Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-07-18
1992-02-25
Rivers, Diana G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514266, 544264, 544276, 544277, 549465, 558 44, 558 51, 560119, 562501, A61K 3152, C07D47318, C07D47334, C07D47316
Patent
active
050914316
DESCRIPTION:
BRIEF SUMMARY
SUMMARY
The present invention relates to nucleoside-type compounds having an optionally substituted purine derivative as the base joined to a carbobicyclic or heterobicyclic moiety. Said compounds are useful as phosphodiesterase inhibitors, in particular as antihypertensives.
The present invention also relates to pharmaceutical compositions comprising said nucleoside-type compounds, methods of preparing said compounds and to a method of treating hypertension comprising administering said compound or composition to a mammal in need of such treatment.
BACKGROUND
Cyclic guanosine monophosphate (cGMP) is known to be an important physiological mediator of vasorelaxation. A major process in vascular smooth muscle contraction is hydrolysis of cGMP by calcium-calmodulin dependent phosphodiesterase (Ca CaM PDE). Since Ca CaM PDE is selective for cGMP, selective inhibition of this enzyme should elevate cGMP levels in vascular smooth muscle and induce vasorelaxation.
Griseolic acid, disclosed in U.S. Pat. No. 4,460,765, is a nucleoside-type compound having an adenine base and a bicyclic sugar moiety and has a structure similar to adenosine 3',5'-cyclic monophosphate (cAMP). cAMP is known to be a mediator of a large number of hormones and griseolic acid similarly appears to inhibit a large variety of phosphodiesterases (PDEs).
DETAILED DESCRIPTION
Compounds of the invention are represented by the formula ##STR1## wherein
R.sub.1 is hydrogen or R.sub.1 and R.sub.2 together may form a double bond;
R.sub.2 is hydrogen or R.sub.2 may form a double bond with either R.sub.1 or X;
R.sub.3 is hydrogen or OH;
R.sub.4 is hydrogen or --(CH.sub.2).sub.n COOR.sub.6 ;
R.sub.5 is R.sub.4 or --CH(COOR.sub.6)(CH.sub.2 COOR.sub.6), provided that R.sub.4 and R.sub.5 are not both hydrogen;
R.sub.6 is hydrogen or lower alkyl;
n is 0-4;
X is --CH.sub.2 --, --NH--, --P-- or when R.sub.1 is hydrogen, X may be --CH.dbd. and form a double bond with R.sub.2 ;
Y is --CH.sub.2 --, --NH--, --P--, --S-- or --O--;
B is ##STR2##
R.sub.8 is --OH or --NH.sub.2 ;
R.sub.9 is hydrogen, lower alkyl or aryl;
R.sub.10 is hydrogen, amino, lower alkylamino, arylamino, lower alkylcarbonylamino, heteroaryl or heteroaryl substituted by 1-3 substituents independently selected from lower alkyl, amino, hydroxy, halogeno, thio, alkylthio and arylthio;
R.sub.11 is hydrogen, halogeno, lower alkyl or aryl; and the pharmaceutically acceptable esters or salts thereof.
The present invention also is directed to a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
The present invention further comprises the use of a compound of formula I for the preparation of a medicament for treating hypertension.
The present invention also is directed at a method for reducing blood pressure in hypertensive animals comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier.
The present invention also is directed at a process for producing a compound of formula I characterized by:
a. reacting a compound of formula Ia with a compound of formula Ba ##STR3## where V is methanesulfonyloxy, halogen or tosyl; or
b. reacting a compound of formula ##STR4## where W is chlorine, bromine, OR or NHR where R is a protecting group and the remaining substituents are as previously defined.
The present invention also is directed at intermediate compounds of the formulae ##STR5## where the substituents are as previously defined.
Those skilled in the art will recognize that tautomerism exists in group B, i.e., ##STR6##
As used herein the term "lower alkyl" refers to straight or branched chain alkyl groups of 1-6 carbon atoms or cycloalkyl groups of 3-6 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, pentyl, hexyl and cyclohexyl.
The term "halogeno" refers to fluoro, chloro, bromo and iodo.
The term "aryl" refers to phenyl or substituted phenyl wherein the substituents are selected from lower alkyl, amino, hydroxy, ha
REFERENCES:
patent: 4460765 (1984-07-01), Naito et al.
patent: 4634706 (1987-01-01), Kaneko et al.
patent: 4822879 (1989-04-01), Nakagawa et al.
patent: 4971972 (1990-11-01), Doll et al.
F. Nakagawa et al., J. Antibiotics, 38 (7), (1985), pp. 823-829.
S. Takahashi et al., J. Antibiotics, 38 (7), (1985), pp. 830-834.
Marquez et al., Med. Res. Rev., 6 (1), (1986), pp. 1-16 and 36-40.
Doll Ronald J.
Tulshian Deen
Magatti Anita W.
Nelson James R.
Rivers Diana G.
Schering Corporation
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