Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-14
2001-10-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S182000
Reexamination Certificate
active
06303603
ABSTRACT:
A subject-matter of the present invention is novel 3-oxo-(2H) -1,2,4-triazine derivatives functionalized in the 5 position, their preparation and their application in therapeutics.
5-HT
1A
receptors have been claimed for their role in various pathologies, such as hypertension, sexual dysfunctioning, anorexia or memory. The main target suggesting the involvement of the 5-HT
1A
receptors is, however, composed of disorders of the central nervous system, such as anxiety and depression. The hypotheses, supported by tests on animal models and clinical studies, suggest that more effective treatments of these pathologies can be envisaged with 5-HT
1A
agonist compounds with a high affinity which are very selective and highly effective.
3,5-Dioxo-(2H,4H)-1,2,4-triazine derivatives and 3,5-dioxo-6-amino-(2H,4H)-1,2,4-triazine derivatives have been claimed previously by the Applicant Company (FR 2,707,294 of Jun. 7, 1993 and FR 2,727,682 of Feb. 12, 1994).
The compounds of the present invention are characterized by their powerful affinity with regard to the 5-HT
1A
receptor in combination with a high selectivity, in particular with regard to D
2
and &agr;
1
receptors, and a high intrinsic activity.
The compounds of the invention correspond to the general formula I
in which
R
1
represents:
hydrogen, when A is an optionally substituted nitrogen atom
a linear or branched C
1
-C
4
alkyl group
a C
1
-C
4
phenylalkyl group, the phenyl nucleus optionally being substituted by one or more groups, such as C
1
-C
4
alkyl, C
1
-C
3
alkoxy, halogen or trifluoromethyl,
R
2
represents:
hydrogen
a linear or branched C
1
-C
4
alkyl radical
a C
1
-C
4
phenyl or phenylalkyl group, the phenyl nucleus optionally being substituted by one or more groups, such as C
1
-C
4
alkyl, C
1
-C
3
alkoxy, halogen or trifluoromethyl,
A represents an oxygen atom or an optionally substituted nitrogen atom NR
3
,
R
3
represents hydrogen or a methyl group,
B represents a group of type
in which Ar itself represents an aromatic structure, such as phenyl, pyridyl or pyrimidyl, optionally substituted by one or more groups, such as C
1
-C
3
alkyl, C
1
-C
3
alkoxy, hydroxyl, trifluoromethyl or halogen, and n can take the integral values from 3 to 5,
in which Ar is as defined in the formula IIa and m can take the integral values 1 and 2,
in which R4 represents hydrogen or a C
1
-C
3
alkyl group and n can take the integral values from 3 to 5.
The invention covers the inorganic or organic salts of compounds of general formula I with pharmaceutically acceptable acids.
In addition, it covers the various enantiomers and diastereoisomers of the compounds which have one or more asymmetric carbons, as well as their mixtures in all proportions, including in particular the racemic mixtures.
Synthesis
The compounds of the present invention can be prepared according to various methods. They can be synthesized by using the synthetic routes described hereinbelow or by using synthetic methods known to a person skilled in the art.
The synthesis of the compounds of general formula I is characterized in that a derivative of general formula III (Scheme 1)
is condensed with an alcohol B-OH IV or an amine BHNR
3
V, R
1
, R
2
, R
3
and B having the same meaning as above in the general formula I.
The compounds III are obtained according to a process (Scheme 1) characterized by the following stages:
1—Condensation of glyoxylic acid with thiosemicarbazide, followed by a basic treatment, such as sodium hydroxide solution,
2—Methylation by methyl iodide in basic aqueous medium, followed by an acidic treatment, such as hydrochloric acid,
3—Sulfuration of the 5 position in the presence of Lawesson's reagent in a solvent such as pyridine,
4—Methylation by methyl iodide in basic aqueous medium, such as sodium hydroxide solution,
5—Alkylation of the 2 position by an alkyl halide R
1
X in the presence of NaH in DMF, X representing C1, Br or
Synthesis of the Compounds III (Scheme 1)
The condensation of intermediates III with the alcohols IV or amines V is carried out in the presence of a base, such as sodium hydride or potassium tert-butoxide in dioxane, THF or toluene.
The optional separation of the enantiomers or diastereoisomers of compounds having one or more asymmetric carbons is generally carried out on the final products by liquid chromatography on a chiral column.
Synthesis of the Alcohols B-OH IV
A—When B represents a group of type
the corresponding alcohols
can be obtained
1) by treating the piperazine
with a haloalcohol
HO—(CH
2
)
n
—Hal VII
in the presence of K
2
CO
3
and optionally of KI, when Hal=Br or Cl, in acetonitrile at reflux,
2) when n=4 or 5, by treating the piperazine VI with a lactone VIII
in the presence of a Lewis acid, such as AlCl
3
, and of triethylamine in dichloromethane, and by then reducing the amide IX formed
with a hydride, such as LiAlH
4
in THF,
3) when Ar represents a heterocycle of pyrimidine type, by treating optionally substituted 2-chloropyrimidine with a hydroxyalkylpiperazine X
bin a solvent, such as toluene, in the presence of an amine, such as triethylamine.
B—When B represents a group of type
1) when m=1,
according to the process disclosed in the Pfizer Patent WO 93 25552 (1992),
2) when m=2, by oxidizing the alcohol XI
under the Swern conditions and by then treating the aldehyde obtained XII
with a Wittig reagent, such as methoxymethyltriphenylphosphonium chloride in TrHF, followed by the hydrolysis in aqueous acidic medium of the enol ether obtained XIII
to result in the corresponding aldehyde XIV
which is reduced to the alcohol with a hydride, such as NaBH
4
in ethanol.
C—W hen B represents a group of type
the corresponding alcohols
can be prepared
1) by treating benzodioxanemethylamine according to the process described in paragraph A-2,
2) by condensing benzodioxanemethanol with an aminoalcohol XV
HO—(CH
2
)
n
—NH
2
XV
Synthesis of the Amines B-NHR
3
V
1) When R
3
=H,
the compounds V are commercial amines or can be obtained conventionally, such as generation of the primary amine from the intermediate phthalimide.
2) When R
3
=Me,
the compounds are obtained from the amines BNH
2
(the method of preparation of which is described hereinabove) by formylating the amine with formic anhydride in a solvent, such as pyridine, to result in the formamide XVI
which is reduced with a hydride, such as LiAlH
4
in THF.
REFERENCES:
patent: WO9501965 (1995-01-01), None
patent: WO9616949 (1996-06-01), None
Dupont-Passelaigue Elisabeth
Koek Wouter
Patoiseau Jean-Francois
Balasubramanian Venkataraman
Pierre Fabre Medicament
Raymond Richard L.
Sage G. Patrick
The Firm of Hueschen and Sage
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