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(12) United States Patent (10) Patent No.: US 7,524,835 B2 Frincke (45) Date of Patent: Apr

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(12) United States Patent (10) Patent No.: US 7,524,835 B2 Frincke (45) Date of Patent: Apr USOO7524835B2 (12) United States Patent (10) Patent No.: US 7,524,835 B2 Frincke (45) Date of Patent: Apr. 28, 2009 (54) TETROL STEROIDS AND ESTERS 5,912,240 A 6/1999 Loria 5,919,465. A 7/1999 Daynes et al. (75) Inventor: James M. Frincke, San Diego, CA (US) 5,922,701 A 7/1999 Araneo (73) Assignee: Hollis-Eden Pharmaceuticals, Inc., San 5,929,060 A 7/1999 Araneo Diego, CA (US) 6,111,118 A 8, 2000 Marwah et al. 6,150,348 A 11/2000 Araneo et al. (*) Notice: Subject to any disclaimer, the term of this 6,187,767 B1 2/2001 Araneo et al. patent is extended or adjusted under 35 6,384,251 B1 5, 2002 Marwah et al. U.S.C. 154(b) by 272 days. 6,476,011 B1 1 1/2002 Reed et al. (21) Appl. No.: 10/607,415 6,667,299 B1 12/2003 Ahlem et al. 6,686,486 B1 2/2004 Marwah et al. (22) Filed: Jun. 25, 2003 6,949,561 B1 9, 2005 Reed et al. 65 Prior Publication D 2003/0232797 Al 12/2003 Kutney et al. (65) rior Publication Data 2004/0019026 A1 1/2004 Schwartz et al. US 2006/OO63749 A1 Mar. 23, 2006 2004/0162425 A1 8/2004 Burgoyne et al. Related U.S. Application Data (63) Continuation of application No. 09/535,675, filed on Mar. 23, 2000, now Pat. No. 6,667,299, which is a FOREIGN PATENT DOCUMENTS continuation-in-part of application No. 09/414.905, filed on Oct. 8, 1999, now abandoned. DE 38 12595 C2 10, 1988 EP O 133995 B1 8, 1984 (60) Provisional application No. 60/190,140, filed on Mar. EP 0289 327 A1 11, 1988 16, 2000, provisional application No. 60/164.048, EP O 429 187 B1 5, 1994 filed on Nov. 8, 1999, provisional application No. 60/140,028, filed on Jun. 16, 1999, provisional appli- EP 1219631 3, 2002 cation No. 60/126,056, filed on Mar. 23, 1999. (51) Int. Cl. A6 IK3I/56 (2006.01) (Continued) C07 L/100 (2006.01) OTHER PUBLICATIONS (52) U.S. Cl. ....................................... 514/182:552/615 (58) Field of Classification Search ................. 514/182: Araghi-Niknam et al., Cytokine Dysregulation and Increased Oxida 552/615 tion IS Prevented by Dehydroepiandrosterone in Mice Infeced with See application file for complete search history. Murine Leukemia Retrovirus, Proc. Soc. Exp. Biol. Med. 216(3):386 391 1997. (56) References Cited U.S. PATENT DOCUMENTS (Continued) 4,602,008 A 7, 1986 KrSek Primary Examiner Barbara P Badio 4,898,694w W4- A 2f1990 SchwartzSee et al. (74) Attorney, Agent, or Firm—Angeloin Castellino 5,001,119 A 3, 1991 Schwartz et al. 5,175,154 A 12/1992 Schwartz et al. (57) ABSTRACT 5,206,008 A 4, 1993 Loria 5,387,583 A 2f1995 Loria 5,424,463 A 6/1995 Lardy et al. The invention provides compositions comprising formula 1 5,461,042 A 10/1995 Loria steroids, e.g., 16C.-bromo-3B-hydroxy-5C.-androstan-17-one 5,489,581 A 2/1996 Daynes et al. hemihydrate and one or more excipients, typically wherein 5,506,223. A 4/1996 Lardy et al. the composition comprises less than about 3% water. The 3.358 A 63. E. al compositions are useful to make improved pharmaceutical 5,583.126 A 3, 1996 E. A. formulations. The invention also provides methods of inter 5.585.37. A 12, 1996 R mittent dosing of steroid compounds such as analogs of 16C.- 5,587369 A 12/1996 Daynes et al. bromo-3B-hydroxy-5C.-androstan-17-one and compositions 5,635,496 A 6/1997 Daynes et al. useful in Such dosing regimens. The invention further pro 5,641,766 A 6/1997 Lardy vides compositions and methods to inhibit pathogen (viral) 5,656,621 A 8, 1997 Schwartz et al. replication, ameliorate symptoms associated with immune 5,686.438 A 1 1/1997 Daynes dysregulation and to modulate immune responses in a subject t 3. SA et al. using certainsteroids and steroid analogs. The invention also 5,811,418W - A 9/1998 DaynesO et al. provides methods to make and use these immunomodulatory 5,827,841 A 10/1998 Daynes et al. compositions and formulations. 5,837,269 A 1 1/1998 Daynes et al. 5,859,000 A 1/1999 Dowell et al. 12 Claims, 6 Drawing Sheets US 7,524,835 B2 Page 2 FOREIGN PATENT DOCUMENTS Pouzar, V., et al, Derivatives of 16a-hydroxy dehydroepiandrosterone with an additional 7-oxo or 7-hydroxy WO 1993005064 3, 1993 Substituent: Synthesis and gas chromatography/mass spectrometry WO 1994O2O111 9, 1994 analysis, Steroids, 2005, 70, pp. 739-749. WO 95,06472 A1 3, 1995 Schwartz, A., et al. Novel dehydroepiandrosterone analogues with WO 96.40152 A1 12, 1996 enhanced biological activity and reduced side effects in mice and WO 98,05338 A2 2, 1998 rats. Cancer Research, 1988, 48, pp. 4817-4822. WO 98,05338 A3 2, 1998 Su, et al., Induction of hepatic mitochondrial glycerophosphate WO 98.55074 A2 12, 1998 dehydrogenase in rats by dehydroepiandrosterone, J. Biochem, 1991, WO 99.24039 A1 5, 1999 110, pp. 207-213. WO 1999O27935 6, 1999 Anderson, R.A., et al. Steroids in the Human Newborn; Lipophilic Gel Separation and Gas Phase Analysis, J. Chromatographic Sci., vol. OTHER PUBLICATIONS 12, pp. 636-641, 1974. Araghi-Niknam et al., Modulation of immune dysfunction during Anderson, R.A., et al. Lipophilic gel and gas-phase analysis of Ste murine leukaemia retrovirus infection of old mice by roid hormones application to the human newborn, J. Chromato dehyroepiandrosterone sulphate (DHEAS), Immunology 90:344-349 graphic Sci., vol. 99, pp. 485-494, 1974. 1997. Brooks, C.J.W., et al. Thin layer and column chromatographic group Bebo et al., Androgens alter the cytokine profile and reduce separations of steroids as trimethylsilyl ethers. Isolation for GLC encephalitogenicity of myelin-reactive T cells, J. Immunol. 162:35 analysis of pregnanediol and estriol in pregnancy urine, Analytical 40 1999. Biochem, pp. 234-282, 1967. Henderson et al., Dehydroepiandrosterone and 16.alpha Casey, M.L., et al. Dehydroepiandrosterone therapeutics: Acetyla bromoepiandrosterone: Inhibitors of Epstein-Barr virus induced tion of DHA in mouse liver, J. Steroid Biochem, vol. 30, No. 1-6, pp. transformation of human lymphocytes, Carcinogenesis, 2(7):683 149-154, 1988. 686, 1981. Chambaz, E., et al. Urinary steroids in neonates: Characterization of Hernandez-Pando et al., The effects of androstenediol and four androstenestetrols by gas chromatography and mass spectrom dehydroepiandrosterone on the course and cytokine profile of tuber etry, Acad. Sc. Paris, vol. 268, Ser. D-2817-2820, 1969 (translation). culosis in BALB/c mice, Immunology 95(2):234-241 1998. Chambers, V.E.M., et al. Microbiological hydroxylation of steroids. Inserra et al., Modulation of cytokine production by Part VIII. The pattern of monohydroxylation of diketones and keto dehydroepiandrosterone(DHEA) plus melatonin (MLT) supplemen alcohols derived from 5o-androstane with cultures of the fungus, tation of old mice, Proc. Soc. Exp. Biol. Med. 218:76-82 1998. Rhizopus nigricans, J.C.S. Perkin 1, pp. 1500-1511, 1973. Kang et al., Dehydroepiandrosterone and 3-endorphin enhance IL-12 Colas, A. The 160-hydroxylation of dehydroepiandrosterone (3 B gene expression, Chem. Abstracts 126(9):99 abstract No. 113406a hydr9xy-androst-5-en-17-one) by rat-liver slices, Biochem. J., vol. 1997. 82, pp. 390-394, 1962. Kang et al., Dehydroepiandrosterone and 3-endorphin enhance IL-12 Conney, A. H., et al. Increased activity of androgen hydroxylases in gene expression, Taehan Misaengmulhak Hoechi (J Korean Soc. liver microsomes of rats pretreated with phenobarbital and other Microbiology) 31(4):399-404 1996 (translation from Korean). drugs, J. Biology. Chem, vol. 238, No. 5, pp. 1611-1617, 1963. Manz et al., Methyl 17B-Carboxyester Derivatives of Natural and Conney, A. H., et al. Drug-induced changes in Steroid metabolism, Synthetic Glucocorticoids: Correlation Between Receptor Binding Ann. N.Y. Acad. Sci., pp. 98-109. and Inhibition of in vitro Phytohaemagglutinin-Induced Lymphocyte Dobriner, K., et al. Abnormal alpha ketosteroid excretion in patients Blastogenesis, J. Clin. Chem. Clin. Biochem. 21(2):69-75 1983. with neo-plastic disease Science, vol. 99 (2581), pp. 494-496, 1944. Sigg et al., Methyl 3-O-acetoxyetien-(8:9 oder 8:14)-ate Preliminary Gardiner, Urinary steroid pattern of the human newborn infant, Communication, Helvetica Chimica Acta, 39(6): 1507-1525 1956 Biochim Biophys Acta, vol. 130, pp. 278-281, 1966. (translation from German). Gustafsson, J. A. Studies on the metabolism of Co-steroids in rat Xia, et al., Anti-AIDS agents. Part 36: 17-Carboxylated steroids as liver, 3. Isolation and biosynthesis of 5o-androstanetriols in rat liver potential anti-HIV agents, BIOORG Med. Chem 7(9): 1907-1911 microsomes, Euro. J. Biochem, vol. 6, pp. 317-324, 1968. 1999. Gustafsson, J. A., Steroids in newborns and infants. Co and C in Yang et al., Inhibition of HIV-1 latency reactivation by faeces from infants, Euro. J. Biochem, vol. 10, pp. 302-311, 1969. dehydroepiandrosterone (DHEA) and an analog of DHEA, Aids Hampl. R. et al., Minireview: 7-hydroxylated derivatives of Research and Human Retroviruses 9(8):747-7541993. dehydroepiandroseterone: What are they good for? Endocrine Regu Zhanget al., Prevention of immune dysfunction and vitamin E loss by lations, vol. 31, pp. 211-218, 1997. dehydroepiandrosterone and melatonin Supplementation during Heinrichs, W. L., et al. The selective stimulation, inhibition, and murine retroivirus infection, Immunology 96:291-297 1999. physicochemical alteration of the 7- and 16O-hydrixylases of Alasandro, M., et al., Effects of starvation and refeeding on the 33-hydroxyandrost-5-3n-17-one and drug-metabolizing enzymes in excretion of urinary steroid metabolites in mice with different genetic hepatic microsomal fractions, Biochem, vol.7.
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