Organic compounds -- part of the class 532-570 series – Organic compounds – Diazoamino
Patent
1995-01-13
1997-04-08
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Diazoamino
424408, 424464, 534560, 534565, 534555, 534775, C07C24524, A01N 3326
Patent
active
056189281
DESCRIPTION:
BRIEF SUMMARY
This invention relates to pyrimidine compounds and is particularly concerned with a class of triazenyl-substituted phenyl pyrimidine, for use in the chemotherapy of certain diseases commonly associated with AIDS or immuno-suppressed conditions resulting, for example, from cancer or organ transplantation.
The use of phenyl pyrimidines and purines in the therapy of diseases such as Pneumocystis carinii pneumonia, which is commonly associated with AIDS patients is known. The. relative potency and selectivity of such compounds is discussed by Broughton and Queener, Antimicroblal Agents and Chemotherapy, July 1991, pages 1348-1355. The pyrimidine trimethoprim and the quinazoline trimetrexate are understood to target the enzyme dihydrofolate reductase (DHFR). Although of high potency, both such compounds have disadvantages in use. Thus trimethoprim used in combination with sulphamethoxazole is associated with a high percentage of adverse reactions in AIDS patients while the more potent trimetrexate has poor selectivity. These problems limit the usefulness of these agents, and they are reserved for use when the disease is so severe that the importance of side effects is diminished. Broughton and Queener also report experiments using pyrimethamine derivatives bearing a wide range of substituents at the meta and/or para position of the phenyl ring. However, the potencies obtained are many times less than those obtained with trimethoprim and trimetrexate while the selectivities obtainable are not sufficient to suggest that such compounds could displace the known drugs for treatment of P. carinii infections and other infections such as Toxoplasma associated with AIDS.
There is thus the need for development of new compounds capable of combatting such infections with sufficient selectivity to enable their use for a wide range of patients.
According to the present invention, there is provided a compound of formula I: ##STR2## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently hydrogen, alkyl or acyl, R.sup.5 is alkyl, X represents a hydrophobic substituent, for example halogen or alkoxy, and n is an integer from 1 to 3, and R.sup.6 and R.sup.7 each represent alkyl, cycloalkyl, or aralkyl, or R.sup.6 and R.sup.7 together with the nitrogen to which they are attached form a heterocyclic ring, with the proviso that one or both of R.sup.6, and R.sup.7, or the heterocyclic ring including R.sup.6 and R.sup.7, carries and/or includes at least one oxygen or sulphur atom, or a salt or N-oxide thereof.
Preferably R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen, although the invention also includes mono- and di-alkylated or acylated derivatives. R.sup.5 is preferably lower alkyl e.g. containing up to 6 carbon atoms or more preferably ethyl.
X is preferably a halogen substituent, preferably chlorine, while n is usually 1. The hydrophobic substituent is preferably positioned meta or para to the pyrimidine ring, more preferably at the para position. Likewise, the triazene substituent is preferably meta or para to the pyrimidine ring and more preferably meta substituted.
A preferred group of compounds of formula I are those in which R.sup.6 and R.sup.7 each independently represent alkyl, or aralkyl, at least one of R.sup.6 or R.sup.7 carrying an oxygen-containing substituent, preferably a hydroxyl group, or including at least one oxygen atom, for example an alkoxyalkyl group or acyloxyalkyl group. Especially preferred are compounds where both of R.sup.6 and R.sup.7 represent a hydroxyethyl group or where one of R.sup.6 and R.sup.7 represents a hydroxyethyl group and the other represents a benzyl group or substituted benzyl group.
Also preferred are compounds where one of R.sup.6 and R.sup.7 represents an acyloxyalkyl group and the other represents a benzyl group or a substituted benzyl group.
A further preferred group of compounds of formula I are those in which R.sup.6 and R.sup.7 together with the nitrogen to which they are attached, form a morpholino group.
A preferred group of compounds in accordance with the i
REFERENCES:
patent: 3162571 (1964-12-01), Adams et al.
patent: 4092305 (1978-05-01), Townsend et al.
Bliss et al, J. Chem. Soc. Perkins Trans. I, 1987, pp. 2217-2228.
Shusterman et al, Molecular Pharmacology, vol. 36 (6), pp. 939-944 (1989).
O'Shea Dennis M.
Rathbone Daniel L.
Stevens Malcolm F. G.
British Technology Group Limited
Higel Floyd D.
LandOfFree
Triazenyl-substituted phenyl pyrimidines and their use in therap does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Triazenyl-substituted phenyl pyrimidines and their use in therap, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Triazenyl-substituted phenyl pyrimidines and their use in therap will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2398571