Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1989-10-06
1991-11-19
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514 81, 544244, 544277, A61K 3152
Patent
active
050666550
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
N.sup.6 -substitution can markedly increase potency of 9-methyladenine at A.sup.1 receptors, while having lesser effects or even decreasing potency at A.sub.2 receptors. Effects of N.sup.6 substituents on adenosine receptor activity of the 9-methyladenines are reminiscent of effects of N.sup.6 -substituents on activity of adenosine, suggesting that N.sup.6 -substituted 9methyladenines bind to adenosine receptors in the same orientation as do N.sup.6 -substituted adenosines. N.sup.6 -Cyclopentyl -9-methyladenine is more potent than 9-methyladenine.
N.sup.6 -Cyclopentyl and several other N.sup.6 -alkyl and N.sup.6 cycloalkyl analogs are selective for A.sub.1 receptors while 9-methyladenine is the most A.sub.2 -receptor selective antagonist. The N.sup.6 -R- and N.sup.6 -S-(1-phenyl-2-propyl)-9-methyladenines, analogous to N.sup.6 -R- and N.sup.6 -S-phenylisopropyladenosine, exhibit stereoselectivity at both A.sub.1 and A.sub.2 receptors.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are represented by the general formula: ##STR1## wherein R.sub.1 is selected from the group consisting of cycloalkyl radicals having from 3 to 7 ring carbon atoms, alkyl radicals having from 2 to 10 carbon atoms, aryl radicals having from 6 to 10 carbon atoms, aralkyl radicals having from 7 to 10 carbon atoms and heteroatom substituted derivatives thereof wherein said heteroatom may be selected from the group consisting of halogen, nitrogen, phosphorus, sulfur and oxygen; R.sub.2 may be hydrogen or R.sub.1, and R.sub.3 is an alkyl group comprising from 1 to 4 carbon atoms.
Preferably the compounds are those wherein R.sub.3 is methyl; wherein R.sub.2 is hydrogen; wherein R.sub.1 is a cycloalkyl having from 4 to 6 carbon atoms in the ring, more preferably phenyl or a substituted phenyl such as 0-fluorophenyl, 3,4,5-trimethoxyphenyl, benzyl, phenethyl, 2-(3pyridylethyl), 2-(3-thienylethyl, or 3-pentyl; or wherein R.sub.2 is selected from the group consisting of methyl and 2-propyl and R.sub.1 is selected from the group consisting of cyclopentyl and phenyl. Most preferably R.sub.1 is a norbornane.
The preparation of 9-methyl adenines is well known. See R. K. Robins, K. J. Dille, and B. E. Christensen, J. Org. Chem., 19, 930 (1954); R. K. Robins and H. H. Lin, J. Am. Chem. Soc., 79, 490 (1957; and J. A. Montgomery and Carroll Temple, Jr., J. Am. Chem. Soc., 79, 5238 (1957).
To prepare N.sup.6 -cyclopentyl-9-methyl Adenine the following additional steps were taken. A mixture of 6-chloro-9-methyl Adenine (0.82 g), cyclopentylamine (0.52 ml), triethylamine (0.53 ml) and ethanol (60 ml), was refluxed for 24 hours. The solution was concentrated in vacuo to a yellow syrup. The syrup was passed through a C-18 column to give 0.78g or 74% yield of with m.p. - 108-109.degree. C. .sup.1 HNMR(Me.sub.2 SO-d6): .delta.1-2(m,9 H); 3.7(S,CH.sub.3); 7.6(d,NH); 8.1(S,1H); 8.2(S,1H).
To prepare N.sup.6 3 -pentyl-9-methyladenine the following steps were taken. A mixture of 6-chloro-9-methyladenine (1.5 g), 3-pentylamine (1.3 ml), triethylamine (1.3 ml) and ethanol (60 ml), was refluxed for 24 hours. The solution was concentrated and passed through a C-18 column to give a white solid having m.p. - 107-109.degree. C.
To prepare N.sup.6 -(2-Aminonorbornanyl)-9-methyl Adenine the following additional steps were taken. A mixture of 1.5 g 6-chloro-9-methyl Adenine, 1.75 g 2-aminonorbornane, 2.9 ml triethylamine and 60 ml ethanol was refluxed overnight. The solution was then concentrated in vacuo and the remainder was passed through C-18 prep-chromatography to give l.6 g (75% yield) m.p. 130-131.degree. C. .sup.1 HNMR(Me.sub.2 SO-d6): .delta.1 -2.6(m,10 H); 3.8(S, CH.sub.3); 4.1(m,1H); 7.2(S,NH); 7.4(S,1H); 7.6(S,1H).
Adenosine receptors have been divided into two subtypes, based on adenylate cyclase activity; A.sub.1 (n.sub.1) receptors mediate inhibition and A.sub.2 (R.sub.a) receptors mediate stimulation of adenylate cyclase activity (for reviews see ref. 1., 2). Some N.sup.6 -substituted adenosine analogs
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Baran Robert J.
Hackler Walter A.
Lee Mary C.
Whitby Research, Inc.
Whittenbaugh Robert
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