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(12) United States Patent (10) Patent No.: US 6,818,650 B2 Griesgraber (45) Date of Patent: Nov

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(12) United States Patent (10) Patent No.: US 6,818,650 B2 Griesgraber (45) Date of Patent: Nov USOO68 1865OB2 (12) United States Patent (10) Patent No.: US 6,818,650 B2 Griesgraber (45) Date of Patent: Nov. 16, 2004 (54) 1H-MIDAZO DIMERS 6,573.273 B1 6/2003 Crooks et al. 6,664,265 B2 12/2003 Crooks et al. .............. 514/293 (75) Inventor: George W. Griesgraber, Eagan, MN 2002/00555.17 A1 5/2002 Smith (US) 2002/0058674 A1 5/2002 Hedenstrom et al. FOREIGN PATENT DOCUMENTS (73) Assignee: 3M Innovative Properties Company, EP O 394 O26 10/1990 St. Paul, MN (US) EP 1 104764 6/2001 JP 9-208584 8/1997 (*) Notice: Subject to any disclaimer, the term of this JP 9-255926 3/1999 patent is extended or adjusted under 35 JP 11-222432 8/1999 U.S.C. 154(b) by 0 days. JP 2000-247884 9/2000 WO WO O1/74343 10/2001 (21) Appl. No.: 10/670,957 WO WO O2/36592 5/2002 WO WO O2/46.188 6/2002 (22) Filed: Sep. 25, 2003 WO WO O2/46189 6/2002 WO WO O2/46190 6/2002 (65) Prior Publication Data WO WO O2/46.191 6/2002 WO WO O2/46.192 6/2002 US 2004/0132766 A1 Jul. 8, 2004 WO WO O2/46193 6/2002 Related U.S. Application Data WO WO O2/46,194 6/2002 (60) Provisional application No. 60/413.848, filed on Sep. 26, WO WO O2/46749 6/2002 2002. WO WO O2/102377 12/2002 WO WO 03/020889 3/2003 (51) Int. Cl.................... A61K 31/4745; CO7D 471/04 WO WO 03/043572 5/2003 (52) U.S. Cl. ......................... 514/293; 546/82; 546/118; WO WO 03/045391 6/2003 514/303 OTHER PUBLICATIONS (58) Field of Search ................................. 514/293,303; Wozniak, et al., “The Amination of 3-nitro-1, 5-naphthy 546/82, 118 ridines by Liquid Ammonia/Potassium Permanganate'. A New and Convenient Amination Method.”, Journal of the (56) References Cited Royal Netherlands Chemical Society, 102, pp 511–513, Dec. 12, 1983. U.S. PATENT DOCUMENTS Brennan, et al., “Automated Bioassay of Interferons in 3,314.941 A 4/1967 Littell et al. Micro-test Plates”, Biotechniques, Jun./Jul.., 78, 1983. 4,689.338 A 8/1987 Gerster Testerman, et al., “Cytokine Induction by the Immunomodu 4,698,348 A 10/1987 Gerster lators Imiquimod and S-27609, Journal of Leukocyte Biol 4,929,624 A 5/1990 Gerster et al. ogy, vol. 58, pp. 365-372, Sep. 1995. 4,988.815. A 1/1991 Andre et al. Bachman, et al., “Synthesis of Substituted Quinolylamines. 5,037,986 A 8/1991 Gerster Derivatives of 4-Amino-7-Chloroquinoline”, J. Org. 5,175.296 A 12/1992 Gerster Chem, 15, pp 1278–1284 (1950). 5,238,944. A 8/1993 Wicket al. Jain, et al., “Chemical and Pharmacological Investigations of 5,266,575 A 11/1993 Gerster Some (D-Substituted Alkylamino-3-aminopyridines”, J. 5,268,376 A 12/1993 Gerster Med. Chem, 11, pp 87–92 (1968). 5,346,905 A 9/1994 Gerster Baranov, et al., Chem. Abs. 85,94362, (1976). 5,352,784. A 10/1994 Nikolaides et al. Berényi, et al., “Ring Transformation of Condensed Dihy 5,367,076 A 11/1994 Gerster 5,389,640 A 2/1995 Gerster et al. dro-as-triazines”, J. Heterocyclic Chem., 18, pp 1537-1540 5,395.937 A 3/1995 Nikolaides et al. (1981). 5,446,153 A 8/1995 Lindstrom et al. Chollet, et al., “Development of a Topically Active Imiqui 5,482.936 A 1/1996 Lindstrom mod Formulation”, Pharmaceutical Development and Tech 5,693,811 A 12/1997 Lindstrom nology, 4(1), pp 35-43 (1999). 5,741,908 A 4/1998 Gerster et al. Izumi, et al., “1 H-Imidazo[4,5-cquinoline Derivatives as 5,756,747 A 5/1998 Gerster et al. Novel Potent TNF-C. Suppressors: Synthesis and Structure 5,939,090 A 8/1999 Beaurline et al. Activity Relationship of 1-, 2- and 4-Substituted 1H-imi 6,039,969 A 3/2000 Tomai et al. dazo[4,5-cpyridines”, Bioorganic & Medicinal Chemistry, 6,069,149 A 5/2000 Nanba et al. 11, pp 2541–2550 (2003). 6,083.505. A 7/2000 Miller et al. * cited by examiner 6,110,929 A 8/2000 Gerster et al. 6,194,425 B1 2/2001 Gerster et al. Primary Examiner-Charanjit S. Aulakh 6,245,776 B1 6/2001 Skwierczynski et al. (74) Attorney, Agent, or Firm-Dean A. Ersfeld 6,331,539 B1 12/2001 Crooks et al. (57) ABSTRACT 6,376,669 B1 4/2002 Rice et al. 6,451,810 B1 9/2002 Coleman et al. 1H-imidazo dimer compounds are useful as immune 6,518.265 B1 2/2003 Kato et al. response modifiers. The compounds and compositions of the 6,525,064 B1 2/2003 Dellaria et al. invention can induce the biosynthesis of various cytokines 6,541,485 B1 4/2003 Crooks et al. and are useful in the treatment of a variety of conditions 6,545,016 B1 4/2003 Dellaria et al. including viral diseases and neoplastic diseases. 6,545,017 B1 4/2003 Dellaria et al. 6,558,951 B1 5/2003 Tomai et al. 23 Claims, No Drawings US 6,818,650 B2 1 2 1H-MIDAZO DIMERS SUMMARY OF THE INVENTION CROSS REFERENCE TO RELATED APPLICATION It has now been found that certain 1H-imidazo dimer This application claims priority to U.S. Provisional Appli compounds induce cytokine biosynthesis. In one aspect, the cation No. 60/413,848, filed Sep. 26, 2002. present invention provides 1H-imidazo dimer compounds of the Formula (I): FIELD OF THE INVENTION (I) The present invention relates to 1H-imidazo dimers and to pharmaceutical compositions containing Such dimers. In addition this invention relates to the use of these dimers as immunomodulators, for inducing cytokine biosynthesis in N1 N N N NN animals, and in the treatment of diseases, including viral and 15 Y-R, R-( neoplastic diseases. This invention further provides methods ul-I-' (-ll. of making the dimerS and intermediates used in their Syn thesis. R4 Nu/A. R4 BACKGROUND OF THE INVENTION The first reliable report on the 1H-imidazo[4,5-c quinoline ring System, Bachman et al., J. Org. Chem. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy wherein A, R, R and R are as defined herein. 8-quinolinyl)-2-methyl-1H-imidazo[4,5-cquinoline for 25 possible use as an antimalarial agent. Subsequently, Synthe The compounds of Formula I are useful as immune ses of various Substituted 1H-imidazo4.5-cquinolines were response modifiers (IRMs) due to their ability to induce reported. For example, Jain et al., J. Med. Chem. 11, pp. cytokine biosynthesis (e.g., induce the biosynthesis or pro 87-92 (1968), synthesized the compound 1-2-(4-piperidyl) duction of one or more cytokines) and otherwise modulate ethyl)-1H-imidazo4.5-cquinoline as a possible anticonvul the immune response when administered to animals. This Sant and cardiovascular agent. Also, Baranov et al., Chem. makes the compounds useful in the treatment of a variety of Abs. 85,94362 (1976), have reported several 2-oxoimidazo conditions Such as Viral diseases, and neoplastic diseases, 4.5-cquinolines, and Berenyi et al., J. Heterocyclic Chem. that are responsive to Such changes in the immune response. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo 4.5-cquinolines. 35 Certain 1H-imidazo4.5-cquinolin-4-amines and 1- and In another aspect, the present invention provides pharma 2-substituted derivatives thereof were later found to be ceutical compositions containing the immune response useful as antiviral agents, bronchodilators and immuno modifier compounds, and methods of inducing cytokine modulators. These are described in, inter alia, U.S. Pat. Nos. 40 biosynthesis in an animal, treating a viral disease in an 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; animal, and treating a neoplastic disease in an animal, by 5,346,905; and 5,389,640, all of which are incorporated administering an effective amount of one or more com herein by reference. pounds of Formula I and/or pharmaceutically acceptable Salts thereof to the animal. Many imidazoquinoline amine, imidazopyridine amine, 6,7-fused cycloalkylimidazopyridine amine, 1,2-bridged 45 imidazoquinoline amine, thiazoloquinoline amine, oxazolo In addition, the invention provides methods of Synthesiz quinoline amine, thiazolopyridine amine, oxazolopyridine ing the compounds of the invention and intermediates useful amine, imidazonaphthyridine and tetrahydroimidazonaph in the Synthesis of these compounds. thyridine amine compounds have demonstrated potent immunostimulating, antiviral and antitumor (including 50 anticancer) activity, and have also been shown to be useful AS used herein, “a,” “an,” “the,” “at least one,” and “one as vaccine adjuvants to enhance protective immune System or more' are used interchangeably. response to vaccines. Such compounds and methods of making them are disclosed in, for example, U.S. Pat. NoS. 55 The terms “comprising” and variations thereof do not 4,689,338; 4,929,624, 5,266,575; 5,268,376; 5,352,784; have a limiting meaning where these terms appear in the 5,389,640; 5,482.936; 5,494,916; 6,110,929; 6,194,425; 6,331,539; 6,376,669; 6,451,810; 6,541,485; 6,573,273; description and claims. 6,545,016; 6,545,017; and 6,525,064, and PCT Publications WO 02/46188, WO 02/46189; WO 02/46190; WO 60 The above Summary of the present invention is not 02/46191; WO O2/46192; and WO 02/46193, the disclosures intended to describe each disclosed embodiment or every of which are specifically incorporated by reference herein.
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