Pyridone derivatives, their preparation and their use as...

Details Pyridone derivatives, their preparation and their use as... Pyridone derivatives, their preparation and their use as...

1999-07-14

2001-06-26

Fan, Jane (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S293000, C546S294000, C546S296000, C546S297000, C546S256000, C546S280400, C546S281400, C546S013000

Reexamination Certificate

active

06252082

ABSTRACT:

The Patent Application EP 677 525 relates to derivatives of aminoboronic acids of formula
which are useful as synthesis intermediates.
The Patent Application EP 718 307 relates to 1-oxo-2-(phenylsulphonylamino)pentylpiperidine derivatives of formula
which are useful in thrombosis-related clinical indications.
The subject of the present invention is pyridone derivatives, their preparation and their use as synthesis intermediates.
The compounds according to the invention correspond to the formula (I)
in which
R represents either an —NO
2
group, or an —NHR
3
group, R
3
being a hydrogen atom, a —COR
4
group (where R
4
is selected from the (C
1
-C
4
)alkyl, aryl and aryl(C
1
-C
4
)alkyl groups), a —COOR
5
group (where R
5
is selected from the (C
1
-C
4
)alkyl and aryl(C
1
-C
4
)alkyl groups), a —CONHR
6
group, an —SO
2
R
6
group (where R
6
is selected from the (C
1
-C
5
)alkyl, aryl and aryl(C
1
-C
4
)alkyl groups), an —SO
2
NR
7
R
8
group (where R
7
and R
8
are each, independently of each other, a hydrogen atom or a (C
1
-C
4
)alkyl group or form with the nitrogen atom carrying them a morpholine group), an aryl(C
1
-C
4
)alkyl group (the aryl group being optionally substituted with a halogen atom, a linear or branched (C
1
-C
5
)alkyl group, a trifluoromethyl group, a cyano group, a (C
1
-C
4
)alkoxycarbonyl group or a (C
1
-C
4
)acylamino group), a heteroaryl(C
1
-C
4
)alkyl group,
R
1
represents either a linear or branched (C
1
-C
4
)alkyl group, or a cyclo(C
1
-C
8
)alkyl group, or an aryl group which is optionally substituted with a halogen atom, a linear or branched (C
1
-C
5
)alkyl group, a trifluoromethyl group, a cyano group, a (C
1
-C
4
)alkoxycarbonyl group or a (C
1
-C
4
)acylamino group, or an aryl(C
1
-C
4
)alkyl group whose aryl group is optionally substituted as above, or a heteroaryl group,
R
2
represents either a hydrogen atom, or a (C
1
-C
4
)alkyl group, or an arylmethyl group,
X represents either an oxygen or sulphur atom, or a a linear or branched (C
1
-C
5
)alkyl group, a trifluoromethyl group, a cyano group, a (C
1
-C
4
)alkoxycarbonyl group or a (C
1
-C
4
)acylamino group), a heteroaryl(C
1
-C
4
)alkyl group,
R
1
represents either a linear or branched (C
1
-C
4
)alkyl group, or a cyclo(C
3
-C
8
)alkyl group, or an aryl group which is optionally substituted with a halogen atom, a linear or branched (C
1
-C
5
)alkyl group, a trifluoromethyl group, a cyano group, a (C
1
-C
4
)alkoxycarbonyl group or a (C
1
-C
4
)acylamino group, or an aryl(C
1
-C
4
)alkyl group whose aryl group is optionally substituted as above, or a heteroaryl group,
R
2
represents either a hydrogen atom, or a (C
1
-C
4
)alkyl group, or an arylmethyl group,
X represents either an oxygen or sulphur atom, or a —CH
2
—, —SO
2
or —NR
1
— group where R
1
is as defined above, and
Y represents either a hydrogen atom, or a linear or branched (C
1
-C
6
)alkyl group.
In the preceding definitions, the aryl groups are carbon-containing aromatic rings, for example phenyl, naphthyl or anthracenyl, and the heteroaryl groups are aromatic heterocycles such as for example pyridine or thiophene.
When Y is different from a hydrogen atom, then the compounds may exist in the form of pure enantiomers or racemates or a mixture of enantiomers which also form part of the invention.
The compounds of formula (Ia) to (Id) in which R
1
represents either a linear or branched (C
1
-C
4
)alkyl group, or a cyclo(C
3
-C
8
)alkyl group, X an oxygen atom, R
2
a hydrogen atom or a (C
1
-C
4
)alkyl group and R
3
and Y are as defined above may be synthesized according to scheme 1.
The compound of formula (II) in which Y is as defined above and Alk represents a (C
1
-C
4
)alkyl group is reacted with a compound of formula R
1
OH under the Mitsunobu conditions, for example in the presence of triphenylphosphine (PPh
3
) and of diethylazodicarboxylate (DEAD) and a compound of formula (Ia) is obtained which corresponds to a compound of formula (I) in which R is an —NO
2
group and X an oxygen atom.
In order to obtain a compound of formula (Ib) which corresponds to a compound of formula (I) in which R is an —NH
2
group and X an oxygen atom, the corresponding compound of formula (Ia) is subjected to a hydrogenation.
In order to obtain a compound of formula (Ic) which corresponds to a compound of formula (I) in which R is an —NHR
3
group, R
3
being as defined above and different from a hydrogen atom and X an oxygen atom, then the corresponding compound of formula (Ib) is treated either with a compound R
3
-Hal where Hal represents a halogen atom, or with a compound of formula R
6
NCO, or it is subjected to a reductive amination when R
3
represents an aryl(C
1
-C
4
)alkyl group.
If it is desired to obtain a compound of formula (Id) which corresponds to a compound of formula (I) in which R is an —NHR
3
group, R
3
being as defined above and different from a hydrogen atom, R
2
a hydrogen atom and X an oxygen atom, then the corresponding compound of formula (Ic) is subjected to a saponification with sodium or lithium hydroxide.
To prepare the compounds of formula (Ie) to (Ii) in which R
1
represents either an aryl group optionally substituted with a halogen atom, a linear or branched (C
1
-C
5
)alkyl group, a trifluoromethyl group, a cyano group or a (C
1
-C
4
)acylamino group, or an aryl(C
1
-C
4
)alkyl group optionally substituted as above, or a heteroaryl group, X represents either a sulphur atom or a —CH
2
—, —SO
2
—or —NR
1
— group, R
2
represents a hydrogen atom or a (C
1
-C
4
)alkyl group and R
3
and Y are as defined above or in which R
1
represents either a linear or branched (C
1
-C
4
)alkyl group, or a cyclo(C
3
-C
8
)alkyl group, X a sulphur atom or an —NR
1
— group, R
2
represents a hydrogen atom or a (C
1
-C
4
)alkyl group and R
3
and Y are as defined above or in which R
1
represents either an aryl group optionally substituted with a halogen atom, a linear or branched (C
1
-C
5
)alkyl group, a trifluoromethyl group, a cyano group or a (C
1
-C
4
)acylamino group, or a heteroaryl group, X represents an oxygen atom, R
2
represents a hydrogen atom or a (C
1
-C
4
)alkyl group and R
3
and Y are as defined above, it is possible to use the process illustrated by scheme 2.
The alcohol function of the compound of formula (II) is converted under conventional conditions in order to obtain a compound of formula (III) in which OP represents a leaving group and then this compound is reacted either with a compound of formula R
1
XH where X is different from —CH
2
—, or with an organometallic of formula R
1
CH
2
Cu(CN)ZnHal where Hal represents a halogen atom (for X=—CH
2
—) and a compound of formula (Ie) is obtained which corresponds to a compound of formula (I) in which R represents an —NO
2
group.
When it is desired to obtain a compound of formula (If) which corresponds to a compound of formula (I) in which R represents an —NH
2
group, then the corresponding compound of formula (Ie) is subjected to a hydrogenation, when X represents an oxygen atom or a —CH
2
—, —SO
2
—or —NR
1
— group, or to a treatment with zinc in acidic medium when X represents a sulphur atom.
In order to obtain a compound of formula (Ig) which corresponds to a compound of formula (I) in which R represents an —NHR
3
group where R
3
is as defined above and is different from a hydrogen atom, then the corresponding compound of formula (If) is treated either with a compound R
3
-Hal where Hal represents a halogen atom, or with a compound of formula R
6
NCO, or it is subjected to a reductive amination when R
3
represents an aryl(C
1
-C
4
)alkyl group.
If it is desired to obtain a compound of formula (Ih) in which R
2
represents a hydrogen atom, then the corresponding compound of formula (Ig) is subjected to a saponfication with sodium or lithium hydroxide.
If it is desired to obtain a compound of formula (Ii) in which R represents an —NO
2
group, X represents a —CH
2
— group and R
2
a hydrogen atom, then the corresponding compound of formula (Ie) is subjected to a saponification with sodium or lithium hydroxide.
To prepare

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