USO08080553B2 (12) United States Patent (10) Patent No.: US 8,080,553 B2 Keith et al. (45) Date of Patent: Dec. 20, 2011 (54) METHODS AND REAGENTS FOR THE 35E, A 12 E. auffmanA. et al.al TREATMENT OF IMMUNON FLAMMATORY 5,326,764 A 7, 1994 Milstone et al. DSORDERS 5,428,040 A 6/1995 Magolda et al. 5,468,729 A 11/1995 Chretien et al. (75) Inventors: Curtis Keith, Boston, MA (US); Alexis 5,639,759 A 6/1997 Magolda et al. 5,668,116 A 9, 1997 Cullis-Hill et al. S.A.Immermann, NA's, SomerV11 MA SSan. le. (US); 5,756,5535,728,712 A 3/19985/1998 IguchiMontana et al.et al. Edward Roydon Jost-Price, West 5,762.918 A 6/1998 Thorpe Roxbury, MA (US); Palaniyandi 3.3 A s 3. als. 1 Manivasakam, West Roxbury, MA 5,874.441 A 2/1999 Magoldaarvey et et al. al. (US); Nicole Hurst, Boston, MA (US); 5,958,926. A 9/1999 Garvey et al. Michael A. Foley, Chestnut Hill, MA 6,010,716 A 1/2000 Saunal et al. (US); Michael S. Slavonic, Quincy, MA 8.83, A 38 S.ekut et al.al (US);S. ENBenjamin suit A. Auspitz, SEEA. Cambridge, E. 6,110,9106,071,514. A 8/20006/2000 GrinnellMagolda etet al.al. MA (US) 6,133,272 A 10/2000 Garvey et al. 6,172,060 B1 1/2001 Garvey et al. (73) Assignee: Zalicus Inc., Cambridge, MA (US) 6,172,068 B1 1/2001 Garvey et al. 6,177,428 B1 1/2001 Garvey et al. (*)c Notice:- r Subject to any disclaimer, the term of this 6, 197,782197,778 B1 3/2001 Garvey et al. patent is extended or adjusted under 35 6.211179 B1 4/2001 Garvey et al. U.S.C. 154(b) by 1504 days. 6,221,881 B1 4/2001 Garvey et al. 6,232,321 B1 5/2001 Garvey et al. (21) Appl. No.: 11/517,593 6,265,427 B1 7/2001 Camden 6,316,457 B1 1 1/2001 Garvey et al. 1-1. 6,331.543 B1 12/2001 Garvey et al. (22) Filed: Sep. 7, 2006 6,337,325 B1 1/2002 Schonharting et al. O O 6,372.254 B1 4/2002 Ting et al. (65) Prior Publication Data 6,383,471 B1 5/2002 Chen et al. 6,403,571 B2 6/2002 Gould et al. US 2007/OO 105O2A1 Jan. 11, 2007 6,462,044 B2 10/2002 Garvey et al. O O 6,515,010 B1 2/2003 Franchini et al. Related U.S. Application Data 6,602,521 B1 8/2003 Ting et al. 6,677,326 B2 1/2004 Bardslev et al. (63) Continuation of application No. 10/966.228, filed on 6,730,321 B2 5, 2004 is: al Oct. 15, 2004, now abandoned. 7,253,155 B2 8, 2007 Keith et al. (60) Provisional application No. 60/512,415, filed on Oct. (Continued) 15, 2003. FOREIGN PATENT DOCUMENTS (51) Int. Cl. CN 1246335 A 3, 2000 AOIN 43/54 (2006.01) (Continued) AOIN 43/90 (2006.01) A 6LX3/57 (2006.01) A 6LX3/59 (2006.01) OTHER PUBLICATIONS CO7D 239/42 (2006.01) Boileau et al. Arthritis & Rheumatism, 2002, vol. 46, No. 10, pp. CO7D40 L/04 (2006.01) 2637-2647.* (52) U.S. Cl. ..................................... 514/258.1; 514/256 (58) Field of Classification Search ............... 514/258.1, (Continued)Continued 514/256 See application file for complete search history. Primary Examiner — Sreeni Padmanabhan Assistant Examiner — Samira Jean-Louis (56) References Cited (74) Attorney, Agent, or Firm — Clark & Elbing LLP U.S. PATENT DOCUMENTS 3,031,450 A 4, 1962 Fischer et al. (57) ABSTRACT 3,934,036 A 1/1976 Irikura 3,944,577 A 3, 1976 Laurent et al. The invention features a method for treating a patient diag 4,034,087 A 7, 1977 Voorhees nosed with, or at risk of developing, an immunoinflammatory 4,107,306 A 8, 1978 Voorhees disorder by administering to the patient a tetra-substituted 4,254,122 A 3/1981 Brown .......................... 514,245 pyrimidopyrimidine, either alone or in combination with one 4,367,217 A 1/1983 Gruber et al. 4,499,093 A 2f1985 Galabov et al. or more additional agents. The invention also features a com 4,554,271 A 1 1/1985 Braughler et al. position containing a tetra-substituted pyrimidopyrimidine in 4,685,911 A 8, 1987 Konno et al. combination with one or more additional agents. 4,879,119 A 11, 1989 Konno et al. 5,051.262 A 9, 1991 Panoz et al. 5,242.921 A 9, 1993 Milstone et al. 22 Claims, No Drawings US 8,080,553 B2 Page 2 U.S. PATENT DOCUMENTS Baxter et al., “Mechanism of Glucocorticoid Action: General Fea 2001/0007083 A1 7/2001 Roorda et al. tures, with Reference to Steroid-Mediated Immunosuppression.” 2001 OO16604 A1 8, 2001 Yu et al. Transplant. Proc. 7:55-65 (1975). 2002fOO19405 A1 2/2002 Garvey et al. Berger et al., “Comparative Carcinogenic Activity of Prednimustine, 2003,0003151 A1 1/2003 Chopra Chlorambucil, Prednisolone and Chlorambucil Plus Prednisolone in 2003, OO23087 A1 1/2003 Garvey et al. Sprague-Dawley Rats.” Arch. Geschwulstforsch 55:429-442 (1985). 2003, OO691.69 A1 4/2003 Macor et al. 2003/0077229 A1 4/2003 Dugger Berger et al., “Long-Term Toxicology Effects of Prednimustine in 2003/0078246 A1* 4/2003 Sackeyfio et al. ............. 514,171 Comparison with Chlorambucil, Prednisolone, and Chlorambucil 2003/0203028 A1 10/2003 Ting et al. Plus Prednisolone in Sprague-Dawley Rats.” Semin. Oncol. 13:8-13 2004/0087486 A1 5, 2004 Hanson (1986). 2004/OO87591 A1 5/2004 Garvey et al. Berkow et al., “The Merck Manual.” fifteenth edition, pp. 797-807 2004/0180812 A1 9, 2004 Dicker et al. (1987). 2005, OO19393 A1 1/2005 Augsburger et al. Berkow et al., “Merck Manual of Medical Information.' Home edi 2005/0O25713 A1 2/2005 Dugger 2005, 0037074 A1 2/2005 ROSS et al. tion, pp. 248-255 (1997). 2005, OO58688 A1 3/2005 Boerger et al. Brunette et al., "Long-term Immunosuppressive Treatment of a Child 2005, 011916.0 A1 6, 2005 Keith et al. with Takayasu's Arteritis and High IgE Immunoglobulins.” Pediatr. 2006/0234991 A1 10, 2006 Keith et al. Nephrol. 10:67-69 (1996). 2007/00105O2 A1 1/2007 Keith et al. Bruserud, “Dipyridamol Inhibits Activation of Human T Lympho 2007,0196491 A1 8, 2007 Venkatesh cytes. In Vitro.” Clin. Immunol. Immunopathol. 42:102-109 (1987). 2007/0213296 A1 9/2007 Zhang Casset al., “A Comparison of the Abilities of Nitrobenzylthioinosine, 2007/0213308 A1 9, 2007 Lessem et al. Dilazep, and Dipyridamole to Protect Human Hematopoietic Cells 2009.0075955 A1 3, 2009 Padval From 7-Deazaadenosine (Tubercidin).” Cancer Res. 52:5879-5886 FOREIGN PATENT DOCUMENTS (1992). EP O3O3 713 B1 5, 1993 Cazenave et al., “Inhibition of Platelet Adherence to a Collagen EP O 543 653 A1 5, 1993 coated Surface by Nonsteroidal Anti-inflammatory Drugs, Pyrimido EP 1 O93814 A1 4/2001 pyrimidine and Tricyclic Compounds, and Lidocaine” J. Lab. Clin. GB 2 292 O79 2, 1996 Med. 83:797-806 (1974). WO WO 89.10.122 11, 1989 Conway et al., “Inhibition of Cartilage and Bone Destruction in WO WO92, 16226 10, 1992 Adjuvant Arthritis in the Rat by a Matrix Metalloproteinase Inhibi WO WO98, 19672 5, 1998 tor.” J. Exp. Med. 182:449-457 (1995). WO WO98,55142 12/1998 Curtin et al., “Potentiation of the Cytotoxicity of Thymidylate WO WO99, 16417 4f1999 Synthase (TS) Inhibitors by Dipyridamole Analogues with Reduced WO WO99/62537 12/1999 O-acid Glycoprotein Binding Br. J. Cancer 80:1738-1746 (1999). WO WOOOf 12076 3, 2000 Eigler et al., “Endogenous Adenosine Curtails Lipopolysaccharide WO WOOOf 12497 3, 2000 WO WOOO,594.75 10, 2000 Stimulated Tumour Necrosis Factor Synthesis.” Scan J. Immunol. WO WOO1? 47572 A2 T 2001 45:132-139 (1997). WO WOO1, 54.679 A2 8, 2001 Feldmann et al., “Anti-TNFO. Therapy of Rheumatoid Arthritis: What WO WOO1? 68056 9, 2001 Have We Learned?” Annu. Rev. Immunol. 19:163-196 (2001). WO WO O2/22 127 A1 3, 2002 Goh et al., “Nitrobenzylthioinosine-binding Protein Overexpression WO WO O2/O69905 9, 2002 in Human Breast, Liver, Stomach and Colorectal Tumour Tissues.” WO WO O2/O85304 A2 10, 2002 Anticancer Res. 15:2575-2580 (1995). WO WO O2/O94227 A1 11, 2002 Griffon-Etienne et al., “Taxane-induced Apoptosis Decompresses WO WOO3,OO6026 1, 2003 Blood Vessels and Lowers Interstitial Fluid Pressure in Solid Tumors: WO WOO3,O3O823 4/2003 Clinical Implications.” Cancer Res. 59: 3776-3782 (1999). WO WO 03/043603 A1 5, 2003 Harada et al., “Renal Amyloidosis Associated with Crescentic WO WO 2004/O19909 A2 3, 2004 WO WO 2004/069254 A2 8, 2004 Glomerulonephritis' Am. J. Nephrol. 4:52-55 (1984). WO WO 2005/020933 A2 3, 2005 Haskö et al., “Adenosine Inhibits IL-12 and TNF-60 Production Via WO WO 2005/03O132 4/2005 Adenosine A Receptor-Dependent and Independent Mechanisms.” WO WO 2005/0372O3 4/2005 FASEB.J. 14:2065-2074 (2000). WO WO 2007/089617 8, 2007 Iijima et al., “Multiple Combined Therapy for Severe Henoch WO WO 2007/103373 9, 2007 Schönlein Nephritis in Children.” Pediatr Nephrol. 12:244-248 OTHER PUBLICATIONS (1998). Konstantinov et al., “Interferon Response to Dipyridamole in Lupus Forrest CMetal. "Adenosine and Cytokine Levels Following Treat Erythematosus Patients” Br: J. Dermatol. 121:59-63 (1989). ment of Rheumatoid Arthritis with Dipyridamole'.