Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1995-01-30
1997-01-14
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 2722, A61K 3170, C07H 19167
Patent
active
055939759
DESCRIPTION:
BRIEF SUMMARY
The present application is the United States national application corresponding to International Application No. PCT. EP93/00972, filed Apr. 21, 1993 and designating the United States.
The present invention relates to adenosine derivatives having A.sub.2 agonist activity and the use thereof in therapy.
Adenosine is known to modulate a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. On central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. At the kidney level, it exerts a diphasic action, inducing vasoconstriction at low concentrations and vasodilatation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an antiaggregant on platelets (Stone T. W., Purine receptors and their pharmacological roles. In: Advances in drug research. Academic Press Limited, 1989, 18, 291-429; Progress Cardiovasc. Dis. 1989, 32, 73-97).
A number of studies showed adenosine actions are mediated by two subtypes of receptors which are located on the cell membrane: an high-affinity one, inhibiting the activity of the enzyme adenylate cyclase (A.sub.1 receptor), and a low-affinity one, stimulating the activity of the same enzyme (A.sub.2 receptor). (J. Med. Chem. 1982, 25, 197-207. Physiol. Rev. 1990, 70(3), 761-845. J. Med. Chem. 1992, 35, 407-422). Both receptors are widely spread in the different systems of the organism. In some tissues, however, only one of said receptors is mainly pre sent. For example, A.sub.1 receptor is prevailing at the cardiac level, whereas the A.sub.2 receptor is present mainly at the vascular level and on platelets.
Therefore, it is clear that compounds capable of interacting selectively with the A.sub.2 receptor could have an interesting pharmacological pattern. In fact, the vasodilating activity, together with the antiaggregating action, can lead to useful therapeutical applications in the treatment of severe cardiovascular pathologies, such as ischemic cardiopathy, hypertension and atherosclerosis.
Moreover, due to the actions on central nervous system, the use of A.sub.2 selective medicaments can be envisaged in the treatment of cerebrovascular ischemia, epilepsy and various emotional disorders, such as anxiety and psychosis.
The prototypical compound having activity on the A.sub.2 receptor is adenosine-5'-N-ethyluronamide or NECA (Mol. Pharmacol., 1986, 25, 331-336). On the other hand, NECA is also active on the A.sub.1 receptor and therefore it lacks selectivity for the adenosine receptors. Being the only available compound having A.sub.2 affinity, NECA was used for pharmacological tests for the receptor binding. Only recently, the use of NECA as a prototypical A.sub.2 agonist has been gradually quit since compounds were found having a certain A.sub.2 receptor selectivity. Said compounds are NECA derivatives which are substituted at the C2-position with phenylamino groups. For example, compound 2-(p-(carboxyethyl)phenylethylamino)-5'-N-ethyluronamide, named CGS 21680 (J. Pharmacol Exp. Ther., 1989, 251, 888-893) has become the reference compound for the pharmacological studies on A.sub.2 receptor.
Purine derivatives having a selective A.sub.2 agonist activity are disclosed, for example, in GB-A-2203149, EP-A-0309112, EP-A-0267878, EP-A-0277917, EP-A-0323807.
Particularly, substitution at the 2-position of the purine group has been considered promising to give the desired selectivity (J. Med. Chem. 1992, 35, 407-422).
2-Alkynylpurine derivatives have been disclosed in EP-A-0219876.
Now it has been found that 2-alkynyladenosine derivatives substituted at the ethyne position with aryl, heterocyclic or hydroxyalkyl groups and in which the riboside residue is substituted by the N-alkyl- (or cycloalkyl)-uronamido, have surprisingly advantageous properties compared with the known compounds.
The compounds of the invention have the following general formula: ##STR3## wherein R is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, phenyl C.sub.1 -C.sub.3 alkyl;
REFERENCES:
Stone T. W., "Purine receptors and their phamacological roles," Advances in Drug Research, 18, (Academic Press Limited, 1989), 291-429.
Belardinelli et al, Progress Cardiovasc. Dis., 1989, 32, 73-97.
Daly, J., J. Med. Chem., 1982, 25 (3), 197-207.
Olsson, et al, Physiol. Rev., 1990, 70 (3), 761-845.
Jacobson, et al, J. Med. Chem., 1992, 3 (3), 407-422.
Bruns, et al, Mol. Pharmacol., 1986, 29, 331-346.
Jarvis, et al, J. Pharmacol Exp. Ther., 1989, 25 (3), 888-893.
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Abiru, et al, Eur. J. Pharmacol., 1991, 196, 69-76.
Homma et al., "Nucleosides and Nucleotides. 112. 2-(1-Hexyn-1-yl)adenosine-5'-uronamides: A New Entry of Selective A.sub.2 Adenosine Receptor Agonists with Potent Antihypertensive Activity," J. Medicinal Chem., 35(15), 2881-2890 (1992).
Conti et al., "Effects of Selective A.sub.1 and A.sub.2 Adenosine Receptor Agonists on Cardiovascular Tissues," Naunyn-Schmiedeberg's Arch. Pharmacol., 348(1), 108-112 (1993).
Crane L. Eric
Dicker Eric S.
Kight John
Magatti Anita W.
Schering Corporation
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