Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1985-08-29
1987-09-22
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 23, 560 52, 560 75, 562435, 562436, 562460, 562463, 562478, 558414, 558423, 549308, 549310, C07C 6976
Patent
active
046956484
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with novel compounds having a potentially inhibitory effect on 15-hydroxy-prostaglandin dehydrogenase (PGDH). The invention is also concerned with the production of these novel compounds and with pharmaceutical compositions containing them.
The future potentialities of PGDH inhibitors, in respect of their usefulness in medicine, have not yet been fully explored. But it is a known fact that prostaglandins play a very important role in the body's regulating system, and for this reason any drugs interfering with either the synthesis or the degradation of prostaglandins may be potentially valuable medical tools. The so-called cytoprotective effect of prostaglandins is relatively well known in the context of ulcer therapies; but nevertheless prostaglandin administration has not been utilized to any major extent for therapeutic purposes because the prostaglandins administered will survive in vivo for only a very short time. A drug inhibiting the degradation of endogenous prostaglandins might conceivably be much more successful than prostaglandin administration.
Endogenous prostaglandins have a major role also in inflammatory processes. In the treatment of rheumatoid arthritis it is therefore at present quite a common practice to employ inhibitors of prostaglandin syntheses; but nowadays this is regarded as merely being a symptomatic treatment, and as a matter of fact certain prostaglandins are now believed to possibly have a very favorable effect. Thus in this context, too, the inhibition of PGDH dependent degradation may be potentially very valuable. Further potentially valuable medical fields of application for the present novel compounds are all those where prostaglandins may function as desirable controlling factors as e.g. in the case of circulatory disorders, cancer, fertility, cell regulation etc.
Examples of previously known compounds having an inhibitory effect on PHDH are such azo compounds as are set forth in EP-A-No. 21229.
These azo compounds, which have been employed earlier, have a number of drawbacks sufficiently severe to considerably impair the usefulness of these compounds in actual practical medicine. The most severe drawback is the fact that animals and humans will metabolically split the azo compounds reductively so as to form two aromatic amines. This type of metabolism occurs to a particularly large extent in (i) the liver and (ii) the large intestine where it is promoted due to the highly reducing conditions created by the intestinal microflora, i.e. the bacteria normally present in the intestine.
Such metabolism is apt to eliminate a considerable portion of the dose administered; already this in itself is a disadvantage. The greatest problem however arises due to the presence of the aforesaid aromatic amines such as for example aniline, chloroaniline etc. In view of the formation of these amines in vivo it is generally impossible to use the azo compounds in practical medicine; only in very special cases can the amine as formed in vivo be considered to be sufficiently harmless to permit a practical therapeutic use of the azo compounds. A lesser but non-negligable disadvantage is the strong coloring involved with these azo compounds--leading, in the most unfavorable cases, to clearly discernible color changes in the patient's skin, eyes etc., which is undesirable.
It is an object of the present invention to provide improved PGDH inhibitors and methods for their production. Further objects are to provide improved pharmaceutical compositions and treating methods involving such inhibitors.
The novel compounds have the following structure: ##STR2## R.sub.1 and R.sub.2 are hydrogen or lower alkyl, preferably R.sub.2 is hydrogen; alkoxy, cyano, carboxy or nitro; at least one of the groups R.sub.4 to R.sub.6 being hydrogen; trifluoromethyl, lower alkoxy, hydroxy, lower acyl, lower alkoxycarbonyl, N,N-diloweralkyl-aminocarbonyl or N,N,-loweralkylene-aminocarbonyl; and R.sub.8 to R.sub.10 may in addition be carboxy; at least two of R.sub.7 to R.sub.11 always bein
REFERENCES:
Chemical Abstract 140495p, vol. 75, 1971.
Chemical Abstract 140497r, vol. 75, 1971.
Chemical Abstract 58068e, vol. 78, 1973.
Agback Karl H.
Agback Tamara
Nygren Alf S.
Killos Paul J.
Pharmacia AB
Philpitt Fred
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