Substituted aryl thioureas and related compounds; inhibitors of viral replication Number:7,094,807 from the United States Patent and Trademark Office (PTO) owispatent The invention provides compounds and pharmaceutically acceptable salts of Formula I ##STR00001## wherein the variables A.sub.1, A.sub.2, R.sub.1, R.sub.2, V, W, X, Y, and Z are defined herein. Certain compounds of Formula I described herein which possess potent antiviral activity. The invention particularly provides compounds of Formula I that are potent and/or selective inhibitors of Hepatitis C virus replication. The invention also provides pharmaceutical compositions containing one or more compound of Formula I, or a salt, solvate, or acylated prodrug of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents.The invention further comprises methods of treating patients suffering from certain infectious diseases by administering to such patients an amount of a compound of Formula I effective to reduce signs or symptoms of the disease or disorder. These infectious diseases include viral infections, particularly HCV infections. The invention is particularly includes methods of treating human patients suffering from an infectious disease, but also encompasses methods of treating other animals, including livestock and domesticated companion animals, suffering from an infectious disease.Methods of treatment include administering a compound of Formula I as a single active agent or administering a compound of Formula I in combination with on or more other therapeutic agent.<H replication, Substituted, Substituted, ary, 7094807.html, Patent, pto, 7094807

Title: Substituted aryl thioureas and related compounds; inhibitors of viral replication

Abstract: The invention provides compounds and pharmaceutically acceptable salts of Formula I ##STR00001## wherein the variables A.sub.1, A.sub.2, R.sub.1, R.sub.2, V, W, X, Y, and Z are defined herein. Certain compounds of Formula I described herein which possess potent antiviral activity. The invention particularly provides compounds of Formula I that are potent and/or selective inhibitors of Hepatitis C virus replication. The invention also provides pharmaceutical compositions containing one or more compound of Formula I, or a salt, solvate, or acylated prodrug of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents.The invention further comprises methods of treating patients suffering from certain infectious diseases by administering to such patients an amount of a compound of Formula I effective to reduce signs or symptoms of the disease or disorder. These infectious diseases include viral infections, particularly HCV infections. The invention is particularly includes methods of treating human patients suffering from an infectious disease, but also encompasses methods of treating other animals, including livestock and domesticated companion animals, suffering from an infectious disease.Methods of treatment include administering a compound of Formula I as a single active agent or administering a compound of Formula I in combination with on or more other therapeutic agent.

Patent Number: 7,094,807 Issued on 08/22/2006 to Chen, et al.

Inventors: Chen; Dawei (Middletown, CT), Deshpande; Milind (Madison, CT), Thurkauf; Andrew (Ridgefield, CT), Phadke; Avinash (Branford, CT), Wang; Xiangzhu (Branford, CT), Shen; Yiping (Branford, CT), Liu; Cuixian (Branford, CT), Quinn; Jesse (Windsor, CT), Ohkanda; Junko (Gakuennishi-machi, JP), Li; Shouming (Cheshire, CT)
Assignee: Achillion Pharmaceuticals, Inc. (New Haven, CT)

Appl. No.: 10/716,175

Filed: November 18, 2003

Current U.S. Class: 514/584 ; 514/585; 564/23; 564/26; 564/27; 564/28; 564/29

Current International Class: A61K 31/17 (20060101); C07C 335/02 (20060101)

Field of Search: 514/584,585 564/23,26,27,28,29

References Cited [Referenced By]

U.S. Patent Documents


3699110	October 1972	Dixon
3931244	January 1976	Archibald et al.
3966968	June 1976	Andree et al.
4044126	August 1977	Cook et al.
4082765	April 1978	Kirkpatrick
4160037	July 1979	Kaugars
4338257	July 1982	Patel
4350706	September 1982	Brouwer et al.
4364923	December 1982	Cook et al.
4414209	November 1983	Cook et al.
4438126	March 1984	Ueda et al.
4522811	June 1985	Eppstein et al.
4533676	August 1985	Sirrenberg et al.
4602109	July 1986	Chou et al.
4607044	August 1986	Wellinga et al.
4638088	January 1987	Chou et al.
4659736	April 1987	Schluter et al.
4665097	May 1987	Cain
4707478	November 1987	Studt et al.
4774260	September 1988	Sirrenberg et al.
4868215	September 1989	Bisabri-ershadi et al.
4873264	October 1989	Chou et al.
4880838	November 1989	Chou et al.
4920135	April 1990	Wellinga et al.
5001266	March 1991	Rigterink et al.
5114918	May 1992	Ishikawa et al.
5135953	August 1992	Potter et al.
5166180	November 1992	Jenkins
5266707	November 1993	Matsumoto et al.
5268389	December 1993	Harrison et al.
5344842	September 1994	Missbach
5424204	June 1995	Aoyama et al.
5437996	August 1995	Kojiri et al.
5449812	September 1995	Schnabel et al.
5589365	December 1996	Kojiri et al.
5591842	January 1997	Kojiri et al.
5656642	August 1997	Fujioka et al.
5693827	December 1997	Harrison et al.
5723409	March 1998	Schnabel et al.
5728699	March 1998	Toriyabe et al.
5840917	November 1998	Oi et al.
5849666	December 1998	Kehne et al.
5874615	February 1999	Verbrugge et al.
5922740	July 1999	Braunlich et al.
6060484	May 2000	Fritz et al.
6093742	July 2000	Salituro et al.
6133258	October 2000	Shishikura et al.
6138826	October 2000	Fijioka et al.
6143780	November 2000	Brouwer et al.
6169092	January 2001	Braunlich et al.
6174905	January 2001	Suzuki et al.
6177074	January 2001	Glue et al.
6207715	March 2001	Bloom et al.
6255349	July 2001	Bloom et al.
6268387	July 2001	Connor et al.
6316492	November 2001	Young et al.
6335350	January 2002	Bloom et al.
6399657	June 2002	Braunlich et al.
6407246	June 2002	Uckun et al.
6420396	July 2002	Albers et al.
6440985	August 2002	Bailey et al.
6528528	March 2003	Connor et al.
6610715	August 2003	Youn et al.
6677360	January 2004	Albers et al.
6677372	January 2004	Braulich et al.
6713502	March 2004	Dhanak et al.
6727267	April 2004	Jaen et al.
6736336	May 2004	Wong
6770666	August 2004	Hashimoto et al.
6780873	August 2004	Crooks et al.
6864289	March 2005	Tohnishi et al.
2002/0099210	July 2002	Alexander et al.
2003/0109578	June 2003	Braunlich et al.
2003/0125318	July 2003	Alanine et al.
2003/0195231	October 2003	Takemoto et al.
2004/0009982	January 2004	Tohnishi et al.
2004/0147535	January 2004	Crooks et al.
2004/0029877	February 2004	Crooks et al.
2004/0034041	February 2004	Dhanak et al.
2004/0082635	April 2004	Hashimoto et al.
2004/0097438	May 2004	Hashimoto et al.
2004/0132727	July 2004	Sakai et al.
2004/0147569	July 2004	Suzuki et al.
2004/0147741	July 2004	Sundermann et al.
2004/0162287	August 2004	Sundermann et al.
2004/0229872	November 2004	Friderichs et al.
2005/0054654	March 2005	Huth et al.

Foreign Patent Documents


2170222	Aug., 1998	CA
0 518 376	Dec., 1992	EP
1 251 130	Oct., 2002	EP
06-003787	Jan., 1994	JP
06-287171	Oct., 1994	JP
11-335375	Dec., 1999	JP
WO 97/03976	Feb., 1997	WO
WO 97/11050	Mar., 1997	WO
WO 97/30047	Aug., 1997	WO
WO 98/42323	Oct., 1998	WO
WO 99/59586	Nov., 1999	WO
WO 00/35864	Jun., 2000	WO
WO 2003037869	May., 2003	WO
WO 2003097604	Nov., 2003	WO
WO 2003097605	Nov., 2003	WO
WO 2003099812	Dec., 2003	WO
WO 2004020416	Mar., 2004	WO

Other References

Rasmussen, C.R. et al.: Improved procedure for the preparation of cycloalkyl-, arylalkyl-, and arylthioureas. Synthesis, vol. 6, pp. 456-459, 1988. cited by examiner .
International Search Report dated Apr. 5, 2004--International Appl. No. PCT/US03/36809, International Filing Date Nov. 18, 2003. cited by other .
Douglas, Irvin B., et al "Some Derivatives of Benzoyl and Furoyl Isothiocyantes and their Use in Synthesizing Heterocyclic Compounds", Journal of the American Chemical Society, vol. 56, No. 3, Mar. 1934, pp. 719-721, American Chemical Society, Washington, DC. cited by other .
Goerdeler, J., et al. "Das dualistische Verhalten von Carbamoyl-isothiocyanaten, I", Liebigs Annalen Der Chemie, vol. 731, 1970, pp. 120-141, Verlag Chemie Weinheim, DE. cited by other .
Goerdeler, J. et al., "Uber Thioacyl-isocyanate, V. Substitulerte Thizolin-dione-(4.5) und ihre thermische Spaltung in Isocyanate und Senfole" Chemische Berichte, vol. 99, No. 11, Nov. 10, 1966 pp. 3572-3581, Verlag Chemie, Weinheim, DE. cited by other .
Kulka, Marshall, "Base-catalysed ring opening of N-(aminothioxemethyl-5-6-dihydro-2-mehtyl-1, 4-oxathiin-3-carboxamides" Canadian Journal of Chemistry, vol. 58, No. 19, Oct. 1, 1980, pp. 2044-2048, National Research Council, Ottawa, CA. cited by other .
Kutschy, P., et al., "Synthesis of some analogues of indole phytoalexins brassinin and methoxybrassenin B and their positional isomers" Collection of Czechoslovak Chemical Communications, vol. 64, No. 2, Feb. 1999, pp. 348-362. cited by other .
Matosiuk, Dariusz, et al., "Synthesis of new 1-aryl-3-piperdinylcarbonylimidazoldine-2-ones and 2-thiones" Acta Poloniae Pharmaceutica--Drug Reasearch, vol. 53, No. 1, 1996, pp. 75-77, Polish Pharmaceutical Society, Warsaw, PL. cited by other .
Matsuo, Masaaki, et al., "New 2-aryliminoimidazolidines. I. Synthesis and antihypertensive properties of 2-(2-phinoxyphenylimino)imidazolidines and related compounds" Chemical and Pharmaceutical Bulletin, vol. 33, No. 10, Oct. 1985, pp. 4409-4421. cited by other .
Mukmeneva, N.A. et al., "3-Benzoylthiourea derivatives as antioxidants for polymers" Russian Journal of Applied Chemistry vol. 67, No. 4, Apr. 1994, pp. 565-567, Consultants Bureau, New York, NY. cited by other .
Otazo-Sanchez, Elena, et al., "Aroylthioureas: new organic ionophores for heavy-metal ion selective electrodes" Journal of the Chemical Society, Perkin Transactions 2, No. 11, Nov. 2001, pp. 2211-2218, Royal Society of Chemistry, Letchworth, GB. cited by other .
Reynaud, P., et al., "Preparation de quelques p-alcoxy-benzoyl-1 p-alcoxyphenyl-3 thiourees: leur activite <in vitro> et <in vivo> sur la souche H37RV du bacille tuberculeux" Chimica Therapeutica, No. 7, Nov. 1966, pp. 421-424, Societe D'Etudes De Chimie Therapeutique, Paris, FR. cited by other .
Sengupta, Anil K., et al., "Studies on potential pesticides, Part V. Synthesis of some new aryl ureas and thioureas and their insecticidal activity" Journal of the Indian chemical Society, vol. 53, No. 1, Jan. 1976, pp. 203-204, Indian Chemical Society, Calcutta, IN. cited by other .
Seth, Punit P., et al., "Efficient solution phase synthesis of 2-(N-acyl)-aminobenzimidazoles" Tetrahedron Letters, vol. 43, No. 41, Oct. 7, 2002, pp. 7303-7306, Elsevier Science Publishers, Amsterdam, NL. cited by other .
Shearer, Barry G., et al., "Substituted N-phenylisothioureas: potent inhibitors of human nitric oxide synthase with neuronal isoform selectivity" Journal of Medicine Chemistry, vol. 40, No. 12, Jun. 6, 1997, pp. 1901-1905, American Chemical Society, Washington, DC. cited by other .
Taniguchi, Kiyoshi, et al., "New 2-aryliminoimidazolidines. II. Synthesis and antihypertensive activity of 2-(biphenylimino)imidazolidines" Chemical and Pharmaceutical Bulletin, vol. 40, No. 1, Jan. 1992, pp. 240-244, Pharmaceutical Society of Japan, Tokyo, JP. cited by other .
Ludovici, Donald W., et al., "Evolution of Anti-HIV Drug Candidates. Part 1: From Alpha-Anilinophenylacetamide (Alpha-APA) to Imidoyl Thiourca (ITU)", Bioorganic & Medicinal Chemistry Letters (2001), 11(17), 2225-2228. cited by other .
Daugulis, O., et al., "N-(3-Acetyl-2,2-Dimethlcyclobutyl)Acetyl-N'-Alky(ARYL)Thioureas", Latvijas Kimijas Zurnals (1993), (6), 714-19. cited by other .
Schuster, Gottfried, et al., "Structrually Dependent Effects of Substituted Thioureas on the Concentration of Potato Virus X in Nicotiana tabacum L. "Samsun"", Zentralblatt fuer Bakteriologie, Parasitenkunde, Infekionskrankheiten und Hygiene, Abteilung 2, Naturwissenschaftliche: Mikrobilogie der Landwirtschaft, derTechnologie und des Umweltschutzes (1978), 133(7-8), 686-9. cited by other .
Mitin, N. I., et al., "Effect of Adamantine-Containing Compounds On Aujeszky's And Avian Influenza Disease Viruses", Fiziolgicheski Akitivnye Veshchestva (1977), 9, 31-5. cited by other .
Mishra, Vibba, et al., "Synthesis Of Aryl Semicarbazone Of 4-aminoacetophenone And Their Anti-HIV Activity", Pharmaceutical Acta Helvetiae (1998), 73(4), 215-218. cited by other .
Misra, Vinay S., et al., "Potential Antiviral And Antituberculous Compounds, II. N-(2-Dibenzothiophenyl)-N'-alkyl and N'-aryl Thioureas, N-(2-Dibenzothiophenyl) and N-(2-Dibenzothiophenyl-5-dioxide) Amidines", Journal fuer Praktische Chemie (Leipzig) (1967), 36(5-6), 256-9. cited by other .
Praceus, C., et al., "Inhibition Of Vaccinia Virus In Vitro By Substituted Monophenylthioureas", Naturwissenschaften (1964), 51(4), 94-5 (with enlargements). cited by other .
Weinstein, Louis, et al., "Studies On The Antiviral Activity Of Urea Derivatives", Antibiotics and Chemotherapy (1957),7 443-8. cited by other .
Rashan, Luay J., et al., "Synthesis And Biological Evaluation Of N-Salicyloyl-N-Benzyl Thiourea And 2,2-Dimethyl-4-Oxo-6-Methoxy benzo-1,3-Dioxin", Farmaco (1991), 46(5), 677-83. cited by other .
Bloom, Jonathan D., et al., "Thioureas Inhibitors Of Herpes Viruses. Part 1: Bis-(aryl)Thiourea Inhibitors Of CMV", Bloorganic & Medicinal Chemistry Letters 13 (2003) 2929-2932. cited by other .
Rasmussen, C.R. et al., "Improved Procedures For The Preparation Of Cycloalkyl-, Arylalkyl-, and Arylthioures", Department of Chemical Research, Janssen Research Foundation, Jun. 1988, 456-459. cited by other .
JP61106551, Diphenyl Ether Derivative, Its Preparation, Insecticide Containing Same As An Active Ingredient (abstract). cited by other .
JP56025148, N-Benzoyl-N'-Phenoxyphenylurea-Based Compound, Andinsecticide Comprising It (abstract). cited by other .
CN1183409 Insecticidal Acaricidal Pyrazoles Compounds And Preparation Thereof (abstract). cited by other .
Alter, H.J. and Seeff, L.B., "Recovery, Persistance, and Sequelae in Hepatitis C Virus Infection: a Perspective on Long-Term Outcome," Seminars in Liver Disease, (2000) 20(1): 17-35. cited by other .
Baltabaev, U.A. et al., "Synthesis of the Nicotinoylthioureas Compounds," Azerbaidzhanskii Kim. Zhur., (2000) 4: 97-99. cited by other .
Baltabaev, U.A. et al., "Antiinflammatory Activity Of New Aryl-and Aroylthioureas," Pharmaceutical Chemistry Journal (2002) 36(2): 24-26. cited by other .
Bartenschlager, R. "The NS3/4A Proteinase of the Hepatitis C Virus: Unraveling Structure and Function of an Unusual Enzyme and a Prime Target for Antiviral Therapy," Journal of Viral Hepatitis, (1999) 6:165-181. cit- ed by other .
Bressanelli, S. et al., "Crystal structure of the RNA-Dependent RNA Polymerase of Hepatitis C Virus," Proceedings of the National Academy of Sciences, USA, (1999) 96:13034-10309. cited by other .
De Francesco, R. et al., "The Hepatitis C Virus NS3 Proteinase: Structure and Function of a Zinc-Containing Serine Proteinase," Therapies for Viral Hepatitis, (1998), pp. 235-245. Edited by R. F. Schinazi, J. -P. Sommadossi & H. C. Thomas. London: International Medical Press. cited by other .
Douglass, I.B. and Forman, L. E. "Nicontinyl Isothiocyanate And Some Of Its Derivatives," Journal of the American Chemical Society (1934) 56(7): 1609. cited by other .
Du, X. et al., "Aryl Ureas Represent a New Class of Anti-Trypanosomal Agents," Chemistry & Biology (2000) 7(9): 733-742. cited by other .
Esteban, J.I. et al., "The Clinical Picture of Acute and Chronic Hepatitis C," Curr. Stud. Hematol. Blood Transf., Hepatitis C Virus, (1998) 62: 102-118. Edited by W. Reesink. Basel, Switzerland: Karger. cited by other .
Fukushi, S. et al., "Complete 5'Noncoding Region is Necessary for the Efficient Internal Initiation of Hepatitis C Virus RNA," Biochemical and Biophysical Research Communications, (1994) 199: 425-432. cited by other .
Fukushi, S. et al., "The Sequence Element of the Internal Ribosome Entry Site and a 25-Kilodalton Cellular Protein Contribute to Efficient Internal Initation of Translation of Hepatitis C Virus RNA," Journal of Virology, (1997) 71:1662-1666. cited by other .
Goerder, J. and Jonas, K. "Uber Thioacyl-isocyanate, V. Substituierte Thiazolin-dione-(4.5) und ihre Thermische Spaltung in Isocyanate und Senfole," Chemische Berichte (1966) 99(11): 3572-3581. cited by other .
Goerdeler, J. and Wobig, D. "Das dualistische Verhalten von Carbomoyl-isothiocyanaten, I," Liebigs Annalen Der Chem (1970) 731: 120-141. cited by other .
Gwack, Y. et al., "Characterization of RNA Binding Activity and RNA Helicase Activtiy of the Hepatitis C Virus NS3 Protein." Biochemical and Biophysical Research Communications (1996) 225: 654-359. cited by other .
Honda, M. et al., "Structural Requirements for Initiation of Translation by Internal Ribosome Entry within Genome-length Hepatitis C Virus RNA," Virology, (1996) 222: 31-42. cited by other .
lacovacci, S. et al., "Replication and mMltiplication of Hepatitis C Virus Genome in Human Foetal Liver Cells," Research in Virology, (1993) 144: 275-279. cited by other .
Khomykh, A.A. and Westaway, E.G., "Subgenomic Replicons of the Flavivrus Kunjin: Construction and Applications," Journal of Virology, (1997) 71: 1497-1505. cited by other .
Kim, J.L. et al., "Crystal Structure of the Hepatitis C Virus NS3 Protease Domain Complexed with a Synthetic NS4A Cofactor Peptide," Cell, (1996) 87: 343-355. cited by other .
Kim, J.L. et al., "Hepatitis C Virus NS3 RNA Helicase Domain with a Bound Oligonucleotide: the Crystal Structure Orovides Insights into the Mode of Unwinding," Structure (1998) 6(1): 89-100. cited by other .
Koscik, D. et al., "New Synthesis of 2-Amino-4-oxopyrido[3,2-e]-1, 3-thiazines and 1-Alkyt(aryl)pryrido[3,2-e]-2-thiouracils," Collection Czechoslovak Chem. Comm. (1983) 48: 3315-3328. cited by other .
Lavanchy, D. et al., "Global Surveillance and Control of Hepatitis C," Journal of Viral Hepatitis (1999) 6: 35-47. cited by other .
Lesburg, C. A. et al., "Crystal Structure of the RNA-Dependent RNA Polymerase from Hepatitis C Virus Reveals a Fully Encircled Active Site," Nature Structural Biology, (1999) 6: 937-943. cited by other .
Liang, T.J. et al., "Pathogenesis, Natural History, Treatment, and Prevention of Hepatitis C," Annals of Internal Medicine (2000) 132: 296-305. cited by other .
Lohmann, V. et al., "Replication of Subgenomic Hepatitis C Virus RNAs in a Hepatoma Cell Line," Science (1999) 285: 110-113. cited by other .
Love, R.A. et al., "The Crystal Structure of Hepatitis C Virus NS3 proteinase reveals a trypsin-like fold and a Structural zinc binding site," Cell (1996) 87:331-342. cited by other .
Manns, M.P. et al., "Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic Hepatitis C: a randomised trial," Lancet (2001):358:958-965. cited by oth- er .
McHutchison, J.G. et al., "Interfon Alfa-2b Alone or in Combination with fRibavirin as Intial Treatment for Chronic Hepatitis C," New England Journal of Medicine (1998) 339(21):1485-1492. cited by other .
Mitin, N.I. et al., "Effect of Adamantyl-Containing Compounds on the viruses of False Rabies and Bird Flu", Fiziologicheski Aktivnye Veshchnya (1977) 9: 31-35. cited by other .
Moriya, K. et al., "The Core Protein of Hepatitis C Virus Induces Hepatocellular Carcinoma in Transgenic Mice," Nature Medicine (1998) 4:1065-1067. cited by other .
Neumann, A. U. et al., "Hepatitis C Viral Dynamics In Vivo and the Antiviral Efficacy of Interferon-Alpha Therapy," Science, (1998) 282: 103-107. cited by other .
Nogrady, T. Medicinal Chemistry A Biochemical Approach, (1985) Oxford University Press, New York, pp. 388-392. cited by other .
Patel, N.B. and Bhaget, P.R. "2-[4"-(p-Acetamidophenylcarbonyl) Piperazin-1"-yl]-3-(N-Aryl-Thioureidocarbonyl) Pryridines As Antibacterial Agents," Indian Journal of Heterocyclic Chemistry (2002) 12: 83-84. cited by other .
Patel, N.B. and Bhaget, P.R. "Antibacterial Study of 2-(p-Tolyl Sulfonamido)-3-(N-Arylthioureido Carbonyl) Pyridine Derivatives" Oriental Journal of Chemistry (2002) 18(3): 551-554. cited by other .
Praceus, Chr. et al., "Inhibition of Vaccinia Virus In Vitro By Substituted Monophenylthioureas," Natrumissenschaften (1964) 51(4): 94-95. cited by other .
Reynaud, P. et al., "P-alcoxy Benzoyl-1 p-Alcoxyphenyl-3 thioureas: Their Activity "In Vitro" and "In Vivo" on the H.sup.37RV of the Tubercular Bacillus," Chimie Therapeutique (1966) 7: 421-424. (machine translation). cited by other .
Santolini, E. et al., "Biosynthesis and Biochemical Properties of the Hepatitis C Virus Core Protein," Journal of Virology (1994) 68: 3631-3641. cited by other .
Schuster, G. "Structurally Dependent Effects of Substituted Thioureas on the Concentration of Potato Virus X in Nictiana tabacum L," Zbl. Bakt. II, Dep. (1978) 133(7-8): 686-689. cited by other .
Simmonds, P. et al., "Classification of hepatitis C Virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region," Journal of General Virology (1993) 74:2391-2399. cited by other .
Stempniak, M. et al., "The NS3 proteinase domain of hepatitis C virus is a zinc-containing enzyme," Journal of Virology (1997) 71:2881-2886. cited by other .
Tanaka, T. et al., "Structure of the 3'terminus of the hepatitis C virus genome," Journal of Virology (1996) 70:3307-3312. cited by other .
Tsukiyama-Kohara, K. et al., "Internal ribosome entry site within hepatitis C virus RNA," Journal of Virology, (1992) 66:1476-1483. cited by other .
Yao, N. et al., "Structure of the hepatitis C virus RNA helicase domain," Nature Structural Biology, (1997) 4:463-467. cited by other .
Zeumam, S. et al., "Hepatitis C virus dynamics in vivo: effect of ribavirin and interferon alfa on viral turnover," Hepatology, (1998) 28:245-252. cited by other .
Zeuzem, S et al., "Peginterferon alfa-2a in patients with chronic hepatitis C," New England Journal of Medicine (2000) 343:1666-1672. cited by other .
List of Compounds in the Available Compound Database of MDL Information Systems, Inc. (MDL), San Leandro, CA (spreadsheet)(26 pp.). cited by othe- r .
List of Compounds available from Chembridge Corp., San Diego, CA (spreadsheet)(60 pp.). cited by other.

Primary Examiner: Aulakh; Charanjit S.
Attorney, Agent or Firm: Cantor Colburn, LLP

Parent Case Text

This application claims priority from U.S. Provisional Application No. 60/427,634 filed Nov. 19, 2002.

Claims

What is claimed is:

1. A pharmaceutical composition comprising therapeutically effective amount of a compound of Formula 1 ##STR00405## or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or excipient, wherein A.sub.1 is an optionally substituted aryl group; A.sub.2 is ##STR00406## R.sub.1 and R.sub.2 are independently hydrogen, or R.sub.1 and R.sub.2 are independently C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.2haloalkyl, and C.sub.1-C.sub.2haloalkoxy, R.sub.11 and R.sub.12 each represent 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, mono- and di-(C.sub.1-C.sub.6alkyl)amino, C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy, and phenyl; and R.sub.13 and R.sub.14 are independently chosen at each occurrence from hydrogen and C.sub.1-C.sub.4alkyl.

2. A pharmaceutical composition according to claim 1 wherein A.sub.1 is an aryl group which is substituted with 0 to 5 substituents independently chosen from: (a) halogen, hydroxy, cyano, amino, nitro, oxo, --COOH, --CONH.sub.2, --SO.sub.2NH.sub.2, --SH, C.sub.1-C.sub.2haloalkyl, and C.sub.1-C.sub.2haloalkoxy, (b) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.6alkenyloxy, C.sub.1-C.sub.4alkoxy(C.sub.1-C.sub.4alkyl), amino(C.sub.1-C.sub.6)alkyl, mono- and di-(C.sub.1-C.sub.6alkyl)amino, mono- and di-(C.sub.1-C.sub.4alkyl)aminoC.sub.1-C.sub.4alkyl, C.sub.2-C.sub.6alkanoyl, C.sub.2-C.sub.8alkanoyloxy, C.sub.1-C.sub.8alkoxycarbonyl, -mono- and di-(C.sub.1-C.sub.6alkyl)carboxamide, (C.sub.3-C.sub.7cycloalkyl)carboxamide, mono- and di-(C.sub.1-C.sub.6alkyl)sulfonamide, C.sub.1-C.sub.6alkylthio, aryl(C.sub.0-C.sub.4alkyl)thio, C.sub.1-C.sub.6alkylsulfinyl, and C.sub.1-C.sub.6alkylsulfonyl, and (c) --GR.sub.a where G is chosen from --(CH.sub.2).sub.n--, C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl, --(CH.sub.2).sub.nO(CH.sub.2).sub.m--, and --(CH.sub.2).sub.nN(CH.sub.2).sub.m--, where n and m are independently 0, 1, 2, 3, or 4; and R.sub.a is chosen from C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.7monocyclic heterocycloalkyl, C.sub.5-C.sub.10bicyclicheterocycloalkyl, indanyl, tetrahydronapthyl, aryl, and heteroaryl; each of which (b) and (c) is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, mono- and di-(C.sub.1-C.sub.4alkyl)amino, C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkoxycarbonyl, C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy, and phenyl; and R.sub.1 and R.sub.2 are each independently hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl.

3. A pharmaceutical composition according to claim 2 in which R.sub.1 and R.sub.2 are independently hydrogen, methyl, or ethyl.

4. A pharmaceutical composition according to claim 3 in which R.sub.1 and R.sub.2 are both hydrogen.

5. A pharmaceutical composition according to any one of claim 2 wherein A.sub.1 is aryl; substituted with 0 to 5 substituents independently chosen from: (a) halogen, hydroxy, cyano, amino, nitro, oxo, --COOH, --CONH.sub.2, --SO.sub.2NH.sub.2, --SH, C.sub.1-C.sub.2haloalkyl, and C.sub.1-C.sub.2haloalkoxy, and (b) C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkoxy, C.sub.2-C.sub.6alkenyloxy, C.sub.1-C.sub.4alkoxy(C.sub.1-C.sub.4alkyl), amino(C.sub.1-C.sub.6)alkyl, mono- and di-(C.sub.1-C.sub.6alkyl)amino, mono- and di-(C.sub.1-C.sub.4alkyl)aminoC.sub.1-C.sub.4alkyl, C.sub.2-C.sub.6alkanoyl, C.sub.2-C.sub.8alkanoyloxy, C.sub.1-C.sub.8alkoxycarbonyl, mono- and di-(C.sub.1-C.sub.6alkyl)carboxamide, (C.sub.3-C.sub.7cycloalkyl)carboxamide, mono- and di-(C.sub.1-C.sub.6alkyl)sulfonamide, C.sub.1-C.sub.6alkylthio, aryl(C.sub.0-C.sub.4alkyl)thio, C.sub.1-C.sub.6alkylsulfinyl, and C.sub.1-C.sub.6alkylsulfonyl, and (c) --GR.sub.a where G is chosen from --(CH.sub.2).sub.n--, C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl, --(CH.sub.2).sub.nO(CH.sub.2).sub.m--, and --(CH.sub.2).sub.nN(CH.sub.2).sub.m--, where n and m are independently 0, 1, 2, 3, or 4; and R.sub.a is chosen from C.sub.3-C.sub.8cycloalkyl, C.sub.2-C.sub.7monocyclic heterocycloalkyl, C.sub.5-C.sub.10bicyclicheterocycloalkyl, indanyl, tetrahydronapthyl, aryl, and heteroaryl; each of which (b) and (c) is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, mono- and di-(C.sub.1-C.sub.4alkyl)amino, C.sub.2-C.sub.4alkanoyl, C.sub.1-C.sub.4alkoxycarbonyl, C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy, and phenyl.

6. A pharmaceutical composition according to claim 5 in which A.sub.1 is substituted with 0 to 5 substituents independently chosen from (a) halogen, hydroxy, cyano, amino, nitro, oxo, C.sub.1-C.sub.2haloalkyl, and C.sub.1-C.sub.2haloalkoxy, and (b) C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.4alkoxy(C.sub.1-C.sub.4alkyl), amino(C.sub.1-C.sub.4)alkyl, mono- and di-(C.sub.1-C.sub.4alkyl)amino, and mono- and di-(C.sub.1-C.sub.4alkyl)aminoC.sub.1-C.sub.4alkyl; and (c) --GR.sub.a where G is from --(CH.sub.2).sub.n--, --(CH.sub.2).sub.nO(CH.sub.2).sub.m--, and --(CH.sub.2).sub.nN(CH.sub.2).sub.m--, and R.sub.a is C.sub.3-C.sub.8cycloalkyl, 5 or 6-membered heterocycloalkyl containing 1 or 2 heteroatoms independently chosen from O, S, and N, 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently chosen from O, S, and N, indanyl, and phenyl, each of which (b) and (c) is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, amino, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, mono- and di-(C.sub.1-C.sub.2alkyl)amino, and C.sub.1-C.sub.2haloalkyl, and C.sub.1-C.sub.2haloalkoxy.

7. A pharmaceutical composition according to claim 6 in which A.sub.1 is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, oxo, C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.4alkoxy(C.sub.1-C.sub.4alkyl), amino(C.sub.1-C.sub.4)alkyl, mono- and di-(C.sub.1-C.sub.4alkyl)amino, and mono- and di-(C.sub.1-C.sub.4alkyl)aminoC.sub.1-C.sub.4alkyl.

8. A pharmaceutical composition according to claim 2 comprising compound of the formula ##STR00407## wherein R.sub.18 represents 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, amino, nitro, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, mono- and di-(C.sub.1-C.sub.4alkyl)amino, C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy, and phenyl.

9. The pharmaceutical composition of claim 1 in which the compound is 1-(3,4-Dichlorophenyl-carbonyl)-3-(3-benzoxy-phenyl)thiourea; 1-(3,4-Dichlorophenyl-carbonyl)-3-(3-phenoxy-phenyl)thiourea; 1-(4-Trifluoromethoxy-phenyl-carbonyl)-3-(3-ethoxybenzyloxy)phenyl)-pheny- l)thiourea; 1-(4-Trifluoromethyl-phenyl-carbonyl)-3-(3-ethoxybenzyloxy)phenyl)-phenyl- )thiourea; 1-(4-Trifluoromethoxyphenyl-carbonyl)-3-(3-phenyloxy)phenyl)-phenyl)thiou- rea; 1-(4-Trifluoromethylphenyl-carbonyl)-3-(3-phenyloxy)phenyl)-phenyl)t- hiourea; 1-(3-((R)-1-Phenylethoxy)phenyl)-3-(4-trifluoromethoxy-phenyl-ca- rbonyl)thiourea; 1-(3-((S)-1-Phenylethoxy)phenyl)-3-(4-trifluoromethylphenyl-carbonyl)-thi- ourea; 1-(3-((S)-1-Phenylethoxy)phenyl)-3-(4-trifluoromethoxyphenyl-carbo- nyl)-thiourea; 1-(3-(Phenethyloxy)phenyl)-3-(4-trifluoromethylphenyl-carbonyl)-thiourea; 1-(3-(Phenethyloxy)phenyl)-3-(4-trifluoromethoxyphenyl-carbonyl)-thioure- a; 1-(4-Cyanophenyl-carbonyl)-3-(3-(benzyloxy)-phenyl)thiourea; 1-(4-Cyanophenyl-carbonyl)-3-(3-phenoxy-phenyl)thiourea; 1-(3-Trifluoromethyl-phenyl-carbonyl)-3-(3-phenoxy-phenyl)thiourea; 1-(3-Difluoromethyl-phenyl-carbonyl)-3-(3-phenoxy-phenyl)thiourea; 1-(3-Trifluoromethyl-4-methoxy-phenyl-carbonyl)-3-(3-phenoxy-phenyl)thiou- rea; 1-(3-Trifluoromethyl-4-methyl-phenyl-carbonyl)-3-(3-benzyloxy-phenyl- )thiourea; and 1-(3-Trifluoromethyl-4-methyl-phenyl-carbonyl)-3-(3-phenoxy-phenyl)thiour- ea.

10. A method for treating Hepatitis C infection comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition according to claim 1.

11. A pharmaceutical composition comprising therapeutically effective amount of a compound of the formula ##STR00408## or a pharmaceutically acceptable salt thereof, wherein R.sub.1 and R.sub.2 are independently hydrogen, methyl, or ethyl; R.sub.18 is 1 to 3 substituents independently chosen from hydroxy, cyano, amino, nitro, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, mono- and di-(C.sub.1-C.sub.4alkyl)amino, C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy, and phenyl; A.sub.2 is a group of the formula ##STR00409## wherein R.sub.11 and R.sub.12 each represent 0 to 3 substituents chosen from halogen, hydroxy, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy, mono- and di-(C.sub.1-C.sub.6alkyl)amino, C.sub.2-C.sub.6alkanoyl, C.sub.1-C.sub.2haloalkyl, C.sub.1-C.sub.2haloalkoxy, and phenyl; and R.sub.13 and R.sub.14 are independently chosen at each occurrence from hydrogen and C.sub.1-C.sub.4alkyl.

12. A method for treating Hepatitis C infection comprising administering to a patient in need of such treatment a therapeutically effective amount of pharmaceutical composition according to claim 11.

Description

FIELD OF THE INVENTION

The present invention provides arylthiourea derivatives and related compounds, useful as antiviral agents. Certain arylthiourea derivatives and related compounds disclosed herein are potent and/or selective inhibitors of viral replication, particularly Hepatitis C virus replication. The invention also provides pharmaceutical compositions containing one or more arylthiourea derivative or related compound and one or more pharmaceutically acceptable carriers, excipients, or diluents. Such pharmaceutical compositions may contain an arylthiourea derivative or related compound as the only active agent or may contain a combination of an arylthiourea derivative or related compound and one or more other pharmaceutically active agents. The invention also provides methods for treating Hepatitis C viral infections in mammals.

BACKGROUND

In the 1940's the disease originally referred to as viral hepatitis was distinguished into two separate disorders termed infectious hepatitis (hepatitis A, HAV) and homologous serum hepatitis (hepatitis B, HBV). Transfusion of blood products had been demonstrated to be a common route of transmission of viral hepatitis. HBV was originally assumed to be the causative agent of post-transfusion hepatitis as the epidemiological and clinical features of the disorder did not fit those of HAV.

Soon after a radioimmunoassay for hepatitis B surface antigen (HBsAg) became available as a tool for identifying patients infected with HBV it became apparent that most patients having post-transfusion hepatitis were negative for HbsAg. Thus, hepatitis following blood transfusion that was not caused by hepatitis A or hepatitis B and was subsequently referred to as non-A, non-B hepatitis.

The causative agent of non-A, non-B hepatitis (hepatitis C virus, HCV) was discovered in 1989 via screening of cDNA expression libraries made from RNA and DNA from chimpanzees infected with serum from a patient with post-transfusion non-A, non-B hepatitis. To identify portions of the genome that encoded viral proteins, the libraries were screened with antibodies from patients who had non-A, non-B hepatitis. These investigators went on to show that the virus they identified was responsible for the vast majority of cases of non-A, non-B hepatitis.

The hepatitis C virus is one of the most prevalent causes of chronic liver disease in the United States. It accounts for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Almost 4 million Americans, or 1.8 percent of the U.S. population, have antibodies to HCV (anti-HCV), indicating ongoing or previous infection with the virus. Hepatitis C causes an estimated 8,000 to 10,000 deaths annually in the United States. Hepatitis C virus (HCV) infection occurs throughout the world, and, prior to its identification, represented the major cause of transfusion-associated hepatitis. The seroprevalence of anti-HCV in blood donors from around the world has been shown to vary between 0.02% and 1.23%. HCV is also a common cause of hepatitis in individuals exposed to blood products. There have been an estimated 150,000 new cases of HCV infection each year in the United States alone during the past decade. The acute phase of HCV infection is usually associated with mild symptoms. However, evidence suggests that only 15%-20% of the infected people will clear HCV. Among the group of chronically infected people, 10-20% will progress to life-threatening conditions known as cirrhosis and another 1-5% will develop a liver cancer called hepatocellular carcinoma. Unfortunately, the entire infected population is at risk for these life-threatening conditions because no one can predict which individual will eventually progress to any of them.

HCV is a small, enveloped, single-stranded positive RNA virus in the Flaviviridae family. The genome is approximately 10,000 nucleotides and encodes a single polyprotein of about 3,000 amino acids. The polyprotein is processed by host cell and viral proteases into three major structural proteins and several non-structural proteins necessary for viral replication. Several different genotypes of HCV with slightly different genomic sequences have since been identified that correlate with differences in response to treatment with interferon alpha.

HCV replicates in infected cells in the cytoplasm, in close association with the endoplasmic reticulum. Incoming positive sense RNA is released and translation is initiated via an internal initiation mechanism. Internal initiation is directed by a cis-acting RNA element at the 5' end of the genome; some reports have suggested that full activity of this internal ribosome entry site, or IRES, is seen with the first 700 nucleotides, which spans the 5' untranslated region (UTR) and the first 123 amino acids of the open reading frame (ORF). All the protein products of HCV are produced by proteolytic cleavage of a large (approximately 3000 amino acid) polyprotein, carried out by one of three proteases: the host signal peptidase, the viral self-cleaving metalloproteinase, NS2, or the viral serine protease NS3/4A. The combined action of these enzymes produces the structural proteins (C, E1 and E2) and non-structural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins that are required for replication and packaging of viral genomic RNA. NS5B is the viral RNA-dependent RNA polymerase (RDRP) that is responsible for the conversion of the input genomic RNA into a negative stranded copy (complimentary RNA, or cRNA; the cRNA then serves as a template for transcription by NS5B of more positive sense genomic/messenger RNA.

An effective vaccine is greatly needed, yet development is unlikely in the near future because: i) lack of an efficient cell culture system and small animal models; ii) a weak neutralizing humoral and protective cellular immune response; iii) marked genetic variability of the virus.

Several institutions and laboratories are attempting to identify and develop anti-HCV drugs. Currently the only effective therapy against HCV is alpha-interferon, which reduces the amount of virus in the liver and blood (viral load) in only a small proportion of infected patients. Alpha interferon was first approved for use in HCV treatment more than ten years ago. Alpha interferon is a host protein that is made in response to viral infections and has natural antiviral activity. These standard forms of interferon, however, are now being replaced by pegylated interferons (peginterferons). Peginterferon is alpha interferon that has been modified chemically by the addition of a large inert molecule of polyethylene glycol. At the present time, the optimal regimen appears to be a 24- or 48-week course of the combination of pegylated alpha interferon and the nucleoside ribavirin, an oral antiviral agent that has activity against a broad range of viruses. By itself, ribavirin has little effect on HCV, but adding it to interferon increases the sustained response rate by two- to three-fold. Nonetheless, response rates to the combination interferon/ribavirin therapy are moderate, in the range 50-60%, although response rates for selected genotypes of HCV (notably genotypes 2 and 3) are typically higher. Among patients who become HCV RNA negative during treatment, a significant proportion relapse when therapy is stopped.

In addition, there are often significant adverse side effects associated with each of these agents. Patients receiving interferon often present with flu-like symptoms. Pegylated interferon has been associated with bone marrow suppressive effects. Importantly, alpha interferon has multiple neuropsychiatric effects. Prolonged therapy can cause marked irritability, anxiety, personality changes, depression, and even suicid