Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-14
2001-02-20
Ford, John M. (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
06191130
ABSTRACT:
A subject-matter of the present invention is novel 1,4-functionalized cyclohexane derivatives, their preparation and their application in human therapeutics.
5-HT
1A
receptors have been claimed for their role in various pathologies, such as hypertension, sexual disfunctioning, anorexia and memory. The main target suggesting the involvement of 5-HT
1A
receptors is, however, 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-H
1A
agonist compounds of 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 the D
2
and &agr;
1
receptors, and a high intrinsic activity.
The compounds of the invention correspond to the general formula I
in which
A represents a group of type
in which Ar itself represents a structure of aromatic type, such as phenyl or pyrimidinyl, optionally substituted by one or more groups, such as C
1-3
alkyl, C
1
-C
3
alkoxy, trifluoromethyl or halogen,
B represents a heterocyclic group of type
3,5-dioxo-(2H,4H)-1,2,4-triazine substituted at the 2-position, IIIa
3-oxo-(2H)-1,2,4-triazine substituted at the 5 position, IIIb
3,5-dioxo-6-amino-(2H,4H)-1,2,4-triazine, IIIc
in which R represents a C
1
-C
3
alkyl group.
The invention covers the salts of the compounds of general formula I with pharmaceutically acceptable acids. In addition, it covers the various “cis” and “trans” isomers and the various enantiomers of the compounds possessing asymmetric carbons.
SYNTHESIS
The compounds of the present invention can be synthesized by using the synthetic routes described hereinbelow or by using synthetic methods known to a person skilled in the art.
Method 1
The synthesis of the compounds of general formula I is characterized in that a derivative of general formula IV
in which A′ represents the IIa or IIb groups described above or IIc
is condensed with an intermediate of type Va or Vb
The intermediate IV in which A′=IIc is advantageously used in the case of the coupling with the derivatives of type Va in order to give access to the compounds I in which A represents IIa with Ar representing an optionally substituted pyrimidinyl group. The compound from the condensation between the intermediates IV in which A′=IIc and Va is debenzylated by treating, for example, with &agr;-chloroethyl chloroformate in methanol and by then condensing with optionally substituted 2-chloropyrimidine in the presence of a base, such as triethylamine in toluene.
The condensation between the derivatives IV and Va can be carried out according to the conditions of the Mitsunobu reaction.
The condensation between the derivatives IV and Vb can be carried out in the presence of a base, such as sodium hydride or potassium tert-butoxide in dioxane or THF.
Method 2
The synthesis of the compounds of general formula I according to Method 2 is characterized in that a derivative of general formula VI
in which A has the same meaning as above, is treated with an intermediate of general formula Vc
The condensation is carried out in the presence of a base, such as triethylamine in butanol.
The optional separation of the enantiomers of compounds obtained according to Method 1 or Method 2 which possess an asymmetric carbon is generally carried out on the final products by liquid chromatography on a chiral column.
Synthesis of the Alcohols IV
a) When A′ represents a group IIa or IIc
the corresponding alcohols IVa or IVc
can be obtained by condensing the piperazine VIIa or VIIb
with cyclohexanedione monoethylene ketal in the presence of a reducing agent, such as NaBH(OAc)
3
in dichloromethane or NaBH
3
CN in ethanol, to result in the intermediate VIIIa or VIIIb
which is hydrolyzed in an aqueous medium, such as hydrochloric acid, to give the ketone IXa or IXb
The ketone IXa is reduced to the alcohol IVa by reducing agents, such as NaBH
4
in ethanol, to give access predominantly to the “trans” alcohols IVa, or LS-selectride in THF, to result predominantly in the “cis” alcohols IVa.
The ketone IXb, reduced in a way analogous to that described above and then debenzylated by treating, for example, with &agr;-chloroethyl chloroformate in methanol, provides the alcohol IVc. This alcohol, condensed with optionally substituted 2-chloro-pyrimidine in a solvent such as toluene, in the presence of a base, such as triethylamine, provides the alcohol IVa with Ar representing a group of pyrimidinyl type.
b) When A′ represents a group IIb
the alcohol IVb can be obtained by condensing the amine X
with cyclohexanedione monoethylene ketal in the presence of a reducing agent, such as NaBH(OAc)
3
in dicholoromethane or NaBH
3
CN in ethanol, to result in the intermediate VIIIc
which is hydrolyzed in aqueous hydrochloric acid medium to give the ketone IXc
The ketone IXc is reduced to the alcohol IVb by reducing agents, such as NaBH
4
in ethanol, to give access predominantly to the “trans” compounds IVb, or LS-selectride in THF, to result predominantly in the “cis” alcohols IVb.
Synthesis of the Amines VI
The amines VI can be obtained from the corresponding ketones IX,
A having the same meaning as above, by treating them with hydroxylamine in an aqueous/alcoholic medium, to result in the imines XI
which are reduced by a hydride, such as LiAlH
4
in THF.
Synthesis of the Intermediates V
The compounds Va and Vc are synthesized according to the methods disclosed previously by the Applicant Company in Patents FR 2,727,682 of Feb. 12, 1994 and FR 2,707,294 of Jun. 7, 1993 respectively.
The compounds Vb can be obtained according to the 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-Methylation of the 2 position by methyl iodide in the presence of NaH in DMF.
REFERENCES:
patent: WO9501965A (1995-01-01), None
patent: WO9616949A (1996-06-01), None
Dupont-Passelaigue Elisabeth
Koek Wouter
Patoiseau Jean-Francois
Ford John M.
Pierre Fabre Medicament
The Firm of Hueschen and Sage
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