkyl are straight or branched, and n' and n' ' , the same or different to each other, are 0-10;

Y is -(CnOalkenyl-, - (C n O alkenyl-CO-, ~0- (CnOalkenyl-0-, -00C- (C n O alkenyl-COO- ; -0- (C n O alkenyl-, -HN- (C n O alkenyl-, -HNCO- (C n O alkenyl-; ~00C- (C n . ) alkenyl- ; - (C n - ) alkenyl-0-CO- (C n -) alkenyl- ; - (C n O alkenyl-CO-0- (C n O alkenyl- ; wherein (C n O alkenyl and (C n .0 alkenyl are straight or branched, and n' and n' ' , the same or different to each other, are 0-10;

Y is -(C n .) alkinyl-, ~ (C n - ) alkinyl-CO- , -0- (C n -)alkinyl-O-, ~OOC- (C n . ) alkinyl-COO- ; ~O- (C n .) alkinyl-, -HN- (C n - ) alkinyl-, -HNCO- (C n . ) alkinyl- ; ~OOC- (C n . ) alkinyl- ; ~ (C n - ) alkinyl-O-CO- (C n - ) alkinyl- ; ~ (C n - )alkinyl-CO-O- (C n " ) alkinyl-; wherein (C n -) alkinyl and (C n - -) alkinyl are straight or branched, and n' and n' ' , the same or different to each other, are 0-10; B is -H; -CONHOH;

wherein

R2 is hydrogen; -COOH; alkyl , alkenyl, alkynyl; aryl ; fluorine, chlorine, bromine; hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy; amino, alkylamino, arylamino; thio; cyano; nitro; acyl; amido; and a 5 or 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or sulphur; and salts thereof.

2. Compounds of general formula according to claim 1, wherein A is an organic thiosulfonate moiety having formula:

R- SO 2 - S- ( I I ) wherein R-SO 2 -S- is linked to -X-Y-B; R is a straight or branched alkyl, selected from the group consisting of methyl, ethyl, propyl; alkenyl, alkinyl; alkylaryl, alkenylaryl, alkinylaryl ; arylalkyl, arylalkenyl, arylalkinyl; or cycloalkyl, cycloalkenyl , cycloalkinyl; or aromatic and/or heterocyclic ring, all substituted or unsubstituted. 3. Compounds of general formula (I) according to claim 1, wherein A is a dithiole-thione derivative having formula:

(III)

wherein

Z is S (sulphur) and at least 1 Z is C=S (thione) ,

T is :

-00C-; or

wherein

Rl is -H; -COOH; -NH 2 ; -OH; -SH;

R2 is hydrogen; -COOH; alkyl, alkenyl, alkynyl; aryl ; fluorine, chlorine, bromine; hydroxyl , alkyloxy, alkenyloxy, aryloxy, acyloxy; amino, alkylamino, arylamino; thio,- cyano; nitro,- acyl; amido; and a 5 or 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or sulphur.

4. Compounds of general formula (I) according to claim 1, wherein A is a linear dithiole-thione derivative having formula:

-T-(CH 2 )ITi-Z^ ^z—(oym—c^

(IV) wherein

Z is S (sulphur) and at least 1 Z is C=S (thione) , m is 0, 1-10; T is : -00C-; or

wherein

Rl is -H; -COOH; -NH 2 ; -OH; -SH;

R2 is hydrogen; -COOH; alkyl, alkenyl, alkynyl; aryl;

fluorine, chlorine, bromine; hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy; amino, alkylamino, arylamino; thio; cyano; nitro; acyl ; amido; and a 5 or 6-ruembered aromatic or non-aromatic ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or sulphur.

5. Salts of compounds of general formula (I) according to claim 1, wherein said salts are pharmaceutical acceptable salts of compounds of formula (I) .

6. Salts according to claim 5, said salts comprising salts of compounds of general formula (I) with alkaline metals and alkaline earth metals, nontoxic amines, aminoacids, inorganic acids comprising hydrochloric acid, phosphoric acid or organic acids comprising fumaric acid, citric acid, tartaric acid.

7. Compounds of general formula (I) according to claim 1, wherein the group A-X-Y is selected from the group comprising thiosulfonate moieties derived from the corresponding precursors having formula: S- (2- carboxyethyl )methanethiosulfonate, S- (2- aminoethyl)methanethiosulfonate and S- (2- hydroxyethyl ) methanethiosulfonate .

8. Compounds of general formula (I) according to claim 1, wherein the polysulfurated group A is

selected from the group comprising dithiole-thione derivatives of the corresponding precursors having formula: 5- (p-hydroxyphenyl) -3H-I , 2-dithiol-3-thione, 1 , 3-dithiol-2-thione-5-carboxylic acid, 3-thioxo-3H- 1 , 2-dithiole-5-carboxylic acid, 3-thioxo-3H-l, 2- dithiole-4-carboxylic acid.

9. Compound of general formula (I) according to claim 1, selected from the group consisting of: a) 2- (methylsulfonylthio) ethyl 4- phenylbutanoate, b) S-7- (hydroxyamino) -7-oxoheptyl methanesulfonothioate, c) S-5-oxo-5- (phenylamino)pentyl methanesulfonothioate, d) N 1 -phenyl-N 8 - (4- (3-thioxo-3Jf-l, 2-dithiol-4- yl)benzoyloxy) octanediamide, e) 4- (5-thioxo-5H-l,2-dithiol-3-yl)phenyl 8- (hydroxyamino) -8-oxooctanoate, f) N-hydroxy-7- (4- (5-thioxo-5H-l, 2-dithiol-3- yl ) phenoxy) heptanamide, g) 4- (5-thioxo-5H-l,2-dithiol-3-yl)phenyl 8-oxo- 8- (phenylamino) octanoate, h) N-phenyl-7- (4- (5-thioxo-5H-l , 2-dithiol- 3yl)phenoxy) heptanamide,

i) 4-(5-thioxo-5H-l,2-dithiol-3-yl)phenyl 4- phenylbutanoate .

10. Compound of general formula (I) according to claim 1, selected from the group comprising: a) N-hydroxy-5- (4- (5-thioxo-5H-l , 2-dithiol-3- yl) phenoxy)pentanamide, b) N- (2-arαinophenyl) -2- (2-methoxy-4- (5-thioxo- 5H-1 , 2-dithiol-3-yl)phenoxy) acetarαide, c) N-(2-aminophenyl) -7- (4- (5-thioxo-5ff-l,2- dithiol-3-yl)phenoxy)heptanamide, d) N 1 -phenyl-N 8 - (2-thioxo-l, 3-dithiole-4- carbonyloxy) octanediamide .

11. Compound of general formula (I) according to claims 1-10 for use as a medicament.

12. Compound of general formula:

A-X-Y-B (I) wherein

A is a polysulfurated group containing 2 or more atoms of sulphur, selected from the group comprising an organic thiosulfonate moiety or a dithiole-thione derivative cyclic or linear or trithiocarbonates ; X is zero or a group capable to link to -Y or -B, selected from a group comprising -COO-; -0~ ; -CONH-; -OCO-; -OCOO-; -CO-; -NH-CO-; Y is zero; ~ (C n - ) alkyl-, - (C n - ) alkyl-CO-, -0-

(Cn ' )alkyl-O-, -0OC-(CnOaIkYl-COO-; -O- (C n - ) alkyl- , -HN- (C n O alkyl-, -HNCO- (C n - ) alchil- ; -OOC- (C n - ) alkyl- ; -(C n O alkyl-0-CO- (C n - - ) alkyl- ; - (C n - ) alkyl-CO-0-

(C n" ) alkyl-; wherein (C n -) alkyl and (C n O alkyl are straight or branched, and n' and n' ' , the same or different to each other, are 0-10;

Y is -(C n -) alkenyl-, - (C n - ) alkenyl-CO- , ~O- (C n -)alkenyl-O-, -00C- (C n . ) alkenyl-COO- ; -0- (C n -) alkenyl-, -HN- (C n' ) alkenyl- , -HNCO- (C n - ) alkenyl- ; -00C- (C n - ) alkenyl- ; -(C n O alkenyl-0-CO- (C n .- ) alkenyl- ;

- (C n' )alkenyl-CO-O- (C n" ) alkenyl-; wherein (C n -) alkenyl and (C n" ) alkenyl are straight or branched, and n' and n' ' , the same or different to each other, are 0-10;

Y is -(Cn ' )alkinyl-, - (C n - ) alkinyl-CO- , -0- (Cn ' )alkinyl-O-, -00C- (C n ' ) alkinyl-COO- ; -O- (C n' )alkinyl-, -HN- (C n - ) alkinyl- , -HNCO- (C n - ) alkinyl- ;

-OOC- (C n' ) alkinyl- ; ~ (C n - ) alkinyl-0-CO- (C n - ) alkinyl- ;

- (C n - )alkinyl-CO-O- (C n -- )alkinyl-; wherein (C n -) alkinyl and (C n" ) alkinyl are straight or branched, and n' and n' ' , the same or different to each other, are 0-10;

B is -H; -CONHOH;

wherein

R2 is hydrogen; -COOH; alkyl, alkenyl, alkynyl; aryl; fluorine, chlorine, bromine; hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy; amino, alkylamino, arylamino; thio; cyano; nitro; acyl; amido; and a 5 or 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or sulphur; and salts thereof for use as a medicament.

13. Compound 5- (p-hydroxyphenyl-3H-l , 2-dithiol- 3-thione) of formula: for use as a medicament.

14. Pharmaceutical composition comprising at least a compound of general formula (I) according to claims 1-13 as an active ingredient and optionally one or more pharmaceutically acceptable adjuvant (s) or carrier (s) .

15. Use of a compound of general formula (I) according to claims 1-13 for the manufacture of a medicament for prevention, treatment and reduction of cancer and inflammatory diseases .

16. Use of the compound 5- (p-hydroxyphenyl-3H-

1, 2-dithiol-3-thione) having formula: for the manufacture of a medicament for prevention, treatment and reduction of cancer and inflammatory diseases .

17. Use of a compound of general formula (I) according to claims 1-13 for the manufacture of a pharmaceutical composition for prevention, treatment and reduction of cancer also in combination with other anticancer treatments comprising radio-therapy, chemo-therapy and radiochemo-therapy.

18. Use of the compound 5- (p-hydroxyphenyl-3H- 1 , 2-dithiol-3-thione) having formula: for the manufacture of a pharmaceutical composition for prevention, treatment and reduction of cancer also in combination with other anticancer treatments comprising radio-therapy, chemo-therapy and radiochemo-therapy .

19. Process for the synthesis of compounds of general formula (I) according to claim 1-13, comprising at least a reaction between a corresponding precursor of an organic thiosulfonate

or dithiole-thione, moiety A or A-X-Y, and a group B wherein A, X, Y, B have the meaning according to claim 1.

20. Process for the synthesis of compounds of general formula (I) according to claim 19, comprising at least a reaction between a corresponding precursor of a polysulfurated group, moiety A or A-X-Y, selected from the group comprising S- (2-carboxyethyl)methanethiosulfonate, S- (2- aminoethyl )methanethiosulfonate, S- (2-hydroxyethyl) methanethiosulfonate, 5- (p-hydroxyphenyl) -3H-1, 2- dithiol-3-thione, 1, 3-dithiol-2-thione-5-carboxylic acid, 3-thioxo-3H-l , 2-dithiol-5-carboxylic acid, 3- thioxo-3H-l, 2-dithiol-4-carboxylic acid and a precursor of group B, wherein B has the meaning according to claim 1.

21. Compounds of general formula (I) according to claim 1, provided that said compound is not 5-(p- hydroxyphenyl-3H-l , 2-dithiol-3-thione) of formula:

22. Compounds of general formula (I) according to claim 1, provided that when B is H, X or Y are not zero .

23. Compounds of general formula (I) according

to claim 3, provided that when A is a cyclic

dithiole-thione derivative of formula (III) , Rl is

R2

-H, T is — , R2 is -H, X is zero, Y is zero, B

is not -H.

Description:

TITLE OF THE INVENTION

"New anticancer compounds"

Background of the invention

This invention relates to new compounds that are inhibitors of histone deacetylase (HDAC) and that release hydrogen sulphide (H 2 S) , whose main biological activity is in the field of cancer and inflammation.

Histone deacetylase is a family of enzymes that binds to DNA and regulates genes transcription. The family of histone deacetylases includes 11 enzymes

(isoforms) and exerts a regulating function in many inflammatory diseases including cancer.

The inhibition of three isoforms, in particular linked to cancer, leads to several beneficial effects such as (i) proliferation inhibition of tumour cells, (ii) induction of apoptosis, (iii) regulation of cellular cycle, (iv) induction of genes suppressing the tumour, (v) blockade of tumour angiogenesis . Target of histone deacetylase enzymes are the acetyl groups (CH 3 CO-) on the histones, that are proteins working as a support around which the DNA of the cell is developed.

The modification of these histones after acetylation (addition of acetyl groups) regulates the

compaction of DNA around histones and therefore controls the genes expression. Therefore if the genes involved are suppressors of tumours, following the variation in their expression, cancer can be developed.

The inhibitors of histone deacetylase are a comparatively new class of drugs, nevertheless some side effects related to the use of some of these compounds have been already observed, especially for their cardiotoxicity.

We have surprisingly found that the polysulfurated derivatives of the present invention have a good inhibitory activity of histone deacetylase and a good tolerability. These compounds inhibit the histone deacetylase enzymes, leading to an accumulation of acetyls in the histones and subsequentially to changes in the defective cellular process typical of cancerous cells.

More recently experimental in vitro and in vivo data indicate that the inhibitors of histone deacetylase can have also anti-inflammatory properties. (Adcock IM, "HDAC inhibitors ad antiinflammatory agents" British Journal of Pharmacology 1-3, 2007) .

The compounds of the present invention are also capable to increase the efficacy of the anticancer radio- and/or chemo- therapy.

Summary of the invention

This invention relates to new derivatives inhibitors of histone deacetylase, comprising in their structural formula a polysulfurated group and that are useful for the treatment of cancer and related pathological conditions. The results have been surprising because not only the safety was dramatically improved but also efficacy was sometimes increased as compared with known HDAC inhibitors.

The polysulfurated groups object of the present invention contain 2 or more atom of sulphur. The polysulfurated groups of the present invention are organic thiosulfonates or cyclic dithiole-thione derivatives such as 5- (4-hydroxyphenyl) -3H-1, 2- dithiol-3-thione, or 4- (4-hydroxyphenyl) -3H-1, 2- dithiol-3-thione, or 4- (3-thioxo-3H-l, 2-dithiol-4- yl) benzoic acid, or 4- (3-thioxo-3H-l, 2-dithiol-5- yl) benzoic acid, 1, 3-dithiol-2-thione-5-carboxylic acid, 3-thioxo-3H-l , 2-dithiole-5-carboxylic acid, 3- thioxo-3H-l , 2-dithiole-4-carboxylic acid, or linear dithiole-thiones or trithiocarbonates .

This invention also relates to processes for

preparing these compounds and to pharmaceutical compositions containing said compounds. Description of the invention

An object of the present invention are new compounds inhibitors of histone deacetylase having general formula:

A-X-Y-B (I) wherein

A is a polysulfurated group containing 2 or more atoms of sulphur, selected from the group comprising an organic thiosulfonate moiety or a dithiole-thione derivative cyclic or linear or trithiocarbonates : more in particular, as a further preferred embodiment, A is an organic thiosulfonate moiety having formula:

R-SO 2 -S- (II) wherein R-SO 2 -S- is linked to -X-Y-B; R is a straight or branched alkyl, such as methyl, ethyl, propyl; alkenyl, alkinyl; alkylaryl, alkenylaryl, alkinylaryl; arylalkyl, arylalkenyl , arylalkinyl ; or cycloalkyl, cycloalkenyl , cycloalkinyl ; or aromatic and/or heterocyclic ring, all substituted or unsubstituted; or more in particular, as a further preferred embodiment, A is a dithiole-thione derivative of

formula:

(III) or (IV)

wherein

Z is S (sulphur) and at least 1 Z is C=S (thione) , m is 0, 1-10;

T is :

-OOC-; or

wherein

Rl is -H; -COOH; -NH 2 ; -OH; -SH;

R2 is hydrogen; -COOH; alkyl , alkenyl, alkynyl; aryl; fluorine, chlorine, bromine; hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy; amino, alkylamino, arylamino; thio; cyano ; nitro; acyl ; amido; and a 5 or 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 heteroatoms selected from nitrogen; oxygen; or sulphur; wherein X is zero or a group capable to link to ~Y or ~B, selected from a group comprising -C00~; -0~ ;

-CONH- ; -OCO- ; -OCOO- ; -CO- ; -NH-CO- ; wherein Y is zero; - (C n - ) alkyl- , - (C n - ) alkyl-CO- , -0- (Cn')alkyl-O-, -00C- (C n - ) alkyl-COO- ; -0- (C n O alkyl- , -HN- (C n O alkyl-, -HNCO- (C n - ) alkyl- ; ~00C- (C n O alkyl- ;

- (C n -) alkyl-0-CO- (C n - - ) alkyl- ; - (C n - ) alkyl -CO-O- (C n" ) alkyl-; wherein (C n O alkyl and (C n O alkyl are straight or branched, and n' and n' ' , the same or different to each other, are 0-10;

Y is -(C n O alkenyl-, - (C n O alkenyl-CO- , -0- (CnOalkenyl-0-, -00C- (C n O alkenyl-COO- ; -O- (CnOalkenyl-, -HN- (C n O alkenyl- , -HNCO- (C n O alkenyl-; -00C- (C n - ) alkenyl- ; - (C n - ) alkenyl-0-CO- (C n O alkenyl- ; -(C n O alkenyl-CO-O- (C n O alkenyl- ; wherein (C n O alkenyl and (C n -O alkenyl are straight or branched, and n' and n'', the same or different to each other, are 0-10;

Y is -(C n Oalkinyl-, - (C n O alkinyl-CO- , -0- (C n 0alkinyl-0-, -00C- (C n O alkinyl-COO- ; -O- (C n Oalkinyl-, -HN- (C n O alkinyl-, -HNCO- (C n O alkinyl- ; -00C- (C n - ) alkinyl- ; - (C n - ) alkinyl-0-CO- (C n - - ) alkinyl- ;

- (C n O alkinyl-CO-0- (C n - 0 alkinyl- ; wherein (C n O alkinyl and (C n Oalkinyl are straight or branched, and n' and n' ' , the same or different to each other, are 0-10; wherein B is -H; -CONHOH;

and R2 is as previously defined; and salts thereof .

As a further preferred embodiment of the present invention, are the compounds of general formula (I) provided that when B is -H, X or Y are not zero.

As a further particularly preferred embodiment of the present invention are the compounds of general formula (I) provided that when A is a cyclic dithiolethione derivative of formula (III)

Rl is -H, T is R2 is -H, X is zero, Y is zero, B is not -H.

A further preferred embodiment of the derivative compounds inhibitors of HDACs according to the present invention, are the compounds of general formula (I) wherein the group A-X-Y is selected from the group comprising thiosulfonate moieties derived from the corresponding precursors having formula: S- (2-carboxyethyl)methanethiosulfonate, S- (2- aminoethyl) methanethiosulfonate and S- (2- hydroxyethyl ) methanethiosulfonate .

A further preferred embodiment of the derivative compounds of inhibitors of HDACs according to the present invention, are the compounds of general formula (I) wherein the polysulfurated group A is selected from the group comprising dithiole-thione derivatives of the corresponding precursors having formula: 5- (p-hydroxyphenyl) -3H-I , 2-dithiol-3-thione, 1 , 3-dithiol~2-thione-5-carboxylic acid, 3-thioxo-3H- 1, 2-dithiole-5-carboxylic acid, 3-thioxo-3H-l , 2- dithiole-4-carboxylic acid.

The compounds containing the polysulfurated group can be linked via different linking groups such as esters, amides, imides, sulfonamides, azo groups, carbamates, carbonates, anhydrides, acetals, thioacetals , etc. The polysulfurated group, i.e. the thiosulfonate moiety or the dithiol-thione derivative, can be also directly linked by an ionic bond to other anticancer compounds as a salt. Bi-functional linkers (Y) , known to the experts in the field, (such as ethyl, propyl, or butyl diols; diamines; hydroxy amines; etc.) can be optionally present when they are necessary to link the polysulfurated group to B.

A further object of the present invention are compounds of general formula (I), provided that said compound is not 5- (p-hydroxyphenyl-3H-1 , 2-dithiol-3- thione) having formula:

As a further object of the present invention are the preferred compounds according to general formula (I) such as : 2- (methylsulfonylthio) ethyl 4-phenylbutanoate

S-7- (hydroxyamino) -7-oxoheptyl methanesulfonothioate

CH 3 -SO 2 -S- (CH 2 ) 6 -CO-NH-OH

S-5-OXO-5- (phenylamino)pentyl methanesulfonothioate

N^phenyl-N 8 - (4- (3-thioxo-3H-l , 2-dithiol-4-yl) benzoyloxy) octanediamide

4- (5-thioxo-5H-l,2-dithiol-3-yl)phenyl 8- (hydroxy amino) -8-oxooctanoate

N-hydroxy-7- (4- (5-thioxo-5H-l, 2-dithiol-3- yl ) phenoxy) heptanamide

4- (5-thioxo-5H-l, 2-dithiol-3-yl)phenyl 8-OXO-8- (phenylamino) octanoate

N-phenyl-7- (4- (5-thioxo-5H-l, 2-dithiol-3-yl)phenoxy) heptanamide

4- (5-thioxo-5H-l, 2-dithiol-3-yl)phenyl 4-phenyl butanoate

N-hydroxy-5- (4- ( 5-thioxo-5H-l , 2-dithiol-3-yl) phenoxy) pentanamide

N- (2-aminophenyl) -2- (2-methoxy-4- (5-thioxo-5JFf-l, 2- dithiol-3-yl )phenoxy) acetamide

N- (2-aminophenyl) -7- (4- ( 5-thioxo-5ff-l, 2-dithiol-3- yl ) phenoxy ) heptanamide

N 1 -phenyl-N 8 - ( 2 -thioxo-1 , 3 -dithiole-4-carbonyloxy) octanediamide

0 O-(CH 2 L-CO-NH-O-C Il-

It has been surprisingly found that the compound 5- (p-hydroxyphenyl-3iJ-l, 2-dithiol-3-thione) having formula:

has a remarkable activity as inhibitor of histone deacetylase .

When the compounds include at least one asymmetric carbon atom, the products can be used in racemic mixture or in form of single enantiomer.

It is a further object of the present invention the pharmaceutical acceptable salts of compounds of general formula (I) , such as for example salts with alkaline metals and alkaline earth metals, non-toxic amines and aminoacids, inorganic acids such as hydrochloric acid, phosphoric acid, etc. or organic acids such as fumaric acid, citric acid, tartaric acid, etc.

Salts of dithiolthiones such as, for example,

1, 3-dithiol-2-thione-5-carboxylic acid, 3-thioxo-3H-

1 , 2-dithiol-5-carboxylic acid, 3-thioxo-3H-l , 2- dithiole-4-carboxylic acid with other anticancer agents are also part of the present invention.

A further object of the present invention is the use as a medicament of compounds of general formula (I) and of the preferred compounds as described above, in particular for prevention, treatment and reduction of cancer and inflammatory diseases .

It is a further object of the present invention the use as a medicament of 5- (p-hydroxyphenyl-3Jtf-l, 2- dithiol-3-thione) having formula: in particular to prevent, treat and reduce cancer and inflammatory diseases.

Further objective of the present invention are pharmaceutical compositions that contain at least a polysulfurated derivative inhibitor of histone deacetylase (according to the present invention as for general formula (I) and the above described preferred compounds) including salts thereof, as an active ingredient, moreover, as a further object of the present invention, in combination with pharmaceutically acceptable adjuvant (s) or carrier (s) .

As a further object of the present invention is the use of compounds according to the present invention, as for general formula (I) and the preferred compounds as described above, for the preparation of pharmaceutical compositions, and therefore the corresponding method, for treating cancer and inflammatory diseases, also in combination with other active ingredients.

As a further object of the present invention is the use of 5- (p-hydroxyphenyl-3H-l, 2-dithiol-3- thione) having formula: for the preparation of pharmaceutical compositions, and therefore the corresponding method, for preventing, treating and reducing cancer and inflammatory diseases, also in combination with other active ingredients .

A further object of the present invention is the process to prepare the pharmaceutical compositions comprising these compounds .

As a further object of the present invention is the method of treatment and prevention of cancer and inflammatory diseases using polysulfurated compounds, and among them in particular the compound 5-(p- hydroxyphenyl-3H-1 , 2-dithiol-3-thione) having formula: of the present invention, alone, or in combination with other anticancer treatments, such as radiotherapy, chemotherapy and radiochemo-therapy.

The results have been surprising because it is possible to increase efficacy of the compounds and to reduce their toxicity.

As a further object of the present invention is the method for the treatment of cancer that includes the combination of a dithiolethione or an organic thiosulfonate with other anticancer compounds such as, for example, DNA alkylating agents (such as cyclophosphamide, chlorambucil, melfalan, busulfan, carmustine, etc.), platinum complexes (such as for example cisplatin, oxaliplatin, carboplatin, etc.), antimetabolites (such as for example, methotrexate,

5-FU, capecitabine, floxuridine, etc.), pyrinαidine derivatives (such as for example, cytarabine, gemcitabine, azacitidine, etc.), purine derivatives

(such as for example mercaptopurine, azathioprine, thioguanine, etc.), antibiotics (such as for example actinomycin, antracycline, doxorubicin, epirubicin, mitoxantrone, bleomycin, mitomycin, etc.), enzymes

(such as for example L-asparaginase) and natural products . Among them for example vinca alkaloids

(vincristine, vinblastine, etc.) taxol derivatives

(paclitaxel, docetaxel, etc.), epipodophyllotoxins

(podophyllotoxin, etoposide, etc.).

An advantage in the use of the derivatives and of the method of treatment object of the present invention is related to the increased biological activity in the treatment of cancer.

The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which will depend upon the route of administration and the nature of the disease to be treated. These pharmaceutical compositions can be prepared by conventional methods, using compatible and pharmaceutically acceptable excipients and vehicles .

Examples of such compositions include capsules, tablets, syrups, powders and granulates for the preparation of extemporaneous solutions, injectable, rectal, nasal, ocular, vaginal preparations, etc.. A preferred route of administration is the oral route.

It is a further object of the present invention the process of the synthesis of the above said derivatives of histone deacetylase inhibitors (according to the present invention as for general formula (I), and the preferred compounds as described above) including salts thereof, said process comprising at least a reaction between a corresponding precursor of an organic thiosulfonate

or dithiol-thione or a trithiocarbonate, moiety A or A-X-Y, and a group B wherein A, X, Y, B have the meaning as above defined.

It is a further object of the present invention a process of the synthesis of the above said derivatives of general formula (I) said process comprising at least a reaction between a corresponding precursor of a polysulfurated group, moiety A or A-X-Y, selected from the group comprising: S- (2-carboxyethyl)methanethiosulfonate, S- (2-aminoethyl)methanethiosulfonate and S- (2- hydroxyethyl) methanethiosulfonate or 5-(4- hydroxyphenyl ) -3H-1, 2-dithiol-3-thione, 1, 3-dithiol- 2-thione-5-carboxylic acid, 3-thioxo-3H-l, 2-dithiol- 5-carboxylic acid, 3-thioxo-3H~l, 2-dithiol-4- carboxylic acid and a precursor of group B wherein B has meaning as above described.

The following non-limitative examples further describe and enable an ordinary skilled in the art to carry out the invention.

EXAMPLE 1. Preparation of 5-(4-hydroxyphenyl)-3H-l,2- dithiole-3-thione

To 280 mmol of sulphur, 40 mmol of anethole in 20 ml of dimethylacetamide is added. After heating at 145 0 C for 6 hours, 2.5 g of anethole dithiolethione

(ADT) are obtained. The product, washed with ether and crystallized by ethyl acetate has a melting point at 110-111 0 C. Then 1.5g of ADT are mixed with 7.5g of pyridine hydrochloride and the mixture is heated for 25 minutes at 215 0 C. After cooling, IN HCl in excess is added and the obtained precipitate is filtered, washed and crystallized from ethanol . The obtained compound, 5- (p-hydroxyphenyl) -3H-1, 2- dithiol-3-thione, melts at 191-192 0 C.

EXAMPLE 2. Synthesis of 4-(5-thioxo-5H-l,2-dithiol- 3-yl)phenyl 8- (hydroxyamino) -8-oxooctanoate To a solution of tetrahydrofurane (THF) in suberoylchloride are added in succession 1 eq. of the compound prepared in example 1 and 1 eq. of anhydrous pyridine. After stirring for 1 hour the THF solution is dried, the residue dissolved in CH 2 Cl 2 and the dichloromethane solution washed with cold water. The organic solution is dried on anhydrous sodium sulfate and evaporated to dryness . After chromatographic separation, the monoester of the compound described in example 1 with suberoyl acid is obtained. 130 mg (0.335 mmol) of this compound, l-[3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDAC) (1.2 eq. ) , dimethylaminopyridine (DMAP) (4 mg, catalytic quantity) are dissolved in 10 ml of CH 2 Cl 2

conveyed on alumina. A dichloromethane solution of 0- (terbutyl) dimethylsilyl hydroxylamine (1 eq) is added dropwise to the solution and the reaction mixture is stirred under nitrogen for 3 hours. The solution after washing with HCl IN and cold water is dried on anhydrous sodium sulphate and evaporated to dryness . The obtained crude compound is chromatographed on silica column eluting with CH 2 CI2 and methanol 1%. A part of the obtained compound (50 mg; 0.097 iranol) is dissolved in CH2CI 2 (2 ml), and after cooling, 0.02 ml of triethylsilane and 0.4 ml of trifluoroacetic acid are added. The cooled reaction is stirred for 30 minutes, the solvent is evaporated and CH2CI 2 is added. The product, kept in refrigerator overnight, crystallizes. After washing the crystals with a CH 2 Cl2/etere (1:1) mixture, the desired product, with a melting point of 93-97 0 C, is obtained. EXAMPLE 3. Synthesis of N-hydroxy-7-(4-(5-thioxo~5H- 1,2-dithiol-3-yl)phenoxy)heptanamide

NaOH (70 mg) in 2 ml of ethanol, the compound prepared in example 1 (400 mg; 1.76 mmol) and after 10 minutes ethyl 7-bromo-eptanoate (0.34 ml; 1.76 mmol) are introduced in a 3-necks glass flask heating at 45 0 C. The mixture is stirred under nitrogen at 80 0 C for 6 hours. After evaporation of the solvent the

obtained crude product is purified on silica column eluting with cyclohexane / CH 2 CI2 (6:4). The obtained red ether (89 mg) is suspended in a mixture of acetic acid (3 ml) and sulfuric acid 50% (0.48 ml) and the mixture is heated at 100 0 C, stirring for 3 hours. Water is added after cooling and the product is extracted with CH 2 CI2. The organic solution dried on anhydrous sodium sulphate is evaporated to dryness and the obtained residue is washed with ethyl ether. The acid above prepared (66.7 mg) , EDAC (1.2 eq. 0.245 mmol; 46.8 mg) , DMAP (2.5 mg) are introduced in a flask with 6 ml of CHCI3. The flask is kept on ice bath stirring under nitrogen for 20'. O- (terbutyl) dimethylsiIyI hydroxylamine (1 eq. ; 30 mg) dissolved in 1.2 ml of CHCl 3 is added dropwise. When all the product is added, the ice bath is removed and the mixture is stirred under nitrogen for 3 hour. Then CH 2 CI2 is added and the mixture is transferred in a separator funnel washing with HCl IN and then cold water. The organic phase is dried on anhydrous sodium sulphate and it is evaporated under vacuum. The obtained product after crystallization with CH2CI 2 has a melting point of 110.6-111.9 0 C.

EXAMPLE 4. Synthesis of 4- (5-thioxo-5H-l f 2-dithiol-3- yl)phenyl 8-0x0-8- (phenylamino)octanoate

Aniline (0.59 ml, 6.4 mmol) is added to a suspension of suberoyl anhydride (Ig; 6.4 mmol) in 12 ml of anhydrous THF stirring under nitrogen for 30'. Water is added and the white precipitate formed is filtered. The monoanilide of suberoyl acid prepared as above described (0.8 mmol), EDAC (193.6 mg 1.0 mmol), DMAP (10.3 mg) in 12 ml of CHCl 3 are introduced in a round flask. The mixture is kept on an ice bath for 20' stirring under nitrogen. The compound prepared in example 1 (0.8 mmol) is added and let to react at room temperature for 2 hours. At the end of the reaction the organic phase is extracted with water and then with a solution of sodium bicarbonate, dried on anhydrous sodium sulphate and evaporated to dryness. The obtained residue washed with CH2CI 2 has a melting point of 177.5-179.5 0 C.

EXAMPLE 5. Synthesis of 4-(5-thioxo-5H-l,2-dithiol-3- yl)phenyl 4-phenylbutanoate

A dichloromethane solution of dicyclohexylcarbodiimide (DCC) (755 mg; 1.2 eq) is added dropwise at room temperature to a suspension in CH2CI2 (25 ml) of the compound prepared in example 1 (680 mg; 3 mmol), 4-phenylbutyric acid (500 mg; 3 mmol), DMAP ( 18.5 mg) . The reaction is stirred for 3 hours at room temperature.

At the end of the reaction the dicyclohexylurea (DCU) is filtered. The filtrated solution is dried and chromatographed on Siθ 2 eluting with cyclohexane/

CH 2 Cl2(7:3). The product crystallizes with ethyl ether and after washing with ether has a melting point of

82.5-83 0 C.

EXAMPLE 6. Synthesis of N 1 -phenyl-N 8 - (4-(3-thioxo-3H-

1, 2-dithiol-4-yl)beiizoyloxy)octanediamide

Step 2: Preparation of 4- (3-thioxo-3H-l, 2-dithiol-4- yl)benzoic acid

4-isopropylbenzoic acid (1.0 g; 6.09 mmol) is suspended in 25 ml of ethanol and to this suspension

0.140 g of cone. H 2 SO 4 are added. The reaction is performed at 100° C, stirring for 9 hours. The solution is evaporated to dryness and the residue is dissolved in CH 2 Cl 2 . The organic phase is washed with a saturated NaHCO 3 solution and then with cold water, dried on anhydrous sodium sulphate and finally evaporated to dryness to obtain an oily colourless product. This product (ethyl 4-isopropyl benzoate,

940 mg; 5.16 mmol) is added dropwise to melted sulfur

(1.2 g) at 146°C under stirring and the reaction mixture is stirred at 220 °C for 24 hours. The temperature is lowered to 110 °C and 3 ml of toluene and 7 ml of acetone are added. After stirring the

reaction mixture at room temperature for 4 hours, the unreacted sulphur is filtered and the obtained solution is evaporated to dryness. The residue is purified by chromatography on silica gel column eluting with CH 2 Cl 2 -cyclohexane (6:4) to give a compound with melting point 157.5-159.5°C . Finally a suspension of this compound (100 mg, 0.35 mmol) in 4.5 ml of acetic acid and 0.72 ml of 9M H 2 SO 4 is stirred at 100 0 C for 4 hours. After cooling, the solution is diluted with water and extracted with a mixture of CH 2 Cl 2 -methanol (9:1). The organic phase is dried on anhydrous sodium sulphate and evaporated to dryness and the residue is washed with ether and CH 2 Cl 2 to obtain a yellow-orange solid, 4-(3-thioxo- 3H-1 , 2-dithiol-4-yl ) benzoic acid, with melting point 240-245 0 C.

Step 2: Synthesis of N 1 -phenyl -N 8 - (4- (3-thioxo-3H-l, 2- di thiol -4-yl )benzoyloxy) octanediamide

A solution of N-hydroxy-N-phenyl octanediamide (SAHA) (100 mg; 0.38 mmol) in 1 ml of dimethylformamide (DMF) is added to a solution of the compound prepared in step 1 (96 mg; 0.38 mmol), N-hydroxybenzotriazole (HOBt) (41.5 mg) 1- [3- (dimethylamino) propyl] -3- ethylcarbodiimide (EDAC) (0.38 mmol) in 2 ml of anhydrous DMF .

The reaction is stirred under nitrogen at room temperature for 24 hours. At the end of the reaction DMF is evaporated and the crude product filtered is washed with water, CH 2 Cl 2 and THF at room temperature. The obtained product has a melting point of 139.5-140 0 C.

EXAMPLE 7. Synthesis of N-phenyl-7-(4-(5-thioxo-5H- 1,2-dithiol-3-yl)phenoxy)heptanamide

NaOH (139 mg; 3.47 mmol) in 4 ml of ethanol, the compound prepared in example 1 (785 mg; 3.47 mmol) and after 15 minutes, ethyl 7-bromo-eptanoate (0.67 ml; 3.47 mmol) and potassium iodide (0.1 eq.) are added, heating at 45 0 C, in a 3 -necks glass flask. The mixture is stirred under nitrogen at 80 0 C for 5 hours . After evaporation of the solvent the obtained crude product is purified on silica column eluting with cyclohexane/CH2Cl 2 (6:4). The obtained red ether (178 mg) is suspended in a mixture of acetic acid (6 ml) and sulphuric acid 50% (1.0 ml) heating at 100 0 C stirring for 2 hours. After cooling, water is added and the product is extracted with CH 2 Cl 2 . The organic solution dried on anhydrous sodium sulphate, is evaporated to dryness and the residue is washed with ethyl ether. The obtained acid has a melting point of 114.8-115.6°C.

The above prepared acid (150 mg; 0.423 mmol) , EDAC (97 mg; 0.5 mmol), DMAP (5.2 mg) with 8 ml of CHCl 3 are introduced in a round flask. The flask is kept on an ice bath and the mixture is stirred under nitrogen for 20'. Aniline (39.4 mg; 0.423 mmol), dissolved in 2 ml of CHCl 3 , is added dropwise. At the end of the addition, the ice bath is removed and the mixture is stirred under nitrogen for 3 hours. CH2CI 2 is added and the mixture is transferred in a separator fennel washing with cold HCl IN and then cold water. The organic phase is dried on anhydrous sodium sulphate and evaporated under vacuum. The product obtained after crystallization with CH 2 CI 2 has a melting point of 149-150 °C.

EXAMPLE 8. Synthesis of S-5-oxo-5-(phenylamino)pentyl methanesulfonothioate

Step 1: Synthesis of 5-methanesulfonylsulfanyl- pentanoic acid

A solution of sodium methanthiosulphonate (2 g; 14.9 mmol) and 5-bromovaleric acid (1.42 mg; 7.84 mmol) in dimethylformamide (DMF, 12 ml) is heated at reflux, stirring under nitrogen for 4 hours. After evaporation to dryness of the solvent, the residue is dissolved in water (70 ml) acidified with 10 ml of a 2N KHSO 4 solution and the solution is extracted with

ethylacetate. The organic phase is extracted with a cold solution of 2N KHSO 4 , then with iced water and finally dried on anhydrous sodium sulphate and evaporated to dryness . An oily yellow product is obtained that crystallizes in refrigerator and, after washing with ether, melts at 64-65 0 C.

Step 2: Synthesis of S-5-oxo-5- (phenylamino)pentyl methanesulfonothioate

A solution of the product prepared in step 1 (250 mg; 1.18 iranol) , EDAC (271 mg; 1.42 mmol) and DMAP (7 mg) in 10 ml of anhydrous dichloromethane is stirred for 30' on an ice bath. After the addition of aniline (110 mg; 1.18 mmol), the reaction mixture is let to rest until it reaches room temperature, and then is stirred for 5 hours. The reaction mixture is extracted several times with water and HCl IM. The organic solution is dried on anhydrous sodium sulphate and evaporated to dryness. An oily yellow product is obtained which crystallizes in refrigerator and, after washing with ether, melts at 64.1-65.7 0 C.

EXAMPLE 9. Antiproliferative activity and inhibition of HDAC

The cytotoxic activity of the compounds was studied in the following stabilized human cell lines of lung

cancer, commercially available: ChaGo Kl (derived from a bronchogenic carcinoma) and NCI-H1915 (isolated from a cerebral metastasis of a big cells carcinoma) .

The cell lines are cultivated in a medium constituted by Dulbecco Modified Eagle's Medium (DMEM) and Ham's F12 in equal parts added with foetal calf serum (10%), L-glutamine (2 mM) , non essential aminoacids (1%) (Mascia Brunelli s.p.a.) and insulin (10 μg/ml) (Sigma) . Cells in exponential phase of growth were used in all the experiments. Valproic acid was used as standard.

The results expressed as % of inhibition are reported in the table:

Compound Antiproliferative activity (%)

ChaGo Kl NCI-H1915

Control 0 0

EXAMPLE 1 10 μM 80 78

EXAMPLE 3 10 μM 77 82

EXAMPLE 6 10 μM 83 84

Valproic acid 500 μM 30 35

Both cellular lines show a clear activity of the compounds at micro molar concentrations .

The activity of regulation of histories H3 and H4 acetylation for the compounds of the present invention was measured and it was found that the compounds are capable to inhibit the histone deacetylase enzyme with a good correlation with the antiproliferative activity.

EXAMPLE 10. Synthesis of N-hydroxy-5-(4-(5-thioxo-5H-

1,2-dithiol-3-yl)phenoxy)pentanamide

The compound prepared in example 1 (890 mg; 3.93 mmol) is added to a solution of sodium hydroxide (157 mg,- 3.93 mmol) in ethanol (4 ml) and the mixture is stirred for 15 minutes. Thereafter ethyl 5- bromopentanoate 98% (838 mg; 0.63 ml) and KI (65 mg; 0.1 eq. ) are added and heated at reflux. After 4 hours the mixture of reaction is cooled and ethanol is evaporated. The crude product is chromatographed on silica gel (eluting with eyelohexane/ethyl acetate, 85:15) and after washing with petrol ether, ethyl 5- (4- (5-thioxo-5H-l , 2-dithiol-3-yl)phenoxy) pentanoate with melting point 81-82 0 C is obtained. The product is suspended in a mixture of acetic acid (5.9 ml) and 50% sulphuric acid (0.9 ml) and heated, under stirring, at 100 0 C for 1.5 h. After cooling, the mixture is diluted with water and extracted with CH2C12. The organic phase is dried on anhydrous sodium sulphate, filtered and evaporated to dryness.

The product, after washing with ethyl ether, has melting point 114.5-117-5 0 C (decomposition)

The obtained product (125 mg; 0.38 rnmol), EDAC (87 mg; 0.45 mmol) and a catalytic quantity of DMAP are dissolved in 6 ml of CHCI 3 and the solution is stirred under nitrogen for 20 minutes on an ice-bath. Thereafter a solution of 0- ( tert-butyldimethylsilyl) hydroxylamine (59 mg, 0.38 mmol) in CHCI 3 is added and the reaction is stirred at room temperature for 3 hours. The solution is diluted with chloroform and washed in separator funnel with HCl 1 N and then with water. The organic phase is dried on anhydrous sodium sulphate, filtered and evaporated to dryness. The product, washed with ethyl ether, has melting point 101.5-103.5 0 C.

EXAMPLE 11. N- (2-aminophβnyl) -2- (2-methoxy-4- (5- thioxo-5H-1,2-dithiol-3-yl)phenoxy) acetamide Step 1: Synthesis of 2- (2-methoxy-4- (5-thioxo-5H-l, 2- di thiol-3-yl)phenoxy) acetic acid Eugenol (3 g; 2.8 ml; 18.27 mmol) is added to a solution of NaOH (741 mg; 18.52 mmol) in methanol

(20 ml) and, after stirring under nitrogen for 10 minutes, methyl bromoacetate (3.74 g; 2.25 ml; 24.44 mmol) is added and the mixture is heated at 55 0 C for 2 hours. At the end of the reaction, the solvent is evaporated under vacuum and a cold solution of 0.1 N NaOH is added to the white residue and the mixture is

extracted with ethyl ether. The organic phase is washed with cold water, dried on anhydrous sodium sulphate and evaporated to dryness. The oily residue is chromatographed on silica gel (eluting with cyclohexane/methylene chloride, 3:1). Elemental sulphur (2.06 g; 64.44 mmol) is melted in a 100 ml round glass flask, stirring at 146 0 C. Methyl 2- (4- alIyI-2-methoxyphenoxy) acetate (2.06 g; 8.72 mmol) previously prepared is added and the mixture is heated at 220 0 C for 2 hours under stirring. At the end of the reaction, the mixture is cooled at room temperature and toluene (2 ml) and acetone (4.7 ml) are added. The suspension is stirred overnight at room temperature and the sulphur in excess is filtered and washed with acetone. The filtered solution is evaporated to dryness and rapidly chromatographed on silica gel, (eluting with methylene chloride/cyclohexane, 98:2). Methyl 2-[2- methoxy-4- (3-thioxo-3ff-l , 2-dithiol-5-yl)phenoxy] acetate, as a red solid with melting point 165-166 0 C is obtained.

A suspension of methyl 2- [2-methoxy-4- (3-thioxo-3H- l,2-dithiol-5-yl)phenoxy] acetate (587 mg; 1.79 mmoli) in acetic acid (24.4 ml) and 50% sulfuric acid (4 ml) is stirred at 100 0 C for 1 hour and 30 minutes. At the end of the reaction, the mixture is cooled on an ice bath and the precipitate is filtered and washed with

water and ethyl ether. The brown product obtained, 2-

(2-methoxγ-4- ( 5-thioxo-5H-l, 2-dithiol-3-yl)phenoxy) acetic acid, has melting point 198-200 0 C. Step 2: The compound (90 mg; 0.286 mmol) prepared in step 1 is dissolved in DMF (1 ml) and EDAC (66 mg; 0.343 mmol) and catalytic quantity of DMAP are added. The solution is stirred under nitrogen for 20 minutes on an ice bath, then a solution of benzene-1, 2-diamine (31 mg; 0.286 mmol) in DMF (0.5 ml) is added and the reaction is stirred overnight. DMF is evaporated, the residue is dissolved in chloroform and the solution is washed with water in a separator funnel. The organic phase is dried on anhydrous sodium sulphate, filtered and evaporated to dryness. The crude product is chromatographed on silica gel (eluting with CH 2 Cl 2 /MeOH, 99:1) and then washed with ethyl ether yielding an orange solid with melting point 170-172.6 0 C. EXAMPLE 12. Synthesis of N-(2-aminophenyl)-7-(4-(5- thioxo-5H-1,2-dithiol-3-y1)phenoxy)heptanamide NaOH (70 mg) in 2 ml of ethanol, the compound prepared in example 1 (400 mg; 1.76 mmol) and ethyl 7-bromo-eptanoate (0.34 ml; 1.76 mmol) are introduced in a 3 -necks glass flask heating at 45 0 C. The mixture is stirred under nitrogen at 80 0 C for 6 hours. After evaporation of the solvent, the obtained

product is purified on silica gel (eluting with cyclohexane/CH2C12, 6:4) . The obtained red ether (89 mg) is suspended in a mixture of acetic acid (3 ml) and 50% sulfuric acid (0.48 ml) and the mixture is heated at 100 0 C, stirring for 6 hours. Water is added after cooling and the product is extracted with CH 2 CI 2 . The organic solution, dried on anhydrous sodium sulphate, is evaporated to dryness and the obtained residue is washed with ethyl ether. o-phenylendiamine (39.65 mg, 0.37 iranol) is added to a solution of the acid above prepared (130 mg, 0.36 mmol), EDAC (83 mg, 0.43 mmol), HOBT (66 mg, 0.43 mmol) and triethylamine (TEA, 0.05 ml) in anhydrous DMF (3 ml) and the mixture is stirred under nitrogen, at room temperature for 24 hours. At the end of the reaction DMF is evaporated and CH2C12 is added. The organic phase is washed with water, dried on anhydrous sodium sulphate and is evaporated to dryness . The crude product is chromatographed on silica gel (eluting with CH 2 Cl 2 /methanol, 99:1). The obtained product, after washing with ethyl ether, has melting point 144-146 OC.

EXAMPLE 13. Synthesis of m-phenyl-N8-(2-thioxo-1,3- dithiole-4-carbonyloxy)octanediamide A solution of N-hydroxy-N-phenyl octanediamide (SAHA, 100 mg; 0.38 mmol) in anhydrous DMF (1 ml) is added to a solution of EDAC (86.8 mg, 0.45 mmol), HOBT

(69.5; 0.45 mmol) and 2-thioxo-l , 3-dithiole-4- carboxylic acid (60 mg; 0.38 mmol) in anhydrous DMF (2 ml) and the mixture is stirred under nitrogen, at room temperature, for 24 hours. At the end of the reaction, DMF is evaporated and the residue dissolved in ethyl acetate. The organic phase is washed with water, dried on anhydrous sodium sulphate and evaporated to dryness. The product is washed with ethyl acetate and ethyl ether and after crystallization with THF has melting point 138-141 0 C (decomposition) .