Benzimidazole derivatives

Details Benzimidazole derivatives Benzimidazole derivatives

2000-03-17

2002-09-24

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S042000, C514S045000, C514S046000, C514S248000, C514S249000, C514S252010, C514S254080, C536S004100, C536S017200, C536S017300, C548S469000

Reexamination Certificate

active

06455507

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to certain 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.
BACKGROUND OF THE INVENTION
Of the DNA viruses, those of the herpes group are the source 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) and type 8 (HHV-8). 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 characterized 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 characterized 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 characterized 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 HCMV disease is characterized by jaundice, hepatosplenomegaly, petechial rash and multiple organ dysfunction and is associated with long-term sequelae such as hearing loss and mental deficiency. Infection can result in retinitis leading to blindness or, in less severe forms, failure to thrive, and susceptibility to chest and ear infections. CMV infection in patients whose immune systems are immature or 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, colitis, esophagistis, hepatitis, meningoencephalitis, pneumonitis, gastrointestinal disorders and neurological diseases. In addition, these CMV disease syndromes can affect patients who are not immunocompromised.
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 tumors, Hodgkin's disease, nasopharyngeal carcinoma, Burkitt lymphoma, non-Hodgkin B-cell lymphoma, thymomas and oral hairy leukoplakia. EBV infections have also been found in association with a variety of epithelial-cell-derived tumors 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 etiology. HHV-8 has been implicated in cancer.
Hepatitis B virus (HBV) is a viral pathogen of world-wide major importance. The virus is etiologically 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.
GB 682,960, GB 690,119 and GB 696,952 disclose benzimidazole glycosides useful as intermediates in the preparation of therapeutic substances. Mochalin et. al. (SU 443035; Zh. Org. Khim. 12(1), 58-63 (1976)) describe the synthesis of certain unsubstituted benzimidazote pyranosides. Gosselin et. al. (
Antiviral Chem. Chemother.
5(4), 243-56, 1994) disclose certain 5,6,-dichlorobenzimidazole arabinopyranosyl compounds with antiviral activity. Townsend et. al. (
Chemical Reviews,
vol. 70 no. 3, 1970) discloses certain 1-glycosylbenzimidazoles. U.S. Pat. No. 5,585,394 discloses 1-benzenesulfonyl-1,3-dihyro-2H-benzimidazol-2-one derivatives which have affinity for the vasopressin and oxytocin receptors. EP 0 521 463 A2 describes certain cyclohexanol analogues for antiviral and anti-parasitic use.
DETAILED DESCRIPTION OF THE INVENTION
It has now been discovered that certain 6-membered ring-containing benzimidazole derivatives are useful for the treatment or prophylaxis of viral infections. According to a first aspect of the present invention, there is provided compounds of formula (I)
wherein:
R
1
is halogen, hydroxy, azido, C
1-8
alkyl, C
1-8
alkoxy, C
2-6
alkenyl, C
2-6
alkynyl, C
6-14
arylC
2-6
alkenyl, C
6-14
arylC
2-6
alkynyl, or —NR
19
R
20
(where R
19
and R
20
may be the same or different and are hydrogen, C
1-8
alkyl, cyanoC
1-8
alkyl, hydroxyC
1-8
alkyl, haloC
1-8
alkyl, C
3-7
cycloalkyl, C
1-8
alkylC
3-7
cycloalkyl, C
2-6
alkenyl, C
3-7
cycloalkylC
1-8
alkyl, C
2-6
alkynyl, C
6-14
aryl, C
6-14
arylC
1-6
alkyl, heterocycleC
1-8
alkyl, C
1-8
alkylcarbonyl, C
6-14
arylsulfonyl, or R
19
R
20
together with the N atom to which they are attached form a 3, 4, 5 or 6 membered heterocyclic ring), OR
21
(where R
21
is hydrogen, C
1-8
alkyl, C
3-7
cycloalkyl, or C
6-14
aryl), or SR
22
(where R
22
is hydrogen, C
1-8
alkyl, hydroxyC
1-8
alkyl, C
3-7
cycloalkyl, or C
6-14
aryl);
R
2
is hydrogen or halogen;
R
3
and R
4
may be the same or different and are hydrogen, halogen, C
1-8
alkyl, C
6-14
aryl, heterocycleC
6-14
aryl, C
1-8
alkoxy, haloC
1-8
alkyl or —SR
24
(where R
24
is hydrogen, C
1-8
alkyl, C
6-14
aryl, or C
6-14
arylC
1-8
alkyl);
Z is a substituent of formula (Ia), (Ib), or (Ic)
wherein:
R
5
is hydrogen, C
1-8
alkyl, haloC
1-8
alkyl or C
1-8
alkoxy;
R
6
is hydrogen, hydroxy, halogen, C
1-8
alkyl, hydroxyC
1-8
alkyl, haloC
1-8
alkyl or C
1-8
alkoxy;
R
7
is hydrogen, hydroxy, halogen, C
1-8
alkyl, hydroxyC
1-8
alkyl, haloC
1-8
alkyl, C
1-8
alkoxy, or R
6
and R
7
together form a ketone or alkene;
R
8
-R
11
may be the same or different and are hydrogen, hydroxy, halogen, C
2-8
alkyl, hydroxyC
1-8
alkyl, haloC
1-8
alkyl, C
1-8
alkoxy, or any of R
8
and R
9
or R
10
and R
11
together form a ketone or alkene;
R
12
-R
18
may be the same or different and are hydrogen, hydroxy, C
1-8
alkyl or hydroxyC
1-8
alkyl;
or a pharmaceutically acceptable derivative thereof,
provided that a compound of formula (I) cannot be 2,5-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-xylopyranosyl)-1H-benzimidazole or 5,6-dimethyl-1-(2,3,4-tri-O-acetyl-beta-D-arabinopyranosyl)-benzimidazole-2-thione;
further provided that when Z is a substituent of formula (

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