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United States Patent (19) 11 Patent Number: 6,077,832 Chamberlain Et Al

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United States Patent (19) 11 Patent Number: 6,077,832 Chamberlain Et Al USOO6077832A United States Patent (19) 11 Patent Number: 6,077,832 Chamberlain et al. (45) Date of Patent: *Jun. 20, 2000 54). ANTIVIRAL BENZIMIDAZOLE OTHER PUBLICATIONS NUCLEOSIDE ANALOGUES AND A METHOD FOR THEIR PREPARATION Methods of Nucleoside Synthesis. Vorbrueggen, Helmut. Res. Lab., Schering A-G., Berlin, D-1000/65, Fed. Rep. 75 Inventors: Stanley Dawes Chamberlain; Susan Ger. NATO Adv. Study Inst. Ser, Ser. A (1979), Mary Daluge; George Walter A26(Nucleoside Analogues: Chem., Biol., Med. Appl.), Koszalka, all of Chapel Hill, N.C. 35-69. Vorbriggen et al., “Nucleoside Synthesis with Trimethylsi 73 Assignee: GlaxoWellcome Inc., Five Moore lyl Triflate and Perchlorate as Catalysts,” Chem. Ber. 114, Drive, N.C. pp. 1234–1255 (1981). Vorbriggen et al., “New Catalysts for the Synthesis of * Notice: This patent issued on a continued pros Nucleosides,” Angew. Chem. Internat. Edit. 14(6), pp. ecution application filed under 37 CFR 421–422 (1974). 1.53(d), and is subject to the twenty year Gordon et al., “Kinetics of Decay in the Expression of patent term provisions of 35 U.S.C. Interferon-Dependent mRNAS Responsible for Resistance 154(a)(2). to Virus.” Proc. Nat. Acad. Sci. USA 77(1), 452–456 (Jan. 21 Appl. No.: 08/765,758 1980). Devivar et al., “Benzimidazole Ribonucleosides: Observa 22 PCT Filed: Jul. 6, 1995 tion of An Unexpected Nitration WHen Performing Non Aqueous Diazotizations with t-butyl Nitrite,” Biorganic C& 86 PCT No.: PCT/GB95/01597 Medicinal Chem. Letters, 2(9), 1105–1110 (Sep. 1992). S371 Date: Jan. 6, 1997 Tigges et al., “Human CD8+ Herpes Simplex Virus-Specific Cytotoxic T-Lymphocyte Clones Recognize Diverse Viron S 102(e) Date: Jan. 6, 1997 Protein Antigens,” J. Virology, 66(3), 1622-1634 (Mar. 87 PCT Pub. No.: WO96/01833 1992). Devivar et al., “Benzimidazole Ribonucleosides: Design, PCT Pub. Date:Jan. 25, 1996 Synthesis, and Antiviral Activity of Certain 2-(Alkylthio 30 Foreign Application Priority Data )–and 2-(benzylthio)-5, 6-dichloro-1-(B-D-ribofuranosyl)benzimidazoles,” J. Jul. 7, 1994 GB United Kingdom ................... 9413724 Medicinal Chem., 37(18), 2942–2949 (Sep. 2, 1994). Townsend et al.(VII), “Design Synthesis, and Antiviral Activity of Certain 2.5, 51) Int. Cl." ......................... A61K31/70; CO7H 19/052 6-Trihalo-1-(B-D-ribofuranosyl)benzimidazoles,” J. Medicinal Chem., 38(20), 4098-4105 (Sep. 25, 1995). 52 U.S. Cl. .............................................. 514/43; 536/28.9 Yankulov et al., “The Transcriptional Elongation Inhibitor 5-6-Dichloro-1-?3-D-ribofuransylbenzimidazole Inhibits Translation Factor IIH-ASSociated Protein Kinase,” J. Biol 58 Field of Search ............................... 536/28.9; 514/43 Chem., 270(41), 23922–23925 (Oct. 13, 1995). 56) References Cited Nassiri et al., “Comparison of Benzimidazole Nucleosides and Ganciclovir on the In Vitro Prol;iferation and Colony U.S. PATENT DOCUMENTS Formation of Human Bone Marrow Progenitor Cells,” Brit 3,399,987 9/1968 Woods et al. ... 548/310.4 ish J. Haematology, 93(2), 273–279 (May 1996). 3,555,040 1/1971 Fricket al. ... ... 548/310.4 Gudmundsson et al., “Synthesis and Antiviral Activity of 3,655,901 4/1972 Jensen et al. 548/310.4 Certain 5'-Modified Analogs of 2.5, 4,002,623 1/1977 Kadin ................... ... 544/132 6–Trichloro-1-(B-D-ribofuranosyl)benzimidazole,” J. 5,248,672 9/1993 Townsend et al. ....................... 514/43 Medicinal Chem., 40(5), 785–793 (Feb. 28, 1997). 5,360,795 11/1994 Townsend et al. ....................... 514/43 Zou et al., “Design, Synthesis, and Antiviral Evaluation of 5,399,580 3/1995 Daluge ............. ... 514/394 2-Chloro-5, 5,473,063 12/1995 Classon et al. ...... ... 536/122 5,534,535 7/1996 Townsend et al. ...... ... 514/394 (List continued on next page.) 5,574,058 11/1996 Townsend et al. ...... ... 514/394 5,646,125 7/1997 Townsend et al. ...... ... 514/43 Primary Examiner Douglas W. Robinson 5,654,283 8/1997 Townsend et al. ....................... 514/43 ASSistant Examiner L. Eric Crane 5,665,709 9/1997 Townsend et al. ....................... 514/43 Attorney, Agent, or Firm-Lorie Ann Morgan FOREIGN PATENT DOCUMENTS 57 ABSTRACT 0 136938 4/1985 European Pat. Off.. 304624 3/1989 European Pat. Off.. The present invention relates to benzimidazole derivatives O 350 467 1/1990 European Pat. Off.. and their use in medical therapy particularly for the treat O 515 156 11/1992 European Pat. Off.. ment or prophylaxis of Virus infections Such as those caused 2130 030 12/1972 Germany. by herpes viruses. The invention also relates to the prepa 9207867 5/1992 WIPO. 92/18517 10/1992 WIPO. ration of the benzimidazole derivatives and pharmaceutical 93/18009 9/1993 WIPO. formulations containing them. 9408456 4/1994 WIPO. 96O1833 1/1996 WIPO. 30 Claims, No Drawings 6,077,832 Page 2 OTHER PUBLICATIONS Revankar, G.R. et al., The Synthesis of 6-dihalo-1-(B-D-ribofuranosyl)benzimidazoles as Poten 2-Chloro-1-3-D-ribofuranosyl-5,6-dimethylbenzimida tial Agents for Human Cytomegalovirus Infections,” J. zole and Certain Related Derivatives (1), J. Heterocycles, Medicinal Chem., 40(5), 811–818 (Feb. 28, 1997). vol. 5, No. 4, pp. 615–620, 1968. (Oct.) Physician's Desk Reference, 52nd Ed., Arky and Sifton (eds.), Medical Economics Co., Montvale, NJ, 1998. only European Patent Office Search Report (Apr. 26, 1996; ref. pp. 2452-2454 supplied (see “Cytovene'). Month of publi no. 1263W 94). cation date is unavailable. The Merck Index, 11th Ed., Budavariet al. (eds.), Merck & European Patent Office Communication (Aug. 6, 1997; ref. Co., Rahway, NJ, 1989, only p. 682 supplied. Month of no. PB1548/EPw). publication date is unavailable. Revankar, G.R. et al., The Synthesis of Gosselin et al., “Synthesis and biological evaluation of new 2-Chloro-1-(B-D-ribofuranosyl)benzimidazole and Cer 5,6-dichlorobenzimidazole nucleoside derivatives', Antivi tain Related Derivatives (1), J. Heterocycles, vol. 5, pp. ral Chem. Chemotherapy, vol. 5, pp. 243-256, (1994) (Issue 477-483, 1968 (Aug.). No. 4). 6,077,832 1 2 ANTIVIRAL BENZMIDAZOLE lymphoproliferative disease which occurs namely in young NUCLEOSIDE ANALOGUES AND A boys, EBV-associated B-cell tumours, Hodgkin’s disease, METHOD FOR THEIR PREPARATION nasopharyngeal carcinoma, Burkitt lymphoma, non Hodgkin B-cell lymphoma, thymomas and oral hairy leuko This application is filed pursuant to 35 U.S.C. S. 371 as a United States National Phase Application of International plakia. EBV infections have also been found in association Application No. PCT/GB95/01597 filed Jul. 6, 1995 which with a variety of epithelial-cell-derived tumours of the upper claims priority from GB 9413724.7 filed Jul. 7, 1994. and lower respiratory tracts including the lung. The present invention relates to benzimidazole deriva HHV-6 has been shown to be a causative agent of tives and their use in medical therapy particularly for the infantum Subitum in children and of kidney rejection and treatment or prophylaxis of virus infections Such as those interstitial pneumonia in kidney and bone marrow transplant caused by herpes viruses. The invention also relates to the patients, respectively, and may be associated with other preparation of the benzimidazole derivatives and pharma diseases Such as multiple Sclerosis. There is also evidence of ceutical formulations containing them. repression of Stem cell counts in bone marrow transplant Of the DNA viruses, those of the herpes group are the 15 patients. HHV-7 is of undetermined disease aetiology. Sources of the most common Viral illnesses in man. The group includes herpes simplex virus types 1 and 2 (HSV), Hepatitis B virus (HBV) is a viral pathogen of world varicella Zoster virus (VZV), cytomegalovirus (CMV), wide major importance. The virus is aetiologically associ Epstein-Barr virus (EBV), human herpesvirus type 6 (HHV ated with primary hepatocellular carcinoma and is thought to 6) and human herpes virus type 7 (HHV-7). HSV-1 and cause 80% of the world’s liver cancer. Clinical effects of HSV-2 are some of the most common infectious agents of infection with HBV range from headache, fever, malaise, man. Most of these viruses are able to persist in the host's nausea, vomiting, anorexia and abdominal pains. Replica neural cells, once infected, individuals are at risk of recur tion of the virus is usually controlled by the immune rent clinical manifestations of infection which can be both response, with a course of recovery lasting weeks or months physically and psychologically distressing. 25 in humans, but infection may be more Severe leading to HSV infection is often characterised by extensive and persistent chronic liver disease outlined above. debilitating lesions of the skin, mouth and/or genitals. Pri mary infections may be Subclinical although tend to be more PCT Patent Specification Nos. WO 92/07867 and WO Severe than infections in individuals previously exposed to 94/08456 describe certain antiviral polysubstituted benzimi the virus. Ocular infection by HSV can lead to keratitis or dazole nucleoside analogues including B-D-ribofuranosyl cataracts thereby endangering the host's Sight. Infection in riboside analogues. PCT Patent Specification No. WO the new-born, in immnunocompromised patients or penetra 93/18009 describes certain antiviral benzimidazole ana tion of the infection into the central nervous System can logues in which the Sugar residue is replaced by a carbocy prove fatal. clic group. VZV is a herpes virus which causes chickenpox and 35 It has now been discovered that certain L-Sugar Substi shingles. Chickenpox is the primary disease produced in a tuted benzimidazole compounds as referred to below, are host without immunity, and in young children is usually a useful for the treatment or prophylaxis of certain viral mild illness characterised by a vesicular rash and fever. infections. According to a first aspect of the present Shingles or Zoster is the recurrent form of the disease which invention, novel compounds of the formula (I) are provided: occurs in adults who were previously infected with VZV.
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