Adenosine derivatives

Details Adenosine derivatives Adenosine derivatives

1998-11-06

1999-12-07

Lee, Howard C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

536 2762, 536 2763, 536 277, A61K 3170, C07H 1916

Patent

active

059983884

DESCRIPTION:

BRIEF SUMMARY
This invention relates to novel adenosine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Thus the invention provides compounds of formula (I) which are agonists at the adenosine A1 receptor. ##STR2## wherein R.sup.1 represents phenyl optionally substituted by one or more substituents selected from halogen, C.sub.1-3 alkyl, trifluoromethyl, nitro, cyano, --CO.sub.2 R.sup.a, --CONR.sup.2 R.sup.a R.sup.b, --COR.sup.a, --SOR.sup.c, --SO.sub.2 R.sup.c, --SO.sub.3 H, --SO.sub.2 NR.sup.a R.sup.b, --OR.sup.a, --NHSO.sub.2 R.sup.c, --NHCOR.sup.a and --NR.sup.a R.sup.b ; alkyl or, when --NR.sup.a R.sup.b is directly attached to said phenyl, R.sup.a and R.sup.b together with the nitrogen atom may form a -5 or -6 or membered heterocyclic ring optionally containing a second heteroatom selected from oxygen or nitrogen, which second nitrogen heteroatom may optionally be further substituted by hydrogen or C.sub.1-3 alkyl; salts and solvates thereof.
It will be appreciated that when R.sup.1 and/or R.sup.2 in compounds of formula (I) contain one or more asymmetric carbon atoms the invention includes all diastereoisomers of compounds of formula (I) and mixtures thereof. Otherwise the stereochemical configuration of compounds of the invention is as depicted in formula (I) above.
As used herein, the term "alkyl" means a straight or branched chain alkyl group. Examples of suitable alkyl groups within R.sup.1 and R.sup.2 include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, 1-butyl and 3-methylbutyl.
As used herein, the term "C.sub.3-6 alkenyl" means a straight or branched chain alkenyl group containing 3 to 6 carbon atoms. Allyl represents an example of a suitable C.sub.3-6 alkenyl group.
The term "halogen" means fluorine, chlorine, bromine or iodine.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. A particularly, suitable pharmaceutically acceptable saft of the compounds of formula (I) is the hydrochloride salt. Other acids such as oxalic, while not, in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. The solvates may be, for example, hydrates.
When R.sup.1 represents a substituted phenyl group the phenyl ring may preferably be substituted by, for example, one or two atoms or groups selected from halogen, hydroxyl, methyl, methoxy, --CO.sub.2 H, --CONH.sub.2 and --SO.sub.2 NH.sub.2.
More preferred phenyl group substituents within R.sup.1 include halogen (in particular, fluorine and chlorine), hydroxyl and methyl. Particularly preferred are halogen (in particular, fluorine or chlorine) and hydroxyl substitution.
R.sup.1 preferably represents a group selected from 3-fluoro-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-2-methylphenyl, 2-fluoro-4-hydroxyphenyl, 3,4-difluorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl and 2,4-difluorophenyl.
A particularly preferred R.sup.1 group is 3-fluoro-4-hydroxyphenyl.
R.sup.2 and R.sup.3 preferably independently represent a C.sub.1-3 alkyl group, especially methyl.
It is to be understood that the present invention covers all combinations of particular and preferred groups mentioned hereinabove.
Particular compounds according to the invention include:
A particularly suitable compound according to the present invention is N-(3-fluoro-4-hydroxyphenyl)-2,5'-O-dimethyladenosine, and pharmaceutically acceptable salts and solvates thereof.
Compounds according to the invention have applicability as inhibitors of lipolysis i.e. they decrease pl

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Journal of the Chinese Chemical Society, vol. 38, No. 3, Jun. 1991, pp. 289-292, XP002038762 A.F. Sayed Ahmed et al: "Synthesis of some antimicrobial purine nucleoside derivatives." See the whoe document.
Journal of Medicinal Chemistry, vol. 35, No. 12, 1992, Washington US, pp. 2253-2260, XP002038763 T.Abiru et al: "Nucleosides and nucleotides. 107. 2-(cycloalkylakynyl)adenosines: adenosine A2 receptor agonists with potent antihypertensive effects." See the whole document.
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