Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene active on t

Details Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene active on t Derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene active on t

1996-04-30

1998-05-05

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514445, 514398, 514380, 514510, 514649, 546300, 548243, 5483241, 549 65, 560129, 558190, C07D23384, A61K 3138

Patent

active

057475130

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP94/02981 filed Sep. 7, 1994.
The present invention relates to compounds active on the cardiovascular system and, in particular, it relates to derivatives of 2-amino-1,2,3,4-tetrahydronaphthalene and to their use in therapeutic field.
It is known that some hydroxylated 2-amino-1,2,3,4-tetrahydronaphthalenes are agonists of dopaminergic receptors and several studies about the structure-activity relationship have been carried out to determine the structure characteristics able to ensure the best dopaminergic activity and to avoid, at the same time, the undesired effects of dopamine.
An interesting review of these studies is collected in a paper published by H. E. Katerinopoulos and D. I. Schuster on Drugs of the Future, vol. 12(3), pages 223-253, (1987).
In spite of the various studies, however, the topology of dopaminergic receptors has not been yet explained and a series of receptor models has been proposed in the last ten years.
In the field of the compounds structurally related to dopamine and/or to 2-amino-1,2,3,4-tetrahydronaphthalene, some authors have found that the presence of a C.sub.3 -C.sub.4 alkyl group on the amino function is one of the requirements for dopaminergic activity while the structural requirements of the second substituent on the amino group have not yet been found.
Nevertheless, there are several examples in literature showing how the structural features of the two substituents can be, in practice, extremely variable and how small changes of the molecule can affect the pharmacological activity both quantitatively and qualitatively in a relevant manner.
Among the most significant examples the following are cited. European patent application No. 72061 (Fisons) describes, among the others, dopamines and amino-tetrahydronaphthalenes having a mono- or di-substituted portion of formula ##STR2## wherein X is a --(CH.sub.2).sub.n -- chain, optionally substituted by hydroxy; n is an integer between 1 and 7; R.sub.1 and R.sub.2, the same or different, are hydrogen, alkyl or phenyl; D.sub.2 is hydrogen, alkyl, phenyl, alkyl substituted by one or more hydroxy, pyridyl, phenyl; alkyl substituted by phenyl substituted, in turn, by halogen, alkyl, amino, alkoxy or nitro; or D.sub.2 may be the phenylethyl moiety of a dopamine or a hydroxy-1,2,3,4-tetrahydronaphthyl moiety.
Among the compounds described in European patent application No. 72061, the compound of formula ##STR3## whose international non-proprietary name is dopexamine (The Merck Index--XI ed., No. 3418, page 538) is the only compound, as far as we know, which has been developed and used in the acute treatment of heart failure.
It is significant that dopexamine, notwithstanding it was the compound of choice among the several compounds described and exemplified in European patent application No. 72061, is an agonist of dopaminergic receptors less active than dopamine and, like dopamine itself, it is not absorbed when 308-330, (1990)!.
European patent application No. 142283 (Fisons) describes a class of compounds which are analogs of dopexamine and in which the amino group of the dopamine moiety is still secondary.
In literature, there are several compounds with a catecholamine structure having the aim of keeping the favorable properties of dopexamine, also when administered by oral route, or of increasing the selectivity towards both dopaminergic receptors.
As far as we know, however, none of these compounds has shown all the required characteristics.
For the specific treatment of hypertension and heart failure still exists among physicians the need of drugs which are dopaminergic agonists more potent than dopamine and not selective towards a particular dopaminergic receptor subtype (D.sub.1 or D.sub.2), which do not interact with other receptor systems and, at the same time, which do not show either the side effects or the disadvantageous therapeutical aspects of dopamine, such as the lack of absorption by oral route and the short action (Goodman and Gilman's--"The Pharmacological Basis of Therapeutics"

REFERENCES:
patent: 5013760 (1991-05-01), Farmer et al.
patent: 5118704 (1992-06-01), Minaskanian et al.

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