AU2011226950B9 - 1-N-phenyl-amino-1H-imidazole derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

1-N-phenyl-amino- 1H-imidazole derivatives and pharmaceutical compositions containing them Abstract 5 The invention relates to the compounds of formula (1), in which RI, R2, R3, R4, Q and Z are as defined in the specification. The invention also relates to the pharmaceutical compositions containing these compounds. The invention generally relates to the field of hormone- and non hormone-dependent cancer and endocrine disorders.

Description

S&F Ref: 767507D1 AUSTRALIA PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address Laboratoire Theramex, of 6 Avenue Albert II, MC-98000, of Applicant: Monaco Actual Inventor(s): Benoit Rondot Christian Blot Eric Duranti Francois Puccio Thierry Clerc Jacqueline Shields Jean Lafay Paule Bonnet Philippe Maillos Igor Duc Address for Service: Spruson & Ferguson St Martins Tower Level 35 31 Market Street Sydney NSW 2000 (CCN 3710000177) Invention Title: 1 -N-phenyl-amino-1 H-imidazole derivatives and pharmaceutical compositions containing them The following statement is a full description of this invention, including the best method of performing it known to me/us: 5845c(5631831_1) 1-N-phenyl-amingo-1H-i1midazole derivatives and phamaceutical compositions containing them, The present Invention relates to 1-N-phenylamino-1H-imidazole derivatives and to pharmaceutical compositions containing them. 5 The invention generally relates to the field of hormone- and non hormone dependent cancer and endocrine disorders. Aromatase is the physiological enzyme responsible for the specific conversion of androgens such as androstenedione or testosterone, into estrogens such as estrone and estradiol, respectively (Simpson ER et al., Endocrine Reviews, 1994, 10 15 : 342-355). Inhibition of aromatase Is, therefore, a strategy of choice to . Interfere with normal or pathological estrogen-induced or estrogen-dependent biological processes such as female sexual differentiation, ovulation, Implantation, pregnancy, breast and endometrial cell proliferation as well as regulations of spermatogenesis or prostate cell proliferation in male or of non 15 reproductive functions such as bone formation or Immune T cell and cytokine balance (see Simpson ER et al., Recent Progress In Hormone Research, 1997, 52 : 185-213 and the whole issues of Endocrine Related Cancer (1999, volume 6, n*2) and Breast Cancer Research Treatment (1998, volume 49, supplement n 0 1)). 20 The enzyme steroid sulfatase (E.C. 3.1.6.2., STS) catalyses the hydrolysis of estrone sulfate to estrone and the DHEA sulfate to DHEA (Dibbelt L, Blol. Chem, Hoppe-Seyler, 1991, 372, 173-185 and Stein C, J. Blol. Chem., 1989, 264, 13865 13872). The steroid sulfatase pathway has been the focus of recent interest In the 25 context of breast cancer,* with regard to the local Intra-tissue formation of estrogens from the abundant circulating pool of estrone sulfate (EiS) (Pasqualinl JR, J. Steroid Blochem. Mol. Biol., 1999, 69, 287-292 and Purohit A, Mol. Cell. Endocrinol., 2001, 171, 129-135). Inhibition of this enzyme would prevent EjS from yielding free estrone (E 1 ), 30 which can be transformed into estradiol (E 2 ) by enzymatic reduction. In addition to the estrone sulfatase pathway, It Is now believed that another potent estrogen, androstenediol (adiol) obtained from DHEA after hydrolysis of DHEA-S, 2 could be another important. contributor, In the support of growth and development of hormone-dependent breast tumors. The formation of estrogens in women is schematically represented in figure 1. In patients with hormone-dependent cancers, aromatase Inhibitors are currently 5 used to prevent estrogen synthesis. However, clinical trials showed a. relative lack of efficacy for patients with estrogen receptor-positive tumors (Castiglione Gertsch M, Eur. J. Cancer, 1996, 32A, 393-395 and Jonat W, Eur. J. Cancer, 1996, 32A, 404-412). As an explanation, steroid sulfatase pathway could be another Important route for estrogen formation in breast tumors. 10 EMATE (Ahmed S, Curr. Med. Chem., 2002, 9, 2, 263-273), estrone-3-sulfamate, is the historical standard steroidal sulfatase inhibitor but has the major drawback of being estrogenic because of its mechanism of Inhibition: the sulfamate moiety is cleaved during the process of enzyme Inactivation, which releases Ei, not from

E

1 S but from EMATE itself (Ahmed S, J. Steroid Biochem. Mol. Biol., 2002, 80, 15 429-440). OH HO H 2 N- O Estradiol EMATE Other non-steroid sulfamate compounds which release derivatives without estrogenic properties have been presented as acceptable drug candidates such 20 as 6,6,7-COUMATE, a standard non-estrogenic sulfatase inhibitor from the literature (Purohlt A, Cancer Res, 2000, 60, 3394-3396).

3 H2N- 3-00 0 0 6,6,7 COUMATE Human carbonic anhydrases catalyse the conversion between carbon dioxide

(CO

2 ) and the bicarbonate Ion (HCO), and are involved In physiological and pathological processes. They indude hormone-dependent and non-hormone 5 dependent cancerogenesis, metastasis invasive process and hypoxic tumors that express these enzymes which are less responsive to classical chemo/radio therapy inhibitors. In particular, EMATE was found to have a human carbonic anhydrase inhibitory potency similar to that of acetazolamide, a well-known sulfonamide human carbonic anhydrase Inhibitor (Winum J and al., J. Med. 10 Chem. 2003, 46, 2197-2204). It is therefore of particular Interest to have compounds with at least one, preferably at least two of the following activities: aromatase Inhibition, steroid sulfatase inhibition and carbonic anhydrase Inhibition. Recently, B. Potter et al. (J. Med. Chem., 46, 2003, 3193-3196) reported that 15 sulfamoylated-derivatives of the aromatase Inhibitor YM 511 Inhibited sulfatase and aromatase activity in JEG-3 cells. ON 20 N N _ N--N Br YM 511 25 Compounds presented as useful for the treatment of estrogen-dependent diseases, are described in US 2003/0008862A. Imidazole derivatives with anti aromatase properties are described In WO 2004/054983.

4 It has now been found that imidazole derivatives which contain a 1-N phenylamino group, demonstrate an unexpectedly high potency to inhibit aromatase and/or steroid sulfatase and/or carbonic anhydrase. Accordingly, one object of this invention Is to provide 1-N-phenylamino-1H 5 imidazole derivatives, which are potent aromatase and/or steroid sulfatase and/or carbonic anhydrase inhibitors. Another object of this invention is to provide a pharmaceutical composition containing, as active ingredient, a 1-N-arlamino-1H-imidazole derivative as depicted below. 10 A further object of this invention is to provide the use of 1-N-phenylamino-1H imidazole derivatives in the manufacture of a medicament for treating or preventing various diseases and for managing reproductive functions in women, in men as well as In female and. male wild or domestic animals. The 1-N-phenylamino-1H-imidazole derivatives of this invention are represented 15 by the following general formula (I): R, R2 (I) R3N .R4 and acid addition salts and stereolsomeric forms thereof, wherein . R, and R 2 are each Independently hydrogen, a (C-C 6 )alkyl or a

(C

3 -Ca)cydoalkyl ; or R 1 and R 2 together form a saturated or unsaturated 5-, 20 6- or 7- membered carbocyclic ring; . Q is (CHz)m-X-(CH2)n-A; " A Is a direct link, 0, S, SO, SO 2 , NR 5 ; " X Is a direct link, CF 2 , 0, S, SO, SO2, C(O), NR 5 or CR 6

R

7 ; " Z is a group selected from: 5

R

8 R8'R (R)p (R0) p

R

8 R R (R,) (R,) and 1(R,) * m and n are each independently 0, 1, 2, 3 or 4; Sp is 1, 2, 3 or 4; 5 * q is 0,1 or 2; . the dotted line means that R 8 and/or R 9 can be on any position of the benzothlophene ring; " R 3 and R 8 are each Independently hydrogen or a hydroxy, cyano, halogen, nitro, (C-C)alkyl, (C-C 6 )alkoxy, trifluoromethyl, (C-C)alkylthlo,

(C

10 C 6 )alkylsulfonyl, acyl, (C-C 6 )alkoxycarbonyl, carboxamido, OPO(ORIO)z, NRioRal, SO 2 NRioRu, OSO 2 NRIORn, OSO 2 0Rio, S0 2 0R 10 , SS0 2 NRIORa,

CF

2

SO

2 0Rio, CF 2 SO2NRioRa,

CF

2 -tetrazolyl or NR1 2

SO

2 NRioRa,

OSO

2

NR

12

SO

2 NRioRnj, CO2R1o, CONRioRu, OCHO, OCONRoR 1 1 , OCSNRiOR, SCONRIoR 1 1 , SCSNRoRaI, tetrazolyl, NRizCONRioRIa, NRio-CHO group; 15 * when Q-Z is (CH2n

R

6 n is 0, 1 or 2 and p is 1, one of R 3 and R 8 is. a hydroxy-, nitro, OPO(ORio)z,

NRIOR

11 , OSO 2 NRioRui,

OSO

2 0R 10 , SO 2 0R 10 , SS0 2 NRioRa 1 , CF 2

SO

2 0Rio,

CF

2

SO

2 NRoRIa,

CF

2 -tetrazolyl,

NR

12

SO

2 NRioRu OSO2NRioSO2NRuR12,

CO

2 Rio,

CONR

1 oRui, OCHO, OCONRioRa 1 , OCSNRioRii, SCONRioRii, SCSNRioRII, 5 tetrazolyl, NRj 2 CONRioRuj,

NR

1 o-CHO group and the other is hydrogen or a hydroxy, cyano, halogen, nitro, (C-C 6 )alkyl, (C-C 6 )alkoxy, trifluoromethyl, (C-c)alkylthlo,

(C-C

6 )alkylsulfonyl, acyl,

(C-C

6 )alkoxycarbonyl, carboxamido, NRioRu, S0 2 NRioRu 1 , OSO2NRioRa,

OSO

2 0R 10 , SO 2 0Rio,

SSO

2 NRioRaj,

CF

2

SO

2 0Rio, CF 2

SO

2 NRioRul,

CF

2 -tetrazolyl, NR2SO 2 NRioRu, 10 OSO2NR1 2 SOzNRioRI, C0 2

R

1 o, CONRioRu, OCHO, OCONRIoRu, OCSNRioRu, SCONRioRu, SCSNRioRu 1 , tetrazolyl,

NR

12 CONRioRai, NRio-CHO group; R. and R 9 are each independently hydrogen or a hydroxy, cyano, halogen, nitro, OPO(ORo)2

,(C-C

6 )alkyl,

(C-C

6 )alkoxy, trifluoromethyl,

(C-C

6 )alkylthlo,

(C-C

6 )alkylsulfonyl, acyl,

(C-C

6 )alkoxycarbonyl, 15 carboxamido, NRioRn,

SO

2 NRioRui,

OSO

2 NRioRII,

OSO

2 ORio, S0 2 0R 10 ,

SSO

2 NRIoRIa, CF2SO 2 0Rio, CF2SO2NRioRu, CFrtetrazolyl, NRj 2

SO

2 NRioRu, OSO2NRizSO2NRioRuI,

CO

2 Ro, CHO, CONR 1 oRu 1 , OCHO, OCONRjoRaj, OCSNRioRa, SCONRioRu1, SCSNRIORu 1 , tetrazolyl, NR1 2 CONRioRai,

NR

1 o-CHO group; 20 e when p Is 2, 3 or 4 the Res can be the same or different; * R 6 and R 7 are independently hydrogen, halogen, a (CrC-)alkyl or a

(C

3 -C)cycloalkyl; . Rs, Rio, Ral and R2 are each Independently hydrogen, hydroxy, a (C-C)alkyl, or a (C 3 -Cs)cycoalkyl; Rio can also be a salt; Rio and R 11 can also form, 25 together with the nitrogen atom to which they are bound, a 5- to 7 membered heterocycle containing one or two heteroatoms selected from 0, S and N; * when Z Is 30 and p is 1, 7 then R 8 and R 9 can also form together with the phenyl ring a benzoxathiazine dioxide, a dihydrobenzoxathiazine dioxide, a benzoxathiazinone dioxide, a benzoxathiazole dioxide, a benzoxadithiadiazine tetraoxide, a benzodithiazine tetraoxide or a benzodioxadithiine tetraoxide; when Z is

R

8 L (RgOp

R

3 and R 4 together with the phenyl ring bearing them can also form a benzofurane or a N methylbenzotriazole, provided that when p is 1 and Q is (CH 2 )n, then R 8 and R 9 are independently a hydroxy, nitro, OPO(ORIO) 2 , NRioR 1 , OS0 2 NRioR 1 , OS0 2

OR

io , S0 2 0Rio, SSO 2 NRioR 1 , CF 2

SO

2 0RIo, CF 2

SO

2 NRioR 1 , CF 2 -tetrazolyl,

NR

12

SO

2 NRioR 1 , OS0 2

NR

2

SO

2 NRioR 1 , C0 2 Rio, CONRioR 1 , OCHO, OCONRioR 1 , OCSNRioR 1 , SCONRioRu 1 , SCSNRIORII, tetrazolyl, NR 12 CONRioR 1 , or NRio-CHO group. According to an aspect of the present invention there is provided an imidazole derivative of formula (I): Ri N 2 RW N Q- Z R4 or an acid addition salt or stereoisomeric form thereof, wherein: * R, and R 2 are each independently hydrogen or a (CI-C 6 )alkyl; * Q is selected from C(O), SO 2 , CONH, C(O)(CH 2 )n, (CH 2 )n(O) or (CH 2 )n in which n is 0, I or 2; * Z is a group selected from: (R)p

(R

9

)

1 ;

-

(R) S\\N \(O)q 7a e pis1; e q is 0, 1 or 2; " the dotted line means that R 8 and/or R 9 can be on any position of the benzothiophene ring; e one of R 3 and R 8 is cyano; and e the other is hydrogen or a hydroxy, halogen, nitro, cyano, (Ci-C 6 )alkoxy, NRioR 1 , OS0 2 NRioR 1 , NR 12

SO

2 NRioR 1 , OSO 2 NRioSO 2

NR

1

R

12 group; * R4 is hydrogen; e R9 is hydrogen, hydroxy, cyano, halogen, nitro, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, trifluoromethyl, acyl, NR ioR 1 , OS0 2 NRioR 1 , NR 1 2 S0 2 NRIOR 1 , C0 2 Rio group; * Rio, R, and R12 are each independently hydrogen or a (Ci-C 6 )alkyl; * when Q-Z is (CH2)n R8 (R,)p in which n is 0, 1 or 2, then the other R3 and R8 is a hydroxyl, nitro, NRioR 1 , OS0 2 NRIORa 1 or

NR

1 2

SO

2 NRIORI, group; * when Z is R 8 (R,)p then R 8 and R9 can also form together with the phenyl ring a benzoxathiazine dioxide, a dihydrobenzoxathiazine dioxide or a benzoxathiazole dioxide. The present invention also concerns the addition salts of the invention compounds or the stereoisomeric forms thereof, when they exist. In the description and claims, the term "(CI-C 6 )alkyl" is understood as meaning a linear or branched hydrocarbon chain having I to 6 carbon atoms. A (Ci-C 6 )alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl radical. Preferred alkyl radicals are those having 1, 2 or 3 carbon atoms. The term "halogen" is understood as meaning a chlorine, bromine, iodine or fluorine atom. The term "(C 3

-C

8 )cycloalkyl" is understood as meaning a saturated monocyclic hydrocarbon having 3 to 8 carbon atoms. A (C 3 -Cs)cycloalkyl radical is for example a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl radical.

7b The term "(C I-C 6 )alkoxy" is understood as meaning a group OR in which R is a (Ci-C 6 )alkyl as defined above. A (Ci-C 6 )alkoxy radical is for example a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, n-pentyloxy or 8 isopentyloxy radical. Preferred alkoxy radicals are those having 1, 2 or 3 carbon atoms. The term "acyl" is understood as meaning a group R-h in which R' is hydrogen or a 0

(C-C

4 )alkyl wherein the term "alkyl" is as defined above. An acyl radical is for 5 example a formyl, an acetyl, a propionyl, a butyryl or a valeryl radical. Preferred acyl radicals are formyl and acetyl. In the definition of Rio, a "salt" Is understood as meaning an alkali metal salt or alkaline earth metal salt, such as a sodium, potassium, magnesium or calcium salt, or a salt with an ammonium or with an organic amine such as triethylamine, 10 ethanolamine or tris-(2-hydroxyethyl)amine. In the context of the invention, this applies to groups having an OR 10 moiety. The 5- to 7-membered heterocycle can be saturated or unsaturated, and includes for example tetrazole, triazole, pyrazole, pyrazolidine, imidazole, imidazolidine, piperidine, piperazine, morpholine, pyrrolidine. 15 Compounds of formula (I) form acid addition salts, for example with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like or with organic carboxylic acids such as acetic acid, proplonic acid, glycolic acid, pyruvic 'acid, oxalic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, 20 methanesulfonic acid and the like. Especially preferred are those salts which are pharmaceutically acceptable. Among the compounds of formula (I), those which fulfil at least one of the following conditions are preferred: 25 * R 3 and R 8 are each independently hydrogen or a hydroxy, cyano, halogen, nitro, (C-C 6 )alkyl, (C-C 6 )alkoxy, trifluoromethyl, (CrC)alkylthlo,

(C-C

6 )alkylsulfonyl, acyl, (C-C 6 )alkoxycarbonyl, carboxamido, NR 1 oRa 1 , SO2NRioRa,

OSO

2 NRioRu, OSO 2

NR

1 2

SO

2

NR

1 ORa, OCHO, NR 1 2 S0 2 NRIORIa group; 30 * R 4 and R 9 are each independently hydrogen or a hydroxy, cyano, halogen, nitro, (C-C 6 )alkyl, (C-C 6 )alkoxy, trifluoromethyl, (C-C 6 )alkylthio, 9

(C-C

6 )alkylsulfonyl, acyl, (C-C 6 )alkoxycarbonyl, carboxamido, NRioR 11 , OSO2NRioRn, C0 2 Ro, CHO, NRizSO2NRioRu group; * R 1 and R 2 are each independently hydrogen or (C-C6)alkyl; * RIO, R 1 1 and R2 are each independently hydrogen or (C-C 6 )alkyl. 5. Particularly preferred compounds of a formula (I) are those in which: 9 one of R 3 and R is a hydroxy, nitro, NRIOR 1 1 , OS0 2 NRioRuI or NR2SO 2 NRioRul group; and * the other is hydrogen or a hydroxy, cyano, halogen, nitro, (CrC 6 )alkyl, 10 (C-C 6 )alkoxy, trifluoromethyl, (CrC)alkylthlo, (C-C 6 )alkylsulfonyl, acyl, (CrC)alkoxycarbonyl, carboxamido, NRiORa 1 , OSO 2 NRioRa NRj 2 S0 2 NRjORuj group. A particularly preferred group of these compounds are those in which: 15 e one of R 3 and R Is hydroxy, cyano, (C-C 6 )alkoxy or OS0 2 NRiORu 1 ; and * the other Is hydrogen or a hydroxy, halogen, nitro, cyano, (C-C 6 )alkoxy, NRioR 1 1 , SO 2 NRu 10 1 1 , OS0 2 NRoRa 1 , NR 12 S0 2 NRioRu, OSO2NRioSO2NRuR1 group. 20 Preferably, the compounds of formula (I) are those in which: * one of R 3 and R 8 is cyano; and - the other is hydrogen or a hydroxy, halogen, nitro, (C-C 6 ) alkoxy, trifluoromethyl, NR 1 ORu 1 , S0 2 NRioRu 1 , OSO 2

NR

10 Ru, NR 1 SO2NRioRal group. 25 Further preferred compounds are those In which: * one of R 4 and R 9 Is hydrogen or a hydroxy, cyano, OSO 2 NRioRu group; and * the other Is hydrogen or a hydroxy, cyano, halogen, nitro, (CrC 6 )alkyl,

(C-C

6 )alkoxy, trifluoromethyl, NRioRa 1 , OSO 2 NRioRu, CO 2

R

1 O, CHO, NR12SO 2 NRioRu group. 30 An other group of preferred compounds are those in which: * R 4 is hydrogen, hydroxy, cyano, or OS0 2 NRIORuI; 10 * R 9 is a hydrogen or a hydroxy, cyano, halogen, nitro, (C-C 6 )alkyl,

(C-C

6 )alkoxy, trifluoromethyl, NRioRa, OSO 2 NRIORa., C0 2

R

10 , CHO group. Especially preferred compounds of formula (I) are those where: 5 * R 4 is hydrogen; and * R 9 is a hydroxyl, cyano, halogen, nitro, (CrC)alkyl, (CrC)alkoxy, trifluoromethyl, NRioRa, OS0 2 NRioRa, CO 2 Ro, CHO or NR 12

SO

2 NRioRu group. 10 Particularly preferred compounds of formula (I) are those In which Z Is: R8R 8 . RP8 p(R)P (R,) p (O)q In which Re and R 9 are as hereinabove defined. 15 In the above defined compounds, R 8 and R 9 are preferably as follows: * Rs Is hydrogen, hydroxy, halogen, nitro, cyano, (CrC)alkoxy, NRIOR 11 , S0 2 NRi 0 Raj, OSO 2 NRIoRa, NR12SO2NRiORu or OS 2 NROSO2NRu 1

R

12 group; * Rg hydrogen or a hydroxy, cyano, halogen, nitro, (CrC)alkyl, (CrC)alkoxy, trifluoromethyl, NR 10

R

1 1 , OSO 2 NRioRa., CO2Rio, CHO, NR 1 2

S

2 NRioRa 1 group. 20 e p and q are as defined above. Among the compounds of formula (I), those In which Q is selected from a direct link, C(O), SO 2 , CONH, C(O)(CH 2 )n, (CH 2 )n(O) or (CH2)n In which n is 0,1 or 2, are also particularly preferred. 25 11 Particularly preferred are the compounds of formula (II) RR III RsR4 in which: Q is (CH 2 )n In which n is 0,1 or 2; 5 e one of R 3 and RB Is a hydroxy, nitro, NRioRa 1 , OSO 2 NRioRa or

NR

12

SO

2 NRIORa, group and the other Is hydrogen or a hydroxy, cyano, halogen, nitro, (C-C 6 )alkyl, (C-C 6 )alkoxy, trifluoromethyl, (CrC)alkylthio,

(C-C

6 )alkylsulfonyl, acyl, (C-C 6 )alkoxycarbonyl, carboxamido, NRioRa 1 ,

OSO

2 NRioRa or NR1 2 SO2NRiORI, group; 10 e R 4 and R 9 are each independently hydrogen, hydroxy, cyano,.halogen, nitro, (CrC)alkyl, (C-C 6 )alkoxy, tifluoromethyl, (C-C 6 )alkylthio,

(C-C

6 )alkylsulfonyl, acyl, (C-C6)alkoxycarbonyl, carboxamido, NRioR 11 , OS0 2 NRiORaj or NR 12

SO

2 NRioRl group. * Rio and R 1 are each Independently hydrogen, a (C-C 6 )alkyl or a 15 (C 3 -Cs)cycloalkyl; . pis1,2,3or4; * R8 and R 9 together with the phenyl ring bearing them can also form a benzoxathlazine dioxide or a dihydrobenzoxathiazine dioxide; * R 3 and R 4 together with the phenyl ring bearing them can also form a 20 benzofurane or a N-methylbenzotrazole. Among these compounds of formula (II), those which fulfil at least one of the following conditions are preferred: * Q is (CH2)n in which n 0, 1 or 2; 25 * R 8 is hydroxy, halogen, nitro, cyano or a (C-C 6 )alkoxy, NRioRa 1 , SO 2 NRioRa, OS0 2 NRioRui or NR 12

SO

2 NRiORl group; 12 * R 9 is hydrogen, hydroxy, cyano, halogen, nitro, (CIC 6 )alkyl, (C-C 6 )alkoxy, trifluoromethyl, NRIOR 11 , OSO 2 NRORu 1 ; * pisl,2,3or4. 5 Most preferred compounds of formula (II) are those in which: * n is 0 or 1; . R 1 and R 2 are each independently hydrogen or (C-C 6 )alkyl; * R 4 and R 9 are each independently hydrogen, halogen, (C-C 6 )alkoxy, acyl, NRioRal, OSO 2

NRI

0 RaI or NRnSO 2 NRioRu. 10 Especially preferred compounds of formula (II) are those In which: Sn is 0 or 1; . R 1 , R 2 and R 4 are each hydrogen; * R 9 is hydrogen, halogen, (CrC)alkoxy or OSO 2

NR

10 Ra. 15 Particularly preferred compounds of formula (II) are those in which: 0 n and p are 1; . R 8 is a hydroxy, halogen, nitro, cyano, (C-C6)alkoxy, NRioR 11 , S0 2 NRioRa, OS0 2

NRI

0

R

1 , NR 12

SO

2 NRioRa, or OS0 2 NRIOS0 2 NRuIR 1 group; 20 . R 9 is a hydroxy, cyano, halogen, nitro, (C-C 6 )alkyl, (C-C 6 )alkoxy, trifluoromethyl, NRIORaI, OS0 2 NRioR 1 , C0 2 RIo or CHO group; * R 3 is cyano, hydroxy, OSO 2

NRI

0 RaI or NR 12

SO

2 NRoRu 1 ; R 4 is hydrogen, hydroxy, halogen, cyano or OSO 2

NRI

0 Ra 1 . 25 Among these compounds, those which fulfil at least one of the following conditions are also preferred: * one of R 3 and R 8 Is hydroxy, cyano or OS0 2 NRoRa, preferably cyano or OSO2NRioRu; and . the other is hydroxy, nitro, NRIOR 11 , OSO 2 NRioRu or NR 12 S0 2 NRIoRII, 30 preferably hydroxy or OSO 2 NRioRul. Among these compounds of formula (II), those wherein RID and RIa are hydrogen are mostly preferred.

13 Particularly preferred are also the compounds of formula (III): R, N P R-Qr Q RR4 in which: 5 . Q Is (CH 2 )m-X-(CH 2 )n-A 0 A is a direct bond or 0, S, SO; SO2, NR 5 ; " X is a direct bond, CF 2 , 0, S, SO, SO2, C(O), NR 5 or CR 6

R

7 ; * m and n are each independently 0, 1, 2, 3 or 4; " R 3 , R 4 , Ra and R 9 are each Independently hydrogen or a hydroxy, cyano, 10 halogen, nitro, (C-C 6 )alkyl, (C-C 6 )alkoxy, benzyloxy, trifluoromethyl,

(C-C

6 )alkylthio, (C-C 6 )alkylsulfonyl, acyl, (C-C 6 )alkoxycarbonyl, NR 10

R

11 , OPO(ORIO)z, OCHO, COOR 10 , S0 2 NRIORuI, OSONRioR 11 , SO2ORio, OSO 2 0R 10 , SS0 2 NRioRa, CONROR 11 , OCONRIoRu, OCSNRioR 1 , SCONR 10

R

11 , SCSNRioRa 1 , NR12SO2NRiORII, tetrazolyl, NRioCONRu 1 OH, NR 1 oSO 2 NRu 1 OH, 15 NOH-CHO, NOHSO 2

NR

0 Ru 1 , or OSO 2 NRi 0 OH group; Sp Is 0,1 or 2. . Rs, R6, R 7 , R 1 0 , R 11 and R 12 are each independently hydrogen, a (C-C 6 )alkyl or a (C 3 -Cs)cydoalkyl; Rio can also be a salt; Rjo and RI, can also form, together with the nitrogen atom to which they are bound, a 5- to 7 20 membered heterocycle containing one or two heteroatoms selected from 0, S and N; * The dotted line means that Q and/or R and/or R 9 can be on any position of the benzothlophene ring. 25 Among the compounds of formula (III) those which fulfil at least one of the following condition are also preferred: 14 " R3 is hydrogen, halogen or cyano; " Re is OS0 2 NRORu 1 or NR 12

SO

2 NRIORaI; * R 9 is hydrogen, halogen, nitro, COORio or cyano; * R 4 is hydrogen, halogen, cyano, (C-C 6 )alkoxy, NRIOR 11 , OSO2NRIOR 11 or 5 NR 1 SO2NRioRu; * Rio, R 1 1 and R are each independently hydrogen or (C-C 6 )alkyi. The compounds of formula (II), wherein Q is (CH 2 )m-X- (CH 2 )n-A where m is 0, 1 or 2 and X is a direct bond, SO 2 or CO, n is 0 and A is a direct bond are also 10 preferred. Particularly preferred are the compounds of formula (V): R R2 R N R3 Q -~N (R 9 )P R4 (IV) In which R 1 , R 2 , R 3 , R 4 , R 8 , R 9 and p are as defined for compounds of formula (I). 15 Particularly preferred compounds of formula (IV) are those In which: * R 3 is cyano or OS0 2 NRIORu 1 ; * R 4 is hydrogen, hydroxyl, halogen, cyano, OS0 2 NRioRuj; * R 8 is hydroxy, cyano, OS0 2

NRIOR

11 , NR 1 0

R

1 11 , NR2SO 2 NRioRaI, OCHO, 20 tetrazolyl; * R 9 is hydrogen, halogen, nitro, cyano or C0 2

R

10 ; and . .Q is as defined above for compounds of formula (I). By virtue of their capability to inhibit the enzymes aromatase and/or steroid 25 sulfatase and/or carbonic anhydrase, the compounds of the present invention can be used alone or in combination with other active ingredients for the 15 treatment or the prevention of any hormone or non hormone-dependent cancer, in humans as well as in wild or domestic animals. Because of their inhibition activity of aromatase and/or steroid sulfatase, the compounds of the Invention are suitable for the management of estrogen-regulated reproductive functions, in 5 humans as well as in wild or domestic animals. In the treatment or prevention of the above conditions, the compounds of the invention can be used alone or in combination with an antiestrogen, a SERM (selective estrogen receptor modulator), an aromatase inhibitor, a carbonic anhydrase inhibitor, an antiandrogen, a steroid sulfatase inhibitor, a lyase 10 Inhibitor, a progestin, or a LH-RH agonist or antagonist. The compounds of the invention can also be used In combination with a radiotherapeutic agent; a chemiotherapeutic agent such as a nitrogenated mustard analogue like cyclophosphamide, melphalan, iphosphamide, or trophosphamide; an ethylenimine like thiotepa; a nltrosourea like carmustine; a lysed agent like 15 temozolomide or dacarbazine; an antimetabolite of folic add like methotrexate or raltitrexed; a purine analogue like thloguanine, cladribine or fludarabine; a pyrimidine analogue like fluorouradl, tegafur or gemcitabine; an alkaloid of vinca or analogue like vinblastine, vincristine or vinorelbine; a podophyllotoxin derivative like etoposide, taxanes, docetaxel or paditaxel; an anthracycine or 20 analogue like doxorubicin, epirublcin, Idarubicin or mitoxantrone; a cytotoxic antibiotic like bleomycin or mitomycin; a platinum compound like dsplatin, carboplatin or oxallplatin; a monoclonal antibody like rituximab; an antineoplastic agent like pentostatin, miltefosine, estramustine, topotecan, irinotecan or bicalutamide; or with a prostaglandin Inhibitor (COX 2/COX 1 Inhibitor). 25 The compounds of the invention can also be used for the control or management of estrogen-regulated reproductive functions such as male or female fertility, pregnancy, abortion or delivery, in humans as well as In wild or domestic animal species, alone or in combination with one or several other therapeutic agents such as a LH-RH agonist or antagonist, an estroprogestative contraceptive, a 30 progestin, an antiprogestin or a prostaglandin inhibitor. Breast tissue being a sensitive target of estrogen-stimulated proliferation and/or differentiation, Inhibitors of aromatase and/or steroid sulfatase and/or carbonic anhydrase can be used In the treatment or prevention of benign breast diseases 16 in women, gynecomastia In men and in benign or malignant breast tumors with or without metastasis both in men and women or In male or female domestic animals. The compounds of the Invention can also be used in the treatment or prevention of benign or malignant disease of the uterus or the ovary. In each 5 case, the compounds of the invention can be used alone or in combination with one or several other sexual endocrine therapeutic agents such as an antiandrogen, an anti-estrogen, a progestin or a LH-RH agonist or antagonist. As the enzyme steroid sulfatase transforms DHEA sulfate into DHEA, a precursor of active androgens (testosterone and dihydrotestosterone), the compounds of 10 the Invention can be used In the treatment or prevention of androgen-dependent diseases such as androgenic alopecia (male pattern loss) (Hoffman R et al., J. Invest. Dermatol., 2001, 117, 1342-1348), hirsutism, acre (Billich A et al., WO 9952890), benign or malignant diseases of the prostate or the testis (Reed MJ, Rev. Endocr. Relat. Cancer, 1993, 45, 51-62), alone or In combination with one 15 or several other sexual endocrine therapeutic agents such as an antiandrogen, an antiestrogen, a SERM, an. antlaromatase, a progestin, a lyase inhibitor or a LH-RH agonist or antagonist. Inhibitors of steroid sulfatase are also potentially involved in the treatment of cognitive dysfunction, because they are able to enhance learning and spatial 20 memory in the rat (Johnson DA, Brain Res, 2000, 865, 286-290). DHEA sulfate as a neurosteroid affects a number of neurotransmitter systems including those involving acetylcholine, glutamate, and GABA, resulting in increased neuronal excitability (Wolf OT, Brain Res. Rev, 1999, 30, 264-288). The compounds of the present Invention are thus also useful for enhancing the cognitive function, 25 especially for the treatment of senile dementia, Including Alzheimer's diseases, by increasing the DHEA levels In the central nervous system. In addition, estrogens are involved In the regulation of the balance between Thi and Th 2 predominant Immune functions and may therefore be useful In the treatment or prevention of gender-dependent auto-immune diseases such as 30 lupus, multiple sclerosis, rheumatoid arthritis and the like (Daynes RA, J. Exp. Med, 1990, 171, 979-996). Steroid sulfatase inhibition was further shown to be protective In models of contact allergy and collagen-induced arthritis in rodents (Suitters AJ, Immunology, 1997, 91, 314-321).

17 Studies using 2-MeOEMATE have shown that steroid sulfatase inhibitors have potent estradiol-independent growth-Inhibitory effect (MacCarthy-Moorogh L, Cancer Research, 2000, 60, 5441-5450). A decrease In tumor volume was surprisingly observed with the compounds of the invention, with low tumor 5 steroid sulfatase Inhibition. In view of this, the compounds of the invention could lead to a decrease in cellular division because of the large interaction between such new chemical entitles and the microtubular network within the cancerous cell, whatever the tissue, including breast, endometrium, uterus, prostate, testis or metastasis generated therefrom. The compounds of the invention could 10 therefore be useful in the treatment of non-estrogen dependent cancer. The compounds of the Invention are of particular value for the treatment or prevention of estrogen-dependent diseases or disorders, i.e. estrogen-induced or estrogen-stimulated diseases or disorders (Golob T, Bioorg. Med. Chem., 2002, 10, 3941-3953). 15 In addition, the compounds of the present Invention are inhibitors of carbonic anhydrase (CA). This property could explain the interest of such compounds in non-hormone-dependent cancer. Immunohilstochemical studies of CA II have shown that it Is expressed in malignant brain tumors (Parkkila A-K. et al., Histochem. J., 1995, 27: 974-982) and gastric and pancreatic carcinomas 20 (Parkkila S et al., Histochem. J., 1995, 27: 133-138), and recent evidence has shown that CA IX and XII are also expressed in some tumors and may be functionally related to oncogenesis. Ivanov et al. (Proc. Nati. Acad. Sci. USA, 1998, 95: 12596-12601) recently hypothesized that tumor-associated CA IX and XII may be Implicated in acidification of the extracellular medium surrounding 25 cancer cells, which would create a microenvironment conducive to tumor growth and spreading. It has been shown that acetazolamide markedly Inhibited invasion capacity in four renal cancer cell lines (Parkkila S et al., Proc. Nati. Acad. Sci. USA, 2000, 97: 2220-2224), an effect attributable to CA II, IX, and XII, which were expressed In these cells. Leukemia cells can easily spread from bone 30 marrow to other organs via circulation, but various leukemias differ in their ability to form extramedullary tumors I.e., metastases. If CA activities were essential for invasion by other cancer cells, one could analogously predict that active CA(s) could also function in leukemia cells.

18 As used herein, the term "combined" or "combination" refers to any protocol for the co-administration of a compound of the invention and one or more other pharmaceutical substances, irrespective of the nature of the time of administration and the variation of dose over time of any of the substances. The 5 co-administration can for example be parallel, sequential or over a period of time. For the treatment/prevention of any of the above-mentioned diseases or disorders, the compounds of the invention may be administered, for example, orally, topically, parenterally, in dosage unit formulations containing conventional 10 non-toxIc pharmaceutically -acceptable carriers, adjuvants and vehides. These dosage forms are given as examples, but other dosage forms may be developed by those skilled in the art of formulation, for the administration of the compounds of the invention. The term parenteral as used herein Includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or 15 infusion techniques. In addition to the treatment of humans, the compounds of the invention are effective In the treatment of warm-blooded animals such as mice, rats, horses, cattle sheep, dogs, cats, etc. The pharmaceutical compositions containing the active ingredients) may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or 20 oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring 25 agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active Ingredients) in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These exciplents may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, 30 calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by 19 known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. 5 They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredients) Is (are) mixed with an inert solid diluent, for example, 10 calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient Is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions' contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients 15 are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolldone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example 20 polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol 25 anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame. 30 Oily suspensions may be formulated by suspending the active ingredients) in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or acetyl alcohol. Sweetening agents 20 such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous 5 suspension by the addition of. water provide the active ingredients) in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional exciplents, for example sweetening, flavouring and colouring agents, may also be present. The 10 pharmaceutical compositions of the invention may also be in the form of an oil in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally occurring phosphatides, for example soybean, lecithin, and esters or partial esters derived from fatty acids 15 and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. The pharmaceutical compositions may be In the form of a sterile injectable 20 aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution In 1,3 25 butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed Induding synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find 30 use in the preparation of Injectables. Dosage levels of the order of from about 0.0001 mg to about 20 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.1 mg to about 2000 mg per patient per day.

21 The amount of active Ingredient that may be combined with the carrier materials . to-produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 0.1 mg to about 400 mg of compound of the invention, 5 typically 0.1 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 200 mg or 400 mg. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of 10 excretion, drug combination and the severity of the particular disease undergoing therapy. According to another object, the Invention relates to a method for the treatment or prevention of the above-mentioned diseases, disorders or conditions. The 15 method comprises administering to a subject (human or animal) in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable acid addition salt thereof. The 1-N-aryl-amino-1lH-imidazole derivatives of formula (I) and their acid addition salts can be prepared following general schemes I a, I b, Ia, HIb, III, IV 20 and V in which (m represents (CH 2 )m and O, represents (CH 2 )n.

22 Scheme Ia RR RRNH2 HalX (R ,)p RKR A (R) 1 2 3 N~H2 .1 H2 R -aRNH, RRNH Hai A (R,)p i RX ARN R 5 2 4 RI OMe H H ' OMe RSR 7 6

R

2 N R2 N R R11 RR'( " , a ( NH Ha l5 (R)p )m n 9)P + O Re 4 8 9 2 According to scheme I a, N,N-disubstituted aniline (3) can be obtained by 5 condensation of the aniline derivative (1) with halogeno derivatives, alcoyl derivatives, sulfonyl derivatives or suifinyl derivatives (2) using standard conditions (March J., Advanced Organic Chem/stry, Fourth edition, Wiley Interscience, New-York). Most of the halogeno derivatives, alcoyl derivatives, sulfonyl derivatives or sulfinyl derivatives (2) are commercially available or are 10 synthesized by usual chemistry methods (see experimental part).

23 Compound (3) Is converted to its nitroso derivative using standard conditions, then reduced to afford the 1,1-disubstituted hydrazine of formula (4). Alternatively, the 1,1-disubstituted hydrazine (4) can be prepared by selective N alkylation of a hydrazine of formula (5) with a compound of formula (2) using the 5 conditions described by U. Lerch and J. Knig (Synthesis, 1983, 2, 157-8) or the conditions described by J. Chung et al. (Tetrahedron Letters, 1992, 33, 4717-20). Then, condensation of (4) with a dialkyloxy-alkyl-isothiocyanate derivative or an ethylenedioxy-alkyl-isocyanate derivative, affords the thiosemicarbazide (6) which is transformed to the 1-amino-imidazole-2-thione (7) by treatment with an 10 acid like acetic acid or sulphuric acid. Desulfurization of (7) In acetic acid, following the conditions described by S.Grivas and E.Ronne in Acta Chemica Scandinavia, 1995, 49, 225-229, gives the final 1-N-phenyl-amino-1H-imidazole (8), which is optionally converted to one of Its add addition salts. 15 Alternatively said compounds (8) where R 3 or R 4 Is an eiectron-withdrawing group can be obtained by condensation of the N-imidazoloanillne (9) with halogeno derivatives, alcoyl derivatives, sulfonyl derivatives or sulfinyl derivatives (2) using standard conditions (March J., Advanced Organic Chemlsty, Fourth 20 edition, Wiley Interscience, New-York). If R 8 Is ester, saponification of compound (8) gives carboxylic derivative by usual chemistry methods. If RN is sulfamide, it.can be directly obtained with correct substituted alcoyl derivative or halogeno derivative (2). 25 if RN Is cyano group, reaction with sodium azide gives tetrazolyl group (Kiyoto K., Synthes/s, 1998, 910-14). The compound (9) is obtained by a process similar to the process disclosed herein above for obtaining the compound (8) starting from the compound (4).

24 Scheme lb R1 R1

R

2 NR2 R , Nf 2 Xl aR N- f X)mR)So(H 10 11 8

R

2 N R~~~, (R N 9)RHp2H

R

4

RN=H

2 O02 12 13 5 According to scheme Ib deprotection of methoxy or benzyloxy derivatives (8) with tribromoborane (McOmie. J.F.W, Tetrahedron, 1968, 24, 2289-92) or piperidine (Nishloka H. Synthesis, 200, 2, 243-46) or by hydrogenation (Felix A., J Org Chem, 1978, 43, 4194-97) gives the hydroxyl compound (10). Reduction of nitro compound (8) by stannous chloride or with ruthenium and hydrazine (WO 10 02051821) gives amino-compound (12) (Matassa V., J Med Chem, 1990, 33, 2621-29). These compounds are transformed into the corresponding sulfamates (11) or aminosulfonylamines (13) by treatment with sodium hydride and sulfamoyl chloride (Nussbaumer. P, J Med Chem, 2002, 45, 4310-20) or by reaction with 15 sulfamoyl chloride in dimethylacetamide (DMAc) (Makoto 0, Tetrahedron /etters, 2000, 41, 7047-51). These hydroxyl compounds can be transformed into formate derivatives by treatment with formyl acetate (Schreiner E.,Bioorg Med Chem Lett, 2004, 14, 25 4999-5002) or Into 1H-imidazole-1-carboxylate derivatives by treatment with N,N'-carbonydiimidazole (Fischer, W., Synthesis, 2002, 1, 29-30) Compounds (10) or (12) having both an amino and an hydroxyl in an ortho position, can be transformed to the corresponding benzoxathiazoles following the 5 conditions proposed by K. K. Andersen (1 OQg Chem, 1991, 56, 23, 6508-6516). When X is CO or CS, reduction of ketone, thioketone, amide, thioamide Is performed following standard conditions (March J., Advanced Organic Chemistry, Fourth edition, Wiley Interscience, New-York). These reduction steps can be effective at any steps of synthesis process. 10 Scheme Ila R2 R2 9 14 15 R R

R

2 R N R- OHR 4 q(O -~OS2H R R I R N m X ) RR RN R S9) lH 1 18 26 According to scheme Ha, compounds (15) can be obtained by the same procedure as compound (3) in scheme Ia starting from compounds (1) and (14) or by condensation of the N-imidazoloaniline (9) with halogeno derivatives, alcoyl derivatives, sulfonyl derivatives or sulfinyl derivatives (14) using standard 5 conditions (March J., Advanced Organic Chem/stry, Fourth edition, Wiley Interscience, New-York). Most of the halogeno derivatives, alcoyl derivatives, sulfonyl derivatives or sulfinyl derivatives (14) are commercially available or are synthesized by usual chemistry methods (see experimental part). If R 0 is ester, saponification of compound (15) gives carboxylic derivative by 10 usual chemistry methods. If R 8 is sulfamide, it can be directly obtained with correct substituted alcoyl derivative or halogeno derivative (14). If R 8 is cyano group, reaction with sodium azide gives tetrazolyl group (Klyoto K., Synthesis, 1998, 910-14). 15 Deprotection of methoxy or benzyloxy benzothlophene (15) with tribromoborane (McOmie. J.F.W, Tetrahedron, 1968, 24, 2289-92) or by hydrogenation (Felix A., J Org Chem, 1978, 43, 4194-97) gives the hydroxy benzothiophene (16). Reduction of nitro benzothiophene compound (15) by stannous chloride gives amlno-benzothiophene (18) (Matassa V., J Med Chem, 1990, 33, 2621-29). 20 These compounds (16) and (18) are transformed into the corresponding sulfamates (17) or aminosulfonylamines (19) using the same conditions as for the synthesis of compounds (11) or (13). Oxidation of sulphur on benzothiophene by hydrogen peroxide in trifluoroacetic 25 acid, following the conditions described by Grivas S. and Ronne E. (Acta Chemica Scandinav/a, 1995, 49, 225-229) or by meta-chloro-per-benzoic acid in methylene chloride gives the oxydised benzothiophenes.(Ong H. H., J Med Chem, 1987, 30, 12, 2295-2303). Reduction of amide, thioamide, ketone, thioketone when X is CO or CS or 30 reduction of oxidised sulphur function is performed following the conditions described by Ellefson C. (J Med Chem, 1981, 24, 1107-10), Hajos J. (Complex Hydrides, Elsevier, New York, 1979) or Drabowicz S. (Org Prep Proced Int, 1977, 9, 63-83) and Bordwell J. (J Am Chem Soc, 1951, 73, 2251-53) or following 27 standard conditions (March J., Advanced Organic Chem/stry, Fourth edition, Wiley Interscience, New-York). These oxidation and reduction steps can be effective at any steps of synthesis process. 5 Scheme b RI RI

R

2 N (R9)p R 2 N (R )p I R8 R ~RaNH + Hal -R R(Oq R 4 (O 9 20 21 RCm OH R NmO R4(O)q R 4 (O)q R R R 2 R 2p NH NH' SO2NH2 R NO~q R(O (O)q R 4 (O)q 24 2s According to scheme Ib, compounds (21) are synthesized following the same synthetic methods as for compounds (3) starting from compounds (1) and (20) 10 or (9) and (20). 3-H-alogeno benzothiophene derivative (21) treated by aqueous metal hydroxide (Svoboda 3., Collect Czech Chem comm, 2000, 65, 7, 1082-92 or Sail D., J Med. Chem, 2000, 43, 4, 649-63) gives 3-hydroxy benzothiophene derivative (22) or 28 treated by aqueous ammonia in acetone or ethanol (Bordwell F., J. A. C. S., 1948, 70, 1955-58) gives 3-amino benzothiophene derivative (24). 2-Hydroxy benzothlophene derivative (22) or 2-amino benzothiophene derivative (24) are performed respectively by deprotection of 2-methoxy benzothiophene 5 derivative (21) with pyridine hydrochloride (Cannizzo S., J Heterocyc//c Chem, 1990, 27, 2175-79) and by reduction of 2-nitro benzothiophene compound (21) by stannous chloride (Matassa V, J Med Chem, 1990, 33, 2621-29). These compounds (22) and (24) can be sulfamoylated to give (23) and (25) using the same conditions as for the synthesis of compounds (11) or (13). 10 Deprotonation of 2-H-benzothiophene derivative (21) with lithium amides or alkyls leads to lithlation at C-2 position. Addition of sulfuryl chloride yields chlorosulfonyl compound that Is treated by aqueous ammonia in acetone (Graham S., J Med Chem, 1989,. 32, 2548-54) to" give 2-sulfonamide 15 benzothlophene derivative (21) or addition of dry Ice followed by hydrolysis gives 2-carboxylic acid benzothiophene derivative (21) (Matecka D., J Med Chem, 1997, 40, 705-16). 3-Carboxylic or carboxamide benzothlophene derivative (21) Is prepared by 20 treatment of 3-H-benzothiophene derivative with trichloroacetyl chloride/aluminium chloride followed by hydrolysis with water (Bonjouklian R., Synth Comm, 1985, 15, 8, 711-13) or aqueous ammonia (Tumbull K., J Heterocycl Chem, 2000, 37, 2, 383-88). 3-Sulfonamide derivative (21) is prepared following the conditions described by 25 Chapman N. (J. Chem. Soc., 1970, 18, 2431-35) or Hageman W. (Ger. Offen., 3435173,11 April 1985). Oxidation of sulfur on benzothlophene and reduction of carboxamide, thioamide, ketone, thioketone, oxydised sulphur function can be performed at any step of 30 synthesis following the same conditions already presented in this description.

29 Scheme III R1 R1 R2 R9 H2+6 . R27R N R2 R N OH' (R 9 )p RY NS H R~% ------- - H N N__ 2 28 29 27N

R

2 R R 31 303 . R 3N NH 2 R N SO NH2 5 According to scheme III, compounds (27) are obtained by condensation of the N imidazoloanlline (9) with isocyanate derivatives (26) usIng standard conditions (March 3., Advanced Organic Chemlstry Fourth edition, Wiley Interscience, New York). Most of the Isocyanate derivatives. (26) are commercially available or are synthesized by usual chemistry methods. 10 Compounds (28) and (30) are synthesized following the same synthetic methods as for compounds (10) and (12) in scheme Ib.

30 Compounds (29) and (31) are synthesized following the same synthetic methods as for compounds (11) and (13) In scheme Ib. Scheme IV 5 R1 R, R2/ a R)pR R, R ,) R (R 9 )p R (R )p 2 N N NH Hal 11 N11 .X., A ')m ()n m n (R )PR (R 9 )p 32 33 According to scheme IV, bi-aryl compounds (33) can be synthesized following the 10 same synthetic methods as for compounds (8) with derivatives (32). Derivatives (32) are commercially available or synthesized by usual chemistry methods (as ex Buraway S, J Chem Soc, 1955, 2557; Tilley J W, J Med Chem, 1989, 32, 8, 1814). 15 Scheme V R R RRH Hal \ X ", A (R 9)p -l~ R' M X - (R )p 9 34 35 20 According to scheme V, compounds (35) are synthesized following the same synthetic methods as for compounds (8) with heterocycles (34) (one or two nitrogen atoms In any positions). Heterocycles (34) are commercially available or synthesized by usual chemistry methods (see following examples). Halogeno pyridine derivatives (34) can be obtained following publications (Biorg Med Chem 31 Lett, 1996, 6, 21, 2613; Myers A G, J Org Chem, 1996, 61, 813; Tetrahedron, 1993, 49, 19, 4085) or from carboxylic acid (WO 0177078). Halogeno pyrimidine derivatives (34) can be obtained from alkyl pyrimidines (Budesinsky, Collect, Czech, Chem Commun, 1968, 33, 7, 2266; Kunieda T, J Am Chem Soc, 1971, 5 93,3487) by usual halogenation (Isoda S, Chem pharm Bull, 1980, 28, 5, 1408; March J., Advanced Organic Chemistry, Fourth edition, Wiley Interscience, New York), or from carbaldehydes (Bredereck, Chem Ber, 1967, 100, 11, 3664; Adams J L, Bloorg Med Chem Lett, 1998, 8, 22, 3111), and carboxylic acids (Huffman K R, J Org Chem, 27, 1962, 551; Daves J Org Chem, 1961, 26, 2755) 10 can be transformed to acid chlorides (34). Halogeno pyrazine derivatives (34) can be obtained from alkyl pyrazines (Lutz W B, J Org Chem, 1964, 29, 415) by bromination, or from carbaldehydes (US 3558625), and carboxylic acids (Sato N, J Heterocycl Chem, 19, 1982, 407-408; Felder P, Helv Chim Acta, 1964, 47, 873) can be transformed to acid chlorides (34). Halogeno pyridazine derivatives (34) 15 can be obtained following Piras' S (Farmaco, 1993, 48, 9, 1249) Yanal, (Heterocycles, 1976, 4, 1331), or by halogenation of alkyl pyridazines (Becker, J Prakt Chem, 1970, 312, 591; DE 1950491) and carboxylic acids (Boger D L, J Am Chem Soc 1987, 109, 9, 2717) can be transformed to add chlorides (34). 20 For all schemes Ila, HIb, III, IV, V, carboxylate derivative, sulfamide derivative and tetrazole derivative are synthesized by the methods already described for scheme Ia and R8 and (R9)p are performed following the same conditions already presented in this description. 25 The groups described for R 3 , R 4 , R and R 9 can be obtained by usual chemistry methods (for references see review on sulfatase (Nussbaumer P, Medecinal Research, 2004, 24, 4, 529-76), on carbonic anhydrase (Supuran C T, Carbonic anhydrase, 2004, C R C press) and articles from Park J D (J Heterocyc Chem, 2000, 37, 2, 383-88), Schreiner E P (Bioorg Med Chem Lett 2004, 14, 4999 30 5002) and Taylor S D (Bioorg Med Chem Lett, 2004, 14, 151-155). The following examples are intended to illustrate and not to limit the scope of the Invention.

32 PREPARATION OF N, N-DISUBSTITUTED HYDRAZINES (4) EXAMPLE 1 N-(4-cyanophenylmethyl)-Nl-(4-methoxyphenyl)hydrazine Chloromethylbenzonitrile (25 g, 164.90 mmol) was Introduced with stirring into 5 a flask containing toluene (200 ml) and triethylamine (46.40 ml, 329.80 mmol). 4-methoxy-phenylhydrazine hydrochloride (28.80 g, 164.90 mmol) was added portionwise and the reaction mixture was stirred 3 h at reflux. After cooling, the mixture was filtered, washed with toluene (50 ml) and with water (200 ml) to give a white solid (27.20 g, 65%), mp: 115 0 C. 10 'H-NMR (DMSO d) : 3.65 (s, 3H), 4.30 (s, 2H), 4.57 (s, 2H), 6.77 (d, 2H), 6.94 (d, 2H), 7.48 (d, 2H), 7.76 (d, 2H). PREPARATION OF IMIDAZOLES (9) EXAMPLE 2 15 4-[N-(1H-imidazol-1-yl)amino]benzonitrile a) 4-[N-(2,3-dihydro-1H-imidazol-1-yl-2-thlone)amino]benzonitrile To a suspension of 4-cyanophenylhydrazine hydrochloride (6.00 g, 35.40 mmol) In ethanol (60 ml) was added dropwise 2,2-dimethoxyethylisothiocyanate (6.25 g, 42.4 mmol) and the reaction mixture was heated to reflux for 2 h. After 20 cooling the solvent was evaporated under vacuum, the resulting oil was diluted with acetic acid/ water (9/1, 32 ml) and the suspension was heated to reflux for 1.5 h and at room temperature ovemight. The resulting residue was poured into water (300 ml) and a brown precipitate was collected. After trituration from ethanol, the brown solid afforded a white solid (4.60 g, 58 %). 25 1 H-NMR (DMSO d) : 6.54 (d, 2H), 7.00 (t, 1H), 7.23 (t, 1H), 7.62 (d, 2H), 9.83 (s, 1H), 12.40 (s, 1H). b) 4-[N-(1H-imidazol-1-yl)amino]benzonitrile 35 % hydrogen peroxide (4.90 ml, 55.5 mmol) was added dropwise to an ice cooled suspension of 4-[N-(2,3-dihydro-1H-imidazol-1-yi-2 30 thione)amino]benzonitrile (4.00 g, 18.50 mmol) in acetic acid (20 ml). When TLC showed complete reaction, the reaction mixture was diluted with water, adjusted to pH 11 with sodium hydroxide, treated with sodium hydrogen sulfite and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and 33 concentrated under vacuum. Flash chromatography on silica gel (toluene / dioxane : 6/4) yielded a pure oil and crystallization from ethanol afforded white crystals (4.40 g, 58 %), mp: 162 0 C. H-NMR (DMSOd 6 ): 6.50 (d, 2H), 7.08 (s, 1H), 7.30 (s, 1H), 7.66 (d, 2H), 7.83 5 (s, 1H). PREPARATION OF BENZOTHIOPHENE DERIVATIVES (14) AND (20) EXAMPLE 3 1-Chloro-3-(3-methoxyphenyl)sulfanyi-propan-2-one 10 To a stirred solution of 1,3-dichloro-2-propanone (12.70 g, 0.1 mol) in methanol/water (100 ml, 1:3) at 0*C Is added a suspension of 3 methoxybenzenethlol (14.02 g, 0.1 mol) and sodium hydroxide (4.00 g, 0.10 g) in water (100 ml). The mixture Is stirred at 0*C for 7 h and at room temperature for 10 h. The precipitated product is extracted with dichloromethane (100 ml), 15 washed with water (80 ml), and dried with sodium sulfate. After removal of the solvent, we obtained the good product (oil, 18.70 g). 'H-NMR (CDCl 3 ): 3.80 (s, 3H), 3.83 (s, 2H), 4.29 (s, 2H), 6.78 (dd, 1H), 6.98 (d, 1H), 6.90 (dd, 1H), 7.21 (t, 1H). EXAMPLE 4 20 3-Chloromethyl-6-methoxy-benzothiophene A solution of the above thio compound (17.50 g, 75.85 mmol) In CH 2

CI

2 (1700 ml) was added dropwise to a solution of BF 3 .Et 2 O (10.60 ml, 83.44 mmol) in

CH

2 Cl 2 (100 ml) at room temperature under nitrogen atmosphere. The mixture was stirred overnight and after hydrolysis with aqueous NaHCO 3 solution, the 25 reaction mixture was stirred until both phases became clear. The CH 2

CI

2 layer was separated, and the aqueous layer was extracted with CH 2

CI

2 . The combined organic phases were dried over Na 2

SO

4 , filtered, and concentrated under vacuum to give an oil (18.00 g). Flash chromatography on silica gel (toluene /petroleum spirit 40-60*C : 5/5) yielded a 1:10 mixture of 3-chloromethyl-4-methoxy 30 benzothiophene: 3-chloromethyl-6-methoxy-benzothiophene as an oil (12.35 g, 58 %). Major isomer 'H-NMR (CDCI 3 ): 3.89 (s, 3H), 4.82 (s, 2H), 7.08 (dd, 1H), 7.30 (s, 1H), 7.35 (d, 1H), 7.78 (d, 1 H).

34 EXAMPLE 5 3-Bromo-6-benzyloxy-benzothiophene N-bromosuccinimide (15.70 g, 83.92 mmol) and p-toluenesulfonic acid (2.70 g, 15.68 mmol) were added to a solution of 6-benzyloxy-benzothlophene 5 (Zhengying C., CN 1370533 A, 21.2 g, 88.33 mmol) In 1,2-dichloroethane (120 ml). The mixture was maintained at 80 0 C for 35 min, cooled In an ice bath, and the succinimide was removed by filtration. The solution was extracted with saturated sodium bicarbonate solution, dried over Na 2

SO

4 , filtered, and concentrated under vacuum to give an oil. Crystallisatlon from pentane afforded 10 a white solid (21.60 g, 92 %, mp: 68 0 C). 'H-NMR (DMSOd 6 ): 5.14 (s, 2H), 7.08 (dd, 1H), 7.25-7.55 (m, 6H), 7.65 (d, 1H), 7.76 (d, 1H). EXAMPLE 6 3-Bromo-6-benzyloxy-benzothiophene-1,1-dioxyde 15 To a solution of 3-bromo-6-benzyloxy-benzothiophene (2.00 g, 6.27 mmol) In dichloromethane (50 ml) and trifluoroacetlc add (1.5 ml) was added 35% aqueous hydrogen peroxide (2.00 ml, 19.54 mmol). After 8 h at 50*C the mixture was hydrolysed with saturated aqueous NaHCO 3 , extracted with dichloromethane, dried over Na 2

SO

4 , filtered, and concentrated under vacuum to 20 give the crude product. Flash chromatography on silica gel (toluene / ethyl acetate: 9/1) yielded a limpid oil (1.10 g, 55%). 1 H-NMR (DMSOd 6 ): 5.20 (s, 21-), 7.20-7.60 (m, 7H), 7.72 (d, 1H-), 7.83 (s, 1H). EXAMPLE 7 (6-Benzyloxy-benzothien-2-yi)methanol 25 To a solution of 6-benzyloxy-benzothlophene-2-carbaldehyde (described by Nomura Y., WO 9635688 Al, 6.50 g, 24.20 mmol) in THF (50 ml) was added dropwise to a -30 0 C cooled suspension of LIAIIH 4 (0.85 g, 22.26 mmol). After warming up to room temperature the mixture was stirred overnight, cooled to 10 0 C, hydrolyzed with ice water, extracted with dichloromethane, dried over 30 Na 2

SO

4 , filtered and concentrated under vacuum to give the crude product. Flash chromatography on silica gel (toluene / ethyl acetate: 7/3) yielded a limpid oil (4.50 g, 69%).

35 1 H-NMR (DMSOd 6 ): 4.68 (s, 2H), 5.13 (s, 2H), 5.60 (s, 1H), 7.00 (dd, 1H), 7.14 (s, 1H), 7.25-7.80 (m, 7H). EXAMPLE 8 6-Benzyloxy-2-(chloromethyl)-benzothiophene 5 Sulfonyl chloride (20 ml) is added to a solution of (6-benzyloxy-benzothien-2-yl) methanol (4.20 g, 15.50 mmol) in dichloromethane (40 ml). The mixture was maintained at reflux for 2 h, cooled at room temperature then concentrated under vacuum to give 4.20 g as an oil. 'H-NMR (CDCl 3 ): 4.75 (s, 2H), 5.04 (s, 2H), 6.95 (dd, 1H), 7.10 (s, 1H), 7.20 10 7.60 (m, 7H). PREPARATION OF IMIDAZOLES OF FORMULA (8, 33, 35) Using the same procedure as described in example 2, but replacing the 4 cyanophenylhydrazine, hydrochloride by: 15 - NI-(4-cyanophenylmethyl)-N-(4-methoxyphenyl)hydrazine, the following compound was obtained: EXAMPLE 9 4-[N-(1H-imidazol-1-yl)-N-(4 methoxyphenyl)amino]methylbenzonitrile 20 1 11-NMR (DMSO d) : 3.70 (s, 3H), 4.90 (s, 2H), 6.60-7.00 (m, 5H), 7.40 (s, 1H), 7.55 (d, 2H), 7.70 (s, 1H), 7.78 (d, 2H). Crystallization from hydrochloric ethanol yielded white crystals (5.70 g, 66 %). mp: 207 0 C 'H-NMR (DMSO d) : 3.70 (s, 3H), 4.97 (s, 2H), 6.93 (d, 2H), 7.13 (d, 2H), 7.45 25 (d, 2H), 7.70 (s, 1H), 7.84 (d, 2H), 8.04 (s, 1H), 8.18 (s, 1H), 9.55 (s, 1H). EXAMPLE IQ 4-[N-(4-hydroxyphenyl)-N-(1H-imidazol-1 yI)amino]methybenzonitrile A solution of boron tribromide (60 ml, 60.00 mmol) in 20 ml of dichloromethane 30 is added to a cold (0-5 0 C) solution of 4-[N-(1H-imidazol-1-yl)-N-(4 methoxyphenyl)amino]methylbenzonitrile (4.60 g, 15.11 mmol). After 1 h at room temperature the mixture was hydrolysed with saturated aqueous NaHCO 3 , filtered, washed with water (50 ml) and with dichloromethane (20 ml) to give a 36 brown solid (4.00 g). Crystallization from acetone yielded a brown solid (3.00 g, 68%) mp: 150 0 C. 'H-NMR (DMSO ) : 4.84 (s, 2H), 6.70 (s, 4H), 6.90 (s, 1-1), 7.45-7.62 (m, 3H), 7.62-7.90 (m, 3H), 9.25 (s, 1H). 5 EXAMPLE 11 4-[N-(4-hydroxyphenylmethyl)-N-(1H-imidazol-1 yl)amino]benzonitrile 4-hydroxybenzylbromide (15.6 g, 84.3 mmol, prepared following Wissner A. et al., J.Med.Chem. 1992, 35, 1650) was added to a mixture of 4-[N-(1H-Imidazol 10 1-yl)amino]benzonitrile (10.00 g, 54.30 mmol) and K 2 C0 3 (8.20 g, 59.70 mmol) in dry THF (150 ml) at room temperature. The mixture was then stirred at room temperature for 2 h and after poured into water and extracted with ethyl acetate, dried over Na 2

SO

4 , filtered, and concentrated under vacuum to give the crude product (16.00 g as solid). Crystallization from ethyl acetate with ethanol yielded 15 the expected product (6.50 g, 41%, mp: 180 0 C) 'H-NMR (DMSO d): 4.80 (s, 2H), 6.65 (d, 2H), 6.91 (s, 1H), 7.04 (d, 1H), 7.20 (s, 1H), 7.56 (s, 1H), 7.63 (d,2H). Using the same procedure but replacing the 4-hydroxybenzylbromide by: 20 - 3-chloro-4-hydroxybenzylbromide - 3-bromo-4-hydroxybenzylbromide - 4-hydroxy-3-methoxybenzylbromide - 2,3,5,6-tetrafluoro-4-hydroxybenzylchloride (prepared following Angyal SJ. et al., J.Chem. Soc. 1950, 2141) 25 - 3-formyl-4-hydroxybenzylchlorIde (prepared following Angyal S.J. et al., J.Chem. Soc. 1950, 2141) - 1-benzyloxy-4-(2-bromo-ethoxy)-benzene (prepared following Brinkman J. and al. Bloorg. Med. Chem. Lett., 1996, 6, 21, 2491-94) - 2-chloro-5-chloromethyl-pyridine 30 - 4-(bromomethyl)benzene sulfonamide (prepared following Colescott R. and all. J. Am. Chem. Soc., 1957, 79, 4232-35) - 4-(chloromethyl)-2-nitro-phenol (prepared following Bayer Patent: DE 132475) 37 - 5-chloromethyl-2-methoxy-benzoic acid (prepared following Leonard F. and all. J. Med. Chem., 1965, 8, 812-15) the following compounds were respectively obtained: EXAMPLE 12 5 4-[N-(3-chloro-4-hydroxyphenylmethyl)-N-(1H-imidazol-1 yI)amino]benzonitrile mp 195 0 C 'H-NMR (DMSOd 6 ) : 4.88 (s, 21-), 6.67 (d, 2H), 6.88 (d, 2H), 6.98 (s, 1H), 7.05 (dd, 1H), 7.24 (d, 1H), 7.33 (s, 111), 7.70 (s,1H), 7.72 (d,2H), 10.28 (s, 1H). 10 EXAMPLE 13 4-[N-(3-bomo-4-hydroxyphenylmethyl)-N-(1H-imidazol-1 yl)amino]benzonitrile mp 198 0 C 1 H-NMR (DMSOd 6 ) : 4.90 (s, 2H), 6.65 (d, 2H), 6.85 (d, 1H), 6.99 (s, 1H), 7.07 15 (d, 1H), 7.30 (s, 1H), 7.40 (s, 1H), 7.65 (s,1H), 7.67 (d,2H), 10.40 (s, 1H). EXAMPLE 14 4-[N-(4-hydroxy-3-methoxyphenylmethyl)-N-(1H-imidazol-1 yl)amino] benzonitrile mp 215 0 C 20 IH-NMR (DMSOd 6 ) : 3.70 (s, 3H), 4.89 (s, 2H), 6.68 (s, 2H), 6.70 (d, 2H), 6.80 (s, 1H), 6.99 (s, 1H), 7.30 (s, 1H), 7.63 (s, 1H), 7.72 (d,211), 9.20 (s, 1H). EXAMPLE 15 4-[N-(2,3,5,6-tetrafluoro-4-hydroxyphenylmethyl)-N-(1H-imidazol-1 yl)amino] benzonitrile 25 mp 243 0 C 'H-NMR (DMSOd 6 ): 5.09 (s, 2H), 6.72 (d, 2H), 7.00 (s, 1H), 7.32 (s, 1H), 7.69 (d, 2H), 7.77 (s, 1H), 11.80 (s, 1H). EXAMPLE 16 4-[N-(3-formyl-4-hydroxyphenylmethyl)-N-(1H-imidazoI-1 30 yI)amino]benzonltrile mp 160 0

C

38 'H-NMR (DMSOd 6 ): 4.95 (s, 2H), 6.70 (d, 2H), 6.90 (s, 1H), 6.96 (d, 1H), 7.35 (s, 1H), 7.44 (dd, 1H), 7.58 (d, 1H), 7.67 (s, 1H), 7.71 (d, 2H), 10.20 (s, 1H), 10.75 (s, 1H). EXAMPLE 17 5 4-{N-[2-(4-benzyloxy-phenoxy)ethyl]-N-(1H-imidazol-1 yl)amino]}benzonitrile 1 H-NMR (DMSO d): 3.95-4.10 (m, 2H), 4.11-4.28 (m, 2H), 5.01 (s, 2H), 6.60 (d, 2H), 6.82 (d, 2H), 7.95 (d, 2H), 7.03-7.50 (m, 7H), 7.69 (d, 2H), 7.88 (s, 1H). EXAMPLE 18 10 4-{N-[(6-chloropyridin-3-yl)methyl]-N-(1H-imidazol-1 yl)amino}benzonitrlle mp 156 0 C 'H-NMR (DMSO d): 5.10 (s, 2H), 6.71 (d, 2H), 7.00 (s, 1H), 7.42 (s, 1H), 7.49 (d, 1H), 7.55-7.90 (m, 4H), 8.34 (d,1H). 15 EXAMPLE 19 4-{[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}benzene sulfonamide mp 150 0 C 'H-NMR (DMSO d) : 5.15 (s, 2H), 6.62 (d, 2H), 7.00 (s, 1H), 7.36 (s, 2H), 7.45 20 (s, 1H), 7.55 (d, 2H), 7.65-7.90 (m, SH). EXAMPLE 20 4-[N-(4-hydroxy-3-nitrophenylmethyl)-N-(1H-imidazol-1 yl)amino]benzonitrile mp 205 0 C 25 'H-NMR (DMSO d) : 4.98 (s, 2H), 6.72 (d, 2H), 7.00 (s, 1H), 7.06 (d, 1H), 7.39 (s, 1H), 7.48 (d, 1H), 7.60-7.78 (m, 3H), 7.82 (s, 1H). EXAMPLE 21 5{([N-(4- anophenyl)-N-(H-imidazol-1-yl)amino]methyl}-2 methoxybenzoic acid 30 mp 187 0 C 'H-NMR (DMSO d) : 3.79 (s, 3H), 5.00 (s, 2H), 6.69 (d, 2H), 6.98 (s, 1H), 7.05 (d, 1H), 7.31 (s, 1H), 7.39 (dd, 1H), 7.55 (d, 1H), 7.62-7.85 (m, 3H).

39 EXAMPLE 22 4-[N-(1H-imidazol-1-y)-N-(4-nitrophenyl)amino]benzonitrile 4-[N-(1H-imidazol-1-yl)amino]benzonitrile (10.00 g, 54.30 mmol) was added portionwise to a suspension of potassium tert-butoxide (6.69 g, 59.73 mM) in 5 DMSO (100 ml) at ( 10-15 0 C) with stirring. The mixture was stirred for 30 mn at room temperature, and then 4-nitro-fluorobenzene (7.60 g, 54.00 mM) in DMSO (15 ml) was added dropwise while keeping the temperature below 30 0 C. After 2h, the mixture was poured into water (800 ml) and the resulting precipitate was collected by filtration and purified by crystallization from ethanol (1.00 g, 48%, 10 mp: 188 0 C). 'H-NMR (DMSOd 6 ) : 7.00 (d, 2H), 7.17 (s, 1H), 7.26 (d, 2H), 7.65 (s, 1H), 7.90 (d, 2H), 8.20 (s,1H), 7.22 (d,2H). Using the same procedure but replacing the 4-nitro-fluorobenzene by: 15 - 6-chloro-nicotinoyl chloride - 4-fluorophenylacetyl chloride - 4-hydroxyphenylacetyl chloride - 4-hydroxyphenylpropanoyl chloride (prepared following Elias H. and all. Macromol. Chem. Phys., 1981, 182, 681-86) 20 - 4-phenylmethoxybenzene sulfonyl chloride (prepared following Toja E. and all. Eur. J.Med.Chem. 1991, 26, 403-13) the following compounds were respectively obtained: EXAMPLE 23 6-chloro-N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)nicotinamide 25 mp 132 0 C 'H-NMR (DMSO d) : 6.98 (s, 1H), 7.40-7.62 (m, 3H), 7.70 (s, 1H), 7.95 (d, 2H), 8.00 (d, 1H), 8.19 (s,1H), 8.57 (d, 1H). EXAMPLE 24 N-(1H-imidazol-1-y)-N-(4-cyanophenyl)-2-(4-fluorophenyl)acetamide 30 mp 131 0 C 1 H-NMR (DMSO d) : 3.57 (s, 2H), 7.00-7.35 (m, 5H), 7.55 (d, 2H), 7.70 (s, 1H), 7.93 (d, 2H), 8.19 (s,1H).

40 EXAMPLE 25 N-(1H-imidazol-1-y)-N-(4-cyanophenyl)-2-( 4 hydroxyphenyl)acetamide 'H-NMR (DMSO d) : 3.32 (s, 2H), 6.65 (d, 2H), 6.87 (d, 2H), 7.08 (s, 1H), 7.50 5 (d, 2H), 7.70 (s, 1H), 7.90 (d, 2H), 8.10 (s, 1H), 9.30 (s, 1H). EXAMPLE 26 N-(4-cyanophenyl)-3-(4-hydroxyphenyl)-N-(1H-imidazol-1 yl)propanamlde mp 172 0 C 10 'H-NMR (DMSO d) : 2.25-2.60 (m, 2H), 2.65-2.90 (m, 2H), 6.63 (d, 2H), 6.90 (d, 2H), 7.08 (s, 1H), 7.51 (d, 2H), 7.61 (s, 1H), 7.90 (d, 2H), 8.10 (s, 1H), 9.20 (s, 1H). EXAMPLE 27 N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)-4-(phenylmethoxy) 15- benzensulfonamide 'H-NMR (CDCl 3 ): 5.14 (s, 2H), 6.93 (t, 1H), 7.00-7.15 (m, 3H), 7.30-7.45 (m, 7H), 7.50 (s, 1H), 7.66 (d, 2H), 7.68 (d, 2H). PREPARATION OF IMIDAZOLES OF FORMULA (15), (21) 20 EXAMPLE 28 5-Nitro-[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)]-benzothiophene-2 carboxamide 5-Nitro-benzothiophene-2-carbonyl chloride (commercial compound, 10.00 g, 41.00 mmol) was added to a mixture of 4-[N-(1H-imidazol-1 25 yl)amino]benzonitrile (7.55 g, 41.00 mmol), TEA (20 ml, 143.00 mmol) in dry. THF (150 ml) at room temperature. The mixture was then stirred at room temperature overnight and the precipitate was filtrated, washed with THF, water to give the crude product as a solid (9.26g). Crystallization with ethanol yielded white crystals (3.50 g, mp: 221 0 C). 30 1 H-NMR (DMSO dQ): 7.10 (s, 1H), 7.54 (s, 1H), 7.70 (d, 2H), 7.82 (s, 1H), 7.98 (d, 2H), 8.15-8.40 (m, 3H), 8.89 (s, 1H).

41 Using the same procedure but replacing the 5-nitro-benzothjophene-2-carbonyI chloride by: 6-methoxy-benzothiophene- 3 -acetyI chloride (described by Sauter F., Monatshefte Fuer Chemie, 1968, 99, 2, 610-15) the following compound was 5 obtained: EXAMPLE 29 N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)-2-(6-methoxy-benzothien-3 yl) acetamide mp: 104 0 C 10 'H-NMR (DMSO d 6 ): 3.75-3.85 (m, 5H), 7.02 (dd, 1H), 7.13 (s, 1H), 7.30 (s, 1H), 7.50-7.75 (m, 4H), 7.80 (s, 1-I), 7.90 (d, 2H), 8.25 (s, 1H). EXAMPLE 30 4-{N-[1H-imidazol-1-yl]-N-[(6-methoxy-benzothien-3 yI)methyl]amino} benzonitrile 15 3-Chloromethyl-6-methoxy-benzothiophene (12.35 g, 58.06 mmol) was added to a mixture of 4-[N-(1H-imidazol-1-yl)aminobenzonitrile (9.72 g, 52.78 mmol),

K

2 C0 3 (14.60 g, 105.56 mmol) and potassium iodide (0.10g, 0.60 mmol) in dry DMF (70 ml) at room temperature. The mixture was then stirred at room temperature overnight and after poured into water and extracted with ethyl 20 acetate, dried over Na 2

SO

4 , filtered, and concentrated under vacuum to give the crude product as solid (14.30 g). Flash chromatography on silica gel (toluene / dioxan: 6/4) yielded the expected product (10.50 g, 55 %, powder). Crystallization with ethanol yielded white crystals (7.30 g, mp: 164 0 C). 1 H-NMR (DMSO d 6 ): 3.80 (s, 3H), 5.25 (s, 2H), 6.74 (d, 2H), 6.93 (s, 1H), 7.02 25 (dd, 1H), 7.28 (s, 1H), 7.40 (s, 1H), 7.53 (s, 1-i), 7.55 (s, 1H), 7.68 (d, 1H), 7.75 (d, 2H). EXAMPLE 31 4-[N-(6-benzyloxy-1,1-dioxido-benzothien-3-yi)-N-(1H-imidazol-1 yl)amino] benzonitrile 30 4-[N-(1H-imidazol-1-yl)amino]benzonitrile (0.50 g, 27.14 mmol) was added portionwise to a suspension of potassium tert-butoxide (0.35 g, 31.00 mmol) In THF (20 ml) at ( 10-15 0 C) with stirring. The mixture was stirred for 30 mn at room temperature, and then 3-bromo-6-benzyloxy-benzothiophene-1,1-dioxyde 42 (1.10 g, 31.33 mM) in THF (5 ml) was added dropwise while keeping the temperature below 30*C. After one night, the mixture was poured into water (200 ml) and extracted with ethyl acetate, dried over Na 2

SO

4 , filtered, and concentrated under vacuum to give the crude product as an oil (2.50 g). Flash 5 chromatography on silica gel (toluene / 1,4-dioxan: 7/3) and crystallisation in ethanol yielded light brown crystals (1.20 g, 95%, mp: 146 0 C). 'H-NMR (DMSO d 6 ): 5.22 (s, 2H), 6.48 (s, 1H), 6.49 (d, 1H), 7.05-7.20 (m, 2H), 7.25-7.50 (m, 8H), 7.60 (d, 1H), 7.73 (s,1H), 7.94 (d, 2H). 10 Using the same procedure but replacing the 3-bromo-6-benzyloxy benzothiophene-1,1-dioxyde by: 6-benzyloxy-2-(chloromethyl)-benzothlophene the following compound was obtained: EXAMPLE 32 15 4-[N-[(6-benzyloxy-benzothien-2-yl)methyl]-N-(1H-imidazol-1 yl)amino] benzonitrile 'H-NMR (DMSO dQ): 5.12 (s, 2H), 5.30 (s, 2H), 6.72 (d, 2H), 7.00 (s, 1H), 7.04 (dd, 1H), 7.23 (s, 1H), 7.27-7.90 (m,11H). 20 PREPARATION OF IMIDAZOLES OF FORMULA (10), (16) EXAMPLE 33 4-{N-[(6-hydroxy-benzothien-3-yl)methyl]-N-[1H-imidazol-1-yi ]amino} benzonitrile A solution of 4-{N-[1H-imidazol-1-yl]-N-[(6-methoxy-benzothien-3 25 yl)methyl]amino} benzonitrile (0.50 g, 1.39 mmol) in 10 ml of methylene chloride is added at room temperature to a solution 1M of boron tribromide in methylene chloride(1.50 ml, 1.52 mmol). After 2h at room temperature the mixture was hydrolysed with saturated aqueous NaHCO 3 , extracted with dichloromethane, dried over Na 2

SO

4 , filtered, and concentrated in vacuum. The crude product was 30 purified by flash chromatography on silica gel (toluene / dioxan: 6/4) to give the expected product (0.30 g, 62 %, powder). Crystallization with ethanol yielded white crystalsl (0.10 g, mp: 169 0

C).

43 1 H-NMR (DMSO dQ): 5.24 (s, 2H), 6.72 (d, 2H), 6.87 (dd, 1H), 6.94 (s, 1H), 7.27 (d, 2H), 7.29 (s, 1H), 7.55 (s, 1H), 7.56 (d, 1H), 7.75 (d, 21-), 9.67 (s, 1H). Using the same procedure but replacing the 4-{N-[1H-imidazol-1-yl]-N-[(6 5 methoxy-benzothiophen-3-yl)methyl]amino}benzonitrile by: N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)-2-(6-methoxy-benzothlen-3-yl) acetamide, the following compound was obtained: EXAMPLE 34 N-(4-cyanophenyl)-N-(1H-imidazol-1-y)-2-(6-hydroxy-benzothien-3 10 yl) acetamide mp 179 0 C 1 H-NMR (DMSO dQ): 3.72 (s, 2H), 6.85 (dd, 1H), 7.10 (d, 2H), 7.25 (d, 1H-), 7.40 7.70 (m, 3H), 7.80 (s, 1H), 7.91 (d, 2H), 8.24 (s, 1H), 9.60 (s, 1H). EXAMPLE 35 15 4-[N-(3-amino-4-hydroxy-phenylmethyl)-N-(1H-imidazol-1-yl)amino] benzonitrile 4-[N-(4-hydroxy-3-nitro-phenylmethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile (2 g, 5.97 mmol) was hydrogenated over a suspension of Pd/C (10 % Wt on carbon, 0.2 g) In ethanol (30 ml). When TLC showed complete reaction, the 20 mixture was filtered on celatum, rinsed with EtOH. The solvent was concentrated under vacuum. Crystallisation from EtOH/petroleum ether yielded orange crystals (1.1 g, 60.5 %, mp: 208 0 C). 1 H-NMR (DMSO d) : 4.60 (s, 2H), 4.79 (s, 2H), 6.80 (d, 1H), 6.40-6.80 (m, 4H), 6.99 (s, 1H), 7.25 (s, 1H), 7.50-7.80 (m, 31-), 9.07 (s, 1H). 25 Using the same procedure but replacing the 4-[N-(4-hydroxy-3-nitro-benzyl)-N (1H-imidazol-1-yl)amino]benzonltrile by: 4-{N-[2-(4-benzyloxy-phenoxy)ethyl]-N-(1H-imidazol-1-yl)amino] - benzonitrile 30 - N-(4-cyanophenyl)-N-(H-imidazol-1-yl)-4-(phenylmethoxy) benzensulfonamide the following compounds were respectively obtained: 44 EXAMPLE 36 4-{N-[2-(4-hydroxyphenoxy)ethyl]-N-(1H-imidazol-1 y)amino}benzonitrile mp 188 0 C 5 1 H-NMR (DMSO d) : 4.99 (t, 2H), 4.17 (t, 2H), 6.40-6.85 (m, 6H), 7.10 (s, 1H), 7.40 (s, 1H), 7.68 (d, 2H), 7.86 (s, 1H), 8.95 (s,1H). EXAMPLE 37 N-(4-cyanophenyl)-N-(1H-imidazol-1-yi)-4-hydroxybenzensulfonamide mp 248 0 C 10 'H-NMR (DMSO d) : 6.95 (d, 2H), 7.00 (s, 1H), 7.24 (s, 1H), 7.49 (d, 2H), 7.52 (d, 2H), 7.88 (s, 1H), 7.92 (d, 2H), 10.95 (s, 1H). EXAMPLE 38 4-[N-[(6-hydmxy-1,1-dioxido-benzothien-3-yi)]-N-(1H-imidazol-1 yI)amino] benzonitrile 15 A mixture of 4-[N-[(6-benzyloxy-1,1-dioxido-benzothien-3-yl)]-N-(1H-imidazol1 yl) amino]benzonitrile (3.00 g, 6.78 mmol), 10% Pd/C (0.50 g), THF (30 ml) and solution of ammonium formate (25% In H 2 0, 30 ml) was stirred at ambient temperature for 6 h and filtered. The mixture was poured Into water and extracted with ethyl acetate, dried over Na 2

SO

4 , filtered, and concentrated under 20 vacuum to give the crude product (2.50 g as solid). Crystallisation from ethanol afforded white crystals (0.80 g, 26 %, mp: 260 0 C). 1 H-NMR (DMSO dQ): 6.25 (s, 1H-), 6.29 (d, 1H), 6.82 (dd, 1H), 7.10 (s, 1H), 7.15 (s, 1H), 7.30 (d, 2H), 7.70 (s, 1H), 7.91 (d,2H), 8.25 (s, 1H). 25 Using the same procedure but replacing the 4-[N-[(6-benzyoxy-1,1-dioxido benzothien-3-y)]-N-(1H-imidazol-1-yl)aminolbenzonitrile by: 4-[N-[(6-benzyloxy-benzothien-2-yl)methyl]-N-(1H-imidazol-1 yl)amino]benzonitrile the following compound was obtained: 30 EXAMPLE 39 4-[N-[(6-hydroxy-benzothien-2-yl)methyl]-N-(1H-imidazol-1 yl)amino] benzonitrile mp 230 0

C

45 'H-NMR (DMSO dQ): 5.28 (s, 2H), 6.70 (d, 2H), 6.82 (dd, 1H), 7.00 (s, 1H), 7.15 7.21 (m, .2H), 7.31 (s, 11-), 7.55 (d, 1H), 7.69-7.80 (m, 3H), 9.63 (s, 1H). PREPARATION OF IMIDAZOLES OF FORMULA (12), (18) 5 EXAMPLE 40 4-[N-(4-aminophenyl)-N-(H-imidazol-1-yl)amino]benzonitrile Hydrazine (1.52 ml, 49.00 mmol) was added portionwise to a suspension of 4-[N (1H-imidazol-1-yl)-N-(4-nitrophenyl)amino]benzonitrile (3.00 g, 9.80 mM) and ruthenium, 5 wt. % on carbon (0.30 g, 0.15 mM) in ethanol (35 ml) at reflux 10 with stirring. When TLC showed complete reaction, the mixture was cooled and the catalyst was filtered. The solvent was concentrated under vacuum. The residue was poured Into water and extracted with dichloromethane, dried over Na 2

SO

4 , filtered, and concentrated under vacuum to give the crude product (2.50g as solid). Crystallization from ethyl acetate with ethanol yielded the 15 expected product (1.30 g, 50%, mp: 147 0 C). 1 H-NMR (DMSOd 6 ): 5.50 (s, 2H), 6.30 (d, 2H), 6.69 (d, 21-), 7.09 (s, 1H), 7.29 (d, 2H), 7.63 (s, 1H), 7.65 (d, 2H), 8.14 (s,1H). EXAMPLE 41 5-Amino-[N-(4-cyanophenyl)-N-(1H-imidazol-1-yi)]-benzothiophene 20 2-carboxamide Stannous chloride dehydrate (13.10 g, 58.00 mmol) was added portionwise to a stirred solution of 5-nitro-[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)] benzothiophene-2-carboxamide (4.50 g, 11.6 mM) In ethanol (100 ml). The mixture was heated under reflux. When TLC showed complete reaction, the 25 mixture was cooled and basified with saturated bicarbonate solution. The mixture was extracted with ethyl acetate, dried over Na 2

SO

4 , filtered, and concentrated under vacuum to give the crude product as a solid (3.90g). Crystallization from methanol yielded the expected product (2.60 g, 63%, mp: 214 0 C). 'H-NMR (DMSOd 6 ): 6.70-6.98 (m, 3H), 7.07 (s, 1H), 7.40-7.25 (m, 4H), 7.26 30 7.96 (m, 3H).

46 GENERAL PROCEDURE OF SULFAMOYLATION PREPARATION OF SULFAMATES (11, 17, 23) AND AMINOSULFONYLAMINES (13, 19, 25) EXAMPLE 42 5 Sulfamic acid 4-[N-(4-cyanophenylmethyl)-N-(1H-imidazol 1y)amino]phenyl ester Sulfamoyl chloride (2.39 g, 20.69 mmol) was added to a solution of 4-[N-(4 hydroxyphenyl)-N-(1H-imidazol-1-yl)amino]methylbenzonitrile (1.00 g, 3.45 mmol) in dry DMAc (36 ml) with Ice- cooling. The mixture was then stirred at 10 room temperature for 6 h. After addition of TEA (3.40 ml, 24.73 ml), the mixture was poured into cold brine and extracted with ethyl acetate, dried over Na 2

SO

4 , filtered, and concentrated under vacuum to give the crude product (0.70 g as solid). Crystallization from ethyl acetate yielded the expected product (0.40 g, 31%, mp: 60 0 C). 15 1 H-NMR (DMSO d) : 5.00 (s, 2H), 6.70 (d, 2H), 6.92 (s, 11-), 7.19 (d, 2H), 7.40 (s, 1H), 7.55 (d, 2H), 7.74 (s, 1H), 7.77 (d, 2H), 7.91 (s, 2H). Using the same procedure but replacing the 4-[N-(4-hydroxyphenyl)-N-(lH imidazol-1-yl)amino]methylbenzonitrile by: * 4-[N-(4-hydroxyphenylmethyl)-N-(1H-imidazol-1 20 yl)amino]benzonitrile .4-[N-(3-chloro-4-hydroxyphenylmethyl)-N-(H-imidazol-1 yl)amino]benzonitrile * 4-[N-(3-bromo-4-hydroxyphenylmethyl)-N-(1H-imidazol-1 yl)amino]benzonitrile 25 . 4-[N-(3-methoxy-4-hydroxyphenylmethyl)-N-(1H-imidazol-1 yl)amino] benzonitrile *4-[N-(2,3,5,6-tetrafluoro-4-hydroxyphenylmethyl)-N-(H-imidazol-1 yl)amino] benzonitrile *4-[N-(3-formyl-4-hydroxyphenylmethyl)-N-(H-imidazol-1-yl)amino] 30 benzonitrile * 4-[N-(4-aminophenyl)-N-(1H-imidazol-1-yl)amino]benzonitrile .N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)-4 hydroxybenzensulfonamide 47 *4-{N-[2-(4-hydroxYPhenoxy)ethyl]-N-(1H-imidazol-1 yI)amino}benzonitrile .N-(1H-imidazol-1-yl)-N-(4-cyanophenyl)-2-(4 hydroxyphenyl)acetamide 5 *N-(4-cyanophenyl)-3-(4-hydroxyphenyl)-N-(1H-imidazol-1 yl)propanam.lid.e e4-[N-(3-amino-4-hydroxyphenylmethyl)-N-(1H-imidazol-1-yl)amino] benzonitrile .5-Amino-[N-(4-cyanophenyl)-N-(lH-imidazol-1-yl)]-benzothlophene 10 2-carboxamide .4-[N-[(6-hydroxy-1,1-dioxido-benzothien-3-y)]-N-(1H-imidazol-1 yl)amino]benzonitrile .N-(4-cyanophenyl)-N-(1H-imidazol-1-yI)-2-[(6-hydroxy-benzothien 2-yl)] acetamide 15 * 4-{N-[(6-hydroxy-benzothien-3-yl)methyl]-N-[1H-imidazol-1-yl ]amino}benzonitrile .4-{N-[(6-hydroxy-benzothien-2-yl)methyl]-N-[1H-imidazol-1-yl ]amino}benzonitrile the following compounds were respectively obtained: 20 EXAMPLE 43 Sulfamic acid-4-{[N-(4-cyanophenyl)-N-(1H-imidazol lyl)amino]methyl}phenyl ester mp 172 0 C 1 H-NMR (DMSOd) : 5.00 (s, 2H), 6.65 (d, 2H), 7.00 (s, 1H), 7.22 Cd, 2H), 7.40 25 (s, 1H), 7.42 (d, 2H), 7.70 (s, 1H), 7.75 ( d, 21-), 8.00 (s, 21-). EXAMPLE 44 Sulfamic acid 2-chloro-4-{[N-(4-cyanophenyl)-N-(1H-imidazol lyl)amino]methyl}phenyl ester 1 H-NMR (DMSOd) : 5.05 (s, 21-1), 6.63 (d, 2H), 7.00 (s, 1H), 7.35-7.45 (m, 3H), 30 7.54 (s, 1H), 7.70 (d, 2H), 7.80 (s, 1H), 8.29 (s, 2H). EXAMPLE 45 Sulfanic acid 2-bromo-4-{[N-(4-cyanophenyl)-N-(1H-imidazol lyl)amino] methyl}phenyl ester, hydrochloride Crystallisation was performed In EtOH/HCI (mp 145 0

C)

48 1 H-NMR (DMSOd) : 5.15 (s, 2H), 6.90 (d, 2H), 7.48 (s, 2H), 7.60-7.85 (s, 5H), 8.08 (s, 1H), 8.32 (s, 2H), 9.51 (s, 1H). EXAMPLE 46 Sulfamic acid 2-methoxy-4-{[N-(4-cyanophenyl)-N-(1H-imidazol 5 lyl)amino] methyl}phenyl ester mp 211 0 C 1 H-NMR (DMSOd 6 ) : 3.77 (s, 3H), 5.02 (s, 2H), 6.75 (d, 2H), 6.92 (d, 1H), 7.05 (s, 2H), 7.25 (d, 1H), 7.45 (s, 1H), 7.71 (d, 2H), 7.80 (s, 1H1), 7.93 (s, 2H). EXAMPLE 47 10 Sulfamic acid 2,3,5,6-tetrafluoro-4-{[N-(4-cyanophenyl)-N-(1H imidazol-iyl)amino] methyl}phenyl ester -H-NMR (DMSOd 6 ) : 5.37 (s, 2H), 5.83 (s, 2H), 6.86 (d, 2H), 7.08 (s, 11H), 7.41 (s, 1H), 7.79 (s, 1H), 7.81 (d, 2H). EXAMPLE 48 15 4-[N-[(2,2-dioxido-1,2,3-benzoxathiazin-6-yl)methyl]-N-(1H-imidazol 1-yl)amino] benzonitrile mp 180 0 C 1 H-NMR (DMSOd 6 ) : 5.17 (s, 2H), 6.67 (d, 2H), 7.02 (s, 1H), 7.46 (s, 1H), 7.50 (d, 2H), 7.74 (d, 2H), 7.82 (dd, 1H), 7.87 (s, 1H), 8.02 (d, 1H), 9.19 (s, 1H). 20 EXAMPLE 49 N-{4-[N-(4-cyanophenyl)-N-(1H-imidazol-1 yI)amino]phenyl}sulfamide mp 121 0 C 1 H-NMR (DMSOd6): 6.38 (d, 2H), 7.09 (s, 1H), 7.20 (s, 1H), 7.22 (d, 2H), 7.51 25 (d, 2H), 7.63 (s, 1H), 7.69 (d, 2H), 8.19 (s, 1H) EXAMPLE 50 Sulfamic acid 4-{[N-(4-cyanophenyl)-N-(1H-imidazol 1yl)amino]sufonyl}phenyl ester, hydrochloride Crystallisation was performed In EtOH/HCI 30 mp 200 0 C IH-NMR (DMSOd 6 ): 7.57 (d, 2H), 7.60 (s, 1H), 7.70 (d, 2H), 7.80-8.10 (m, 5H), 8.40 (s, 2H), 9.30 (s, 1H).

49 EXAMPLE 51 Sulfamic acid 4-{2-[N-(4-cyanophenyl)-N-(1H-imidazol lyl)amino]ethoxy} phenyl ester mp 174 0 C 5 IH-NMR (DMSOd 6 ): 4.08 (t, 2H), 4.23 (t, 2H), 6.60 (d, 2H), 6.95 (d, 2H), 7.10 (s, 1H), 7.18 (d, 2H), 7.42 (s, 1H), 7.70 (d, 2H), 7.88 (s, 3H). EXAMPLE 52 Sulfamic acid 4-{[N(4-cyanophenyl)-N-(1H-imidazol-1yl)-carbamoyl] methyl} phenyl ester 10 'H-NMR (DMSOd 6 ): 3.32 (s, 2H), 7.12 (s, 1H), 7.18-7.32 (m, 4H), 7.50-7.60 (d, 2H), 7.71 (s, 1H), 7.85-8.05 (in, 4H), 8.20 (s, 1H). EXAMPLE 53 Sulfamic acid 4-{[N-(4-cyanophenyl)-N-(1H-imidazol-1yl)amino]-3 oxopropyl} phenyl ester 15 mp 100 0 C 1 H-NMR (DMSOd 6 ): 2.45 (t, 2H), 3.85 (t, 2H), 7.10 (s, 1H); 7.12-7.30 (m, 4H), 7.55 (d, 2H), 7.65 (s, 1H), 7.90 (m, 4H), 8.12 (s, 1H). EXAMPLE 54 Sulfamic acid 3-(aminosulfonyl)amino-4-{[N-(4-cyanophenyl)-N-(1H 20 Imidazol-lyl)amino]methyl}phenyl ester mp 197 0 C IH-NMR (DMSOd 6 ): 5.00 (s, 2H), 6.71 (d, 2H), 6.93 (d, 1H), 7.02 (s, 2H), 7.21 (d, 1H), 7.48 (s, 1H), 7.61 (d, 2H), 7.74 (s, 1H), 7.92 (s, 2H), 8.10 (s, 2H). EXAMPLE 55 25 5-(Aminosulfonyl)amino-[N-(4-cyanophenyl)-N-(1H-imidazol-1-y)] benzothiophene-2-carboxamide mp: 169 0 C 'H-NMR (DMSO d): 6.87 (d, 1H), 7.05-7.30 (m, 4H), 7.56 (s, 1H), 7.67 (d, 2H), 7.80-8.10 (m, 4H), 7.86 (s, 1H), 9.65 (s, 1H). 30 EXAMPLE 56 Sulfamic acid 3-[N-(4-cyanophenyl)-N-(H-imidazo-1yl)amino]-1,1 dioxido-benzothien-6-yi ester mp 172 0

C

50 1 H-NMR (DMSO d): 6.24 (s,~1H), 6.29 (d, 1H), 6.85 (dd, 1H), 7.15 (s, 1H), 7.20 (s, 1H), 7.30 (d, 2H), 7.65 (s, 1H), 7.95 (d, 2H), 8.05 (s, 2H), 8.25 (s, 1H). EXAMPLE 57 Sulfamic acid 3-{2-[N-(4-cyanophenyl)-N-(1H-imidazol-1yl)amino]-2 5 oxoethyl}-benzothien-6-yI ester 'H-NMR (DMSO d): 3.84 (s, 2H), 7.15 (s, 1H), 7.28-7.37 (dd, 1H), 7.51-7.65 (m, 3H), 7.80-7.98 (m, 5H), 8.01 (s, 2H), 8.29 (s, 1H). EXAMPLE 58 Sulfamic acid 3-{[N-(4-cyanophenyl)-N-(1H-imidazol 10 lyl)amino]methyl}-benzothien-6-yI ester mp 193 0 C 'H-NMR (DMSO d 6 ): 5.30 (s, 2H), 6.80 (d, 2H), 6.97 (s, 1H), 7.30-7.40 (m, 2H), 7.56 (s, 1H), 7.68 (s, 1H), 7.75 (d, 2H), 7.80-7.95 (m, 2H), 8.05 (s, 2H). EXAMPLE 59 15 Sulfamic acid 2-{[N-(4-cyanophenyl)-N-(1H-imldazol lyl)amino]methyl}-benzothien-6-yI ester mp 178 *C IH-NMR (DMSO d 6 ): 5.17 (s, 2H), 6.65 (d, 2H), 6.89 (dd, 1H), 6.94 (s, 1H),. 7.20 (d, 2H), 7.27 (s, IH), 7.45 (s, 1H), 7.58 (d, 1H), 7.72 (d, 2H), 8.00 (s, 2H). 20 Using the same procedure as example 13 but replacing the 4-[N-(4 hydroxyphenyl)-N-(1H-imidazol-1-yl)amlino]methylbenzonitrile by: 4-[N-(3-bromo-4-hydroxyphenylmethyl)-N-(H-imidazol-1 yl)amino]benzonitrile 25 The following compounds was obtained as a by-product: EXAMPLE 60 2-Bromo-4-{[N-(4-cyanophenyl)-N-(1H-imidazol yl)amino]methyl}phenyl amidimidodisulfate acid mp 220 0 C 30 IH-NMR (DMSOd 6 ) : 5.00 (s, 2H), 5.70 (s, 2H), 6.65 (d, 2H), 7.03 (s, 1H), 7.42 (dd, 1H), 7.50 (s, 1H), 7.55 (d, 1H), 7.65 (d, 1H), 7.72 (d, 2H), 7.81 (s, 1H).

51 PREPARATION OF OTHER COMPOUNDS (8) EXAMPLE 61 4-[N-[(2,2-dioxido-3,4-dihydro-1,2,3-benzoxathiazin-6-yl)methyl]-N (1H-imidazol-1-yl)amino]benzonitrile 5 To a suspension of 4[N-[(2,2-dioxido-1,2,3-benzoxathiazin-6-yl)methyl]-N-(1H imidazol-1-yl)amino]benzonitrile (0.40 g, 1.05 mmol) In methanol (8 ml) was added portionwise NaBH 4 (0.08 g, 2.11 mmol) and the reaction mixture was stirred at room temperature for 3 h. After addition of a saturated solution of

NH

4 CI (3 ml) and water (40 ml), the precipitate obtained was filtered, washed 10 with water and dried to give a white solid. Crystallization from ethyl acetate with ethanol yielded the expected product (0.40 g, 82%, mp: 190 0 C). IH-NMR (DMSOd 6 ): 4.55 (d, 2H), 5.04 (s, 2H), 6.64 (d, 2H), 7.02 (s, 1H), 7..03 (d, 1H), 7.27 (d, 1H), 7.30 (s, 1H), 7.41 (s, 1H), 7.70 (d, 2H), 7.85 (s, 1H), 8.56 (t, 1H). 15 EXAMPLE 62 5-([N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyi}-2 hydroxybenzoic acid A mixture of 5-{[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}-2 methoxybenzoic acid (1.00g, 2.85 mmol) and piperidine (0.42mi, 8.57 mmol) in 20 dimethylacetamide (DMA) (2 ml) was heated at 150 0 C. When starting material had disappeared (TLC monitoring), the solvent was removed in vacuo. Flash c hromatography on silica gel (MeOH / dichloromethane : 5/95) and crystallization from ethanol afforded white crystals (53 mg, 6 %, mp: 260 0 C). 'H-NMR (DMSO d) : 4.85 (s, 2H), 6.54 (d, 1H), 6.66 (d, 2H), 6.95 (s, 11-), 7.05 25 (dd, 1H), 7.24 (s, 1H), 7.50-7.60 (m, 2H), 7.68 (d, 2H). EXAMPLE 63 4-[N-(1H-imidazol-1-y)-N-(phenyl)amino]benzonitrile 4-[N-(1H-imidazol-1-yl)-N-(4-nitrophenyl)amino]benzonitrile (3.91 g, 12.80 mmol) was placed in a hydrogenation flask and dissolved in acetic anhydride (60 30 ml) and acetic acid (60 ml). Palladium 10 % on C, 0.20 g) was added, and the bottle was attached to a Parr hydrogenation apparatus. Hydrogenation was carried out with shaking for 3 h at 25 psi H 2 . The catalyst was removed by filtration and the solution was cooled in a bath for 30 mn. Sodium nitrite (0.97 g, 52 14.00 mmol) was added to the mixture, and the vessels are lightly capped. The flask is kept In the Ice bath for 2 h and allowed to warm to room temperature overnight. The mixture was poured Into Ice/water and the solid was filtered, washed with water (50 ml) to give crude product. Flash chromatography 5 (toluen/dioxan: 6/4) and crystallization from ethyl acetate with ethanol yielded the expected product (0.40 g, 8 %, mp: 162 0 C). 'H-NMR (DMSO d) : 6.60 (d, 2H), 7.00-7.50 (m, 9H), 7.69 (s, 1H). PREPARATION OF BENZOXATHIAZOLE (8) 10 EXAMPLE 64 4-[N-(3-tosylamino-4-hydroxy-benzyl)-N-(1H-mldazol-1 yl)amino]benzonitrIle Tosyl chloride (3.5 g, 18.59 mmol) In CH 2 Cl 2 (20 ml) was added dropwise to a solution of (TX 1840) (5.4 g, 17.7 mmol) and pyridine (19.47 mmol, 1.6 ml) In 15 CH 2

C

2 (50 ml) at 0*C. The mixture was then stirred at room temperature for 4h then poured into water and extracted with EtOAc, dried over Na 2

SO

4 , filtered and concentrated under vacuum to give the crude product (8.1 g as orange solid). Flash chromatography on silica gel (toluene dioxane 7/3) yielded yellow solid. 20 'H-NMR (DMSO d) : 2.32 (s, 3H), 4.85 (s, 2H), 6.60 (d, 2H), 6.62 (s, 1H), 6.80 (dd, 1H), 6.97 (s, 1H), 7.10-7.30 (m, 5H), 7.00 (d, 2H), 7.03 (s, 1H), 7.52 (d, 211), 9.45 (s, 211). EXAMPLE 65. 4-[N-[(2,2-dioxido-3-tosyl-3H-1,2,3-benzoxathiazol-5-yl)methyl]-N 25 (1H-imidazol-1-yl)amino]benzonitrile Sulfuryl chloride (0.60 ml, 7.40 mmol) In dichloromethane (50 ml) was added dropwise with stirring over a 30 mn period to 4-[N-(3-tosylamino-4-hydroxy benzyl)-N-(1H-imidazol-1-yl)amino]benzonitrile (3.40 g, 7.40 mmo) and triethylamine (2.10 ml, 14.81 mmol) in dichloromethane (6 ml) at -78 0 C. After 30 an additional 15 mn, the mixture was allowed to room temperature for 4 h. The reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under vacuum.

53 Flash chromatography on silica gel (toluene / dioxane : 5/5) yielded a pure oil (1.60 g, 41 %). 'H-NMR (DMSO d) : 2.39 (s, 3H), 5.18 (s, 2H), 6.80 (d, 2H), 7.00-7.50 (m, 6H), 7.60-7.85 (m, 5H), 8.02 (s, 1H). 5 EXAMPLE 66 4-[N-[(2,2-dioxido-3H-1,2,3-benzoxathiazol-5-yl)methyl]-N-(1H imidazol-1-yl)amino]benzonitrile Potassium fluoride (0.36 g, 6.14 mmol) In water (5 ml) was added to 4-[N-[(2,2 dioxido-3-tosyl-3H-1,2,3-benzoxathiazol-5-yl)methyl]-N-(1H-imidazol-1 10 yl)amino]benzonitrile (1.60 g, 3.07 mmol) in acetonitrile (15 ml) at room temperature. The solution was stirred overnight, concentrated, extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under vacuum. Flash chromatography on silica gel (toluene / dioxane : 5/5) yielded an oil and crystallization from ethanol yielded the expected 15 product (0.17 g, 15 %, mp: 230 0 C). 'H-NMR (DMSO d) : 4.84 (s, 2H), 6.38 (dd, 111), 6.42 (d, 111), 6.63 (d, 1H), 6.69 (d, 2H), 7.15 (s, 1H), 7.43 (S, 111), 7.70 (d, 21-), 8.02 (S, 111). PREPARATION OF PHENYL UREAS (27) 20 EXAMPLE 67 N-(4-cyanopheny)-N-(1H-imidazol-1-yi)-N'-phenylurea Phenyl isocyanate (3,6 ml, 32,6 mmol) was added to a solution of 4-[N-(1H lmidazol-1-yl)amino] benzonitrile (5 g, 27.17 mmol) in THF (50 ml). The mixture was stirred at 50 0 C overnight and after evaporation was crystallised In 25 acetone/EtOH to give white crystals (2.5 g, 30.3 %, 178 0 C). 1H-NMR (DMSO d): 6.59 (s, 1H), 7.05-7.40 (m, 9H), 7.52 (d, 2H), 7.83 (s, 1H).

54 BIOLOGICAL TEST RESULTS INHIBITION OF STEROID SULFATASE, AROMATASE AND CARBONIC ANHYDRASE II IN VITRO Estrone sulfate (ES) is a major circulating plasma estrogen that Is converted by 5 the steroid sulfatase enzyme into estrone (E 1 ), which in turn can be transformed Into estradiol (E2) by enzymatic reduction. The inhibition of E 2 synthesis by aromatase inhibitors has been clinically proved to be a good way to halt the progress of hormone-dependent breast tumors. More recently, the Inhibition of the steroid sulfatase pathway emerged as an 10 alternative. Therefore, the development of compounds able to inhibit both' aromatase and steroid sulfatase inhibition appears as a new and suitable approach to Inhibit tumor growth. Human carbonic anhydrases catalyses the conversion between carbon dioxide

(CO

2 ) and the bicarbonate ion (HCOj), and are involved in numerous 15 physiological and pathological processes. They include hormone-dependent and non-hormone-dependent cancerogenesis, metastasis process and hypoxic tumors that are less responsive to classical chemo/radio-therapy. The inhibition of human carbonic anhydrases could be therefore a valuable additional activity for dual aromatase and sulfatase Inhibitor (DASI) compounds. In particular, EMATE 20 was found to have a human carbonic anhydrases inhibitory potency similar to that of acetazolamide, a well-known sulfonamide human carbonic anhydrases inhibitor. The aim of these experiments was to evaluate in vitro the inhibitory potential of new compounds on aromatase and/or steroid sulfatase activity. In addition, inhibition on human carbonic anhydrase II activity (as an exemple of 25 human carbonic anhydrase) for some of them were evaluated in comparison with 6,6,7 COUMATE and acetazolamide. Materials & Methods a) Aromatase activity 30 The JEG-3 cell line, derived from a human placental choriocarcinoma, constitutively overexpresses human aromatase and represents a relevant model for assaying putative aromatase inhibitors in vitro. Aromatase activity was determined by the tritiated water method. In brief, cells were first seeded into 55 96-well microplates in decomplemented fetal calf serum (dFCS) supplemented medium. 24 hours later, cells were rinsed and fresh medium containing 1p- 3

H

androstenedione as aromatase substrate was added together with test compounds at concentrations ranging from 10-2 M to 10-5 M. After 2 hours of 5 incubation, a fraction of the medium was transferred to homologous new 96-well microplates and a dextran-coated charcoal solution was added to each well. Following standing on ice for 10 minutes, microplates were centrifuged (1500 g; 4 0 C). All steroids, including the radioactive substrate and the newly biosynthesized estrogens, were adsorbed on charcoal; only 3 H-water specifically 10 formed during aromatisation of- 1p- 3 H-androstenedione, remained in the supernatant. The radioactivity in the supernatant was measured by liquid sdntillation counting. In parallel, cell solubilization was performed in ethylenediamine tetraacetate solution. DNA content was measured by a standard fluorimetric method using the Hoechst 33258 fluorochrome. Finally, aromatase 15 activity was expressed in fmoles of 3 H-water formed/2 hours/pg DNA and aromatase inhibition as a percentage of control activity without inhibitor. A non linear fit analysis (GraphPad Prism Software) of % of inhibition vs. Inhibitor concentration allowed the determination of the 50 % inhibitory concentration

(IC

50 ) : the lowest IC 50 s correspond to the most potent inhibitors (Table 1). 20 b) Steroid sulfate ase activity The JEG-3 cell line is intrinsically very rich in human estrone sulfatase and therefore is a useful biological system to evaluate new steroid sulfatase inhibitors in vitro. Assays were carried out with cells in logarithmic growth phase on 96-well 25 microplates. 24h before studies, cells were seeded in decomplemented fetal calf serum (dFCS) supplemented medium. The medium was removed 24h later and cells were rinsed with PBS to eliminate any trace of dFCS. Then, 3

H-E

1 S was added in dFCS free medium, followed by test compounds at concentrations ranging from 1012 M to 10-s M. After 4 h of treatment, the medium was 30 transferred into 96-deep-well microplates and centrifuged at 200 x g for 10 min to pellet cells before toluene extraction. A fraction of the medium was used for toluene extraction in order to separate the conjugated substrate from non conjugated products. The radioactivity in the toluene phase was measured by 56 liquid scintillation counting. In parallel, after cell solubilization in a ethylenediamine tetraacetate solution, DNA content was measured by a standard fluorimetric method using the Hoechst 33258 fluorochrome. Finally, estrone sulfatase activity was expressed in pmoles of 3 H-E, + 3

H-E

2 formed/4 hours/mg 5 DNA and estrone sulfatase Inhibition as a percentage of control activity without inhibitor. A non linear fit analysis (GraphPad Prism Software) of % Inhibition vs. Inhibitor concentration allowed the determination of the 50 % inhibitory concentration (ICso): the lowest IC 50 s correspond to the most potent inhibitors (Table 1). 10 c) Dual ammatase and steroid suifatase activities In order to evaluate the inhibitory potency of DASI compounds in parallel on both human aromatase and steroid sulfatase activities, a new in vitro model was set up using JEG-3 cells. The experimental conditions of the steroid sulfatase 15 model previously described was adopted with slight modifications: the presence of the two substrates 3

-HE

1 S and 1p- 3 H-androstenedione Into the medium and an incubation period of 2 hours. Results were expressed In pmoles of product formed ( 3

H-E

1 + 3

H-E

2 or 3

H

2 0)/2 hours/mg DNA (Table 1). 20 d} Alkaline phosphatase actiity Ishlkawa cells were plated Into 96-well microplates 48 hours before studies. The next day, the medium was replaced by phenol red free medium supplemented with 5 % charcoal-stripped dFCS. 24 hours later, the medium was renewed and compounds were added to the plated cells and Incubated for an additional four 25 day period. For each compound, the tested concentrations ranged from 1012 M to 10'5 M, and the final vehicle concentration did not exceed 0.1 %. At the end of the incubation period, alkaline phosphatase activity (APase) was assayed by a method involving the hydrolysis of p-nitrophenyl phosphate to p-nitrophenol and spectrophotometric determination of the product at 405 nm. 30 In brief, the microplates were first rinsed twice with cold phosphate buffered solution and then placed at -80* C for at least 15 minutes. After thawing at room temperature, 50 pl ice-cold solution containing 5 mM p-nitrophenyl phosphate was added to each well. After a 15 to 60 minute incubation period at room 57 temperature, the intensity of the yellow color generated by the production of p nitrophenol was measured Into each well at 405 nm. For each tested concentration, APase activity, reflected by absorbance, was first expressed as fold increase over control (FI) and then as percentage of E 2 activity 5 (10-8 M) chosen equal to 100 %. Sigmoidal dose-response curves were plotted (GraphPad Prism Software) and 50 % effective concentrations (EC 50 ) were calculated for each compound (Table 1). e) Human carbonic anhydrase IT activity 10 This assay was performed as described In the literature (Armstrong J. et al. Purification and properties of human erythrocyte carbonic anhydrases, J Blol Chem, 1966, 241: 5137-5149). Briefly, in this assay, human carbonic anhydrase II catalyses the conversion of p-nitrophenyl acetate Into p-nitrophenol. The potential inhibitory effect of test compounds was evaluated by colorimetric 15 determination of p-nitrophenol produced during the enzymatic reaction. The optical density levels obtained without Inhibitor will be referred to as "total activity". The levels obtained without Inhibitor and without the enzyme will be referred to as "blank" in order to assess any Interference with the substrate during the assay (Table 2). 20 Table 1: Inhibition of aromatase, estrone sulfatase and estrogenic potency - ~Arohmataie activity . Sulfatase. actrvt ~ ~ 1Y ' Cw (nM) ) n S MO 't un s M _ nE;$. letrozole 0.47 0.08 8 ndb 6 nd 1 6.93& 1.07 a 6 nd b anastrozole 6 nd 1 2.5*±0.6 c 4 ndc nd 8 3 2 .5 0.5b 4 A* .nd 4 ndc 4 3.6 0.8c 4 Ex 11 0.17 0.01 a 8 nd b 4 nd 4 58 * - Estrogeitc Arorntase~tiV~t~rSIfiltseacI .. "4ptfy 0.17 0.03a 8 Ex1 .05 0.02 c 4 nd c 4 n EX 14 0.21 0.05 a 4 nd ~ 1 nd 4 Ex 20 0.3 a 1 ndb 4 nd 4 Ex 22 0.32 ±O.40 a 4 -- nd 1. Ex 26 50.68a 1 fldb 1- Ex 30 0.06 c 1 -- - - Ex 35 2.2 ±O.7 c 4 nd c 4 Ex 36 0.61l±o.21 c 4 nd c 4 - Ex 37 52.0 9.6 c 4 nd c 4 - Ex 40 0.67 0.10 a 8 ---- nd 3 Ex41 4.3c 1 --

-

Ex 43 0.57 ±0.168a 4 S.S 1.1b 4 nd 4 Ex 45 0.13--±O.07 c 4 3.4-± 0.4 c 4 nd 4 Ex 46 0.79 0.26 a 4 1 3 8

±

2

.

5 b 4 nd 4 Ex 48 0.82 0.128a 4 2657 ± 257 b 4 nd 1 Ex 51 0.34 0.13 c 4 597.2 ±67.4 c 4 Ex 61 1.06 0.218a 4 nd 1 4 nd 1 Ex 62 81.8 c 1 nd c 1 A *:su/famlc acid, 3-cyc/oheptyrnethylbezoth/lophen-6-Y-1,1 -dioxide-ester (described In W02004/101 545) nd: not detected Mater/a/s & mefthds:, a armatase activity a/one; b sulfatase activity a/one; Cdual 5aromatase and sulfatase actvity d estrogenic potency 59 Among the tested compounds, Ex 43, Ex 45 and Ex 46 showed a strong Inhibition (ICso about 10 nM) of human estrone sulfatase activity. In addition, the same compounds were shown to be strong inhibitors of aromatase activity (IC 50 < 1 nM). Despite this dual activity, They were not estrogenic In vitro. 5 Table 2: Inhibition of human carbonic anhydrase II acetazolamide 11.3 t 1.9 4 6,6,7 COUMATE 16.1 * 1.5 4 EX 45 16.2 3.3 4 EX 51 6.5 0.9 4 Ex 45 and Ex 51 inhibited human carbonic anhydrase II /n vitro. 10 ANTI UTEROTROPHIC/ANTI STEROID SULFATASE ACTIVITY IN VIVO Wistar female rats were ovarlectomized and left to rest for 4 weeks. Prior to treatment, the absence of cyclicity was checked by vaginal smears. Animals were supplemented with estrone sulfate (EIS) at 50 pg/kg/day s.c., alone or combined with oral administration of potential sulfatase inhibitors, at 1 mg/kg/day for 4 15 days, The uteri were removed, freed of adjacent tissue and wet weighed (Table 3). Estrone sulfatase activity is measured according to the method described by Purohit et al., with slight modifications. Briefly, uteri were thawed, weighed and homogenized. Aliquots of the supernatant were treated with dextran-coated 20 charcoal and assayed for sulfatase. EIS activity is assessed after 30 min of incubation with 5 nM of 3

H-E

1 S and 20 pM of unlabelled E 1 S as substrate. Estrone sulfatase activity Is expressed as pmol /h/mg protein and reported as percentage of inhibition vs E 1 S; for uterus weights, results are expressed as % of inhibition of the EIS induced stimulation 25 60 Table 3: Inhibition of uterus weight 6,6,7 COUMATE 81 8 Ex 45 70 8 Since there Is a direct linear correlation between sulfatase inhibition and uterus weight inhibition (WO 2004/101545), it can be concluded that this uterus activity 5 results from-significant inhibition of EiS (> 90%). Ex 45 was chosen as a potential inhibitor of estrone sulfatase activity because of its lack of estrogenicity, and significant steroid sulfatase inhibition. These In vivo results were in agreement with In vitro results obtained in JEG-3 cells. 10 INHIBITION OF ESTRADIOL PEAK, AS IN VIVO AROMATASE INHIBITION MODEL The aim of this experimentation was to determine a dose-related activity of test compounds in comparison with anastrozole on 170-estradiol level 24 hours after one oral administration in female rats. Anastrozole, Is a potent, non steroidal 15 inhibitor of aromatase, which significantly inhibits estradiol levels at 3 pg/kg, 24 hours after one single oral administration In female rats. One hundred IOPS Wistar female rats, weighing 180 to 200 g, were accommodated by four in stainless steel mesh cages. Animals were allowed free access to a standard diet from Harlan Teklad 2016 pellets. Vaginal smears were performed for each 20 animal, each morning, in order to establish the different phases of cycle. The rats which did not exhibit a regular estrous cycle, were excluded from the experimentation. Starting at 4.00 pm, animals received an oral administration of formulations. 24 hours later, samples of serum were collected and estradiol level were determined as previously described (Table 4). 25 61 Table 4: Inhibition of estradiol peak Anastrozole 56 Ex 45 28 Ex 45 inhibited estradiol peak In vivo. 5 INHIBITION OF TUMOR GROWTH MCF-7 xenograft into nude mice MCF-7 cells, derived from human breast adenocarcinoma, are injected subcutaneously in ovariectomized athymic nude mice supplemented with a daily administration of subcutaneous estrone sulfate. Xenograft volumes are 10 determined weekly. When tumor volumes reach significant increase, tested compound is orally administered at 1mg/kg/day for 8 weeks. Xenografts are measured, removed, weighed, and deep frozen for the determination of sulfatase activity, according to methods used for rat uteri 15 ER+ Human breast tumor tissue xenoarafted into nude rats MCF-7 cells (ATCC), derived from human breast adenocarcinoma, were injected subcutaneously in ovarlectomized athymic nude mice supplemented with a daily administration of subcutaneous estradiol. Xenograft volumes were determined weekly. After 8 weeks, tumor volumes reached 1000 mm3, providing 20 500 mg samples of estrogen responsive tissues for each animals.. At this time each tumor was sliced and regrafted into naive ovariectomized nude rat (Rnu/Rnu). Then animals were treated with estrone sulfate as' precursor of estradiol by the steroid sulfatase pathway. When tumor volumes reached significant increase, distinct from the placebo, animals were randomized and 25 separated in two groups. The first group was treated with Ex 45 and supplemented with daily administration of estrone sulfate. The second one was sham administered with the vehicle and supplemented with the same dosage of estrone sulfate. Ex 45 was orally administered at 5mg/kg/day for 5 weeks.

62 Xenografts were measured weekly by electronic Caliper and compared to the estrone sulfate group. (Table 5). Table 5: Inhibition of human breast tumor Treatment Time Day 7 Day 28 Day 35 Day 42 EIS + Ex 45 0 -26 -44 -39 5 When animals were treated with Ex 45, tumor volumes did not increased. On the other hand, simultaneously, groups only treated with estrone sulfate (ElS), tumor volumes were higher. At the end of the experiments, after five weeks of daily treatment, Ex 45 led to a 40% decrease in tumor volume, showing a clear 10 and well established anticancerous potency. JEG-3 xenoaraft into nude mice The JEG-3 cell line over-expresses both human aromatase and estrone sulfatase enzymes. It Is injected subcutaneously into ovariectomized athymic nude mice 15 supplemented with a daily administration of subcutaneous estrone sulfate with or without test compounds (administered at 5mg/kg/day). In that particular case, and according to their semi-liquid status (chorlocarcinoma origin), tumor measures are irrelevant. Nevertheless, an indirect effect of estradiol which is mainly synthesised by the tumour tissue, is obtained on uteri weights. On the 20 other hand, because of the aromatase and sulfatase overexpression in such tumours, enzyme levels are measurable. Enzyme activities are determined according to the above-mentioned methods JEG-3 xenograft within nude rat supplemented with estrone sulfate and A4 25 androstenedione 15 days before JEG-3 cell injection into rats, blood samples are taken to measure basal levels of estradiol plasma. Then, JEG-3 cells are injected subcutaneously In 63 ovariectomized athymic (Rnu/Rnu) nude rat. Animals are supplemented with a daily administration of subcutaneous estrone sulfate and A4-androstenedione with or without tested compound (administered at 1mg/kg/day). After a 21-day period, blood sampling are performed one day after cancerous xenograft and at 5 the end of the experiment. In this experiment estrone sulfate and A4 androstenedione are the precursors of estradiol. The effect of estradiol is reflected on the uterus weight after sacrifice. Plasma hormone levels are assayed at the end of the experiments according to the supplier's standard method (DSL,Webster,TX,USA). 10

Claims (35)

1. An imidazole derivative of formula (I): R1 R 2 N RN Q Z R 4 or an acid addition salt or stereoisomeric form thereof, wherein: e R, and R 2 are each independently hydrogen or a (Ci-C 6 )alkyl; e Q is selected from C(O), SO 2 , CONH, C(O)(CH 2 )n, (CH 2 )n(O) or (CH 2 )n in which n is 0, I or 2; " Z is a group selected from: P'8 ~ R 8 ,'R (Rp (R,--- R)P * pisi; e qis0,lor2; e the dotted line means that R 8 and/or R 9 can be on any position of the benzothiophene ring; e one of R 3 and R 8 is cyano; and * the other is hydrogen or a hydroxy, halogen, nitro, cyano, (C 1 -C 6 )alkoxy, NRioR 1 , OS0 2 NRIOR 1 , NR 12 SO 2 NRioR 1 , OSO 2 NRioSO 2 NRI R 12 group; * R 4 is hydrogen; * R 9 is hydrogen, hydroxy, cyano, halogen, nitro, (Ci-C 6 )alkyl, (Ci-CW)alkoxy, trifluoromethyl, acyl, NRIOR 1 , OS0 2 NRIOR 1 , NR2SO2NRIOR 1, C0 2 Rio group; * Rio, R 1 and R 12 are each independently hydrogen or a (CI-C 6 )alkyl; " when Q-Z is 65 (CH2)n R 8 (R 9 ), in which n is 0, 1 or 2, then the other R 3 and R 8 is a hydroxyl, nitro, NRioR 1 , OSO 2 NRioR 1 or NR 1 2 SO 2 NRioRI, group; when Z is R 8 O i (Rg)P then R 8 and R 9 can also form together with the phenyl ring a benzoxathiazine dioxide, a dihydrobenzoxathiazine dioxide or a benzoxathiazole dioxide.

2. The derivative according to claim 1, or an acid addition salt or stereoisomeric form thereof, wherein the otherR 3 and R 8 is hydrogen or a hydroxy, halogen, nitro, (CI-C 6 ) alkoxy, NRIOR 1 , OS0 2 NRIOR 1 , NR 12 SO 2 NRioR 1 group.

3. The derivative according to claim 1, or an acid addition salt or stereoisomeric form thereof, wherein R 9 is hydrogen or a hydroxy, cyano, halogen, nitro, (Ci-C 6 )alkyl, (C, C 6 )alkoxy, trifluoromethyl, NRIOR 1 , OSO 2 NRioR,,, C0 2 Rio, CHO, NR 12 SO 2 NR 0 R, I group.

4. The derivative according to claim 3, or an acid addition salt or stereoisomeric form thereof, wherein R 9 is hydroxy, cyano, halogen, nitro, (Ci-C 6 )alkyl, (CI-C 6 )alkoxy, trifluoromethyl, NRioR 1 , OSO 2 NRioR 1 , C0 2 Rio, CHO or NR1 2 SO 2 NRioR 1 .

5. The derivative according to claim 1, or an acid addition salt or stereoisomeric form thereof, in which: * Rgis hydrogen, hydroxy, halogen, nitro, cyano, (Ci-C 6 )alkoxy, NRIORII, OS0 2 NRioR 1 , NR1 2 SO 2 NRioRI, or OSO 2 NRioSO 2 NRlIR 12 group; " R 9 is hydrogen or a hydroxy, cyano, halogen, nitro, (Ci-CW)alkyl, (Ci-C 6 )alkoxy, trifluoromethyl, NRIORII, OSO 2 NRIORII, CO 2 Rjo, CHO, NR1 2 SO 2 NRioRI, group; e p and q are as defined in claim 1.

6. The derivative according to claim 1, or an acid addition salt or stereoisomeric form thereof, wherein: * Zis Re 66 in which R 8 , R 9 and p are as defined in claim I.

7. The derivative according to claim 6, or an acid addition salt or stereoisomeric form thereof, wherein: * Zis R 8 * Q is (CH 2 )n 1 in which n is 0, 1 or 2; e Rg is hydroxy, nitro, NRIOR 1, OS0 2 NRIOR 1 , or NR 12 SO 2 NRioR I group; * R 9 is hydrogen, hydroxy, cyano, halogen, nitro, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, trifluoromethyl, NRIOR 1 , OS0 2 NRioR 1 ; e p is as defined in claim 1.

8. The derivative according to claim 6 or 7, or an acid addition salt or stereoisomeric form thereof, wherein: e n is 0 or 1; e RI, R 2 and R 4 are each hydrogen; " R 9 is hydrogen, halogen, (Ci-C 6 )alkyl or OS0 2 NRIORII.

9. The derivative according to any one of claims 6 to 8, or an acid addition salt or stereoisomeric form thereof, wherein the other of R 3 and R 8 is hydroxy, nitro, NR 1 oR 1 , OSO 2 NRioR 1 or NR 2 SO 2 NRIOR .

10. The derivative according to claim 9, or an acid addition salt or stereoisomeric form thereof, wherein the other of R 3 and R 8 is hydroxy or OS0 2 NRioR 1 .

11. The derivative according to claim 1, or an acid addition salt or stereoisomeric form thereof, wherein: " Z is R 8' (Rg) - - P CCS (o)q in which: * R 8 , R9, p and q are as defined in claim 1; e the dotted line means that Q and/or R 8 and/or R 9 can be on any position of the benzothiophene ring. 67

12. The derivative according to claim 11, or an acid addition salt or stereoisomeric form thereof, wherein R 8 is OS0 2 NRioR I or NR 12 SO 2 NRIORII.

13. The derivative according to claim I 1 or 12, wherein R 9 is hydrogen, halogen, nitro, COORio or cyano.

14. The derivative according to any one of claims 1 to 13, wherein Q is SO 2 or CO.

15. The derivative according to claim 11, wherein R 3 is hydrogen, halogen or cyano.

16. The derivative according to claim 1, or an acid addition salt or stereoisomeric form thereof, wherein: * Z is a group: R8 (R,), N in which R 8 , R 9 and p are as defined in claim 1.

17. The derivative according to any one of claims 1 to 16, or an acid addition salt or stereoisomeric form thereof, wherein Rio and R, are hydrogen.

18. The derivative according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance. 68

19. A pharmaceutical composition comprising a derivative according to any one of claims 1 to 17, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19, comprising from 0.1 s to 400 mg of said derivative.

21. Use of a derivative according to any one of claims I to 17 or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for the treatment or prevention of hormone- or non hormone-dependent tumors, wherein said derivative is optionally combined with a sexual endocrine 10 therapeutic agent.

22. Use of a derivative according to any one of claims I to 17 or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for the control or management of reproductive functions, wherein said derivative is optionally combined with a LH-RH agonist or antagonist, an is estroprogestative contraceptive, a progestin, an anti-progestin or a prostaglandin.

23. Use of a derivative according to any one of claims 1 to 17 or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for the treatment or prevention of benign or malignant diseases of the breast, the uterus or the ovary, wherein said derivative is optionally combined with an 20 antiandrogen, an anti-estrogen, a progestin or a LH-RH agonist or antagonist.

24. Use of a derivative according to any one of claims I to 17 or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for the treatment or prevention of androgen-dependent diseases or benign or malignant diseases of the prostate or the testis, wherein said derivative is optionally 25 combined with an antiandrogen, a progestin, a lyase inhibitor or a LH-RH agonist or antagonist.

25. Use of a derivative according to any one of claims I to 17 or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for the treatment or prevention of cognitive function disorders, especially 30 senile dementia, in particular Alzheimer's disease.

26. Use of a derivative according to any one of claims 1 to 17 or a pharmaceutically acceptable acid addition salt thereof in the manufacture of a medicament for the treatment or prevention of immunodisorders.

27. Use of a derivative according to any one of claims I to 17 or a 35 pharmaceutically acceptable acid addition salt thereof in the manufacture of a 69 medicament for the treatment or prevention of pathologies in which inhibition of aromatase and/or steroid sulfatase and/or carbonic anhydrase is required.

28. A method of treating a disease in which aromatase and/or steroid sulfatase and/or carbonic anhydrase is involved, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 17.

29. The imidazole derivative according to any one of claims I to 10 and 17, which is selected from the following compounds: 4-[N-(] H-imidazol- 1 -yl)-N-(4-methoxyphenyl)amino]methylbenzonitrile; 4-[N-(4-hydroxyphenyl)-N-(1 H-imidazol- 1 -yl)amino]methylbenzonitrile; 4-[N-(4-hydroxyphenylmethyl)-N-(I H-imidazol- I -yl)amino]benzonitrile; 4-[N-(3-chloro-4-hydroxyphenylmethyl)-N-(I H-imidazol-] -yl)amino]benzonitrile; 4-[N-(3-bromo-4-hydroxyphenylmethyl)-N-(I H-imidazol- I -yl)amino]benzonitrile; 4-[N-(4-hydroxy-3-methoxyphenylmethyl)-N-(1H-imidazol-l-yl)amino] benzonitrile; 4-[N-(3-formyl-4-hydroxyphenylmethyl)-N-(1 H-imidazol-1 -yl)amino]benzonitrile; 4-[N-(4-hydroxy-3-nitrophenylmethyl)-N-(I H-imidazol-1 -yl)amino]benzonitrile; 4-[N-(1 H-imidazol- I -yl)-N-(4-nitrophenyl)amino]benzonitrile; N-(I H-imidazol- 1 -yl)-N-(4-cyanophenyl)-2-(4-fluorophenyl)acetamide; N-(l H-imidazol- 1 -yl)-N-(4-cyanophenyl)-2-(4-hydroxyphenyl)acetamide; N-(4-cyanophenyl)-3-(4-hydroxyphenyl)-N-(1 H-imidazol- 1 -yl)propanamide; N-(4-cyanophenyl)-N-(1 H-imidazol- I -yl)-4-(phenylmethoxy)-benzensulfonamide; 4-[N-(3-amino-4-hydroxy-phenylmethyl)-N-(I H-imidazol-1 -yl)amino] benzonitrile; 4-{N-[2-(4-hydroxyphenoxy)ethyl]-N-(1 H-imidazol- 1 -yl)amino}benzonitrile; N-(4-cyanophenyl)-N-(1 H-imidazol- 1 -yl)-4-hydroxybenzensulfonamide; 4-[N-(4-aminophenyl)-N-(1 H-imidazol- 1 -yl)amino]benzonitrile; Sulfamic acid 4-[N-(4-cyanophenylmethyl)-N-(1H-imidazol- I yl)amino]phenyl ester; Sulfamic acid-4- { [N-(4-cyanophenyl)-N-(I H-imidazol-1 yl)amino]methyl}phenyl ester; Sulfamic acid 2-chloro-4-{ [N-(4-cyanophenyl)-N-(l H-imidazol- I yl)amino]methyl}phenyl ester; Sulfamic acid 2-bromo-4-{[N-(4-cyanophenyl)-N-(1H-imidazol-lyl)amino] methyl}phenyl ester , hydrochloride; Sulfamic acid 2-methoxy-4-{ [N-(4-cyanophenyl)-N-(l H-imidazol- 1 yl)amino] methyl}phenyl ester; Sulfamic acid 2,3,5,6-tetrafluoro-4-{[N-(4-cyanophenyl)-N-(1H-imidazol-lyl)amino] methyl}phenyl ester; 70 4-[N-[(2,2-dioxido- l,2,3-benzoxathiazin-6-yl)methyl]-N-(1 H-imidazol- 1 -yl)amino] benzonitrile; N-{4-[N-(4-cyanophenyl)-N-(] H-imidazol-I -yl)amino]phenyl}sulfamide; Sulfamic acid 4-{[N-(4-cyanophenyl)-N-(1 H-imidazol-1yl)amino]sulfonyl}phenyl ester, hydrochloride; Sulfamic acid 4-{2-[N-(4-cyanophenyl)-N-(1 H-imidazol- I yl)amino]ethoxy} phenyl ester; Sulfamic acid 4-{[N-(4-cyanophenyl)-N-(1H-imidazol-1yl)-carbamoyl]-methyl} phenyl ester; Sulfamic acid 4-{ [N-(4-cyanophenyl)-N-(1 H-imidazol-l yl)amino]-3-oxopropyl} phenyl ester; Sulfamic acid 3-(aminosulfonyl)amino-4-{ [N-(4-cyanophenyl)-N-(I H-imidazol Iyl)amino]methyl}phenyl ester; 4-[N-[(2,2-dioxido-3,4-dihydro-1,2,3-benzoxathiazin-6-yl)methyl]-N-(1H-imidazol-1 yl)amino]benzonitrile; 5-{ [N-(4-cyanophenyl)-N-(l H-imidazol- 1 -yl)amino]methyl} -2-hydroxybenzoic acid; 4-[N-(3-tosylamino-4-hydroxy-benzyl)-N-(I H-imidazol- 1 -yl)amino]benzonitrile; 4-[N-[(2,2-dioxido-3-tosyl-3 H-1,2,3-benzoxathiazol-5-yl)methyl]-N-(1 H-imidazol- 1 yl)aminolbenzonitrile; 4-[N-[(2,2-dioxido-3H- 1,2,3-benzoxathiazol-5-yl)methyl]-N-(1 H-imidazol- I yl)aminolbenzonitrile; N-(4-cyanopheny)-N-(1 H-imidazol- I -yl)-N'-phenylurea.

30. The imidazole derivative according to claim 29, which is selected from the following compounds: Sulfamic acid 4-[N-(4-cyanophenylmethyl)-N-(I H-imidazol-lyl)amino]phenyl ester; Sulfamic acid-4-{ [N-(4-cyanophenyl)-N-(I H-imidazol-1yl)amino]methyl}phenyl ester; Sulfamic acid 2-chloro-4-{[N-(4-cyanophenyl)-N-(1 H-imidazol-1 yl)amino]methyl}phenyl ester; Sulfamic acid 2-bromo-4-{ [N-(4-cyanophenyl)-N-(I H-imidazol- 1 yl)amino] methyl}phenyl ester, hydrochloride; Sulfamic acid 2-methoxy-4-{[N-(4-cyanophenyl)-N-(1 H-imidazol-1 yl)amino] methyl}phenyl ester; Sulfamic acid 2,3,5,6-tetrafluoro-4- {[N-(4-cyanophenyl)-N-(l H-imidazol- 1 yl)amino] methyl}phenyl ester; 4-[N-[(2,2-dioxido-l,2,3-benzoxathiazin-6-yl)methyl]-N-(1 H-imidazol-1-yl)amino] benzonitrile; 71 Sulfamic acid 4-{[N-(4-cyanophenyl)-N-(1 H-imidazol-1yl)amino]sulfonyl}phenyl ester, hydrochloride; Sulfamic acid 4- { 2-[N-(4-cyanophenyl)-N-(1 H-imidazol- 1 yl)amino]ethoxy} phenyl ester; Sulfamic acid 4- {[N-(4-cyanophenyl)-N-(1 H-imidazol- I yl)-carbamoyl]-methyl} phenyl ester; Sulfamic acid 4- {[N-(4-cyanophenyl)-N-(1 H-imidazol- 1 yl)amino]-3-oxopropyl} phenyl ester; Sulfamic acid 3-(aminosulfonyl)amino-4-{ [N-(4-cyanophenyl)-N-(1 H-imidazol I yl)amino]methyl}phenyl ester.

31. The imidazole derivative according to claim 30, which is sulfamic acid 2-bromo 4- {[N-(4-cyanophenyl)-N-(1 H-imidazol- I yl)amino] methyl} phenyl ester, hydrochloride.

32. The imidazole derivative according to any one of claims I to 5, 11 to 15 and 17, which is selected from the following compounds: 5-Nitro-[N-(4-cyanophenyl)-N-(1 H-imidazol- 1 -yl)]-benzothiophene-2-carboxamide; N-(4-cyanophenyl)-N-(l H-imidazol- I -yl)-2-(6-methoxy-benzothien-3-yl) acetamide; 4-{N-[1H-imidazol-1-yl]-N-[(6-methoxy-benzothien-3-yl)methyl]amino} benzonitrile; 4-[N-(6-benzyloxy- 1,1 -dioxido-benzothien-3-yl)-N-(l H-imidazol- 1 -yl)amino] benzonitrile; 4-[N-[(6-benzyloxy-benzothien-2-yl)methyl]-N-(1 H-imidazol- 1 -yl)amino] benzonitrile; 4- {N-[(6-hydroxy-benzothien-3 -yl)methyl]-N- [1 H-imidazol- 1 -yl-]amino} benzonitrile; N-(4-cyanophenyl)-N-(] H-imidazol- 1 -yI)-2-(6-hydroxy-benzothien-3 -yl) acetamide; 4-[N-[(6-hydroxy- 1, 1 -dioxido-benzothien-3-yl)]-N-(1 H-imidazol- 1 -yl)amino] benzonitrile; 4-[N-[(6-hydroxy-benzothien-2-yl)methyl]-N-( IH-imidazol-1-yl)amino] benzonitrile; 5-Amino-[N-(4-cyanophenyl)-N-(l H-imidazol- I -yl)]-benzothiophene-2-carboxamide; 5-(Aminosulfonyl)amino-[N-(4-cyanophenyl)-N-(1 H-imidazol- I -yl)]-benzothiophene-2 carboxamide; Sulfamic acid 3-[N-(4-cyanophenyl)-N-(1H-imidazol-1yl)amino]-1,1-dioxido-benzothien 6-yl ester; Sulfamic acid 3-{2-[N-(4-cyanophenyl)-N-( IH-imidazol-1yl)amino]-2-oxoethyl} benzothien-6-yl ester; Sulfamic acid 3-{[N-(4-cyanophenyl)-N-( IH-imidazol-l yl)amino]methyl}-benzothien-6 yl ester; Sulfamic acid 2- { [N-(4-cyanophenyl)-N-(1 H-imidazol- 1 yl)amino]methyl} -benzothien-6 yl ester. 72

33. The imidazole derivative according to claim 32, which is selected among the following compounds: Sulfamic acid 3-[N-(4-cyanophenyl)-N-(1 H-imidazol- 1 yl)amino]- 1, 1 -dioxido-benzothien 6-yl ester; Sulfamic acid 3-{2-[N-(4-cyanophenyl)-N-(1 H-imidazol-1yl)amino]-2-oxoethyl} benzothien-6-yl ester; Sulfamic acid 3-{ [N-(4-cyanophenyl)-N-(I H-imidazol-1yl)amino]methyl}-benzothien-6 yl ester; Sulfamic acid 2- { [N-(4-cyanophcnyl)-N-(1 H-imidazol- 1 yl)amino]methyl}-benzothien-6 yl ester;

34. The imidazole derivative according to any one of claims I to 5, 16 and 17, which is selected from the following compounds: 4-{N-[(6-chloropyridin-3-yl)methyl]-N-(1 H-imidazol-1-yl)amino}benzonitrile; 6-chloro-N-(4-cyanophenyl)-N-(1 H-imidazol- 1 -yl)nicotinamide.

35. An imidazole derivative selected from the following compounds: 4-[N-(2,3,5,6-tetrafluoro-4-hydroxyphenylmethyl)-N-(1 H-imidazol- I -yl)amino] benzonitrile; 4- {[N-(4-cyanophenyl)-N-(1 H-imidazol- I -yl)amino]methyl} benzene sulfonamide; 5- { [N-(4-cyanophenyl)-N-(l H-imidazol- I -yl)amino]methyl} -2-methoxybenzoic acid; 4-[N-(1 H-imidazol- I -yl)-N-(phenyl)amino]benzonitrile. Dated 10 January 2013 Laboratoire Theramex Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON