Substituted phthalides, a process for their preparations and...

Details Substituted phthalides, a process for their preparations and... Substituted phthalides, a process for their preparations and...

2002-12-26

2004-02-10

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S462000, C514S466000, C549S304000, C549S307000

Reexamination Certificate

active

06689808

ABSTRACT:

The present invention relates to new substituted phthalides, to a process for their preparation and to pharmaceutical compositions containing them.
Epilepsy is a collective term used to describe a group of chronic convulsive disorders having in common the occurrence of brief episodes (seizures) associated with loss or disturbance of consciousness. There are many anti-epilepsy drugs available in clinical applications, such as Phenobarbital, Phenytoin, Zolenzepine, Ethosuximide, Paramethadione, Valproic acid. Although these medicines are able to protect patients from convulsion of various epilepsies to different extents, adverse effects and tolerance usually prevent long-term therapy. New compounds with novel structural features and with new mechanisms of action are needed in order to improve the therapeutic effect and eliminate or reduce the adverse response.
The compounds of the present invention are new, devoid of any toxicity and exhibit interesting pharmacological properties as anti-convulsants. Furthermore, they are potent calcium and sodium channel blockers conferring on them neuroprotective and cognition-enhancing properties.
More specifically, the present invention relates to compounds of formula (I):
wherein:
R
1
represents a linear or branched (C
1
-C
12
)alkyl group or a ureido group,
R
2
represents a hydrogen atom or a linear or branched (C
1
-C
12
)alkyl group,
or R
1
and R
2
, together with the carbon atom carrying them, form a cycloalkyl group containing 5 or 6 carbon atoms,
R
3
represents a group CN, NO
2
, NR
a
R′
a
, NR
a
SO
2
R′
a
, NR
a
CZR
5
or CZNR
a
R′
a
wherein Z represents an oxygen or sulphur atom and R
5
represents a group OR
a
, R
a
or NR
a
R′
a
(wherein R
a
and R′
a
, which may be the same or different, represent a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group, a (C
3
-C
8
)cycloalkyl group, a (C
3
-C
8
)cycloalkyl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched, a phenyl group or a phenyl-(C
1
-C
6
)alkyl group in which the alkyl moiety is linear or branched),
R
4
represents a hydrogen atom or a group R
3
as defined hereinbefore,
it being understood that:
the phenyl or phenylalkyl groups may be substituted on the benzene ring by one or more substituents selected from linear or branched (C
1
-C
6
)alkyl, hydroxy, linear or branched (C
1
-C
6
)alkoxy, amino, linear or branched (C
1
-C
6
)alkylamino, di-(C
1
-C
6
)alkylamino in which each allyl moiety is linear or branched, NO
2
and halogen atoms,
the alkyl group may be substituted by one or more substituents selected from hydroxy, carboxy, linear or branched (C
1
-C
6
)alkyl, linear or branched (C
1
-C
6
)alkoxy and halogen atoms,
the cycloalkyl and cycloalkylalkyl groups may be substituted on the cyclic moiety by one or more substituents selected from hydroxy, carboxy, linear or branched (C
1
-C
6
)alkoxy and halogen atoms,
and provided that the compound of formula (I) cannot represent 3-methyl-, 3-ethyl-, 3,3-diethyl- or 3,3-diethyl-6-nitro-phthalide or 3-methyl- or 3,3-dimethyl-6-amino-phthalide or 3,3-dimethyl-6-(dimethylamino)-phthalide, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are compounds of formula (I) wherein R
4
represents a hydrogen atom.
The group R
1
is preferably a linear or branched (C
1
-C
12
)alkyl group and, more especially, the groups methyl, ethyl and n-butyl, or R
1
and R
2
, together with the carbon atom carrying them, form a ring having 5 or 6 carbon atoms.
Advantageously, the invention relates to compounds of formula (I) wherein R
3
represents a nitro group or a group NR
a
R′
a
(wherein R
a
and R′
a
are as defined hereinbefore) such as, for example, the groups amino, formamido, isopropylanino or dimethylamino.
Even more preferably, the invention relates to compounds of formula (I) that are:
6-amino-3-butyl-phthalide,
(+)-(3R)-6-amino-3-butyl-phthalide,
3-butyl-6-isopropylamino-phthalide,
6-amino-3,3-spiro-tetramethylene-phthalide,
3-butyl-6-formamido-phthalide,
6-amino-3,3-diethyl-phthalide.
The enantiomers and diastereoisomers, as well as the addition salts with a pharmaceutically acceptable acid or base, of the preferred compounds of the invention form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material a compound of formula (II):
wherein R
1
and R
2
are as defined hereinbefore,
which is nitrated under conditions of electrophilic substitution to yield the compound of formula (I/a), a particular case of the compounds of formula (I):
wherein R
1
and R
2
are as defined hereinbefore,
which may be hydrogenated chemically or by means of catalytic hydrogenation to obtain the compound of formula (I/b), a particular case of the compounds of formula (I):
wherein R
1
and R
2
are as defined hereinbefore,
which may be:
either subjected to the action of one or two molecules of a compound of formula (III):
R
1
a
−X  (III)
wherein R
1
a
may take any of the meanings of R
a
except for a hydrogen atom and X represents a leaving group such as a halogen atom or a tosyl group, to yield the compound of formula (I/c), a particular case of the compounds of formula (I):
wherein R
1
, R
2
, R
a
and R
1
a
are as defined hereinbefore,
or subjected to the action of a compound of formula (IV):
wherein Z is as defined hereinbefore and R′
5
represents a group R
a
or OR
a
(wherein R
a
is as defined hereinbefore),
to obtain the compound of formula (I/d), a particular case of the compounds of formula (I):
wherein R
1
, R
2
, Z and R′
5
are as defined hereinbefore,
which may be subjected to the action of a compound of formula (III) to yield the compound of formula (I/e), a particular case of the compounds of formula (I):
wherein R
1
, R
2
, R
5
, R′
5
and Z are as defined hereinbefore,
or subjected to the action of a compound of formula (V):
Z═C═N—R
a
  (V)
wherein Z and R
a
are as defined hereinbefore, to obtain the compound of formula (I/f), a particular case of the compounds of formula (I):
wherein R
1
, R
2
, Z and R
a
are as defined hereinbefore,
which may be subjected to the action of a compound of formula (III) to yield the compound of formula (I/g), a particular case of the compounds of formula (I):
wherein R
1
, R
2
, R
a
, R′
a
, R
1
a
and Z are as defined hereinbefore,
or subjected to the successive action of nitrous acid and then CuCN to yield the compound of formula (I/h), a particular case of the compounds of formula (I):
wherein R
1
and R
2
are as defined hereinbefore,
which may be hydrolysed in an acid or basic medium to yield the compound of formula (I/i), a particular case of the compounds of formula (I):
wherein R
1
and R
2
are as defined hereinbefore,
which may be subjected to the action of a compound of formula (III) to obtain the compound of formula (I/j), a particular case of the compounds of formula (I):
wherein R
1
, R
2
, R
a
and R
1
a
are as defined hereinbefore,
which compounds of formulae (I/i) and (I/j) may be subjected to the action of a thionating agent such as Lawesson's reagent to yield the compound of formula (I/k), a particular case of the compounds of formula (I):
wherein R
1
, R
2
, R
a
and R′
a
are as defined hereinbefore,
which compound

Affiliated with

Also associated with

Rating

Substituted phthalides, a process for their preparations and... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted phthalides, a process for their preparations and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted phthalides, a process for their preparations and... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3277187