Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-02
2002-03-12
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S210010, C514S210190, C514S210200, C540S001000, C546S275100, C546S276400, C546S194000, C546S309000
Reexamination Certificate
active
06355631
ABSTRACT:
The present invention relates to pharmaceutical compositions containing, as active ingredient, at least one compound of formula:
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
2
and R
3
represent phenyl radicals, R
1
represents a radical —N(R
4
)SO
2
R
6
, R
4
represents a phenyl radical and R
6
represents a methyl 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 part of the invention.
In formula (I)
R
1
represents a radical —N(R
4
)R
5
, —N(R
4
)—CO—R
5
, —N(R
4
)—SO
2
R
6
,
R
2
and R
3
, 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, trifluoromethoxy, —CO—alk, cyano, —COOH, COOalk, —CONR
7
R
8
, —CO—NH—NR
9
R
10
, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or —alk—NR
7
R
8
radicals; or a heteroaromatic chosen from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 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, cyano, —COOH, COOalk, —CO—NH—NR
9
R
10
, —CONR
7
R
8
, —alk—NR
9
R
10
, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl radical,
R
4
represents a radical —C(R
11
)(R
12
)—Het, —Het, —(CR
11
)(R
12
)—Ar, Ar, cycloalkyl or norbornyl,
R
5
represents a hydrogen atom or a hydroxyalkyl, —alk—COOalk, —alk—CONR
7
R
8
, —alk—NR
7
R
8
, alkoxy, Ar, Het, —CH
2
Ar, —CH
2
Het or alkyl radical optionally substituted with one or more halogen atoms,
R
6
represents a hydroxyalkyl, —alk—COOalk, —alk—CONR
7
R
8
, —alk—NR
7
R
8
, alkoxy, Ar, Het, —CH
2
Ar, —CH
2
Het or alkyl radical optionally substituted with 1 or more halogen atoms,
R
7
and R
8
, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R
7
and R
8
together form with the nitrogen atom to which they are attached a 3- to 10-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
9
and R
10
, which are identical or different, represent a hydrogen atom or an alkyl, —COOalk, cycloalkyl, alkylcycloalkyl, —alk—O—alk or hydroxyalkyl radical or alternatively R
9
and R
10
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, —COalk, —COOalk, —CO—NHalk, —CS—NHalk, oxo, hydroxyalkyl, —alkyl—O—alk or —CO—NH
2
radicals,
R
11
represents a hydrogen atom or a hydroxyalkyl, —alk—COOalk, —alk—CONR
7
R
8
, —alk—NR
7
R
8
, alkoxyalkyl, Ar, Het, —CH
2
Ar, —CH
2
Het or alkyl radical optionally substituted with one or more halogen atoms,
R
12
represents a hydrogen atom or a hydroxyalkyl, —alk—COOalk, —alk—CONR
7
R
8
, —alk—NR
7
R
8
, alkoxyalkyl or alkyl radical optionally substituted with one or more halogen atoms, or alternatively R
11
and R
12
together form with the carbon atom to which they are attached a 3- to 10-membered saturated mono- or bicyclic ring, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
Ar represents a phenyl, naphthyl or indenyl radical, these different radicals being optionally substituted with one or more halogen atoms or alkyl, alkoxy, —CO—alk, cyano, —COOH, —COOalk, —CONR
13
R
14
, —CO—NH—NR
15
R
16
, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, —alk—NR
15
R
16
, —NR
15
R
16
, alkylthioalkyl, formyl, CF
3
, OCF
3
, Het, —O—alk—NH—cycloalkyl, SO
2
NH
2
, hydroxyl, hydroxyalkyl, —NHCOalk, NHCOOalk radicals or on 2 adjacent carbon atoms with 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, alkoxycarbonyl, oxo or hydroxyl radicals, the nitrogen-containing heterocycles being optionally in their N-oxidized form,
R
13
and R
14
, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R
13
and R
14
together form with the nitrogen atom to which they are attached a 3- to 10-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
15
and R
16
, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R
15
and R
16
together form with the nitrogen atom to which they are attached a 3- to 10-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, alk, represents an alkyl or alkylene radical.
In the preceding definitions and in those which follow, unless otherwise stated, 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.
Among the alkyl radicals, there may be mentioned the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl radicals. Among the alkoxy radicals, there may be mentioned the methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and pentyloxy radicals.
Among the cycloalkyl radicals, there may be mentioned in 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, quinazoline, quinoxaline, quinoline, pyrazole, pyrrole, pyridine, imidazole, indole, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, piperazine, triazole, furan, tetrahydroisoquinoline, tetrahydroquinoline, these heterocycles being optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, oxo, hydroxyl, OCF
3
or CF
3
radicals.
The compounds of formula (I) may be provided in the form of enantiomers and of diastereoisomers. These isomers and mixtures thereof also form part of the invention.
Preferably, the compounds of formula (I) are those for which
R
1
represents a radical —N(R
4
)R
5
or —N(R
4
)—SO
2
R
6
,
R
2
represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, —CO—alk, cyano, —CONR
7
R
8
, hydroxyalkyl or —alk—NR
7
R
8
radicals; or a heteroaromatic chosen from the pyridyl, pyrimidyl, 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
7
R
8
, —alk—NR
9
R
10
, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl or hydroxyalkyl radical,
R
3
represents either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, —CO—alk, cyano, —CO
Achard Daniel
Bouchard Herve
Bouquerel Jean
Filoche Bruno
Grisoni Serge
Aventis Pharma S.A.
Newman Irving
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