Optically active phenyl pyrimidine derivatives as analgesic agen

Details Optically active phenyl pyrimidine derivatives as analgesic agen Optically active phenyl pyrimidine derivatives as analgesic agen

1998-02-26

2000-09-26

Ford, John M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

544322, 544223, 544325, A61K 31505, C07D23902, C07D23922

Patent

active

061243086

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a pyrimidine compound, its preparation, pharmaceutical formulations containing it and its use in therapy.
EP-A-21121 discloses a group of 3,5-diamino-6-(substituted phenyl)-1,2,4-triazines which are active in the treatment of central nervous system (CNS) disorders, for example in the treatment of epilepsy. One such triazine is 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine which is alternatively called lamotrigine.
EP-0372934-A discloses pyrimidine compounds useful in the treatment of CNS disorders. Example 18 of EP-0372934-A discloses 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine.
According to the present invention, there is provided the pyrimidine of formula (I): ##STR2## and acid addition salts thereof.
The pyrimidine of formula (I) is R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine. It is substantially free of the corresponding S(+)enantiomer, S(+)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine. The S(+)enantiomer has the formula (II): ##STR3##
The R(-)enantiomer of the invention has more desirable properties than lamotrigine: it is less active against dihydrofolate reductase (DHFR) and is more active in analgesic and anticonvulsant tests. It also has more desirable properties than the S(+)enantiomer. Thus: enantiomer, for example it is less rapidly metabolised and therefore has a longer half-life (duration of action); S(+)enantiomer; S(+)enantiomer; and S(+)enantiomer.
It is surprising that the R(-)enantiomer is better then the S(+)enantiomer in all of these respects. The R(-)enantiomer can be provided substantially pure. Thus, the ratio R(-)enantiomer: S(+)enantiomer may be at least 94:6 such as at least 98:2 or at least 99:1. Preferably the R(-)enantiomer is provided having an isomeric purity of at least 99.5%.
The R(-)enantiomer and acid addition salts thereof can be prepared according to the invention by a first process which comprises: pyrimidine with a suitable chiral acid and recrystallising the resulting salt so as to obtain a salt which consists substantially only of the salt with R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine; and another acid addition salt as appropriate.
The resolution step (i) is achieved with a suitable chiral acid in a suitable solvent. Preferably the acid is (-)-dibenzoyl-L-tartaric acid. Other suitable acids may be determined by testing. Preferably the solvent is ethanol. Again, though, other suitable solvents may be determined by testing.
The resulting salt, which may be isolated, consists predominantly of the salt with R(-)-2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine. A minor proportion of the salt with the S(+)enantiomer may be present. The proportion of the salt with the R(-)enantiomer can be increased by effecting one or more, for example two or three, recrystallisations in step (i).
To this end, the crystalline salt obtained as a result of resolution may be dissolved in a solvent therefor. This may be achieved by warming. The salt is recrystallised from the resulting solution. That may be achieved by allowing the solution to cool. The solvent may be ethanol. The proportion of the salt with the R(-)enantiomer can thus be increased until it is substantially pure, i.e. until substantially only the salt with the R(-) enantiomer is present.
The mother liquor from the resolution step and the mother liquor from the or each recrystallisation step are enriched with the S(+)enantiomer. One or more of these liquors or the pooled liquors may be treated with a base such as sodium hydroxide to remove any residual chiral acid and to afford thereby the free base. The free base obtained may be dried.
The free base enriched in the S(+) enantiomer cain then be converted to the racemate. That may be achieved by heating under reflux in a solvent, such as toluene, for example for from 12 to 48 hours. The racemate thus obtained can then be recycled to step (i) of the present process. Yields can thus be increased.
The salt that is obtained in step (i) is the salt of th

REFERENCES:
patent: 5684005 (1997-11-01), Miller et al.

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