Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1997-01-06
2000-06-20
Robinson, Douglas W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 289, A61K 3170, C07H 19052
Patent
active
060778326
DESCRIPTION:
BRIEF SUMMARY
This application is filed pursuant to 35 U.S.C. .sctn. 371 as a United States National Phase Application of International Application No. PCT/GB95/01597 filed Jul. 6, 1995 which claims priority from GB 9413724.7 filed Jul. 7, 1994.
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 immnunocompromised 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 .beta.-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
REFERENCES:
patent: 3399987 (1968-09-01), Woods et al.
patent: 3555040 (1971-01-01), Frick et al.
patent: 3655901 (1972-04-01), Jensen et al.
patent: 4002623 (1977-01-01), Kadin
patent: 5248672 (1993-09-01), Townsend et al.
patent: 5360795 (1994-11-01), Townsend et al.
patent: 5399580 (1995-03-01), Daluge
patent: 5473063 (1995-12-01), Classon et al.
patent: 5534535 (1996-07-01), Townsend et al.
patent: 5574058 (1996-11-01), Townsend et al.
patent: 5646125 (1997-07-01), Townsend et al.
patent: 5654283 (1997-08-01), Townsend et al.
patent: 5665709 (1997-09-01), Townsend et al.
Methods of Nucleoside Synthesis. Vorbrueggen, Helmut. Res. Lab., Schering A.-G., Berlin, D-1000/65, Fed. Rep. Ger. NATO Adv. Study Inst. Ser., Ser. A (1979), A26(Nucleoside Analogues: Chem., Biol., Med. Appl.), 35-69.
Vorbruggen et al., "Nucleoside Synthesis with Trimethylsilyl Triflate and Perchlorate as Catalysts," Chem. Ber. 114, pp. 1234-1255 (1981).
Vorbruggen et al., "New Catalysts for the Synthesis of Nucleosides," Angew. Chem. Internat. Edit. 14(6), pp. 421-422 (1974).
Gordon et al., "Kinetics of Decay in the Expression of Interferon-Dependent mRNAs Responsible for Resistance to Virus," Proc. Nat. Acad. Sci. USA 77(1), 452-456 (Jan. 1980).
Devivar et al., "Benzimidazole Ribonucleosides: Observation of An Unexpected Nitration WHen Performing Non-Aqueous Diazotizations with t-butyl Nitrite," Biorganic & Medicinal Chem. Letters, 2(9), 1105-1110 (Sep. 1992).
Tigges et al., "Human CD8+ Herpes Simplex Virus-Specific Cytotoxic T-Lymphocyte Clones Recognize Diverse Viron Protein Antigens," J. Virology, 66(3), 1622-1634 (Mar. 1992).
Devivar et al., "Benzimidazole Ribonucleosides: Design, Synthesis, and Antiviral Activity of Certain 2-(Alkylthio)-and 2-(benzylthio)-5,6-dichloro-1-(.beta.-D-ribofuranosyl)benzimidazoles," J. Medicinal Chem., 37(18), 2942-2949 (Sep. 2, 1994).
Townsend et al.(VII), "Design Synthesis, and Antiviral Activity of Certain 2,5,6-Trihalo-1-(.beta.-D-ribofuranosyl)benzimidazoles," J. Medicinal Chem., 38(20), 4098-4105 (Sep. 25, 1995).
Yankulov et al., "The Transcriptional Elongation Inhibitor 5-6-Dichloro-1-.beta.-D-ribofuransylbenzimidazole Inhibits Translation Factor IIH-Associated Protein Kinase," J. Biol Chem., 270(41), 23922-23925 (Oct. 13, 1995).
Nassiri et al., "Comparison of Benzimidazole Nucleosides and Ganciclovir on the In Vitro Prol;iferation and Colony Formation of Human Bone Marrow Progenitor Cells," British J. Haematology, 93(2), 273-279 (May 1996).
Gudmundsson et al., "Synthesis and Antiviral Activity of Certain 5'-Modified Analogs of 2,5,6-Trichloro-1-(.beta.-D-ribofuranosyl)benzimidazole," J. Medicinal Chem., 40(5), 785-793 (Feb. 28, 1997).
Zou et al., "Design, Synthesis, and Antiviral Evaluation of 2-Chloro-5,6-dihalo-1-(.beta.-D-ribofuranosyl)benzimidazoles as Potential Agents for Human Cytomegalovirus Infections," J. Medicinal Chem., 40(5), 811-818 (Feb. 28, 1997).
Physician's Desk Reference, 52nd Ed., Arky and Sifton (eds.), Medical Economics Co., Montvale, NJ, 1998. only pp. 2452-2454 supplied (see "Cytovene"). Month of publication date is unavailable.
The Merck Index, 11th Ed., Budavari et al. (eds.), Merck & Co., Rahway, NJ, 1989, only p. 682 supplied. Month of publication date is unavailable.
Revankar, G.R. et al., The Synthesis of 2-Chloro-1-(.beta.-D-ribofuranosyl)benzimidazole and Certain Related Derivatives (1), J. Heterocycles, vol. 5, pp. 477-483, 1968 (Aug.).
Revankar, G.R. et al., The Synthesis of 2-Chloro-1-.beta.-D-ribofuranosyl-5,6-dimethylbenzimidazole and Certain Related Derivatives (1), J. Heterocycles, vol. 5, No. 4, pp. 615-620, 1968. (Oct.)
European Patent Office Search Report (Apr. 26, 1996; ref. no. 1263W 94).
European Patent Office Communication (Aug. 6, 1997; ref. no. PB1548/EPw).
Gosselin et al., "Synthesis and biological evaluation of new 5,6-dichlorobenzimidazole nucleoside derivatives", Antiviral Chem. Chemotherapy, vol. 5, pp. 243-256, (1994) (Issue No. 4).
Chamberlain Stanley Dawes
Daluge Susan Mary
Koszalka George Walter
Crane L. Eric
Glaxo Wellcome Inc.
Morgan Lorie Ann
Robinson Douglas W.
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