ZA200206916B - Pharmaceutical compositions containing 3-amino-azetidine derivatives, novel derivatives and preparation thereof. - Google Patents

Pharmaceutical compositions containing 3-amino-azetidine derivatives, novel derivatives and preparation thereof. Download PDF

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ZA200206916B
ZA200206916B ZA200206916A ZA200206916A ZA200206916B ZA 200206916 B ZA200206916 B ZA 200206916B ZA 200206916 A ZA200206916 A ZA 200206916A ZA 200206916 A ZA200206916 A ZA 200206916A ZA 200206916 B ZA200206916 B ZA 200206916B
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alkyl
radical
radicals
alk
substituted
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ZA200206916A
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Daniel Achard
Herve Bouchard
Jean Bouquerel
Bruno Filoche
Serge Grisoni
Augustin Hittinger
Michael Myers
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Aventis Pharma Sa
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Description

! ! w!
PHARMACEUTICAL CCMPOSITIONS CONTAINING
3-AMINOAZETIDINE DERIVATIVES, NOVEL
DERIVATIVES AND THEIR PREPARATION
3 ie present 1nNvention re.ates TO pharmaceutical compositions containing, as ac-.ve ingredient, at least one compound of formula:
R,
R A iy ’
R, or one of its pharmaceutically acceptable salts, to the novel derivatives of formula (I), to their pharmaceutically acceptable salts and to their preparation.
The compound of formula (I) for which R- and
R; represent phenyl radicals, R; represents a radical -N (Rs) -Y-Rg, ¥Y is SO,, Rs represents a methyl radical and
Rg represents a phenyl radical is described as a synthesis intermediate in Patent WO 99/01451. The other compounds and their pharmaceutically acceptable salts are novel and as such form parts of the invention.
In formula (I)
R, represents a radical -NHCOR; or -N (Rs) -Y-Rg,
Y is CO or SOj,
A
> 4 v ® 2
R- and Rj3, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted oz substituted with one or more halogen atoms cr alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoro- methoxy, -CC-alx, cyanc, —-CCCH, -CCCalk, -CCh=-=., -CO-NH-NRoRi;, alkylsulfanyl, alkylsulfinyl, alkyl- sulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR-R; radicals; or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyil, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4- tetrahydro-isoquinolyl, thiazolyl and thienyl rings, it being possible for these hetercaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NRgRig, -CONRsRg, -alk-NRgR;g, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl radical,
R; represents a radical -alk-S0:-R;;, -alk-SC,-CH=CH-Rij,
Het substituted with -S0;-R;; or phenyl substituted with =-S0,-Ry; or -alk-S0-.-Riq,
Rs represents a hydrogen atom or an alkyl radical,
R¢ represents a phenylalkyl, Het or Ar radical,
[ ® 3
R- and Rs, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R- and Rg together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mcno- or bicyclic heterocycle, optionally containing another netercatom chosen Irom oxygen, sullur ana nitrogen and being optionally substituted with one or more alkyl radicals,
Res and Rie, which are identical or different, represent a hydrogen atom or an alkyl, -C0OOalk, cycloalkyl, alkylcycloalkyl, -alk-0O-alk or hydroxyalkyl radical or alternatively Ro and Rip together form with the nitrogen atom to which they are attached a 3- to 1C-membered saturated or unsaturated monoc- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH;, radicals,
Ry: represents an alkyl, Ar or Het radical,
Ar represents a phenyl, naphthyl or indenyl radical, these radicals being opticnally substituted with one or more halecgen atoms or alkyl, alkoxy, cyano, -CO-alk, -COOH, -COOalk, -CONR;2R;3, -CO-NH-NR;4R;;, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NRijjR;s, -NRizR;s, alkylthioalkyl, formyl, hydroxyl, hydroxyalkyl, Het, -0-alk-NH-cycloalkyl, CCF;, CF3, -NH-CO-alk, -SO:NH:,
® -NH-COCHs, -NH-CCOalk or Het radicals, or alternatively, on 2 adjacent carbon atoms, with a dioxymethylene,
Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one ) 5 or more heteroatoms chosen from oxygen, sulfur and nitrogen opticha..y Substitutea with cone or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo, hydroxyl, OCF; or CF: radicals, the nitrogen- containing heterocycles being opticnally in their
N-oxidized form,
Ri; and R;sz, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R:- and R;3 together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated mono- or bicyclic heterocycle, optionally containing another hetercatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ry4 and Ris, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-0O-alk or hydroxyalkyl radical or alternatively Ri; and Rs together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -CO0Calk,
. ® 5 -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -aik-0O-alk cor -CO-NH.: radicals, alk represents an alkyl or alkylene radical.
In the preceding definitions and in those which follow, unless otherwise stated, the alkyl and aiky.ene radicals ana portions and the alkoxy radicans and portions are in the form of a straight or branched chain and contain 1 to © carbon atoms and the cycloalkyl radicals contain 3 to 10 carbon atoms.
Among the alkyl radicals, there may be mentioned the methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, 1so-butyl, tert-butyl, pentyl and hexyl radicals. Among the alkoxy radicals, there may be mentioned the methoxy, ethoxy, n-propoxy, 1l1so-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and pentyloxy radicals.
Among the cycloalkyl radicals, there may be mentioned the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals.
The term halogen comprises chlorine, fluorine, bromine and iodine.
Among the heterocycles represented by Het, the following heterocycles may be mentioned: benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, guinazoline, guinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, pyrrolidine,
® triazole, furan, tetrahydroisoguincline, tetrahydroquinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo, hydroxyl,
OCF; or CF, radicals.
The compcunas oi Iformu.a ,-, May be groviaea in the form of enantiomers and of diasterecisomers.
These optical i1scmers and mixtures therccf also Ifcrm part of the invention.
Preferably, the compounds of formula (I) are those for which
R: represents a radical -N (Rs) -Y-Rg,
Y is SO,
R; represents either a phenyl which 1s unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifliuoromethoxy, cyano, -CONR+Rg, hydroxyalkyl or -alk-NRyRg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, thiazolyl and thienyl rings, it being possible for these hetercaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR-Rg, -alk-NRgRip, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical,
Rs; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR7Rg, hydroxyalkyl or -alk-NR;Rg radicals; or a
_ heteroaromatic chosen from the pyridyl, pyrimidy_Z, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or substituted with a halcgen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR-R:, —&LK-INRsRip, awkyisu.sianyi, a&rKyisuriiny., a-rxy_suiicny~ or hydroxyalkyl radical,
R: represents a hydrogen atom cr an alkyl radical,
R¢ represents a naphthyl, phenylalkyl, Het or phenyl radical opticnally substituted with one or more halogen atoms or alkyl, alkoxy, cyano, -CO-alk, COOalk, -CONR::R33, —alk—-NRi4R;s, -NR:4Ris, hydroxyl, hydroxvalkyl,
Het, OCF;3;, CF3, -NH-CO-alk, -8S0:NH- or -NH-COOalk radicals, or alternatively, on 2 adjacent carbon atoms, with dioxymethylene,
R- and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Rs and Rg together form with the nitrogen atom to which they are attached a 3- toc lO0-membered saturated mono- or bicyclic heterocycle, optionally containing another hetercatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
R. and Rig, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical or alternatively Rg and Rip; together form with the nitrogen atom to which they are attached a 3- to 1l0-membered
® saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another hetercatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, oxo or -CO-NH- radicals,
Riz and Riz, WLRICh are Identica. or Gifferent, represent a hydrogen atom or an alkyl radical or alternatively R-- and R;; together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated monc- or bicyclic heterocycle, opticnally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ris and Ris, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical or alternatively Rijs and Ris together form with the nitrogen atom to which they are attached a 3- toc 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, oxo, hydroxyalkyl or —-CO-NH, radicals,
Het represents a 3- to l0-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl,

Claims (14)

. ® 01/64633 58 PCT/FR01/00601 CLAIMS
1. Pharmaceutical composition containing, as active ingredient, a compound of formula: R, BN Rs al 0 “Ry in which R; represents a radical -NHCOR; or ~-N(Rs)-Y-Rg, Y is CO or S03, R; and Rj, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoro- methoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR-Rg, -CO-NH-NRgRi1p, alkylsulfanyl, alkylsulfinyl, alkyl- sulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NRjRg radicals; or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4- tetrahydroisoquinolyl, thiazolyl and thienyl rings, it
. ® 59 being possible for these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NRoR;g, -CONR7Rz, -alk-NRsR::, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl radical, Rs represents a radical -alk-S0;-Ri;, -alk-S0,-CH=CH-R;i, Het substituted with -S0,-R;: or phenyl substituted with -50;-R11 or -alk-S0O;-R;;, Rs represents a hydrogen atom or an alkyl radical, Re represents a phenylalkyl, Het or Ar radical, R; and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ry and Rg together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, Rg and Ryp, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively Rg and Rip; together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally
. ® 60 substituted with one or more alkyl, -COalk, -COCalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-0O-alk or -CO-NH,; radicals, R:; represents an alkyl, Ar or Het radical,
Ar represents a phenyl, naphthyl or indenyl radical, these radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, cyano, -CO-alk, -COCH, -COOalk, =-CONR;zR;3, -CO-NH-NRj4R;s5, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NRisRi5, -NR:4R:s,
alkylthioalkyl, formyl, hydroxyl, hydroxyalkyl, Het, -0O-alk-NH-cycloalkyl, OCF;, CFj3, -NH-CO-alk, -SO,NH-, -NH-COCH;, -NH-COOalk or Het radicals or alternatively, on 2 adjacent carbon atoms, with a dioxymethylene,
Het represents a 3- to 1l0-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo, hydroxyl, OCF; or CF; radicals, the nitrogen-
containing heterocycles being optionally in their N-oxidized form,
Riz and Ris, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ri, and R;3 together form with the nitrogen atom to which they are attached a 3- to l1l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being cpticnally substituted with c¢ne or more alkyl radicals, R;; and Ris, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, «cycloalkyl, > aiky.Ccycloalkys, -aix-J-a.xK CY NyQroxya.sy. radical. oC: aiternatively R:; and Ris together form with the nitrogen atom to which they are attached a 3- to 1{0-memberea saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another hetercatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one c¢r more alkyl, -CCalk, -CCCalk, ~CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, =-alk-O-alk or -CO-NH, radicals, alk represents an alkyl or alkylene radical, the alkyl and alkylene radicals and portions and the alkoxy radicals and portions are in the form of a straight or branched chain and contain 1 to 6 carbon atoms and the cycloalkyl radicals contain 3 to 10 carbon atoms, an optical isomer of such a compound or one of its pharmaceutically acceptable salts.
2. Composition according to claim 1 for which in the compound of formula (I) Het 1s chosen from benzimidazole, benzoxazole, benzothiazole, benzothiophene, cinnoline, thiophene, gquinazoline, guinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, pyrrolidine,
; ® 62 triazole, furan, tetrahydroisoguinoline, tetrahydro- quinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo, hydroxyl, OCF; or CF3 radicals.
3. Pharmaceutical composition containing, as active ingredient, at least one compound of formula (I) according to claim 1 in which Ri, represents a radical -N(R;)-Y-Rg, Y is SOg, R; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, ~CONRjRg, hydroxyalkyl or -alk-NRsyRs radicals; or a heteroaromatic chosen from the pyridyl, pyrimidinyl, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR;Rg, ~alk-NRgRjg, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical, R; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, ~CONR7Rg, hydroxyalkyl or -alk-NR-sRg radicals; or a heteroaromatic chosen from the pyridyl, pyrimidinyl, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or
. ® 63 substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR-R:, —alk-NRgRig, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical, S Fe represents a LydIOJel. alll CI &l. cor,. rauliac.,
KR: represents a naphthyl, phenylalkyl, Het or phenyl radical optionally substituted with one or more halogen atoms or alkyl, alkoxy, cyano, -CO-alk, COOalk, -CONR1zR33, —-alk-NRisRis, -NRj4Ris, hydroxyl, hydroxyalkyl,
Het, OCF;, CF3, -NH-CO-alk, -SO;NH: or -NH~-COOalk radicals, or alternatively, on 2 adjacent carbon atoms, with dioxymethylene, Ry; and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Rs,
and Rg together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, Res and Rip, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical or alternatively Re and Rjp together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally
_ substituted with one or more alkyl, oxo or =CO-NE- radicals, R:; and Rj3, which are identical or different, represent : a hydrogen atom or an alkyl radical or alternatively R:- > ana no: Together Icorm willl The nilicyel. alll we wWih.CTh they are attached a 3- to l0-mempbered saturaled mono- or bicyclic heterocycle, optionally containing ancther heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
R.; and Rys, which are identical or different, represent a hydrogen atom or an alkyl, cyclecalkyl, alkylcycloalkyl or hydroxyalkyl radical ox alternatively Ry; and Rs together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, oxo, hydroxyalkyl or —-CO-NH: radicals, Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen opticnally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo or hydroxyl radicals, the nitrogen-containing heterocycles being optionally in their N-oxidized form and, preferably, Het represents a heterocycle chosen
® from the following heterocycles: benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, guinazoline, quinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, z Lnlaclaziie, Ioral., Lela, Udlel8Cgusi.cline anc tetrahydroguinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, oxo, hydroxyl, OCF: or CFs radicals, an optical isomer of such a compound or one of its pharmaceutically acceptable salts.
4. Pharmaceutical composition containing, as active ingredient, at least one compound cof formula (I) according to claim 1 in which
R. represents a radical -N(Rsg)-Y-Rg, Y is S02,
R. represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy or hydrexyalkyl radicals; or a heteroaromatic chosen from pyridyl and pyrimidyl rings, 1t being possible for f these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl or trifluoromethoxy radical, Ry represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy or hydroxyalkyl radicals; or a heteroaromatic chosen from
; ® 66 pyridyl and pyrimidyl rings, 1f being possible for - these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl or trifluoromethoxy radical, = ~: represents a NYyarogen atom CX an a.xKy. raalla.,
R. represents a naphthyl, phenylalkyl, Het or phenvl radical opticnally substituted with one or more halogen atoms or alkyl, alkoxy, -NRisRis, hydroxyl, hydroxyalkyl, OCF3, CF; or -SO;NH, radicals, or alternatively, on 2 adjacent carbon atoms, with dioxymethylene, Ry; and Ris, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical or alternatively Ris and Ri; together form with the nitrogen atom to which they are attached a 3- to 1l0-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, oxo, hydroxyalkyl or -CO-NH, radicals, Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo or hydroxyl radicals, the nitrogen-containing heterocycles being opticnally in their N-oxidized form and, preferably, Het represents a heterocycle chosen
. ® 67 from the following heterocycles: benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, quinoline, pyrrole, pyridine, pyrimidine, thiazcle, thiadiazole, furan, tetrahydroisogquinoliine and z TetranyarcguinoLine, these neterocyiles pelng cpticnally substituted wlth cne or mere halogen atoms or alkyl, alkoxy, vinyl, oxo, hydroxyl, CCE. or CF. radicals, an optical isomer of such a compound or one of its pharmaceutically acceptable salts.
5. Compounds cf formula: R, Al R, in which
R. represents a radical -NHCOR; or —-N(Rs)-Y-Rg, Y is CO or SOp, R- and Ri, which are identical or different, represent either an aromatic chosen from phenyl, naphthyl and indenyl, these aromatics being unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoro- methoxy, -CO-alk, cyano, ~-COOH, -COOalk, -CONR:Rg, -CO-NH-NRgR;p, alkylsulfanyl, alkylsulfinyl, alkyl-
. ® 68 sulfonyl, alkylsulfanylalkyl, alkylsulfinylalkvl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR-R: radicals; or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,
<,3-dinhydropenzoiuryi, Z,3-alnycdrobenzotnieny., pyrimidinyl, furyl, imidazclyl, isochromanyl, - iscquinolyl, pyrrolyl, pyridyl, quinolvyi, 1,2,3,4- tetrahydro-isoquinolyl, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, =-COOalk, -CO-NH-NRgR;g, -CONRyRg, —-alk-NRgRig, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl or hydroxyalkyl radical,
R, represents a radical -alk-S0:-R;;, -alk-S0-.-CH=CH-Rii, Het substituted with -S0,-R;; or phenyl substituted with ~-S50-.—-R;; or -alk-S0:-Rqq,
Rs represents a hydrogen atom or an alkyl radical,
R¢ represents a phenylalkyl, Het or Ar radical,
R; and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ry and Rg together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono-
or bicyclic heterocycle, optionally containing another hetercatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
. ® 69
R. and R.;, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-0O-alk or hydroxyalkyl radical or alternatively Re and Rip together form with the nitrogen S) &Tom TC which They are attached a 2- To Llo-heiwsred saturated or unsaturated mono- or bicyclic heterocycle, cptionally containing another heteroatom chosen from cxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -CCOalk, -CO-NHalk, =-CS-NHalk, oxo, hydroxyalkyl, -alk-0O-alk or -CC-NH; radicals, R:; represents an alkyl, Ar or Het radical, Ar represents a phenyl, naphthyl cor indenyl radical, these radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, cyano, -CO-alk, ~-COOH, -COOalk, -CONRi3R;3, —-CO-NH-NR;4Ris, alkylsulfanvyl, alkylsulfinyl, alkylsulfonyl, -alk-NRigR;5, -NRisRis, alkylthiocalkyl, formyl, hydroxyl, hydroxyalkyl, Het, -0O-alk-NH-cycloalkyl, OCF;, CF; -NH-CO-alk, -SO:NH, ~-NH-COCH;, -NH-COOalk or Het radicals, or alternatively, cn 2 adjacent carbon atoms, with a dioxymethylene, Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo, hydroxyl, OCF; or CF; radicals, the nitrogen-
. ® 70 containing heterocycles being optionally in their N-oxidized form, Riz and R;3, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R:- z &Nna& Ki: TCgetner form wlth Tne nitrogen atom To which they are attached a 3- to l10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, R;; and Ris, which are identical or different, represent a hydrogen atom or an alkyl, -CO0Oalk, cycloalkyl, alkylcycloalkyl, -alk-0O-alk or hydroxyalkyl radical or alternatively Rj; and R)s together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another hetercatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, =-COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-0O-alk or -CO-NH; radicals, alk represents an alkyl or alkylene radical, the alkyl and alkylene radicals and portions and the alkoxy radicals and portions are in the form of a straight or branched chain and contain 1 to 6 carbon atoms and the cycloalkyl radicals contain 3 to 10 carbon atoms,
® 7 their optical isomers and their pharmaceutically acceptable salts, with the exception of the compound for which fcr which R: and Rs; represent phenyl radicals, R; represents a radical =-N/R:)-V-R., VY is 80-, R: represents a methyl radical and R; represents a phenyl radical.
6. Compcunds cof formula (I) according to claim 5 for which Het is chosen from benzimidazole, benzoxazole, Dbenzothiazole, Dbenzothiophene, c¢innoline, thiophene, guinazoline, guinoxaline, guinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, pyrrolidine, triazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo, hydroxyl, OCF: or CF; radicals for which R,; and Rs; represent phenyl radicals, R; represents a radical -N{(Rg)-Y-R¢, Y 1s S80, Rs represents a methyl radical and R¢ represents a phenyl radical.
7. Compounds of formula (I) according to claim 5 in which R: represents a radical -N(Rs)-Y-Reg, Y is SO,
R. represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR-Rg, hydroxyalkyl or -alk-NR;Rg radicals; or a
. ® 72 heteroaromatic chosen from the pyridyl, pyrimidinyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy,
hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR-R:, -alk-NRsRip;, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical, R3; represents either a phenyl which 1s unsubstituted or substituted with one or more halogen atoms or alkyl,
alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR7Rg, hydroxyalkyl or -alk-NR-R; radicals; or a hetercaromatic chosen from the pyridyl, pyrimidinyl, thiazolyl and thienyl rings, it being possible for these heterocaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, -CONR-Rg, -alk-NRgRi1p, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical,
Rs represents a hydrogen atom or an alkyl radical,
Rs represents a naphthyl, phenylalkyl, Het or phenyl radical optionally substituted with one or more halogen atoms or alkyl, alkoxy, cyano, -CO-alk, COOalk, -CONR;2R13, -alk-NRigRis, -NRi4R;5, hydroxyl, hydroxyalkyl, Het, OCF;, CFi3;, -NH-CO-alk, -SO:NH; or -NH-COOalk radicals, or alternatively, on 2 adjacent carbon atoms, with dioxymethylene,
R; and Rg, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R;
® and Re together form with the nitrogen atom to which they are attached a 3- to l0-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and Zz Lelng oSpricnalsly substituted With one Cr mors aLdy.
R. and Ry, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radicas or alternatively Rg and Rig together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, oxo or -CO-NH- radicals, Riz and Ri3, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ri: and Rijs; together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another hetercatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, Ris and R;s, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical or alternatively Ry; and Ris together form with the nitrogen
® atom to which they are attached a 3- tc 1l-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally z SUDSTITUTEd Wilh One Or more a.Ky., OXC, nNVAICHYa_-Xy.
ocr ~CO-NH: radicals, Het represents a 3- to 1l0-membered unsaturated or saturated mono- or bicyclic heterocycle contalning one or more heteroatoms chosen from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo or hydroxyl radicals, the nitrogen-containing heterocycles being optionally in their N-oxidized form and, preferably, Het represents a heterocycle chosen from the following heterocycles: benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, guinazoline, guinoxaline, quinoline, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, furan, tetrahydroiscoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, oxo, hydroxyl, OCF; or CF; radicals, their optical isomers and their pharmaceutically acceptable salts, with the exception of the compound for which R; and Rj represent phenyl radicals, R; represents a radical
. ® 75 ~N{Rz)~-Y-Rg, Y is S50:, R: represents a methyl. radical and R¢ represents a phenyl radical.
8. Compounds of formula (I) according to claim 5 in which z XR. represents a racicar —iiiRs, —I-Ra, Y is SO,
R. represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluorocmethoxy or hydroxyalkyl radicals; or a heteroaromatic chosen from pyridyl and pyrimidyl rings, it being possible for oT these heteroaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl or trifluoromethoxy radical, R; represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy or hydroxyalkyl radicals; or a hetercaromatic chosen from pyridyl and pyrimidyl rings, it being possible for ST these hetercaromatics to be unsubstituted or substituted with a halogen atom or an alkyl, alkoxy, hydroxyl, trifluoromethyl or trifluoromethoxy radical, Rs represents a hydrogen atom or an alkyl radical, R¢ represents a naphthyl, phenylalkyl, Het or phenyl radical optionally substituted with one or more halogen atoms or alkyl, alkoxy, -NRi4Ri;s, hydroxyl, hydroxyalkyl, OCF3, CF3 or —-SO;NH; radicals, or alternatively, on 2 adjacent carbon atoms, with dioxymethylene,
' x i 76
R.; and R::, which are identical cr different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical cr N alternatively Rjs and Ris together form with the nitrogen z atcm TC whicn Chey are atTacnea & -- TC Ll-mempered saturated Cr unsaturated menc- or plicyciic heterccyalc, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, oxo, hydroxyalkyl or ~CO-NH, radicals, Het represents a 3- tc 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, alkoxycarbonyl, oxo or hydroxyl radicals, the nitrogen-containing heterocycles being optionally in their N-oxidized form and, preferably, Het represents a heterocycle chosen from the following heterocycles: benzimidazole, benzoxazole, benzothiazole, benzothiophene, thiophene, guinoline, pyrrole, pyridine, pyrimidine, thiazole, thiadiazole, furan, tetrahydroisoquinoline and tetrahydroquinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, vinyl, oxo, hydroxyl, OCF; or CFs radicals, their optical isomers and their pharmaceutically acceptable salts,
® with the exception of the compound for which R: ana R: represent phenyl radicals, R; represents a radical -N(Rs)-Y-Rgs, Y is SO;, Rs represents a methyl radical and R¢ represents a phenyl radical. fo
9. Process for preparing the compounds of formuta (I) accerding to claim 5 fcr which R&R. represents a radical ~NHCOR,;, characterized in that ar acid R,COOH for which Rs; has the same meanings as in claim 5 is reacted with a derivative of formula: R, SY a} NH, in which Rp; and R3; have the same meanings as in claim 5, the product isolated and optionally converted to a pharmaceutically acceptable sal=:.
10. Process for preparing the compounds of formula (I) according to claim 5 for which R; represents a radical -N(Rs)-Y-R¢, characterized in that a derivative of formula: R, 4 1 NH,
® in which R: and Rs; have the same mcanings as In claim S is reacted with a derivative Hal-Y-R¢ for which Y and Rs have the same meanings as in claim 5 and Hal rerresents a halogen atom, opticnally followed by a derivative Z Ha.-alX, Hal represents a na.ogen atom and a_.x represents an alkyl radical {1-6C in the fcrm of =z stralght or branched chain) to give the compcunds for which Rs 1s an alkyl radical, the product isolated and optionally converted to a pharmaceutically acceptable salt.
11. Process for preparing the compounds of formula (I) according to claim 5, characterized in that a derivative R-—-CHBr-R3 for which R; and Rs have the same meanings as in claim 5 is reacted with a derivative of formula: R, in which R; has the same meanings as in claim 5, the product isclated and optionally converted to a pharmaceutically acceptable salt.
12. Process for preparing the compounds of formula (I) according to claim 5 for which R; represents a radical -N(Rs)-Y-Rg in which Re¢ is a phenyl radical substituted with a hydroxyl radical, characterized in that a corresponding compound of formula (I) for which R, represents a radical -N(Rs)-Y-Re¢ in which R¢ 1s a phenyl radical substituted with an alkoxy radical is
Lt E ® hydrolyzed, the product isolated and cpticnally converted to a pharmaceutically acceptable salt.
13. Process for preparing the compounds of formula (I) according to claim 5 for which R. represents & radicCa. -—iinhz;—Y-nR¢ in WhRiCh =e 2S & pneny. racical substituted with a hydroxy {1Clalkyl radical, characterized in that diisobutylaluminum hydride is reacted with a corresponding compound of formula (I; for which R; represents a radical -N{Rs)-Y-R¢ in which Re is a phenyl radical substituted with an alkoxycarbonyl radical, the product isolated and optionally converted to a pharmaceutically acceptable salt.
14. Process for preparing the compounds of formula (I) according tc claim 5 for which R, represents a radical -N(Rs)-Y-Rg in which Rg is a phenyl radical substituted with a l-pyrrolidinyl radical, characterized in that pyrrolidine is reacted with a corresponding compound of formula (I) for which R; represents a radical -N(Rs)-Y-Rg in which R¢ 1s a phenyl radical substituted with a fluorine atom, the product isolated and optionally converted to a pharmaceutically acceptable salt.
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