Title of Invention

"SUBSTITUTED 1-N-PHENYL-AMINO-1H-IMIDAZOLE COMPOUND AND PHARMACEUTICAL COMPOSITION THEREOF"

Abstract The present invention relates to a substituted 1-N-Phenyl-Amino-H-Imidazole Compound of formula (I); in which R1, R2, R3, R4, Q and Z are as defined in the specification. The invention also relates to the pharmaceutical compositions containing these compounds.
Full Text Comlpomtions Containing then.
The present invention relates to l-N-phenytemino-lH-imidazote derivatives and
to pharmaceutical compositions containing them.
The invention generally relates to the field of hormone- and non hormonedependent
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,
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 nonreproductive
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
The enzyme steroid sulfatase (E.G. 3.1.6.2., STS) catalyses the hydrolysis of
estrone sulfate to estrone and the DHEA sulfate to DHEA (Dibbdt L, Biol. Chem,
Hoppe-Seer, 1991, 372, 173-185 and Stein C, 1 Biol. Chem., 1989, 264,13865-
13872).
The steroid sulfatase pathway has been the focus of recent interest in the
context of breast cancer, with regard to the local intra-tissue formation of
estrogens from the abundant circulating pool of estrone sulfate (EtS) (Pasqualini
JR, 1 Steroid Btochem. Md. Biol., 1999, 69, 287-292 and Purohit A, Mol. Cell.
Endocrinol., 2001,171,129-135).
Inhibition of this enzyme would prevent EiS from yielding free estrone (Ei),
which can be transformed into estradiol (E2) 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,
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
used to prevent estrogen synthesis. However, dinical trials showed a relative lack
of efficacy for patients with estrogen receptor-positive tumors (Castiglbne-
Gertsch M, Eur. J. Cancer, 19%, 32A, 393-395 and Jonat W, Eur. J. Cancer,
19%, 32A, 404-412). As an explanation, steroid sulfatase pathway could be
another important route for estrogen formation in breast tumors. '
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 Et, not from
E,S but from EMATE itself (Ahmed S, X Steroid Btocnem. Mot. Bid., 2002, 80,
429-440).
(Figure Removed)

Estradiol EMATE
Other non-steroid sulfamate compounds which release derivatives without
estrogenic properties have been presented as acceptable drug candidates such
as 6,6,7-COUMATE, a standard non-estrogenic sulfatase inhibitor from the
literature (Purohit A, Cancer Res, 2000, 60, 3394-33%).
6,6,7 COUMATE
Human carbonic anhydrases catalyse the conversion between carbon dioxide
(C02) and the bicarbonate ion (HCO3), and are involved in physiological and
pathological processes. They include hormone-dependent and non-hormonedependent
cancerogenesis, metastasis invasive process and hypoxic tumors that
express these enzymes which are less responsive to classical chemo/radbtherapy
inhibitors. In particular, EMATE was found to have a human carbonic
anhydrase inhibitory potency similar to that of acetazolamide, a well-Jcnown
sulfonamide human carbonic anhydrase inhibitor (Wfnum J and at., J. Med.
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
sutfatase inhibition and carbonic anhydrase inhibition.
Recently, B. Potter et al. (J. Med. Chem., 46, 2003, 3193-31%) reported that
sulfamoylated-derivatives of the aromatase inhibitor YM 511 inhibited sulfatase
and aromatase activity in JEG-3 cells.
(Figure Removed)
Compounds presented as useful for the treatment of estrogen-dependent
diseases, are described in US 2003/0008862A. Imidazole derivatives with antiaromatase
properties are described in WO 2004/054983.
It has now been found that imkJazote derivatives which contain a 1-Nphenylamino
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-phenylamiho-lHimidazote
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 l-N-arylamirto-lH-imidazole derivative as
depicted below.
A further object of this invention is to provide the use of 1-N-phenylamino-lHimidazole
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 l-N-phenytemino-lH-imidazote derivatives of this invention are represented
by the following general formula (I):
(Figure Removed)

and acid addition salts and stereoisomeric forms thereof, wherein :
• R] and R2 are each independently hydrogen, a (or a
()cydoalkyl ; or and R2 together form a saturated or unsaturated 5-,
6- or 7- membered carbocyclic ring;
is (CH2)m-X-(CH2)n-A;
• A is a direct link, 0, S, SO, SO2/ NR5;
• X is a direct link, CF2, O, S, SO, SO2, C(0), NR5 or
• Z is a group selected from:
and
• m and n are each independently 0,1, 2,3 or 4;
• p is 1, 2, 3 or 4;
• q is 0,1 or 2;
• the clotted line means that Re and/or Rcan be on any position of the
benzothtophene ring;
• R3 and Ra are each independently hydrogen or a hydroxy, cyano, halogen,
nitro, (C1-C6alkyl, (C1-C6alkoxy, trifluoromethyl, (C1-C6lkylthto,
C1-C6alkylsulfonyl, acyl, (C1-C6alkoxycarbonyl, carboxamido, OPO(OR10)2,
NRioR SO2NR10Ru, OSO2NR10R11, OS02OR10 S02OR10, SSO2NR10R11,
CF2SO2OR10, CF2SO2NR10R11 CF2-tetrazolyl or NR12SO2NR10R11
OS02NR12SO2NR10R11 CO2R10/ CONR10RU, OCHO, OCONRR
SCONR10R, SCSNRioRn, tBtrazdyl, NR12CONR10Ru, NR10-CHO group;
• when Q-Z is
n is 0, 1 or 2 and p is 1, one of R3 and RB is a hydroxy, ntoo, OPO(OR
NR10R, OS02NR10ROSO2jOR SOOR SSO2NR10R CFSOOR
CFSOzNRtoR, OVtetrazolyl, NR12S02NR10RU OSO2NR1oSO2NR1iR12/ GO2R
CONR10R, OCHO, OCONR1()R OCSNR10R10SCONR10R10 SCSNR10R
tetrazolyl, NR12OONR10Rn, NR10-CHO group and the other is hydrogen or a
hydroxy, cyano, hatogen, nitro, (C1-C6alkyl, C1-C6alkoxy, trifluoromethyl,
C1-C6lkytthto, C1-C6^lkylsulfbnyl, acyl, C1-C6)alkoxycarbonyl,
carboxamido, NRioRn, S02NRi0Rii, OSCfeNRioRn, OSCbORw, SO^Rw,
SSOzNRioRti, CF2SO2OR10,, CF2SO2NRj0Rn, CF2-tetrazolyl, NR12S02NRi0Rn,
OSO2NR12SO2NR10Ru, CX)2R10, CONR10Ru, OCHO, OCONR10Rn, OCSNRioRn,
SCONR10R, SCSNRi10Rn, tetrazolyl, NR12CONR10Rn, NR10-CHO group;
R and R are each independently hydrogen or a hydroxy, cyano, halogen,
nitro, OPO(ORio)2 ,(C1-C6alkyl, ((C1-C6alkoxy, trifluoromethyl,
(C1-C6alkyfthio, ((C1-C6)allcylsulfonyl, acyl, ((C1-C6lkoxycartxxiyl,
carboxamido, NR10RU, SOjNRioRn, OSO2NR10R11, OSO2OR10
CF2SO2OR11, CF2SO2NR10R11, CF2-tetrazolyl,
R, CHO, CONR10RU, OCHO, OCONRwRu,
. SCSNR10R11. tetrazolyl, NR12CONR10Rm NR10-CHO
group;
• when pis2, 3or4theR9Scanbethe same or different;
• R and R7 are independently hydrogen, halogen, a ((C1-C6)alkyl or a
(C1-C6)cydoallcyl;
• R5 RIO, RH and Ri2 are each independently hydrogen, hydroxy, a (C1-C6alkyl,
or ((C1-C6)cydoalkyl; R10 can also be a salt; RIO and Ru can also form,
together with the nitrogen atom to which they are bound, a 5- to 7-
membered heterocycte containing one or two heteroatoms selected from 0, S
andN;
• when Z is
and p is 1,
then Rand R 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
tetraoxkle or a benzodioxadithiine tetraoxide;
when Z is
R3 and Rtogether with the phenyl ring bearing them can also form a
benzofurane or a N-methylbenzotriazole, provided that when p is 1 and Q is
(CH2)n, then Rand R are independently a hydroxy, nitro, OPO(ORi0)2,
NR10Ru, OSONRjoRn, OSOOR, ,, SSOzNR^Rn, CF2SO2OR10,
, CF2-tetrazolyl, NRizSOzNRwRu, OSOzNRuSOzNRujRu, GOjRjo,
OCHO, OCONRIORn, OCSNRjoRu, SCONRloRu, SCSNR10RU,
tetrazotyl, NR12CONRioRii, or NR10-CHO group.
The present invention also concerns the addition salts of the invention
compounds or the stereoisomeric forms thereof, when they exist
In the description and dawns, the term "(C1-C6kyT is understood as meaning a
linear or branched hydrocarbon chain having 1 to 6 carbon atoms. A(C1-C6alkyl
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 "((C1-C6ydoalkyl" is understood as meaning a saturated monocydic
hydrocarbon having 3 to 8 carbon atoms. A ((C1-C6ycloalkyl radical is for
example a cydopropyl, cyclobutyl, cydopentyl, cyclohexyl, cydoheptyl or
cyclooctyl radical.
The term "(C1-C6koxy" js understood as meaning a group OR in which R is a
(d-QOalkyl as defined above. A (C1-C6)alkoxy radical is for example a methoxy,
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, n-pentyloxy or
isoperrtytoxy radical. Preferred alkoxy radicals are those having 1, 2 or 3 carbon
atoms.
The term "acyl" is understood as meaning a group R1—c in which R' is hydrogen or a
(Figure Removed)

(C1-C6alkyi wherein the term "alkyl" is as defined above. An acyl radical is for
example a formyl, an acetyl, a proptonyl, a butyryl or a vateryl 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 amirte such as triethylamine,
ethanolamine or tris-(2-hydroxyethyl)amine. In the context of the invention, this
applies to groups having an ORi0 moiety.
The 5- to 7-membered heterocyde can be saturated or unsaturated, and includes
for example tetrazote, triazote, pyrazote, pyrazolidine, imkJazoie, imidazolidine,
piperklne, piperazhne, morphoKne, pyrroHcHne.
Compounds of formula (I) form add 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 carboxyttc adds such as acetic acid,
proptonk: add, glycolic acid, pyruvic acid, oxalic acid, malic add, fumaric acid,
tartaric add, citric add, benzoic acid, dnnamic add, mandelic acid,
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:
• R3 and R8 are each independently hydrogen or a hydroxy, cyano, halogen,
nitro, (C1-C6alkyl, (C1-C6lkoxy, trifluoromethyl, (C1-C6alkylthio,
(C1-C6alkyteulfonyl, acyl, (C1-C6alkoxycarbonyl, carboxamido, NRioRn,
S02NR10RU/ OS02NRioRii, OSO2NRi2SO2NR10Rn, OCHO, NRi2S02NR10R11
group;
• R4 and Rg are each independently hydrogen or a hydroxy, cyano, halogen,
nitro, (C1-C6alkyl, (C1-C6alkoxy, trifluoromethyl, (C1-C6alkylthio,
(C1-C6alkylsuffonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido,
OSO2NRioRn, CO2R10, CHO, NR12SO2NRioRu group;
RI and R2 are each independently hydrogen or (C1-C6)alkyl;
RIO, RH and RIZ are each independently hydrogen or (C1-C6)alkyl.
Particularty preferred compounds of a formula (I) are those in which:
• one of R3 and Re is a hydroxy, nitro, NR10Rn, OSOjNRwRu or NR12SO2NRi0Ru
group; and
• the other is hydrogen or a hydroxy, cyano, halogen, nitro, (C1-C6)alkyl,
(C1-C6)alkoxy, trifluoromethyl, (C1-C6alkylthio, (C1-C6Jalkylsulfonyl, acyl,
(Ci-Q)alkoxycarbonyl, carboxamido, NR10Rn, OSO2NRj0Rii NRi2SO2NRi0Ru
group.
A particularly preferred group of these compounds are those in which:
• one of R3 and Re is hydroxy, cyano, C1-C6)altaD • the other is hydrogen or a hydroxy, halogen, nitro, cyano, (C1-C6)alkoxy,
NR10RU, SO2NR11 OSQNR10R NRuSQzNRoR, O S O N R O z N R g r Preferably, the compounds of formula (I) are those in which:
• one of R3 and RB is cyano; and
• the other is hydrogen or a hydroxy, halogen, nitro, (C1-C6) alkoxy,
trifluoromethyl, N R R , SO2NR10R11 OS02NRi0Rn, NRuSO2NRi0Ru group.
Further preferred compounds are those in which:
• one of R, and Rg is hydrogen or a hydroxy, cyano, OSO2NRi0Rn group; and
• the other is hydrogen or a hydroxy, cyano, halogen, nitro, C1-C6alkyl,
C1-C6alkoxy, trifluoromethyl, NRi0Rn, OS02NR10Rn, CO2R10, CHO,
NR12SO2NRi0Rii group.
An other group of preferred compounds are those in which:
• R4 is hydrogen, hydroxy, cyano, or
(Figure Removed)

R6 i s a hydrogen or a hydroxy, cyano, halogen, nitro, (C1-C6)alkyl,
(C1-C6alkoxy, trifluoromethyl, NRioRu/ OSOzNRioRn., CO2Rio, CHO group.
Especially preferred compounds of formula (I) are those where:
• ft, is hydrogen; and
• R is a hydroxyl, cyano, halogen, nitro, C1-C6allcyl, (C1-C6alkoxy,
trifluoromethyl, NRioRu, OSO2NRR COR, CHO or
group.
Particularly preferred compounds of formula (I) are those in which 2 is:
in which Re and Rg are as hereinabove defined.
In the above defined compounds, RB and RS are preferably as fbttows:
• Re is hydrogen, hydroxy, halogen, nitro, cyano, RR, OSCNRR, NRSONRR or OSO2NR10SO2NRuRi2 group;
• Rg hydrogen or a hydroxy, cyano, halogen, nitro, (C1-C6alkyl, C1-C6)alkoxy,
trifluoromethyl, NRioRu, OSO2NR10Ru., CC^Rio, CHO, NRi2SO2NR10R11 group.
• p and q are as defined above.
Among the compounds of formula (I), those in which Q is selected from a direct
link, C(0), SO2 CONH, C(O)(CH2)n, (CH2)n(0) or (CH2)n in which n is 0,1 or 2, are
also particularly preferred.
Particularly preferred are the compounds of formula (II)
(ID
in which:
• Q is (CH2)n in which n is 0,1 or 2;
• one of R3 and Re is a hydroxy, nitro, NR10RU, OSC^NRioRn or
NRi2SO2NRioRn group and the other is hydrogen or a hydroxy, cyano,
halogen, nitro, (Q-Q^lkyl, (Ci-Q)alkoxy, trifluoromethyl, (Q-Q^lkytthio,
acyl, (Q-QOalkoxycarbonyl, carboxamido, NRtoRu,
or NR,2SO2NR10Rii group;
• R and Ra are each independently hydrogen, hydroxy, cyano, halogen,
nitro, (C1-C6)alkyl/ (C1-C6alkoxy, trifluoromethyl, (C1-C6)alkylthio,
(C1-C6alkyteulfonyl, acyl, (C1-C6koxycarbonyl, carboxamido, NRi0Rn,
OSO2NRioR11 or NRuSQzNRn&i group .
• RIO and RH are each independently hydrogen, a (C1-C6alkyl- or a
(C1-C6)cydoalkyl;
• p is 1, 2, 3 or 4;
• R8 and R9together with the phenyl ring bearing them can also form a
benzoxathiazine dioxide or a dihydrobenzoxathiazine dioxide;
• R3 and R4 together with the phenyl ring bearing them can also form a
benzofurane or a N-methylbenzotriazole.
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;
• R8 is hydroxy, halogen, nitro, cyano or a (C1-C6 .// alkoxy, NRioRu, S 0 2NRR,
OSO2NRi0R11or NR12SO2NR10RU group;
• R8is hydrogen, hydroxy, cyano, halogen, nitro, (C1-C6alkyl/ (C1-C6)a»koxy,
trifluoromethyl, NR10R11 OSO2NR10R11
• is 1, 2, 3 or 4.
Most preferred compounds of formula (II) are those in which:
• n is 0 or 1;
• RI and R2 are each independently hydrogen or (C1-C6)alkyl;
• R4 and R, are each independently hydrogen, halogen, (C1-C6alkoxy, acyl,
, OSOzNRjoRn or
Especially preferred compounds of formula (II) are those in which:
is 0 or 1;
• RI, R2 and R, are each hydrogen;
• R« is hydrogen, halogen, (C1-C6)alkoxy or OSO2NRuRu.
Particularly preferred compounds of formula (n) are those in which:
• n and p are 1;
• Re is a hydroxy, halogen, nitre, cyano, (C1-C6alkoxy, NR10RU,
OSOzNRjoRii, NRizSCbNRioRu, or OSOzNRwSOjNRuRu group;
• Rg is a hydroxy, cyano, halogen, nitro, (C1-C6alkyl, (C1-C6)alkoxy,
trifluoromethyl, NRioR11 OSOzNRioRn, CO2R10or CHO group;
• R3 is cyano, hydroxy, OSO2NR10R11 or NRi12O2NR10Ri10
• R is hydrogen, hydroxy, halogen, cyano or OSO2NRi10R11
Among these compounds, those which fulfil at least one of the following
conditions are also preferred:
• one of R3 and RB is hydroxy, cyano or OSO2NRi0Rn, preferably cyano or
OS02NRioR11; and
• the other is hydroxy, nitro, NR10Ru, OSO2NR10R11 or NR12SO2NR10RU,
preferably hydroxy or O S O 2 N R 1 0 R 1 1 A m o n g these compounds of formula (II), those wherein are mostly preferred.
Particularly preferred are also the compounds of formula (III):
(Figure Removed)

in which:
• Qis(CH2)m-X-(CH2)n-A-;
• A is a direct bond or 0, S, SO, SOz, NR5;
• Xisadirectbond,CF2,O,S,SO,S02,C(O),NR5orCR6R7;
• m and n are each independently 0,1, 2,3 or 4;
• R, k,, R and R» are each independently hydrogen or a hydroxy, cyano,
halogen, nftro, (C1-C6)alkyl, C1-C6)alkoxy, benzytoxy, trifluoromethyl,
(C1-C6)alkylthio, (C1-C6lkyteuffony), acyi, C1-C6)alkoxycarbonyl, NR10Rll7
OPO(ORjo)2, OCHO, COOR, SOzNRwR11OS^NR11R11, SCbORio, OSO2OR10,
SSOzNRigRii, CONR10Rn, OCONR10R11 OCSNR10RU, SCONR10RU,
SCSNR10R11, NR12S02NR11R11, tetrazolyl, NR10CONR11OH, NRi0SO2NR11H,
NOH-CHO, NOHS02NR110R11, or OSO2NR10OH group;
• pis 0,1 or 2.
• R5 R6, R7, RIO, RH and RJ2 are each independently hydrogen, a (C1-C6alkyl
or a (C1-C6cydoalkyl; R10 can also be a salt; R10 and R11 can also form,
together with the nitrogen atom to which they are bound, a 5- to 7-
membered heterocyde containing one or two heteroatoms selected from 0,
S and N;
• The dotted line means that Q and/or R8and/or R9 can be on any position of
the benzothiophene ring.
Among the compounds of formula (III) those which fulfil at least one of the
following condition are also preferred:
(Figure Removed)

• R3 is hydrogen, halogen or cyano;
R is OSONR or
• R is hydrogen, halogen, nitro, COO)Rio or cyano;
• R4 is hydrogen, halogen, cyano, (C1-C6alkoxy, NRi0Rn/ OSO2NRioRu or
• R10R11 and R11are each independently hydrogen or (C1-C6alkyl.
The compounds of formula (HI), wherein Q is (CH2)m-X- (CH2)n-A where m is 0, 1
or 2 and X is a direct bond, SCb or CO, n is 0 and A is a direct bond are also
preferred.
Particularly preferred are the compounds of formula (IV):
(Figure Removed)
in which R11 RZ, R3, R4, Re, R8 and p are as defined for compounds of formula (I).
Particularly preferred compounds of formula (IV) are those in which:
• R3 is cyano or OSO2NR10Rn;
• R4 is hydrogen, hydroxyl, halogen, cyano, OSO2NRi0Rn;
• R is hydroxy, cyano, OS02NRi0Rn, N R R , NRi2SO2NR10Rn, OCHO,
tetrazolyl;
• R is hydrogen, halogen, nitro, cyano or C02R; and
• Q is as defined above for compounds of formula (I).
By virtue of their capability to inhibit the enzymes aromatase and/or steroid
sulfatase and/or carbonic anhydrase, the compounds of the present invention
can be used alone or in combination with other active ingredients for the
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 suifatase, the compounds of the invention
are suitable for the management of estrogen-regulated reproductive functions, in
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 cgrbontc
anhydrase inhibitor, an antiandrogen, a steroid suifatase inhibitor, a lyase
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
chemiotnerapeutic agent such as a nitrogenated mustard analogue like
cydophosphamide, melphalan, iphosphamide, or trophosphamide; an
ethytenimine like thbtepa; a nitrosourea like carmustine; a lysed agent like
temozolomide or dacarbazine; an antimetabofte of foKc add ike methotrexate or
rattjtrexed; a purine analogue Ike thioguanine, dadribine or fludarabine; a
pyrirrodine analogue Ike fluorouracil, tegafur or gemdtabine; an alkaloid of vinca
or analogue fike vinbiastine, vincristme or vinoreJbine; a podophyHotoxin
derivative Ike etoposide, taxanes, docetaxel or paditaxel; an anthracydine or
analogue like doxorubidn, epirubidn, idarubidn or mitoxantrone; a cytotoxic
antibiotic like bteomycin or mitomycin; a platinum compound like dsplatin,
carboplatin or oxaliplatin; 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).
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
spedes, alone or in combination with one or several other therapeutic agents
such as a LH-RH agonist or antagonist, an estroprogestative contraceptive, a
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 suifatase and/or carbonic
anhydrase can be used in the treatment or prevention of benign breast diseases
in women, gynecomastia hi 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
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
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, acne (Billfch 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
or several other sexual endocrine therapeutic agents such as an antiandrogen, an
arrtiestrogen, a SERM, an antiaromatase, 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
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 acetyteholine, 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,
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 Th2 predominant immune functions and may therefore be useful in the
treatment or prevention of gender-dependent auto-immune diseases such as
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).
Studies using 2-MeOEMATE have shown that steroid sulfatase inhibitors have
potent estradid-independent growth-inhibitory effiect (MacCartny-Moorogh L,
Cancer Research, 2000, 60, 5441-5450). A decrease in tumor volume was
surprisingly observed with the compounds of the invention, with tow tumor
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 entities 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
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 (Gotob T, Btoorg. Med. Chem., 2002,
10, 3941-3953).
In addition, the compounds of the present invention are inhibitors of caYbonic
anhydrase (CA). This property could explain the interest of such compounds in
non-hormone-dependent cancer. Immunohistochemical studies of CA II have
shown that it is expressed in malignant brain tumors (Parkkila A-K. et al.,
Histochern. 1, 1995, 27: 974-982) and gastric and pancreatic carcinomas
(Parkkila S et al., Histochem. 1, 1995, 27: 133-138), and recent evidence has
shown that CA IX and Xn 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
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
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.
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
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
non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. 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, intrastemal injection or
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
oily suspensions, dispersibte 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
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 excipients may be for
example, inert diluents, such as calcium carbonate, sodium carbonate, lactose,
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
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.
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 ingredient(s) is (are) mixed with an inert solid diluent, for example,
•r
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 dive oil.
Aqueous suspensions contain the active ingredient(s) in admixture with
excipients suitable for the manufacture of aqueous suspensions. Such excipients
are suspending agents, for example sodium carboxymethylceUulose,
methytcethrfose, hydroxypropylrnetnyteellulose, sodium alginate,
polyvinylpyrroKdone, gum tragacanth and gum acacia; dispersing or wetting
agents may be a naturally-occurring phosphabde, for example lecithin, or
condensation products of an alkytene oxide with fatty acids, for example
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 hexftol such as polyoxyethytene sorbitol monooleate, or condensation
products of ethylene oxide with partial esters derived from fatty acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate. The aqueous
suspensions may also contain one or more preservatives, for example ethyl, or npropyl,
p-hydroxybenzoate, one or more colouring agents, one or more
flavouring agents, and one or more sweetening agents, such as sucrose,
saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient(s) 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
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
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 excipients, for example
sweetening, flavouring and colouring agents, may also be present. The
pharmaceutical compositions of the invention may also be in the form of an oilin-
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
and hexitol anhydrides, for example sorbrtan monooleate, and condensation
products of the said partial esters with ethytene oxide, for example
potyoxyethytene sorbitan monooleate. The emulsions may also contain
sweetening and flavouring agents.
The pharmaceutical compositions may be in the form of a sterile injectabte
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-
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 including
synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find
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.
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,
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
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
method comprises administering to a subject (human or animal) in need thereof
a therapeuticaHy effective amount of a compound of the invention or a
pharmaceutically acceptable acid addition salt thereof.
The 1-N-aryl-aminolH-irnidazole derivatives of formula (I) and their acid
addition salts can be prepared following general schemes I a, I b, Ila, lib, m, IV
and V in which ()m represents (CH2)m and ()„ represents (CH2)n.
Scheme la
(Figure Removed)

According to scheme I a, N,N-disubstituted aniline (3) can be obtained by
condensation of the aniline derivative (1) with halogeno derivatives, alcoyl
derivatives, sulfonyl derivatives or sulfinyl derivatives (2) using standard
conditions (March 1, Advanced Organic Chemistry, Fourth edition, Wiley
Interscience, New-York). Most of the halogeno derivatives, alcoyl derivatives,
sulfonyl derivatives or sulfinyl derivatives (2) are commercially available or are
synthesized by usual chemistry methods (see experimental part).
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 Nalkylation
of a hydrazine of formula (5) with a compound of formula (2) using the
conditions described by U. Lerch and J. Konig (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 dialkytoxy-alkyl-isothiocyanate derivative or an
ethylenedioxy-alkyl-isocyanate derivative, affords the thtosemicarbazide (6)
which is transformed to the l-amino-imidazole-2-thione (7) by treatment with an
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-lH-imidazole (8), which is optionally converted to one of
its acid addition salts.
Alternatively said compounds (8) where R3 or R4is an electron-withdrawing
group can be obtained by condensation of the N-imidazoloaniline (9) with
halogeno derivatives, alcoyl derivatives, sulfonyl derivatives or sutfinyl derivatives
(2) using standard conditions (March J., Advanced Organic Chemistry, Fourth
edition, WileyInterscience, New-York).
If R8 is ester, saponification of compound (8) gives carboxylic derivative by usual
chemistry methods.
If R8 is sulfamide, it can be directly obtained with correct substituted alcoyl
derivative or halogeno derivative (2).
if R8is cyano group, reaction with sodium azide gives tetrazolyl group (Kiypto K.,
Synthesis, 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).
According to scheme Ib deprotection of methoxy or benzyloxy derivatives (8)
(Figure Removed)

with tribromoborane (McOmie. J.F.W, Tetrahedron, 1968, 24, 2289-92) or
piperidine (Nishtoka 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
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
sulfamoyl chloride in dimethylacetamide (DMAc) (Makoto 0, Tetrahedron tetters,
2000, 41, 7047-51).
These hydroxyl compounds can be transformed into formate derivatives by
treatment with formyl acetate (Schreiner E.,B/oorg Med Chem Lett, 2004, 14,
4999-5002) or into IH-imidazole-l-carboxylate derivatives by treatment with
N,N-arbonykJiimidazote (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
conditions proposed by K. K. Andersen (J Org 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 Intersdence, New-York). These reduction steps can be
effective at any steps of synthesis process.
(Figure Removed)

According to scheme Ha, compounds (15) can be obtained by the same
procedure as compound (3) in scheme la starting from compounds (1) and (14)
or by condensation of the N-imidazotoaniline (9) with halogeno derivatives, alcoyl
derivatives, sulfonyl derivatives or sulfinyl derivatives (14) using standard
conditions (March X, Advanced Organic Chemistry, Fourth edition, Wiley
Intersdence, 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 Ro is ester, saponification of compound (15) gives carboxylic derivative by
usual chemistry methods.
If Re is sulfamide, it can be directly obtained with correct substituted alcoyl
derivative or halogeno derivative (14).
if R« is cyano group, reaction with sodium azkJe gives tetrazolyt group (Kiyoto K.,
Synthesis, 1998,910-14).
Deprotection of methoxy or benzytaxy benzothtophene (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 benzothtophene (16).
Reduction of nitro benzothiophene compound (15) by starwous chloride gives
aminobenzothiophene (18) (Matassa V., J Med Chem, 1990,33, 2621-29).
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
acid, following the conditions described by Grivas S. and Ronne E. (Acta Chemica
Scandinavia, 1995, 49, 225-229) or by rneta-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, thtoamide, ketone, thioketone when X is CO or CS or
reduction of oxidised sulphur function is performed following the conditions
described by Eltefson C. (J Med Chem, 1981, 24, 1107-10), Hajos I (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
standard conditions (March J., Advanced Organic Chemistry, Fourth edition,
Wiley Interstience, New-York). These oxidation and reduction steps can be
effective at arty steps of synthesis process.
(Figure Removed)

According to scheme lib, compounds (21) are synthesized following the same
synthetic methods as for compounds (3) starting from compounds (1) and (20)
or (9) and (20).
3-Halogeno benzothiophene derivative (21) treated by aqueous metal hydroxide
(Svoboda X, Collect Czech Chem comm, 2000, 65, 7, 1082-92 or Sail D., 3 Med
Chem, 2000, 43, 4, 649-63) gives 3-hydroxy benzothiophene derivative (22) or
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 benzothiophene derivative (22) or 2-amino benzothiophene derivative
(24) are performed respectively by deprotection of 2-methoxy benzothiophene
derivative (21) with pyridine hydrochloride (Cannizzo S., J Hetervcydic Chem,
1990, 27, 2175-79) and by reduction of 2-nitro benzothiophene compound (21)
by stannous chloride (Matassa V, 3 Med Chem, 1990,33, 2621-29).
These compounds (22) and (24) can be sulfamoyiated to give (23) and (25)
using the same conditions as for the synthesis of compounds (11) or (13).
Deprotonation of 2-H-benzothiophene derivative (21) with lithium amides or
alkyls leads to lithiation at C-2 position. Addition of sulfuryl chloride yields
chlorosulfbnyl compound that is treated by aqueous ammonia in acetone
(Graham S., J Med Chem, 1989, 32, 2548-54) to give 2-sulfonamide
benzothiophene derivative (21) or addition of dry ice followed by hydrolysis gives
2 1997, 40, 705-16).
3-CarboxyRc or carboxamide benzothiophene derivative (21) is prepared by
treatment of 3-H-benzotNophene derivative with trichtoroacetyl
chloride/aluminium chloride followed by hydrolysis with water (Bonjouklian R.,
Synth Comm, 1985, 15, 8, 711-13) or aqueous ammonia (Turnbull K., J
Hetenocycl Chem, 2000,37, 2, 383-88).
3-SulfonamkJe derivative (21) is prepared following the conditions described by
Chapman N. (J. Chem. Sex:., 1970, 18, 2431-35) or Hageman W. (Ger. Offen.,
3435173,11 April 1985).
Oxidation of sulfur on benzothiophene and reduction of carboxamide, thioamide,
ketone, thioketone, oxydised sulphur function can be performed at any step of
synthesis following the same conditions already presented in this description.
(Figure Removed)

According to scheme HI, compounds (27) are obtained by condensation of the Nimidazoloaniline
(9) with isocyanate derivatives (26) using standard conditions
(March 1, Advanced Organic Chemistry, Fourth edition, Wiley Interscience, New-
York). Most of the isocyanate derivatives (26) are commercially available or are
synthesized by usual chemistry methods.
Compounds (28) and (30) are synthesized following the same synthetic methods
as for compounds (10) and (12) in scheme Ib.
Compounds (29) and (31) are synthesized following the same synthetic methods
as for compounds (11) and (13) in scheme Ib.
(Figure Removed)

According to scheme IV, bi-aryl compounds (33) can be synthesized following the
same synthetic methods as for compounds (8) with derivatives (32). Derivatives
(32) are commerriaNy available or synthesized by usual chemistry methods (as
ex Buraway S, J Chem Soc, 1955, 2557; Tiltey 3 W, J Med Chem, 1989, 32, 8,
1814).
According to scheme V, compounds (35) are synthesized following the same
(Figure Removed)

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
Lett, 19%, 6, 21, 2613; Myers A G, 3 Org Chem, 19%, 61, 813; Tetrahedron,
1993, 49, 19, 4085) or from carboxylic acid (WO 0177078). Hatogeno pynmidine
derivatives (34) can be obtained from alkyl pyrimkjines (Budesinsky, Collect,
Czech, Chem Commun, 1968, 33, 7, 2266; Kunieda T, 3 Am Chem Soc, 1971,
93,3487) by usual hatogenation (Isoda S, Chem pharm Bull, 1980, 28, 5, 1408;
March 1, Advanced Organic Chemistry, Fourth edition, Wiley Interscience, New-
York), or from carbaldehydes (Bredereck, Chem Ber, 1967, 100, 11, 3664;
Adams 3 L, Bioorg Med Chem Lett, 1998, 8, 22, 3111), and carboxylic acids
(Huffman K R, 3 Org Chem, 27, 1%2, 551; Daves 3 Org Chem, 1961, 26, 2755)
can be transformed to acid chlorides (34). Halogeno pyrazine derivatives (34)
can be obtained from alkyl pyrazines (Lutz W B, 3 Org Chem, 1%4, 29, 415) by
bromination, or from carbaldehydes (US 3558625), and carboxylic acids (Sato N,
3 Heterocyd Chem, 19, 1982, 407-408; Felder P, Helv Chim Acta, 1964, 47, 873)
can be transformed to acid chlorides (34). Halogeno pyridazine derivatives (34)
can be obtained following Piras S (Farmaco, 1993, 48, 9, 1249) Yanai,
(Heterocydes, 1976, 4, 1331), or by halogenation of alkyl pyridazines (Becker, 3
Prakt Chem, 1970, 312, 591; DE 1950491) and carboxytic acids (Boger D L, J Am
Chem Soc 1987,109,9, 2717) can be transformed to acid chlorides (34).
For all schemes Ha, lib, in, IV, V, carboxylate derivative, sulfamkJe derivative
and tetrazole derivative are synthesized by the methods already described for
scheme la and R8 and (R9)p are performed following the same conditions
already presented in this description.
The groups described for R3, R*, RB and Rg can be obtained by usual chemistry
methods (for references see review on sulfatase (Nussbaumer P, Medednal
Research, 2004, 24, 4, 529-76), on carbonic anhydrase (Supuran C T, Carbonic
anhydrase, 2004, C R C press) and articles from Park 3 D (_7 Heterocyd Chem,
2000, 37, 2, 383-88), Schreiner E P (Bioorg Med Chem Lett, 2004, 14, 4999-
5002) and Taylor S D (Bioorg Med Chem Lett, 2004, 14, 151-155).
u
The following examples are intended to illustrate and not to limit the scope of the
invention.
PREPARATION OF N, N-DISUBSTUUTED HYDRAZINES (4)
EXAMPLE 1
N1-(4-cyanophenylmethyl)-N1-(4-methoxyphenyl)hydrazine
Chloromethylbenzonitrile (25 g, 164.90 mmol) was introduced with stirring into
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
portjonwise 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°C.
XH-NMR (DMSOd6) : 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)
EXAMPJJE2
4-[N-(lH-imidazol-l-yl)amino]benzonitnle
a ) 4 - [ N K 2 3 - l - y
To a suspension of 4-cyanophenylhydrazine hydrochloride (6.00 g, 35.40 mmol)
in ethanol (60 ml) was added dropwise 2,2^1imethoxyethyl»sothiocyanate (6.25
g, 42.4 mmol) and the reaction mixture was heated to reflux for 2 h. After
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 overnight. 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 %).
*H-NMR (DMSO d6): 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-(lH-imidazol-l-yl)amino]benzonitrile
35 % hydrogen peroxide (4.90 ml, 55.5 mmol) was added dropwise to an icecooled
suspension of 4-[N-(2,3-dihydro-lH-imidazol-l-yl-2-
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
concentrated under vacuum. Rash 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°C
'H-NMR (DMSOd6): 6.50 (d, 2H), 7.08 (s, 1H), 7.30 (s, 1H), 7.66 (d, 2H), 7.83
(s, 1H).
PREPARATION OF BENZOTHIOPHENE DERIVATIVES (14) AND (20)
EXAMPLES
l-Chloro-3-(3-methoxyphenyl)sulfanyl-propan-2-one
To a stirred solution of l,3-dichtoro-2-propanone (12.70 g, 0.1 mol) in
methanol/water (100 ml, 1:3) at 0°C is added a suspension of 3-
metnoxybenzenethiol (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 dichtoromethane (100 ml),
washed with water (80 ml), and dried with sodium sutfate. After removal of the
solvent, we obtained the good product (oil, 18.70 g).
'H-NMR (): 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).
3-Ch(oromethyl-6-methoxy-benzothiophene
A solution of the above thto compound (17.50 g, 75.85 mmol) in CH2d2 (1700
ml) was added dropwise to a solution of BF3.Et20 (10.60 ml, 83.44 mmol) in
CH (100 ml) at room temperature under nitrogen atmosphere. The mixture
•?»
was stirred overnight and after hydrolysis with aqueous NaHC03 solution, the
reaction mixture was stirred until both phases became dear. The CH2CI2 layer
was separated, and the aqueous layer was extracted with CH2Q2. The combined
organic phases were dried over Na2SO4, filtered, and concentrated under vacuum
to give an oil (18.00 g). Rash chromatography on silica gel (toluene /petroleum
spirit 40-60°C : 5/5) yielded a 1:10 mixture of 3-chloromethyl-4-methoxybenzothiophene:
3-chloromethyl-6-methoxy-benzothiophene as an oil (12.35 g,
58 %).
Major isomer 1H-NMR (CDCl3): 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).
EXAMPLES
3-Bromo-6-benzyloxy-benzothiophene
N-bromosuccinJmlde (15.70 g, 83.92 mmol) and p-toluenesulfonic acid (2.70 g,
15.68 mmol) were added to a solution of 6-benzyloxy-benzothiophene
(Zhengying C, CN 1370533 A, 21.2 g, 88.33 mmd) in 1,2-dfchloroethane (120
ml). The mixture was maintained at 80°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 Na2SCU, filtered, and
concentrated under vacuum to give an oil. Crystallisation from pentane afforded
a white solid (21.60 g, 92 %, mp: 68°C).
'H-NMR (DMSOdfi): 5.14 (s, 2H), 7.08 (dd, 1H), 7.25-7.55 (m, 6H), 7.65 (d, 1H),
7.76 (d, 1H).
EXAMPLES
3-Bromo-6-benzyioxy-bcnzothiophenc- 1,1-dioxyde
To a solution of 3-brorno-6-benzytoxy-beruothiophene (2.00 g, 6.27 mmol) in
dichloromethane (50 ml) and trffluoroacetic acid (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 NaHCO3, extracted with
dichloromethane, dried over NazSO4filtered, and concentrated under vacuum to
give the crude product Rash chromatography on silica gel (toluene / ethyl
acetate: 9/1) yielded a limpid oil (1.10 g, 55%).
'H-NMR (DMSOd6): 5.20 (s, 2H), 7.20-7.60 (m, 7H), 7.72 (d, 1H), 7.83 (s, 1H).
EXAMPLE
(6-Benzyloxy-benzothien-2-yl)methanol
To a solution of 6-benzyloxy-benzothiophene-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°C cooled suspension of LiAIH4 (0.85 g, 22.26 mmol). After
warming up to room temperature the mixture was stirred overnight, cooled to -
10°C, hydrolyzed with ice water, extracted with dichloromethane, dried over
* Na2SO4, 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%).
'H-NMR (DMSOd6): 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).
EXAMPLES
6-Benzyloxy-2-(chloromethyl)-benzothiophene
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 (CDQ3): 4.75 (s, 2H), 5.04 (s, 2H), 6.95 (dd, 1H), 7.10 (s, 1H); 7.20-
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-
cyanophenyihydrazine, hydrochloride by:
- N-(4-cyanophenylmetnyl-tJX4-methoxypnenyl)nydrazine,
the following compound was obtained:
EXAMPLE 9
4-[N-{lH-imidazol-l-y1)-N-(4-
methoxyphenyl)amino]methylbenzonitrile
'H-NMR (DMSO 4) : 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°C
'H-NMR (DMSO d6): 3.70 (s, 3H), 4.97 (s, 2H), 6.93 (d, 2H), 7.13 (d, 2H), 7.45
(d, 2H), 7.70 (s, 1H), 7.84 (d, 2H), 8.04 (s, 1H), 8.18 (s, 1H), 9.55 (s, 1H).
EXAMPLE 10
4-[N-(4-hydroxyphenyl)-N-(lH-imidazol-lyl)
amino]methylbenzonitrile
A solution of boron tribromide (60 ml, 60.00 mmol) in 20 ml of dichloromethane
is added to a cold (0-5°C) solution of 4-[N-(lH-imidazol-l-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 NaHC03,
filtered, washed witti water (50 ml) and with dichloromethane (20 ml) to give a
brown solid (4.00 g). Crystallization from acetone yielded a brown solid (3.00 g,
68%) mp: 150°C.
'H-NMR (DMSO d6): 4.84 (s, 2H), 6.70 (s, 4H), 6.90 (s, 1H), 7.45-7.62 (m, 3H),
7.62-7.90 (m, 3H), 9.25 (s, 1H).
EXAMPLE 11
4-[N-(4-hydroxyphenylmethyl)-N-(lH-imidazol-lyl)
amino]benzonitrile
4-hydroxybenzylbromide (15.6 g, 84.3 mmol, prepared following Wissner A. et
at., J.Med.Chem. 1992, 35, 1650) was added to a mixture of 4-[N-(lH-imjdazoll-
yl)amino]benzonitrile (10.00 g, 54.30 mmol) and K2CO3 (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 NazSO2 filtered, and concentrated under vacuum to give the crude
product (16.00 g as solid). Crystallization from ethyl acetate with ethand yielded
the expected product (6.50 g, 41%, mp: 180°Q
'H-NMR (DMSO d6) : 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:
- 3 - 3-brorno-4-hydroxybenzylbromide
- 4-hydroxy-3-methoxybenzylbromide
- 2,3,5,6-tetrafluoro-4-hydroxybenzylchloride (prepared following Angyal
SJ. et al., IChem. Soc. 1950, 2141)
- 3-formyl-4-hydroxybenzylchloride (prepared following Angyal SJ. et al.,
J.Chem. Soc. 1950, 2141)
- l-benzyloxy-4-(2-bromo-ethoxy)-benzene (prepared following Brinkman J.
and al. Bioorg. Med. Chem. Lett, 1996, 6, 21, 2491-94)
- 2-chtoro-5-chloromethyl-pyridine
- 4-(bromomethyl)benzene sulfbnamide (prepared following Colescott R.
and all. 1 Am. Chem. Soc., 1957, 79, 4232-35)
- 4-(chloromethyl)-2-nitro-phenol (prepared following Bayer Patent: DE
132475)
zsr
- 5-chloromethyl-2-methoxy-benzok: acid (prepared following Leonard F.
and all. 3. Med. Chem., 1965, 8, 812-15)
the following compounds were respectively obtained:
EXAMPLE 12
4-[N-(3-chloro-4-hydroxyphenylm€thyl)-N-(lH-imidazol-lyi)
amino]benzonitrile
mp 195°C
'H-NMR (DMSOde): 4.88 (s, 2H), 6.67 (d, 2H), 6.88 (d, 2H), 6.98 (s, 1H), 7.05
(dd, 1H), 7.24 (d, 1H), 7.33 (s, 1H), 7.70 (s,lH), 7.72 (d,2H), 10.28 (s, 1H).
EXAMPLE 13
4-[N-(3-bromo-4-hydroxyphenylmethyl)-N-(lH-imidazol-lyl)
amino]benzonitrile
mp 198°C
'H-NMR (DMSOde) : 4.90 (s, 2H), 6.65 (d, 2H), 6.85 (d, 1H), 6.99 (s, 1H), 7.07
(d, 1H), 7.30 (s, 1H), 7.40 (s, 1H), 7.65 (s,!H), 7.67 (d,2H), 10.40 (s, 1H).
EXAMPLE 14
4-[N-(4-hydroxy-3-methoxyph«nyimethyi)-N-(lH-imidazol-ly1)
ainino] benzonitrile
mp215°C
*H-NMR (DMSOde) : 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,2H), 9.20 (s, 1H).
EXAMPLE 15
4-[N-(2,3,5,6-tetrafluoro-4-hydroxyphenylmethyl)-N-(lH-imidazol-lyl)
amino] benzonitrile
mp 243°C
'H-NMR (DMSOde): 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-(lH-imidazol-lyl)
amino]benzonitrile
mp 160°C
'H-NMR (DMSOd6): 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
4-{N-[2-(4-benzytoxy-phenoxy)ethyl]-N-(lH-imidazol-lyl)
amino]}benzonitrile
^-NMR (DMSO d6): 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
4-{N-[(6-chk>ropyridin-3-yl)methyl]-N-(lH-imida2ol-lyl)
amino}benzonitrile
mp 156°C
'H-NMR (DMSO ds): 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,lH).
EXAMPLE 19
4-{[NK4-cyaiKH>henyl)-N-(lH-mkIazo)-l-yi)amino]methyl}ben2ene
sulfonanude
mp!50°C
1H-NMR (DMSO dj) : 5.15 (s, 2H), 6.62 (d, 2H), 7.00 (s, 1H), 7.36 (s, 2H), 7.45
(s, 1H), 7.55 (d, 2H), 7.65-7.90 (m, 5H).
EXAMPLE 20
4-[N-(4-hydroxy-3-nitrophenylmethyl)-N-(lH-imidazol-lyl)
amino]benzonitrile
mp 205°C
XH-NMR (DMSO ): 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-cyanophenyl)-N-(lH-imidazol-l-yl)amino]methyl}-2-
methoxybenzoic add
mp 187°C
'H-NMR (DMSO dg) : 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).
EXAMPLE 2?
4-[N-(lH-imidazol-l-yI)-N-(4-nitrophenyl)amino]benzonitrite
4-[N-(lH-imidazol-l-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
DMSO (100 ml) at (10-15°Q 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°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%,
mp: 188°C).
'H-NMR (DMSOde) : 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:
- 6-choro-rocot)noyl chloride
- 4-fluorophenylacetyl chloride
- 4-hydroxyphenylacetyl chloride
- 4-hydroxyphenylpropanoyl chloride (prepared following Bias H. and
an. MacromoJ. Chem. Phys., 1981,182, 681-86)
- 4-phenylmethoxybenzene sulfbnyl 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-(lH-imidazol-l-yl)nicotinamide
mp 132°C
'H-NMR (DMSO de): 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-(lH-imidazol-l-yl)-N-(4-cyanophenyl)-2-(4-fluorophenyl)acetamide
mp 131°C
'H-NMR (DMSO d6) : 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).
EXAMPLE 25
N-(lH-imidazol-l-yt)-N-(4-cyai»ophenyl)-2-(4-
hydroxyphenyl)acetainide
'H-NMR (DMSO d6) : 3.32 (s, 2H), 6.65 (d, 2H), 6.87 (d, 2H), 7.08 (s, 1H), 7.50
(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-(lH-imidazol-lyl)
propanamide
mp 172°C
1H-NMR (DMSO de) : 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-cyanophenyI)-N-(lH-imldazol-l-yl)-4-(phenylmethoxy)-
'H-NMR (CDC3) : 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)
EXAMPLE 28
5-Nitro-[N-(4-cyanopheny1)-N-(lH-imidazol-l-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-(lH-imidazol-lyl)
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°C).
1H-NMR(DMSO d6): 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).
Using the same procedure but replacing the 5-nitro-benzothiophene-2-carbonyl
chloride by:
6-methoxy-benzothk>phene-3-acetyl chloride (described by Sauter F.,
Monatshefte Fuer Chemie, 1968, 99, 2, 610-15) the following compound was
obtained:
EXAMPLE 29
N-(4-cyanophcnyl)-N-(lH-imida2ol-l-yl)-2-(6-methoxy-b€nzothien-3-
yl) acetamide
mp: 104°C
'H-NMR (DMSO de): 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, 1H), 7.90 (d, 2H), 8.25 (s, 1H).
EXAMPLE 30
4-{N-[lH-imidazol-l-yl]-N-[(6-methoxy-benzothien-3-
yl)metliyl]amino} benzonitrile
3-Oiloromettiyl-6-rnethoxy-benzothiophene (12.35 g, 58.06 mmol) was added to
a mixture of 4-[N-(lHHmklazol-l-yl)arnino]ben2onitrile (9.72 g, 52.78 mmol),
KjCQj (14.60 g, 105.56 mmol) and potassium iodide (O.lOg, 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
acetate, dried over Na2SO4, 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°C).
'H-NMR (DMSO de): 3.80 (s, 3H), 5.25 (s, 2H), 6.74 (d, 2H), 6.93 (s, 1H), 7.02
(dd, 1H), 7.28 (s, 1H), 7.40 (s, 1H), 7.53 (s, 1H), 7.55 (s, 1H), 7.68 (d, 1H), 7.75
(d, 2H).
EXAMPLE 31
4-[N-(6-benzyloxy-l,l-dioxido-benzothien-3-yl)-N-(lH-imidazol-lyl)
amino] benzonitrile
4-[N-(lH-imidazol-l-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°C) with stirring. The mixture was stirred for 30 mn at
room temperature, and then 3-bromo-6-benzyloxy-benzothiophene-l,l-dioxyde
(1.10 g, 31.33 mM) in THF (5 ml) was added dropwise white keeping the
temperature below 30°C. After one night, the mixture was poured into water
(200 ml) and extracted with ethyl acetate, dried over Na2SO4, filtered, and
concentrated under vacuum to give the crude product as an oil (2.50 g). Rash
chromatography on silica gel (toluene / 1,4-dtoxan: 7/3) and crystallisation in
ethanol yielded light brown crystals (1.20 g, 95%, mp: 146°C).
'H-NMR (DMSO ds): 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,lH), 7.94 (d, 2H).
Using the same procedure but replacing the 3-bromo-6-benzyloxybenzothtophene-
l,l-dioxyde by:
6-benzytoxy-2-(chloromethyl)-benzothiophene
the following compound was obtained:
EXAMPLE 32
4-[N-[(6-benzytoxy-benzothlen-2-y1)methy1]-N-(lH-im»dazol-lyl)
amino] benzonitrile
'H-NMR (DMSO (fc): 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,HH).
PREPARATION OF IMIDAZOLES OF FORMULA (10), (16)
w
EXAMPLE 33
4- ]amino> benzonitrile
A solution of 4-{N-[lH-imidazol-l-yl]-N-[(6-metfrioxy-benzothien-3-
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 NaHCO3, extracted with dichloromethane,
dried over Na2S04, filtered, and concentrated in vacuum. The crude product was
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°C).
'H-NMR (DMSO d6): 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, 2H), 9.67 (s, 1H).
Using the same procedure but replacing the 4-{N-[lH-im»dazol-l-yl]iN-[(6-
m e t r » x y - b e n z o t h i c p n e n - 3 - y l ) m e t o b y :
NK4-yanophenyl)-NKlH-imklazol-l-yl)-2K6-methoxy-ben2othien-3-yl)-
acetamide, the following compound was obtained:
EXAMPLE 34
N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)-2-(6-hydroxy-benzothien-3-
yl) acetamkie
mp 179°C
'H-NMR (DMSO cfe): 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).
4-[N(3-amino-4-ydroxy-phenylrnethy)-N-(lH-irnidazol-1-yl)amino]
(2
g, 5.97 mmol) was hydrogenated over a suspension of Pd/C (10 % Wt on
carbon, 0.2 g) 'm ethanol (30 ml). When TLC showed complete reaction, the
mixture was filtered on celatum, rinsed with Eto. The solvent was concentrated
under vacuum. Crystallisation from EtoH/petroleum ether yielded orange crystals
(1.1 g, 60.5 %, mp: 208°C).
'H-NMR (DMSO de) : 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, 3H), 9.07 (s, 1H).
'9
Using the same procedure but replacing the 4-[N-(4-hydroxy-3-nitro-benzyl)-N-
(iH-imidazd-l-yl)amino]benzonitrile by:
-4-{N-[2-(4-benzyloxy-phenoxy)ethyl]-N-(lH-imidazol-l-yl)amino]}
- benzonitrile
- N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)-4-(phenylmethoxy)-
benzensulfonamide
the following compounds were respectively obtained:
EXAMPLE 36
4-CN-[2-(4-hydroxyphenoxy)ethyl]-N-(lH-imidazol-lyl)
amino}benzonitrile
mp!88°C
'H-NMR (DMSO d6: 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,lH).
EXAMPLE 37
N-(4-cyanophenyl)-N-(lH-imldazol-l-yl)-4-hydroxybenzcnsulfonamide
mp 248°C
'H-NMR (DMSO d6): 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-tN-[(6-hydroxy-l,l-dloxkk)-benzothien-3-yl)]-N-(lH-imidazol-lyl)
antino] bmzonnriw
A mixture of 4-[N-[(6-benzytoxyyl)
amino]benzonitrite (3.00 g, 6.78 mmol), 10% Pd/C (0.50 g), THF (30 ml) and
solution of ammonium formate (25% in H20, 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 NaiSQ*, filtered, and concentrated under
vacuum to give the crude product (2.50 g as solid). Crystallisation from ethanol
afforded white crystals (0.80 g, 26 %, mp: 260°Q.
'H-NMR (DMSO de): 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).
Using the same procedure but replacing the 4-[N-[(6-benzyloxy-l,l-dbxidobenzothien-
3-yl)]-N-(lH-imidazol-l-yl)amino]benzonitrileby:
4-[N-[(6-benzykxy-benzothien-2-yOmethyl]-N-(lH-imidazol-lyl)
amino]benzonitrile
the following compound was obtained:
EXAMPLE 39
4-[N-[(6-hydroxy-benzothien-2-yl)methyl]-N-(lH-imidazol-l-
•>
yl)amino] benzonitrile
mp 230°C
'H-NMR (DMSO d6): 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, 1H), 7.55 (d, 1H), 7.69-7.80 (m, 3H), 9.63 (s, 1H).
PREPARATION OF IMIDAZOLES OF FORMULA (12), (18)
EXAMPLE 40
4-[N-(4-aminophenyl)-N-(lH-imWazol-l-yl)amino]benzonitrile
Hydrazine (1.52 ml, 49.00 mmol) was added portkxiwise to a suspension of 4-[N-
(!H-imidazol-l-yl)^-(4-nitrophenyl)arnino]benH>nitrile (3.00 g, 9.80 mM) and
ruthenium, 5 wt. % on carbon (0.30 g, 0.15 mM) in ethanol (35 ml) at reflux
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
Na2SO4, filtered, and concentrated under vacuum to give the crude product
(2.50g as solid). Crystallization from ethyl acetate with ethanol yielded the
expected product (1.30 g, 50%, mp: 147°Q.
1H-NMR (DMSOd6) : 5.50 (s, 2H), 6.30 (d, 2H), 6.69 (d, 2H), 7.09 (s, 1H), 7.29
(d, 2H), 7.63 (s, 1H), 7.65 (d, 2H), 8.14 (s,lH).
EXAMPLE 41
5-AmirK>-[N-(4-€yarK>phenyi>N-(lHHmidazol-l-y1)]-beim>thk>phene-
2-carboxamide
Stannous chloride dihydrate (13.10 g, 58.00 mmol) was added portionwise to a
stirred solution of 5-nitro-[N-(4-cyanophenyl)-N-(lH-imida2ol-l-yl)]-
benzothtophene-2-carboxamide (4.50 g, 11.6 mM) in ethanol (100 ml). The
mixture was heated under reflux. When TLC showed complete reaction, the
mixture was cooled and basified with saturated bicarbonate solution. The mixture
was extracted with ethyl acetate, dried over Na2SO4, 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°C).
-NMR (DMSOde): 6.70-6.98 (m, 3H), 7.07 (s, 1H), 7.40-7.25 (m, 4H), 7.26-
7.96 (m, 3H).
GENERAL PROCEDURE OF SULFAMOYLATION
PREPARATION OF SULFAMATES (11, 17, 23) AND
AMINOSULFONYLAMINES (13,19, 25)
EXAMPLE 42
Sulfamk add 4-[N-(4-cyanophenylmethyl)-N-(lH-imidazollyl)
amino]phenyl ester
Sulfamoyl chloride (2.39 g, 20.69 mmol) was added to a solution of 4-[N-(4-
hydroxyphenyl)^-(lH^midazol-l-yl)amino]methylbenzonitrile (1.00 g, 3.45
mmol) in dry DMAc (36 ml) with ice cooling. The mixture was then stirred at
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 Na2S04,
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°Q.
1H-NMR (DMSO cfc) : 5.00 (s, 2H), 6.70 (d, 2H), 6.92 (s, 1H), 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-(lHknidazol-
l-yl)anMno]rnethylben2onitrile by:
• 4-[N-(4-ydroxyphenylrnethyl)-N-(lH-imidazol-lyl)
amino]benzonitrile
• 4-[N-(3-chloro-4-hydroxyphenylmethyl)-N-(lH-imidazol-lyl)
amino]benzonitrile
• 4-[N-(3-bromo-4-hydroxyphenylmethyl)-N-( 1 H-imidazol-1-
yl)amino]benzonitrile
• 4-[N-(3-methoxy-4-hydroxyphenylmethyl)-N-(lH-imidazol-lyl)
amino] benzonitrile
• 4-[N-(2,3,5,6-tetrafluoro-4-hydroxyphenylmethyl)-N-(lH-imidazol-lyl)
amino] benzonitrile
• 4-[N-(3-formyl-4-hydroxyphenylmethyl)-N-( 1 H-imidazol- l-yl)amino]
benzonitrile
• 4-[N-(4-aminophenyl)-N-(lH-imidazol-l-yl)amino]benzonitrile
• N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)-4-
hydroxybenzensulfonamide
•4-{N-[2-(4-hydroxyphenoxy)ethyl]-N-(lH-imidazol-lyl)
amino}benzonitrile
• N-(lH-imidazol-l-yl)-N-(4-cyanophenyl)-2-(4-
hydroxyphenyl)acetamide
• N-(4-cyanophenyl)-3-(4-hydroxyphenyl)-N-(lH-imidazol-lyl)
propanamide
•4-[N-(3-amino-4-hydroxyphenylmethyl)-N-(lH-imidazol-l-yl)amino]
benzonitrile
• 5-Amino-[N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)]-benz6thiophene-
2-carboxamide
• 4-[N-[(6-hydroxy-l,l-dJoxido-benzothien-3-yl)]-N-(lH-imidazol-lyl)
amino]benzonitrile
• N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)-2-[(6-hydroxy-benzothien-
2-yl)] acetamide
•4HN-[(6-hydroxy^)enzothien-3-yl)rnethyl]-N-[lH-irnidazol-l-yl-
]amlno}benzonltrile
•4^-[(6-hydroxy^nzotWen-2-yl)methyl]-N-[lH-Jmidazol-l-yl-
]amino}benzonitrile
the following compounds were respectively obtained:
EXAMPLE 43
Sutfamic acid-4-C[N-(4-cyanophenyt)-N-(lH-imidazollyl)
amino]methy)phenyt ester
mp 172°C
'H-NMR (DMSOd6): 5.00 (s, 2H), 6.65 (d, 2H), 7.00 (s, 1H), 7.22 (d, 2H), 7.40
(s, 1H), 7.42 (d, 2H), 7.70 (s, 1H), 7.75 ( d, 2H), 8.00 (s, 2H).
EXAM RLE 44
Sulfamic add 2-chloro-4-C[N-(4-cyanophenyl)-N-(lH-imidazollyl)
amino]methyl}phenyl ester
'H-NMR (DMSOd6) : 5.05 (s, 2H), 6.63 (d, 2H), 7.00 (s, 1H), 7.35-7.45 (m, 3H),
7.54 (s, 1H), 7.70 (d, 2H), 7.80 (s, 1H), 8.29 (s, 2H).
EXAMPLE 45
Sulfamic acid 2-bromo-4-([N-(4-cyanophenyl)-N-(lH-imidazollyl)
amino] methyl>phenyl ester, hydrochloride
Crystallisation was performed in EtOH/HCl (mp 145°C)
'H-NMR (DMSOd6 : 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-(lH-imidazollyl)
amino] methyl}phenyl ester
rnp 211°C
'H-NMR (DMSOde) : 3.77 (s, 3H), 5.02 (s, 2H), 6.75 (d, 2H), 6.92 (d, 1HJ, 7.05
(s, 2H), 7.25 (d, 1H), 7.45 (s, 1H), 7.71 (d, 2H), 7.80 (s, 1H), 7.93 (s, 2H).i
EXAMPLE 47
Sulfamic add 2,3,5,6-tetrafluoro-4-{[N-(4-cyanophenyl)-N-(lHimidazol-
lyl)amino] methy}phenyl ester
1H-NMR (DMSOde) : 5.37 (s, 2H), 5.83 (s, 2H), 6.86 (d, 2H), 7.08 (s, 1H), 7.41
(s, 1H), 7.79 (s, 1H), 7.81 (d, 2H).
EXAMPLE 8
l-yl)amino] benzonitrite
mpl80°C
'H-NMR (DMSOde) : 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).
EXAMPLE 49
N-C4-[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)
amino]phenyl}sulfamide
mp 121°C
'H-NMR (DMSOde) : 6.38 (d, 2H), 7.09 (s, 1H), 7.20 (s, 1H), 7.22 (d, 2H), 7.51
(d, 2H), 7.63 (s, 1H), 7.69 (d, 2H), 8.19 (s, 1H)
EXAMPLE 50
Sulfamic add 4~C[N-(4-cyanophenyl)-N-(lH-imidazollyl)
amino]sulfonyl}phenyl ester, hydrochioride
Crystallisation was performed in EtoH/HCI
mp 200°C
'H-NMR (DMSOde) : 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).
EXAMPLE 51
Sulfamic add 4~[2-[N-{4-cyanophenyl)-N-{lH-imidazollyl)
amino]ethoxy} phenyl ester
mp 174°C
'H-NMR (DMSOd6): 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
Sutfamk add 4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)-carbamoyl]-
methyi} phenyl ester
'H-NMR (DMSOds): 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 (m, 4H), 8.20 (s, 1H).
EXAMPLE 53
Sulfamk add 4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]-3-
oxopropyl} phenyl ester
'H-NMR (DMSOds) : 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
Sutfamk add 3-{aminoonyl)ino-4- lyl)amino]methyl}phenyl ester
mp 197°C
^-NMR (DMSOdg): 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
5-(Aminosulfonyl)amino-[N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)]-
benzothfophene-2-carboxamide
mp: 169°C
1H-NMR (DMSO de): 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).
EXAMPLE 56
Sulfamic add 3-[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amin-l,ldioxido-
benzothien-6-yl ester
mp 172°C
'H-NMR (DMSO ds): 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
Surfamic acid 3-{2-[N-(4-cyanopheny1)-N-(lH-imidazol-lyl)arnino]-2-
oxoethyl}-benzotttien-6-yl ester
'H-NMR (DMSO ds): 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 *
Surfamic add 3-{[N-(4-cyanophenyl)-N-(lH-imidazo4-
lyl)amino]methyl}-benzothien-6~yl ester
mp 193°C
'H-NMR (DMSO ds): 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
Sutfamic add 2-C[N-(4-cyaoophenyi)-N-{lH-imidazollyt)
amino]met!vyl}-benzothien-6-yl ester
mp!78°C
'H-NMR (DMSO ds): 5.17 (s, 2H), 6.65 (d, 2H), 6.89 (dd, 1H), 6.94 (s, 1H), 7.20
(d, 2H), 7.27 (s, 1H), 7.45 (s, 1H), 7.58 (d, 1H), 7.72 (d, 2H), 8.00 (s, 2H).
Using the same procedure as example 13 but replacing the 4-[N-(4-
hydroxyphenyl)-N-(lH-imldazol-l-yl)arnino]rnethylbenzonitrile by:
• 4-[N-(3-bromo-4-hydroxyphenylmethyl)-N-( IH-imidazol-1-
yl)amino]benzonitrile
The following compounds was obtained as a by-product:
EXAMPLE 60
2-Bromo-4-{[N-(4-cyanophenyl)-N-(lH-imidazollyl)
amino]methyl>phenyl amidimidodisurfate add
mp 220°C
JH-NMR (DMSOd6): 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).
PREPARATION OF OTHER COMPOUNDS (8)
EXAMPLE 61
4-[N-[(2,2-dioxido-3,4-dihydro-l,2,3-benzoxathiaZin-6-yl)methyl]-N-
(lH-imidazol-l-yl)amino]bcnzonitrile
To a suspension of 4-[N-[(22dtoxido-l123-benzoxathiazin-e-y)methy]-NKlHimidazol-
l-yl)amino]benzonitrile (0.40 g, 1.05 mmol) in methanol (8 ml) was
added portionwise NaBH4 (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,d (3 ml) and water (40 ml), the precipitate obtained was filtered, washed
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°C).
'H-NMR (DMSOd6): 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).
EXAMPLES!
5~[[N-{4-cyanophenyl)-N-(lH-imidazol-l-yl)amino]mcthyl>-2-
hydroxybenzoic add
A mixture of 5H[N-4yarK)phenyl)-N-(lHHmiclazol-1-)amir»]rnethyl}-2-
methoxybenzoic acid (l.OOg, 2.85 mmol) and piperidne (0.42ml, 8.57 mmol) in
dimethylacetamide (DMA) (2 ml) was heated at 150°C. When starting material
had disappeared (TLC monitoring), the solvent was removed in vacuo. Rash
chromatography on silica gel (MeOH / dichloromethane : 5/95) and crystallization
from ethanol afforded white crystals (53 mg, 6 %, mp: 260°C).
'H-NMR (DMSO cfc): 4.85 (s, 2H), 6.54 (d, 1H), 6.66 (d, 2H), 6.95 (s, 1H), 7.05
(dd, 1H), 7.24 (s, 1H), 7.50-7.60 (m, 2H), 7.68 (d, 2H).
EXAMPLE 63
4-[N-(lH-imidazol-l-yl)-N-(phenyl)amino]benzonitrile
4-[N-(lH-imidazol-l-yl)-N-(4-nitrophenyl)amino]benzonitrile (3.91 g, 12.80
mmol) was placed in a hydrogenation flask and dissolved in acetic anhydride (60
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 H2. The catalyst was removed by
filtration and the solution was cooled in a bath for 30 mn. Sodium nitrite (0.97 g,
14.00 mmoi) 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
(toluen/dioxan: 6/4) and crystallization from ethyl acetate with ethanol yielded
the expected product (0.40 g, 8 %, mp: 162°Q.
'H-NMR (DMSO de) : 6.60 (d, 2H), 7.00-7.50 (m, 9H), 7.69 (s, 1H).
PREPARATION OF BENZOXATHIAZOLE (8)
EXAMPLE 64
4-[N-(3-to$ylamino-4-hydroxy-benzyl)-N-(lH-imidazoJ-lyl)
amino]benzonitrile
Tosyl chloride (3.5 g, 18.59 mmol) in CH2CL2 (20 ml) was added dropwise to a
solution of (TX 1840) (5.4 g, 17.7 mmol) and pvridine (19.47 mmol, 1.6 ml) in
The mixture was then stirred at room temperature for 4h then poured into water
and extracted with EtOAc, dried over NazSO4 filtered and concentrated under
vacuum to give the crude product (8.1 g as orange solid).
Rash chromatography on silica gel (toluene dtoxane 7/3) yielded yellow solid.
'H-NMR (DMSO de) : 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,
2H), 9.45 (s, 2H).
EXAMPLE 65
4-tN-[(2,2-dioxido-3-tosyl-3H-l,2,3-benzoxathiazol-5-yl)methyl]-N-
(lH-imidazol-l-yl)amino]benzonitrile
Sulfuryl chloride (0.60 ml, 7.40 mmol) in dichbromethane (50 ml) was added
dropwise with stirring over a 30 mn period to 4-[N-(3-tosylamino-4-hydroxybenzyl)-
N-(lH-imidazol-l-yl)amino]benzonitrile (3.40 g, 7.40 mmol) and
triethylamine (2.10 ml, 14.81 mmol) in dichloromethane (6 ml) at -78°C. After
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.
Flash chromatography on silica gel (toluene / dioxane : 5/5) yielded a pure oil
(1.60 g, 41 %).
'H-NMR (DMSO cfe): 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).
EXAMPLE 66
4-[N-[(2,2-dioxido-3H-l,2,3-benzoxathiazol-5-y1)methyl]-N-(lHimidazol-
l-yl)amino]benzonitrile
Potassium fluoride (0.36 g, 6.14 mmd) in water (5 ml) was added to 4-[l^[(2,2-
dtoxick>3-tosyl-3H-l,2,3-beruoxathiazol-5-yl)methyl]-N-(lH-imidazol-lyl)
amino]benzonitrile (1.60 g, 3.07 mmd) 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. Rash chromatography on silica gel (toluene /
dioxane : 5/5) yielded an oil and crystallization from ethanol yielded the expected
product (0.17 g, 15 %, mp: 230°Q.
1H-NMR (DMSO d*) : 4.84 (s, 2H), 6.38 (dd, 1H), 6.42 (d, 1H), 6.63 (d, 1H), 6.69
(d, 2H), 7.15 (S, 1H), 7.43 (S, 1H), 7.70 (d, 2H), 8.02 (S, 1H).
9
PREPARATION OF PHENYL UREAS (27)
EXAMPLES?
N-(4-cyanopheny)-N-(lH-imida2ol-l-yl)-N'-phenylurea
Phenyl isocyanate (3,6 ml, 32,6 mmol) was added to a solution of 4-[N-(lHimidazol-
l-y!)amino] benzonitrile (5 g, 27.17 mmol) in THF (50 ml). The mixture
was stirred at 50°C overnight and after evaporation was crystallised in
acetone/EtOH to give white crystals (2.5 g, 30.3 %, 178°C).
^-NMR (DMSO d6) : 6.59 (s, 1H), 7.05-7.40 (m, 9H), 7.52 (d, 2H), 7.83
(s, 1H).
BIOLOGICAL TEST RESULTS
INHIBITION OF STEROID SULFATASE, AROMATASE AND CARBONIC
ANHYDRASE II IN VITRO
Estrone sulfate (EiS) is a major circulating plasma estrogen that is converted by
the steroid sulfatase enzyme into estrone (EO, which in turn can be transformed
into estradiol (E2) by enzymatic reduction.
•9
The inhibition of E2 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
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
((Xb) and the bicarbonate ion (HCO3 and are involved in numerous
physiological and pathological processes. They indude 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
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
human carbonic anhydrase) for some of them were evaluated in comparison with
6,6,7 COUMATE and acetazolamide.
Materials & Methods
a} Aromatase activity
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
%-well microplates in deoxnptemented fetal calf serum (dFCS) supplemented
medium. 24 hours later, cells were rinsed and fresh medium containing lp-3Handrostenedbne
as aromatase substrate was added together with test
compounds at concentrations ranging from 10 12 M to 10"5 M. After 2 hours of
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°C). All steroids, including the radioactive substrate and the newly
biosynthesized estrogens, were adsorbed on charcoal; only 3H-water specifically
formed during aromatisation of l(3-3H-androstenedior»e, remained in the
supernatant. The radioactivity in the supernatant was measured by" liquid
scintillation counting. In parallel, cell solubilization was performed in
ethylenediamine tetraacetate solution. DMA content was measured by a standard
fluorimetric method using the Hoechst 33258 fluorochrome. Finally, aromatase
activity was expressed in fmotes of 3H-water formed/2 hours/ug DMA and
aromatase inhibition as a percentage of control activity without inhibitor. A nonlinear
fit analysis (GraphPad Prism Software) of % of inhibition vs. inhibitor
concentration allowed the determination of the 50 % inhibitory concentration
: the lowest IC^s correspond to the most potent inhibitors (Table 1).
b) Steroid sulfatBse 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
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, 3H-EiS was
added in dFCS free medium, followed by test compounds at concentrations
ranging from 10"12 M to 10"5 M. After 4 h of treatment, the medium was
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 nonconjugated
products. The radioactivity in the toluene phase was measured by
Ofliquid
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 pmotes of 3H-E1 + 3H-E2 formed/4 hours /mg
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 (IC50): the lowesIC50 correspond to the most potent inhibitors
(Table 1).
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
model previously described was adopted with slight modifications: the presence
of the two substrates 3-HEiS and Ip-'H-androstenedione into the medium and an
incubation period of 2 hours. Results were expressed in pmotes of product
formed (3H-E1 + 3H-E2 or 3HzO)/2 hours/mg DNA (Table 1).
Ishikawa 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 fourday
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-nitrophenpl and
spectrophotometric determination of the product at 405 nm.
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 pi ice-cold solution containing 5 mM p-nitrophenyl phosphate
was added to each well. After a 15 to 60 minute incubation period at room
temperature, the intensity of the yellow color generated by the production of pnitrophenot
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 (R) and then as percentage of E2 activity
(10-8 M) chosen equal to 100 %. Sigmoidal dose-response curves were plotted
(GraphPad Prism Software) and 50 % effective concentrations (EC50) were
calculated for each compound (Table 1).
This assay was performed as described in the literature (Armstrong J. et al.
Purification and properties of human erythrocyte carbonic anhydrases, J Biol
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 cotorimetric
determination of p-nitrophenol produced during the enzymatic reaction. The
optical density levels obtained without inhibitor will be referred to as total
activity1'. The levels obtained without inhibitor and without the enzyme will be
9
referred to as "Wank" in order to assess any interference with the substrate
during the assay (Table 2).
(Table Removed)

A*:sulfamk:acid, S-cydoheptylrnethylbenzothiophen-6-y1,1dioxide-ester
(described in nd: not detected
Materials & methods:a aromatase activity alone; " sulfatase activity alone; c dual
aromatase and sulfatase activity,d estrogenic potency.
Among the tested compounds, Ex 43, Ex 45 and Ex 46 showed a strong inhibition
about 10 nM) of human estrone sulfatase activity. In addition, the same
compounds were shown to be strong inhibitors of aromatase activity (IC50 1
nM). Despite this dual activity, They were not estrogenic in vitro.
Ex 45 and Ex 51 inhibited human carbonic anhydrase n in vitro.
(Table Removed)

ANTI UTEROTROPHIC/ANTI STEROID SULFATASE ACTIVITY IN VIVO
Wistar female rats were ovariectomized and left to rest for 4 weeks. Prior to
treatment, the absence of cydidty was checked by vaginal smears. Animate were
supplemented with estrone sulfate (EjS) at 50 pg/kg/day s.c., alone or combined
with oral administration of potential sulfatase inhibitors, at 1 mg/kg/day for 4
days. The uteri were removed, freed of adjacent tissue and wet weighed
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
charcoal and assayed for sulfatase. EtS activity is assessed after 30 min of
incubation with 5 nM of 3H-EiS and 20 pM of unlabelled EtS as substrate. Estrone
sulfatase activity is expressed as pmol /h/mg protein and reported as percentage
of inhibition vs EtS; for uterus weights, results are expressed as % of inhibition
of the EiS induced stimulation
(Table Removed)


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
results from_significant inhibition of EtS (> 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.
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 anastrozote on 17B-estradiol level 24 hours after
one oral administration in female rats. Anastrozole, is a potent, non steroidal
inhibitor of aromatase, which significantly inhibits estradfol levels at 3 ug/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
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).
(Table Removed)
.
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
determined weekly. When tumor volumes reach significant increase, tested
compound is orally administered at Img/kg/day for 8 weeks. Xenografts are
measured, removed, weighed, and deep frozen for the determination of sutfatase
activity, according to methods used for rat uteri
ER+ Human breast tumor tissue xenoorafted into nude rats
MCF-7 cells (ATCQ, derived from human breast adenocarcinoma, were
injected subcutaneously in ovariectomized 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
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
w
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.
Xenografts were measured weekly by electronic Caliper and compared to the
estrone sulfate group. (Table 5).
(Table Removed)
When animals were treated with Ex 45, tumor volumes did not increased. On the
other hand, simultaneously, groups only treated with estrone sulfate (E1S),
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 dear
and welt established anticancerous potency.
JEG-3 xenoaraft into nude mice
The JEG-3 ceH line over-expresses both human aromatase and estrone sutfatase
enzymes. It is injected subcutaneously into ovariectomized athymic nude mice
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 (choriocarcinoma 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
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 xenoaraft within nude rat supplemented with estrone sulfate and A4-
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
ovariectonrmized athymic (Rnu/Rnu) nude rat Animals are supplemented with a
daily administration of subcutaneous estrone sulfate and 4-androstenedione
with or without tested compound (administered at Img/kg/day). After a 21-day
period, blood sampling are performed one day after cancerous xenograft and at
the end of the experiment In this experiment estrone sulfate and A4-
androstenedione are the precursors of estradtol. 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).









We Claim:
1. An imidazole compound of formula (I) :
(Formula Removed)
and acid addition salts thereof, wherein:
• R1 and R2 are each hydrogen;
. Q is (CH2)m-X-(CH2)n-A;
• A is a direct link, O, SO2 or NR5;
• X is a direct link, O, SO2, C(O) or NR5;
• Z is a group selected from:
(Formula Removed)
• m and n are each independently O, 1, 2, 3 or 4;
• p is 1, 2, 3 or 4;
• q is O,1 or 2;
• the dotted line means that R8 and/or R9 can be on any position of the
benzothiophene ring;
• R3 and R8 are each independently hydrogen or a hydroxy, cyano, halogen,
nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluorom ethyl, (C1-C6)alkylthio, (C1-
C6)alkylsulfonyl, acyl selected among formyl, acetyl, propionyl, butyryl and
valeryl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11 or
OSO2NR12SO2NR10R11 group;
• when Q-Z is
(Formula Removed)
n is O, 1 or 2 and p is 1, one of R3 and R8 is a hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR10SO2NR11R12, CONR10R11, and the other is hydrogen or a hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, carboxamido, NR11R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11 group;
• R4 and R9 are each independently hydrogen or a hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl selected among formyl, acetyl, propionyl, butyryl and valeryl; carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CHO group;
• when p is 2, 3 or 4 the R9s can be the same or different;
• R6 and R7 are independently hydrogen;
• R5, R10, R11 and Ri2 are each hydrogen;
• when Z is
(Formula Removed)
and p is 1,
then R8 and R9 can also form together with the phenyl ring a benzoxathiazine
dioxide.
2. A compound as claimed in claim 1, and acid addition salts thereof, wherein:
• one of R3 and R8 is a hydroxy, nitro, NR10R11, OSO2NR10R11 or NR12SO2NR10R11 group; and
• the other is hydrogen or a hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl
selected among formyl, acetyl, propionyl, butyryl and valeryl, carboxamido, NR10R11, OSO2NR10R11, NR12SO2NR10R11 group;
3. A compound as claimed in claim 1 or 2, and acid addition salts thereof,
wherein:
• one of R3 and R8 is hydroxy, cyano, (C1-C6)alkoxy or OSO2NR10R11; and
• the other is hydrogen or a hydroxy, halogen, nitro, cyano, (C1-C6)alkoxy, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR10SO2NR11R12 group.
4. A compound as claimed in any one of claim 1 to 3, and acid addition salts
thereof, wherein:
• one of R3 and R8 is cyano; and
• the other is hydrogen or a hydroxy, halogen, nitro, (C1-C6) alkoxy, NR10R11,
SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11 group.
5. A compound as claimed in any one of claims 1 to 4, and acid addition
salts thereof, wherein:
• R4 and R9 are each independently hydrogen, hydroxy, cyano, halogen, nitro,
(C1-C6)alkyl, (C1-C6alkoxy, trifluoromethyl, (C1-C6)alkylthio,
(C1-C6)alkylsulfonyl, acyl selected among formyl, acetyl, propionyl, butyryl
and valeryl, carboxamido, NR10R11, OSO2NR10R11, NR12SO2NR10R11, CO2R10 or
CHO group.
6. A compound as claimed in claim 5, and acid addition salts thereof,
wherein:
• one of R4 and Rg is hydrogen or a hydroxy, cyano or OSO2NR10R11; and
• the other is hydrogen or a hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11., CO2R10, CHO, NR12SO2NR10R11 group.
7. A compound as claimed in claim 6, and acid addition salts thereof,
wherein:
• R4 is hydrogen, hydroxy, cyano or OSO2NR10R11;
• R9 is a hydrogen or a hydroxy, cyano, halogen, nitro, (C1-C6)alkyl,
(C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10, CHO group.
8. A compound as claimed in claim 7, and acid addition salts thereof,
wherein:
• R4 is hydrogen; and
• R9 is hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy,
trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10, CHO or NR12SO2NR10R11.
9. A compound as claimed in any one of claims 1 to 8, and acid addition
salts thereof, wherein Z is:
(Formula Removed)
in which:
• R8 is hydrogen, hydroxy, halogen, nitro, cyano, (C1-C6)alkoxy, NR10R11,
SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11 or OSO2NR10SO2NR11R12 group;
• R9 hydrogen or a hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11., CHO, NR12SO2NR10R11 group;
• p and q are as defined in claim 1.
10. A compound as claimed in any one of claims 1 to 9, and acid addition
salts thereof, wherein Q is selected from a direct link, C(O), SO2, CONH,
C(O)(CH2)n, (CH2)n(O) or (CH2)n in which n is 0, 1 or 2.
11. A compound as claimed in claim 1, and acid addition salts thereof,
wherein:
• Z is
(Formula Removed)
• Q is (CH2)n in which n is O, 1 or 2;
• one of R3 and R8 is a hydroxy, nitro, NR10R11, OSO2NR10R11 or NR12SO2NR10R11 group and the other is hydrogen or a hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl selected among formyl, acetyl, propionyl, butyryl and valeryl, carboxamido, NR10R11, OSO2NR10R11 or NR12SO2NR10R11 group;
• R4 and R9 are each independently hydrogen, hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl selected among formyl, acetyl, propionyl, butyryl and valeryl, carboxamido, NR10R11, OSO2NR10R11 or NR12SO2NR10R11 group;
• R10 and R11 are each hydrogen;
• p is 1, 2, 3 or 4;
• R8 and R9 together with the phenyl ring bearing them can also form a benzoxathiazine dioxide.
12. A compound as claimed in claim 11, and acid addition salts thereof, wherein:
• Z is
(Formula Removed)
• Q is (CH2)n in which n O, 1 or 2;
• R8 is hydroxy, halogen, nitro, cyano or a (C1-C6)alkoxy, NR10R11, SO2NR10R11, OSO2NR10R11, or NR12SO2NR10R11 group;
• R9 is hydrogen, hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11;
• p is as defined in claim 1.
13. A compound as claimed in claim 12, and acid addition salts thereof,
wherein:
• n is 0 or 1;
• R4 and R9 are each independently hydrogen, halogen, (C1-C6)alkoxy, acyl selected among formyl, acetyl, propionyl, butyryl and valeryl, NR10R11, OSO2NR10R11 or NR12SO2NR10R11.
14. A compound as claimed in any one of claims 11 to 13, and acid addition
salts thereof, wherein:
• n is 0 or 1;
• R1, R2 and R4 are each hydrogen;
• R9 is hydrogen, halogen, (C1-C6)alkyl or OSO2NR10R11.
15. A compound as claimed in any one of claims 11 to 14, and acid addition
salts thereof, wherein:
• n and p are 1;
• R8 is a hydroxy, halogen, nitro, cyano, (C1-C6)alkoxy, NR10R11, SO2NR10R11,
OSO2NR10R11, NR12SO2IMR10R11 or OSO2NR10SO2NR11R12 group;
• R9 a hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11 or CHO group;
• R3 is cyano, hydroxy, OSO2NR11R11 or NR12SO2NR10R11;
• R4 is hydrogen, hydroxy, halogen, cyano or OSO2NR10R11.

16 A compound as claimed in any one of claims 12 to 15, and acid addition salts thereof, wherein one of R3 and R8 is hydroxy, cyano or OSO2NR10R11 and the other is hydroxy, nitro, NR10R11, OSO2NR10R11 or NR12SO2NR10R11.
17 A compound as claimed in claim 16, and acid addition salts thereof, wherein one of R3 and R8 is cyano or OSO2NR10R11 and the other is hydroxy or OSO2NR10R11.
18 A compound as claimed in claims 1 or 2, and acid addition salts thereof, wherein:
(Formula Removed)

in which:
. Q is (CH2)m-X-(CH2)n-A-;
• A is a direct bond or O, SO2 or NR5;
• X is a direct bond, O, SO2, C(O) or NR5;
• m and n are each independently O, 1, 2, 3 or 4;
• R3, R4, R8 and R9 are each independently hydrogen or a hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, benzyloxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl selected among formyl, acetyl, propionyl, butyryl and valeryl, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11 group;
• q is O,1 or 2;
• p is 1, 2, 3 or 4;
• R5, R6, R7, R10, R11 and R12 are each hydrogen;
• The dotted line means that R8 and/or R9 can be on any position of the benzothiophene ring.
19 A compound as claimed in claim 18, and acid addition salts thereof, wherein
Rs is OSO2NR10R11 or NR12SO2NR10R11.
20 A compound as claimed in c laim 18 or 19, wherein R9 is hydrogen, halogen, nitro, COOR10 or cyano.
21 A compound as claimed in any one of claims 18 to 2O, wherein R4 is hydrogen, halogen, cyano, (C1-C6)alkoxy, NR10R11, OSO2NR10R11 or NR12SO2NR10R11.
22 A compound as claimed in any one of claims 18 to 21, wherein Q is
(CH2)m-X-(CH2)n-A where m is O, 1 or 2 and X is a direct bond, SO2 or CO, n is 0 and A is a direct bond.
23 A compound as claimed in any one of claims 18 to 22, wherein R3 is hydrogen, halogen or cyano.
24 A compound as claimed in claim 1 or 2, and acid addition salts thereof, wherein:
• Z is a group:
(Formula Removed)
in which R8, R9 and p are as defined in claim 1.
25 A compound as claimed in claim 24, and acid addition salts thereof,
wherein:
• R3 is cyano or OSO2NR10R11;
• R4 is hydrogen, hydroxyl, halogen, cyano, OSO2NR10R11;
Rs is hydroxy, cyano, OSO2NR10R11, NR10R11, NR12SO2NR10R11, OCHO or tetrazolyl;
• R9 is hydrogen, halogen, nitro, cyano or CO2R10; and
• Q is as defined is claim 10.

26 A compound as claimed in any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance.
27 A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 25, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
28 The pharmaceutical composition according to claim 27, comprising from 0.1 to 400 mg of said derivative.
29. An imidazole derivative according to anyone of claims 1 to 17, which is selected among the following compounds:
4-[N-(1H-imidazol-l-yl)-N-(4-methoxyphenyl)amino]methylbenzonitrile;
4-[N-(4-hydroxyphenyl)-N-(lH-imidazol-l-yl)amino]methylbenzonitrile;
4-[N-(4-hydroxyphenylmethyl)-N-(lH-imidazol-l-yl)amino]benzonitrile;
4-[N-(3-chloro-4-hydroxyphenylmethyl)-N-(lH-imidazol-l-yl)amino]benzonitrile;
4-[N-(3-bromo-4-hydroxyphenylmethyl)-N-(lH-imidazol-l-yl)amino]benzonitrile;
4-[N-(4-hydroxy-3-methoxyphenylmethyl)-N-(lH-imidazol-l-yl)amino]
benzonitrile;
4-[N-(2,3,5,6-tetrafluoro-4-hydroxyphenylmethyl)-N-(1H-imidazol-l-yl)amino]
benzonitrile;
4-[N-(3-formyl-4-hydroxyphenylmethyl)-N-(lH-imidazol-l-yl)amino]benzonitrile;
4-{[N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)amino]methyl}benzene sulfonamide;
4-[N-(4-hydroxy-3-nitrophenylmethyl)-N-(lH-imidazol-l-yl)amino]benzonitrile;
5-{[N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)amino]methyl}-2-methoxy benzoic
acid;
4-[N-(lH-imidazol-l-yl)-N-(4-nitrophenyl)amino]benzonitrile;
N-(lH-imidazol-l-yl)-N-(4-cyanophenyl)-2-(4-fluorophenyl)acetamide;
N-(lH-imidazol-l-yl)-N-(4-cyanophenyl)-2-(4-hydroxyphenyl)acetamide;
N-(4-cyanophenyl)-3-(4-hydroxyphenyl)-N-(lH-imidazol-l-yl)propanamide;
N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)-4-(phenylmethoxy)-benzensulfonamide;
4-[N-(3-amino-4-hydroxy-phenylmethyl)-N-(lH-imidazol-l-yl)amino] benzonitrile;
4-{N-[2-(4-hydroxyphenoxy)ethyl]-N-(lH-imidazol-l-yl)amino}benzonitrile;
N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)-4-hydroxybenzensulfonamide;
4-[N-(4-aminophenyl)-N-(lH-imidazol-l-yl)amino]benzonitrile;
Sulfamic acid 4-[N-(4-cyanophenylmethyl)-N-(lH-imidazol-lyl)amino]phenyl
ester;
Sulfamic acid-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]methyl}phenyl
ester;
Sulfamic acid 2-chloro-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-
lyl)amino]methyl}phenyl ester;
Sulfamic acid 2-bromo-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]
methyl}phenyl ester, hydrochloride;
Sulfamic acid 2-methoxy-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]
methyl}phenyl ester;
Sulfamic acid 2,3,5,6-tetrafluoro-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-
lyl)amino] methyl}phenyl ester;
4-[N-[(2,2-dioxido-l,2,3-benzoxathiazin-6-yl)methyl]-N-(lH-imidazol-l-yl)amino]
benzonitrile;
N-{4-[N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)amino]phenyl}sulfamide;
Sulfamic acid 4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]sulfonyl}phenyl
ester, hydrochloride;
Sulfamic acid 4-{2-[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]ethoxy} phenyl
ester;
Sulfamic acid 4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)-carbamoyl]-methyl}
phenyl ester;
Sulfamic acid 4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]-3-oxopropyl}
phenyl ester;
Sulfamic acid 3-(aminosulfonyl)amino-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-
lyl)amino]methyl}phenyl ester;
2-Bromo-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]methyl}phenyl
amidimidodisulfate acid;
4-[N-[(2,2-dioxido-3,4-dihydro-l,2,3-benzoxathiazin-6-yl)methyl]-N-(lH-imidazol-
l-yl)amino]benzonitrile;
5-{[N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)amino]methyl}-2-hydroxybenzoic
acid;
4-[N-(lH-imidazol-l-yl)-N-(phenyl)amino]benzonitrile
4-[N-(3-tosylamino-4-hydroxy-benzyl)-N-(lH-imidazol-l-yl)amino]benzonitrile;
4-[N-[(2,2-dioxido-3-tosyl-3H-l,2,3-benzoxathiazol-5-yl)methyl]-N-(lH-imidazol-
l-yl)amino]benzonitri le;
4-[N-[(2,2-dioxido-3H-l,2,3-benzoxathiazol-5-yl)methyl]-N-(lH-imidazol-l-
yl)amino]benzonitri le;
N-(4-cyanopheny)-N-(lH-imidazol-l-yl)-N'-phenylurea.
30. An imidazole derivative according to claim 29, which is selected among
the following compounds:
Sulfamic acid 4-[N-(4-cyanophenylmethy l)-N-(lH-imidazol-lyl)amino]phenyl
ester;
Sulfamic acid-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]methyl}phenyl
ester;
Sulfamic acid 2-chloro-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-
lyl)amino]methyl}phenyl ester;
Sulfamic acid 2-bromo-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]
methyl}phenyl ester, hydrochloride;
Sulfamic acid 2-methoxy-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]
methyl}phenyl ester;
Sulfamic acid 2,3,5,6-tetrafluoro-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-
lyl)amino] methyl}phenyl ester;
4-[N-[(2,2-dioxido-l,2,3-benzoxathiazin-6-yl)methyl]-N-(lH-imidazol-l-yl)amino]
benzonitrile;
Sulfamic acid 4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]sulfonyl}phenyl
ester, hydrochloride;
Sulfamic acid 4-{2-[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]ethoxy} phenyl
ester;
Sulfamic acid 4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)-carbamoyl]-methyl}
phenyl ester;
Sulfamic acid 4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]-3-oxopropyl}
phenyl ester;
Sulfamic acid 3-(aminosulfonyl)amino-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-
lyl)amino]methyl}phenyl ester;
31. An imidazole derivative according to claim 3O, which is Sulfamic acid 2-bromo-4-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino] methyl}phenyl ester, hydrochloride;
32. An imidazole derivative according to anyone of claims 1 to 10 and 18, which is selected among the following compounds:
5-Nitro-[N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)]-benzothiophene-2-
carboxamide;
N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)-2-(6-methoxy-benzothien-3-yl)
acetamide;
4-{N-[lH-imidazol-l-yl]-N-[(6-methoxy-benzothien-3-yl)methyl]amino}
benzonitrile;
4-[N-(6-benzyloxy-l,l-dioxido-benzothien-3-yl)-N-(lH-imidazol-l-yl)amino]
benzonitrile;
4-[N-[(6-benzyloxy-benzothien-2-yl)methyl]-N-(lH-imidazol-l-yl)amino]
benzonitrile;
4-{N-[(6-hydroxy-benzothien-3-yl)methyl]-N-[lH-imidazol-l-yl-]amino}
benzonitrile;
N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)-2-(6-hydroxy-benzothien-3-yl)
acetamide;
4-[N-[(6-hydroxy-l,l-dioxido-benzothien-3-yl)]-N-(lH-imidazol-l-yl)amino]
benzonitrile;
4-[N-[(6-hydroxy-benzothien-2-yl)methyl]-N-(lH-imidazol-l-yl)amino]
benzonitrile;
5-Amino-[N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)]-benzothiophene-2-
carboxamide;
5-(Aminosulfonyl)amino-[N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)]-
benzothiophene -2-carboxamide;
Sulfamic acid 3-[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]-l,l-dioxido-
benzothien-6-yl ester;
Sulfamic acid 3-{2-[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]-2-oxoethyl}-
benzothien-6-yl ester;
Sulfamic acid 3-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]methyl}-
benzothien-6-yl ester;
Sulfamic acid 2-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]methyl}-
benzothien-6-yl ester.
33. An imidazole derivative according to claim 32, which is selected among the following compounds:
Sulfamic acid 3-[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]-l,l-dioxido-
benzothien-6-yl ester;
Sulfamic acid 3-{2-[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]-2-oxoethyl}-
benzothien-6-yl ester;
Sulfamic acid 3-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]methyl}-
benzothien-6-yl ester;
Sulfamic acid 2-{[N-(4-cyanophenyl)-N-(lH-imidazol-lyl)amino]methyl}-
benzothien-6-yl ester;
34. An imidazole derivative according to anyone of claims 1 to 10 and 25,
which is selected among the following compounds:
4-{N-[(6-chloropyridin-3-yl)methyl]-N-(lH-imidazol-l-yl)amino}benzonitrile
6-chloro-N-(4-cyanophenyl)-N-(lH-imidazol-l-yl)nicotinamide.
35. An imidazole compound and/or a compound and/or a pharmaceutical
composition and/or an imidazole derivative substantially as herein described with
reference to the given examples.

Documents:

3428-DELNP-2006-Abstract-(03-08-2010).pdf

3428-delnp-2006-abstract.pdf

3428-DELNP-2006-Claims-(03-08-2010).pdf

3428-delnp-2006-claims.pdf

3428-delnp-2006-Correspondence (Others)- (23-05-2011).pdf

3428-DELNP-2006-Correspondence-Others-(03-08-2010).pdf

3428-delnp-2006-Correspondence-Others-(07-04-2011).pdf

3428-DELNP-2006-Correspondence-Others.pdf

3428-delnp-2006-description (complete).pdf

3428-delnp-2006-drawings.pdf

3428-DELNP-2006-Form-1-(03-08-2010).pdf

3428-DELNP-2006-Form-1.pdf

3428-DELNP-2006-Form-18.pdf

3428-DELNP-2006-Form-2-(03-08-2010).pdf

3428-delnp-2006-form-2.pdf

3428-delnp-2006-form-26.pdf

3428-DELNP-2006-Form-3-(03-08-2010).pdf

3428-delnp-2006-form-3.pdf

3428-delnp-2006-form-5.pdf

3428-DELNP-2006-GPA-(03-08-2010).pdf

3428-delnp-2006-pct-301.pdf

3428-delnp-2006-pct-304.pdf

3428-delnp-2006-pct-308.pdf

3428-DELNP-2006-Petition 137-(03-08-2010).pdf

abstract.jpg


Patent Number 248580
Indian Patent Application Number 3428/DELNP/2006
PG Journal Number 30/2011
Publication Date 29-Jul-2011
Grant Date 26-Jul-2011
Date of Filing 14-Jun-2006
Name of Patentee LABORATOIRE THERAMEX
Applicant Address 6 AVENUE PRINCE HEREDITAIRE ALBERT, MC-98000 MONACO.
Inventors:
# Inventor's Name Inventor's Address
1 RONDOT, BENOIT PARC DE MONTFORT, LOT 8, CHEMIN DU CAMINON, F-06480 LA COLLE SUR LOUP, FRANCE.
2 CLERC, THIERRY 3 ALLEE DU TRAQUET, F-31320 VIGOULET AUZIL, FRANCE.
3 DURANTI, ERIC 258 AVENUE DES FILAGNES, F-06700 SAINT LAURENT DU VAR, FRANCE.
4 BLOT, CHRISTIAN 1582 ROUTE DE CAGNES, F-06480 LA COLLE SUR LOUP, FRANCE.
5 MAILLOS, PHILIPPE 38 CHEMIN DE LA BOURDETTE, F-81500 LABASTIDE SAINT GEORGES, FRANCE.
6 BONNET, PAULE VILLA LES ROCAILLES, CHEMIN GLENA, 37 ROUTE DE SOSPEL, F-06500 MENTON, FRANCE.
7 PUCCIO, FRANCOIS 74 AVENUE DU MONT ALBAN, F-06300 NICE, FRANCE.
8 LAFAY, JEAN 1 RUE CLEMENT ADER, F-06100 NICE, FRANCE.
9 SHIELDS, JACQUELINE 6 AVENUE GEORGE SAND, F-06100 NICE, FRANCE.
10 DUC, IGOR VILLA CASIMIR, 26 RUE BORNIOL, F-06400 CANNES, FRANCE.
PCT International Classification Number C07D 233/56
PCT International Application Number PCT/EP2004/014847
PCT International Filing date 2004-12-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 03293152.9 2003-12-15 EUROPEAN UNION
2 04292681.6 2004-11-12 EUROPEAN UNION