Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-07-01
1999-12-07
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514394, 514395, 5483061, 5483074, 5483104, A01N 4300
Patent
active
059983981
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to benzimidazole derivatives and their use in medical therapy particularly for the treatment or prophylaxis of virus infections such as those caused by herpes viruses. The invention also relates to their preparation and pharmaceutical formulations containing them.
Of the DNA viruses, those of the herpes group are the sources of the most common viral illnesses in man. The group includes herpes simplex virus types 1 and 2 (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6) and human herpes virus type 7 (HHV-7). HSV-1 and HSV-2 are some of the most common infectious agents of man. Most of these viruses are able to persist in the host's neural cells; once infected, individuals are at risk of recurrent clinical manifestations of infection which can be both physically and psychologically distressing.
In common with other herpes viruses, infection with CMV leads to a lifelong association of virus and host Congenital infection following infection of the mother during pregnancy may give rise to clinical effects such as death or gross disease (microcephaly, hepatosplenomegaly, jaundice, mental retardation), retinitis leading to blindness or, in less severe forms, failure to thrive, and susceptibility to chest and ear infections. CMV infection in patients who are immunocompromised for example as a result of malignancy, treatment with immunosuppressive drugs following transplantation or infection with Human Immunodeficiency Virus may give rise to refinitis, pneumonifts, gastrointestinal disorders and neurological diseases.
It has now been found that certain substituted benzimidazole compounds referred to below have activity against viruses particularly CMV. According to one aspect the present invention provides compounds of formula (I) ##STR1## wherein:
R.sup.1 represents;
H, C.sub.1-4 alkyl, C.sub.3-5 cycloalkyl;
R.sup.2 represents;
H, C.sub.1-4 alkyl; or
R.sup.1 and R.sup.2 together form with the nitrogen a 4 or 5 membered heterocyclic ring;
R.sup.3 represents BR.sup.4 or R.sup.4, wherein B represents a bridging group -C(O)NH--, --C(O)NC.sub.1-4 alkyl-, or --C(O)O-- and R.sup.4 represents H, C.sub.1-4 alkyl, C.sub.2-6 alkenyl or halo (preferably fluoro); and
each n is independently selected from an integer 0, 1, or 2 (preferably 0 or 1); and geometric isomers or mixtures thereof; and physiologically functional derivatives thereof.
Preferred compound of formula (I) include compound wherein:
R.sup.1 represents:
H, C.sub.1-4 alkyl, C.sub.3-5 cycloalkyl;
R.sup.2 represents H, C.sub.1-4 alkyl; or
R.sup.1 and R.sup.2 together form with the nitrogen a 4- or 5-membered heterocyclic ring;
R.sup.3 represents I, Cl, Br, F, CH.sub.3 or H;
n is an integer 0, 1 or 2.
Preferred compounds of formula (I) include and R.sup.2 group is isopropyl; or R.sup.2 group is tertbutyl; an azetidenyl group. is 0 or 1.
It will be appreciated that compounds of formula (I) may exist as geometric (.alpha. and .beta.) isomers and mixtures thereof.
Preferred geometric isomers of the compounds of formula (I) are 1.alpha., 2.alpha., 4.beta. isomers (or, equivalently, 1.beta., 2.beta., 4.alpha. isomers) and 1.alpha., 2.beta., 4.alpha. (or, equivalently, 1.beta., 2.alpha., 4.beta. isomers).
Preferred compounds of formula (I) are: 4a)-4-[5,6-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl]-1,2-cyclopent anediol; 4a)-4-[5,6-Dichloro-2-(azetidinyl)1H-benzimidazol-1-yl]-1,2-cyclopentanedi ol; 4a)-4-[5,6-Dichloro-2-(tert-butylamino)-1H-benzimidazol-1-yl]-1,2-cyclopen tanediol; 4.beta.)-4-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-1,2-cy clopentanediol; 4.alpha.)-[4-(5,6-Dichloro-2-(isopropylamino)-1H-benzimidazole-1-yl]-2-cyc lopentanediol; 4.beta.)-[4-(5,6-Dichloro-2-(cyclopropylamino)1H-benzimidazol-1-yl)-1,2-cy clopentylene]dimethanol;
(1.alpha., 2.alpha., 4.beta.)-[4-(5,6,-Dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl 1,2-cyclopentylene]dimethanol; 4.beta.)-[4-Fluoro-5,6-dichloro-2-(isopropylamino)-1H-benzimidazol-1-yl)-1 ,2-cyclopentylene]di
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Andersen Marc Werner
Daluge Susan Mary
Glaxo Wellcome Inc.
Morgan Lorie Ann
Powers Fiona T.
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