N-cyano-N'-pyridylguanidines as serotonin antagonists

Details N-cyano-N'-pyridylguanidines as serotonin antagonists N-cyano-N'-pyridylguanidines as serotonin antagonists

1995-03-15

1996-10-08

Davis, Zinna Northington

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514344, 514349, 546286, 546287, 546288, 546289, 546294, 546296, 546297, 546306, C07D21375, A61K 3144

Patent

active

055631606

DESCRIPTION:

BRIEF SUMMARY
This application is a Section 371 national phase filing of PCT/DK93/00291, filed Sep. 13, 1993.
The present invention relates to a series of compounds, their pharmaceutically acceptable salts, and their N-oxides, to methods for preparing the said compounds, salts or N-oxides, to pharmaceutical compositions containing said compounds, to dosage units of the compositions, and to methods of treating patients, using said compositions and dosage units.
The new compounds, which are useful in the human and veterinary therapy, have the general formula (I) ##STR1## or their tautomeric forms, the attachment to the pyridine ring being in the 3- or 4-position, in which R',R" are the same or different and stand for hydrogen, halogen, or trifluoromethyl, hydroxy, C.sub.1 -C.sub.4 alkyl or alkoxy, nitro, or cyano groups. Alkylene stands for a straight or branched C.sub.1 -C.sub.8 carbon chain, which may be substituted by hydroxy or halogen, nitro or cyano groups. X stands for oxygen, for --S(O).sub.n -- where n stands for an integer from 0 to 2, or for .dbd.N--R.sub.1 where R.sub.1 is hydrogen or C.sub.1 -C.sub.4 alkyl. R stands for hydrogen or for one or more C.sub.1 -C.sub.4 alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, cyano, carboxamido, sulfamoyl or nitro radicals.
In the case where the present compounds contain one or more asymmetric carbon atoms, these compounds may form optical isomers or diastereoisomers. The present invention also comprises such isomers, and mixtures of same.
Pharmaceutically acceptable salts of compounds of formula I include hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, arylsulphonates, citrates, tartrates, maleates, these examples being considered as non-limiting for the invention.
Among the preferred compounds of the invention are those of formula I, in which the attachment to the pyridine ring is in the 4-position, and/or in which alkylene stands for a straight C.sub.3 -C.sub.6 carbon chain, and/or in which X stands for oxygen.
N-alkyl-N'-cyano-N"-pyridylguanidines, described in United Kingdom Patent No. 1,489,879, are potent potassium channel activators with a pronounced effect as pre-capillary vasodilators, reducing the total peripheral resistance in animals and in man, and are thus useful as antihypertensives. The introduction of aryloxy-containing radicals into the aliphatic groups from the cited patent has led to structures showing more specific pharmacological effects on isolated tissues and cells and with no or a negligible effect on .sup.86 Rb-efflux from potassium channels, as compared with the established effect of compounds covered by the above-mentioned U.K. Patent. Among the compounds represented by the formula (I) of the present invention, some have surprisingly proved to be serotonin (5HT) antagonists, as demonstrated in isolated rat fundus strips and in 5HT induced rat paw oedemas, making them potentially useful for treatment of diseases, in which 5HT is involved in the pathologic reaction, e.g. asthma, allergy and CNS disorders.
To study the affinity of the present compounds for serotonin.sub.2 (5HT.sub.2) receptors the inhibition of [.sup.3 H]ketanserin binding to specific 5HT.sub.2 receptors in rat cortical membranes was determined by the method described in Leysen et al.: [.sup.3 H]Ketanserin: a selective tritiated ligand for serotonin.sub.2 receptor binding sites. Molecular Pharmacology 21: 301-314 (1982). The results are shown in Table 1.


TABLE 1 ______________________________________ 5HT.sub.2 receptor binding exerted by compounds of the following examples of the present invention. Per cent binding Compound from 10.sup.-9 M 10.sup.-7 M 10.sup.-5 M ______________________________________ Example No. 5 34.5 60.1 95.4 Example No. 14 41.3 66.5 98.4 Example No. 18 21.3 41.1 54.2 ______________________________________
These results show that the compounds of the present invention inhibit the binding of ketanserin to 5HT.sub.2 receptors and therefore have high affinity for such receptors.
Some members of the present class

REFERENCES:
C. Kaergaard Neilsen, et al: "Synthesis and hypotensive activity of N-alkyl-A''-cyano-N'-pyridylguanidines", Journal of Medicinal Chemistry, vol. 21, No. 8, 1978, pp. 73-781.
Batra, S.et al: "Effect of Diverse Categories of Drugs on Human Colon Tumour Cell Proliferation", Anticancer Research vol. 11, No. 3, Jun. 1991, pp. 1221-1224.

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