Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-13
2001-07-17
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S233200, C514S248000, C544S115000, C544S234000
Reexamination Certificate
active
06262045
ABSTRACT:
This application is a national stage application of PCT/FR98/01667, filed Jul. 28, 1998, which claims priority to French patent application 97/09692, filed Jul. 30, 1997.
The subject-matter of the present invention is compounds of general formula (I)
in which
X represents a hydrogen or halogen atom or a methyl, methoxy or phenylmethoxy group,
Y represents a hydrogen atom, 1 or 2 halogen atoms or a hydroxyl, methoxy, nitro or methyl group,
R
1
represents a hydrogen atom or a (C
1
-C
4
)alkyl group,
R
2
and R
3
each represent, independently of one another, a hydrogen atom, a (C
1
-C
4
)alkyl group or a phenylmethyl group,
or else R
2
and R
3
form, with the nitrogen atom which carries them, an azetidinyl, pyrrolidinyl, 3-ethoxypyrrolidinyl, piperidinyl, morpholinyl, 4-methylpiperazinyl or 1,3-thiazolidinyl group, the respective formulae of which are as follows:
The preferred compounds are those in the general formula of which X is in the 8 or 9 position and represents a hydrogen or halogen atom, Y represents a hydrogen atom, R
1
represents a methyl or ethyl group, R
2
represents a hydrogen atom or a methyl group and R
3
represents a methyl group or else R
2
and R
3
form, with the nitrogen atom which carries them, an azetidinyl or pyrrolidinyl ring.
The compounds of general formula (I) can be prepared by processes illustrated in the following schemes.
According to Scheme 1, a compound of general formula (II), in which X and R
1
are as defined above and R′ represents a (C
1
-C
4
)alkyl group, is reacted with oxalyl chloride, in an aprotic solvent, such as toluene, between 50° C. and the reflux temperature, the reaction intermediate is then treated at room temperature with an alcohol of general formula R″OH, in which R″ represents a (C
1
-C
4
)alkyl group, in order to obtain the diester of general formula (III), or else the compound of general formula (II) is reacted with an alkyl chloroglyoxylate in a polar aprotic solvent, such as dichloromethane, at room temperature, in the presence of a Lewis acid, for example titanium tetrachloride, in order to obtain the diester of general formula (III).
The latter is subsequently treated in acetic acid, first at room temperature and then at the reflux temperature, with a phenylhydrazine optionally substituted by a Y group as defined above, in order to obtain an ester of general formula (IV). When R
1
represents an alkyl group, this ester is converted to the corresponding alcohol, of general formula (V), by reduction by means of a reducing agent, such as sodium borohydride, in a solvent, such as tetrahydrofuran, in the presence of an alcohol, for example methanol. This alcohol (V) is subsequently converted to the halogenated compound of general formula (VIII) by any reaction known to a person skilled in the art, either, for example, treatment with carbon tetrabromide in the presence of triphenylphosphine, in a solvent such as dichloromethane, or else by the action of a chlorinating agent, such as methanesulphonyl chloride, in a mixture of solvents, such as tetrahydrofuran and pyridine.
A nucleophilic substitution reaction with the cyanide ion is subsequently carried out, either in a mixture of polar solvents, such as dimethylformamide and water, at a temperature of 20 to 80° C., or in a two-phase mixture, such as water and dichloromethane, between room temperature and the reflux temperature, in the presence of a phase transfer agent, in order to obtain the compound of general formula (IX).
An acidic hydrolysis is subsequently carried out, for example by using a mixture of acetic acid and of hydrochloric acid, at the reflux temperature, or else a basic hydrolysis is subsequently carried out, for example by using potassium hydroxide in a mixture of solvents, such as water and 2-methoxyethanol, at the reflux temperature, in order to obtain the compound of general formula (X).
This acid is subsequently converted to the secondary or tertiary amide of general formula (I) by reaction with an amine of general formula HNR
2
R
3
, in which R
2
and R
3
are as defined above, via the intermediacy, for example, of the imidazolide obtained by reaction with 1,1′-carbonylbis-1H-imidazole.
It is possible, if a final compound of general formula (I) in which R
1
represents hydrogen is desired, to convert a compound of general formula (IV) in which R
1
represents hydrogen to a compound of general formula (IV) in which R
1
represents a protective group, such as the methoxymethyl group, for example, by an alkylation reaction known to a person skilled in the art. The conversions according to Scheme 1 are continued until the compound of general formula (IX) is obtained and then an acidic hydrolysis of the latter, which at the same time removes the methoxymethyl protective group, results in a compound of general formula (X) in which R
1
represents a hydrogen atom.
According to Scheme 2, the compound of general formula (II) as defined above is converted to a compound of general formula (VI) by any method known to a person skilled in the art, for example by an electrophilic reaction in acidic medium. The latter is subsequently treated in acetic acid, first at room temperature and then at the reflux temperature, with a phenylhydrazine optionally substituted by a Y group as defined above. A compound of general formula (VII) is obtained, which is converted to the corresponding halogenated derivative of general formula (VIII) by a radical-type reaction, for example by using N-bromosuccinimide, in a solvent such as carbon tetrachloride, in the presence of an agent such as 2,2′-azobis(2-methylpropionitrile). The compound of general formula (VIII) is subsequently treated as described with respect to Scheme 1.
It is possible, if desired, to convert a compound of general formula (I) in which X represents a halogen atom to a compound of general formula (I) in which X represents a methyl group by any coupling reaction known to a person skilled in the art, for example by using tetramethyltin in the presence of a
palladium complex.
Likewise, a compound of general formula (I), in which Y represents a methoxy group, can be converted to a compound in the formula of which Y represents a hydroxyl group by any known method, for example by the action of boron tribromide, in a chlorinated solvent, such as dichloromethane.
It is also possible, if desired, to convert a compound of general formula (I) in which X represents a chlorine atom to a compound of general formula (I) in which R represents hydrogen, for example by hydrogenation in the presence of palladium-on-charcoal.
According to Scheme 3, a compound of general formula (V), in which R
1
represents an alkyl group and X represents a chlorine atom, is converted to a compound of general formula (XI) by oxidation of the alcohol functional group, for example by using manganese dioxide in a solvent such as dichloromethane. The aldehyde (XI) is subsequently converted to a nitrile of general formula (XII) by reaction with (4-methylbenzenesulphonyl)methyl isocyanide (“TosMIC”) in a solvent, such as 1,2-dimethoxyethane, in the presence of a base, such as potassium 1,1-dimethylethoxide. The nitrile (XII) is subsequently converted to an ester of general formula (XIII), in which R″ represents a lower alkyl group, by the action of an acid, such as hydrogen chloride, in an alcoholic solvent of formula R″OH.
Finally, this ester (XIII) is converted to the secondary or tertiary amide of general formula (I) by reaction with an amine of general formula HNR
2
R
3
, in which R
2
and R
3
are as defined above, for example in the presence of a trialkylaluminium derivative, in a solvent such as toluene.
The starting compounds of general formula (II), mainly when R
1
represents hydrogen, are described in the literature. If desired, the compound in the formula of which R
1
represents hydrogen can be subjected to an alkylation reaction in order to result in a compound in the formula of which R
1
represents an alkyl group.
REFERENCES:
patent: 4985560 (1991-01-01), Sabb et al.
patent: 5756501 (1
Bartsch Regine
Dubois Laurent
Evanno Yannick
Froissant Jacques
Gille Catherine
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
McKenzie Thomas
Sanofi-Synthelabo
Shah Mukund J.
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