Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1999-07-16
2000-05-16
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C07C21100
Patent
active
060639644
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to compounds active in the cardiovascular field, and specifically to hydroxymethyl derivatives of tetrahydronaphtylamines and to the therapeutical use thereof.
The patent application DE 28 03 582 refers to 2-aminotetralin derivatives optionally substituted in 5-position by a hydroxymethyl group, but none of the exemplified compounds have this specific residue.
This event is clear in view of McDermed, J. D. et al., J. Med. Chem., 1975, 18(4), 362-367 which disclose the synthesis and dopaminergic activity of some 2-aminotetralins, and particularly of 2-(dipropylamino)-1,2,3,4-tetrahydro-5,6-dihydroxy-naphthalene. The 5-hydroxymethyl-2-aminotetralins are excluded from the pharmacological evaluation because it is impossible to synthesise them. Precisely the Authors affirm not to be able to deprotect the hydroxy group in 6-position without decomposing the hydroxymethyl group in 5-position even when protected.
As far as we know, until now no one was able to synthesise 5-hydroxymethyl-6-hydroxy-2-aminotetralins, and consequently to test their pharmacological activity.
Therefore the present invention relates to compounds of formula I ##STR2## wherein R.sub.1 and R.sub.2 are independently hydrogen or an optionally branched C.sub.1-4 alkyl group;
The compounds of formula I have at least an asymmetric centre marked by an asterisk, and thus may be in form of stereoisomers.
Objects of the present invention are compounds of formula I in form of stereoisonieric mixture so as in form of single stereoisomers.
The compounds of formula I are agonist of the dopaminergic receptors, also orally active. They are therapeutically useful in the cardiovascular field, specifically in the treatment of arterial hypertension, heart and renal failure, in the treatment of peripheral arteriopathies, cerebrovascular insufficiencies, ischemic cardiopathy and arrhythmia, and in the central nervous system, particularly in the treatment of Parkinson's disease, depression and as prolactin inhibitors.
Specific example of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl, n-propyl being preferred.
Preferred compounds of formula I are the one wherein the carbon atom marked by an asterisk has the S configuration.
Pharmaceutical acceptable salts of the compounds of formula I are those with organic and inorganic acids such as, for example, hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, acetic, benzoic, maleic, fumaric, succinic, tartaric, citric, aspartic, methansulfonic and 3,7-di-t.butylnaphthalen-1,5-disulfonic acid (dibudinic acid).
The preparation of the compounds of formula I is another object of the present invention in that it has been carried out overcoming a prior art prejudice, i.e. it was impossible to obtain the compounds of formula I and particularly to deprotect the hydroxy group in 6-position while maintaining the hydroxymethyl group in 5-position even when protected, as already said above.
The preparation starts from the naphthylamine of formula II, optionally in form of salt ##STR3## wherein R.sub.1 and R.sub.2 are as defined above and PG are protective groups suitable for the hydroxy moiety such as benzyl and methyl, which is synthesised, for example, as described in the patent application WO 95/07885. The protective group in 5-position is removed with iodotrimethylsylane. Before this reaction it may be desirable, but not compulsory, to protect the amino group in the case it is primary or secondary, i.e. when at least one of R.sub.1 and R.sub.2 is hydrogen, with a suitable protecting group such as, for example, trifluoroacetyl in the case of a secondary amine, or phthalimido in the case of a primary amine. It is thereby obtained the compound of formula III ##STR4## wherein PG is as defined above, and A is a R.sub.1 -N-R.sub.2 group wherein R.sub.1 and R.sub.2 are as defined above or suitably protected primary or secondary amino group.
At this point of the synthetic route, if it starts from a compound of formula II with a primary or secondary amino gr
REFERENCES:
John D. McDermed et al., "Synthesis and Pharmacology of Some 2-Aminotetralins", Journal of Medicinal Chemistry, vol. 18, No.4, pp. 362-367, 1975.
Sugihara, H et al, Chem. Pharm. Bull (1978) 26 (2) 394-404.
Beer, Margaret et al. Biochem. Pharmacol (1988) 37(6) 1145-51.
Inatomi N et al. Arzneim-Forsch (1980) 30(2) 276-85.
Cavalleri Paolo
Marchini Francesco
Montanari Stefania
Santangelo Francesco
Killos Paul J.
Zambon Group S.p.A.
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