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(12) United States Patent (10) Patent No.: US 7,776,829 B2 Birck Et Al

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(12) United States Patent (10) Patent No.: US 7,776,829 B2 Birck Et Al USOO7776829B2 (12) United States Patent (10) Patent No.: US 7,776,829 B2 Birck et al. (45) Date of Patent: Aug. 17, 2010 (54) USE OF 15-DEOXYSPERGUALIN FOR THE Schorlemmer et al., “Preclinical Studies with 15-Deoxyspergualin in TREATMENT OF HYPERREACTIVE Various Animal Models for Autoimmune Diseases'. Animals of the NFLAMMLATORY DISEASES AND New York Academy of Sciences, vol. 685, 1993, pp. 155-174, also AUTOIMMUNE DISEASES referred to as XP 000974478. Schorlemmer et al. “Curative Effects of 15-Deoxyspergualin on Murine Systemic Lupus Erythematosus-Like Disease in MRL/1 (75) Inventors: Rainer Birck, Mannheim (DE): Autoimmune Mice'. International Journal of Immunotherapy, vol.7. Johannes Drexler, Kronberg (DE); No. 4, 1991, pp. 169-180, also referred to as XP 000974488. Osamu Hotta, Miyagi (JP); Rainer Lebreton et al. "Structure-Immunosuppressive Activity Relation Nowack, Lindau (DE); Johannes Fokku ships of New Analogues of 15-Deoxyspergualin. 1. Structural Modi Van Der Woude, Mannheim (DE) fications of the Hydroxyglycine Moiety”, Journal of Medicinal Chemistry, American Chemical Society, vol. 42, Jan. 28, 1996, pp. (73) Assignees: Euro Nippon Kayaku GmbH, 277-290, also referred to as XP 000.97 1394. Frankfurt am Main (DE); Nippon Schorlemmer et al., “Immunosuppressive Activity of 15 Kayaku Kabushiki Raisha, Tokyo (JP) Deoxyspergualin (15-DOS) on Various Models of Rheumatoid Arthritis'. Drugs under Experimental and clinical Research, vol. 17. (*) Notice: Subject to any disclaimer, the term of this No. 10/11, 1991, pp. 471-483, also referred to as XP 00097446. patent is extended or adjusted under 35 Schorlemmer et al., “Immunosuppressive Therapy of Organ-Specific U.S.C. 154(b) by 157 days. Nephritic Autoimmune Diseases with 15- Deoxyspergualin'. Agents and Actions, vol.39, 1993, pp. C121-C124, also referred to as XP (21) Appl. No.: 11/463,848 OOO974491. Katayama, "Experimental Lung Transplantation in Rats: Antirejec (22) Filed: Aug. 10, 2006 tion Effects of FK506 and 15-Deoxyspergualin', MIE Medical Jour nal, vol. 40, No. 2, Aug. 1990, pp. 215-228, also referred to as XP (65) Prior Publication Data OOO974487. Goral et al., "15- Deoxyspergualin Prolongs Survival During Acute US 2006/O293391 A1 Dec. 28, 2006 Graft Versus Host Disease'. Journal of Allergy and Clinical Immu nology, vol. 99, No. 1, 1997, also referred to as XP 000957371. Related U.S. Application Data Choi et al. “Immunomodulator Therapy in Inflammatory Bowel Dis (62) Division of application No. 09/979,365, filed as appli ease', Digestive Diseases and Sciences, 1994, vol. 39, No. 9, also cation No. PCT/EP00/03430 on Apr. 14, 2000, now referred to as XP 000974490. Pat. No. 7,153,887. Birck et al., "15- Deoxyspergualin Induces Remission in Wegener's Granulomatosis: Report of Three Cases”. Journal of the American Society of Nephrology, vol. 10, Sep. 1999, also referred to as XP (51) Int. Cl. OOO974913. A6 IK 38/00 (2006.01) Bumgardner et al., “New Immunosuppressive Agents'. Gastroenter (52) U.S. Cl. ........................................................ S14/20 ology Clinics of North America, vol. 22, No. 2, 1993, also referred to (58) Field of Classification Search ........... ... None as XPOOO974492. See application file for complete search history. Schorlemmer et al., "15- Deoxyspergualin 15-DOS) Has a Curative (56) References Cited Effect on the Development of SLE-Like Autoimmune Disease in MRL/1Mice”, Agents and Actions, vol. 34, No. 1/02, 1991, pp. U.S. PATENT DOCUMENTS 151-155, also referred to as XP 000.974941. Kalden et al., “Immunological Treatment of Autoimmune Diseases'. 5,250.442 A 10/1993 Cabezas ..................... 436,509 Advances in Immunology, vol. 68, 1998, pp. 333-418, also referred to 5,624,938 A 4, 1997 Pernis ........................ 514/313 as XPOOO974494. 5,679,651 A * 10/1997 Richardson .................. 514,49 6,083,503 A 7/2000 Lenardo .................. 424,184.1 Transplantation, vol. 51, p. 712-715, 1991. Drugs Exp. Clin. Res., vol. 17, p. 471-483, 1991. FOREIGN PATENT DOCUMENTS Drugs Exp. Clin. Res., vol. 17, p. 461–469, 1991. DE 1971 1803 A1 9, 1998 (Continued) DE 1972843.6 A1 1, 1999 EP O 673 646 B1 9, 1995 Primary Examiner Frederick Krass EP O 678297 A1 10, 1995 Assistant Examiner—Marcos SZnaidman WO WO99/O3504 1, 1999 (74) Attorney, Agent, or Firm—Frommer Lawrence & Haug LLP OTHER PUBLICATIONS (57) ABSTRACT Schorlemmer et. al., International Journal of Immunotherapy (1991) VII (4) 169-180.* Burmgardner et. al., Gastroenterology Clinics of North America The invention describes the use of deoxyspergualin (DSG) or (1993) 22:421-449.* an analogue thereof for the preparation of a medicament for Drugs Facts and Comparison, 49th edition (1995) 1467-1472.* the treatment of and/or prophylaxis against hyperreactive Mae et al., CAS accession # 1994-12723 corresponding to Journal of inflammatory diseases and autoimmune diseases, wherein the Antibiotics (1994)47:90-94.* Okada et al., “Immunosuppressant Deoxyspergualin Induces treatment is performed in cycles. Apoptotic Cell Death in Dividing Cells'. Immunology 1998, pp. 370-376. 34 Claims, 1 Drawing Sheet US 7,776,829 B2 Page 2 OTHER PUBLICATIONS "Autoimmune Diseases Poorly Understood. Difficult to Treat”. CNN.com, Jul. 4, 2000. Clin. Exp. Immunol., vol. 91, p. 232-236, 1993. "Tips for Getting a Proper Diagnosis of Autoimmune Disease'. Scand. J. Immunol., vol. 36, p. 415-420, 1992. Infocus, vol. 10, No. 2, Jun. 2002. J. Am. Soc. Nephrol., vol. 3, p. 1765-1774, 1993. “Immunosuppressive Effect of Deoxyspergualin in Proliferative Clin. Exp. Immunol., vol. 95, p. 502-808, 1994. Glomerulonephritis'. Hotta et al., American Journal of Kidney Dis Agents Actions, vol.39, p. C121-C124, 1993. eases, Nov. 1999, 34(5), 894-901. Scand. J. Immunol., vol.39, p. 333-336, 1994. “Unique Action of an Immunosuppressive Agent, Deoxyspergualin, J. Neuro. Sci., vol. 112, p. 209-215, 1992. One Hematopoiesis in Mice'. Memoto et al., Experimental Hema Auotimmunity, vol. 8, p. 43-51, 1990. tology, 1997, 25(13), 1339-1346. Autoimmune Diseases: Overview:, The National Women's Health "Deoxyspergualin: A New Immunosuppressive Drug for the Treat Information Center, Oct. 2003, 2000. ment of Autoimmune Disease'. Nikolic-Paterson et al., Nephron “Positive Results of Phase I Study Put LymphoStat-B on Fact Track 995, 70(4), 391-6. d for Drug Development”, 2001, Lupus Foundation of America, Inc. Effect of 15-Deoxyspergulain on Graft-V-Host Disease in Mice'. “Multiple Sclerosis: An Autoimmune Disease of the Central Nervous Nemoto et al., Transplant Proc., 1987, 19(5), 3985-6. System'. Vandana Mathrani, 2000. Third Web Report on Seredip. * cited by examiner U.S. Patent Aug. 17, 2010 US 7,776,829 B2 F igure 1 15-DSG treatment N lymphocytes neutrophils E. leucocytes SOSYNNYRSYSSESYONASSS(No.No.S. EZZZZZZZZZZZ ZZZZZZZZJ ZZZZZZZZZZ ZZZZZZZZZZ No.w, 2:ZZZZZ 1 2 3 4 5 6 7 8 9 101112131415No. 1617 1819202122 Time days - Example - - - Example ll ?JOOSSVAE 10 1 Follow up months) US 7,776,829 B2 1. 2 USE OF 15-DEOXYSPERGUALIN FOR THE system as chronic immuno-proliferative syndrome, mono TREATMENT OF HYPERREACTIVE clonal gammopathies, Morbus Hodgkin and Non-Hodgkin NFLAMMATORY DISEASES AND Lymphoma and chronic proliferative CD8-cell disease. The AUTOMMUNE DISEASES diseases which may be treated according to the invention generally encompass those mentioned in Peter/Pichler, “Kli The invention relates to the use of deoxyspergualin or nische Immunologie, 2nd ed., Urban & Schwarzenberg, analogues thereof for the preparation of a medicament for the 1996, p. X-XIV (Teil C. Klinik). treatment of hyperreactive inflammatory diseases, as vascu Therapies for many hyperreactive inflammatory diseases litis, and autoimmune diseases. and autoimmune diseases have to be regarded as insufficient. 10 In many instances this is due to severe side effects of the BACKGROUND OF THE INVENTION medicaments used. For example, for hyperreactive inflamma tory diseases as Alzheimer's disease, pancreatitis and sepsis, Hyperreactive inflammatory diseases are characterized in there are no adequate treatments. that the body hyperreacts to nonspecific stimuli with an Regarding vasculitis, early attempts of treatment include uncontrolled inflammation reaction. This inflammatory reac 15 the use of oral corticosteroids (OCS). Later, cyclophospha tion (hyperreactivity) causes pathological changes leading to mid was added in steroid-resistant disease. A standard treat the onset of the disease and its chronic establishment. Con ment of Wegener's granulomatosis, a form of vasculits, is a cerning a definition and examples of hyperreactive inflam combination of cyclophosphamide (CYC) and oral corticos matory diseases reference is made to EP-0 673 646, explicitly teroids (OCS) Various therapeutic regimen including Pred incorporated herein. Vasculitis is an example of such a hyper nisolone and cyclophosphamide or AZathioprine are dis reactive inflammatory disease. closed in "Oxford Textbook for Clinical Nephrology, pp. A general approach to vasculitis nomenclature and a set of 890, referenced above. However, those therapies suffer from definitions was agreed by consensus (Jennette et al., 1994, several drawbacks, including a relatively high number of “Nomenclature of systemic vasculitides. Proposal of an inter therapy-resistant cases, a considerable relapse rate and side national consensus conference' Arthritis and Rheumatism, 25 effects. For example, long-term treatment with CYC carries 37, 187-92), and is incorporated herein by reference. Accord the risk of serious drug-related morbidity
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