Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-07-27
2002-04-02
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C568S718000, C568S719000, C568S730000
Reexamination Certificate
active
06365775
ABSTRACT:
A subject of the invention is new biphenyl compounds, their preparation process and the intermediates of this process, their use as medicaments and the pharmaceutical compositions containing them.
A subject of the invention is the compounds of general formula (I):
in which [X] represent the following aromatic carbocycles:
in which R
1
represents an alkyl radical containing from 1 to 4 carbon atoms or a hydrogen atom, R
2
represents an alkyl radical containing from 1 to 4 carbon atoms or a hydrogen atom, R
3
represents a hydrogen atom, a halogen atom, an alkyl radical containing from 1 to 4 carbon atoms or an alkoxy radical containing from 1 to 4 carbon atoms, R
4
in para or meta position represents a hydrogen atom, a halogen atom, a hydroxyl radical, an alkyl, alkenyl or alkynyl radical containing at most 4 carbon atoms, an alkoxy, alkylthio radical in which alkyl contains from 1 to 4 carbon atoms, an —NR
A
R
B
group in which R
A
and R
B
identical or different represent a hydrogen atom, an alkyl radical containing from 1 to 4 carbon atoms or form together with the nitrogen to which they are linked a saturated heterocycle with 5 or 6 members optionally containing a second heteroatom chosen from nitrogen, oxygen and sulphur, their —NR
A
R
B
group being optionally in oxidized form, a group of general formula —O—(CH
2
)
n
—NR
A
R
B
in which n is an integer which varies from 2 to 7 and in which —NR
A
R
B
is as defined previously, R
5
represents a hydrogen atom or a halogen atom, R
6
and R
7
identical or different represent a hydrogen atom, a halogen atom, an alkyl radical containing from 1 to 4 carbon atoms, or a phenyl radical optionally substituted in meta or para position by an R
4
radical as defined previously as well as the addition salts with acids or bases, with the exception of the compounds of formula (I) in which [X] represents the group (A) in which R
1
, R
2
, R
3
are hydrogen atoms and R
4
represents a hdyroxyl radical and those in which [X] represents the group (B) in which R
5
, R
6
and R
7
are hydrogen atoms or R
5
and R
6
are hydrogen atoms and R
7
represents an alkyl radical containing from 1 to 4 carbon atoms.
When R
1
, R
2
, R
3
, R
4
, R
6
, R
7
, R
A
and R
B
represent an alkyl radical containing from 1 to 4 carbon atoms, it is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl radical. When R
3
, R
4
, R
5
, R
6
and R
7
are halogen atoms, it is fluorine, chlorine, bromine or iodine. Preferably, it is chlorine. When R
4
is an alkenyl radical containing at most 4 carbon atoms, preferably it is a vinyl or propenyl radical. When R
4
is an alkynyl radical containing at most 4 carbon atoms, preferably it is an ethynyl or propynyl radical. When R
3
or R
4
represent an alkyloxy radical containing from 1 to 4 carbon atoms, preferably it is a methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy radical. When R
4
is an alkylthio radical containing from 1 to 4 carbon atoms, preferably it is a methylthio, ethylthio, propylthio, isopropylthio or butylthio radical. When R
4
is an NR
A
R
B
radical in which R
A
and R
B
identical or different represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, preferably it is an amino, methylamino, ethylamino, dimethylamino, diethylamino or methylethylamino radical. When R
4
is an —NR
A
R
B
group in which R
A
and R
B
form with the nitrogen a saturated heterocycle, preferably it is pyrrolidino, piperidino, piperazino, morpholino or thiomorpholino groups, each of these amino groups being optionally in oxidized form.
Naturally the invention extends to the salts of the compounds de formula (I), in particular when the compounds of formula (I) contain an amino function. These are the salts formed for example with the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonics such as methane- and ethanesulphonics, arenesulphonics, such as benzene and paratoluene sulphonics and arylcarboxylics.
These are also the salts formed under the action of a base or an alkali or alkaline-earth metal, in order to obtain for example derivatives such as sodium or potassium alcoholate or derivatives such as potassium or sodium phenolate.
A more particular subject of the invention is the compounds of general formula (I) as defined previously in which [X] is the aromatic carbocycle of general formula (A).
A more particular subject of the invention is the products of general formula (I) as defined previously in which [X] is the aromatic carbocycle of general formula (B).
A more particular subject of the invention is the products of general formula (I) as defined above, corresponding to general formula (I′):
in which R′
1
, R′
2
and R′
3
represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, R′
4
in meta or para position represents a hydrogen atom, a halogen atom, a hydroxyl radical, an alkyl radical, an —NR
A
R
B
group or an —O—(CH
2
)
n
—NR
A
RA
B
group, n, R
A
and R
B
being as defined previously, as well as the addition salts with acids. When R′
4
is an —O—(CH
2
)
n
—NR
A
R
B
group, it is preferably the —O—(CH
2
)
2
—NMe
2
group.
A more particular subject of the invention is the products of general formula (I) as defined previously corresponding to general formula (I′) in which R′
1
, R′
2
and R′
3
are hydrogen atoms.
A quite particular subject of the invention is the compound of general formula (I) as defined previously in which R
6
represents a halogen atom or an
—O—(CH
2
)
2
—N(CH
3
)
2
group and R
7
represents a hydrogen atom.
A quite particular subject of the invention is the compound of general formula (I) as defined above the names of which follow:
5-[4-[2-(dimethylamino) ethoxy]phenyl]6-(4-hydroxyphenyl) 2-naphthalenol,
1,5-dichloro-6-(4-hydroxyphenyl)-2-naphthalenol,
5-chloro-6-(4-hydroxyphenyl)-2-naphthalenol.
A subject of the invention is also a preparation process for the products of formula (I) as defined above characterized in that a product of formula (II):
in which [X] is as defined previously, P′ represents a protective group, and G represents a halogen atom or an OSO
2
CF
3
group is subjected to the action, in the presence of a catalyst, of a product of formula (III):
in which Y represents a halogen atom, a B(OH)
2
groups or an Sn(R)
3
group, in which R represents an alkyl group containing from 1 to 8 carbon atoms and P represents a protective group identical to or different from P′, in order to obtain a product of formula (IV):
in which P, P′ and [X] have the same meaning as previously, which product of formula (IV) is subjected to one or more deprotection reactions in order to obtain the product of formula (I) as defined previously which, if appropriate is subjected to the action of an acid or base in order to obtain the corresponding salt.
The formation of the biphenyls of formula (IV) by coupling the aromatic compound of formula (II) with the aromatic compound of formula (III) is carried out in the presence of a catalyst chosen from the derivatives of palladium or in the presence of copper in the case where Y is an iodine atom and can therefore be carried out under the conditions described in the following articles:
A. Huth, I. Beetz and I. Schumann Tetrahedron (1989) 45 6679: Conditions: Na
2
CO
3
2M/Pd(P&phgr;
3
)
4
/Toluene/LiCl/EtOH/&Dgr;)
J. K. Stille Ang. Chem. Int. Ed. (1986) 25 508: Conditions: Pd(P&phgr;
3
)
4
/LiCl/Dioxane/&Dgr;)
T. Oh-e, N. Migawa and A. Suzuki J. Org. Chem. (1993) 58 2201-2208: Conditions: K
3
PO
4
/Dioxane/&Dgr;)
P. E. Fank Chem. Rev. (1964) 38 139: Conditions: Cu/DMF/120° C. in the case where Y is an iodine atom.
E. Erdik Tetrahedron (1992) 48 9577: Conditions: nBuLi/THF/−78° C.-2) ZnCl2-3) ArBr/Pd(P&phgr;
3
)
4
/)&Dgr;4)HCl/MeOH.
A subject of the invention is also a
Aventis Pharma S.A.
Bierman, Muserlian and Lucas
Kumar Shailendra
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