Biphenyl compounds and use thereof as oestrogenic agents

Details Biphenyl compounds and use thereof as oestrogenic agents Biphenyl compounds and use thereof as oestrogenic agents

1998-09-28

2001-09-11

Padmanabhan, Sreeni (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ketone doai

C514S700000, C514S726000, C514S731000, C568S337000, C568S442000, C568S716000, C568S734000

Reexamination Certificate

active

06288126

ABSTRACT:

The present invention relates to the use as medicaments of biphenyl compounds, the pharmaceutical compositions containing them, new biphenyl compounds, their preparation process and the intermediates of this process.
A subject of the invention is as medicaments the compounds of general formula (I):
in which R
1
, and R
2
, identical or different, represent a hydrogen atom, a halogen atom, a hydroxyl radical, a trifluoromethyl radical, a nitro radical, an amino radical, an alkyloxy, alkylthio, alkylamino or dialkylamino radical, in which the alkyl contains from 1 to 8 carbon atoms, an —NR
A
R
B
group, in which R
A
and R
B
form with the nitrogen atom to which they are linked a saturated or unsaturated heterocycle with 5 to 6 members optionally containing another heteroatom chosen from N, O and S, a linear or branched alkyl, alkenyl or alkynyl radical, each containing at most 8 carbon atoms and optionally substituted, an aryl radical containing from 6 to 14 carbon atoms and optionally substituted, an aralkyl radical containing from 7 to 15 carbon atoms and optionally substituted, or a CH(OH)—Y or C(O)—Y radical in which Y represents a substituted or non-substituted alkyl, alkenyl or alkynyl radical containing from 1 to 8 carbon atoms, or a substituted or non-substituted aryl group containing from 6 to 14 carbon atoms, or also R
1
can form together with R
3
a —CH═CH—CH═CH— group, R
3
and R
4
, identical or different, represent a hydrogen atom, a halogen atom or an alkyl radical containing from 1 to 8 carbon atoms, or R
3
can form together with R
1
a —CH═CH—CH═CH— group, R
6
and R
7
identical or different, represent a hydrogen atom or a halogen atom, R
8
represents a hydrogen atom or an optionally substituted benzyl radical and R
5
, represents an [A]—CH
3
, —[A]—C(OH)ZZ′ or —[A]—C(O)Z″ group in which —[A]— represents a linear or branched alkylene, alkenylene or alkynylene radical each containing at most 8 carbon atoms or a single bond, and Z, Z′ and Z″ represent a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing up to 8 carbon atoms or an aryl radical containing from 6 to 14 carbon atoms and optionally substituted, as well as their addition salts with pharmaceutically acceptable acids and bases, it being understood that there are excluded the compounds in which R
5
represents the [A]—C(O)—Z″ group in which [A] is a single bond, Z″ is an alkyl radical containing from 1 to 8 carbon atoms and R
1
, R
2
, R
3
, R
4
, R
6
, R
7
and R
8
are hydrogen atoms.
By halogen atom is meant fluorine, iodine, bromine and chlorine.
By alkyloxy radical containing from 1 to 8 carbon atoms, is preferably meant the radical chosen from methoxy, ethoxy, propoxy, butoxy and pentoxy.
By alkylthio radical containing from 1 to 8 carbon atoms, is preferably meant the radical chosen from methylthio, ethylthio, propylthio, isopropylthio and butylthio.
By alkylamino radical containing from 1 to 8 carbon atoms is preferably meant the radical chosen from methylamino, ethylamino, propylamino, butylamino, pentylamino.
By dialkylamino radical each containing from 1 to 8 carbon atoms is preferably meant the radical chosen from dimethylamino, diethylamino and methylethylamino.
By —NR
A
R
B
group is preferably meant the group chosen from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl and pyrrolyl.
By linear or branched alkyl, alkenyl or alkynyl radical, each containing at most 8 carbon atoms is preferably meant the radical chosen from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethyl pentyl, 3,3-dimethyl pentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl 3-ethylpentyl, vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl, isobutenyl, ethynyl, propynyl, propargyl, butynyl and isobutynyl and most particularly the methyl, ethyl, vinyl, propenyl, ethynyl and propynyl radical.
By aryl radical containing from 6 to 14 carbon atoms and aralkyl containing from 7 to 15 carbon atoms and optionally substituted, is preferably meant a phenyl or benzyl radical optionally substituted by a halogen atom chosen from fluorine, chlorine, bromine and iodine, an alkyl radical having from 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, an alkoxy radical having from 1 to 8 carbon atoms such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, an alkylthio radical having from 1 to 8 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, an amino, alkylamino radical having from 1 to 8 carbon atoms such as methylamino or ethylamino, dialkylamino having 2 to 16 carbon atoms such as dimethylamino, diethylamino, methylethylamino, each of these dialkylamino radicals being optionally in oxidized form, an aminoalkyl radical having from 1 to 8 carbon atoms such as aminomethyl or aminoethyl, a dialkylaminoalkyl radical having from 3 to 16 carbon atoms such as dimethylamino methyl or ethyl, a dialkylaminoalkyloxy radical having from 3 to 16 carbon atoms such as in particular the dimethylamino ethyloxy radical, a hydroxyl group, a free, esterified carboxy group such as alkoxy carbonyl for example methoxy carbonyl or ethoxy carbonyl or salified by a sodium or potassium atom, a cyano radical, a trifluoromethyl radical, a nitro radical, a formyl radical, a carbamoyl radical, an acyl group such as acetyl, propionyl, butyryl or benzoyl, acyloxy having up to 12 carbon atoms such as acetoxy or a group of formula:
—O—CO—(CH
2
)
m
CO
2
H
in which m is an integer ranging from 1 to 5, an alkenyl radical such as vinyl or propenyl, an alkynyl radical such as ethynyl or propynyl, an aryl radical such as phenyl, furyl, thienyl or aralkyl such as benzyl.
The expression “optionally substituted aryl” indicates that one or more substituents, identical or different, can be present in the ortho, meta or para position.
When R
1
and R
2
are substituted alkyl, alkenyl or alkynyl radicals, they are the substituents as defined above.
The invention naturally extends to the salts of the compounds of formula (I), such as for example the salts formed when the compounds of formula (I) contain an amino function, with hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic acids such as methane or ethanesulphonic acids, arenesulphonic acids, such as benzene or paratoluene sulphonic acids and arylcarboxylic acids, or when the compounds of formula (I) contain an acid function, with the salts of the alkali or alkaline earth metals or ammonium optionally substituted.
A particular subject of the invention as medicaments is the compounds of formula (I) as defined previously corresponding to general formula (I′):
in which
either R′
5
represents an —[A]—CHO radical as defined previously and R
1
, R
2
, R
3
, R
4
, R
6
, R
7
and R
8
are as defined previously, it being understood that when [A] represents a single bond and R
3
, R
4
, R
6
, R
7
and R
8
are hydrogen atoms, R
1
and R
2
cannot simultaneously represent a hydrogen atom, or R′
5
represents an —[A]—C(OH)ZZ′ group as defined previously and R
1
, R
2
, R
3
, R
4
, R
6
, R
7
and R
8
are as defined previously, it being understood that when [A] represents a single bond and R
3
, R
4
, R
6
, R
7
and R
8
are hydrogen atoms, R
1
and R
2
cannot simultaneously represent a hydrogen atom, or R′
5
represents an —[A]—CH
3
radical as defined previously and R
1
, R
2
, R
3
, R
4
, R
6
, R
7
and R
8
are as defined previously, it being understood that when R
3
, R
4
, R
6
, R
7
and R
8
are hydrogen atoms, R
1
and R
2
cannot simultaneously each represent a hydrogen atom, and it being understood that R
1
, R
2
, R
3
or R
4
cannot represent an alkyl radic

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