ZA200306638B

ZA200306638B - Use of certain steroids for treatment of blood cell deficiencies.

Info

Publication number: ZA200306638B
Application number: ZA200306638A
Authority: ZA
Inventors: Clarence Nathaniel Ahlem; Christopher L Reading; James Martin Frincke; Dwight Stickney; Henry Lardy; Padma Marwah; Ashok Marwah; Patrick T Prendergast
Original assignee: Hollis Eden Pharmaceutical Inc
Priority date: 2001-03-01
Filing date: 2002-03-01
Publication date: 2004-08-26

Description

USE OF CERTAIN STEROIDS FOR TREATMENT OF BLOOD CELL DEFICIENCIES

: FIELD OF THE INVENTION

[0001] The invention relates to methods to make or use compounds, such as 16a- bromo-3B-hydroxy-5a-androstane-17-one (16a-bromoepiandrosterone or hereafter "BrEA”) 3,7,16,17-tetrahydroxyandrost-5-ene, 3,7,16,17-tetrahydroxyandrostane, 3,17-dihydroxy-16- haloandrostane, methyl 2,3 4-trihydroxy-1-0-(7,17-dioxoandrost-5-ene-3p-yl)--D- glucopyranosiduronate and related compounds. The invention relates to the use of compounds to treat a number of conditions, such as thrombocytopenia and neutropenia.

DESCRIPTION OF THE INVENTION

[0002] Methods to prepare dehydroepiandrosterone ("DHEA") and other steroids and their biological properties have been described, see, e.g., U.S. patent numbers 2833793, 2911418,3148198, 3471480, 3976691, 4268441,4427649, 4542129, 4666898, 4956355, 5001119,5043165, 5077284, 5028631, 5110810,5157031,5162198, 5175154, 5277907, 5292730,5296481, 5372996, 5387583, 5407684,5424463, 5461042, 5478566, 5506223, 56518725,5527788, 5527789, 5532230, 5559107, 5562910, 5583126, 5585371, 5587369, 5591736,5593981, 5610150, 5635496, 5641766,5641768, 5656621, 5660835, 5686438, 5696106,5700793, 5707983, 5709878, 5710143,5714481, 5728688, 5736537, 5744462, 5753237,5756482, 5776921, 5776923, 5780460,5795880, 5798347, 5798348, 5804576, 5807848,5807849,5811418, 5824313, 5824668,5824671,5827841, 5837269, 5837700, 5843932,5846963, 5859000, 5872114 and 5872147;German patent numbers 2035738 and 2705917; PCT publication numbers WO 95/21617, WO 97/48367, WO 98/05338, WO 98/50040, WO 98/50041, WO 98/58650; European publication number 0020029; ER. Glazier, J. Org. Chem. 1962 27:2937-2938, Ben-David, et al., Proc. Soc.

Expt. Biol. Med. 1967 125:1136-1140, Coleman et al., Diabetes 1982 31:830, Oertel, et al.,

J. Steroid Biochem. 1972 3:493-496, Pashko, et al., Carcinogenesis 1981 2:717-721,

Schwartz et al., Nutr. Cancer 1981 3:46-53; Dyner et al., J. Acquired Immune Deficiency } Syndromes 1993 6:459-465; A.A. Afanasii and Y.A. Titov, Total Steroid Synthesis, Plenum

Press, New York, 1970, see, e.g., p 1-304. . [0003] The use DHEA and other steroids in various applications have been described, e.g., U.S. patent numbers 5869090, 5863910, 5856340, 5824668, 5804576, 5753237, 5714481,5709878, 5407684, 5206008, 5077284,4978532, 4898694, 4542129,

3711606 and 3710795.U.S. patent 4956355 and PCT publication number WO 97/48367, have described the use of certain steroid compounds to treat certain virus or bacterial infections, such as human immunodeficiency virus (“HIV”) infection.

[0004] Various biological effects and/or metabolic conversions of steroid compounds . 5 have also been described, e.g., Batta et al., J. Biol. Chem. 1986 25:127-133, Belli et al.,

Liver 1991 11:162-169, Bhattacharjee et al., Anal. Biochem. 1992 201:233-236, Blake et al.,

Int. J. Peptide Protein Res. 1982 20:97-101, 1986 25:127-133, Bonaventura, Am. J. Obstet.

Gynecol. 1978 131:403-409, Bucala et al., J. Steroid Biochem. 1986 25:127-133, Carey et al., Biochem. 1981 20:3637-3648, Chen et al., Carcinogenesis 1999 20:249-254, Chen et al, Carcinogenesis 1998 19:2187-2193, Chow et al., Antisense Res. Dev. 1994 4:81-86,

Citro et al., Dis. Colon Rectum 1994 37(2 Suppl):S127-S132, Cleary, Proc. Soc. Exp. Biol.

Med. 1991 196:8-16, Cleary, Int. J. Biochem. 1990 22:205-210, Crawford et al., Lab. Invest. 1994 71:42-51, Danenberg etal., Antimicrob. Agents Chemother. 1992 36:2275-2279,

Dotzlaw et al., Cancer Res. 1999 59:529-532, Falany et al., J. Steroid Biochem. Mol. Biol. 1994 48:369-375, Faredin et al., J. Investigative Dermatol. 1969 52:357-361, Galigniana et al., Mol. Pharmacol. 1999 55:317-323, Goto et al., J. Chromatogr. 1983 276:289-300, Grenot

Biochem. 1992 31:7609-7621, Hofbauer et al., Life Sci. 1999 64:671-679, Huijghebaert et al., J. Lipid Res. 1986 27:742-752, Hurd et al., Oncogene 1999 18:1067-1072, lida et al., J.

Lipid Res. 1995 36:628-638, Jellinck et al., Steroids 1967 10:329-346, Jonsson et al., J.

Pediatr. Gastroenterol. Nutr. 1995 20:394-402, Kalimi et al, Mol. Cell. Biochem. 1994 131:99-108, Kramer et al., J. Biol. Chem. 1994 269:10621-10627, LaRochelle et al., Steroids 1984 43: 209-217, Liao et al., Carcinogenesis 1998 19:2173-2180, Lillienau etal., J. Clin.

Invest. 1992 89:420-431, Loria, Psychoneuroendocrinology 1997 22:5103-S108, Luscher et al Mol. Immunol. 1983 20:1099-1105, Manna et al., J. Biol. Chem. 1999 274:5909-5918,

Marschall et al., J. Biol. Chem. 1989 264:12989-12993, Medh et al., Cancer Res. 1998 15:3684-3693, Mohan et al., Steroids 1992 57:244-247, Munoz de Toro et al., J. Steroid

Biochem. Mol. Biol. 1998 67:333-339, Padgett et al., J. Neuroimmunol. 1998 84:61, Padgett etal, Ann. N.Y. Acad. Sci. 1995 774:323, Padgett et al., J. Immunol. 1994 153:1544-1552,

Pashko et al., Carcinogenesis 1984 5:463-466, Pashko et al., Carcinogenesis 1981 2.717,

Petrylak et al,, J. Clin. Oncology 1999 17:958-967, Podesta et al., Steroids 1996 61.622-626,

Regelson et al., Ann. N.Y. Acad. Sci. 1994 719:564, Schmassmann et al., Gastroenterology . 1993 104:1171-1181,Schmassmann et al., Hepatology 1990 11:989-996, Schreiber et al.,

Lancet 353:459-461, Schreiber, Neth. J. Med. 1998 53:524-31, Schwartz et al., Cancer Res. ] 1988 48:4817, Shahidi et al., Biochem. Biophys. Res. Commun. 1999 254559-565, Steer et al., Ann. Rheum. Dis. 1998 57:732-737, Suzuki et al., Steroids 1998 63:672-677, Suzuki et al., Steroids 1996 61:296-301, Swaan et al., Bioconjugate Chem. 1997 8:520-525, Tang et al, Anticancer Drug Res. 1998 13:815-824, Thomas et al., J. Steroid Biochem. 1986 25:103- 108, Utsumi et al., Cancer Res. 1999 59:377-381, Vanden Heuvel, J. Nutr. 1999 129(2S

Suppl.):575S-580S, Wang et al., Endocrinology 1998 139:3903-3912,Wong et al., J. Biol.

Chem. 1999 274:5443-5453, Xie et al., Endocrinology 1999 140:219-227, Yen et al., Lipids 1977 12:409-413, Zackheim et al., Arch. Dermatology 1998 134:949-954, Zhang et al.,

Biochim. Biophys. Acta 1991 1096:179-186, Zhu et al., Carcinogenesis 1988 19:2101-21 06.

[0005] Mammalian immune responses to infections or other conditions are often characterized by responses mediated by different effector cell populations. In some situations, helper T cells designated Th1 in the murine system, facilitate immune effector functions that are typically dominated by celi-mediated responses. in other cases, helper T cells designated Th2 cells facilitate immune effector functions that are typically dominated by humoral responses. A vigorous Th1 response is usually desirable to help clear infections or to slow the progression of an infection. When a subject's immune response is biased fo, or dominated by, a Th2-type response, the cytokines associated with the Th2 response tend to suppress the immune system's capacity to mount a vigorous Th1 response at the same time. The converse is also generally true. When mammalian immune responses begin to result in an increasing Th2 response, the Th1 response to the same condition tends to weaken. Insufficient Th1 responses may be associated with progression of some infections or other conditions, see, e.g., M. Clerici and G.M. Shearer, Immunol. Today 14:107-111, 1993; M. Clerici and G.M. Shearer, Immunol. Today 15:575-681, 1994. The invention provides compounds and compositions useful to enhance Th1 immune responses.

[0006] Hemopoiesis or hematopoiesis is the formation and development of the various types of blood cells and their progenitor cells. Mature cells are found in circulation or tissues such as the lymph nodes or the thymus. Many of the stem cells that give rise to mature forms reside in the bone marrow, although some may circulate in the blood for some time. Clinical blood cell deficiencies such as thrombocytopenia, neutropenia orerythropenia can arise from causes such as impaired hemopoiesis or abnormal loss or destruction of mature or immature blood cells.

[0007] Thrombocytopenia ("TP"), abnormally low platelet counts, can arise from impaired platelet production, sequestration of platelets in the spleen or abnormal loss of circulating platelets. Impaired produdion can result from causes such as chemotherapies or

A radiation therapies. Abnormal loss of circulating platelets is often associated with autoreactive antibodies that bind to platelets and reduce their life span. These underlying . causes give rise to the various clinical forms of TP, such as autoimmune neonatal TP, immune thrombocytopenic purpra, radiation induced TP, chemotherapy induced TP and amegakaryocitic TP.

[0008] A number of treatment options are available and the selection of a treatment typically depends on the source of the disorder and its severity. Treatments include } administering one or more of glucocorticoid steroids (e.g., prednisone, prednisolone), human

IgG antibodies, anti-Rh(D)" antibodies for Rh(D)" patients, an androgen such as danazol, } 5 vinca alkaloids (e.g., vincristine, vinblastine), thrombopoietin and immunosuppresants (e.g., azathioprine, cyclophosphamide). Splenectomy is also indicated, for example when first line treatments fail. The goal of treatment is typically to increase platelet counts to 20,000 mm™ or more typically to at least about 50,000 mm™ and to maintain these levels.

[0009] Although the treatment options to increase platelet levels are generally known, they usually have a number of drawbacks. For example, infusion of IgG antibodies is not always effective and the treatment is relatively expensive. Other treatments, such as prednisone are also not always effective and they typically are discontinued or tapered off after several weeks due to toxicity or unwanted side effects. Splenectomy, which is relatively expensive and invasive, is also not always effective.

[0010] The sources of thrombocytopenia and treatment options have been described. See, e.g., Hematology - Basic Principles and Practice, 3" edition, R. Hoffman,

E.J. Benz Jr. et al., editors, Churchill Livingstone, New York, 2000 (see, e.g., Chapters 126- 129 and 131 at pages 2096-2154 and 2172-2186), PCT publication WO 200035466.

[0011] Neutropenia ("NP"), is considered to exist clinically when neutrophils drop to below a level considered normal. NP can arise from impaired production of neutrophil precursors or mature neutrophils, movement of neutrophils from the circulation to tissue, abnormal circulating neutrophil loss or a combination of these causes. Impaired neutrophil production can be acquired from, e.g., treatment with a cytotoxic or cytostatic drug, chemotherapy, radiation therapy or an autoimmune response. The abnormal loss of circulating neutrophils in autoimmunity is associated with autoreactive antbodies that bind to the cells and reduce their life span. These underlying causes give rise to the various clinical forms of NP, such as postinfectious NP, drug-induced NP, autoimmune NP, or chronic idiopathic NP.

[0012] The sources of NP and treatment options have been described. See, e.g.,

Hematology - Basic Principles and Practice, 3" edition, R. Hoffman, E.J. Benz Jr. et al., editors, Churchill Livingstone, New York, 2000 (see, e.g., Chapters 19, 41, 51,79, 134 and . 137 at pages 297-331, 720-762, 939-979, 1443-1500, 2220-2248 and 2257-2263).

[0013] The use of 3p-hydroxyandrost-5-ene-17-one, 3,17 p-dihydroxyandrost-5-ene . and other steroids to modulate immune functions or to stimulate myelopoiesis has been described, see, e.g., M.-H. Whitnall et al., Int". J. Inmunopharmacology 2000 22:1-14. U.S. patents 5,162,198, 5,206,008, 5,292,730, 5,407,684, 5,461,042, 5,461,768, 5,478,566,

5,585,371, 5,635,496, 5,641,766, 5,753,237, 5,837,269, 5,885,977 and 5,919,465, PCT publication nos. W093/20696 and W099/25333. |. Porsova-Dutoit et al., Physiological Res. 2000 49 (Suppl. 1):543-S56, R.L. Jesse et al., Ann. N. Y. Acad. Sci. 1995 774:281-290 and

U.S. patent 5,532,230, 5,811,418 and 5,846,963 discuss the capacity of 33-hydroxyandrost- . 5 5-ene-17-one, its 3-sulfate derivative and other steroids to affect platelet and neutrophil aggregation or their adhesion to endothelial cells.

[0014] U.S. patents 4,908,358 and 4,902,681 describe the capacity of compounds such as 5a-pregnan-3,20-dione, cortexolone, 17-hydroxyprogesterone and 160- methylprogesterone to inhibit the clearance of antibody-coated cells from circulation in disorders such as immune thrombocytopenic purpura or immune hemolytic anemia.

[0015] U.S. patents 5,532,230, 5,686,438, 5,753,640 and 5,811,418 and J. Bratt and

M. Heimburger, Scand. J. Rheumatol. 1999 28:308-313 describe the capacity of compounds such as 3B, 7p-dihydroxyandrost-5-ene-17-one, prednisolone, and 3p-hydroxyandrost-5-ene- 17-one to limit tissue damage in ischemic tissues by inhibiting adhesion of cells such as neutrophils to endothelial cells or to treat pulmonary hypertension.

[0016] U.S. patent 5,859,000 describes the capacity of compounds such as 38,7p- dihydroxyandrost-5-ene-17-one and 3p-hydroxyandrost-5-ene-17-one to reduce mast cell mediated allergic reactions.

[0017] U.S. patent 5,763,433 and PCT publication WO 96/35428 describe the capacity of compounds related to dehydroepiandrosterone and 16a- halodehydroepiandrosterone to modulate immune responses and to treat conditions certain "immune related conditions such as systemic lupus erythematosus.

[0018] U.S. patents 5,925,630, 5,939,545 and 5,962,443 describe the capacity of 19- nur-pregnane steroids, 3a-hydroxy-5a-pregnan-20-one and related steroids to modulate certain neurological activities such as hypothalamic function and GABA receptor activity.

[0019] Some proteins such as interleukin-6 ("IL-6"), erythropoietin ("EPO") and thrombopoietin ("TPO") have been examined for their capacity to enhance various aspects hemopoiesis, e.g., Hematology - Basic Principles and Practice, 3" edition, R. Hoffman, E.J.

Benz Jr. et al., editors, Churchill Livingstone, New York, 2000 (see, e.g., Chapter 14 at pages 154-202), O.J. Borge etal., Blood 1996 88:2859-2870, M. Cremer et al., Ann.

Hematol. 1999 78:401-407, Y. Sasaki et al., Blood 1999 94:1952-1960, U.S. patent ) 5,879,673. Recombinant IL-6 was shown in model systems to affect platelet counts in peripheral circulation, e.g., Stahl et al., Blood 1991 78:1467-1475, although significant ) toxicities are associated with its administration to humans, e.g., Andus et al., FEBS Lett. 1987 221:18, J. Gauldie et al., P.N.A.S. U.S.A. 1987 84:7251-7255, T. Geiger et al., Eur. J.

Immunol. 1988 18:717-721. The IL-6 molecule has been described in detail, e.g., publication no. WO 88/00206. Administration of proteins is typically expensive, given factors such as the complexity of producing pharmaceutical grade material.

[0020] The capacity of various compounds or agents such as deuterium oxide, lithium and butyrate to affect or to participate in biological functions of cells such as neutrophils has been described. See, e.g., M.F. Tsan and RM. Turkall, Inflammation 1982 6:387-396, M. Nakamura et al., Exp. Cell Res. 1976 102:429-431, P. Blier et al., Int. Clin.

Psychopharmacol. 1998 13:137-140, N. Turkozkan et al., Int. J. Biochem. 1993 25:1501- 1504, L.V. Deriy et al., Biochem. Biophys. Res. Commun. 2000 275:241-246,M.T.

Eighetany et al., Leuk. Res. 1997 21:801-806, E. Brandt et al., J. Leukocyte Biol. 2000 68:125-130, M. Boussac and J. Garin, Electrophoresis 2000 21:665-672, M. Niwa et al., Life

Sci. 2000 18:1525-1534, DA. Moulding etal., J. Leukocyte Biol. 1999 65:875-882 and D.

Moulding et al., Biologicals 1996 24:301-306.

[0021] There is a current need for cost-effective pharmaceutical agents or treatment methods that are more effective in treating deficiencies of blood cells or reducing their symptoms. The present invention provides therapeutic agents and treatment methods to treat hemopoiesis deficiencies and disorders such as TP and NP. The agents and methods are thus useful to reduce one or more symptoms associated with any of these conditions.

Also, the use of the invention agents and methods can be combined with one or more conventional reatments for these disorders.

[0022] Summary of invention embodiments. The invention provides for the use of a compound of formula 1 to prepare a medicament for the treatment of a blood cel! deficiency in a subject wherein formula 1 has the structure

RY RS R*

R10 Re 12 S R*

R® R10 | 1a BD Re

R® “] lo R” R

RI—A2_ 4 fe 6 {20 hz R

R' wh lo R

[0023] R R 1

[0024] wherein, each R', R?, R%, R*, R®, R® and R' independently are -H, -OH, -

ORM, -SR™ -N(R™),, -0-Si-(R"),, -CHO, -CHS, -CH=NH, -CN, -SCN, -NO,, -OSO;H, -

OPO;H, an ester, a thioester, a thionoester, a phosphoester, a phosphothioester, a ] phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally } substituted heteroaryl moiety, an optionally substituted heterocycle, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonudeotide, a polymer, or,

[0025] one or more of both R?, R?, R® or R* together comprise an independenty selected spiro ring, or

[0026] one more of R', R%, R%, R*, R®, R® and R" are =0, =S, =N-OH, =CH,, or a spiro ring and the hydrogen atom or the second variable group that is bonded to the same carbon atom is absent, or,

[0027] one or more of two adjacent R'-R°® and R'° comprise an independently selected acetal, thioacetal, ketal or thioketal moiety, or

[0028] all R® and R* together comprise a structure of formula 2

R10 RS

RO R® D

R R10

R® ~ 9 R10 R

R! 2 R?

R! R10 R2

[0029] RY RY 2;

[0030] R’ is -C(R™)-, -C(R™),-C(R™),-, -C(R™)-C(R™),-C(R™)z-, -C(R™°),-O-

C(R"),-, -C(R™),-S-C(R%),-, -C(R'),-NR*R-C(R"°),-, -O-, -O-C(R")2~, -S-, -8-C(R"), -

NRPR- or -NRPR-C(R%),-;

[0031] R® and R® independentlyare -C(R").-, -C(R");-C(R")-, -O-, -0-C(R")-, -S-, -S-C(R")-, -NR"R- or NRPR-C(R™),-, or one or both of R® or R® independently are absent, leaving a 5-memberedring;

[0032] R'® independentlyis C, alkyl; -

[0033] RR independentlyis -H or a protecting group;

[0034] D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are ] 25 optionally independently substituted with -O-, -S- or -NR™- or where 1, 2 or 3 hydrogen atoms of the heterocycle or where 1, 2 or 3 hydrogen atoms of the 4-, 5-, 6- or 7-membered ) ring are substituted with -OH, -OR™, -SR™?, -N(R™®),, -0-Si~(R")s, -CHO, -CHS, -CH=NH, -

CN, -SCN, -NO,, -OS0;H, -OPOsH, an ester, a thioester, a thionoester, a phosphoester, a phosphothioester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid,

a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted heterocycle, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or,

[0035] one more of the ring carbons in D are substituted with =O, =§, =N-OH, =CH,, or a spiro ring, or

[0036] two adjacent D ring carbons comprise an independently selected acetal, thioacetai, ketai or thioketal moiety, or

[0037] D comprises two 5- or 6-membered rings, wherein the rings are fused or are linked by 1 or 2 bonds, or a metabolic precursor or a biologically active metabolite thereof. In some of these embodiments 1, 2, 3, 4 or more R' atthe 1, 4, 6, 8, 9, 12 and 14 positions are not hydrogen. in other embodiments, they are all hydrogen atoms.

[0038] The invention also provides for the use of a formula 1 compound to prepare a medicament for the treatment of a disease, condition or symptom that is caused by or associated with one or more of an autoimmune condition, an immune suppression condition, an infection, a cancer, a precancer, an inflammation condition, a neurological condition, a cardiovascular condition or a side-effect of radiation exposure or chemotherapy or a delayed adverse or unwanted effect of radiation exposure in a subject in need thereof. In some of these embodiments, the medicament is for administration to the subject or delivery to the subject's tissues beginning at least 1 day after the subject has been exposed to a dose of radiation that will cause or could potentially cause the one or more delayed adverse or unwanted effects of the radiation exposure or wherein the medicament is for administration to the subject or delivery to the subject's tissues beginning at least 1 day after the subject has been exposed to at least one subdose of a planned course of radiation exposures that will cause or could potentially cause the one or more delayed adverse effects or unwanted effects of the radiation exposure. In some of these embodiments 1, 2, 3, 4 or more R™ at the 1,4, 6, 8,9, 12 and 14 positions are not hydrogen. In other embodiments, they are all hydrogen atoms. :

[0039] Invention embodiments also provide a method to modulate an immune or : . cellular response in a subject in need thereof comprising administering to the subject, or delivering to the subject's tissues, an effective amount of a compound of formula 1

R10 5 RS

R10 R® N\ R . RS R10 HD—R3 7 7 R® p

R 2 ri R10 R2

R10 R10 1

[0040] wherein,

[0041] each R', R% R? R* R® R® and R" independently are -H, -OH, -ORR, -SR™®,

N(R™),, -0-Si-(R™)s, -CHO, -CHS, -CH=NH, -CN, -SCN, -NO,, -OS0;H, -OPO;H, an ester, a thioester, a thionoester, a phosphoester, a phosphothioester, a phosphonoester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group, a carbonate, a carbamate, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted heterocycle, an optionaly substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonudeotide, a polymer, or,

[0042] one or more of both R’, R?, R® or R* together comprise an independenty selected spiro ring, or .

[0043] one more of R', R?, R?, R*, R®, R® and R" independently are =O, =S, =N-OH, =CH,, or a spiro ring, and the hydrogen atom or the second variable group that is bonded to the same carbon atom is absent, or,

[0044] one or more of two adjacent R'-R® and R'™ comprise an independently selected acetal, thioacetal, ketal or thioketal moiety, or

[0045] all R® and R* together comprise a structure of formula 2

R10 i” r0 R° Db

R® R10 ss 7

R® Leo R

R! 2 R?

R' Y R10 R2

[0046] RY? RY 2,

[0047] R” is -C(R"),-, -C(R"%),-C(R),-, -C(R°),-C(R"*),-C(R"),~, -C(R"),-O-

C(R"),-, -G(R"),-S-C(R"),-, -C(R"),-NR™-C(R™),-, -O-, -0-C(R™),-, -S-, -S-C(R"");-, -

NRPR- or -NRPR-C(R"),-;

[0048] R® and R® independently are -C(R'),-, -C(R"),-C(R"),-, -O-, -O-C(R").~, -S-, -S-C(R").-, -NR™- or -NRPR-C(R"),~, or one or both of R® or R® independently are absent, leaving a 5-membered ring;

[0049] R™ independentlyis C.. alkyl;

[0050] RPR independentlyis -H or a protecting group;

[0051] D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are optionally independently substituted with -O-, -S- or -NR™- or where 1, 2 or 3 hydrogen atoms of the heterocycle or where 1, 2 or 3 hydrogen atoms of the 4-, 5-, 6- or 7-membered ring are independenty substituted with -OH, -OR™R, -SRPR, -N(RPR),, -O-Si-(R™),, -CHO, -

CHS, -CH=NH, -CN, -SCN, -NO,, -OS0O4H, -OPO3H, an ester, a thioester, a thionoester, a phosphoester, a phosphothioester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, an acyl group, a thioacyl group,a carbonate, a carbamate, a halogen, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl moiety, an optionally substituted heteroaryl moiety, an optionally substituted heterocycle, an optionally substituted monosaccharide, an optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or,

[0052] one more of the ring carbons in D are substituted with =O, =S, =N-OH, =CHs,, or a spiro ring, or

[0053] two adjacent D ring carbons comprise an independently selected acetal, thioacetal, ketal or thioketal moiety, or

[0054] D comprises two 5- or 6-membered rings, wherein the rings are fused or are linked by 1 or 2 bonds, or a metabolic precursor or a biologically active metabolite thereof, optionally provided that if the subject is in need of enhanced hemopoiesis, the compound is not 5-androstene-3p-ol-17-one, 5-androstene-3,17p-diol, 5-androstene-38,7p,17p-triol or a derivative of any of these three compounds that can convert to these compounds by hydrolysis. Immune and cellular response modulation includes enhancing Th1 immune - responses, reducing Th2 immune responses, reducing inflammation and enhandng hemopoiesis. These compounds are useful in treating the diseases, conditions and : symptoms described herein.

[0055] Other embodiments include a method to enhance the expression of one or more cytokines or interleukins that facilitate Th1 or Tc1 immune responses in a subject or to reduce the expression of one or more cytokines or interleukins that facilitate Th2 or Tc2 immune response in a subject comprising administering to the subject an effective amount of of a formula 1 compound, whereby the subject's Th1 or Tc1 immune response is enhanced ot the subject's undesired Th2 or Tc2 immune response is reduced.

[0056] A further embodiment is a method to modulate a subject's innate immunity,

Th1 immune responses, Tc1 immune responses, Th2 immune responses, Tc2 immune responses, or inflammation comprising administering an effective amount of a formula 1 compound to a subject or delivering the formula 1 compound to the subject's tissues.

[0057] The formula 1 compounds are useful to prepare a medicament for use in the treatment of one or more of the diseases, conditions or symptoms described herein.

[0058] Other embodiments are as described elsewhere in the specification including the numbered embodiments and the claims.

[0059] Definitions. As used herein and unless otherwise stated or implied by context, terms that are used herein have the meanings that are defined here. The descriptions of embodiments and examples that are described illustrate the invention and they are not intended to limit it in any way. Unless otherwise contraindicated or implied, e.g., by including mutually exclusive elements or options, in these definitions and throughout this specification, the terms "a" and "an" mean one or more and the term "or" means and/or.

[0060] An “invention formulation”, “formulation” or the like means a composition that one can administer to a subject, e.g., human or animal, without further manipulations that change the ingredients or the ingredient proportions that are present. Formulations are suitable for human or veterinary applications and would typically have expeded characteristics for the formulation, e.g., parenteral formulations for human use would usually be sterile.

[0061] An “invention composition”, "composition" or the like means a composition, that is a formulation or that can be an intermediate one can use to make the formulations, i.e., a change(s) in an ingredient(s) or its amount(s) may be needed to make a formulation.

Compositions may also comprise other types of materials, e.g., reagents for assays or cells that are optionally contacted with a formula 1 compound or mixtures of compounds. Thus, . invention compositions include compositions where further processing may be required before it is a formulation, e.g., mixing or addition of a desired amount of an ingredient.

[0062] Phrases such as "administration of a compound of formula 1", "treatment with aformula 1 compound" or similar terms mean that the compound(s) is administered to, or delivered to, the subject or to the subject's tissues by one or more suitable methods, e.g., by an oral, topical, parenteral, buccal or sublingual route.

[0063] Expressions such as “a formula 1 compound(s)’, “a formula 1 compound” and the like mean invention compositions or formulations where one or more than one formula 1 compound is present, e.g., in a composition, or is used in the disclosed method, typically 1, 2, 3 or 4, usually 1. Any reference to a "formula 1 compound”, "one or more compounds of formula 1" or the like means that the formula 1 compound can have the formula 2 structure or any other structure disclosed herein that is within the definition of formula 1 compounds.

[0064] Reference to subject matter "as disclosed herein” such as a "therapeutic treatment or agent as disclosed herein”, a "dosing protocol as disclosed herein” or a "clinical condition or symptom as disclosed herein" or the like means a treatment, agent, protocol, condition, symptom or the like that is described herein or in any reference that is cited herein.

[0065] An "excipient, "carrier", "pharmaceutically acceptable carrier” or similar terms mean one or more component(s) or ingredient(s) that is acceptable in the sense of being compatible with the other ingredients of invention compositions or formulations and not overly deleterious to the patient, animal, tissues or cells to which the formulation is to be administered.

[0066] As used here, “excipients” include liquids, such as benzyl benzoate, cottonseed oil, N,N-dimethylacetamide, a C,.1» alcohol (e.g., ethanol), glycerol, peanut oil, a polyethylene glycol (“PEG”), vitamin E, poppyseed oil, propylene glycol, safflower oil, sesame oil, soybean oil and vegetable oil. Any solid excipient may be a fine powder or granulated. Excipients, as used herein may optionally exclude one or more excipient, e.g., chloroform, dioxane, vegetable oil, DMSO, other excipients or any combination of these.

Excipients include one or more components typically used in the pharmaceutical formulation arts, e.g., one, two or more of fillers, binders, disintegrants, dispersants, preservatives, glidants and lubricants. Exemplary excipients include povidone, crospovidone, corn starch, carboxymethyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, gum arabic, polysorbate 80, butylparaben, propylparaben, methylparaben, BHA, EDTA, sodium lauryl sulfate, sodium chloride, potassium chloride, titanium dioxide, magnesium stearate, castor oil, olive oil, vegetable oil, buffering agents such as sodium hydroxide, monobasic . sodium phosphate, dibasic sodium phosphate, potassium hydroxide, monobasic potassium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, potassium carbonate, potassium bicarbonate, ammonium hydroxide, ammouium chloride, saccharides such as mannitol, glucose, fructose, sucrose or lactose any of which may be compressible or any of which may be spray dried.

[0067] A “subject” means a human or animal. Usually the animal is a mammal or vertebrate such as a primate, rodent, lagomorph, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g.,

Rhesus or Pan. Rodents and lagomorphs include mice, rats, woodchucks, ferrets, rabbits and hamsters. Domestic and game animals include cows, horses, pigs, sheep, deer, bison, buffalo, mink, felines, e.g., domestic cat, canines, e.g., dog, wolf and fox, avian species, e.g., chicken, turkey, emu and ostrich, and fish, e.g., trout, catfish and salmon. Subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species such as humans, primates or rodents. Other subsets of subjects include subjects of a given species or group of species of varying ages, e.g., young humans, e.g., about 1 week of age to about 9 years of age, adolescent humans, e.g., about 10-19 years of age, adult humans, e.g., about 20-100 years of age, and mature adult or elderly humans, e.g., at least about 55 years of age, at least about 60 years of age, at least about 65 years of age ora range of ages such as about 60-100 years of age. Thus, as used herein, prevention or treatment of a disease, condition or symptom may include or exclude any subset of subjects that are grouped by age.

[0068] The terms "effective amount”, "effective dose" or the like mean an amount of a formula 1 compound that is sufficient to elicit a desired response, e.g., restoration of normal immune responsiveness in an immunodeficient subject to which it is administered or to detectable modulation or amelioration of an immune or cellular parameter or a clinical condition or symptom. An effective amount may be a a single dose or two or more subdoses of a forlula 1 compound administered in one day, or it may be administered as multiple doses over a period of time, e.g., over 2 days to about 1 year.

[0069] References such as "a disease”, "a disorder”, "a condition”, "a symptom’ or "a complication” or the like mean that one or more disease, disorder, condition, symptom or complication may be treated.

[0070] Terms such as "use", "treat", "treatment", "address" or the like in the context of using the formula 1 compounds in the treatment methods or other methods disclosed herein mean that a formula 1 compound is administered to a subject, delivered to the subject's tissues or contacted with tissues, cells or cell free systems, e.g., as described herein or a reference cited herein. Typically such use or treatment results in detectable . improvement in or amelioration of the condition or symptom being treated. Such amelioration may be transient, e.g., lasting for at least a few, e.g., about 1 to 24, hours or days, e.g., about 1-,7 days, or amelioration may be prolonged, e.g., lasting about 8 to about 60 days or more, or it may be permanent. A treatment may slow the progression or severity of a disease or symptom. A use or treatment may result in detectable modulation in a relevant immune parameter such as modulation of the level or activity of a target effector or suppressor immune cell population, interleukin, cytokine, chemokine, immunoglobulin or modulation of the level or activity of a relevant transcription factor, enzyme or cell biological activity. A treatment with the compounds may be used to prevent the onset of a disease, symptom or complication or to ameliorate a preexisting disease, condition, symptom or complication, or to facilitate elimination of a disease, condition, symptom or complication.

[0071] "Ameliorate”, "amelioration", "improvement" or the like means a detectable improvement or a detectable change consistent with improvement occurs in a subject or in at least a minority of subjects, e.g., in atleast about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100% or in a range aboutbetween any two of these values. Such improvement or change may be observed in treated subjects as compared to subjects not treated with a formula 1 compound, where the untreated subjects have, or are subject to developing, the same or similar disease, condition, symptom or the like. Amelioration of a disease, condition, symptom or assay parameter may be determined subjectively or objectively, e.g., self assessment by a subject(s), by a clinician's assessment or by conducting an appropriate assay or measurement, including, €.g., a quality of life assessment, a slowed progression of a disease(s) or condition(s), a reduced severity of a disease(s) or condition(s), or a suitable assay(s) for the level or activity(ies) of a biomolecule(s), cell(s) or by detection of cell migration within a subject. Amelioration may be transient, prolonged or permanent or it may be variable atrelevanttimes during or after a formula 1 compound is administered to a subject or is used in an assay or other method described herein or a cited reference, e.g., within about 1 hour of the administration or use of a formula 1 compound to about 3, 6, 9 months or more after a subject(s) has received a formula 1 compound.

[0072] The "modulation" of, e.g., a symptom, level or biological activity of a molecule, replication of a pathogen, cellular response, cellular activity or the like, means that the cell, level or activity, or the like is detectably increased or decreased. Such increase or decrease may be observed in treated subjects as compared to subjects not treated with a formula 1 compound, where the untreated subjects have, or are subject to developing, the same or similar disease, condition, symptom or the like. Such increases or decreases may be at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, . 95%, 98%, 100%, 150%, 200%, 250%, 300%, 400%, 500% or more or about within any range about between any two of these values. Modulation may be determined subjectively or : objectively, e.g., by the subject's self assessment, by a clinician's assessment or by conducting an appropriate assay or measurement, including, e.g., quality of life assessments or suitable assays for the level or activity of molecules, cells or cell migration within a

Claims

CLAIMS What is claimed is:

1. Use of a compound to prepare a medicament for the treatment of a blood cell deficiency in a subject wherein the compound has the structure R10 5 RE R10 i. RIO R812 "\ RY \ RO R® D J R R10 14 y x J R R10 il “1 Yo go] fo RT R R® ” RY | R™ " RI—AR_ 4 Ae 6 R' AR R? R R10 R10 or R10 R10 wherein, each R', R? R? R® R°® and R" independently are -H, -OH, -ORR, - SR™, -N(R™),, =0, =8, =NOH, =CH,, -0-Si-(R"?)s, -CHO, -CHS, -CH=NH, -CN, -SCN, - NO,, -OSO;H, -OPO;H, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether, acyl group, thioacyl group, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide, a spiro ring or a polymer, or one or more of E two adjacent R'-R® and R*® comprise an independently selected acetal, thioacetal, ketal or thioketal; one R*is -OH, -OR™R, -SH, -SR™®, -0-Si-(R")s, -N(RR),, thioester, BN _ phosphoester, phosphothioester, sulfite ester, sulfate ester, thioether, carbamate, carbonate, polymer, an ether optionally selected from -OCHj3 and -OC,H;s or an ester optionally selected from -O-C(O)-CH; and -O-C(O)-C,Hs and the other R* is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, thioacyl, heterocycle, -SCN or -CN; Ris -C(R")-, -C(R"*)-C(R™)-, -C(R™)2-C(R*)-C(R™)z-, -C(R")2-O-C(R"),-, - . C(R'),-S-C(R"),-, -C(R"),-NRPR-C(R),-, -O-, -O-C(R'®),-, -S-, -S-C(R"°),-, -NR™®- or - LY NRPR-C(R"%),-; . -369- AMENDED SHEET 25.10.2004

R® and R® independently are -C(R*)-, -C(R'%),-C(R")-, -O-, -O-C(R")-, -S-, -S- C(R'%),-, -NR™R- or -NR"R-C(R").-, or one or both of R® or R® independently are absent, leaving a 5-membered ring,

R" independently is C1. alkyl;

R™ independently are -H or a protecting group;

D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are optionally independently substituted with -O-, -S- or -NR"®- or where 1, 2 or 3 hydrogen atoms of the heterocycle or where 1, 2 or 3 hydrogen atoms of the 4-, 5-, 6- or 7-membered ring are substituted with -OH, -OR™, -SR™, -N(R"®),, -O-Si-(R")s, -CHO, - CHS, -CH=NH, -CN, -SCN, -NO,, -OSO;H, -OPO;H, an ester, a thioester, a thionoester, a phosphoester, a phosphothioester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, acyl, thioacyl, carbonate, carbamate, a thioacetal, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or, one more of the ring carbons in D are substituted with =O, =S, =N-OH, =CH,, or a spiro ring, or two adjacent D ring carbons comprise an independently selected acetal, thioacetal, ketal or thioketal moiety, or D comprises two 5- or 6- membered rings, wherein the rings are fused or are linked by 1 or 2 bonds, or a metabolic precursor or a biologically active metabolite thereof, provided that 1, 2 or 3 R* atthe 1, 4, 6, 8, 9, 12 and 14 positions are not hydrogen and

(a) one R'is -OH, -OR™®, -SR™R, -N(R™),, -O-8i-(R")s, -SCN, -NO,, -OSO;H, - OPO;H, -NH-C(0)-C;. optionally substituted alkyl, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer, and the other R' is -CHO, -CHS, -CH=NH, -CN, -C(O)-NH-C,., optionally substituted alkyl, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle; or

(b) one R?is -OH, -OR™®, -SR™®, -N(R™),, -O-Si-(R"%)s, -SCN, -NO,, -OSO;H, - OPO;H, -NH-C(0)-C,.5 optionally substituted alkyl, ester, thioester, thionoester,

-370- AMENDED SHEET 25.10.2004 :

phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer, and the other R%is -CHO, -CHS, -CH=NH, -CN, -C(0)-NH-C1.50 optionally substituted alkyl, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle; or

(c) one R® is OH, -OR™®, -SR™, -N(R™),, -O-Si-(R")3, -SCN, -NO,, -OSO;H, - OPO;H, -NH-C(0O)-C +.» optionally substituted alkyl, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer, and the other Ris -H, -CHO, -CHS, -CH=NH, -CN, -C(0O)-NH-C,.,, optionally substituted alkyl, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle; or

(d) a double bond is present at the 5-6 position and optionally at the 1-2 or 16-17 positions and R® is -CHR’- where the R™ is -OH, -OR™R, -SRPR, -N(RPR),, -O-Si-(R"?),, - SCN, -NO,, -OS0O;H, -OPO;H, -NH-C(0)-C,.» optionally substituted alkyl, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer or C,.5 optionally substituted alkyl; or

(e) a double bond is present at the 5-6 position and optionally at the 1-2 or 16-17 positions and R’ is -O-, -S-, -NH-, -CHR™- where the R'is -OH, -SH, =O, =S, -CN, - SCN, -NO,, -F, -Cl, -Br, -l, ether, thioether, ester, thioester or C,» optionally substituted alkyl; or

(f) a double bond is present at the 5-6 position and optionally at the 1-2 or 16-17 positions and R® is -O-, -S-, -NH-, -CHR'’- where the R'® is -SCN, -NO,, -F or C1. optionally substituted alkyl; or

(g) a double bond is present at the 5-6 position and optionally at the 1-2 or 16-17 positions and R® is -O-, -S-, -NH-, -CHR"- where the R'® is -OH, -SH, =O, =S, -CN, - SCN, -NO,, -F, -Cl, -Br, I, ether, thioether, ester, thioester or C5, optionally substituted alkyl.

-371- AMENDED SHEET 25.10.2004

2. Use according to claim 1 wherein one or two R atthe 1, 4,6, 8,9, 12 and 14 positions independently are -OH, -OR™, =O, -SH, -SR™, -N(R™),, =S, -F, -C|, - Br, -1, C1-C8 optionally substituted alkyl, thioester, thioether, optionally substituted monosaccharide, optionally substituted oligosaccharide, amino acid, amide, carbamate, carbamate, polymer, an ether optionally selected from -OCH; and -OC.Hs, or an ester optionally selected from -O-C(O)-CH; and -O-C(O)-C,Hs.

3. Use according to claim 1 or 2 wherein (a) R* in the B-configuration is -OH, -OR™, -SH, -SR™, -O-Si-(R")s, -N(R™), thioester, phosphoester, phosphothioester, sulfite ester, sulfate ester, thioether, carbamate, amide, carbonate, polymer, an ether optionally selected from -OCH, and - OC,Hs or an ester optionally selected from -O-C(O)-CHs and -O-C(0)-C,Hs and R* in the a-configuration is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, thioacyl, -SCN or -CN; or (b) R* in the a-configuration is -OH, -ORR, -SH, -SR™, -O-Si-(R");, -N(R™),, thioester, phosphoester, phosphothioester, sulfite ester, sulfate ester, thioether, carbamate, amide, carbonate, polymer, an ether optionally selected from -OCH,; and - OCH; or an ester optionally selected from -O-C(Q)-CHj; and -O-C(0)-C;Hs and R* in the B-configuration is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, thioacyl, -SCN or -CN. 4, Use according to claim 1, 2 or 3 wherein (a) the one or two R'® at the 4, 6 and 9 positions are independently selected from -F, -Cl and -OH; or : (b) one of R', R%, R® and R* is -O-C(0)-0-C,.; optionally substituted alkyl, -O- C(O)-N-C,.2 optionally substituted alkyl, -N-C(O)-O-C;.o optionally substituted alkyl or - S-C(0)-0-C1.4 optionally substituted alkyl.

5. Use according to claim 1, 2, 3 or 4 wherein (a) one R*is -OH, -SH, - N(RFF),, ester, ether, carbonate, amino acid or carbamate and the other R* is -CHs, - C,Hs, -CCH, -CCCH,, -CH=CH, or Cs alkyl or (b) R™ at the 9-position is -F or -Cl. -372- AMENDED SHEET 25.10.2004

6. Use according to claim 1 wherein the subject has thrombocytopenia or neutropenia or the subject is susceptible to developing thrombocytopenia or neutropenia.

7. Use according to claim 1 wherein the subject's circulating platelets, red cells, myelomonocytic cells, or their precursor cells, in circulation or in tissue is detectably increased.

8. Use according to claim 7 wherein the subject's circulating neutrophils or platelets are detectably increased.

9. Use according to claim 7 wherein the subject's circulating red cells are detectably increased.

10. Use according to claim 7 wherein the subject has a cancer or precancer or wherein the blood cell deficiency is associated with radiation exposure or an immunosuppressive chemotherapy wherein the immunosuppressive chemotherapy optionally is a cancer chemotherapy or a glucocorticoid therapy.

11. Use according to claim 7 wherein the subject is has renal failure.

12. Use according to any preceding claim wherein the subject is a human or a primate.

13. A compound of formula V Rs Riz SA: Rg . R AN Ry2 J RY ALC RA

R, . Nl PZ NT X g -373- AMENDED SHEET 25.10.2004 or a pharmaceutically acceptable salt, ester, amide, prodrug or analog wherein, the dotted lines are single or double bonds, X is oxygen, sulfur, =CH, or =NOH, one of Ry and R; is -H and the other is a glucuronide having the formula Ry 0) TL Re” Ripa wherein R; is an alkyl ester wherein the alkyl moiety is optionally substituted, and Rs, Ry and Roa independently are -ORy,, where Ry, is H, a protecting group or optionally substituted alkyl; Rs and Rs independently or together are -H, -OH, -OR™, =0, -SH, =S, -SR™, ester, thioester, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or optionally substituted alkyl; R™ is -C(R")-, -C(R")-C(R")-, -C(R™)-C(R™),-C(R*)z-, -C(R"*)-O-C(R")-, - C(R"%),-S-C(R"),-, -C(R"),-NR™-C(R"),-, -O-, -O-C(R").-, -S-, -S-C(R®),-, -NR"*- or - NRPR-C(R"),~; R® and R* independently are -C(R'%),-, -C(R'%),-C(R""),-, -O-, -O-C(R"),-, -S-, - S-C(R™),-, -NR™- or -NR™-C(R),-, or one or both of R* or R* independently are absent, leaving a 5-membered ring; each R'® independently is -H, -OH, -OR™:, -SR™, -N(R™),, -0-Si-(R"®)5, -CHO, - CHS, -CH=NH, -CN, -SCN, -NO,, -OSO3H, -OPOsH, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether, acyl group, thioacyl group, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer;

R.. and Ry; independently are -H, -OH, -OR™ or optionally substituted alkyl; and R™ independently are -H or a protecting group, wherein the compound is optionally substituted at one or two of the 1-, 4-, 6-, 8-, 9-, 12- and 14-positions with an independently selected moiety selected from -OH, - ORR, -SR™, -N(R"®),, -O-Si-(R™)s, -CHO, -CHS, -CH=NH, -CN, -SCN, -NO,, -OSO;H, - OPO3H, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, -374- AMENDED SHEET 25.10.2004 phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether, acyl group, thioacyl group, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, nucleoside, nucleotide, oligonucleotide and polymer.

14. The compound of claim 13, wherein Ry, is an ester or wherein a double bond is present at the 4-5 position or at the 16-17 position.

15. The compound of claim 13 or 14, wherein (a) Ry, is -H and Ry; is -CH; or -C;Hs, (b) one or two of the 1-, 4-, 6-, 8-, 12- and 14-positions is substituted, (c) the 9- position is substituted, optionally wherein the substituent at the 9-position is -F, -Cl, -OH or C4.50 optionally substituted alkyl or (d) a double bond is present at the 5-6 position or at the 1-2 and 5-6 positions.

16. A formulation comprising a compound of claim 13, 14 or 15 and one or more excipients.

17. A compound of formula VII Ryz 3s 8A WRg R \ Riz y ROAT RA R;,0 7 Pa tl Ry VII or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein the dotted lines are optional double bonds; one of R; and R, is -H and the other is a glucuronide group having the formula -375- AMENDED SHEET 25.10.2004

. R; 0 ra Ry Rioa :

R; is an alkyl ester wherein the alkyl moiety is optionally substituted;

Rs, Rg and R404 independently are -OR44, where Ry, is -H, a protecting group or optionally substituted alkyl;

Rs and Rs independently or together are -H, -OH, -OR™, =0, -SH, -SR™, =S, ester, thioester, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or optionally substituted alkyl;

Ry, is -H or a protecting group;

R™ is -C(R")z-, -C(R")-C(R™)-, -C(R™)-C(R™),-C(R")2-, -C(R')-O-C(R"™).-, - C(R"),-S-C(R"),-, -C(R"),-NR™-C(R"),-, -O-, -O-C(R®),-, -S-~, -S-C(R"’),-, -NR™- or - NRPR-C(R'),-;

R% and R*! independently are -C(R'®),-, -C(R"*),-C(R®).-, -O-, -O-C(R")-, -S-, - S-C(R"),-, -NR"?- or -NRPR-C(R"),-, or one or both of R* or R* independently are absent, leaving a 5-membered ring;

each R' independently is -H, -OH, -ORR, -SRPR, -NH,, -NHRR, -N(R™®),, -O-Si- (R™)s, -CHO, -CHS, -CH=NH, -CN, -SCN, -NO,, -OSO;H, -OPO:H, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether, acyl group, thioacyl group, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer;

R,2 and Ry; independently are -H, -OH, -OR™ or optionally substituted alkyl; and

RR independently are -H or a protecting group,

wherein the compound is optionally substituted at one or two of the 1-, 4-, 6-, 8-, 9-, 12- and 14-positions with an independently selected moiety selected from -OH, - OR™, -SR™, -N(R™),, -0-Si-(R")s, -CHO, -CHS, -CH=NH, -CN, -SCN, -NO,, -OSO;H, - OPO3H, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether,

-376- AMENDED SHEET 25.10.2004 acyl group, thioacyl group, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, nucleoside, nucleotide, ~ oligonucleotide and polymer.

18. The compound of Claim 17, wherein one of R; and R, is a hydrogen atom and the other one of R, and R; is the glucuronide.

19. The compound of Claim 17 or 18, wherein one of Rs and Rg is a -H or optionally substituted alkyl and the other one of Rs and Rs is an ester optionally selected from acetoxy and propionoxy.

20. The compound of Claim 17, 18 or 19, wherein Ry is -H or -CHs and Ry; is -CHj; or -C,Hs.

21. The compound of claim 17 wherein (i) the compound is methyl-2,3,4-tri-O-acetyl-1-O-(3p,17p-diacetoxyandrost-5- ene-7p-yl)-B-D-gluco-pyranosiduronate, methyl 1-O-(3p,17p-diacetoxyandrost-5-ene-7f3- yl)-B-D-gluco-pyranosiduronate or methyl-2,3,4-tri-O-acetyl-1 -O-(3p-acetoxy-1 7- oxoandrost-5-ene-7a-yl)-p-D-glucopyranosiduronate, or a pharmaceutically acceptable salt, ester, ether, amide, or prodrug thereof, or (ii) one or two of the 1-, 4-, 6-, 8-, 12- and 14-positions is substituted, or (iii) the 9-position is substituted, optionally wherein the substituent at the 9- position is -F, -Cl, -OH or C,.o, optionally substituted alkyl, or (iv) a double bond is present at the 5-6 position or at the 1-2 and 5-6 positions, or (v) Riz is -H and Ry3 is -CH; or -C,Hs.

23. A compound of formula IX -377- AMENDED SHEET 25.10.2004

Riz 3s REA Na Riz p : ROA? z R7A Rr ~ 2 tl R; FY %s x or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, :

wherein one of R, and R; is -H and the other is -O-C(0)-OR,4, where Ry, is -H, a protecting group or optionally substituted alkyl;

one of Rs, and Rs is -H or optionally substituted alkyl and the other is -OH, -OR™%, =Q, -SH, =S, -SRR, ester, thioester, ether, thioether, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide;

R,, and R; independently or together are -H, -OH, -OR™, =0, -SH, =8S, -SR™}, ester, thioester, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or optionally substituted alkyl;

R™ is -C(R")-, -C(R"),-C(R"),-, -C(R"*),-C(R"%)-C(R"°),-, -C(R"%),-O-C(R"),-, - C(R"%),-S-C(R"),-, -C(R"*),-NR"R-C(R?),-, -O-, -O-C(R"?),-, -S-, -S-C(R"%),-, -NR™R- or - N RPR-C(R").~;

R® and R*! independently are -C(R'®),-, -C(R"),-C(R"’),-, -O-, -O-C(R"),-, -S-, - S-C(R™),-, -NR™- or -NRPR-C(R"°),-, or one or both of R® or R® independently are absent, leaving a 5-membered ring;

each R" independently is -H, -OH, -OR™®, -SRPR, -NH,, -NHR®, -N(R™?),, -O-Si- (R™)s, -CHO, -CHS, -CH=NH, -CN, -SCN, -NO,, -OSO;H, -OPO;H, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether, acyl group, thioacyl group, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, - optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer;

Rs, and R,; independently are -H, -OH, -OR™R, -SH, -SRR or optionally substituted alkyl;

R™ independently are -H or a protecting group,

-378- AMENDED SHEET 25.10.2004 wherein the compound is (i) substituted at one or two of the 1-, 4-, 6-, 8-, 9-, 12- and 14-positions with an independently selected moiety selected from -OH, -ORR, - SR™, -N(R™R),, -0-Si-(R"™)s, -CHO, -CHS, -CH=NH, -CN, -SCN, -NO,, -OSO3H, - OPOsH, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether, acyl group, thioacyl group, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, nucleoside, nucleotide, oligonucleotide and polymer, (ii) a double bond is present at the 16-17 position or (iii) the compound is 3B-carbomethoxyandrost-5-ene-7,17-dione, 3B-carboallyloxyandrost-5- ene-7,17-dione, 3p-carboethoxyandrost-5-ene-7,17-dione, 3B-carboisobutoxyandrost-5- ene-7,17-dione, 3B,17B-dicaromethoxyandrost-5-ene-7-one, 3f3-carbooctyloxyandrost-5- ene-7,17-dione, 3B-carbo(9-fluorenyl)methoxyandrost-5-ene-7,17-dione, 3B- carbomethoxyandrost-5-ene-7,17-diol, 3-carboethoxyandrost-5-ene-78,178-diol, 3- carbooctyloxyandrost-5-ene-7,17B-diol or a pharmaceutically acceptable salt, ester, ether, amide, or prodrug of any of these compounds.

24. The compound of claim 23, wherein Ry, is an ester.

25. The compound of claim 23 or 24, wherein one of R; and R; is a hydrogen atom and the other one of Ry and R; is -O-C(O)-OR 4.

26. The compound of claim 24 or 25, wherein Ry, is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, n- octyl, n-dodecyl, 1-ethoxyethyl, 9-fluorenylmethyl, -CH,-C(O)CH; and -C(O)CHs.

27. The compound of claim 23 or 24, wherein Rs and Rs independently or together are -H, -OH, =O, -O-C(0)-OCHs, -O-C(0)-OC;Hs, -0-C(0)-OC3H;, -O-C(O)- OC Hs, -O-C(0)-OCH,C,H3, -O-C(O)-OCH,C3H; or -O-C(0)-O-(CH,),-0-C.Hs.

28. The compound of claim 23 or 24, wherein R;; is -H and R,; is -CHj3 or - C,Hs. -379- : AMENDED SHEET 25.10.2004

29. The compound of claim 23 selected from the group consisting of 3p- carbomethoxyandrost-5-ene-7,17-dione, 3p-carboallyloxyandrost-5-ene-7,17-dione, 3f- carboethoxyandrost-5-ene-7,17-dione, 3B-carboisobutoxyandrost-5-ene-7,17-dione, 3B,17B-dicaromethoxyandrost-5-ene-7-one, 38-carbooctyloxyandrost-5-ene-7,17-dione, 3B-carbo(9-fluorenyl)methoxyandrost-5-ene-7,17-dione, 3p-carbomethoxyandrost-5-ene- 7,17B-diol, 3B-carboethoxyandrost-5-ene-78,17B-diol, and 3B-carbooctyloxyandrost-5- ene-7B,17B-diol, or a pharmaceutically acceptable salt, ester, ether, amide, or prodrug thereof.

30. A formulation comprising a compound of claim 17, 18, 19, 23, 24, 25, 26, 27, 28 or 29 and one or more excipients.

31. Use of a compound according to claim 1, 2, 3, 4, 17, 23 or 29 to prepare a medicament for the treatment of a disease, condition or symptom that is caused by or associated with one or more of an autoimmune condition, an immune suppression condition, an infection, a cancer, a precancer, an inflammation condition, a neurological : condition, a cardiovascular condition, a pulmonary condition or a side-effect of radiation exposure or chemotherapy or a delayed adverse or unwanted effect of radiation exposure in a subject in need thereof, wherein for treatment of the delayed adverse effect of radiation exposure, the medicament is for administration to the subject or delivery to the subject's tissues beginning at least 1 day after the subject has been exposed to a dose of radiation that will cause or could potentially cause the one or more delayed adverse or unwanted effects of the radiation exposure or wherein the medicament is for administration to the subject or delivery to the subject's tissues beginning at least 1 day after the subject has been exposed to at least one subdose of a planned course of radiation exposures that will cause or could potentially cause the one or more delayed adverse effects or unwanted effects of the radiation exposure.

32. Use according to claim 31 wherein the subject has, or is subject to developing, a delayed adverse or unwanted effect of radiation exposure, and wherein the subject has received or will receive a total radiation dose of at least about 0.5 Gy to about 300 Gy, at least about Gy 1 to about 200 Gy or at least about Gy 2 to about 150 -380- : AMENDED SHEET 25.10.2004

Gy, wherein the subject received the radiation dose in a single dose or in two or more divided doses.

33. Use according to claim 32 wherein the symptom or condition associated with one or more delayed adverse effect of radiation is one or more of encephalopathy, myelopathy, nausea, vomiting, diarrhea, acute inflammation, chronic inflammation, edema, pain, headache, depression, fever, malaise, weakness, hair loss, skin atrophy, skin ulceration, skin lesion, keratosis, telangiectasia, infection, hypoplasia, atrophy, fibrosis, fibrosing alveolitis, pneumonitis, bone marrow hypoplasia or hemorrhage.

34. Use according to claim 33 wherein the symptom or condition associated with one or more delayed adverse or unwanted effect of the radiation exposure is caused by or associated with radiation damage to one or more of bone marrow cells, bowel epithelium, bone marrow, testicles, ovaries, brain nerves or tissue, peripheral nerves, spinal cord nerves or tissue or skin epithelium.

35. Use according to claim 31 wherein the subject has, or is subject to developing, an autoimmune, allergy or inflammatory condition, optionally selected from multiple sclerosis, systemic lupus erythematosus, chronic asthma, acute asthma, Crohn's disease, ulcerative colitis, osteoarthritis, rheumatoid arthritis, psoriatic arthritis or psoriasis.

36. Use according to claim 31 wherein the subject has, or is subject to ~ developing, an infection optionally selected from a DNA virus infection, an RNA virus infection, a fungal infection, a bacterial infection or a parasite infection.

37. Use according to claim 31 wherein the subject has, or is subject to developing, a neurological condition optionally selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, insomnia, migraine headache, epilepsy, schizophrenia, depression or memory impairment.

38. Use according to claim 31 wherein the subject has, or is subject to developing, a cardiovascular or metabolic condition optionally selected from congestive cardiomyopathy, hypertrophic cardiomyopathy, myocardial fibrosis, an aneurysm, an -381- AMENDED SHEET 25.10.2004 arterial occlusive disease, atherosclerosis, arteriosclerosis, thrombosis, cerebral infarction, obesity, type | diabetes, type | diabetes, hypertension, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or impaired fatty acid metabolism.

39. Use according to claim 31 wherein the subject has, or is subject to developing, a cancer, a precancer or a hyperproliferation condition optionally selected from breast cancer, lung cancer, colon cancer, prostate cancer, myelodysplastic syndrome, actinic keratosis, leiomyoma, fibromyoma, benign or precancerous intestinal or bowel polyps or benign prostatic hyperplasia.

40. Use according to claim 31 wherein the subject has, or is subject to developing, a pulmonary disorder optionally selected from chronic bronchitis, lung fibrosis, right ventricular hypertrophy, pulmonary hypertension, emphysema, asthma or a chronic obstructive pulmonary disease.

44. Use of a compound of claim 17 or 23 for the preparation of a medicament. 45, Use of a compound for the preparation of a medicament, wherein the compound has the structure RY 0s Re | RY os 4 RT R812 \ R , RT R® D R R [4 J R R R10 : <a R’ R ze’ 7 R**1 Yo RO | R© R® R10 R R! 3 4_ A. 6 R’ LZ R? 1 J R? 1 YY 2 / R10 R2 R R10 R R R10 R10 or R10 R10 wherein, R' independently or together are -H, -OH, -OR™, -SR™, -N(R™),, =0, =S, =N- OH, =CH,, -O-Si-(R")s, -CHO, -CHS, -CH=NH, -CN, -SCN, -NO,, -OSO3H, -OPO;H, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether, acyl group, thioacyl group, carbonate, carbamate, halogen, optionally substituted alkyl, -382- AMENDED SHEET 25.10.2004 optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide, a polymer or a spiro ring;

each R%, R?, R®, R® and R' independently or together are -H, -OH, -OR™, -SRP}, -N(R™),, =0, =8, =N-OH, =CH,, -0-Si-(R");, -CHO, -CHS, -CH=NH, -CN, -SCN, -NO,, - OSO;H, -OPO;H, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether, acyl group, thioacyl group, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide, a polymer, a spiro ring or,

one or more of two adjacent R'-R® and R'® comprise an independently selected acetal, thioacetal, ketal or thioketal moiety, or

R* independently or together are -OH, -OR™R, -SR™, -N(R™),, =S, =N-OH, =CH,, -0-Si-(R™);, “CHO, -CHS, -CH=NH, -CN, -SCN, -NO,, -OSOH, -OPO;H, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether, acyl group, thioacyl group, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide, a polymer or a spiro ring;

Ris -C(R"%),-, -C(R'%),-C(R®).-, ~C(R")-C(R'®),-C(R"),-, -C(R"),-O-C(R"®),-, - C(R"),-S-C(R"),-, -C(R"),-NR™-C(R"),-, -O-, -O-C(R"),-, -S-, -S-C(R'®),-, -NR™R- or - NR™R-C(R"),-;

R® and R® independently are -C(R'),-, -C(R'%),-C(R"°),-, -O-, -O-C(R"),-, -S-, -S- C(R"),-, -NR™R- or -NRPR-C(R"),-, or one or both of R® or R® independently are absent, leaving a 5-membered ring;

R" independently is C,.; alkyl;

R™ independently are -H or a protecting group;

D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring

-383- AMENDED SHEET 25.10.2004 are optionally independently substituted with -O-, -S- or -NR"R- or where 1, 2 or 3 hydrogen atoms of the heterocycle or where 1, 2 or 3 hydrogen atoms of the 4-, 5-, 6- or 7-membered ring are substituted with -OH, -OR™, -SRPR, -N(R™®),, -O-Si-(R"),, -CHO, - CHS, -CH=NH, -CN, -SCN, -NO,, -OSO3H, -OPO3H, =0, =S, =N-OH, =CH,, a spiro ring, an ester, a thioester, a thionoester, a phosphoester, a phosphothioester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, acyl, thioacyl, carbonate, carbamate, a thioacetal, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or,

two adjacent D ring carbons comprise an independently selected acetal, thioacetal, ketal or thioketal moiety, or D comprises two 5- or 6-membered rings, wherein the rings are fused or are linked by 1 or 2 bonds, or a metabolic precursor or a biologically active metabolite thereof, provided that 1,2 or 3 RY atthe 1, 4, 6, 8, 9, 12 and 14 positions are not hydrogen and one or more of the following structural features are present:

(a) one R'is -OH, -ORR, -SR™, -N(R™),, -O-Si-(R"®)3, -SCN, -NO,, -OSO;H, - OPOzH, -NH-C(0)-C,.5, optionally substituted alkyl, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer, and the other R' is

-CHO, -CHS, -CH=NH, -CN, -C(0)-NH-C;._, optionally substituted alkyl, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

- (b)R" are -H and one each of R?, R® and R* independently are -OH, -OR™, - SR™, -N(R™),, -O-Si-(R™)s, -NO,, -OSO;H, -OPO;H, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether, acyl group, thioacyl group, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer,

-384- AMENDED SHEET 25.10.2004

(c) one R? is -OH, -OR™, -SR™, -N(R™®),, -O-Si-(R*)s, -SCN, -NO,, -OSO;H, - OPO;H, -NH-C(0)-C,.5 optionally substituted alkyl, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer, and the other R?is -CHO, -CHS, -CH=NH, -CN, -C(O)-NH-C,., optionally substituted alkyl, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, (d) one R¥is -OH, -OR"®, -SR™®, -N(R™®),, -O-Si-(R™)s, -SCN, -NO,, -OSO;H, - OPO;H, -NH-C(0)-C,.5, optionally substituted alkyl, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer, and the other R® is -CHO, -CHS, -CH=NH, -CN, -C(O)-NH-C,.,, optionally substituted alkyl, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, or ‘ (e) a double bond is present at the 16-17 position.

46. A formulation comprising one or more excipients and a compound of claim 45, wherein the formulation optionally is a sterile parenteral liquid formulation, an oral formulation, a buccal formulation, a sublingual formulation or an aerosol formulation.

47. Use of a compound for the preparation of a medicament, wherein the compound has the structure R10 5 RY R10 i. RO RE 12 \ R* ; RO R8 D J R R10 14 b x J R R10 ; RO%1 lio R" R RO = Lio R R—A_4 Re. 6 R’ 2 R? r lio Y L2 RP 1 YY S10 2 R' R10 R R10 R or R R10 R R10 R -385- AMENDED SHEET 25.10.2004 wherein,

each R', R% R?, R* R® R® and R" independently or together are -H, -OH, -OR™, -SRPR, -N(R™),, -N3, =0, =8, =N-OH, =CH,, -O-Si-(R");, -CHO, -CHS, -CH=NH, -CN, - SCN, -NO,, -OSO;H, -OPO3H, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amide, amino acid, peptide, ether, thioether, acyl group, thioacy! group, carbonate, carbamate, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide, a polymer, a spiro ring or, one or more of two adjacent R'-R® and R'® comprise an independently selected acetal, thioacetal, ketal or thioketal moiety, or

Ris -C(R")z-, -C(R")2-C(R"),-, -C(R™),-C(R")2-C(R""), -C(R"),-0-C(R")-, - C(R"),-S-C(R"%),-, -C(R"*)-NR"?-C(R")-, -O-, -O-C(R'%),-, -S-, -S-C(R"),-, -NR™- or - NRPR-C(R),-;

R® and R? independently are -C(R"),-, -C(R),-C(R™),-, -O-, -O-C(R"%),-, -S-, -S- C(R").-, -NRPR- or -NR"R-C(R"°),-, or one or both of R® or R® independently are absent, leaving a 5-membered ring;

R" independently is C1. alkyl;

R™ independently is -H or a protecting group;

D is a heterocycle or a 4-, 5-, 6- or 7-membered ring that comprises saturated carbon atoms, wherein 1, 2 or 3 ring carbon atoms of the 4-, 5-, 6- or 7-membered ring are optionally independently substituted with -O-, -S- or -NR™®- or where 1, 2 or 3 hydrogen atoms of the heterocycle or where 1, 2 or 3 hydrogen atoms of the 4-, 5-, 6- or 7-membered ring are substituted with -OH, -OR™, -SR™, -N(R™),, -N3, -O-Si-(R")s, - CHO, -CHS, -CH=NH, -CN, -SCN, -NO,, -OSO3H, -OPO3H, =O, =S, =N-OH, =CH,, a spiro ring, an ester, a thioester, a thionoester, a phosphoester, a phosphothioester, a phosphiniester, a sulfite ester, a sulfate ester, an amide, an amino acid, a peptide, an ether, a thioether, acyl, thioacyl, carbonate, carbamate, a thioacetal, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted monosaccharide, optionally substituted oligosaccharide, a nucleoside, a nucleotide, an oligonucleotide or a polymer, or, two adjacent D ring carbons comprise an independently selected acetal, thioacetal, ketal or thioketal moiety,

-386- AMENDED SHEET 25.10.2004 or D comprises two 5- or 6-membered rings, wherein the rings are fused or are linked by 1 or 2 bonds, or a metabolic precursor ora biologically active metabolite thereof, provided that 1, 2 or 3 R" at the 1, 4, 6, 8, 9, 12 and 14 positions are not hydrogen and one or more of the following structural features are present:

(a) R™ at the 1-position is -OH, -OR™, =0, -SH, -SR™, =8, -N(R™),, -N3, =NOH, -0-Si-(R")s, -SCN, -NO,, -OSO3H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, halogen, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, and one R* is or both R* independently are a halogen, -SH, -SR™, =S, -SCN, thioether, -S-C(O)-optionally substituted alkyl, -N(R™),, -N3, =NOH, -NO,, -NH-C(O)-optionally substituted alkyl or - NH-C(O)-O-optionally substituted alkyl; or (b) R™ at the 1-position is -OH, -OR™, =0, -SH, -SR™, =S, -N(R™®),, -N3, =NOH, -0-Si-(R"®)s, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, halogen, ester,

~ thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester,

sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, and one R? is or both R? independently are -SH, -SRPR, =S, -SCN, thioether, -S-C(O)-optionally substituted alkyl, - N(R™®),, -N3, =NOH, -NO,, -NH-C(O)-optionally substituted alkyl or -NH-C(O)-O- optionally substituted alkyl; or

(c) R" at the 1-position is -OH, -OR™, =0, -SH, -SR™, =S, -N(R™),, -N;, =NOH, -0-8i-(R"),, -SCN, -NO,, -OSO;H, -OPO3H, -CHO, -CHS, -CH=NH, -CN, halogen, ester,

: thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, substituted . alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, and -387- . AMENDED SHEET 25.10.2004 one RZ is or both R? independently are -OH, -OR™, =O, -SH, -SR™®, =S, - N(RR),, -N3, =NOH, -O-Si~(R")3, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, ~ phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer, and one R®is or both R® independently are -OH, -OR™, =0, -SH, -SRR, =§, - N(R), -N3, =NOH, -O-Si-(R")s, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted oligosaccharide or a polymer, and one R* is or both R* independently are -OH, -OR™®, =O, -SH, -SR™®, =§, - N(R"®),, -N5, =NOH, -O-Si-(R*);, -SCN, -NO,, -OSO;H, -OPO;H, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer; or (d) R™ at the 1-position is -OH, -ORFR, =0, -SH, -SR™, =, -N(R™),, -N3, =NOH, : -0-Si-(R")3, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, -Cl, -Br, -I, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, and one R®is or both R® independently are -OH, -OR™R, =O, -SH, -SR™®, =§, - N(R™®),, -N3, =NOH, -O-Si~(R"®)5, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, substituted monosaccharide, optionally substituted oligosaccharide or a polymer, one R*is or both R* independently are -OH, -OR™, =O, -SH, -SRR, =S, - N(R™),, -N3, =NOH, -O-Si-(R"),, -SCN, -NO,, -OSO3H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, -388- AMENDED SHEET 25.10.2004 phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide or a polymer; and

R® is -O-, -S-, -NH-, -CHSH-, -CHSR™:-, -C(S)-, -CHN(R™),-, -CHN;-, ~-C(NOH)-, -CH(O-Si-(R")3)-, -CH(SCN)-, -CH(NO,)-, -CH(OSO;H)-, -CH(OPO;H)-, -CH(CHO), - CH(CHS), -CH(CH=NH})-, -CH(CN)-, -CH(thioester)-, -CH(thionoester)-, - CH(phosphoester)-, -CH(phosphothioester)-, -CH(phosphonoester)-, - CH(phosphiniester)-, -CH(sulfite ester), -CH(sulfate ester)-, -CH(amino acid)-, - CH(peptide)-, -CH(thioether)-, -CH(N-C(O)-O-optionally substituted alkyl)-, -CH(N-C(O)- O-optionally substituted alkenyl)-, -CH(N-C(O)-O-optionally substituted alkynyl)-, - CH(optionally substituted monosaccharide)-, -CH(optionally substituted oligosaccharide)-, -CH(polymer)-; -C(R"),-C(R")-, -O-C(R")-, -S-C(R").-, -NR""- C(R").-, or R® is absent, leaving a 5-membered ring;

(e) R™ at the 6-position is -OH, -OR™, =0, -SH, -SR™, =S, -N(R™),, -N3, =NOH, -0-Si-(R")s, -SCN, -NO,, -OSO3H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, halogen, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

one Ris or both R® independently are -SH, -SR™, =S, -NHR™, -N;, =NOH, - SCN, -NO,, -NH-C(O)-optionally substituted alkyl or -NH-C(O)-O-optionally substituted alkyl, thioether, and one R* is or both R* independently are -OH, -OR™?, =0, -SH, -SR™, =§, - N(R™),, -N3, =NOH, -O-8i-(R"™)s, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH,

-CN, halogen, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl or optionally substituted heteroaryl; or

(f) R" at the 6-position is -H, -OH, -OR™, =0, -SH, -SR™®, =8, -N(R™®),, -N3, =NOH, -O-Si-(R")3, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, halogen, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester,

-389- AMENDED SHEET 25.10.2004 phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

one R' is or both R' independently are -OH, -OR™®, -SH, -SR™, =8, -N(R™),, - Ns, =NOH, -O-Si-(R")s, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, halogen, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, and one R? is or both R? independently are -SH, -SR™, =S, -NHR™, -Nj, =NOH, - SCN, -NO,, -NH-C(O)-optionally substituted alkyl or -NH-C(O)-O-optionally substituted alkyl, thioether, and one R* is or both R* independently are -OH, -OR™, =O, -SH, -SR™, =S, - N(RPR),, -N3, =NOH, -0-Si-(R")5, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, halogen, ester, thioester, thionoester, phosphoester, phosphothioester, . phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle; or

(9) R™ at the 6-position is -OH, -OR™, =0, -SH, -SRR, =S, -N(R™®),, -N;, =NOH, -0-Si-(R™);, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, halogen, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, and R’ is -O-, -NR™®-, -S-, -C(R"%),-C(R"),-, -C(R").-C(R"®),-C(R"%),-, -C(R'%),-O- C(R"),-, -C(R"),-S-C(R"),-, -C(R"*),-NR™-C(R°),-, -O-C(R"%),-, -S-C(R"),- or -NRR- C(R")-;

-390- AMENDED SHEET 25.10.2004

(h) R™ at the 6-position is -OH, -OR™?, =0, -SH, -SR™;, =S, -N(R™),, -N3, =NOH, -0-Si-(R")3, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, -F, -Br, -I, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, and Ris -O-, -NR™., -8-, -C(R"%),-C(R"),-, -O-C(R%),-, -S-C(R").-, -NR™R-C(R"°),- or R® is absent, leaving a 5-membered ring; or

(i) R" at the 6-position is -OH, -OR™, =0, -SH, -SR™, =S, -N(R™),, -N3, =NOH, - O-Si-(R"®)3, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, -F, -Br, -I,

ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, and R® is -NR™®-, -S-, -C(R"),-C(R"°),-, -O-C(R")z-, -S-C(R"),-, -NR™-C(R"),- or R® is absent, leaving a 5-membered ring; or

(i) R' at the 6-position is -OH, -OR™, =0, -SH, -SR™}, =S, -N(RPR),, -N;, =NOH, - O-Si-(R™)s, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, -F, -Br, I, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

one R'is or both R' independently are -OH, -ORPR, -SH, -SRR, =§, -N(R),, - Ns, =NOH, -0-Si-(R")s, -SCN, -NO,, -OSO;H, -OPO;H, -CHO, -CHS, -CH=NH, -CN, halogen, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, and

R® is -O-; or

-391- AMENDED SHEET 25.10.2004

(k) R' at the 12-position is -OH, -OR™®, =0, -SH, -SR™R, =S, - N(RPR),, -N3, =NOH, -0-Si-(R")s, -SCN, -NO,, -0SO3H, -OPO;H, -CHO, - CHS, -CH=NH, -CN, halogen, ester, thioester, thionoester, phosphoester, phosphothioester, phosphonoester, phosphiniester, sulfite ester, sulfate ester, amino acid, peptide, amide, ether, thioether, carbonate, carbamate, optionally substituted monosaccharide, optionally substituted oligosaccharide, a polymer, acyl, thioacyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle, and one R? is or both R? independently are -SH, -SR™, =S, -N(R™),, - N3, =NOH, -0O-Si-(R"%)3, -SCN, -NO,, -S-C(O)-optionally substituted alkyl, thioether, -N-C(O)-optionally substituted alkyl or -N-C(O)-O-optionally substituted alkyl, or one R® is or both R® independently are -SH, -SR™, =S, -N(RPR),, - Na, =NOH, -O-Si-(R"®)s, -SCN, -NO, -S-C(O)-optionally substituted alkyl, thioether, -N-C(O)-optionally substituted alkyl or -N-C(O)-O-optionally substituted alkyl, or one R* is or both R* independently are -SH, -SR™, =S, -N(RPR),, -Ns, =NOH, -0-Si-(R")3, -SCN, -NO,, -S-C(O)-optionally substituted alkyl, thioether, - N-C(O)-optionally substituted alkyl or -N-C(O)-O-optionally substituted alkyl.

48. A formulation comprising one or more excipients and a compound of claim } 47, wherein the formulation optionally is a sterile parenteral liquid formulation, an oral formulation, a buccal formulation, a sublingual formulation or an aerosol formulation. -392- AMENDED SHEET 25.10.2004