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(12) United States Patent (10) Patent No.: US 7,112,677 B2 Griesgraber (45) Date of Patent: Sep

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(12) United States Patent (10) Patent No.: US 7,112,677 B2 Griesgraber (45) Date of Patent: Sep US007 112677B2 (12) United States Patent (10) Patent No.: US 7,112,677 B2 Griesgraber (45) Date of Patent: Sep. 26, 2006 (54) 1H-IMIDAZO DIMERS 6,525,064 B1 2/2003 Dellaria et al. 6,541,485 B1 4/2003 Crooks et al. (75) Inventor: George W. Griesgraber, Eagan, MN 6,545,016 B1 4/2003 Dellaria et al. (US) 6,545,017 B1 4/2003 Dellaria et al. (73) Assignee: 3M Innovative Properties Company, 6,558,951 B1 5/2003 Tomai et al. St. Paul, MN (US) 6,573,273 B1 6/2003 Crooks et al. 6,664,265 B1 12/2003 Crooks et al. (*) Notice: Subject to any disclaimer, the term of this 2002fOO555.17 A1 5, 2002 Smith patent is extended or adjusted under 35 2002fOO58674 A1 5, 2002 HedenStrom et al. U.S.C. 154(b) by 28 days. (21) Appl. No.: 10/912,908 FOREIGN PATENT DOCUMENTS (22) Filed: Oct. 8, 2004 EP O 394 O26 10, 1990 (65) Prior Publication Data EP 1 104764 6, 2001 US 2005/OO26947 A1 Feb. 3, 2005 JP 9-208584 8, 1997 JP 9-255926 3, 1999 Related U.S. Application Data JP 11-222432 8, 1999 (62) Division of application No. 10/670,957, filed on Sep. JP 2000-247884 (ABS) 9, 2000 25, 2003, now Pat. No. 6,818,650. WO WOO 1/74343 10, 2001 WO WO O2,36592 5, 2002 (60) Provisional application No. 60/413,848, filed on Sep. WO WO O2/46.188 6, 2002 26, 2002. WO WO O2/46189 6, 2002 (51) Int. Cl. WO WO O2/46190 6, 2002 C07D 471/02 (2006.01) WO WO O2/46.191 6, 2002 (52) U.S. Cl. ........................................... 546/41; 546/41 WO WO O246.192 6, 2002 (58) Field of Classification Search ................... 546/41 WO WO O2/46193 6, 2002 See application file for complete search history. WO WO O2/46.194 6, 2002 WO WO O2/46749 6, 2002 (56) References Cited WO WO O2/102377 12/2002 U.S. PATENT DOCUMENTS WO WO O3,O2O889 3, 2003 WO WO 03/043572 5, 2003 3,314,941 A 4, 1967 Littell et al. 4,689.338 A 8, 1987 Gerster WO WO 03/045391 6, 2003 4,698,348 A 10, 1987 Gerster 4,929,624 A 5, 1990 Gerster et al. 4,988,815 A 1/1991 Andre et al. 5,037,986 A 8, 1991 Gerster OTHER PUBLICATIONS 5,175,296 A 12/1992 Gerster 5,238,944 A 8, 1993 Wicket al. Wozniak, et al. “The Amination of 3-nitro-1, 5-naphthyridines by 5,266,575 A 11/1993 Gerster Liquid Ammonia/Potassium Permanganate''. A New and Conve 5,268,376 A 12/1993 Gester nient Amination Method.”, Journal of the Royal Netherlands 5,346,905 A 9, 1994 Gerster Chemical Society, 102, pp. 511-513, Dec. 12, 1983. 5,352,784. A 10, 1994 Nikolaides et al. Brennan, et al., “Automated Bioassay of Interferons in Micro-test 5,367,076 A 11/1994 Gerster Plates'. Biotechniques, Jun./Jul. 78, 1983. 5,389,640 A 2f1995 Gerster et al. 5,395.937 A 3, 1995 Nikolaides et al. (Continued) 5,446,153 A 8, 1995 Lindstrom et al. 5,482.936 A 1/1996 Lindstrom Primary Examiner Celia Chang 5,693,811 A 12/1997 Lindstrom Assistant Examiner—R. James Balls 5,741,908 A 4, 1998 Gerster et al. (74) Attorney, Agent, or Firm—Dean A. Ersfeld 5,756,747 A 5, 1998 Gerster et al. 5,939,090 A 8, 1999 Beaurline et al. (57) ABSTRACT 6,039,969 A 3, 2000 Tomai et al. 6,069,149 A 5, 2000 Nanba et al. 6,083,505 A 7/2000 Miller et al. 1H-imidazo dimer compounds are useful as immune 6,110,929 A 8, 2000 Gerster et al. response modifiers. The compounds and compositions of the 6,194,425 B1 2/2001 Gerster et al. 6,245,776 B1 6/2001 Skwierczynski et al. invention can induce the biosynthesis of various cytokines 6,331,539 B1 12/2001 Crooks et al. and are useful in the treatment of a variety of conditions 6,376,669 B1 4/2002 Rice et al. including viral diseases and neoplastic diseases. 6,451,810 B1 9, 2002 Coleman et al. 6,518,265 B1 2/2003 Kato et al. 2 Claims, No Drawings US 7,112,677 B2 Page 2 OTHER PUBLICATIONS Baranov, et al., Chem. Abs. 85,94362, (1976). Testerman, et al., “Cytokine Induction by the Immunomodulators Berényi, et al., “Ring Transformation of Condensed Dihydro-as Imiquimod and S-276.09", Journal of Leukocyte Biology, vol. 58, triazines”. J. Heterocyclic Chem., 18, pp. 1537-1540 (1981). pp. 365-372, Sep. 1995. Chollet, et al., “Development of a Topically Active Imiquimod Bachman, et al. “Synthesis of Substituted Quinolylamines. Deriva Formulation”, Pharmaceutical Development and Technology, 4(1), tives of 4-Amino-7-Chloroquinoline'. J. Org. Chem, 15, pp. 1278 pp. 35-43 (1999). 1284 (1950). Izumi, et al., "1H-Imidazo[4,5-cquinoline Derivatives as Novel Jain, et al., "Chemical and Pharmacological Investigations of Some Potent TNF-C. Suppressors: Synthesis and Structure-Activity Rela (D-Substituted Alkylamino-3-aminopyridines”. J. Med. Chem., 11. tionship of 1-, 2- and 4-Substituted 1H-imidazo[4,5-cpyridines', pp. 87-92 (1968). Bioorganic & Medicinal Chemistry, 11, pp. 2541-2550 (2003). US 7,112,677 B2 1. 2 1H-MIDAZO DIMERS Despite these recent discoveries of compounds that are useful as immune response modifiers, there is a continuing CROSS REFERENCE TO RELATED need for compounds that have the ability to modulate the APPLICATION immune response, by induction of cytokine biosynthesis or This application is a divisional of U.S. application Ser. other mechanisms. No. 10/670,957, filed Sep. 25, 2003, now U.S. Pat. No. SUMMARY OF THE INVENTION 6,818,650 now allowed, which claims the benefit of U.S. Provisional Application No. 60/413,848, filed Sep. 26, 2002. It has now been found that certain 1H-imidazo dimer 10 compounds induce cytokine biosynthesis. In one aspect, the FIELD OF THE INVENTION present invention provides 1H-imidazo dimer compounds of the Formula (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 15 (I) immunomodulators, for inducing cytokine biosynthesis in NH2 NH2 animals, and in the treatment of diseases, including viral and neoplastic diseases. This invention further provides methods N1 N N y NN of making the dimers and intermediates used in their syn thesis. R 21 y- -( 2 R3 BACKGROUND OF THE INVENTION l, N, -/ The first reliable report on the 1H-imidazo[4,5-cquino 25 line ring system, Bachman et al., J. Org. Chem. 15. wherein A. R. R. and R are as defined herein. 1278–1284 (1950) describes the synthesis of 1-(6-methoxy The compounds of Formula I are useful as immune 8-quinolinyl)-2-methyl-1H-imidazo 4.5-cquinoline for response modifiers (IRMs) due to their ability to induce possible use as an antimalarial agent. Subsequently, synthe cytokine biosynthesis (e.g., induce the biosynthesis or pro ses of various Substituted 1H-imidazo 4.5-c quinolines 30 duction of one or more cytokines) and otherwise modulate were reported. For example, Jain et al., J. Med. Chem. 11, the immune response when administered to animals. This pp. 87-92 (1968), synthesized the compound 1-2-(4-pip makes the compounds useful in the treatment of a variety of eridyl)ethyl-1H-imidazo[4,5-cquinoline as a possible anti conditions such as viral diseases, and neoplastic diseases, convulsant and cardiovascular agent. Also, Baranov et al., 35 that are responsive to Such changes in the immune response. Chem. Abs. 85,94362 (1976), have reported several 2-ox In another aspect, the present invention provides pharma oimidazo 4.5-cquinolines, and Berenyi et al., J. Heterocy ceutical compositions containing the immune response clic Chem. 18, 1537–1540 (1981), have reported certain modifier compounds, and methods of inducing cytokine 2-oxoimidazo 4.5-cquinolines. biosynthesis in an animal, treating a viral disease in an Certain 1H-imidazo 4.5-cquinolin-4-amines and 1- and 40 animal, and treating a neoplastic disease in an animal, by 2-substituted derivatives thereof were later found to be administering an effective amount of one or more com useful as antiviral agents, bronchodilators and immuno pounds of Formula I and/or pharmaceutically acceptable modulators. These are described in, interalia, U.S. Pat. Nos. salts thereof to the animal. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 45 In addition, the invention provides methods of synthesiz 5,346,905; and 5,389,640, all of which are incorporated ing the compounds of the invention and intermediates useful herein by reference. in the synthesis of these compounds. Many imidazoquinoline amine, imidazopyridine amine, As used herein, “a,” “an,” “the.” “at least one,' and “one 6.7-fused cycloalkylimidazopyridine amine, 1.2-bridged or more are used interchangeably. imidazoquinoline amine, thiazoloquinoline amine, oxazolo 50 The terms “comprising and variations thereof do not quinoline amine, thiazolopyridine amine, oxazolopyridine have a limiting meaning where these terms appear in the amine, imidazonaphthyridine and tetrahydroimidazonaph description and claims. thyridine amine compounds have demonstrated potent The above summary of the present invention is not immunostimulating, antiviral and antitumor (including anti 55 intended to describe each disclosed embodiment or every cancer) activity, and have also been shown to be useful as implementation of the present invention.
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