Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-01-21
2001-10-23
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C544S132000
Reexamination Certificate
active
06307043
ABSTRACT:
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 the preparation of the benzimidazole derivatives 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.
HSV infection is often characterised by extensive and debilitating lesions of the skin, mouth and/or genitals. Primary infections may be subclinical although tend to be more severe than infections in individuals previously exposed to the virus. Ocular infection by HSV can lead to keratitis or cataracts thereby endangering the host's sight. Infection in the new-born, in immunocompromised patients or penetration of the infection into the central nervous system can prove fatal.
VZV is a herpes virus which causes chickenpox and shingles. Chickenpox is the primary disease produced in a host without immunity, and in young children is usually a mild illness characterised by a vesicular rash and fever. Shingles or zoster is the recurrent form of the disease which occurs in adults who were previously infected with VZV. The clinical manifestations of shingles are characterised by neuralgia and a vesicular skin rash that is unilateral and dermatomal in distribution. Spread of inflammation may lead to paralysis or convulsions. Coma can occur if the meninges become affected. VZV is of serious concern in patients receiving immunosuppressive drugs for transplant purposes or for treatment of malignant neoplasia and is a serious complication of AIDS patients due to their impaired immune system.
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 retinitis, pneumonitis, gastrointestinal disorders and neurological diseases.
The main disease caused by EBV is acute or chronic infectious mononucleosis (glandular fever). Examples of other EBV or EBV associated diseases include lymphoproliferative disease which frequently occurs in persons with congenital or acquired cellular immune deficiency, X-inked lymphoproliferative disease which occurs namely in young boys, EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngeal carcinoma, Burkitt lymphoma, non-Hodgkin &bgr;-cell lymphoma, thymomas and oral hairy leukoplakia EBV infections have also been found in association with a variety of epithelial-cell-derived tumours of the upper and lower respiratory tracts including the lung.
HHV-6 has been shown to be a causative agent of infantum subitum in children and of kidney rejection and interstitial pneumonia in kidney and bone marrow transplant patients, respectively, and may be associated with other diseases such as multiple sclerosis. There is also evidence of repression of stem cell counts in bone marrow transplant patients. HHV-7 is of undetermined disease aetiology.
Hepatitis B virus (HBV) is a viral pathogen of world-wide major importance. The virus is aetiologically associated with primary hepatocellular carcinoma and is thought to cause 80% of the world's liver cancer. Clinical effects of infection with HBV range from headache, fever, malaise, nausea, vomiting, anorexia and abdominal pains. Replication of the virus is usually controlled by the immune response, with a course of recovery lasting weeks or months in humans, but infection may be more severe leading to persistent chronic liver disease outlined above.
PCT Patent Specification Nos. WO 92/07867 and WO 94/08456 describe certain antiviral polysubstituted benzimidazole nucleoside analogues including &bgr;-D-ribofuranosyl riboside analogues. PCT Patent Specification No. WO 93/18009 describes certain antiviral benzmidazole analogues in which the sugar residue is replaced by a carbocyclic group.
It has now been discovered that certain L-sugar substituted benzimidazole compounds as referred to below, are useful for the treatment or prophylaxis of certain viral infections. According to a first aspect of the present invention, novel compounds of the formula (I) are provided:
wherein R represents hydrogen, a halo atom, —NR
1
R
2
where R
1
and R
2
, which may be the same or different, are each independently selected from hydrogen, C
1-6
alkyl, cyanoC
1-6
alkyl, hydroxyC
1-6
alkyl, haloC
1-6
alkyl, C
3-7
cycloalkyl, C
1-6
alkylC
3-7
cycloalkyl, C
2-6
alkenyl, C
3-7
cycloalkylC
1-6
alkyl, C
2-6
alkynyl, aryl, arylC
1-6
alkyl, heterocyclicC
1-6
alkyl, —COC
1-6
alkyl or R
1
R
2
together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring and pharmaceutically acceptable derivatives thereof.
A further suitable group of compounds of formula (I) is that of formula (Ia)
wherein R represents hydrogen or —NR
1
R
2
, which may be the same or different, are each independently selected from hydrogen, C
1-6
alkyl, cyanoC
1-6
alkyl, hydroxyC
1-6
alkyl, haloC
1-6
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, aryl, arylC
1-6
alkyl, heterocyclicC
1-6
alkyl, —COC
1-6
alkyl (provided that R
1
R
2
are not both hydrogen) or R
1
R
2
together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring and pharmaceutically acceptable derivatives thereof.
Examples of compounds of formula (I) include the following &bgr; anomers of formula (Ib)
wherein R represents a halo atom or —NR
1
R
2
wherein R
1
represents hydrogen and R
2
is selected from C
1-6
alkyl, hydroxyC
1-6
alkyl, C
3-7
cycloalkyl, C
1-6
alkylC
3-7
cycloalkyl, C
2-6
alkenyl, C
2-6
alkynyl, aryl, arylalkyl, or R
1
and R
2
, which may be the same or different, are both C
1-6
alkyl, or R
1
R
2
together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring and pharmaceutically acceptable derivatives thereof.
In the alternative, compounds of formula (Ib) are compounds wherein R represents a halo atom or a monoC
1-6
alkylamino, mono(C
1-6
hydroxyalkyl)amino, di-C
1-6
alkylamino, C
3-7
cycloalkylamino, C
1-6
alkyl-C
3-7
cycloalkylamino, C
2-6
alkenylamino, C
2-6
alkynylamino, arylamino, arylalkylamino, or a group of formula —N(CH
2
)
n
, wherein n is 2, 3, 4 or 5 and pharmaceutically acceptable derivatives thereof.
Further examples of compounds of formula (I) above include Examples 1 to 38 as described hereinafter.
As used herein the term alkyl as a group or part of a group means a straight or branched chain alkyl group. Such alkyl groups preferably have 1-6 carbon atoms, most preferably 1 to 4 and in particular include methyl, ethyl, i-propyl, t-butyl. References to alkenyl groups include groups which may be in the E- or Z-form or a mixture thereof and which when they contain at least three carbon atoms, may be branched. The term halo includes chloro, bromo, fluoro and iodo. The term haloC
1-6
alkyl means an alkyl group in which one or more hydrogens is replaced by halo and preferably containing one, two or three halo
Chamberlain Stanley Dawes
Tidwell Jeffrey H.
Crane E
Geist Gary
Glaxo Wellcome Inc.
Morgan Lorie Ann
LandOfFree
Benzimidazole and its ribonucleoside does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Benzimidazole and its ribonucleoside, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzimidazole and its ribonucleoside will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2599091