Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1980-09-03
1983-01-11
Gerstl, Robert
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
2604109R, 260413, 424277, 424317, 546342, 560 17, 560 35, 560 51, 560 60, 562427, 562440, 562462, 562470, 562502, G07C 53136, G07C 5726
Patent
active
043683320
DESCRIPTION:
BRIEF SUMMARY
This invention relates to biologically active compounds and in particular to certain novel compounds exhibiting activity at thromboxane receptor sites.
Thromboxane A.sub.2 (TXA.sub.2), which is derived from arachidonic acid via prostaglandin H.sub.2 (PGH.sub.2), is implicated in several potentially noxious actions on various body systems, including platelet aggregation, bronchoconstriction and pulmonary and systemic vasoconstriction. Thus TXA.sub.2 may be involved in the normal sealing of blood vessels following injury but in addition may contribute to pathological intravascular clotting or thrombosis. Moreover, the constrictor actions of TXA.sub.2 on bronchiolar, pulmonary vascular and systemic vascular smooth muscle may be important in the development of several anaphylactic conditions including bronchial asthma. There is also some evidence to implicate PGH.sub.2 and TXA.sub.2 in the genesis of inflammation.
It is an object of the present invention to provide compounds having activity at thromboxane receptor sites, and most especially to to provide compounds which are inhibitors of thromboxane activity and are therefore of interest in one or more areas of medical treatment including the treatment of thrombotic disorders, the treatment of anaphylactic disease states, and treatments utilising anti-inflammatory agents.
Accordingly the present invention comprises a compound being a bicyclo[2,2,1]heptane or hept-2Z-ene which is substituted at the 5-position by a 6-carboxyhex-2-enyl group or a modification thereof as defined herein, and at the 6-position by an aldoxime or ketoxime group which is O-substituted by an aliphatic hydrocarbon residue, an aromatic residue or a aliphatic hydrocarbon residue substituted directly or through an oxygen or sulphur atom by an aromatic residue.
Certain of the compounds containing a modified 6-carboxyhex-2-enyl group act through the conversion of the modified group back to the unmodified group in vivo. In addition to such bioprecursors, the invention also extends in general to other pharmaceutically acceptable bioprecursors for the bicyclo[2,2,1]heptanes and hept-2Z-enes described above, such a bioprecursor being a compound having a structural formula different from the active compound but which upon administration is converted thereto in vivo.
Modifications of the 6-carboxyhex-2-enyl group which may be made in compounds according to the present invention are of two types. Firstly, there are modifications which involve alteration of the hex-2-enyl group by one, or where appropriate by a combination, of the following: (a) reduction of the double bond optionally accompanied by the replacement of a carbon atom at the 5, 6 or even 7 position relative to the C.sub.1 of the carboxylic acid group by a sulphur or particularly an oxygen atom; (b) alteration of the position of the double bond, for example to the 4,5 position; and (c) shortening or lengthening of the carbon chain, particularly by one or two methylene groups and conveniently at the end of the chain adjacent to the carboxy group.
The second form of modification, which may if desired be combined with a modification of the first type, involves conversion of the carboxy group to a functional derivative including salts thereof. Functional derivatives described in the prostaglandin art are of particular interest, including esters such as alkyl esters, amides such as those containing the group --CONHSO.sub.2 CH.sub.3 and variants thereon, and salts with various physiologically acceptable cations. Specific examples of salts are those with an alkali metal such as sodium or with quaternary ammonium ions or amines such as tris. As mentioned above, it will be appreciated that many of such compounds are in fact bioprecursors for the corresponding compound containing a carboxy group to which they are converted in vivo.
Ketoxime groups, --C(R).dbd.NOR', in which R' is as defined above for the O-substituent, more usually contain organic groups R of the same general type as described for R', for example particularly aliphatic hydrocarbon
REFERENCES:
patent: 3946065 (1978-02-01), Matsui et al.
patent: 4073933 (1976-03-01), Shimomura et al.
Fitzpatrick et al., Nature 275, 764, (1978).
Hensby et al., Advances in Prostaglandin and Thromboxane Research Pole, p. 864, (1976).
Leeney et al., Prostaglandins II, 953, (1976).
Katsube et al., Ag. & Biol. Chemistry, 36, 1997, (1972).
Jones Robert L.
Wilson Norman H.
Gerstl Robert
National Research Development Corporation
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