L-benzimidazole nucleosides

Details L-benzimidazole nucleosides L-benzimidazole nucleosides

1998-07-13

2001-03-20

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S028900, C514S394000

Reexamination Certificate

active

06204249

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-linked lymphoproliferative disease which occurs namely in young boys, EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngeal carcinoma, Burkitt lymphoma, non-Hodgkin 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 -D-ribofuranosyl riboside analogues. PCT Patent Specification No. WO 93/18009 describes certain antiviral benzimidazole 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
1
represents hydrogen, a halo atom or azido;
—NR
8
R
9
where R
8
and R
9
, which may be the same or different, are each independently selected from hydrogen, hydroxyl, C
1-12
alkyl, for example C
1-6
alkyl (where the alkyl moiety may be optionally substituted by one or more substituents selected from halo, amino, azido, hydroxy, cyano, NO
2
, NHR
10
, SO
2
R
10
, SR
10
, OR
10
, COR
10
and haloC
1-6
alkyl where R
10
is C
1-6
alkyl, C
3-6
alkenyl, C
2-6
alkynyl, or aryl), C
2-8
alkenyl, C
1-6
alkoxy, C
3-7
cycloalkyl, C
2-8
alkynyl, C
3-7
cycloalkenyl, C
3-7
cycloalkylC
1-6
alkyl, aryl, arylC
1-6
alkyl, heteroaryl, heteroarylC
1-6
alkyl, heterocyclyl and heterocyclylC
1-6
alkyl, or R
8
R
9
together with the N atom to which they are attached form a 3,4,5 or 6 membered heterocyclic ring;
—NHNR
11
R
12
where R
11
and R
12
, which may be the same or different, each represent hydrogen or C
1-6
alkyl;
—N═NC
1-6
alkyl or —NHOC
1-6
alkyl;
R
2
represents hydrogen, halo atom, C
1-6
alkyl or C
2-6
alkenyl;
R
3
and R
4
, which may be the same of different, each represent hydrogen, halogen or NO
2
;
R
5
and R
6
, which may be the same or different, each represent hydrogen or hydroxy;
R
7
represents hydrogen, CH
3
or CH
2
R
13
where R
13
may be selected from hydroxy, a halo atom and OR
14
(where R
14
is hydrogen, C
1-8
alkyl, aryl or arylC
1-6
alkyl);
with the proviso that when R
2
represents hydrogen, R
3
and R
4
each represent chloro, R
5
and R
6
represent an erythro hydroxy group and R
7
is —CH
2
OH then R
1
represents azido, —NR
8
R
9
where R
8
and R
9
, which may be the same or different, are each independently selected from hydroxyl, C
1-6
alkyl (where the alkyl moiety is substituted by one or more substituents selected from amino, azido, NO
2
, NHR
10
, SO
2
R
10
, SR
10
, OR
10
, haloC
1-6
alkyl where R
10
is as hereinbefore defined), C
7-12
alkyl (where the alkyl moiety is optionally substituted by one or more substituents selected from halo, amino, azido, hydroxy, cyano, NO
2
, NHR
10
, SO
2
R
10
SR
10
, OR
10
, COR
10
and haloC
1-6
alkyl where R
10
is as hereinbefore defined), C
1-6
alkoxy, C
3-7
cycloalkenyl, heteroaryl, heteroaryl C
1-6
alkyl and heterocyclyl; —NHNR
11
R
12
where R
11
and R
12
are as hereinbefore defined; —N═NC
1-6
alkyl or —NHOC1-6 alkyl;
or a pharmaceutically acceptable derivative thereof.
The present invention further provides compounds of formula (I) wherein the sugar moiety is selected from the following:
Further examples of compounds of formula (I) above include Examples 1 to 65 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. Reference

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