Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-08-16
1993-06-29
Rizzo, Nicholas S.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544267, 544273, C07D47308, A61K 3152
Patent
active
052235041
DESCRIPTION:
BRIEF SUMMARY
This application is the national stage of international application PCT/GB/90/02027 filed Dec. 27th, 1990, and claims priority to British Application 8929208.0 filed Dec. 27th, 1989.
This invention relates to new therapeutically useful xanthine derivatives, to processes for their preparation and pharmaceutical compositions containing them.
It is known that cyclic adenosine monophosphate (AMP, a cyclic nucleotide) is an important mediator of cellular function, and when its intracellular concentration is increased e.g. via adenylate cyclase stimulation, effects such as smooth muscle relaxation, cardiac stimulation and inhibition of secretory cells are provoked.
The phosphodiesterases (PDE) are the enzymes responsible for the destruction of cyclic nucleotides and like stimulants of nucleotide cyclases, PDE inhibitors also increase levels of cyclic AMP and are effective as bronchodilators, vasodilators, cardiac stimulants, etc.
Many xanthine derivatives, such as theophylline, have been described as PDE inhibitors, however, its lack of selectivity against the different types of PDE is be one reason for the undesirable side effect profile seen with theophylline in man.
There are currently known to be at least 7 different types of PDE enzymes. Inhibition of PDE III (a cyclic guanosine monophosphate inhibited, high affinity cyclic adenosine monophosphate enzyme, see Reeves et al., 1987. Biochem J. 241, 535) increases intracellular cyclic adenosine monophosphate concentrations and effects include a specific cardiac stimulation. Selective inhibition of PDE IV, (a particular cyclic AMP phosphodiesterase, see Reeves et al. 1987) on the other hand increases intracellular cyclic adenosine monophosphate concentrations and produces responses associated with these increases but without directly producing cardiac stimulation. Thus selective PDE IV inhibitors are useful in the treatment of diseases in which the production of cardiac stimulation is not appropiate (e.g. asthma).
We have now unexpectedly found that xanthine derivatives with a substituted phenyl group in position 3 and a 3-6 carbon atom chain in position 1, potently inhibit type IV-PDE and are much weaker at inhibiting the type III enzyme, and for this reason they are useful in the treatment of disease without directly producing cardiac stimulation.
The new xanthine derivatives of the present invention are accordingly those compounds of the general formula: ##STR2## wherein R1 represents a straight or branched chain alkyl, alkenyl or alkynyl group containing from 3 to 6 (preferably or 4) carbon atoms, and R2 and R3 each represent hydrogen or halogen or a methyl, methoxy, nitro or trifluoromethyl group or R2 and R3 form together a methylenedioxy or ethylenedioxy group; with the proviso that R.sup.2 and R.sup.3 are not both hydrogen, and pharmacologically acceptable salts thereof formed with an alkali metal base or a nitrogen-containing organic base.
Preferred compounds of general formula I are those wherein R.sup.1 a straight chain alkyl group or those wherein R.sup.1 represents a n- or isopropyl, n-,iso or tert-butyl or n-hexyl group, R2 and R3 which may be the same or different represent hydrogen or halogen e.g. F, Cl or Br, or a methoxy group or R.sup.2 and R.sup.3 together represent methylenedioxy. Of outstanding interest are
According to a further feature of the present invention, the xanthine derivatives of general formula I can be prepared from the corresponding 6-aminouracil of the general formula: ##STR3## (wherein R1, R2 and R3 are as hereinbefore defined) by nitrosation, preferably with sodium nitrite and formic acid in an excess of formamide, preferably at a temperature of 40.degree. C. to 80.degree. C. In the reaction, the corresponding 5-nitroso derivative of general formula III is first formed in the reaction mixture: ##STR4## (wherein R1, R2 and R3 are as hereinbefore defined). A reducing agent such as sodium dithionite is then slowly added to the reaction mixture, preferably at a temperature of 90.degree. C. to 120.degree. C. This reduces the 5-n
REFERENCES:
patent: 4233303 (1980-11-01), Bergstrand et al.
Gristwood Robert W.
Mauri Jacinto M.
Noverola Armando V.
Soto Jose M. P.
Laboratorios Almirall SA
Rizzo Nicholas S.
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