N-(W-substituted alkyl)-'-(imidazol-4-yl)alkyl)guanidine

Details N-(W-substituted alkyl)-'-(imidazol-4-yl)alkyl)guanidine N-(W-substituted alkyl)-'-(imidazol-4-yl)alkyl)guanidine

1988-11-23

1991-04-23

Lee, Mary C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

548342, 548343, C07D23364

Patent

active

050100955

DESCRIPTION:

BRIEF SUMMARY
The invention relates to a N-(.omega.-substituted alkyl)-N'-[(imidazol-4-yl)alkyl]guanidine.
Impromidine, or N-[2-(5-methylimidazol-4-yl methylthio)ethyl]-N'-[3-(imidazol-4-yl)propyl]guanidine is known as a specific and the most potent histamine H.sub.2 -agonist, Dependent on the used test system it either behaves like a partial or like a complete agonist having a potency of 5-800 times that of histamine (Proc. VIIIth Internat. Symp. Med. Chem. Uppsala, pages 202-203 (1985) Eds R. Dahlbom and J. L. G. Nilsson). Because of its effect on the release of histamine from mast cells, there might be some use of impromidine in the treatment of allergic conditions. However, a major drawback for the clinical use of impromidine is its relatively high potency in stimulating the gastric acid secretion and its effect on vasoconstriction and vasodilation.
Now a series of new impromidine-related compounds was discovered, said compounds having a high histamine H.sub.2 -agonistic acitivity on the guinea-pig right atrium with a relatively low activity on the guinea-pig gastric acid secretion and a potent histamine H.sub.1 -antagonism as tested on both the guinea-pig ileum and the guinea-pig trachea. Because of this combination of histamine H.sub.1 -antagonism and H.sub.2 -agonism in one compound, these compounds are of clinical significance for e.g. the treatment of congestive heart failures and some allergic conditions.
These new compounds are N-(.omega.-substituted alkyl)-N'-[imidazol-4-yl)alkyl]guanidines of formula 1, wherein: 5H-dibenzo-[a-d]-cyclohepten-5-yl group, or is (b) ##STR1## wherein Y.sub.1 is a R-substituted phenyl group and (10,11-dihydro)-5H-dibenzo-[a,d]-cyclohepten-5-ylidene group, represents an optional bond, with the understanding that from the R-substituted phenyl rings one or more may be replaced by a R-substituted heterocyclic aromatic ring and their acid addition salts.
Possibly present R-substituted heterocyclic aromatic rings are for example: 2-, 3- and 4-pyridinyl, 4-imidazolyl, 4-thiazolyl, 2-guanidino-4-thiazolyl, 2- and 3-furanyl, 2-dimethylaminomethyl-5-furanyl, etc.
The results of pharmacological tests with said new compounds are summarized in Table A (H.sub.1 -activity) and Table B (H.sub.2 -activity). The values for the H.sub.1 -activity given are the mean of at least two experiments in quadruplicate, while the values for the H.sub.2 -activity result from at least two experiments in duplicate.
In Table A the tested compounds are defined by a formula, and the meaning of R.sub.1 and n in the formula are stated in the table. In addition the compound have serial numbers corresponding with the serial numbers used in Table B. It is remarked that the last three compounds in the two tables do not fall within the invention, but are stated for comparison.


TABLE A __________________________________________________________________________ Histamine H.sub.1 -activity ##STR2## Ileum Trachea R.sub.1 n (pA.sub.2 0,2) pA.sub.2 .+-. 0,2) __________________________________________________________________________ I II ##STR3## ##STR4## 6,5 6,4 6,2 not determined III ##STR5## 3 7,5 7,6 IV V ##STR6## ##STR7## 6,4 6,6 6,5 not determined VI ##STR8## 3 6,6 6,8 VII ##STR9## 3 6,4 6,0 VIII IX ##STR10## ##STR11## 6,2 6,3 not determined not determined ##STR12## 3 6,7 6,2 XI ##STR13## 3 7,6 7,8 XII ##STR14## 3 5,5 not determined XIII Impromidine 5,5 not determined XIV Diphenhydramine 8,0 not determined __________________________________________________________________________


TABLE B ______________________________________ Histamine H.sub.2 -activity atrium gastric fundus .alpha. pD.sub.2 (.+-.0,1) .alpha. pD.sub.2 (.+-.0,2) ______________________________________ I 1,0 6,8 1,0 6,1 II 0,8 4,8 0,5 4,9 III 0,9 5,5 0,4 5,8 IV 0,8 5,9 not determined V 0 4,0 0 4,0 VI 0,8 5,9 0,4 5,5 VII 0,8 5,9 not determined VIII 0,9 5,6 0 5,0 IX 1,0 7,7 not determined X 1,0 7,0 0,9 5,6 XI 1,0 6,4 0,7 6,5 XII 1,0 7,2 1,0 7,6 XV His

REFERENCES:
patent: 4013659 (1977-03-01), Durant et al.
patent: 4098898 (1978-07-01), Durant et al.
patent: 4166860 (1979-09-01), Douglas et al.
patent: 4192879 (1980-03-01), Durant et al.
Sterk, et al., "Histaminergic Compounds", Eur. J. Med. Che., 22 (6), 491-8, 1987.

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