OA11715A - Use of 17-ketosteroid compounds and derivatives, metabolites and precursors thereof in the treatmentof malaria and the treatment of African and American trypanosomiasis. - Google Patents

Abstract

The invention provides the use of 17-ketosteroid compounds, as well as derivatives, metabolites and precursors of such compounds, and pharmaceutically acceptable salts of any of these compounds, collectively defined herein as the "compounds of the present invention", in the treatment of malaria, African Trypanosomiasis and American Trypanosomiasis, or to ameliorate or reduce one or more symptoms associated with a Plasmodium or Trypanosoma infection. The present invention is further directed to the use of such compounds in the treatment or prevention of one or more kind of parasites and/or one or more diseases caused by such parasites, against one or more kind of Mycoplasma and/or one or more diseases caused by such Mycoplasmas and/or against one or more of the following indications or infections: (a) hairy Leukoplakia, (b) oral candidosis, (c) mouth ulcerations-aphthous/herpetic/bacterial, (d) fungal candida, (e) human papilloma virus, (f) molluscum contagiosum, (g) squamous oral carcinoma, (h) Kaposi's sarcoma oral lesions, (i) periodontitis, (j) necrotizing gingivitis, (k) orafacial herpes zoster, and (1) rotaviruses, as well as all other indications and infections. The compounds of the present invention may also be used to ameliorate or reduce one or more symptoms associated with any infection or condition disclosed herein.

Description

11715

USE OF 17-KETOSTEROID COMPOUNDS AND DERIVATIVES, METABOLITES ANDPRECURSORS THEREOF IN THE TREATMENT OF MALARIA' AND THE

TREATMENT OF AFRICAN AND AMERICAN TRYPANOSOMIASIS

5 BACKGROUND OF THE INVENTION

The présent invention is directed to the use of 17-ketosteroid compounds, as well as dérivatives, métabolites and precursors of such compounds, and pharmaceutically acceptable saltsof any of these compounds, collectively defined herein as the "compounds of the présentinvention", optionally together with one or more additional administration and/or treatment (as 10 described below) in the treatment of malaria, African Trypanosomiasis and American

Trypanosomiasis. The présent invention is further directed to the use of such compounds (andcombinations) in the treatment of one or more kind of parasites and/or one or more diSeases causedby such parasites, against one or more kind of Mycoplasma and/or one or more diseases caused bysuch Mycoplasmas and/or against one or more of the following indications or infections: (a) hairy 15 Leukoplakia, (b) oral candidosis, (c) mouth ulcerations-aphthous/herpetic/bacterial, (d) fungal candida, (e) human papilloma virus, (f) molluscum contagiosum, (g) squamous oral carcinoma, (h)Kaposi's sarcoma oral lésions, (i) periodontitis, (j) necrotizing gingivitis, (k) orafacial herpeszoster, and (1) rotaviruses, as well as ail other indications and infections disclosed in U.S. PatentNo. 5,292,725, the entire disclosure of which is hereby incorporated by reference, (in particular, 20 the disclosure from column 1, line 13 through column 4, line 25).

In the case of malaria, infection of man occurs by mosquito bites, during which “sporozoites" are introduced into the human bloodstream. Sporozoites travel through thebloodstream, and eventually reach and penetrate parenchymal cells of the liver (sporozoites canremain in the blood for up to 1 hour). 25 The preerythrocytic cycle, the first cycle of growth and reproduction, lasts about one week and takes place in the liver. The preerythrocytic cycle libérâtes several thousand merozoites, whichthen pass into the blood.

The merozoites parasitize érythrocytes. Growth and reproduction take place in red blood cells,bringing about rhythmic fever attacks and other symptoms as the number of parasites in the blood 30 increases. In the course of the erythrocytic growth cycle, upon entering a red cell, the parasite assumes a ring form with a central vacuole. After about 6 hours, the vacuole gradually disappears as the parasite increases in size until it nearly fills the red cell. During the last 12 hours of the growth cycle, nuclear fission occurs from which, on average, about sixteen merozoites are formed.

The growing parasite is termed a trophozoite and, after nuclear fission has started, it is called a 35 schizont. . \v 1 11715

The malaria parasite feeds on hemoglobin, utilizing the protein portion of the molécule andleaving the heme portion, which accumulâtes to form malarial pigment. It has beén shown by EMthat the parasite feeds by phagocytosis, engulfing red cell cytoplasm; digestion takes place in foodvacuoles, where the pigment accumulâtes until it is released into the plasma when the host cell 5 ruptures and the merozoites escape. Shortly after the parasite has started reproducing in the blood,the sexual forms or gamétocytes begin to appear in the red cells; Gamétocytes may survive forseveral days in the mammalian hosf but they cannot develop further unless they are ingested by asuitable mosquito host. The single nucléus of the gamétocyte distinguishes it ffom the fully-grownasexual forms. 10 Sleeping sickness is caused by T. gambiense and T. rhodesiense and is transmitted ffom man to man or ffom animais to man by tsetse flies (Glossina). In the mammalian host, theorganisms inhabit the blood but may penetrate other organs where they occur in intercêllularspaces. In a drop of blood, the trypanosomes appear as minute, wriggling objects.

When a tsetse fly feeds, its toothed proboscis tears the skin, causing a small hemorrhage to 15 form. If trypanosomes are présent, they are sucked into the gut of the fly with the blood drawn up ffom this pool. For the fïrst few days after an infective feed, the trypanosomes are found in themidgut. Then sonie travel forwards to the proventriculus. For development to be successful, somemust pass right forward to near the tip of the proboscis where the opening of the salivary duct islocated. They must then pass up the duct to the salivary glands where forms develop which are 20 infective to the mammal. These are called metacyclic trypanosomes because they appear at the endof the developmental cycle. Reproduction takes place at ail sites in the fly. The time required forthis cycle is 2-3 weeks or even longer. Not only do the trypanosomes alter in morphology in theinsect host, but they also differ physiologically ffom the blood stream forms.

If a tsetse fly harboring a mature infection bites man, metacyclic trypanosomes may be 25 injected along with saliva. In the early stages of an infection, the parasites may be found in theblood. A characteristic feature is that the number of trypanosomes builds up to a peak and thendéclinés, and these cycles are repeated. The trypanosomes stimulate the host to produce antibody,which agglutinâtes and lyses the organisms. Some of the trypanosomes become résistant toantibody and so a new population develops cf different antigenic type; these flourish until spécifie 30 antibody is again formed to destroy them. At later stages of the infection, the trypanosomes become scarce or absent from the blood but invade the central nervous System to cause sleepingsickness.

Trypanosomes can establish and develop in a wide range of mammalian species, and hâvebeen isolated ffom many species of African game animais. In these hosts, the association seems to 35 be a benign one and the mammal remains in good healtft. But the same trypanosomes in man or in 1 2 ' 11716 man's domestic animais are highly pa'thogenic. Trypanosomiasis of domestic animais is an urgentproblem in large areas of Africa where stock cannot be reared because of the presence of tsetseflies and game animais.

Chagas disease (American Trypanosomiasis) is caused by T cruzi. It is transmitted by5 blood-feeding insects ofthe family Triatomidae.

After infection in man, the parasite soon leaves the blood and settles in tïssues, mostfrequently in cardiac, striated or smooth muscle. Here they lose their flagella and round up. Next,they multiply and clusters of several hundred cells may be formed, displacing muscle fibers. Aftera time, the colony starts to disperse; the cells elongate, each develops a flagellum and the new 10 trypanosomes enter the circulation. The trypanosomes remain in the circulation for several daysand then agairi dtsappear into the tissues to undergo another reproductive cycle. In chronicinfections, the tissue phase prédominâtes, since the blood forms can rarely be detectefl.

If an insect feeds on blood containing trypanosomes, these trypanosomes becomeestablished first in the midgut. In the midgut, the trypanosomes multiply rapidly and within a few 15 days some pass into the hindgut and infective forms begin to appear in the feces. In contrast to theAfrican trypanosomes, where the infective forms are situated anteriorly in the vector and areintroduced into man by inoculation, the infective forms of T. cruzi are located atthe posterior endofthe vector's gut and infection is by contamination. Triatomid insects ingest a large amount ofblood relative to their body weight and the ingested blood is concentrated by fluid excrétion while 20 the insect feeds. In this way, infective trypanosomes are deposited on the skin of the host. Thetrypanosomes cannot penetrate unbroken skin but may gain entry through the puncture wound.Since the insects are noctumal and feed in the facial areas, the trypanosomes are commonlysmeared into eyes, mouth or nose where they penetrate mucous membranes. T. cruzi develops in several species of insects, ail ofwhich fonction as hosts. Iften insects 25 were allowed to feed on an infected person, ail ten would probably become infected. Laboratoryreared or "clean" insects are often used in diagnosis. T. cruzi has been found in many species ofwild animais and in reduviid insects in Centraland South America and in some ofthe Southern States of the USA. Human infection in the USA israre, but in parts of Central and South America, the incidence of infection in man may be as high 30 as 20 per cent. It has been established that some 3-5 million people are at risk to the infection. The infection may be spread from man to man or from animais to man. Domestic dogs and cats are réservoirs in urban areas. Drugs that are effective against the African trypanosomes hâve no action on human infections with T. cruzi-, no curative drugs hâve yet been discovered that combat this

parasite. V 3 Î17Î5 A number of steroid compounds and their uses hâve been described. See, e.g., U.S. patentnumbers 4956355, 5859000, 4268441, 4666898, 5837269, 5827841, 5811418, 5824313, 5686438,5635496, 5587369, 5583126, 5562910, 5532230, 5518725, 5736537, 5843932, 5837700, 5824671, 5807849, 5798347, 5780460, 5776923, 5728688, 5610150, 5593981, 5372996, 5110810, 5807848, 5 5707983, 5641766, 5585371, 5506223, 5424463, 5296481, 5292730, 5776921, 5641768, 5559107, 5478566, 5461042, 5407684, 5387583, 5277907, 5206008, 5077284, 5162198, 5660835, 5527789, 5756482, 5709878, 5804576, 5744462, 5714481, 5700793, 5696106, 5656621, 5175154, 5157031,

5028631, 5001 1 19, 4898694, 5824668, 5710143, 5795880, 5527788, 5591736, 5861390 and PCTpublication numbers WO 98/05338, WO 95/21617, WO 98/50040, WO 98/50041 and WO 10 97/48367, ali of which are incorporated herein by reference. A number of flavonoids, methods to obtain them and their uses hâve been described. See, e.g., J.A. Manthey and B.S. Buslig, editors, Flavonoids in the living System, Advances~inexperimental medicine and biology, volume 439, Plénum Press, New York, 1998, chapter 15(pages 191-225), chapter 16 (pages 227-235) and chapter 17 (pages 237-247), which are 15 incorporated herein by reference.

SUMMARY OF THE INVENTION

In accordance with one aspect of the présent invention, it now has been discovered thatsurprisingly, Trypanosome parasites, e.g., the malaria parasites, may be treated with compounds(or pharmaceutically acceptable salts thereoi) of the following formula 1

wherein

Ql is-C(Ri)2-or-C(O)-; Q2 is -C(R!)2-, -C(R!)(Y)-, -C(Y)- or -CH2-CH2-; Q3 is -H or-C(Ri)3-; Q4 is -C(Ri)2-, -C(O)-, hydroxyvinylidine (-CH(CH=CHOH)-) or methyl methylene (-CH'(CH)3-); 4 10 11715 Q5 is-C(Rj)2- or-C(O)-; X and Y independently are -OH, -H, Iower alkyl (e.g., Cj.g alkyl), -O-C(0)-R5,-C(0)-OR5, halogen (i.e., -F, -Cl, -Br or -I) or =O; each Rj independently is -H, -F, -Cl, -Br, -I, -OH, Cj.g alkoxy, or Cj.g alkyl; R2 is -H, -OH, -F, -Cl, -Br, -I, Cj.g alkyl, Cj.g alkoxy, -OR3, an ester (e.g., -O-C(O)-R4 or -Ç(O)-O-R4), a thioester (e.g., -O-C(S)-R4 or -C(S)-O-R4), a thioacetal (e.g., -S-C(O)-R4, or -C(O)-S-R4), a sulfate ester (e.g., -O-S(O)(O)-O-R4), a sulfonate ester (e.g., -O-S(O)-O-R4) or acarbamate (e.g., -0-C(O)-NH-R4 or -NH-C(O)-O-R4) or r2» together with the Rj that is bonded tothe same carbon atom is =0; R3 is -S(0)(O)-OM, -S(O)(O)-O-CH2-CH(O-C(O)-R6)-CH2-O-C(O)-R6,-P(O)(O)-O-CH2-CH(O-C(O)-R7)-CH2-O-C(O)-R7, a glucuronide group of structure (A)

15 20 25 30 or R3 is C1 _ J 8 alkyl, C2-I8 alkenyl, C2-I8 alkynyl, a C;.;8 ester or a Ci_j g thioester, where anyof the foregoing C1 _ j 8 or C2-I8 moieties are optionally substïtuted at one or more hydrogen atomswith one or more independently selected -ORPr, (including -OH), -NHRPr, (including -NH2) or -SRPr, (including -SH) groups, orR3 is a Ci_i8 fatty acid, C2-10 alkynyl, (J)n-phenyI-Ci_5-alkyl,(J)n-phenyI-C2-5-alkenyl; R4 is -H, a protecting group, optionally substituted C [. 1 g alkyl, optionally substïtuted Cp18 alkenyl, optionally substituted C1 _j g alkynyl, optionally substituted aryl, optionally substitutedæyl-Çi-ô alkyl, optionally substituted aryl-C2-6 alkenyl, optionally substituted ary!-C2_6 alkynyl,optionally substituted heterocycle-C ι_β alkyl, optionally substituted C2-6 alkenyl-heterocycle,optionally substituted C2-6 alkynyl-hieterocycle or an optionally substituted heterocycle, where anyof the foregoing moieties are optionally substituted at one, two, three, four, five or more carbon orhydrogen atoms with one or more independently selected -O-, -S-, -NR^R- (including -ΝΉ-), -NH-C(O)-, -ORPr (including -OH), -NHRPR (including -NH2), -SRPr (including -SH), =O, =S, =N-OH, -CN, -NO2, -F, -Cl, -Br or -I groups or atoms; each R5 independently is straight or branched C 14 alkyl;each Rg independently is straight or branched Cj.]4 alkyl; each R7 independently is straight or branched C ]. ] 4 alkyl or a glucuronide group ofstructure (A); each RPr independently is -H or an independently selected protecting group;nisO, 1,2 or 3; 5 11715 each J independently is -F, -Cl, -Br, -I, Cj_4 alkyl, C]_4 alkenyl, Cj.4 alkoxy, carboxy,nitro, sulfate, sulfonyl, a Cj-g carboxyl ester or a Cj.g sulfate ester; M is hydrogen, sodium, -S(0)(0)-0-CH2-CH(0-C(0)-Rô)-CH2-0-C(0)-Rô, -P(O)(O)-O-CH2-CH(O-C(O)-R.7)-CH2-O-C(O)-R7 or a glucuronide group of structure (A); 5 the dotted lines in formula 1 represent an optional double bond, provided that there are not double bonds at both the 4-5 and 5-6 positions and provided that when a double bond is présent,zéro or 1 Rj group is bonded to carbon atoms at the 1-, 2-, 4-, 5-, 6- or 17 positions so that thesecarbon atoms are tetravalent; and the salts, stereoisomers, positional isomers, métabolites, analogs, precursors, hydrates, 10 tautomers, ionized forms and solvatés thereof. The formula 1 compounds are collectively referredherein to as the “compounds of the invention” or the “compounds of the présent invention”.

In addition, as discussed above, the présent invention is directed to the treatmént ofsleeping sickness and the treatment of Chagas disease by administering one or more of thecompounds of the présent invention. Also, the présent invention relates to the use of the 15 compounds of the présent invention in the treatment of one or more kind of parasites and/or one ormore diseases caused by such parasites, against one or more kind of Mycoplasma and/or one ormore diseases caused by such Mycoptasmas and/or against one or more of the followingindications or infections: (a) hairy Leukoplakia, (b) oral candidosis, (c) mouth ulcérations(aphthous/herpetic/bacterial), (d) fungal candida, (e) human papilloma virus, (f) molluscum 20 contagiosum, (g) squamous oral carcinoma, (h) Kaposi's sarcoma oral lésions, (i) periodontitis, (j)necrotizing gingivitis, (k) orafacial herpes zoster, and (1) rotaviruses, as well as ail otherindications and infections disclosed in U.S. Patent No. 5,292,725, which is incorporated herein byreference.

Accordingly, the présent invention provides a method for treating these parasitic infections 25 which comprises administering to an afflicted host a therapeutically effective amount of acompound (or a pharmaceutically acceptable sait thereof) having the structure of Formula 1(defmed above), as well as dérivatives, métabolites, and precursors thereof, as defîned herein.

The présent invention is further directed to a method for treating any of the conditionsdescribed herein by administering a compound that inhibits glucose-ôphosphate dehydrogenase. 30 Another invention embodiment comprises a method to treat or pîevent a Trypanosome or

Plasmodium infection comprising administering to a subject a compound of the invention simultaneously or sequentially with a compound of formula 2A or 2B 1 \JL— 6 11715

wherein a double or a single bond is présent at the dotted line and, when a double bond is présent, 5 (i) the optionally substituted phenyl ring at the 2- or 3-position is présent and the Rg that is bonded to the carbon is absent, and (iî) one Rg at the adjacent 2- or 3-position is absent;

Xl is-O-or-C(Rg)2-; X2is-C(O)-or-C(R11)2-; each Rg independently is -H, -OH, halogen, Cj.g alkyl, Ομβ alkoxy, glucuronide, a1 θ C1-25 fhtty acid, the residue of a formula 2A or 2B compound where a hydrogen atom is removed to form the formula 2A or 2B compound radical, -CH2CH=C(CH3)2, glucoside, a group havingstructure (B) or (C),

RlO is Ci_g alkyl, Ομ^ alkoxy, neohesperidoside, apioglucoside, rutinoside, glucoside,galactoside, rhamnoside, arabinoside, or a stereoisomer, hydrate, analog, dérivative or métaboliteof any of these moieties, any of which are optionally independently substituted at one or morehydrogen atoms with -OH, halogen, Cj.g alkyl, Cj-6 alkoxy, glucuronide or a Ομ25 fatty acid orRlO is -H, -OH or halogen;

7 11715 each R] i independently is -H, -OH, halogen, Cj_g aikyl, Cj_6 alkoxy, glucuronide, a Cj.25 fatty acid, or both Rj j together are =0; and the salts, stereoisomers, positional isomers, métabolites, analogs, precursors, hydrates,tautomers, ionized forms and solvatés thereof.

5 DETAILED DESCRIPTION OF THE INVENTION

As used herein and unless otherwise stated or implied by context, the following ternis hâve the meanings defined here. A “patient” or “subject” means a human or animal, Usually the animal is a vertebrate suchas a primate, rodent, domestic animal or game animal. Primates include chimpanzees, 10 cynomologous monkeys, spider monkeys, and macaques, e.g., Rhésus. Rodents include mice, rats,woodchucks, ferrets, rabbits and hamsters. Domestic and game animais include cows, horses, pigs,deer, bison, buffalo, felines, e.g., domestic cat, canines, e.g., dog, avians, e.g., chicken^ emu,ostrich, and fish, e.g., trout, catfish and salmon. Patient or subject includes any subset of theforegoing, e.g., ail of the above, but excluding one or more groups or species such as humans, 15 primates or rodents. “Aikyl” as used herein, unless stated to the contrary, is a Ci-Cj 8 hydrocarbon containing1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 î, 12, 13, 14, 15, 16, 17 or 18 carbon atoms in the form of normal,secondary, tertiary, cyclic or mixed structures. Examples are -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, - 20 CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH3, -CH(CH2CH3)2, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, -CH2CH2CH(CH3)2, -CH2CH(CH3)CH2CH3, -CH2C(CH3)3, -CH2CH2CH2CH2CH2CH3, -CH(CH3)CH2CH2CH2CH3, -CH(CH2CH3)(CH2CH2CH3), -C(CH3)2CH2CH2CH3, -CH(CH3)CH(CH3)CH2CH3, -CH(CH3)CH2CH(CH3)2, -C(CH3)(CH2CH3)2, -CH(CH2CH3)CH(CH3)2, -C(CH3)2CH(CH3)2, -CH(CH3)C(CH3)3, 25 cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclobutylmethyl, 1-cyclopropyl-l-ethyl,2-cyclopropyl-l-ethyl, cyclohexyl, cyclopentylmethyl, 1-cyclobutyl-1-ethyl, 2-cyclobutyl-l-ethyI, 1-cyclopropyl-1-propyl, 2-cyclopropyl-l-propyl, 3-cyclopropyl-l-propyI, 2-cyclopropyl-2-propyl,and l-cyclopropyl-2'propyl.. “Alkenyl” as used herein, unless stated todhe contrary, is C2-Cj8 hydrocarbon comprising 30 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms in the form of normal, secondary, tertiary, cyclic or mixed structures and comprising 1, 2, 3 or more double bondsbetween adjacent carbon atoms. Examples are -CH=CH2, -CH=CHCH3, -CH2CH=CH2> -C(=CH2)(CH3), -CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=C(CH3)2j -CH2C(=CH2)(CH3), -C(=CH2)CH2CH3, -C(CH3)=CHCH3, -CH(CH3)CH=CH2, -

8

C=CHCH2CH2CH3, -CHCH-CHCH2CH3, -CHCH2CH=CHCH3, -CHCH2CH2CH=CH2, -C(=CH2)CH2CH2CH3, -C(CH3)=CH2CH2CH3, -CH(CH3)CH=CHCH3, - CH(CH3)CH2CH=CH2,-CH2CH=C(CH3)2, 1-cyclopent-l-enyI, l-cydopent-2-enyl, 1-cyclopent-3-enyI, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, and l-cyclohex-3-enyl. “Alkynyl” as used herein, unless stated to the contrary, is Cn-Cis hydrocarbon comprising1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms in the form of normal, secondary, tertiary, cyclic or mixed structures and comprising 1, 2, 3 or more triple bonds betweenadjacent carbon atoms. Examples are -CCH, -CCCH3, -CH2CCH, -CCCH2CH3, -CH2CCCH3, -CH2CH2CCH, -CH(CH3)CCH, -CCCH2CH2CH3, -CH2CCCH2CH3, -CH2CH2CCCH3 and - 10 CH2CH2CH2CCH. “Halogen” or “halo” means fluorine (-F), chlorine (-Cl), bromine (-Br) or iodine (-1) and ïfmore than one halogen is referred to (e.g., two or more variable groups may be a halogen), eachhalogen is independently selected. 15 “Steroid nucléus” means 4 fused rings having the formula 1 structure. “PEG” means an ethylene glycol polymer that contains about 20 to about 2000000 linked monomers, typically about 50-1000 linked monomers, usually about 100-300. Polyethylencglycols include PEGs containing various numbers of linked monomers, e.g., PEG20, PEG30,PEG40, PEG60, PEG80, PEG100, PEG115, PEG 200, PEG 300, PEG400, PEG500, PEG600, PEG1000, PEG1500, PEG2000, PEG 3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000, 20 PEG11000, PEG12000, PEG2000000 and any mixtures thereof.

An "excipient" or a “carrier” means a component or an ingrédient that is acceptable in thesense of being compatible with the other ingrédients of compositions or formulations as disclosedherein and not overly deleterious to the patient or animal to which the formulation is to beadministered. As used here, excipients and carriers include liquids, including benzyl benzoate, 25 cottonseed oil, Ν,Ν-dimethylacetamide, a C2-12 alcohol (e.g., éthanol), glycerol, peanut oïl, aPEG, vitamin E, poppyseed oil, propylene glycol, safflower oil, sesame oil, soybean oil andvegetable oil. Excipients, as used herein may exclude solvents such as chloroform, dioxane orDMSO. Excipients comprise one or more components typically used in the pharmaceuticalformulation arts, e.g., fillers, binders, disintegrants and lubricants. 30 Unless otherwise specified, expressions that refer to “a formula 1 compound(s)”, a “compound of the invention”, a “formula 2A or 2B compound”, a “plasma concentration- enhanching compound” and the like mean compositions or methods, e.g., methods to treat a

infection as disclosed herein, where one or more than one formula 1 or formula 2A or 2B compound is présent, typically 1, 2, 3 or 4, usually 1. 1 9

“Alcohol” as used herein, includes excipients, means an alcohoi that comprises a ϋμ 12alkyl moiety substituted at one or more hydrogen atoms with one or more hydroxyl groups, usually one, two or three. Alcohols include, e.g., éthanol, n-propanol, /-propanol, π-butanol, /-butanol, r-butanol, /-butanol, n-pentanol, z-pentanol, π-hexanol, cyclohexanol, n-heptanol, n-octanol, n- 5 nonanol, n-decanol and benzyl alcohol. The carbon atoms in alcohols can be straight, branched orcyclic. Alcohol includes any subset of the foregoïng, e.g., C2.4 alcohols (alcohols having 2, 3 or 4carbon atoms). “Ester” means a moiety that comprises a -C(O)-O- structure. Typically, esters as used herecomprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) 10 and 0 to about 10 independently selected heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucléus at R^ through the -C(O)-O- structure, e.g., organicmoiety-C(O)-O-steroid or organic moiety-0-C(0)-steroid. The organic moiety usually comprisesone or more of any of the organic groups described above, e.g., Cj_20 alkyl moieties, C2-20alkenyl moieties, C2-2O alkynyl moieties, aryl moieties, C2-9 heterocycles or substituted15 dérivatives of any of these, e.g., comprising 1, 2, 3, 4 or more substituents, where each substituentis independently chosen. Typical substitutions for hydrogen or carbon atoms in these organicgToups include 1, 2, 3, 4 or more, usually 1, 2, or 3 -O-, -S-, -NRPR- (including -ΝΉ-), -C(O)-, =O,=S, -N(RPR)2 (including -NH2), -C(O)ORPR (including -C(O)OH), -OC(O)RPR (including -O-C(O)-H), -ORPR (including -OH), -SRPR (including -SH), -NO2, -CN, -NHC(O)-, -C(O)NH-, -20 OC(O)-, -C(O)O-, -O-A8, -S-A8, -C(O)-A8, -OC(O)-A8, -C(O)O-A8, =N-, -N=, =N-OH, - OPO3(RPP-)2, -OSO3H2 or halogen moieties or atoms, where each RPR is -H, an independentlyselected protecting group or both RPR· together comprise a protecting group, and A8 is ϋμβ alkyl,C2-8 alkenyl, C2-8 alkynyl, Cj_4 alkyl-aryl (e.g., benzyl), aryl (e.g. phenyl) or CQ.4 alkyl-C2-9heterocycle. Substitutions are independently chosen. The organic moiety includes compounds25 defined by the R4 variable. The organic moieties exclude obviously unstable moieties, e.g., -O-O-,except where such unstable moieties are transient species that one can use to make a compoundwith sufïïcient Chemical stability for the one or more of the uses described herein. Thesubstitutions listed above are typically substituents that one can use to replace one or more carbonatoms, e.g., -O- or -C(O)-, or one or more hydrogen atom, e.g., halogen, -NH2 or -OH. 30 “Thioester” means a moiety that comprises a -C(S)-O- structure. Typically, thioesters as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbonatoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to aformula 1 steroid nucléus at R^ through the -C(S)-O- structure, e.g., organic moiety-C(S)-0-steroidor organic moiety-O-C(S)-steroid. The organic moiety usually comprises one or more of any of35 the organic groups described above, e.g., C1.20 alkyl moieties, C2-20 alkenyl moieties, C2-20alkynyl moieties, aryl moieties, C2-9 heterocycles or substituted dérivatives of any of these, e.g.,comprising 1, 2, 3, 4 or more substituents, where each substituent is independently chosen.

Typical substitutions for hydrogen or carbon atoms in these organic groups include 1, 2, 3, 4 or t 10 10 15 20 25 30 117151171g more, usually 1, 2, or 3 -O-, -S-, -NR.PR- (including -NH-), -C(O)-, =O, =S, -N(RPR)2 (including -NH2), -C(O)ORPR (including -C(O)OH), -OC(O)rPR (including -O-C(O)-H), -ORPR (including -OH), -SRPR (including -SH), -NO2, -CN, -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -O-A8, -S-A8, -C(O)-A8, -OC(O)-A8, -C(O)O-A8, =N-, -N=, =N-OH, -OPO3(RPR)2, -OSO3H2 or halogenmoieties or atoms, where each RPR is -H, an independently selected protecting group or both rPR-together comprise a protecting group, and A8 is Cj.8 alkyl, C2.g alkenyl, C2_g alkynyl, Cj_4alkyl-aryl (e.g., benzyl), aryl (e.g. phenyl) or Co-4 alkyl-C2_9 heterocycle. Substitutions areindependently chosen. The organic moiety includes compounds defîned by the R4 variable. Theorganic moieties exclude obviously unstable moieties, e.g., -O-O-, except where such unstablemoieties are transient species that one can use to make a compound with sufficient Chemicalstability for the one or more of the uses described herein. The substitutions listed above aretypicaliy substituents that one can use to replace one or more carbon atoms, e.g., -O- or -C(O)-, orone or more hydrogen atom, e.g., halogen, -NH2 or -OH. “Thioacetal” means a moiety that comprises a -C(O)-S- structure. Typicaliy, thioacetals asused here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbonatoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety is bonded to aformula 1 steroid nucléus at R2 through the -C(O)-S- structure, e.g., organic moiety-C(O)-S-steroidor organic moiety-S-C(O)-steroid. The organic moiety is as described above for thioesters. “Carbamate” means an organic moiety as described for ester that comprises 1, 2, 3, 4 ormore -O-C(O)NRPP- structures where RPR is -H, a protecting group or an organic moiety asdescribed for ester. Typicaliy, carbamate groups as used here comprise an organic moietycontaining about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0 to about 10 heteroatoms(e.g., O, S, N, P, Si), where the organic moiety is bonded to a formula 1 steroid nucléus at R2through the -O-C(O)-NRPR- structure, e.g., organic moïety-NRPR-C(O)-O-steroid or organicmoiety-O-C(O)-NRPR-steroid. The organic moiety is as described above for thioesters. “Sulfate ester” means a moiety that comprises a -0-S(O)(O)-O- structure. Typicaliy,sulfate esters as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g.,about 2-12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organicmoiety is bonded to a formula 1 steroid nucléus at R2 through the -O-S(O)(O)-O- structure, e.g.,organic moiety-Ô-S(O)(O)-O-steroid. The organic moiety is as described above for thioesters. “Sulfite ester” means a moiety that comprises a -O-S(O)-O- structure. Typicaliy, sulfiteesters as used here comprise an organic moiety containing about 1-50 carbon atoms (e.g., about 2-12 carbon atoms) and 0 to about 10 heteroatoms (e.g., O, S, N, P, Si), where the organic moiety isbonded to a formula 1 steroid nucléus at R2 through the -0-S(0)-0- structure, e.g., organic moiety-O-S(O)-O-steroid. The organic moiety is as described above for thioesters.

The compositions disclosed herein optionally comprise salts of the formula 1 and 2 compounds that comprise an ionizable moiety or a polar moiety. As used herein, “salts” includecomplexes that comprise moieties of opposite charge. Ionizable moieties include -O-S(0)(O)-OHor a -NH2 group at R2 and polar moieties include -OH. Salts include pharmaceutically acceptable 35

11 10 15 20

H salts that comprise, for example, an uncharged moiety or a monovalent anion moiety or amonovalent cation moiety. Salts include compounds derived by combination of appropriate anionssuch as înorganic acids. Suitable acids include those having sufficient acidity to form a stable sait,preferably acids of low toxicity. For example, one may form invention salts from acid addition ofcertain înorganic acids, e.g., HF, HCl, HBr, HT, H2SO4> ΗβΡΟζ}, to basic centers, typically amines that may be présent in formula 1, 2A or 2B compounds. Or one may use certain organic acids, e.g.,organic sulfonic acids, organic carboxylic acids in the same manner. Exemplary organic sulfonicacids include Cg.]g aryl sulfonic acids, C6-16 heteroaryl sulfonic acids and Cj.jζ alkyl sulfonicacids such as phenyl, α-naphthyl, (3-naphthyl, (5)-camphor, methyl, ethyl, n-propyl, i-propyl, n-butyl, r-butyl, i-butyl, f-butyl, pentyl and hexyl sulfonic acids. Exemplary organic carboxylicacids include Ci _16 alkyl, Οβ-ΐβ aryl carboxylic acids and C4.I6 heteroaryl carboxylic acids suchas acetic, glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric, fumaric, succinic, malic,maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic and 2-phenoxybenzoic. Salts also include the invention compound salts with one or more amino acids.Many amino acids are suitable, especially the naturally occurring amino acids found as proteincomponents, although the amino acid typically is one bearing a side chain with a basic or acidicgroup, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine,alanine, isoleucine, or leucine. Salts are usually biologically compatible or pharmaceuticallyacceptable or non-toxic, particularly for mammalian cells. Salts that are biologically toxic aregenerally used as synthetic intermediates for making other invention compounds.

The neohesperidosïde, rutinoside and glucoside groups hâve the structures

OU , respectively wherein one or more of the hydrogen atoms are optionally independently substituted with hydroxy,haiogen, Cj.g alkyl, alkoxy, glucuronide or a Cj_25 fatty acid.

Heterocvcle. “Heterocycle” or “heterocyclic” inciudes by way of example and notlimitation these heterocycles described in Paquette, Léo A.; "Principles of Modem HeterocyclicChemistry" (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The 25 12 10 15 20 25 30 35 715

Chemistry of Heterocyclic Compounds, A sériés of Monographs” (John Wiley & Sons, New York,1950 to présent), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. 1960,82:5566; and U.S. patent 5763483, ail of which are incorporated herein by reference.

Examples of heterocycles include by way of example and not limitation pyridyl, thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrroIidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinoliriyl, decahydroquinolinyl,octahydroisoquinolinyl, azocinyl, triazinyl, 6H-l,2,5-thiadiazinyl, 2H,6H-l,5,2dithiazinyl, thienyl,thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl,isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indoIyI, lH-indazoly,purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinfîolinyl,pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,phenanthrolinyl, phenazinyl, plienothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl,imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl,quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.

By way of example and not limitation, carbon bonded heterocycles are bonded at position2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of apyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2,3,4, or 5 of a furan, tetrahydrofuran,thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole orthiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine,position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1,3,4,5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyI, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl,6-pyrazinyl, 2-thiazolyl, 4-thiazoIyI, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles are bonded at position1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine,2-imidazoline, 3 -imidazoIine, pyrazole, pyrazoline·, 2-pyrazoline, 3-pyrazoline, piperidine,piperazine, indole, indoline, lH-indazole, position 2 ofa isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline. Typically, nitrogen bonded heterocyclesinclude 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl. “Heteroaryl” means an aromatic ring or two or more fused rings that contain one or morearomatic rings where the ring or fused rings comprise 1 ,*2, 3 or more heteroatoms, usually oxygen

13 10 15 20 25 30 11715 (-O-), nitrogen (-NX-) or sulfur (-S-) where X is -H, a protecting group or Cj.g alkyl, usually -H.Examples are as described for heterocycle.

Protecting groups. Various groups that the formula 1, 2A or 2B compounds may compriseinclude, e.g., substituted alkyl groups, substituted alkenyl groups, esters or substitutedheterocycles, which can contain one or more reactive moieties such as hydroxyl, or thiol.Intermediates used to make formula 1 or formula 2A or 2B compounds may be protected as isapparent in the art. Noncyclic and cyclic protecting groups and corresponding cleavage reactionsare described in "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley &Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (hereafter “Greene”). In the context of theprésent invention, these protecting groups are groups that can be removed from the molécule of theinvention without irreversibly changing the covalent bond structure or oxidation/reduction State ofthe remainder of the molécule. For example, the protecting group, -X, that is bondecfto a -OX or -NHX group can be removed to form. -OH or -NHp, respectively, without affecting other covalentbonds in the molécule. At times, when desired, more than one protecting group can be removed ata time, or they can be removed sequentially. In compounds of the invention containing more thanone protecting group, the protecting groups are the same or different.

Protecting groups are intended to be removed by known procedures, although it will beunderstood that the protected intermediates fall within the scope of this invention. The removal ofthe protecting group may be arduous or straightforward, depending upon the économies and natureof the conversions involved. In general, one will use a protecting group with exocyclic amines orwith carboxyl groups during synthesis of a formula 1 compound. For most therapeutic applicationsamine groups should be deprotected. Protecting groups commonly are employed to protect againstcovalent modification of a sensitive group in reactions such as alkylation or acylation. Ordinarily,protecting groups are removed by, e.g. hydrolysis, élimination or aminolysis. Thus, simplefunctional considérations will suffïce to guide the sélection of a réversible or an irréversibleprotecting group at a given locus on the invention compounds. Suitable protecting groups andcriteria for their sélection are described in T.W. Greene and P.G.M. Wuts, Eds. "Protective Groupsin Organic Synthesis" 2nd édition, Wiley Press, at pps. 10-142, 143-174, 175-223, 224-276, 277-308, 309-405 and 406-454, which is incorporated herein by reference. Détermination of whether a group is a protecting group is made in the conventionalmanner, e.g., as illustrated by Kocienski, Philip J.; "Protecting Groups" (Georg Thieme VerlagStuttgart, New York, 1994) (hereafter “Kocienski”), Section 1.1, page 2, and Greene Chapter 1,pages 1-9; and U.S. patent 5763483, ail of which are incorporated herein by reference. Inparticular, a group is a protecting group if when, based on mole ratio, 90% of that protecting grouphas been removed by a deprotection reaction, no more "than 50%, preferably 25%, more preferably

35 14 11715 ] 0%, of the deprotected product molécules of the invention hâve undergone changes to theircovalent bond structure or oxidation/reduction state other than those occasioned'by the removal ofthe protecting group. When multiple protecting groups of the same type are présent in themolécule, the mole ratios are determined when ail of the groups of that type are removed. When 5 multiple protecting groups of different types are présent in the molécule, each type of protectinggroup is treated (and the mole ratios are determined) independently or together with othersdépending on whether the deprotection reaction conditions pertinent to one type are also pertinentto the other types présent. In one embodiment of the invention, a group is a protecting group ifwhen, based on mole ratio determined by conventional techniques, 90% of that protecting group 10 has been removed by a conventional deprotection reaction, no more than 50%, preferably 25%,more preferably 10%, of the deprotected product molécules of the invention hâve undergoneirréversible changes to their covalent bond structure or oxidation/reduction state othetThan thoseoccasioned by the removal of the protecting group. Irréversible changes require Chemical reactions(beyond those resulting from aqueous hydrolysis, acid/base neutralization or conventional 15 séparation, isolation or purification) to restore the covalent bond structure or oxidation/reductionstate of the deprotected molécule of the invention.

Protecting groups are also described in detail together with general concepts and spécifiestrategies for their use in Kocienski, Philip J.; "Protecting Groups" (Georg Thieme VerlagStuttgart, New York, 1994), which is incorporated by reference in its entirety herein. In particular 20 Chapter 1, Protecting Groups: An OverView, pages 1-20, Chapter 2, Hydroxyl Protecting Groups,pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl ProtectingGroups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184, Chapter 6, AminoProtecting Groups, pages 185-243, Chapter 7, Epilog, pages 244-252, and Index, pages 253-260,are incorporated with specificity in the context of their contents. More particularly, Sections 2.3 25 Silyl Ethers, 2.4 Alkyl Ethers, 2.5 Alkoxyalkyl Ethers (Acetais), 2.6 Reviews (hydroxy and thiolprotecting groups), 3.2 Acetais, 3.3 Silylene Dérivatives, 3.4 1,1,3,3-

Tetraisopropyldisiloxanylidene Dérivatives, 3.5 Reviews (diol protecting groups), 4.2 Esters, 4.32,6,7-Trioxabicyclo[2.2.2]octanes [OBO] and Other Ortho Esters, 4.4 Oxazolines, 4.5 Reviews .(carboxyl protecting groups), 5.2 O,O-Acetals, 5.3 S,S-Acetals, 5.4 O,S-Acetals, 5.5 Reviews30 (carbonyl protecting groups), 6.2 N-Acyl Dérivatives, 6.3 N-Sulfonyl Dérivatives, 6.4 N-SulfenylDérivatives, 6.5 N-Alkyl Dérivatives, 6.6 N-Silyl Dérivatives, 6.7 Imine Dérivatives, and 6.8Reviews (amino protecting groups), are each incorporated with specificity where protection/deprotection of the requisite functionalities is discussed. Further still, the tables "Indexto the Principal Protecting Groups" appearing on the inside front cover and facing page,

15 "Abbreviations" at page xiv, and "reagents and Solvents" at page xv are each incorporated in theirentirety herein at this location.

Typical hydroxy protecting groups are described in Greene at pages 14-118 and includeEthers (Methyl); Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t-5 Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p-

Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-10 methoxytetrahydropyranyl, 4-MethoxytetrahydrothiopyranyI, 4-MethoxytetrahydropthïopyranylS.S-Dioxido, 1 -[(2-Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-Dioxan-2-yl,Tetrahydrofuranyl, Tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyi-4,7-methanobenzofuran-2-yl); Substituted Ethyl Ethers (1-Ethoxyethyl, l-(2-Chloroethoxy)ethyl, 1-Methyl-l-methoxyethyl, 1-Methyl-1-benzyloxyethyl, 1-Methyl-l-benzyloxy-2-fluoroethyl, 2,2,2-15 Trichloroethyl, 2-TrimethylsilyIethyl, 2-(PhenyIselenyl)ethyl, t-Butyl, Allyl, p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl); Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p~Cyanobenzyl, p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-Oxido, Diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl, alpha-Naphthyldiphenylmethyl, p-20 methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl,4-(4'-Bromophenacyloxy)phenyldiphenyimethyI, 4,4', 4"-Tris(4,5- dichlorophthalimidophenyl)methyl, 4,4', 4"-Tris(levulinoyloxyphenyl)methyl, 4,4', 4"-Tris(benzoyloxyphenyl)methyl, 3-(Imidazol-l-ylmethyl)bis(4', 4"-dimethoxyphenyl)methyl, 1,1-Bis(4-methoxyphenyl)-l'-pyrenylmethyl, 9-Anthryl, 9-(9-Phenyl)xanthenyI, 9-(9-Phenyl-10-25 oxo)anthryl, l,3-Benzodithiolan-2-yl, Benzisothiazolyl, S,S-Dioxido); Silyl Ethers (Trimethylsilyl,Triethylsilyl, Triisopropylsilyl, Dimethylisopropylsilyl, Diethylisopropylsily, Dimethylthexylsilyl,t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl,Diphenylmethylsilyl, t-Butylmethoxyphenylsilyl); Esters (Formate, Benzoylformate, Acetate,Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate, 30 Triphenylmethoxyacetate, Phenoxyacetate, p-Chlorophenoxyacetate, p-poly-Phenylacetate, 3-Phenylpropionate, 4-Oxopentanoate (Levulinate), 4,4-(Ethylenedithio)pentanoate, Pivaloate,Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate, 2,4,6-Trimethylbenzoate (Mesitoate); Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, 35 Isobutyl, Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-MethoXybenzyl, 3,4-Dimethoxybenzyl, ο- i 16 10 15 20 25 30

Nitrobenzyl. p-Nitrobenzyl, S-Benzyl Thiocarbonate, 4-Ethoxy-l-naphthyl, Methyl

Dithiocarbonate); Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate, 4-Nitro-4-methylpentanoate, o-(Dibromomethyl)benzoate, 2-Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate, 4-(Methylthiomethoxy)butyrate, 2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-( 1,1,3,3-tetramethyIbutyl)phenoxyacetate, 2,4-Bis( 1,1-dimethylpropyl)phenoxyacetate, Chorodiphenylacetate, Isobutyrate, Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate), o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, a-Naphthoate,Nitrate, Alkyl N,N,N', N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate, Borate,Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); and Sulfonates (Sulfate, Methanesulfonate(Mesylate), Benzylsulfonate, Tosylate).

More typically hydroxy protecting groups include subtituted methyl ethers, substitutedbenzyl ethers, silyl ethers, and esters including sulfonic acid esters, still more typically, trialkylsilylethers, tosylates and acétates.

Typical 1,2- and 1,3-diol protecting groups are described in Greene at pages 118-142 andinclude Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2-TrichIoroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene,Dimethoxymethylene, 1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene, alpha-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Dérivative, alpha-(N,N-Dimethylamino)benzylidene Dérivative, 2-Oxacyclopentylidene); and Silyl Dérivatives (Di-t-butylsilylene Group, 1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene) Dérivative, Tetra-t-butoxydisiloxane-l,3-diylidene Dérivative, Cyclic Carbonates, Cyclic Boronates, Ethyl Boronate,Phenyl Boronate).

More typically, 1,2- and 1,3-diol protecting groups include epoxides and acetonides.

Typical amino protecting groups are described in Greene at pages 315-385 and includeCarbamates (Methyl and Ethyl, 9-Fluorenylmethyl, 9(2-Sulfo)fluoroenylmethyl, 9-(2,7-Dibromo)fluorenylmeihyi, 2,7-Di-t-buthyI-[9-( 10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]-methyl, 4-Methoxyphenacyl); Substituted Ethyl (2,2,2-Trichoroethyl, 2-Trimethylsilylethyl, 2-Phenylethyl, l-(l-Adamantyl)-l-methylethyl, l.l-Dimethyl-2-haloethyl, l,l-Dimethyl-2,2-dibromoethyl, l,l-Dimethyl-2,2,2-trichloroethyl, 1-Methyl-l-(4-biphenylyi)ethyl, l-(3,5-Di-t-butylphenyl)-l-methylethyl, 2-(2'- and 4'-Pyridyl)ethyl, 2-(N,N-Dicyclohexylcarboxamido)ethyl, t-Butyl, 1-Adamantyl, Vinyl, Allyl, 1-IsopropylallyI, Cinnamyl, 4-Nitrocinnamyl, 8-QuinolyI, N- » 35 17 11715 10 15 20 25 30 35

Hydroxypiperidinyl, Alkyldithio, Benzyl, p-Methoxybenzyl, p-Nitrobenzyl, p-Bromobenzyl, p-Chorobenzyl, 2,4-Dichlorobenzyl, 4-Methylsulfinylbenzyl, 9-Anthrylmethyl, Diphenylmethyl);Groups With Assisted Cleavage (2-Methylthioethyl, 2-Methylsulfonylethyl, 2-(p-

Toluenesulfonyl)ethyl, [2-(l,3-Dithianyl)]methyl, 4-Methylthiophenyl, 2,4-Dimethylthiophenyl, 2-Phosphonioethyl, 2-Triphenylphosphonioisopropyl, l,l-Dimethyl-2-cyanoethyl, m-Choro-p-acyloxybenzyl, p-(Dihydroxyboryl)benzyl, 5-Benzisoxazolylmethyl, 2-(Trifluoromethyl)-6-chromonylmethyl); Groups Capable of Photolytic Cleavage (m-Nitrophenyl, 3,5-Dimethoxybenzyl, o-Nitrobenzyl, 3,4-Dimethoxy-6-nitrobenzyl, Phenyl(o-nitrophenyl)methyl);Urea-Type Dérivatives (Phenothiazinyl-(lO)-carbonyl Dérivative, N'-p-

Toluenesulfonylaminocarbonyl, N'-Phenylaminothiocarbonyl); Miscellaneous Carbamates (t-Amyl, S-Benzyl Thiocarbamate, p-Cyanobenzyl, Cyclobutyl, Cyclohexyl, Cyclopentyl,Cyclopropylmethyl, p-Decyloxybenzyl, Diisopropylmethyl, 2,2-Dimethoxycarbonylvmyl, o-(N,N-Dimethylcarboxamido)benzyl, l,l-Dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-Dimethylpropynyl, Di(2-pyridyl)methyl, 2-Furanylmethyl, 2-Iodoethyl, Isobomyl, Isobutyl,Isonicotinyl, p-(p'-Methoxyphenylazo)benzyl, 1-Methylcyclobutyl, 1-Methylcyclohexyl, 1-Methyl-1-cyclopropylmethyl, l-Methyl-l-(3,5-dimethoxyphenyl)ethyl, l-Methyl-l-(p-phenyiazophenyl)ethyl, 1-Methyl-l-phenylethyl, l-Methyl-l-(4-pyridyi)ethyl, Phenyl, p-(Phenylazo)benzyl, 2,4,6-Tri-t-butyIphenyl, 4-(Trimethylammonium)benzyl, 2,4,6-Trimethylbenzyl); Amides (N-Formyl, N-Acetyl, N-Choroacetyl, N-Trichoroacetyl, N-Trifluoroacetyl, N-Phenylacetyl, N-3-Phenylpropionyl, N-Picolinoyl, N-3-Pyridylcarboxamide, N-Benzoylphenylalanyl Dérivative, N-Benzoyl, N-p-Phenylbenzoyl); Amides With AssistedCleavage (N-o-Nitrophenylacetyl, N-o-Nitrophenoxyacetyl, N-Acetoacetyl, (N-Dithiobenzyloxycarbonylamino)acetyl, N-3-(p-Hydroxyphenyl)propionyl, N-3-(o-Nitrophenyl)propionyl, N-2-Methyl-2-(o-nitrophenoxy)propionyl, N-2-Methyl-2-(o-phenylazophenoxy)propionyl, N-4-Chlorobutyryl, N-3-Methyl-3-nitrobutyryl, N-o-Nitrocinnamoyl, N-Acetylmethionine Dérivative, N-o-Nitrobenzoyl, N-o- (Benzoyloxymethyl)benzoyl, 4,5-Diphenyl-3-oxazolin-2-one); Cyclic Imide Dérivatives (N-Phthalimide, N-Dithiasuccinoyl, N-2,3-DiphenyImaleoyl, N-2,5-Dimethylpyrrolyl, N-l, 1,4,4-

Tetramethyldisilylazacyclopentane Adduct, 5-Substituted l,3-Dimethyl-l,3,5-triazacyciohexan-2-one, 5-Substituted l,3-Dibenzyl-l,3,5-triazacycIohexan-2-one, 1-Substituted 3,5-Dinitro-4-pyridonyl); N-AIkyl and N-Aryl Amines (N-Methyl, N-Allyl, N-[2-(TrimethylsilyI)ethoxy]methyl,N-3-Acetoxypropyl, N-(l-Isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quatemary Ammonium Salts,N-Benzyl, N-Di(4-methoxyphenyI)methyl, N-5-Dibenzosuberyl, N-Triphenylmethyl, N-(4-Methoxyphenyl)diphenylmethyl, N-9-Phenylfluorenyl, N-2,7-Dichloro-9-fluorenylmethylene, N-Ferrocenylmethyl, N-2-PicolylamineΝ'-Oxide); Imine Dérivatives (N-l,l-DÎmethylthiomethylene,

18 11715 N-Benzylidene, N-p-methoxybenylidene, N-Diphenylmethylene, N-[(2-Pyridyl)mesityl]methylene,N,(N',N'-Dimethylàminomethylene, Ν,Ν'-Isopropylidene, N-p-Nitrobenzylidenê, N-Salicylidene,N-5-Chlorosalicylidene, N-(5-Chloro-2-hydroxyphenyl)phenylmethylene, N-Cyclohexylidene);Enamine Dérivative (N-(5,5-Dimethyl-3-oxo- 1-cyclohexenyl)); N-Metal Dérivatives (N-Borane 5 Dérivatives, N-Diphenylborinic Acid Dérivative, N-[Phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, N-Copper or N-Zinc Chelate); N-N Dérivatives (N-Nitro, N-Nitroso, Ν’-Oxide); N-P Dérivatives (N-Diphenylphosphinyl, N-Dimethylthiophosphinyl, N-Diphenylthïophosphinyi, N-Dialkyl Phosphoryl, N-Dibenzyl Phosphoryl, N-Diphenyl Phosphoryl);N-Si Dérivatives; N-S Dérivatives; N-Sulfenyl Dérivatives (N-Benzenesulfenyl, N-o- 10 Nitrobenzenesulfenyl, N-2,4-DinitrobenzenesulfenyI, N-Pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl, N-Triphenylmethylsulfenyl, N-3-NitropyridinesuIfenyl); andN-SulfonylDérivatives (N-p-Toluenesulfonyl, N-Benzenesulfonyl,N-2,3,6-Trimethyl-4- methoxybenzenesulfonyl, N-2,4,6-Trimethoxybenzenesulfonyl, N-2,6-Dimethyl-4-methoxybenzenesulfonyl, N-Pentamethylbenzenesulfonyl, N-2,3,5,6,-TetramethyI-4- 15 methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2,4,6- Trimethylbenzenesulfonyl, N-2,6-Dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-Pentamethylchroman-6-suIfonyl, N-Methanesulfonyl, N-.beta.-Trimethylsilyethanesulfonyl, N-9-AnthracenesulfonyI, N-4-(4', 8'-Dimethoxynaphthylmethyl)benzenesulfonyl, N-Benzylsulfonyl, N-Trifluoromethylsulfonyl, N-Phenacylsulfonyl). 20 More typically, amino protecting groups include carbamates and amides, still more typically, N-acetyl groups.

Stereoisomers. The formula 1 and formula 2A or 2B compounds include enriched orresolved optical isomers at any or ail asymmetric atoms as are apparent from the depictions. Bothracemic and diasteromeric mixtures, as well as the individual optical isomers can be isolated or 25 synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, andthese are ail within the scope of the invention. Chiral centers may be found in inventioncompounds at, for example, Rj, R^ or R4.

One or more of the following methods are used to préparé the enantiomerically enriched or pure isomers herein. The methods are listed in approximately their order of preference, i.e.; one30 ordinarily should employ stereospecific synthesis from chiral precursors before chromatographie résolution before spontaneous crystallization. 35

Stereospecific synthesis is described in the examples. Methods of this type convenientlyare used when the appropriate chiral starting material is available and reaction steps are chosen thatdo not resuit in undesired racemization at chiral sites. One advantage of stereospecific synthesis isthat it does not produce undesired enantiomers that must be removed from the final product, i 19 11715 thereby lowering overall synthetic yield. In general, those skilled in the art would understand whatstarting materials and reaction conditions should be used to obtain the desired enantiomericallyenriched or pure isomers by stereospecific synthesis.

If a suitable stereospecific synthesis cannot be empirically designed or determined withroutine expérimentation then those skilled in the art would turn to other methods. One method ofgeneral utîlity is chromatographie resolution of enantiomers on chiral chromatography resins.These resins are packed in columns, commonly called Pirkle columns, and are commerciallyavailable. The columns contain a chiral stationary phase. The racemate is placed in solution and loaded onto the column, and thereafter separated by HPLC. See for example, Proceedings10 Chromatographie Society - International Symposium on Chiral Séparations, Sept. 3-4, 1987, which is incorporated herein by reference. Examples of chiral columns that could be used to screen for the optimal séparation technique would include Diacel Chriacel OD, Regis Pirkle Codaient D-phenylglycine, Regis Pirkle Type 1 A, Astec Cyclobond II, Astec Cyclobond III, Serva Chiral D-DL=Daltosil 100, Bakerbond DNBLeu, Sumipax OA-lOOO, Merck Cellulose Triacetate column, 15 Astec Cyclobond I-Beta, or Regis Pirkle Covalent D-Naphthylalanine. Not ail of these columnsare iikely to be effective with every racemic mixture. However, those skilled in the art understandthat a certain amount of routine screening may be required to identify the most effective stationaryphase. When using such columns it is désirable to employ embodiments of the compounds of thisinvention in which the charges are not neutralized, e.g., where acidic functionalities such as 20 carboxyl are not esterified or amidated.

Another method entails converting the enantiomers in the mixture to diasteriomers with chiral auxiliaries and then separating the conjugates by ordinary column chromatography. This is avery suitable method, particularly when the embodiment contains a free hydroxyl that will form asait or covalent bond to a chiral auxiliary. Chirally pure amino acids, organic acids or 25 organosulfonic acids are ail worthwhile exploring as chiral auxiliaries, ail of which are well knownin the art. Salts with such auxiliaries can be formed, or they can be covalently (but reversibly)bonded to the functional group. 30

Enzymatic resolution is another method of potential value. In such methods one préparéscovalent dérivatives of the enantiomers in the racemic mixture, generally lower alkyl esters, andthen exposes the dérivative to enzymatic cleavage,-generally hydrolysis. For this method to be successful an enzyme must be chosen that is capable of stereospecific cleavage, so it is ffequentlynecessary to routinely screen several enzymes. If esters are to be cleaved, then one selects a group of esterases, phosphatases, and lipases and détermines their activity on the dérivative. Typicalesterases are from liver, pancréas or other animal organs, and include porcine liver esterase. 1 20 if the enatiomeric mixture séparâtes from solution or a melt as a conglomerate, i.e,, amixture of enantiomerically pure crystals, then the crystals can be mechanically sèparated, therebyproducing the enantiomerically enriched préparation. This method, however, is not practical forlarge-scale préparations and is of limited value fortrue racemic compounds. 5 Asymmetric synthesis is another technique for achieving enantiomeric enrichment. For example, a chiral protecting group is reacted with the group to be protected and the reactionmixture allowed to equilibrate. If the reaction is enantiomerically spécifie then the product will beenriched in that enantiomer.

Further guidance in the séparation of enantiomeric mixtures can be found, by way of10 example and not limitation, in "Enantiomers, Racemates, and resolutions", Jean Jacques, AndréCollet, and Samuel H. Wilen (Krieger Publishing Company, Malabar, FL, 1991, ISBN 0-89464-618-4): Part 2, Resolution of Enantiomer Mixture, pages 217-435; more particularly, Section 4,Resolution by Direct Crystallization, pages 217-251, section 5, Formation and Séparation ofDiastereomers, pages 251-369, section 6, Crystallization-Induced Asymmetric Transformations, 15 pages 369-378, and section 7, Experimental Aspects and Art of Resolutions, pages 378-435; stillmore particularly, section 5.1.4, Resolution of Alcohols, Transformation of Alcohols into Salt-Forming Dérivatives, pages 263-266, section 5.2.3, Covalent Dérivatives of Alcohols, Thiols, andPhénols, pages 332-335, section 5.1.1, Resolution of Acids, pages 257-259, section 5.1.2,Resolution of Bases, pages 259-260, section 5.1.3, Resolution of Amino Acids, page 261-263, 20 section 5.2.1, Covalent Dérivatives of Acids, page 329, section 5.2.2, Covalent dérivatives ofAmines, pages 330-33 1, section 5.2.4, Covalent Dérivatives of Aldéhydes, Ketones, andSulfoxides, pages 335-339, and section 5.2.7, Chromatographie Behavior of CovalentDiastereomers, pages 348-354, ail of which are incorporated herein by reference.

Embodiments include compositions that transiently occur when a method step or operation25 is performed. For example, when a formula 1 compound is contacted with an excipient, e.g., water, a cyclodextrin, a PEG, an alcohol, propylene glycol, benzyl alcohol or benzyl benzoate, thecomposition before addition of one ingrédient with another is a non-homogenous mixture. As theingrédients are contacted, the mixture's homogeneity increases and the proportion of ingrédientsrelative to each other approa'ches a desired value. Thus, sonie compositions as disclosed herein, 30 optionally contain less than about 3% w/w water, e.g., less than 0.5% w/w water, can compriseabout 0.0001-99% w/w of a formula 1 compound such as 16a-bromoepiandrosterone and one ormore excipients. These transient compositions are intermediates that necessarily arise when onemakes an invention composition or formulation and they are included in invention embodiments tothe extent that they are patentable.

21

Formula 1 compounds. The formula 1 compounds, or the “compounds of the invention”,are useful to treat a subject having, or prevent infection of a subject with, one. or moreTrypanosome parasites.

For preferred formula 1 compounds, the Rj moiety bonded to the steroid ring is generally5 in the β-configuration, two Rj are bonded to ÇF? and X is a double bonded oxygen moiety (=O).

Typically, one of the R^ bonded to Q2 is hydrogen in the β-confîguration, the other Rj bonded toQ2 is hydrogen or a halogen, usually bromine, in the α-confîguration and a double bond is présentat the 5-6 positions. Such preferred compounds include déhydroépiandrostérone (“DHEA”) and16a-bromodehydroepiandrosterone (“Br-DHEA”). 10 Other preferred formula 1 compounds include 17-ketosteriods of formula 1 where a double bond is présent at the 5-6 positions, X is =0, Q2 is -CH2- or -CHBr-, R2 is -H, -S(O)(O)-OH, -S(O)(O)-ONa, -S(O)(O)-O-CH2-CH(O-C(O)-R^)-CH2-O-C(O)-R6 (wfiere R6independently is Ci_i4 straight or branched alkyl), -P(O)(O)-O-CH2-CH(O-C(O)R7)-CH2-O-C(O)-R7 (where R7 independently is a glucuronide group or C ] _ 14 straight or branched alkyl) or 15 R2 is a glucuronide group. Other preferred compounds include compound having the structures20-43

22 11715

23

L 24

25 10 15

wherein for each of structures 20-43 Q3 and Qg are each -C(Ri)3 wherein each Rj is independently selected; X and Y independently are -OH, -H, lower alkyl (e.g., Cj.g alkyl), -C(O)-O-R5, -O-C(O)- R5, halogen or, X and Y together with the Rj at the same position independently are a ketone(=O); each R{ is independently selected and has the définition given above; andR2 and R5 hâve the définitions given above.

In some embodiments, the formula 1 compound has the structure 20-43 and 2, 3, 4, 5 or 6

Rj groups independently are -OH, halogen or alkoxy, and the remaining R} are ail hydrogen; R2 is-OH, an ester a thioester or a carbamate, or R2, together with the Rj at the 3-position comprises=0; Y is -H, -OH, a halogen or -O-C(O)-Rg, or Y, together with the Ri at the 16-positioncomprises =O; X is -OH or -O-C(O)-R5, or X, together with the Rj at the 17-position comprises=O; and Q3 and Qg independently are -CH3 or -CH2OH. Such embodiments include structure 20-43 compounds where two -OH are présent at the 3-position, the 16-position or at the 17-position.

Preferred invention embodiments include compounds havingthe formula 44

R44O

44 wherein Y is hydrogen or bromine, R44 is -H, -S(O)(O)-OH, -S(0)(O)-ONa, -S(O)(O)-O-CH2-CH(0-C(0)-Rg)-CH2-O-C(0)-Rg, -P(O)(O)-O-CH2-CH(O-C(O)-R7)-CH2-O-C(O)-R7 or aglucuronide group of structure (A). In other preferred embodiments, Y and R44 in formula 44 areboth hydrogen'. An especially preferred compound is déhydroépiandrostérone (Y and R44 informula 44 are both hydrogen and the double bond at the 5-6 position is présent). In otherembodiments, the compound is epiandrosterone (Y and R44 in formula 44 are both hydrogen and 20 26 i n r· the double bond at the 5-6 position is absent). A 16-haloepiandrosterone with a F, Cl, Br or I at the16 position can also be used as an antiviral agent, e.g., 16a-bromoepiandrosterone. Otherpreferred compounds are (i) 16a-bromodehydroepiandrosterone, (ii) dehydroepiandrosterone-3-sulfate (Y is -H and R44 is -S(O)(O)-OM in formula 44 are both hydrogen and the double bond at 5 the 5-6 position is présent) and (iii) 5P-androstan-3f3-ol-17-one. Related embodiments comprisecompounds related to formula 44 compounds comprise the formula 44 compounds wherein 1, 2, 3,4, 5 or 6 hydrogen atoms that are bonded to.the steroid nucléus are substituted with independentlyselected -OH, -Br, -Cl, -F, -I, -OCH3 or -OC2H5 atoms or groups.

In other embodiments, the 17-ketosteroids of formula 1 are dehydro-epiandrosterone where 10 R44 in formula 44 is a -S(0)(0)-0-CH2-CH(0-C(0)-R6)-CH2-0-C(0)-R5, -P(O)(O)-O-CH2- CH(O-C(O)-R7)-CH2-O-C(O)-R.7 or a glucuronide group of structure (A), Y is hydrogen and the5-6 double bond is présent. Other formula 44 compounds include conjugates of déhydroépiandrostérone wherein Y is hydrogen, a double bond is présent at the 5-6 position andR44 is hexyl sulfate, dodecyl sulfate, octadecyl sulfate, octadecanoyl sulfate, O- 15 dihexadecylglycerol sulfate, hexadecane sulfonate, dioctadecanoylglycerol phosphate or O-hexadecylglycerol phosphate.

In another preferred aspect of the invention, the steroid of formula 1 is a compound offormula 45 20

25 OR53; and R53 is Ci_i8 alkyl, C2-I8 alkenyl, C2-I8 alkynyl, a Cj_i8 ester, aC]_i8 thioester,wherein any of the foregoing Cj_i 8 or C2_i8 groups is substituted at one or more hydrogen atomswith one or more independently selected -O-, -S-, -OH, -NH2, -SH or =0 groups or R53 isthioacetal, a sulfate ester, a sulfonate ester, a carbamate or a thioester. In one preferred aspect . R49is -0-C(O)-Cr-.2-CH2-CH(R54)-CH(R55)-CH2R56 wherein R54 is -NH2, -OH, -SH, -O-PO3, -SO3 or-OSÛ3; R55 is -H, -NH2, -OH, -SH, -O-PO3, -SO3 or -OSO3; and R56 is Cj.ig alkyl, C2-1 8 alkenyl, C2-i 8 alkynyl, a C j _ ] g ester, a C|_i8 thioester, wherein any of the foregoing Cj_i g orC2-18 groups is substituted at one or more hydrogen atoms with one or more independentlyselected -OH, -NH2 or -SH groups, and the precursors, métabolites and analogs thereof. Relatedembodiments comprise compounds related to formula 44 compounds comprise the formula 45 30 27 11 7 1 5 compounds wherein 1, 2, 3, 4, 5 or 6 hydrogen atoms that are bonded to the steroid nucléus aresubstituted with independently selected -OH, -Br, -Cl, -F, -I, -OCH3 or -OC2H5 atoms or groups.

In other preferred embodiments, the formula 1 compounds hâve the formula IB or IC

10 15 20 25 wherein each Ri independently is -H, -OH, a halogen, -CHCHo, -CHCHCH3, -CCH, -CCCH3, or,or, the other moiety that is bonded to the same carbon atom is absent and R] is =O; R2 is -H, -OH,a halogen, Ci.8 alkoxy, -S-C(O)-(CH2)m-R4, -C(O)-S-(CH2)m-R4, -O-S(O)(O)-(CH2)m-R4, -O-S(O)(O)-O-(CH2)m-R4, -O-C(O)-NH-(CH2)m-R4, -NH-C(O)-O-(CH2)m-R4, -O-C(S)-(CH2)m-R4, -C(S)-O-(CH2)m-R4» -O-C(O)-(CH2)m-R4 or -C(O)-O-(CH2)m-R4; R4 is -H, -CH3, -C2H5,-C3H7, -C2H4OH, -C3HgOH, -CH2-CH2-O-CH3, -CH2-CH2-O-CH2-CH3, -CH2-CH2-O-CH2-CH2OH, a C3.5 alkenyl group, a C3.5 alkynyl group, benzyl or phenyl, wherein the phenyl orbenzyl groups are optionally substituted with 1, 2, or 3 independently selected halogen, Ci_4alkoxy, -OH, -SH, -O- or -NH- moieties; and Q3 and Qg independently are -H, -CH3 or -CH2OH;and Q2 is -C(R})2- or -CH2-CH2-, In these embodiments, Q3 and Qg are usually both in the β-configuration, typically they are -CH3, Q2 usually comprises -CH2-, -C(O)-, -CH(Br)-, -CH(I)-, or-CH(OH)- with the Br, I or OH moieties in the α-configuration, or Q2 comprises =0, and Rj at the7-position is -H, -OH or =O. Related embodiments comprise compounds related to formula 44compounds comprise the formula IA or IB compounds wherein 1, 2, 3, 4, 5 or 6 hydrogen atomsthat are bonded to the steroid nucléus are substituted with independently selected -OH, -Br, -CI, -F,-I, -OCH3 or -OC2H5 atoms or groups.

The formula 1 compounds can exist in a crystalline or polymorphie form. Métabolites. Also falling within the scope ofthis invention are the in vivo métabolites of the compounds of the invention, to the extent such products are novel and unobvious overthe priorart. Such products may resuit for example from the oxidation, réduction, hydrolysis, amidation,estérification and the like ofthe administered formula 1 compound, due to enzymatic or Chemicalprocesses. Accordingly, the invention includes novel and unobvious compounds produced by aprocess comprising contacting a compound of this invention with a subject, e.g., a human, rodentor a primate, for a period of time sufficient to yield a metabolic product thereof. Such productstypically are identified by preparing a radiolabelled (e.g. C14 or H3) compound of the invention,administering it parenterally or orally in a détectable dose (e.g. greater than about 0.5 mg/kg) to ananimal such as rat, mouse, guinea pig, primate, or to a human, allowing sufficient time for V- 30 28 ί 1 7 1 5 metabolism to occur (typically about 30 seconds to about 30 hours) and isolating its conversionproducts from the urine, blood or other biological samples. These products are ea'sily isolated sincethey are labeled (others are isolated by the use of antibodies capable of binding epitopes survivingin the métabolite). The métabolite structures are determined in conventional fashion, e.g. by 5 HPLC, MS or NMR analysis. In general, analysis of métabolites is done in the same way asconventional drug metabolism studies well-known to those skilled in the art. The conversionproducts, so long as they are not otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention even if they possess no therapeutic activityoftheir own. 10 The following description exemplifies embodiments ofthe formula 1 compounds.

Group I. Exemplary embodiments include the formula 1 compounds named in table B based on the compound structure désignations defined in table A. Each compound naîhed in TableB is depicted as a compound of formula 4

15 where Q3 and Qg are both -CH3, Q4 is -CH2- and R2, Rl A, and Y and X hâve the structuresdesignated in Table A. The compounds named according to Tables A and B are referred to as“group 1” compounds.

Compounds named in Table B are designated by numbers assigned to R2, RlA, Y and Xaccording to the following compound naming convention, R2 .R] A.Y.X, using the numbered 20 Chemical structures depicted in Table A. As shown in formula 4, R2 is in the 3P-position and hydrogen fills the remaining valence or R2 is double bonded to the 3 carbon, R} A is an Rj groupat the 7p-position or R] A isan R] group double bonded to the 7 carbon, Y is in the 16a-positionand hydrogen fills the remaining valence or R2 is double bonded to the 16 carbon and X is in the f 17(3-position and hydrogen fills the remaining valence or X is double bonded to the 17 carbon. 25 When R2, Ri A, Y or X is a divalent moiety, e.g., =0, the hydrogen at the corresponding position is absent. Thus, the group 1 compound named 1.2.1.1 spécifiés a formula 4 structure with a β- hydroxyl bonded to carbons at the 3- and 7-positions (the variable groups R2 and R] A » 29 17½ respectively), an α-bromine bonded to carbon 16 (the variable group Y) and double bonded oxygen

10 15

TABLE A R2 1 -OH R1A 1 -H 2 =0 2 -OH 3 -O-P(O)(O)-OH 3 =O 4 -0-P(0)(0)-0-CH2-CH(0-C(0)-CH3)-CH2-0-C(0)CH3 4 -CH3 5 -O-S(O)(O)-OH 5 -OCH3 6 -O-S(O)(O)-O-Na+ 6 -OC2H5 7 -O-S(O)(O)-OC2H5 7 -OCH2CH2CH3 8 -0-S(0)(0)-0-CH2-CH(0-C(0)-CH3)-CH2-0-C(0)CH3 8 -OCH(CH3)CH3 9 -O-S(O)(O)-OCH2CH2CH2CH3 9 -OCH2CH2CH2CH3 10 -O-S(O)(O)-OC(CH3)3 10 -OC(CH3)3 20 25

Y 1 -Br 2 -Cl

3 -I

4 -F

5 -H

6 -OH 7 =0 8 -O-C(O)-CH3 9 -O-C(O)-CH2CH3 10 -O-CfQTCHoCHoCH^

X 1 =o

2 -OH

3 -H

4 -F 5 -Cl 6 -Br

7 -I 8 -O-C(O)-CH3 9 -O-C(O)-CH2CH3 10 -O-CfO)-CH2CH2CH3

30

TABLE B 11715 1.1.1.1, 1.1.1.2, 1.1.1.3, 1.1.1.4, 1.1.1.5, 1.1.1.6, 1.1.1.7, 1.1.1.8, 1.1.1.9, 1.1.1.10, 1.1.2.1, 1.1.2.2, 1.1.2.3, 1.1.2.4, 1.1.2.5, 1.1.2.6, 1.1.2.7, 1.1.2.8, 1.1.2.9, 1.1.2.10, 1.1.3.1, 1.1.3.2, 1.1.3.3, 1.1.3.4, 1.1.3.5, 1.1.3.6, 1.1.3.7, 1.1.3.8, 1.1.3.9, 1.1.3.10, 1.1.4.1, 1.1.4.2, 1.1.4.3, 1.1.4.4, 1.1.4.5, 1.1.4.6, 1.1.4.7, 1.1.4.8, 1.1.4.9, 1.1.4.10, 1.1.5.1, 1.1.5.2, 1.1.5.3, 1.1.5.4, 1.1.5.5, 1.1.5.6, 1.1.5.7, 1.1.5.8, 1.1.5.9, 1.1.5.10, 1.1.6.1, 1.1.6.2, 1.1.6.3, 1.1.6.4, 1.1.6.5, 1.1.6.6, 1.1.6.7, 1.1.6.8, 1.1.6.9, 1.1.6.10, 1.1.7.1, 1.1.7.2, 1.1.7.3, 1.1.7.4, 1.1.7.5, 1.1.7.6, 1.1.7.7, 1.1.7.8, 1.1.7.9, 1.1.7.10, 1.1.8.1, 1,1.8.2, 1.1.8.3, 1.1.8.4, 1.1.8.5, 1.1.8.6, 1.1.8.7, 1.1.8.8, 1.1.8.9, 1.1.8.10, 1.1.9.1, 1.1.9.2, 1.1.9.3, 1.1.9.4, 1.1.9.5, 1.1.9.6, 1.1.9.7, 1.1.9.8, 1.1.9.9, 1.1.9.10, 1.1.10.1, 1.1.10.2, 1.1.10.3, 1.1.10.4, 1.1.10.5, 1.1.10.6, 1.1.10.7, 1.1.10.8, 1.1.10.9, 1.1.10.10, 1.2.1.1, 1.2.1.2, 1.2.1.3, 1.2.1.4, 1.2.1.5, 1.2.1.6, 1.2.1.7, 1.2.1.8, 1.2.1.9, 1.2.1.10, 1.2.2.1, 1.2.2.2, 1.2.2.3, 1.2.2.4, 1.2.2.5, 1.2.2.6, 1.2.2.7, 1.2.2.8, 1.2.2.9, 1.2.2.10, 1.2.3.1, 1.2.3.2, 1.2.3.3, 1.2.3.4, 1.2.3.5, 1.2.3.6, 1.2.3.7, 1.2.3.8, 1.2τ3.9, 1.2.3.10, 1.2.4.1, 1.2.4.2, 1.2.4.3, 1.2.4.4, 1.2.4.5, 1.2.4.6, 1.2.4.7, 1.2.4.8, 1.2.4.9, 1.2.4.10, 1.2.5.1, 1.2.5.2, 1.2.5.3, 1.2.5.4, 1.2.5.5, 1.2.5.6, 1.2.5.7, 1.2.5.8, 1.2.5.9, 1.2.5.10, 1.2.6.1, 1.2.6.2, 1.2.6.3, 1.2.6.4, 1.2.6.5, 1.2.6.6, 1.2.6.7, 1.2.6.8, 1.2.6.9, 1.2.6.10, 1.2.7.1, 1.2.7.2, 1.2.7.3, 1.2.7.4, 1.2.7.5, 1.2.7.6, 1.2.7.7, 1.2.7.8, 1.2.7.9, 1.2.7.10, 1.2.8.1, 1.2.8.2, 1.2.8.3, 1.2.8.4, 1.2.8.5, 1.2.8.6, 1.2.8.7, 1.2.8.8, 1.2.8.9, 1.2.8.10, 1:2.9.1, 1.2.9.2, 1.2.9.3, 1.2.9.4, 1.2.9.5, 1.2.9.6, 1.2.9.7, 1.2.9.8, 1.2.9.9, 1.2.9.10, 1.2.10.1, 1.2.10.2, 1.2.10.3, 1.2.10.4, 1.2.10.5, 1.2.10.6, 1.2.10.7, 1.2.10.8, 1.2.10.9, 1.2.10.10, 1.3.1.1, 1.3.1.2, 1.3.1.3, 1.3.1.4, 1.3.1.5, 1.3.1.6, 1.3.1.7, 1.3.1.8, 1.3.1.9, 1.3.1.10, 1.3.2.1, 1.3.2.2, 1.3.2.3, 1.3.2.4, 1.3.2.5, 1.3.2.6, 1.3.2.7, 1.3.2.8, 1.3.2.9, 1.3.2.10, 1.3.3.1, 1.3.3.2, 1.3.3.3, 1.3.3.4, 1.3.3.5, 1.3.3.6, 1.3.3.7, 1.3.3.8, 1.3.3.9, 1.3.3.10, 1.3.4.1, 1.3.4.2, 1.3.4.3, 1.3.4.4, 1.3.4.5, 1.3.4.6, 1.3.4.7, 1.3.4.8, 1.3.4.9, 1.3.4.10, 1.3.5.1, 1.3.5.2, 1.3.5.3, 1.3.5.4, 1.3.5.5, 1.3.5.6, 1.3.5.7, 1.3.5.8, 1.3.5.9, 1.3.5.10, 1.3.6.1, 1.3.6.2, 1.3.6.3, 1.3.6.4, 1.3.6.5, 1.3.6.6, 1.3.6.7, 1.3.6.8, 1.3.6.9, 1.3.6.10, 1.3.7.1, 1.3.7.2, 1.3.7.3, 1.3.7.4, 1.3.7.5, 1.3.7.6, 1.3.7.7, 1.3.7.8, 1.3.7.9, 1.3.7.10, 1.3.8.1, 1.3.8.2, 1.3.8.3, 1.3.8.4, 1.3.8.5, 1.3.8.6, 1.3.8.7, 1.3.8.8, 1.3.8.9, 1.3.8.10, 1.3.9.1, 1.3.9.2, 1.3.9.3, 1.3.9.4, 1.3.9.5, 1.3.9.6, 1.3.9.7, 1.3.9.8, 1.3.9.9, 1.3.9.10, 1.3.10.1, 1.3.10.2, 1.3.10.3, 1.3.10.4, 1.3.10.5, 1.3.10.6, 1.3.10.7, 1.3.10.8, 1.3.10.9, 1.3.10.10, 1.4.1.1, 1.4.1.2, 1.4.1.3, 1.4.1.4, 1.4.1.5, 1.4.1.6, 1.4.1.7, 1.4.1.8, 1.4.1.9, 1.4.1.10, 1.4.2.1, 1.4.2.2, 1.4.2.3, 1.4.2.4, 1.4.2.5, 1.4.2.6, 1.4.2.7, 1.4.2.8, 1.4.2.9, 1.4.2.10, 1.4.3.1, 1.4.3.2, 1.4.3.3, 1.4.3.4, 1.4.3.5, 1.4.3.6, 1.4.3.7, 1.4.3.8, 1.4.3.9, 1.4.3.10, 1.4.4.1, 1.4.4.2, ί.4.4.3, j.4.4.4, 1.4.4.5, 1.4.4.6, L4.4.7, 1.4.4.8, 1.4.4.9, 1.4.4.10, 1.4.5.1, 1.4.5.2, 1.4.5.3, 1.4.5.4, 1.4.5.5, 1.4.5.6, 1.4.5.7, 1.4.5.8, 1.4.5.9, 1.4.5.10, 1.4.6.1, 1.4.6.2, 1.4.6.3, 1.4.6.4, 1.4.6.5, 1.4.6.6, 1.4.6.7, 1.4.6.8, 1.4.6.9, 1.4.6.10, 1.4.7.1, 1.4.7.2, 1.4.7.3, 1.4.7.4, 1.4.7.5, 1.4.7.6, 1.4.7.7, 1.4.7.8, 1.4.7.9, 1.4.7.10, 1.4.8.1, 1.4.8.2, 1.4.8.3, 1.4.8.4, 1.4.8.5, 1.4.8.6, 1.4.8.7, 1.4.8.8, 1.4.8.9, 1.4.8.10, 1.4.9.1, 1.4.9.2, 1.4.9.3, 1.4.9.4, 1.4.9.5, 1.4.9.6, 1.4.9.7, 1.4.9.8, 1.4.9.9, 1.4.9.10, 1.4.10.1, 1.4.10.2, 1.4.10.3, 1.4.10.4, 1.4.10.5, 1.4.10.6-, 1.4.10.7, 1.4.10.8, 1.4.10.9, 1.4.10.10, 1.5.1.1, 1.5.1.2, 1.5.1.3, 1.5.1.4, 1.5.1.5, 1.5.1.6, 1.5.1.7, 1.5.1.8, 1.5.1.9, 1.5.1.10, 1.5.2.1, 1.5.2.2, 31 715 1.5.2.3, 1.5.2.4, 1.5.2.5, 1.5.2.6, 1.5.2.7, 1.5.2.8, 1.5.2.9, 1.5.2.10, 1.5.3.1, 1.5.3.2, 1.5.3.3, 1.5.3.4, 1.5.3.5, 1.5.3.6, 1.5.3.7, 1.5.3.8, 1.5.3.9, 1.5.3.10, 1.5.4.1, 1.5.4.2, 1.5.4.3, 1.5.4.4, 1.5.4.5, 1.5.4.6, 1.5.4.7, 1.5.4.8, 1.5.4.9, 1.5.4.10, 1.5.5.1, 1.5.5.2, 1.5.5.3, 1.5.5.4, 1.5.5.5, 1.5.5.6, 1.5.5.7, 1.5.5.8, 1.5.5.9, 1.5.5.10, 1.5.6.1, 1.5.6.2, 1.5.6.3, 1.5.6.4, 1.5.6.5, 1.5.6.6, 1.5.6.7, Ι.5.6.8, 1.5.6.9, 1.5.6.10, 5 1.5.7.1, 1.5.7.2, 1.5.7.3, 1.5.7.4, 1.5.7.5, 1.5.7.6, 1.5.7.7, 1.5.7.8, 1.5.7.9, 1.5.7.10, 1.5.8.1, 1.5.8.2, 1.5.8.3, 1.5.8.4, 1.5.8.5, 1.5.8.6, 1.5.8.7, 1.5.8.8, 1.5.8.9, 1.5.8.10, 1.5.9.1, 1.5.9.2, 1.5.9.3, 1.5.9.4, 1.5.9.5, 1.5.9.6, 1.5.9.7, 1.5.9.8, 1.5.9.9, 1.5.9.10, 1.5.10.1, 1.5.10.2, 1.5.10.3, 1.5.10.4, 1.5.10.5, 1.5.10.6, 1.5.10.7, 1.5.10.8, 1.5.10.9, 1.5.10.10, 1.6.1.1, 1.6.1.2, 1.6.1.3, 1.6.1.4, 1.6.1.5, 1.6.1.6, 1.6.1.7, 1.6.1.8, 1.6.1.9, 1.6.1.10, 1.6.2.1, 1.6.2.2, 1.6.2.3, 1.6.2.4, 1.6.2.5, 1.6.2.6, 1.6.2.7, 1.6.2.8, 10 1.6.2.9, 1.6.2.10, 1.6.3.1, 1.6.3.2, 1.6.3.3, 1.6.3.4, 1.6.3.5, 1.6.3.6, 1.6.3.7, 1.6.3.8, 1.6.3.9, 1.6.3.10, 1.6.4.1, 1.6.4.2, 1.6.4.3, 1.6.4.4, 1.6.4.5, 1.6.4.6, 1.6.4.7, 1.6.4.8, 1.6.4.9, 1.6.4.10, 1.6.5.1, 1.6.5.2, 1.6.5.3, 1.6.5.4, 1.6.5.5, 1.6.5.6, 1.6.5.7, 1.6.5.8, 1.6.5.9, 1.6.5.10, 1.6.6.1, 1.6.6.2, 1.6Æ.3, 1.6.6,4, 1.6.6.5, 1.6.6.6, 1.6.6.7, 1.6.6.8, 1.6.6.9, 1.6.6.10, 1.6.7.1, 1.6.7.2, 1.6.7.3, 1.6.7.4, 1.6.7.5, 1.6.7.6, 1.6.7.7, 1.6.7.8, 1.6.7.9, 1.6.7.10, 1.6.8.1, 1.6.8.2, 1.6.8.3, 1.6.8.4, 1.6.8.5, 1.6.8.6, 1.6.8.7, 1.6.8.8, 15 1.6.8.9, 1.6.8.10, 1.6.9.1, 1.6.9.2, 1.6.9.3, 1.6.9.4, 1.6.9.5, 1.6.9.6, 1.6.9.7, 1.6.9.8, 1.6.9.9, 1.6.9.10, 1.6.10.1, 1.6.10.2, 1.6.10.3, 1.6.10.4, 1.6.10.5, 1.6.10.6, 1.6.10.7, 1.6.10.8, 1.6.10.9, 1.6.10.10, 1.7.1.1, 1.7.1.2, 1.7.1.3, 1.7.1.4, 1.7.1.5, 1.7.1.6, 1.7.1.7, 1.7.1.8, 1.7.1.9, 1.7.1.10, 1.7.2.1, 1.7.2.2, 1.7.2.3, 1.7.2.4, 1.7.2.5, Ι.7.2.6, 1.7.2.7, 1.7.2.8, 1.7.2.9, 1.7.2.10, 1.7.3.1, 1.7.3.2, 1.7.3.3, 1.7.3.4, 1.7.3.5, 1.7.3.6, 1.7.3.7, 1.7.3.8, 1.7.3.9, 1.7.3.10, 1.7.4.1, 1.7.4.2, 1.7.4.3, 1.7.4.4, 1.7.4.5, 1.7.4.6, 20 1.7.4.7, 1.7.4.8, 1.7.4.9, 1.7.4.10, 1.7.5.1, 1.7.5.2, 1.7.5.3, 1.7.5.4, 1.7.5.5, 1.7.5.6, 1.7.5.7, 1.7.5.8, 1.7.5.9, 1.7.5.10, 1.7.6.1, 1.7.6.2, 1.7.6.3, 1.7.6.4, 1.7.6.5, 1.7.6.6, 1.7.6.7, 1.7.6.8, 1.7.6.9, 1.7.6.10, 1.7.7.1, 1.7.7.2, 1.7.7.3, 1.7.7.4, 1.7.7.5, 1.7.7.6, 1.7.7.7, 1.7.7.8, 1.7.7.9, 1.7.7.10, 1.7.8.1, 1.7.8.2, 1.7.8.3, 1.7.8.4, 1.7.8.5, 1.7.8.6, 1.7.8.7, 1.7.8.8, 1.7.8.9, 1.7.8.10, 1.7.9.1, 1.7.9.2, 1.7.9.3, 1.7.9.4, 1.7.9.5, 1.7.9.6, 1.7.9.7, 1.7.9.8, 1.7.9.9, 1.7.9.10, 1.7.10.1, 1.7.10.2, 1.7.10.3, 1.7.10.4, 1.7.10.5, 25 1.7.10.6, 1.7.10.7, 1.7.10.8, 1.7.10.9, 1.7.10.10, 1.8.1.1, 1.8.1.2, 1.8.1.3, 1.8.1.4, 1.8.1.5, 1.8.1.6, 1.8.1.7, 1.8.1.8, 1.8.1.9, 1.8.1.10, 1.8.2.1, 1.8.2.2, 1.8.2.3, 1.8.2.4, 1.8.2.5, 1.8.2.6, 1.8.2.7, 1.8.2.8, 1.8.2.9, 1.8.2.10, 1.8.3.1, 1.8.3.2, 1.8.3.3, 1.8.3.4, 1.8.3.5, 1.8.3.6, 1.8.3.7, 1.8.3.8, 1.8.3.9, 1.8.3.10, 1.8.4.1, 1.8.4.2, 1.8.4.3, 1.8.4.4, 1.8.4.5, 1.8.4.6, 1.8.4.7, 1.8.4.8, 1.8.4.9, 1.8.4.10, 1.8.5.1, 1.8.5.2, 1.8.5.3, 1.8.5.4, 1.8.5.5, 1.8.5.6, 1.8.5.7, 1.8.5.8, 1.8.5.9, 1.8.5.10, 1.8.6.1, 1.8.6.2, 1.8.6.3, 1.8.6.4, 30 1.8.6.5, 1.8.6.6, 1.8.6.7, 1.8.6.8, 1.8.6.9, 1.8.6.10, 1.8.7.1, 1.8.7.2, 1.8.7.3, 1.8.7.4, 1.8.7.5, 1.8.7.6, 1.8.7.7, 1.8.7.8, 1.8.7.9, 1.8.7.10, 1.8.8.1, 1.8.8.2, 1.8.8.3, 1.8.8.4, 1.8.8.5, 1.8.8.6, 1.8.8.7, 1.8.8.8, 1.8.8.9, 1.8.8.10, 1.8.9.1, 1.8.9.2, 1.8.9.3, 1.8.9.4, 1.8.9.5, 1.8.9.6, 1.8.9.7, 1.8.9.8, 1.8.9.9, 1.8.9.10, 1.8.10.1, 1.8.10.2, 1.8.10.3, 1.8.10.4, 1.8.10.5, 1.8.10.6, 1.8.10.7, 1.8.10.8, 1.8.10.9, 1.8.10.10, 1.9.1.1, 1.9.1.2, 1.9.1.3, 1.9.1.4, 1.9.1.5, 1.9.1.6, 1.9.1.7, 1.9.1.8, 1.9.1.9, 1.9.1.10, 1.9.2.1, 1.9.2.2, 35 1.9.2.3, 1.9.2.4, 1.9.2.5, 1.9.2.6, 1.9.2.7, 1.9.2.8, 1.9.2.9, 1.9.2.10, 1.9.3.1, 1.9.3.2, 1.9.3.3, 1.9.3.4, 32 11715 1.9.3.5, 1.9.3.6, 1.9.3.7, 1.9.3.8, 1.9.3.9, 1.9.3.10, 1.9.4.1, 1.9.4.2, 1.9.4.3, 1.9.4.4, 1.9.4.5, 1.9.4.6, 1.9.4.7, 1.9.4.8, 1.9.4.9, 1.9.4.10, 1.9.5.1, 1.9.5.2, 1.9.5.3, 1.9.5.4, 1.9.5.5, 1.9.5.6, 1.9.5.7, 1.9.5.8, 1.9.5.9, 1.9.5.10, 1.9.6.1, 1.9.6.2, 1.9.6.3, 1.9.6.4, 1.9.6.5, 1.9.6.6, 1.9.6.7, 1.9.6.8, 1.9.6.9, 1.9.6.10, 1.9.7.1, 1.9.7.2, 1.9.7.3, 1.9.7.4, 1.9.7.5, 1.9.7.6, 1.9.7.7, 3.9.7.8, 1.9.7.9, 1.9.7.10, 1.9.8.1, 1.9.8.2, 1.9.8.3, 1.9.8.4, 1.9.8.5, 1.9.8.6, 1.9.8.7, 1.9.8.8, 1.9.8.9, 1.9.8.10, 1.9.9.1, 1.9.9.2, 1.9.9.3, 1.9.9.4, 1.9.9.5, 1.9.9.6, 1.9.9.7, 1.9.9.8, 1.9.9.9, 1.9.9.10, 1.9.10.1, 1.9.10.2, 1.9.10.3, 1.9.10.4, 1.9.10.5, 1.9.10.6, 1.9.10.7, 1.9.10.8, 1.9.10.9, 1.9.10.10, 1.10.1.1, 1.10.1.2, 1.10.1.3, 1.10.1.4, 1.10.1.5, 1.10.1.6, 1.10.1.7, 1.10.1.8, 1.10.1.9, 1.10.1.10, 1.10.2.1, 1.10.2.2, 1.10.2.3, 1.10.2.4, 1.10.2.5, 1.10.2.6, 1.10.2.7, 1.10.2.8, 1.10.2.9, 1.10.2.10, 1.10.3.1, 1.10.3.2, 3.10.3.3, 1.10.3.4, 1.10.3.5, 1.10.3.6, 1.10.3.7, 1.10.3.8, 1.10.3.9, 1.10.3.10, 1.10.4.1, 1.10.4.2, 1.10.4.3, 1.10.4.4, 1.10.4.5, 1.10.4.6, 1.10.4.7, 1.10.4.8, 1.10.4.9, 1.10.4.10, 1.10.5.1, 1.10.5.2, 1.10.5.3, 1.10.5.4, 1.10.5.5, 1.10.5.6, 1.10.5.7, 1.10.5.8, 1.10.5.9, 1.10.5.10, 1.10.6.1, 1.10.6.2, 1.10.6.3, 1.10.6.4, hlO.6.5, 1.10.6.6, 1.10.6.7, 1.10.6.8, 1.10.6.9, 1.10.6.10, 1.10.7.1, 1.10.7.2, 1.10.7.3, 1.10.7.4, 1.10.7.5, 1.10.7.6, 1.10.7.7, 1.10.7.8, 1.10.7.9, 1.10.7.10, 1.10.8.1, 1.10.8.2, 1.10.8.3, 1.10.8.4, 1.10.8.5, 1.10.8.6, 1.10.8.7, 1.10.8.8, 1.10.8.9, 1.10.8.10, 1.10.9.1, 1.10.9.2, 1.10.9.3, 1.10.9.4, 1.10.9.5, 1.10.9.6, 1.10.9.7, 1.10.9.8, 1.10.9.9, 1.10.9.10, 1.10.10.1, 1.10.10.2, 1.10.10.3, 1.10.10.4, 1.10.10.5, 1.10.10.6, 1.10.10.7, 1.10.10.8, 1.10.10.9, 1.10.10.10, 2.1.1.1,2.1.1.2,2.1.1.3,2.1.1.4, 2.1.1.5, 2.1.1.6, 2.1.1.7, 2.1.1.8, 2.1.1.9, 2.1.1.10, 2.1.2.1, 2.1.2.2, 2.I.2.3, 2.1.2.4, 2.1.2.5, 2.1.2.6, 2.1.2.7, 2.1.2.8, 2.1.2.9, 2.1.2.10, 2.1.3.1, 2.1.3.2, 2.1.3.3, 2.1.3.4, 2.1.3.5, 2.1.3.6, 2.1.3.7, 2.1.3.8, 2.1.3.9, 2.1.3.10, 2.1.4.1,2.1.4.2, 2.1.4.3, 2.1.4.4, 2.1.4.5, 2.1.4.6, 2.1.4.7, 2.1.4.8, 2.1.4.9, 2.1.4.10, 2.1.5.1, 2.1.5.2, 2.1.5.3, 2.1.5.4, 2.1.5.5, 2.1.5.6, 2.1.5.7, 2.1.5.8, 2.1.5.9, 2.1.5.10, 2.1.6.1, 2.1.6.2, 2.1.6.3, 2.1.6.4, 2.1.6.5, 2.1.6.6, 2.1.6.7, 2.1.6.8, 2.1.6.9, 2.1.6.10, 2.1.7.1, 2.1.7.2, 2.1.7.3, 2.1.7.4, 2.1.7.5, 2.1.7.6, 2.1.7.7, 2.1.7.8, 2.1.7.9, 2.1.7.10, 2.1.8.1, 2.1.8.2, 2.1.8.3, 2.1.8.4, 2.1.8.5, 2.1.8.6, 2.1.8.7, 2.1.8.8, 2.1.8.9, 2.1.8.10, 2.1.9.1, 2.1.9.2, 2.1.9.3, 2.1.9.4, 2.1.9.5, 2.1.9.6, 2.1.9.7, 2.1.9.8, 2.1.9.9, 2.1.9.10, 2.1.10.1, 2.1.10.2, 2.1.10.3, 2.1.10.4, 2.1.10.5, 2.1.10.6, 2.1.10.7, 2.1.10.8, 2.1.10.9, 2.1.10.10, 2.2.1.1, 2.2.1.2, 2.2.1.3, 2.2.1.4, 2.2.1.5, 2.2.1.6, 2.2.1.7, 2.2.1.8, 2.2.1.9, 2.2.1.10, 2.2.2.1, 2.2.2.2, 2.2.2.3, 2.2.2.4, 2.2.2.5, 2.2.2.6, 2.2.2.7, 2.2.2.8, 2.2.2.9, 2.2.2.10, 2.2.3.1, 2.2.3.2, 2.2.3.3, 2.2.3.4, 2.2.3.5, 2.2.3.6, 2.2.3.7, 2.2.3.8, 2.2.3.9, 2.2.3.10, 2.2.4.1, 2.2.4.2, 2.2.4.3, 2.2.4.4, 2.2.4.5, 2.2.4.6, 2.2.4.7, 2.2.4.8, 2.2.4.9, 2.2.4.10, 2.2.5.1, 2.2.5.2, 2.2.5.3, 2.2.5.4, 2.2.5.5, 2.2.5.6, 2.2.5.7, 2.2.5.8, 2.2.5.9, 2.2.5.10, 2.2.6.1, 2.2.6.2, 2.2.6.3, 2.2.6.4, 2.2.6.5, 2.2.6.6, 2.2.6.7, 2.2.6.8, 2.2.6.9, 2.2.6.10, 2.2.7.1, 2.2.7.2, 2.2.7.3, 2.2.7.4, 2.2.7.5, 2.2.7.6, 2.2.7.7, 2.2.7.8, 2.2.7.9, 2.2.7.10, 2.2.8.1, 2.2.8.2, 2.2.8.3, 2.2.8.4, 2.2.8.5, 2.2.8.6, 2.2.8.7, 2.2.8.8, 2.2.8.9, 2.2.8.10, 2.2.9.1, 2.2.9.2, 2.2.9.3, 2.2.9.4, 2.2.9.5, 2.2.9.6, 2.2.9.7, 2.2.9.8, 2.2.9.9, 2.2.9.10, 2.2.10.1, 2.2.10.2, 2.2.10.3, 2.2.10.4, 2.2.10.5, 2.2.10.6, 2.2.10.7, 2.2.10.8, 2.2.10.9, 2.2.10.10, 2.3.1.1, 2.3.1.2, 2.3.1.3, 2.3.1.4, 2.3.1.5, 2.3.1.6, 2.3.1.7, 2.3.1.8, 2.3.1.9; 2.3.1.10, 2.3.2.1,2.3.2.2, 2.3.2.3, 2.3.2.4, 33 :1715. 23.2.5, 2.3.2.6, 2.3.2.7, 2.3.2.8, 2.3.2.9, 2.3.2.10, 2.3.3.1, 2.3.3.2, 2.3.3.3, 2.3.3.4, 2.3.3.5, 2.3.3.6, 2.3.3.7, 2.3.3.8, 2.3.3.9, 2.3.3.10, 2.3.4.1, 2.3.4.2, 2.3.4.3, 2.3.4.4, 2.3.4.5, 2.3.4.6, 2.3.4.7, 2.3.4.8, 2.3.4.9, 2.3.4.10, 2.3.5.1, 2.3.5.2, 2.3.5.3, 2.3.5.4, 2.3.5.5, 2.3.5.6, 2.3.5.7, 2.3.5.8, 2.3.5.9, 2.3.5.10, 2.3.6.1.2.3.6.2, 2.3.6.3, 2.3.6.4, 2.3.6.5, 2.3.6.6, 2.3.6.7, 2.3.6.8, 2.3.6.9, 2.3.6.10, 2.3.7.1, 2.3.7.2, 5 2.3.7.3,2.3.7.4, 2.3.7.5, 2.3.7.6, 2.3.7.7, 2.3.7.8, 2.3.7.9, 2.3.7.10, 2.3.8.1, 2.3.8.2, 2.3.8.3, 2.3.8.4, 2.3.8.5, 2.3.8.6, 2.3.8.7, 2.3.8.8, 2.3.8.9, 2.3.8.10, 2.3.9.1, 2.3.9.2, 2.3.9.3, 2.3.9.4, 2.3.9.5, 2.3.9.6, 2.3.9.7, 2.3.9.8, 2.3.9.9, 2.3.9.10, 2.3.10.1, 2.3.10.2, 2.3.10.3, 2.3.10.4, 2.3.10.5, 2.3.10.6, 2.3.10.7,2.3.10.8, 2.3.10.9, 2.3.10.10, 2.4.1.1, 2.4.1.2, 2.4.1.3, 2.4.1.4, 2.4.1.5, 2.4.1.6, 2.4.1.7, 2.4.1.8, 2.4.1.9, 2.4.1.10, 2.4.2.1,2.4.2.2, 2.4.2.3, 2.4.2.4, 2.4.2.5, 2.4.2.6, 2.4.2.7, 2.4.2.8, 2.4.2.9, 2.4.2.10, 10 2.4.3.1,2.4.3.2, 2.4.3.3, 2.4.3.4, 2.4.3.5, 2.4.3.6, 2.4.3.7, 2.4.3.8, 2.4.3.9, 2.4.3.10, 2.4.4.1, 2.4.4.2, 2.4.4.3, 2.4.4.4, 2.4.4.5, 2.4.4.6, 2.4.4.7, 2.4.4.8, 2.4.4.9, 2.4.4.10, 2.4.5.1, 2.4.5.2, 2.4.5.3, 2.4.5.4, 2.4.5.5, 2.4.5.6, 2.4.5.7, 2.4.5.8, 2.4.5.9, 2.4.5.10, 2.4.6.1, 2.4.6.2, 2.4.6.3, 2.4.6.4, 2.4.15.5,2.4.6.6, 2.4.6.7, 2.4.6.8, 2.4.6.9, 2.4.6.10, 2.4.7.1, 2.4.7.2, 2.4.7.3, 2.4.7.4, 2.4.7.5, 2.4.7.6, 2.4.7.7, 2.4.7.8, 2.4.7.9, 2.4.7.10, 2.4.8.1, 2.4.8.2, 2.4.8.3, 2.4.8.4, 2.4.8.5, 2.4.8.6, 2.4.8.7, 2.4.8.8, 2.4.8.9, 2.4.8.10, 15 2.4.9.1, 2.4.9.2, 2.4.9.3, 2.4.9.4, 2.4.9.5, 2.4.9.6, 2.4.9.7, 2.4.9.8, 2.4.9.9, 2.4.9.10, 2.4.10.1, 2.4.10.2, 2.4.10.3, 2.4.10.4, 2.4.10.5, 2.4.10.6, 2,4.10.7, 2.4.10.8, 2.4.10.9, 2.4.10.10, 2.5.1.1, 2.5.1.2, 2.5.1.3, 2.5.1.4, 2.5.1.5, 2.5.1.6, 2.5.1.7, 2.5.1.8, 2.5.1.9, 2.5.1.10, 2.5.2.1, 2.5.2.2, 2.5.2.3, 2.5.2.4, 2.5.2.5, 2.5.2.6, 2.5.2.7, 2.5.2.8, 2.5.2.9, 2.5.2.10, 2.5.3.1, 2.5.3.2, 2.5.3.3, 2.5.3.4, 2.5.3.5, 2.5.3.6, 2.5.3.7, 2.5.3.8, 2.5.3.9, 2.5.3.10, 2.5.4.1, 2.5.4.2, 2.5.4.3, 2.5.4.4, 2.5.4.5, 2.5.4.6, 2.5.4.7, 20 2.5.4.8, 2.5.4.9, 2.5.4.10, 2.5.5.1, 2.5.5.2, 2.5.5.3, 2.5.5.4, 2.5.5.5, 2.5.5.6, 2.5.5.7, 2.5.5.8, 2.5.5.9, 2.5.5.10, 2.5.6.1,2.5.6.2, 2.5.6.3, 2.5.6.4, 2.5.6.5, 2.5.6.6, 2.5.6.7, 2.5.6.8, 2.5.6.9, 2.5.6.10, 2.5.7.1, 2.5.7.2, 2.5.7.3, 2.5.7.4, 2.5.7.5, 2.5.7.6, 2.5.7.7, 2.5.7.8, 2.5.7.9, 2.5.7.10, 2.5.8.1, 2.5.8.2, 2.5.8.3, 2.5.8.4, 2.5.8.5, 2.5.8.6, 2.5.8.7, 2.5.8.8, 2:5.8.9, 2.5.8.10, 2.5.9.1,2.5.9.2, 2.5.9.3, 2.5.9.4, 2.5.9.5, 2.5.9.6, 2.5.9.7, 2.5.9.8, 2.5.9.9, 2.5.9.10, 2.5.10.1, 2.5.10.2, 2.5.10.3, 2.5.10.4, 2.5.10.5, 2.5.10.6, 25 2.5.10.7, 2.5.10.8, 2.5.10.9, 2.5.10.10, 2.6.1.1, 2.6.1.2, 2.6.1.3, 2.6.1.4, 2.6.1.5, 2.6.1.6, 2.6.1.7, 2.6.1.8, 2.6.1.9, 2.6.1.10, 2.6.2.1, 2.6.2.2, 2.6.2.3, 2.6.2.4, 2.6.2.5,2.6.2.6, 2.6.2.7, 2.6.2.8, 2.6.2.9, 2.6.2.10, 2.6.3.1, 2.6.3.2, 2.6.3.3, 2.6.3.4, 2.6.3.5, 2.6.3.6, 2.6.3.7, 2.6.3.8, 2.6.3.9, 2.6.3.10, 2.6.4.1, 2.6.4.2, 2.6.4.3, 2.6.4.4, 2.6.4.5, 2.6.4.6, 2.6.4.7, 2.6.4.8, 2.6.4.9, 2.6.4.10, 2.6.5.1,2.6.5.2, 2.6.5.3, 2.6.5.4, 2.6.5.5, 2.6.5.6, 2.6.5.7, 2.6.5.8, 2.6.5.9, 2.6.5.10, 2.6.6.1, 2.6.6.2, 2.6.6.3, 2.6.6.4, 2.6.6.5, 30 2.6.6.6, 2.6.6.7, 2.6.6.8, 2.6.6.9, 2.6.6.10, 2.6.7.1, 2.6.7.2, 2.6.7.3, 2.6.7.4, 2.6.7.5, 2.6.7.6, 2.6.7.7, 2.6.7.8, 2.6.7.9, 2.6.7.10, 2.6.8.1,2.6.8.2, 2.6.8.3, 2.6.8.4, 2.6.8.5, 2.6.8.6, 2.6.8.7, 2.6.8.8, 2.6.8.9, 2.6.8.10, 2.6.9.1, 2.6.9.2, 2.6.9.3, 2.6.9.4, 2.6.9.5, 2.6.9.6, 2.6.9.7, 2.6.9.8, 2.6.9.9, 2.6.9.10, 2.6.10.1, 2.6.10.2, 2.6.10.3, 2.6.10.4, 2.6.10.5, 2.6.10.6, 2.6.10.7, 2.6.10.8, 2.6.10.9, 2.6.10.10, 2.7.1.1.2.7.1.2.2.7.1.3.2.7.1.4, 2.7.1.5,2.7.1.6,2.7.1.7, 2.7.1.8, 2.7.1.9,2.7.1.10,2.7.2.1,2.7.2.2, 35 2.7.2.3, 2.7.2.4, 2.7.2.5, 2.7.2.6, 2.7.2.7, 2.7.2.8, 2.7.2.9,‘ 2.7.2.10, 2.7.3.1, 2.7.3.2, 2.7.3.3, 2.7.3.4,

34 2.7.3.5, 2.7.3.6, 2.7.3.7, 2.7.3,.8, 2.7.3.9, 2.7.3.10, 2.7.4.1, 2.7.4.2, 2.7.4.3, 2.7.4.4, 2.7.4.5, 2.7.4.6, 2.7.4.7, 2.7.4.8, 2.7.4.9, 2.7.4.10, 2.7.5.1, 2.7.5.2, 2.7.5.3, 2.7.5.4, 2.7.5.5, 2.7.5.6, 2.7.5.7, 2.7.5.8, 2.7.5.9, 2.7.5.10, 2.7.6.1,2.7.6.2, 2.7.6.3, 2.7.6.4, 2.7.6.5, 2.7.6.6, 2.7.6.7, 2.7.6.8, 2.7.6.9, 2.7.6.10, 2.7.7.1,2.7.7.2, 2.7.7.3, 2.7.7.4, 2.7.7.5, 2.7.7.6, 2.7.7.7, 2.7.7.8, 2.7.7.9, 2.7.7.10, 2.7.8.1, 2.7.8.2, 5 2.7.8.3, 2.7.8.4, 2.7.8.5, 2.7.8.6, 2.7.8.7, 2.7.8.8, 2.7.8.9, 2.7.8.10, 2.7.9.1, 2.7.9.2, 2.7.9.3, 2.7.9.4, 2.7.9.5, 2.7.9.6, 2.7.9.7, 2.7.9.8, 2.7.9.9, 2.7.9.10, 2.7.10.1, 2.7.10.2, 2.7.10.3, 2.7.10.4, 2.7.10.5, 2.7.10.6, 2.7.10.7, 2.7.10.8, 2.7.10.9, 2.7.10.10, 2.8.1.1, 2.8.1.2, 2.8.1.3, 2.8.1.4, 2.8.1.5,2.8.1.6, 2.8.1.7, 2.8.1.8, 2.8.1.9, 2.8.1.10, 2.8.2.1, 2.8.2.2, 2.8.2.3, 2.8.2.4, 2.8.2.5, 2.8.2.6, 2.8.2.7, 2.8.2.8, 2.8.2.9, 2.8.2.10, 2.8.3.1, 2.8.3.2, 2.8.3.3, 2.8.3.4, 2.8.3.5, 2.8.3.6, 2.8.3.7, 2.8.3.8, 2.8.3.9, 2.8.3.10, 10 2.8.4.1, 2.8.4.2, 2.8.4.3, 2.8.4.4, 2.8.4.5, 2.8.4.6, 2.8.4.7, 2.8.4.8, 2.8.4.9, 2.8.4.10, 2.8.5.1,2.8.5.2, 2.8.5.3, 2.8.5.4, 2.8.5.5, 2.8.5.6, 2.8.5.7, 2.8.5.8, 2.8.5.9, 2.8.5.10, 2.8.6.1, 2.8.6.2, 2.8.6.3, 2.8.6.4, 2.8.6.5, 2.8.6.6, 2.8.6.7, 2.8.6.8, 2.8.6.9, 2.8.6.10, 2.8.7.1,2.8.7.2, 2.8.7.3, 2.8.7.4, 2.877.5, 2.8.7.6, 2.8.7.7, 2.8.7.8, 2.8.7.9, 2.8.7.10, 2.8.8.1, 2.8.8.2, 2.8.8.3, 2.8.8.4, 2.8.8.5, 2.8.8.6, 2.8.8.7, 2.8.8.8, 2.8.8.9, 2.8.8.10, 2.8.9.1, 2.8.9.2, 2.8.9.3, 2.8.9.4, 2.8.9.5, 2.8.9.6, 2.8.9.7, 2.8.9.8, 2.8.9.9, 2.8.9.10, 15 2.8.10.1,2.8.10.2, 2.8.10.3, 2.8.10.4, 2.8.10.5, 2.8.10.6, 2.8.10.7, 2.8.10.8, 2.8.10.9, 2.8.10.10, 2.9.1.1, 2.9.1.2, 2.9.1.3, 2.9.1.4, 2.9.1.5, 2.9.1.6, 2.9.1.7, 2.9.1.8, 2.9.1.9, 2.9.1.10, 2.9.2.1,2.9.2.2, 2.9.2.3, 2.9.2.4, 2.9.2.5, 2.9.2.6, 2.9.2.7, 2.9.2.8, 2.9.2.9, 2.9.2.10, 2.9.3.1, 2.9.3.2, 2.9.3.3, 2.9.3.4, 2.9.3.5, 2.9.3.6, 2.9.3.7, 2.9.3.8, 2.9.3.9, 2.9.3.10, 2.9.4.1, 2.9.4.2, 2.9.4.3, 2.9.4.4, 2.9.4.5, 2.9.4.6, 2.9.4.7, 2.9.4.8, 2.9.4.9, 2.9.4.10, 2.9.5.1, 2.9.5.2, 2.9.5.3, 2.9.5.4, 2.9.5.5, 2.9.5.6, 2.9.5.7, 2.9.5.8, 20 2.9.5.9, 2.9.5.10, 2.9.6.1, 2.9.6.2, 2.9.6.3, 2.9.6.4, 2.9.6.5, 2.9.6.6, 2.9.6.7, 2.9.6.8, 2.9.6.9, 2.9.6.10, 2.9.7.1, 2.9.7.2, 2.9.7.3, 2.9.7.4, 2.9.7.5, 2.9.7.6, 2.9.7.7, 2.9.7.8, 2.9.7.9, 2.9.7.10, 2.9.8.1, 2.9.8.2, 2.9.8.3, 2.9.8.4, 2.9.8.5, 2.9.8.6, 2.9.8.7, 2.9.8.8, 2.9.8.9, 2.9.8.10, 2.9.9.1, 2.9.9.2, 2.9.9.3, 2.9.9.4, 2.9.9.5, 2.9.9.6, 2.9.9.7, 2.9.9.8, 2.9.9.9, 2.9.9.10, 2.9.10.1, 2.9.10.2, 2.9.10.3, 2.9.10.4, 2.9.10.5, 2.9.10.6, 2.9.10.7, 2.9.10.8, 2.9.10.9, 2.9.10.10, 2.10.1.1, 2.10.1.2,2.10.1.3, 2.10.1.4, 2.10.1.5, 25 2.10.1.6, 2.10.1.7, 2.10.1.8, 2.10.1.9, 2.10.1.10, 2.10.2.1, 2.10.2.2, 2.10.2.3, 2.10.2.4, 2.10.2.5, 2.10.2.6, 2.10.2.7, 2.10.2.8, 2.10.2.9, 2.10.2,10, 2.10.3.1, 2.10.3.2, 2.10.3.3, 2.10.3.4, 2.10.3.5, 2.10.3.6, 2.10.3.7, 2.10.3.8, 2.10.3.9, 2.10.3.10, 2.10.4.1, 2.10.4.2, 2.10.4.3, 2.10.4.4, 2.10.4.5, 2.10.4.6, 2.10.4.7, 2.10.4.8, 2.10.4.9, 2.10.4.10, 2.10.5.1, 2.10.5.2, 2.10.5.3, 2.10.5.4, 2.10.5.5, 2.10.5.6, 2.10.5.7, 2.10.5.8, 2.10.5.9, 2.10.5.10, 2.10.6.1, 2.10.6.2, 2.10.6.3, 2.10.6.4, 2.10.6.5, 30 2.10.6.6, 2.10.6.7, 2.10.6.8, 2.10.6.9, 2.10.6.10, 2:10.7.1, 2.10.7.2, 2.10.7.3, 2.10.7.4, 2.10.7.5, 2.10.7.6, 2.10.7.7, 2.10.7.8, 2.10.7.9, 2.10.7.10, 2.10.8.1,2.10.8.2, 2.10.8.3, 2.10.8.4, 2.10.8.5, 2.10.8.6, 2.10.8.7, 2.10.8.8, 2.10.8.9, 2.10.8.10, 2.10.9.1, 2.10.9.2, 2.10.9.3, 2.10.9.4, 2.10.9.5, 2.10.9.6, 2.10.9.7, 2.10.9.8, 2.10.9.9, 2.10.9.10, 2.10.10.1, 2.10.10.2, 2.10.10.3, 2.10.10.4, 2.10.10.5.2.10.10.6, 2.10.10.7,2.10.10.8,2.10.10.9,2.10.10.10,3.1.1.1,3.1.1.2,3.1.1.3,3.1.1.4, 35 3.1.1.5, 3.1.1.6, 3.1.1.7, 3.1.1.8,3.1.1.9,3.1.1.10,3.1.2:1,3.1.2.2,3.1.2.3,3.1.2.4, 3.1.2.5,3.1.2.6,

L 35 3.1.2.7, 3.1.2.8, 3.1.2.9, 3.1.2.10, 3.1.3.1, 3.1.3.2, 3.1.3.3, 3.1.3.4, 3.1.3.5, 3.1.3.6, 3.1.3.7, 3.1.3.8, 3.1.3.9,3.1.3.10,3.1.4.1,3.1.4.2,3.1.4,3,3.1.4.4, 3.1.4.5, 3.1.4.6,3.1.4.7, 3.1.4.8, 3.1.4.9, 3.1.4.10, 3.1.5.1, 3.1.5.2, 3.1.5.3, 3.1.5.4, 3.1.5.5, 3.1.5.6, 3.1.5.7, 3.1.5.8, 3.1.5.9, 3.1.5.10, 3.1.6.1, 3.1.6.2, 3.1.6.3, 3.1.6.4, 3.1.6.5, 3.1.6.6, 3.1.6.7, 3.1.6.8, 3.1.6.9, 3.1.6.10, 3.1.7.1, 3.1.7.2, 3.1.7.3, 3.1.7.4, 5 3.1.7.5, 3.1.7.6, 3.1.7.7, 3.1.7.8, 3.1.7.9,3.1.7.10, 3.1.8.1, 3.1.8.2, 3.1.8.3, 3.1.8.4, 3.1.8.5, 3.1.8.6, 3.1.8.7, 3.1.8.8, 3.1.8.9, 3.1.8.10, 3.1.9.1, 3.1.9.2, 3.1.9.3, 3.1.9.4, 3.1.9.5, 3.1.9.6, 3.1.9.7, 3.1.9.8, 3.1.9.9, 3.1.9.10, 3.1.10.1, 3.1.10.2, 3.1.10.3, 3.1.10.4, 3.1.10.5, 3.1.10.6, 3.1.10.7, 3.1.10.8, 3.1.10.9, 3.1.10.10, 3.2.1.1, 3.2.1.2, 3,2.1.3, 3.2.1.4, 3.2.1.5,3.2.1.6, 3.2.1.7, 3.2.1.8, 3.2.1.9, 3.2.1.10, 3.2.2.1, 3.2.2.2, 3.2.2.3, 3.2.2.4, 3.2.2.5, 3.2.2.6, 3.2.2.7, 3.2.2.8, 3.2.2.9, 3.2.2.10, 3.2.3.1, 10 3.2.3.2, 3.2.3.3, 3.2.3.4, 3.2.3.5, 3.2.3.6, 3.2.3.7, 3.2.3.8, 3.2.3.9, 3.2.3.10, 3.2.4.1, 3.2.4.2, 3.2.4.3, 3.2.4.4, 3.2.4.5, 3.2.4.6, 3.2.4.7, 3.2.4.8, 3.2.4.9, 3.2.4.10, 3.2.5.1, 3.2.5.2, 3.2.5.3, 3.2.5.4, 3.2.5.5, 3.2.5.6, 3.2.5.7, 3.2.5.8, 3.2.5.9, 3.2.5.10, 3.2.6.1, 3.2.6.2, 3.2.6.3, 3.2.6.4, 3.2.6.5, 3.2.6.6, 3.2.6.7, 3.2.6.8, 3.2.6.9, 3.2.6.10, 3.2.7.1, 3.2.7.2, 3.2.7.3, 3.2.7.4, 3.2.7.5, 3.2.7.6, 3.2.7.7, 3.2.7.8, 3.2.7.9, 3.2.7.10, 3.2.8.1,3.2.8.2, 3.2.8.3, 3.2.8.4, 3.2.8.5, 3.2.8.6, 3.2.8.7, 3.2.8.8, 3.2.8.9, 3.2.8.10, 3.2.9.1, 15 3.2.9.2, 3.2.9.3, 3.2.9.4, 3.2.9.5, 3.2.9.6, 3.2.9.7, 3.2.9.8, 3.2.9.9, 3,2.9.10, 3.2.10.1, 3.2.10.2, 3.2.10.3, 3.2.10.4, 3.2.10.5, 3.2.10.6, 3.2.10.7, 3.2.10.8, 3.2.10.9, 3.2.10.10, 3.3.1.1, 3.3.1.2, 3.3.1.3, 3.3.1.4, 3.3.1.5, 3.3.1.6, 3.3.1.7, 3.3.1.8, 3.3.1.9, 3.3.1.10, 3.3.2.1, 3.3.2.2, 3.3.2.3, 3.3.2.4, 3.3.2.5, 3.3.2.6, 3.3.2.7, 3.3.2.8, 3.3.2.9, 3.3.2.10, 3.3.3.1, 3.3.3.2, 3.3.3.3, 3.3.3.4, 3.3.3.5, 3.3.3.6, 3.3.3.7, 3.3.3.8, 3.3.3.9, 3.3.3.10, 3.3.4.1, 3.3.4.2, 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3.10.9.5, 15 3.10.9.6, 3.10.9.7, 3.10.9.8, 3.10.9.9, 3.10.9.10, 3.10.10.1,3.10.10.2, 3.10.10.3, 3.10.10.4, 3.10.10.5, 3.10.10.6,3.10.10.7,3.10.10.8,3.10.10.9,3,10.10.10,4.1.1.1, 4.1.1.2,4.1.1.3,4.1.1.4, 4.1.1.5, 4.1.1.6, 4.1.1.7, 4.1.1.8, 4.1.1.9, 4.1.1.10, 4.1.2.1, 4.1.2.2, 4.1.2.3, 4.1.2.4, 4.1.2.5, 4.1.2.6, 4.1.2.7, 4.1.2.8, 4.1.2.9, 4.1.2.10, 4.1.3.1, 4.1.3.2, 4.1.3.3, 4.1.3.4, 4.1.3.5, 4.1.3.6, 4.1.3.7, 4.1.3.8, 4.1.3.9, 4.1.3.10, 4.1.4.1, 4.1.4.2, 4.1.4.3, 4.1.4.4, 4.1.4.5, 4.1.4.6, 4.1.4.7, 4.1.4.8, 4.1.4.9, 4.1.4.10, 20 4.1.5.1, 4.1.5.2, 4.1.5.3, 4.1.5.4, 4.1.5.5, 4.1.5.6, 4.1.5.7, 4.1.5.8, 4.1.5.9, 4.1.5.10, 4.1.6.1, 4.1.6.2, 4.1.6.3, 4.1.6.4, 4.1.6.5, 4.1.6.6, 4.1.6.7, 4.1.6.8, 4.1.6.9, 4.1.6.10, 4.1.7.1, 4.1.7.2, 4.1.7.3, 4.1.7.4, 4.1.7.5, 4.1.7.6, 4.1.7.7, 4.1.7.8, 4.1.7.9, 4.1.7.10, 4.1.8.1,4.1.8.2, 4.1.8.3, 4.1.8.4, 4.1.8.5, 4.1.8.6, 4.1.8.7, 4.1.8.8, 4.1.8.9, 4.1.8.10, 4.1.9.1,4.1.9.2, 4.1.9.3, 4.1.9.4, 4.1.9.5, 4.1.9.6, 4.1.9.7, 4.1.9.8, 4.1.9.9, 4.1.9.10,4.1.10.1,4.1.10.2,4.1.10.3, 4.1.10.4, 4.1.10.5,4.1.10.6,4.1.10.7,4.1.10.8, 25 4.1.10.9, 4.1.10.10, 4.2.1.1,4.2.1.2,4.2.1.3, 4.2.1.4,4.2.1.5,4.2.1.6,4.2.1.7, 4.2.1.8, 4.2.1.9, 4.2.1.10, 4.2.2.1, 4.2.2.2, 4.2.2.3, 4.2.2.4, 4.2.2.5, 4.2.2.6, 4.2.2.7, 4.2.2.8, 4.2.2.9, 4.2.2.10, 4.2.3.1, 4.2.3.2, 4.2.3.3, 4.2.3.4, 4.2.3.5, 4.2.3.6, 4.2.3.7, 4.2.3.8, 4.2.3.9, 4.2.3.10, 4.2.4.1, 4.2.4.2, 4.2.4.3, 4.2.4.4, 4.2.4.5, 4.2.4.6, 4.2.4.7, 4.2.4.8, 4.2.4.9, 4.2.4.10, 4.2.5.1, 4.2.5.2, 4.2.5.3, 4.2.5.4, 4.2.5.5, 4.2.5.6, 4.2.5.7, 4.2.5.8, 4.2.5.9, 4.2.5.10, 4.2.6.1,4.2.6.2, 4.2.6.3, 4.2.6.4, 4.2.6.5, 4.2.6.6, 4.2.6.7, 30 4.2.6.8, 4.2.6.9, 4.2.6.10, 4.2.7.1, 4.2.7.2, 4.2.7.3,4.2.7.4, 4.2.7.5, 4.2.7.6, 4.2.7.7, 4.2.7.8, 4.2.7.9, 4.2.7.10, 4.2.8.1, 4.2.8.2, 4.2.8.3, 4.2.8.4, 4.2.8.5, 4.2.8.6, 4.2.8.7, 4.2.8.8, 4.2.8.9, 4.2.8.10, 4.2.9.1, 4.2.9.2, 4.2.9.3, 4.2.9.4, 4.2.9.5, 4.2.9.6, 4.2.9.7, 4.2.9.8, 4.2.9.9, 4.2.9.10, 4.2.10.1, 4.2.10.2, 4.2.10.3, 4.2.10.4, 4.2.10.5, 4.2.10.6, 4.2.10.7, 4.2.10.8, 4.2.10.9, 4.2.10.10, 4.3.1.1, 4.3.1.2, 4.3.1.3, 4.3.1.4, 4.3.1.5, 4.3.1.6, 4.3.1.7, 4.3.1.8, 4.3.1.9, 4.3.1.10, 4.3.2.1,4.3.2.2, 4.3.2.3, 4.3.2.4, 35 4.3.2.5, 4.3.2.6, 4.3.2.7, 4.3.2.8, 4.3.2.9, 4.3.2.10, 4.3.3.1, 4.3.3.2, 4.3.3.3, 4.3.3.4, 4.3.3.5, 4.3.3.6, 38 ίο 15 20 25 30 35 1171 4.3.3.7, 4.3.3.8, 4.3.3.9, 4.3.3.10, 4.3.4.1, 4.3.4.2, 4.3.4.3, 4.3.4.4, 4.3.4.5, 4.3.4.6, 4.3.4.7, 4.3.4.8, 4.3.4.9, 4.3.4.10, 4.3.5.1, 4.3.5.2, 4.3.5.3, 4.3.5.4, 4.3.5.5, 4.3.5.6, 4.3.5.7, 4.3.5.8, 4.3.5.9, 4.3.5.10, 4.3.6.1, 4.3.6.2, 4.3.6.3, 4.3.6.4, 4.3.6.5, 4.3.6.6, 4.3.6.7, 4.3.6.8, 4.3.6.9, 4.3.6.10, 4.3.7.1, 4.3.7.2, 4.3.7.3, 4.3.7.4, 4.3.7.5, 4.3.7.6, 4.3.7.7, 4.3.7.8, 4.3.7.9, 4.3.7.10, 4.3.8.1,4.3.8.2, 4.3.8.3, 4.3.8.4, 4.3.8.5, 4.3.8.6, 4.3.8.7, 4.3.8.8, 4.3.8.9, 4.3.8.10, 4.3.9.1,4.3.9.2, 4.3.9.3, 4.3.9.4, 4.3.9.5, 4.3.9.6, 4.3.9.7, 4.3.9.8, 4.3.9.9, 4.3.9.10,4.3.10.1,4.3.10.2,4.3.10.3, 4.3.10.4,4.3.10.5,4.3.10.6, 4.3.10.7, 4.3.10.8, 4.3.10.9, 4.3.10.10, 4.4.1.1, 4.4.1.2, 4.4.1.3, 4.4.1.4, 4.4.1.5, 4.4.1.6, 4.4.1.7, 4.4.1.8, 4.4.1.9, 4.4.1.10, 4.4.2.1, 4.4.2.2, 4.4.2.3, 4.4.2.4, 4.4.2.5, 4.4.2.6, 4.4.2.7, 4.4.2.8, 4.4.2.9, 4.4.2.10, 4.4.3.1, 4.4.3.2, 4.4.3.3, 4.4.3.4, 4.4.3.5, 4.4.3.6, 4.4.3.7, 4.4.3.8, 4.4.3.9, 4.4.3.10, 4.4.4.1, 4.4.4.2, 4.4.4.3, 4.4.4.4, 4.4.4.5, 4.4.4.6, 4.4.4.7, 4.4.4.8, 4.4.4.9, 4.4.4.10, 4.4.5.1,4.4.5.2, 4.4.5.3, 4.4.5.4, 4.4.5.5, 4.4.5.6, 4.4.5.7, 4.4.5.8, 4.4.5.9, 4.4.5.10, 4.4.6.1, 4.4.6.2, 4.4.6.3, 4.4.6.4, 4.4.6.5, 4.4.6.6, 4.4.6.7, 4.4.6.8, 4.4.6.9, 4.4.6.10, 4.4.7.1,4.4.7.2, 4.4.7.3, 4.4.7.4, 4.4.7.5, 4.4.7.6, 4.4.7.7, 4.4.7.8, 4.4.7, -9, 4.4.7.10, 4.4.8.1,4.4.8.2, 4.4.8.3, 4.4.8.4,14.4.8.5, 4.4.8.6, 4.4.8.7, 4.4.8.8, 4.4.8.9, 4.4.8.10, 4.4.9.1, 4.4.9.2, 4.4.9.3, 4.4.9.4, 4.4.9.5, 4.4.9.6, 4.4.9.7, 4.4.9.8, 4.4.9.9, 4.4.9.10, 4.4.10.1, 4.4.10.2, 4.4.10.3,4.4.10.4, 4.4.10.5, 4.4.10.6,4.4.10.7, 4.4.10.8, 4.4.10.9,4.4.10.10,4.5.1.1, 4.5.1.2, 4.5.1.3, 4.5.1.4, 4.5.1.5, 4.5.1.6, 4.5.1.7, 4.5.1.8, 4.5.1.9, 4.5.1.10, 4.5.2.1, 4.5.2.2, 4.5.2.3, 4.5.2.4, 4.5.2.5, 4.5.2.6, 4.5.2.7, 4.5.2.8, 4.5.2.9, 4.5.2.10, 4.5.3.1, 4.5.3.2, 4.5.3.3, 4.5.3.4, 4.5.3.5, 4.5.3.6, 4.5.3.7, 4.5.3.8, 4.5.3.9, 4.5.3.10, 4.5.4.1, 4.5.4.2, 4.5.4.3, 4.5.4.4, 4.5.4.5, 4.5.4.6, 4.5.4.7, 4.5.4.8, 4.5.4.9, 4.5.4.10, 4.5.5.1, 4.5.5.2, 4.5.5.3, 4.5.5.4, 4.5.5.5, 4.5.5.6, 4.5.5.7, 4.5.5.8, 4.5.5.9, 4.5.5.10, 4.5.6.1,4.5.6.2, 4.5.6.3, 4.5.6.4, 4.5.6.5, 4.5.6.6, 4.5.6.7, 4.5.6.8, 4.5.6.9, 4.5.6.10, 4.5.7.1, 4.5.7.2, 4.5.7.3, 4.5.7.4, 4.5.7.5, 4.5.7.6, 4.5.7.7, 4.5.7.8, 4.5.7.9, 4.5.7.10, 4.5.8.1, 4.5.8.2, 4.5.8.3, 4.5.8.4, 4.5.8.5, 4.5.8.6, 4.5.8.7, 4.5.8.8, 4.5.8.9, 4.5.8.10, 4.5.9.1, 4.5.9.2, 4.5.9.3, 4.5.9.4, 4.5.9.5, 4.5.9.6, 4.5.9.7, 4.5.9.8, 4.5.9.9, 4.5.9.10, 4.5.10.1, 4.5.10.2, 4.5.10.3, 4.5.10.4, 4.5.10.5, 4.5.10.6, 4.5.10.7, 4.5.10.8, 4.5.10.9, 4.5.10.10, 4.6.1.1, 4.6.1.2, 4.6.1.3, 4.6.1.4, 4.6.1.5, 4.6.1.6, 4.6.1.7, 4.6.1.8, 4.6.1.9, 4.6.1.10, 4.6.2.1,4.6.2.2, 4.6.2.3, 4.6.2.4, 4.6.2.5, 4.6.2.6, 4.6.2.7, 4.6.2.8, 4.6.2.9, 4.6.2.10, 4.6.3.1, 4.6.3.2, 4.6.3.3, 4.6.3.4, 4.6.3.5, 4.6.3.6, 4.6.3.7, 4.6.3.8, 4.6.3.9, 4.6.3.10, 4.6.4.1, 4.6.4.2, 4.6.4.3, 4.6.4.4, 4.6.4.5, 4.6.4.6, 4.6.4.7, 4.6.4.8, 4.6.4.9, 4.6.4.10, 4.6.5.1, 4.6.5.2, 4.6.5.3, 4.6.5.4, 4.6.5.5, 4.6.5.6, 4.6.5.7, 4.6.5.8, 4.6.5.9, 4.6.5.10, 4.6.6.1,4.6.6.2, 4.6.6.3, 4.6.6.4, 4.6.6.5, 4.6.6.6, 4.6.6.7, 4.6.6.8, 4.6.6.9, 4.6.6.10, 4.6.7.1, 4.6.7.2, 4.6.7.3,4.6.7.4, 4.6.7.5, 4.6.7.6, 4.6.7.7, 4.6.7.8, 4.6.7.9, 4.6.7.10, 4.6.8.1, 4.6.8.2, 4.6.8.3, 4,6.8.4, 4.6.8.5, 4.6.8.6, 4.6.8.7, 4.6.8.8, 4.6.8.9, 4.6.8.10, 4.6.9.1,4.6.9.2, 4.6.9.3, 4.6.9.4, 4.6.9.5, 4.6.9.6, 4.6.9.7, 4.6.9.8, 4.6.9.9, 4.6.9.10, 4.6.10.1, 4.6.10.2, 4.6.10.3, 4.6.10.4, 4.6.10.5, 4.6.10.6, 4.6.10.7, 4.6.10.8, 4.6.10.9, 4.6.10.10, 4.7.1.1.4.7.1.2, 4.7.1.3, 4.7.1.4, 4.7.1.5, 4.7.1.6, 4.7.1.7, 4.7.1.8, 4.7.1.9, 4.7.1.10, 4.7.2.1, 4.7.2.2, 4.7.2.3, 4.7.2.4, 4.7.2.5, 4.7.2.6, 4.7.2.7, 4.7.2.8, 4.7.2.9, 4.7.2.10, 4.7.3.1, 4.7.3.2, 4.7.3.3, 4.7.3.4, 4..7.3.5, 4.7.3.6, 4.7.3.7, 4.7.3.8, 4.7.3.9, 4.7.3.10, 4.7.4.h, 4.7.4.2, 4.7.4.3, 4.7.4.4, 4.7.4.5, 4.7.4.6, \ 1/ν-^ 39 10 15 20 25 30 35 * Π 1 r ! î υ 4.7.4.7, 4.7.4.8, 4.7.4.9, 4.7.4.10,4.7.5.1, 4.7.5.2, 4.7.5.3, 4.7.5.4, 4.7.5.5, 4.7.5.6, 4.7.5.7,4.7.5.8, 4.7.5.9, 4.7.5.10, 4.7.6.1, 4.7.6.2, 4.7.6.3, 4.7.6.4, 4.7.6.5, 4.7.6.6, 4.7.6.7, 4.7.6.8-. 4.7.6.9, 4.7.6.10, 4.7.7.1, 4.7.7.2, 4.7.7.3, 4.7.7.4, 4.7.7.5, 4.7.7,6, 4.7.7.7, 4.7.7.8, 4.7.7.9, 4.7.7.10, 4.7.8.1, 4.7.8.2, 4.7.8.3, 4.7.8.4, 4.7.8.5, 4.7.8.6, 4.7.8.7, 4.7.8.8, 4.7.8.9, 4.7.8.10, 4.7.9.1, 4.7.9.2, 4.7.9.3, 4.7.9.4, 4.7.9.5, 4.7.9.6, 4.7.9.7, 4.7.9.8, 4.7.9.9, 4.7.9.10, 4.7.10.1, 4.7.10.2, 4.7.10.3, 4.7.10.4, 4.7.10.5, 4.7.10.6, 4.7.10.7, 4.7.10.8, 4.7.10.9, 4.7.10.10,4.8.1.1, 4.8.1.2, 4.8.1.3, 4.8.1.4, 4.8.1.5, 4.8.1.6, 4.8.1.7, 4.8.1.8, 4.8.1.9, 4.8.1.10, 4.8.2.1, 4.8.2.2, 4.8.2.3, 4.8.2.4, 4.8.2.5, 4.8.2.6, 4.8.2.7, 4.8.2.8, 4.8.2.9, 4.8.2.10, 4.8.3.1, 4.8.3.2, 4.8.3.3, 4.8.3.4, 4.8.3.5, 4.8.3.6, 4.8.3.7, 4.8.3.8, 4.8.3.9, 4.8.3.10, 4.8.4.1, 4.8.4.2, 4.8.4.3, 4.8.4.4, 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5.10.1.9, 5.10.1.10, 5.10.2.1, 5.10.2.2, 5.10.2.3, 5.10.2.4, 5.10.2.5, 5.10.2.6, 5.10.2.7, 5.10.2.8, 5.10.2.9, 5.10.2.10, 5.10.3.1, 5.10.3.2, 5.10.3.3, 5.10.3.4, 5.10.3.5, 5.10.3.6, 5.10.3.7, 5.10.3.8, 5.10.3.9, 5.10.3.10, 5.10.4.1, 5.10.4.2, 5.10.4.3, 5.10.4.4, 5.10.4.5, 5.10.4.6, 5.10.4.7, 5.10.4.8, 5.10.4.9, 5.10.4.10, 5.10.5.1, 5.10.5.2, 5.10.5.3, 5.10.5.4, 5.10.5.5, 10 5.10.5.6, 5.10.5.7, 5.10.5.8, 5.10.5.9, 5.10.5.10, 5.10.6.1, 5.10.6.2, 5.10.6.3, 5.10.6.4, 5.10.6.5, 5.10.6.6, 5.10.6.7, 5.10.6.8, 5.10.6.9, 5.10.6.10, 5.10.7.1, 5.10.7.2, 5.10.7.3, 5.10.7.4, 5.10.7.5, 5.10.7.6, 5.10.7.7, 5.10.7.8, 5.10.7.9, 5.10.7.10, 5.10.8.1, 5.10.8.2, 5.10.8.3, 5.10.8.4, 5.10.8.5, 5.10.8.6, 5.10.8.7, 5.10.8.8, 5.10.8.9, 5.10.8.10, 5.10.9.1, 5.10.9.2, 5.10.9.3, 5.10.9.4, 5.10.9.5, 5.10.9.6, 5.10.9.7, 5.10.9.8, 5.10.9.9, 5.10.9.10, 5.10.10.1, 5.10.10.2, 5.10.10.3, 5.10.10.4, 15 5.10.10.5, 5.10.10.6, 5.10.10.7, 5.10.10.8, 5.10.10.9, 5.10.10.10, 6.1.1.1, 6.1.1.2, 6.1.1.3, 6.1.1.4, 6.1.1.5, 6.1.1.6, 6.1.1.7, 6.1.1.8, 6.1.1.9, 6.1.1.10, 6.1.2.1, 6.1.2.2, 6.1.2.3, 6.1.2.4, 6.1.2.5, 6.1.2.6, 6.1.2.7, 6.1.2.8, 6.1.2.9, 6.1.2.10, 6.1.3.1, 6.1.3.2, 6.1.3.3, 6.1.3.4, 6.1.3.5, 6.1.3.6, 6.1.3.7, 6.1.3.8, 6.1.3.9, 6.1.3.10, 6.1.4.1, 6.1.4.2, 6.1.4.3, 6.1.4.4, 6.1.4.5, 6.1.4.6, 6.1.4.7, 6.1.4.8, 6.1.4.9, 6.1.4.10, 6.1.5.1, 6.1.5.2, 6.1.5.3, 6.1.5.4, 6.1.5.5, 6.1.5.6, 6.1.5.7, 6.1.5.8, 6.1.5.9, 6.1.5.10, 6.1.6.1, 6.1.6.2, 20 6.1.6.3, 6.1.6.4, 6.1.6.5, 6.1.6.6, 6.1.6.7, 6.1.6.8, 6.1.6.9, 6.1.6.10, 6.1.7.1, 6.1.7.2, 6.1.7.3, 6.1.7.4, 6.1.7.5, 6.1.7.6, 6.1.7.7, 6.1.7.8, 6.1.7.9, 6.1.7.10, 6.1.8.1, 6.1.8.2, 6.1.8.3, 6.1.8.4, 6.1.8.5, 6.1.8.6, 6.1.8.7, 6.1.8.8, 6.1.8.9, 6.1.8.10, 6.1.9.1, 6.1.9.2, 6.1.9.3, 6.1.9.4, 6.1.9.5, 6.1.9.6, 6.1.9.7, 6.1.9.8, 6.1.9.9, 6.1.9.10, 6.1.10.1, 6.1.10.2, 6.1.10.3, 6.1.10.4, 6.1.10.5, 6.1.10.6, 6.1.10.7, 6.1.10.8, 6.1.10.9, 6.1.10.10, 6.2.1.1, 6.2.3.2, 6.2.1.3, 6.2.1.4, 6.2.1.5, 6.2.1.6, 6.2.1.7, 6.2.1.8, 6.2.1.9, 25 6.2.1.10, 6.2.2.1, 6.2.2.2, 6.2.2.3, 6.2.2.4, 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7.9.9.9, 7.9.9.10, 7.9.10.1, 7.9.10.2, 7.9.10.3, 7.9.10.4, 7.9.10.5, 7.9.10.6, 7.9.10.7, 7.9.10.8, 7.9.10.9, 7.9.10.10, 7.10.1.1, 7.10.1.2, 7.10.1.3, 7.10.1.4, 7.10.1.5, 5 7.10.1.6, 7.10.1.7, 7.10.1.8, 7.10.1.9, 7.10.1.10, 7.10.2.1, 7.10.2.2, 7.10.2.3, 7.10.2.4, 7.10.2.5, 7.10.2.6, 7.10.2.7, 7.10.2.8, 7.10.2.9, 7.10.2.10, 7.10.3.1, 7.10.3.2, 7.10.3.3, 7.10.3.4, 7.10.3.5, 7.10.3.6, 7.10.3.7, 7.10.3.8, 7.10.3.9, 7.10.3.10, 7.10.4.1, 7.10.4.2, 7.10.4.3, 7.10.4.4, 7.10.4.5, 7.10.4.6, 7.10.4.7, 7.10.4.8, 7.10.4.9, 7.10.4.10, 7.10.5.1, 7.10.5.2, 7.10.5.3, 7.10.5.4, 7.10.5.5, 7.10.5.6, 7.10.5.7, 7.10.5.8, 7.10.5.9, 7.10.5.10, 7.10.6.1, 7.10.6.2, 7.10.6.3, 7.10.6.4, 7.10.6.5, 10 7.10.6.6, 7.10.6.7, 7.10.6.8, 7.10.6.9, 7.10.6.10, 7.10.7.1, 7.10.7.2, 7.10.7.3, 7.10.7.4, 7.10.7.5, 7.10.7.6, 7.10.7.7, 7.10.7.8, 7.10.7.9, 7.10.7.10, 7.10.8.1, 7.10.8.2, 7.10.8.3, 7.10.8.4, 7.10.8.5, 7.10.8.6, 7.10.8.7, 7.10.8.8, 7.10.8.9, 7.10.8.10, 7.10.9.1, 7.10.9.2, 7.10.9.3, 7.10.9.4, 7.10.9.5, 7.10.9.6, 7.10.9.7, 7.10.9.8, 7.10.9.9, 7.10.9.10, 7.10.10.1, 7.10.10.2, 7.10.10.3, 7.10.10.4, 7.10.10.5, 7.10.10.6, 7.10.10.7, 7.10.10.8, 7.10.10.9, 7.10.10.10, 8.1.1.1, 8.1.1.2, 8.1.1.3, 8.1.1.4, 15 8.1.1.5, 8.1.1.6, 8.1.1.7, 8.1.1.8, 8.1.1.9, 8.1.1.10, 8.1.2.1, 8.1.2.2, 8.1.2.3, 8.1.2.4, 8.1.2.5, 8.1.2.6, 8.1.2.7, 8.1.2.8, 8.1.2.9, 8.1.2.10, 8.1.3.1, 8.1.3.2, 8.1.3.3, 8.1.3.4, 8.1.3.5, 8.1.3.6, 8.1.3.7, 8.1.3.8, 8.1.3.9, 8.1.3.10, 8.1.4.1, 8.1.4.2, 8.1.4.3, 8.1.4.4, 8.1.4.5, 8.1.4.6, 8.1.4.7, 8.1.4.8, 8.1.4.9, 8.1.4.10, 8.1.5.1, 8.1.5.2, 8.1.5.3, 8.1.5.4, 8.1.5.5, 8.1.5.6, 8.1.5.7, 8.1.5.8, 8.1.5.9, 8.1.5.10, 8.1.6.1, 8.1.6.2, 8.1.6.3, 8.1.6.4, 8.1.6.5, 8.1.6.6, 8.1.6.7, 8.1.6.8, 8.1.6.9, 8.1.6.10, 8.1.7.1, 8.1.7.2, 8.1.7.3, 8.1.7.4, 20 8.1.7.5, 8.1.7.6, 8.1.7.7, 8.1.7.8, 8.1.7.9, 8.1.7.10, 8.1.8.1, 8.1.8.2, 8.1.8.3, 8.1.8.4, 8.1.8.5, 8.1.8.6, 8.1.8.7, 8.1.8.8, 8.1.8.9, 8.1.8.10, 8.1.9.1, 8.1.9.2, 8.1.9.3, 8.1.9.4, 8.1.9.5,8.1.9.6, 8.1.9.7, 8.1.9.8, 8.1.9.9, 8.1.9.10, 8.1.10.1, 8.1.10.2, 8.1.10.3, 8.1.10.4, 8.1.10.5, 8.1.10.6, 8.1.10.7, 8.1.10.8, 8.1.10.9, 8.1.10.10, 8.2.1.1, 8.2.1.2, 8.2.1.3, 8.2.1.4, 8.2.1.5, 8.2.1.6, 8.2.1/7, 8.2.1.8, 8.2.1.9, 8.2.1.10, 8.2.2.1, 8.2.2.2, 8.2.2.3, 8.2.2.4, 8.2.2.5, 8.2.2.6, 8.2.2.7, 8.2.2.8, 8.2.2.9, 8.2.2.10, 8.2.3.1, 25 8.2.3.2, 8.2.3.3, 8.2.3.4, 8.2.3.5, 8.2.3.6, 8.2.3.7, 8.2.3.8, 8.2.3.9, 8.2.3.10, 8.2.4.1, 8.2.4.2, 8.2.4.3, 8.2.4.4, 8.2.4.5, 8.2.4.6, 8.2.4.7, 8.2.4.8, 8.2.4.9, 8.2.4.10, 8.2.5.1, 8.2.5.2, 8.2.5.3, 8.2.5.4, 8.2.5.5, 8.2.5.6, 8.2.5.7, 8.2.5.8, 8.2.5.9, 8.2.5.10, 8.2.6.1, 8.2.6.2, 8.2.6.3, 8.2.6.4, 8.2.6.5, 8.2.6.6, 8.2.6.7, 8.2.6.8, 8.2.6.9, 8.2.6.10, 8.2.7.1, 8.2.7.2, 8.2.7.3, 8.2.7.4, 8.2.7.5, 8.2.7.6, 8.2.7.7, 8.2.7.8, 8.2.7.9, 8.2.7.10, 8.2.8.1, 8.2.8.2, 8.2.8.3, 8.2.8.4, 8.2.8.5, 8.2.8.6, 8.2.8.7, 8.2.8.8, 8.2.8.9, 8.2.8.10, 8.2.9.1, 30 8.2.9.2, 8.2.9.3, 8.2.9.4, 8.2.9.5, 8.2.9.6, 8.2.9.7, 8,2.9.8, 8.2.9.9, 8.2.9.10, 8.2.10.1, 8.2.10.2, 8.2.10.3, 8.2.10.4, 8.2.10.5, 8.2.10.6, 8.2.10.7, 8.2.10.8, 8.2.10.9, 8.2.10.10, 8.3.1.1, 8.3.1.2, 8.3.1.3, 8.3.1.4, 8.3.1.5, 8.3.1.6, 8.3.1.7, 8.3.1.8, 8.3.1.9, 8.3.1.10, 8.3.2.1, 8.3.2.2, 8.3.2.3, 8.3.2.4, 8.3.2.5, 8.3.2.6, 8.3.2.7, 8.3.2.8, 8.3.2.9, 8.3.2.10, 8.3.3.1, 8.3.3.2, 8.3.3.3, 8.3.3.4, 8.3.3.5, 8.3.3.6, 8.3.3.7, 8.3.3.8, 8.3.3.9, 8.3.3.10, 8.3.4.1, 8.3.4.2, 8.3.4.3, 8.3.4.4, 8.3.4.5, 8.3.4.6, 8.3.4.7, 8.3.4.8, 35 8.3.4.9, 8.3.4.10, 8.3.5.1, 8.3.5.2, 8.3.5.3, 8.3.5.4, 8.3.5.5, 8.3.5.6, 8.3.5.7, 8.3.5.8, 8.3.5.9, 8.3.5.10,

L 48 11715 8.3.6.1, 8.3.6.2, 8.3.6.3, 8.3.6.4, 8.3.6.5, 8.3.6.6, 8.3.6.7, 8.3.6.8, 8.3.6,9, 8.3.6.10, 8.3.7.1, 8.3.7.2, 8.3.7.3, 8.3.7.4, 8.3.7.5, 8.3.7.6, 8.3.7.7, 8.3.7.8, 8.3.7.9, 8.3.7.10, 8.3.8.1, 8.3.8.2, 8.3.8.3, 8.3.8.4, 8.3.8.5, 8.3.8.6, 8.3.8.7, 8.3.8.8, 8.3.8.9, 8.3.8.10, 8.3.9.1, 8.3.9.2, 8.3.9.3, 8.3.9.4, 8.3.9.5, 8.3.9.6, 8.3.9.7, 8.3.9.8, 8.3.9.9, 8.3.9.10, 8.3.10.1, 8.3.10.2, 8.3.10.3, 8.3.10.4, 8.3.10.5, 8.3.10.6, 8.3.10.7, 5 8.3.10.8, 8.3.10.9, 8.3.10.10, 8.4.1.1, 8.4.1.2, 8.4.1.3, 8.4.1.4, 8.4.1.5, 8.4.1.6, 8.4.1.7, 8.4.1.8, 8.4.1.9, 8.4.1.10, 8.4.2.1, 8.4.2.2, 8.4.2.3, 8.4.2.4, 8.4.2.5, 8.4.2.6, 8.4.2.7, 8.4.2.8, 8.4.2.9, 8.4.2.10, 8.4.3.1, 8.4.3.2, 8.4.3.3, 8.4.3.4, 8.4.3.5, 8.4.3.6, 8.4.3.7, 8.4.3.8, 8.4.3.9, 8.4.3.10, 8.4.4.1, 8.4.4.2, 8.4.4.3, 8.4.4.4, 8.4.4.5, 8.4.4.6, 8.4.4.7, 8.4.4.8, 8.4.4.9, 8.4.4.10, 8.4.5.1, 8.4.5.2, 8.4.5.3, 8.4.5.4, 8.4.5.5, 8.4.5.6, 8.4.5.7, 8.4.5.8, 8.4.5.9, 8.4.5.10, 8.4.6.1, 8.4.6.2, 8.4.6.3, 8.4.6.4, 8.4.6.5, 8.4.6.6, 10 8.4.6.7, 8.4.6.8, 8.4.6.9, 8.4.6.10, 8.4.7.1, 8.4.7.2, 8.4.7.3, 8.4.7.4, 8.4.7.5, 8.4.7.6, 8.4.7.7, 8.4.7.8, 8.4.7.9, 8.4.7.10, 8.4.8.1, 8.4.8.2, 8.4.8.3, 8.4.8.4, 8.4.8.5, 8.4.8.6, 8.4.8.7, 8.4.8.8, 8.4.8.9, 8.4.8.10, 8.4.9.1, 8.4.9.2, 8.4.9.3, 8.4.9.4, 8.4.9.5, 8.4.9.6, 8.4.9.7, 8.4.9.8, 8.4.9.9, 8.4.9.10, 8.4710.1, 8.4.10.2, 8.4.10.3, 8.4.10.4, 8.4.10.5, 8.4.10.6, 8.4.10.7, 8.4.10.8, 8.4.10.9, 8.4.10.10, 8.5.1.1, 8.5.1.2, 8.5.1.3, 8.5.1.4, 8.5.1.5, 8.5.1.6, 8.5.1.7, 8.5.1.8, 8.5.1.9, 8.5.1.10, 8.5.2.1, 8.5.2.2, 8.5.2.3, 15 8.5.2.4, 8.5.2.5, 8.5.2.6, 8.5.2.7, 8.5.2.8, 8.5.2.9, 8.5.2.10, 8.5.3.1, 8.5.3.2, 8.5.3.3, 8.5.3.4, 8.5.3.5, 8.5.3.6, 8.5.3.7, 8.5.3.8, 8.5.3.9, 8.5.3.10, 8.5.4.1, 8.5.4.2, 8.5.4.3, 8.5.4.4, 8.5.4.5, 8.5.4.6, 8.5.4.7, 8.5.4.8, 8.5.4.9, 8.5.4.10, 8.5.5.1, 8.5.5.2, 8.5.5.3, 8.5.5.4, 8.5.5.5, 8.5.5.6, 8.5.5.7, 8.5.5.8, 8.5.5.9,'8.5.5.10, 8.5.6.1, 8.5.6.2, 8.5.6.3, 8.5.6.4, 8.5.6.5, 8.5.6.6, 8.5.6.7, 8.5.6.8, 8.5.6.9, 8.5.6.10, 8.5.7.1, 8.5.7.2, 8.5.7.3, 8.5.7.4, 8.5.7.5, 8.5.7.6, 8.5.7.7, 8.5.7.8, 8.5.7.9, 8.5.7.10, 8.5.8.1, 8.5.8.2, 8.5.8.3, 20 8.5.8.4, 8.5.8.5, 8.5.8.6, 8.5.8.7, 8.5.8.8, 8.5.8.9, 8.5.8.10, 8.5.9.1, 8.5.9.2, 8.5.9.3, 8.5.9.4, 8.5.9.5, 8.5.9.6, 8.5.9.7, 8.5.9.8, 8.5.9.9, 8.5.9.10, 8.5.10.1, 8.5.10.2, 8.5.10.3, 8.5.10.4, 8.5.10.5, 8.5.10.6, 8.5.10.7, 8.5.10.8, 8.5.10.9, 8.5.10.10, 8.6.1.1, 8.6.1.2, 8.6.1.3, 8.6.1.4, 8.6.1.5, 8.6.1.6, 8.6.1.7, 8.6.1.8, 8.6.1.9, 8.6.1.10, 8.6.2.1, 8.6.2.2, 8.6.2.3, 8.6.2.4, 8.6.2.5, 8.6.2.6, 8.6.2.7, 8.6.2.8, 8.6.2.9, 8.6.2.10, 8.6.3.1, 8.6.3.2, 8.6.3.3, 8.6.3.4, 8.6.3.5, 8.6.3.6, 8.6.3.7, 8.6.3.8, 8.6.3.9, 8.6.3.10, 8.6.4.1, 25 8.6.4.2, 8.6.4.3, 8.6.4.4, 8.6.4.5, 8.6.4.6, 8.6.4.7, 8.6.4.8, 8.6.4.9, 8.6.4.10, 8.6.5.1, 8.6.5.2, 8.6.5.3, 8.6.5.4, 8.6.5.5, 8.6.5.6, 8.6.5.7, 8.6.5.8, 8.6.5.9, 8.6.5.10, 8.6.6.1, 8.6.6.2, 8.6.6.3, 8.6.6.4, 8.6.6.5, 8.6.6.6, 8.6.6.7, 8.6.6.8, 8.6.6.9, 8.6.6.10, 8.6.7.1, 8.6.7.2, 8.6.7.3, 8.6.7.4, 8.6.7.5, 8.6.7.6, 8.6.7.7, 8.6.7.8, 8.6.7.9, 8.6.7.10, 8.6,8.1, 8.6.8.2, 8.6.8.3, 8.6.8.4, 8.6.8.5, 8.6.8.6, 8.6.8.7, 8.6.8.8, 8.6.8.9, 8.6.8.10, 8.6.9.1, 8.6.9.2, 8.6.9.3, 8.6.9.4, 8.6.9.5, 8.6.9.6, 8.6.9.7, 8.6.9.8, 8.6.9.9, 8.6.9.10, 30 8.6.10.1, 8.6.10.2, 8.6.10.3, 8.6.10.4.. 8.6.10.5, 8.6.10.6, 8.6.10.7, 8.6.10.8, 8.6.10.9, 8.6.10.10, 8.7.1.1, 8.7.1.2, 8.7.1.3, 8.7.1.4, 8.7.1.5, 8.7.1.6, 8.7.1.7, 8.7.1.8, 8.7.1.9, 8.7.1.10, 8.7.2.1, 8.7.2.2, 8.7.2.3, 8.7.2.4, 8.7.2.5, 8.7.2.6, 8.7.2.7, 8.7.2.8, 8.7.2.9, 8.7.2.10, 8.7.3.1, 8.7.3.2, 8.7.3.3, 8.7.3.4, 8.7.3.5, 8.7.3.6, 8.7.3.7, 8.7.3.8, 8.7.3.9, 8.7.3.10, 8.7.4.1, 8.7.4.2, 8.7.4.3, 8.7.4.4, 8.7.4.5, 8.7.4.6, 8.7.4.7, 8.7.4.8, 8.7.4.9, 8.7.4.10, 8.7.5.1, 8.7.5.2, 8.7.5.3, 8.7.5.4, 8.7.5.5, 8.7.5.6, 8.7.5.7, 8.7.5.8, 35 8.7.5.9, 8.7.5.10, 8.7.6.1, 8.7.6.2, 8.7.6.3, 8.7.6.4, 8.7.65, 8.7.6.6, 8.7.6.7, 8.7.6.8, 8.7.6.9, 8.7.6.10,

U 49 10 15 20 25 30 8.7.7.1, 8.7.7.2, 8.7.7.3, 8.7.7.4, 8.7.7.5, 8.7.7.6, 8.7.7.7, 8.7.7.8, 8.7.7.9, 8.7.7.10, 8.7.8.1, 8.7.8.2, 8.7.8.3, 8.7.8.4, 8.7.8.5, 8.7.8.6, 8.7.8.7, 8.7.8.8, 8.7.8.9, 8.7.8.10, 8.7.9.1, 8.7.9.2, 8.7.9.3, 8.7.9.4, 8.7.9.5, 8.7.9.6, 8.7.9.7, 8.7.9.8, 8.7.9.9, 8.7.9.10, 8.7.10.1, 8.7.10.2, 8.7.10.3, 8.7.10.4, 8.7.10.5, 8.7.10.6, 8.7.10.7, 8.7.10.8, 8.7.10.9, 8.7.10.10, 8.8.1.1, 8.8.1.2, 8.8.1.3, 8.8.1.4, 8.8.1.5, 8.8.1.6, 8.8.1.7, 8.8.1.8, 8.8.1.9, 8.8.1.10, 8.8.2.1, 8.8.2.2, 8.8.2.3, 8.8.2.4, 8.8.2.5, 8.8.2.6, 8.8.2.7, 8.8.2.8, 8.8.2.9, 8.8.2.10, 8.8.3.1, 8.8.3.2, 8.8.3.3, 8.8.3.4, 8.8.3.5, 8.8.3.6, 8.8.3.7, 8.8.3.8, 8.8.3.9, 8.8.3.10, 8.8.4.1, 8.8.4.2, 8.8.4.3, 8.8.4.4, 8.8.4.5, 8.8.4.6, 8.8.4.7, 8.8.4.8, 8.8.4.9, 8.8.4.10, 8.8.5.1, 8.8.5.2, 8.8.5.3, 8.8.5.4, 8.8.5.5, 8.8.5.6, 8.8.5.7, 8.8.5.8, 8.8.5.9, 8.8.5.10, 8.8.6.1, 8.8.6.2, 8.8.6.3, 8.8.6.4, 8.8.6.5, 8.8.6.6, 8.8.6.7, 8.8.6.8, 8.8.6.9, 8.8.6.10, 8.8.7.1, 8.8,7.2, 8.8.7.3, 8.8.7.4, 8.8.7.5, 8.8.7.6, 8.8.7.7, 8.8.7.8, 8.8.7.9, 8.8.7.10, 8.8.8.1, 8.8.8.2, 8.8.8.3, 8.8.8.4, 8.8.8.5, 8.8.8.6, 8.8.8.7, 8.8.8.8, 8.8.8.9, 8.8.8.10, 8.8.9.1, 8.8.9.2, 8.8.9.3, 8.8.9.4, 8.8.9.5, 8.8.9.6, 8.8.9.7, 8.8.9.8, 8.8.9.9, 8.8.9.10, 8.8.10.1, 8.8.10.2, 8.8.10.3, 8.8.10.4, 8.8.10.5, 8.8.10.6, 8.8.10.7, 8.8.10.8, 8.8.10.9, 8.8:10.10, 8.9.1.1, 8.9.1.2, 8.9.1.3, 8.9.1.4, 8.9.1.5, 8.9.1.6, 8.9.1.7, 8.9.1.8, 8.9.1.9, 8.9.1.10, 8.9.2.1, 8.9.2.2, 8.9.2.3, 8.9.2.4, 8.9.2.5, 8.9.2.6, 8.9.2.7, 8.9.2.8, 8.9.2.9, 8.9.2.10, 8.9.3.1, 8.9.3.2, 8.9.3.3, 8.9.3.4, 8.9.3.5, 8.9.3.6, 8.9.3.7, 8.9.3.8, 8.9.3.9, 8.9.3.10, 8.9.4.1, 8.9.4.2, 8,9.4.3, 8.9.4.4, 8.9.4.5, 8.9.4.6, 8.9.4.7, 8.9.4.8, 8.9.4.9, 8.9.4.10, 8.9.5.1, 8.9.5.2, 8.9.5.3, 8.9.5.4, 8.9.5.5, 8.9.5.6, 8.9.5.7, 8.9.5.8, 8.9.5.9, 8.9.5.10, 8.9.6.1, 8.9.6.2, 8.9.6.3, 8.9.6.4, 8.9.6.5, 8.9.6.6, 8.9.6.7, 8.9.6.8, 8.9.6.9, 8.9.6.10, 8.9.7.1, 8.9.7.2, 8.9.7.3, 8.9.7.4, 8.9.7.5, 8.9.7.6, 8.9.7.7, 8.9.7.8, 8.9.7.9, 8.9.7.10, 8.9.8.1, 8.9.8.2, 8.9.8.3, 8.9.8.4, 8.9.8.5, 8.9.8.6, 8.9.8.7, 8.9.8.8, 8.9.8.9, 8.9.8.10, 8.9.9.1, 8.9.9.2, 8.9.9.3, 8.9.9.4, 8.9.9.5, 8.9.9.6, 8.9.9.7, 8.9.9.8, 8.9.9.9, 8.9.9.10, 8.9.10.1, 8.9.10.2, 8.9.10.3, 8.9.10.4, 8.9.10.5, 8.9.10.6, 8.9.10.7, 8.9.10.8, 8.9.10.9, 8.9.10.10, 8.10.1.1, 8.10.1.2, 8.10.1.3, 8.10.1.4, 8.10.1.5, 8.10.1.6, 8.10.1.7, 8.10.1.8, 8.10.1.9, 8.10.1.10, 8.10.2.1, 8.10.2.2, 8.10.2.3, 8.10.2.4, 8.10.2.5, 8.10.2.6, 8.10.2.7, 8.10.2.8, 8.10.2.9, 8.10.2.10, 8.10.3.1, 8.10.3.2, 8.10.3.3, 8.10.3.4, 8.10.3.5, 8.10.3.6, 8.10.3.7, 8.10.3.8, 8.10.3.9, 8.10.3.10, 8.10.4.1, 8.10.4.2, 8.10.4.3, 8.10.4.4, 8.10.4.5, 8.10.4.6, 8.10.4.7, 8.10.4.8, 8.10.4.9, 8.10.4.10, 8.10.5.1, 8.10.5.2, 8.10.5.3, 8.10.5.4, 8.10.5.5, 8.10.5.6, 8.10.5.7, 8.10.5.8, 8.10.5.9, 8.10.5.10, 8.10.6.1, 8.10.6.2, 8.10.6.3, 8.10.6.4, 8.10.6.5, 8.10.6.6, 8.10.6.7, 8.10.6.8, 8.10.6.9, 8.10.6.10, 8.10.7.1, 8.10.7.2, 8.10.7.3, 8.10.7.4, 8.10.7.5, 8.10.7.6, 8.10.7.7, 8.10.7.8, 8.10.7.9, 8.10.7.10, 8.10.8.1, 8.10.8.2, 8.10.8.3, 8.10.8.4, 8.10.8.5, 8.10.8.6, 8.10.8.7, 8.10.8.8, 8.10.8.9, 8.10.8.10, 8.10.9.1, 8.10.9.2, 8.10.9.3, 8.10.9.4, 8.10.9.5, 8.10.9.6, 8.10.9.7, 8.10.9.8, 8.10.9.9, 8.10.9.10, 8.10.10.1, 8.10.10.2, 8.10.10.3, 8.10.10.4, 8.10.10.5, 8.10.10.6, 8.10.10.7, 8.10.10.8, 8.10.10.9, 8.10.10.10, 9.1.1.1, 9.1.1.2, 9.1.1.3, 9.1.1.4, 9.1.1.5, 9.1.1.6, 9.1.1.7, 9.1.1.8, 9.1.1.9, 9.1.1.10, 9.1.2.1,9.1.2.2, 9.1.2.3, 9.1.2.4, 9.1.2.5, 9.1.2.6, 9.1.2.7, 9.1.2.8, 9.1.2.9, 9.1.2.10, 9.1.3.1, 9.1.3.2, 9.1.3.3, 9.1.3.4, 9.1.3.5, 9.1.3.6, 9.1.3.7, 9.1.3.8, 9.1.3.9, 9.1.3.10, 9.1.4.1, 9.1.4.2, 9.1.4.3, 9.1.4.4, 9.1.4.5, 9.1.4.6, 9.1.4.7, 9.1.4.8, 9.1.4.9, 9.1.4.10, 9.1.5.1, 9.1.5.2, 9.1.5.3, 9.1.5.4, 9.1.5.5, 9.1.5.6, 9.1.5.7,9.1.5.8, 9.1.5.9, 9.1.5.10, 9.1.6.1, 9.1.6.2, vw. 35 50 11715 9.1.6.3, 9.1.6.4, 9.1.6.5, 9.1.6.6, 9.1.6.7, 9.1.6.8, 9.1.6.9, 9.1.6.10, 9.1.7.1, 9.1.7.2, 9.1.7.3, 9.1.7.4, 9.1.7.5, 9.1.7.6, 9.1.7.7, 9.1.7.8, 9.1.7.9, 9.1.7.10, 9.1.8.1, 9.1.8.2, 9.1.8.3, 9.1.8.'4, 9.1.8.5, 9.1.8.6, 9.1.8.7, 9.1.8.8, 9.1.8.9, 9.1.8.10, 9.1.9.1, 9.1.9.2, 9.1.9.3, 9.1.9.4, 9.1.9.5, 9.1.9.6, 9.1.9.7, 9.1.9.8, 9.1.9.9, 9.1.9.10, 9.1.10.1, 9.1.10.2, 9.1.10.3, 9.1.10.4, 9.1.10.5, 9.1.10.6, 9.1.10.7, 9.1.10.8, 5 9.1.10.9, 9.1.10.10, 9.2.1.1, 9.2.1.2, 9.2.1.3, 9.2.1.4, 9.2.1.5, 9.2.1.6, 9.2.1.7, 9.2.1.8, 9.2.1.9, 9.2.1.10, 9.2.2.1, 9.2.2.2, 9.2.2.3, 9.2.2.4, 9.2.2.5, 9.2.2.6, 9.2.2.7, 9.2.2.8, 9.2.2.9, 9.2.2.10, 9.2.3.1, 9.2.3.2, 9.2.3.3, 9.2.3.4, 9.2.3.5, 9.2.3.6, 9.2.3.7, 9.2.3.8, 9.2.3.9, 9.2.3.10, 9.2.4.1, 9.2.4.2, 9.2.4.3, 9.2.4.4, 9.2.4.5, 9.2.4.6, 9.2.4.7, 9.2.4.8, 9.2.4.9, 9.2.4.10, 9.2.5.1, 9.2.5.2, 9.2.5.3, 9.2.5.4, 9.2.5.5, 9.2.5.6, 9.2.5.7, 9.2.5.8, 9.2.S.9, 9.2.5.10, 9.2.6.1, 9.2.6.2, 9.2.6.3, 9.2.6.4, 9.2.6.5, 9.2.6.6, 9.2.6.7, 10 9.2.6.8, 9.2.6.9, 9.2.6.10, 9.2.7.1, 9.2.7.2, 9.2.7.3, 9.2.7.4, 9.2.7.5, 9.2.7.6, 9.2.7.7, 9.2.7.8, 9.2.7.9, 9.2.7.10, 9.2.8.1, 9.2.8.2, 9.2.8.3, 9.2.8.4, 9.2.8.5, 9.2.8.6, 9.2.8.7, 9.2.8.8, 9.2.8.9, 9.2.8.10, 9.2.9.1, 9.2.9.2, 9.2.9.3, 9.2.9.4, 9.2.9.5, 9.2.9.6, 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9.10.8.1, 9.10.8.2, 9.10.8.3, 9.10.8.4, 9.10.8.5, 9.10.8.6, 9.10.8.7, 9.10.8.8, 9.10.8.9, 9.10.8.10, 9.10.9.1,9.10.9.2, 9.10.9.3, 9.10.9.4, 9.10.9.5, 9.10.9.6, 9.10.9.7, 9.10.9.8, 9.10.9.9, 9.10.9.10, 9.10.10.1,9.10.10.2, 9.10.10.3, 9.10.10:4, 9.10.10.5.9.10.10.6, 9.10.10.7, 9.10.10.8, 9.10.10.9, 9.10.10.10, 10.1.1.1, 10.1.1.2, 10.1.1.3, 10.1.1.4, 10.1.1.5, 10.1.1.6, 10.1.1.7, Î0.1.1.8, 10.1.1.9, 10.1.1.10, 10.1.2.1, 10.1.2.2, 10.1.2.3, 10.1.2.4, 10.1.2.5, 10.1.2.6, 10.1.2.7, 10.1.2.8, 10.1.2.9, 10.1.2.10, 10.1.3.1, 10.1.3.2, 10.1.3.3, 10.1.3.4, 10.1.3.5, 10.1.3.6, 10.1.3.7, 10.1.3.8, 10.1.3.9, 10.1.3.10, 10.1.4.1, 10.1.4.2, 10.1.4.3, 10.1.4.4, 10.1.4.5, 10.1.4.6, 10.1.4.7, 10.1.4.8, 10.1.4.9, 10.1.4.10, 10.1.5.1, 10.1.5.2, 10.1.5.3, 10.1.5.4, 10.1.5.5, 10.1.5.6, 10.1.5.7, 10.1.5.8, 10.1.5.9, 10.1.5.10, 10.1.6.1, 10.1.6.2, 10.1.6.3, 10.1.6.4, 10.1.6.5, 10.1.6.6, 10.1.6.7, 10.1.6.8, 10.1.6.9, 10.1.6.10, 10.1.7.1, 10.1.7.2, 10.1.7.3, 10.1.7.4, 10.1.7.5, 10.1.7.6, 10.1.7.7, 10.1.7.8, 10.1.7.9, 10.1.7.10, 10.1.8.1, 10.1.8.2, 10.1.8.3, 10.1.8.4, 10.1.8.5, 10.1.8.6, 10.1.8.7, 10.1.8.8, 10.1.8.9, 10.1.8.10, 10.1.9.1, 10.1.9.2, 10.1.9.3, 10.1.9.4, 10.1.9.5, 10.1.9.6, 10.1.9.7, 10.1.9.8, 10.1.9.9, 10.1.9.10, 10.1.10.1, 10.1.10.2, 10.1.10.3, 10.1.10.4, 10.1.10.5, 10.1.10.6, 10.1.10.7, 10.1.10.8, 10.1.10.9, 10.1.10.10, 10.2.1.1, 10.2.1.2, 10.2.1.3, 10.2.1.4, 10.2.1.5, 10.2.1.6, 10.2.1.7, 10.2.1.8, 10.2.1.9, 10.2.1.10, 10.2.2.1, 10.2.2.2, 10.2.2.3, 10.2.2.4, 10.2.2.5, 10.2.2.6, 10.2.2.7, 10.2.2.8, 10.2.2.9, 10.2.2.10, 10.2.3.1, 10.2.3.2, 10.2.3.3, 10.2.3.4, 10.2.3.5, 10.2.3.6, 10.2.3.7, 10.2.3.8, 10.2.3.9, 10.2.3.10, 10.2.4.1, 10.2.4.2, 10.2.4.3, 10.2.4.4, 10.2.4.5, 10.2.4.6, 10.2.4.7, 10.2.4.8, 10.2.4.9, 10.2.4.10, 10.2.5.1, 10.2.5.2, 10.2.5.3, 10.2.5.4, 10.2.5.5, 10.2.5.6, 10.2.5.7, 10.2.5.8, 10.2.5.9, 10.2.5.10, 10.2.6.1, 10.2.6.2, 10.2.6.3, 10.2.6.4, 10.2.6.5, 10.2.6.6, 10.2.6.7, 10.2.6.8, 10.2.6.9, 10.2.6.10, 10.2.7.1, 10.2.7.2, 10.2.7.3, 10.2.7.4, 10.2.7.5, 10.2.7.6, 10.2.7.7, 10.2J.8, 10.2.7.9, 10.2.7.10, 10.2.8.1, 10.2.8.2, 10.2.8.3, 10.2.8.4, 10.2.8.5, 10.2.8.6, 10.2.8.7, 10.2.8.8, 10.2.8.9, 10.2.8.10, 10.2.9.1, 10.2.9.2, 10.2.9.3, 10.2.9.4, 10.2.9.5, 10.2.9.6, 10.2.9.7, 10.2.9.8, 10.2.9.9, 10.2.9.10, 10.2.10.1, 10.2.10.2, 10.2.10.3, 10.2.10.4, 10.2.10.5, 10.2.10.6, 10.2.10.7, 10.2.10.8, 10.2.10.9, 10.2.10.10, 10.3.1.1,10.3.1.2, 10.3.1.3, 10.3.1.4, 10.3.1.5, 10.3.1.6, 10.3.1.7, 10.3.1.8, 10.3.1.9, 10.3.1.10, 10.3.2.1,10.3.2.2, 10.3.2.3, 10.3.2.4, 10.3.2.5, 10.3.2.6, 10.3.2.7, 1-0.3.2.8, 10.3.2.9, 10.3.2.10, 10.3.3.1, y 35 • 53 11715 10 15 20 25 30 10.3.3.2, 10.3.3.3, 10.3.3.4, 10.3.3.5, 10.3.3.6, 10.3.3.7, 10.3.3.8, 10.3.3.9, 10.3.3.10, 10.3.4.1, 10.3.4.2, 10.3.4.3, 10.3.4.4, 10.3.4,5, 10.3.4.6, 10.3.4.7, 10.3.4.8, 10.3.4.9, 10.3.4.10, 10.3.5.1, 10.3.5.2, 10.3.5.3, 10.3.5.4, 10.3.5.5, 10.3.5.6, 10.3.5.7, 10.3.5.8, 10.3.5.9, 10.3.5.10, 10.3.6.1, 10.3.6.2, 10.3.6.3, 10.3.6.4, 10.3.6.5, 10.3.6.6, 10.3.6.7, 10.3.6.8, 10.3.6.9, 10.3.6.10, 10.3.7.1, 10.3.7.2, 10.3.7.3, 10.3.7.4, 10.3.7.5, 10.3.7.6, 10.3.7.7, 10.3.7.8, 10.3.7.9, 10.3.7.10, 10.3.8.1, 10.3.8.2, 10.3.8.3, 10.3.8.4, 10.3.8.5, 10.3.8.6, 10.3.8.7, 10.3.8.8, 10.3.8.9, 10.3.8.10, 10.3.9.1, 10.3.9.2, 10.3.9.3, 10.3.9.4, 10.3.9.5, 10.3.9.6, 10.3.9.7, 10.3.9.8, 10.3.9.9, 10.3.9.10, 10.3.10.1, 10.3.10.2, 10.3.10.3, 10.3.10.4, 10.3.10.5, 10.3.10.6, 10.3.10.7, 10.3.10.8, 10.3.10.9, 10.3.10.10, 10.4.1.1, 10.4.1.2, 10.4.1.3, 10.4.1.4, 10.4.1.5, 10.4.1.6, 10.4.1.7, 10.4.1.8, 10.4.1.9, 10.4.1.10, 10.4.2.1, 10.4.2.2, 10.4.2.3, 10.4.2.4, 10.4.2.5, 10.4.2.6, 10.4.2.7, 10.4.2.8, 10.4.2.9, 10.4.2.10, 10.4.3.1, 10.4.3.2, 10.4.3.3, 10.4.3.4, 10.4.3.5, 10.4.3.6, 10.4.3.7, 10.4.3.8, 10.4.3.9, 10.4.3.10, 10.4.4.1, 10.4.4.2, 10.4.4.3, 10.4.4.4, 10.4.4.5, 10.4.4.6, 10.4.4.7, 10.4.4.8, 10.4.4.9, 10.4.4.10, 10.4.5.1, 10.4.5.2, 10.4.5.3, 10.4.5.4, 10.4.5.5, 10.4.5.6, 10.4.5.7, 10.4.5.8, 10.4.5.9, 10.4.5.10, 10.4.6.1, 10.4.6.2, 10.4.6.3, 10.4.6.4, 10.4.6.5, 10.4.6.6, 10.4.6.7, 10.4.6.8, 10.4.6.9, 10.4.6.10, 10.4.7.1, 10.4.7.2, 10.4.7.3, 10.4.7.4, 10.4.7.5, 10.4.7.6, 10.4.7.7, 10.4.7.8, 10.4.7.9, 10.4.7.10, 10.4.8.1, 10.4.8.2, 10.4.8.3, 10.4.8.4, 10.4.8.5, 10.4.8.6, 10.4.8.7, 10.4.8.8, 10.4.8.9, 10.4.8.10, 10.4.9.1, 10.4.9.2, 10.4.9.3, 10.4.9.4, 10.4.9.5, 10.4.9.6, 10.4.9.7, 10.4.9.8, 10.4.9.9, 10.4.9.10, 10.4.10.1, 10.4.10.2, 10.4.10.3, 10.4.10.4, 10.4.10.5, 10.4.10.6, 10.4.10.7, 10.4.10.8, 10.4.10.9, 10.4.10.10, 10.5.1.1, 10.5.1.2, 10.5.1.3, 10.5.1.4, 10.5.1.5, 10.5.1.6, 10.5.1.7, 10.5.1.8, 10.5.1.9, 10.5.1.10, 10.5.2.1, 10.5.2.2, 10.5.2.3, 10.5.2.4, 10.5.2.5, 10.5.2.6, 10.5.2.7, 10.5.2.8, 10.5.2.9, 10.5.2.10, 10.5.3.1, 10.5.3.2, 10.5.3.3, 10.5.3.4, 10.5.3.5, 10.5.3.6, 10.5.3.7, 10.5.3.8, 10.5.3.9, 10.5.3.10, 10.5.4.1, 10.5.4.2, 10.5.4.3, 10.5.4.4, 10.5.4.5, 10.5.4.6, 10.5.4.7, 10.5.4.8, 10.5.4.9, 10.5.4.10, 10.5.5.1, 10.5.5.2, 10.5.5.3, 10.5.5.4, 10.5.5.5, 10.5.5.6, 10.5.5.7, 10.5.5.8, 10.5.5.9, 10.5.5.10, 10.5.6.1, 10.5.6.2, 10.5.6.3, 10.5.6.4, 10.5.6.5, 10.5.6.6, 10.5.6.7, 10.5.6.8, 10.5.6.9, 10.5.6.10, 10.5.7.1, 10.5.7.2, 10.5.7.3, 10.5.7.4, 10.5.7.5, 10.5.7.6, 10.5.7.7, 10.5.7.8, 10.5.7.9, 10.5.7.10, 10.5.8.1, 10.5.8.2, 10.5.8.3, 10.5.8.4, 10.5.8.5, 10.5.8.6, 10.5.8.7, 10.5.8.8, 10.5.8.9, 10.5.8.10, 10.5.9.1, 10.5.9.2, 10.5.9.3, 10.5.9.4, 10.5.9.5, 10.5.9.6, 10.5.9.7, 10.5.9.8, 10.5.9.9, 10.5.9.10, 10.5.10.1, 10.5.10.2, 10.5.10.3, 10.5.10.4, 10.5.10.5, 10.5.10.6, 10.5.10.7, 10.5.10.8, 10.5.10.9, 10.5.10.10, 10.6.1.1, 10.6.1.2, 10.6.1.3, 10.6.1.4, 10.6.1.5, 10.6.1.6, 10.6.1.7, 10.6.1.8, 10.6.1.9, 10.6.1.10, 10.6.2.1, 10.6.2.2, 10.6.2.3, 10.6.2.4, 10.6.2.5, 10.6.2.6, 10.6.2.7, 10.6.2.8, 10.6.2.9, 10.6.2.10, 10.6.3.1, 10.6.3.2, 10.6.3.3, 10.6.3.4, 10.6.3.5, 10.6.3.6, 10.6.3.7, 10.6.3.8, 10.6.3.9, 10.6.3.10, 10.6.4.1, 10.6.4.2, 10.6.4.3, 10.6.4.4, 10.6.4.5, 10.6.4.6, 10.6.4.7, 10.6.4.8, 10.6.4.9, 10.6.4.10, 10.6.5.1, 10.6.5.2, 10.6.5.3, 10.6.5.4, 10.6.5.5, 10.6.5.6, 10.6.5.7, 10.6.5.8, 10.6.5.9, 10.6.5.10, 10.6.6.1, 10.6.6.2, 10.6.6.3, 10.6.6.4, 10.6.6.5, 10.6.6.6, 10.6.6.7, 10.6.6.8, 10.6.6.9, 10.6.6.10, 10.6.7.1, 10.6.7.2, 10.6.7.3, 10.6.7.4,.10.6.7.5, 10.6.7.6, 10.6.7.7, 10.6.7.8, 35 54 ''11715 10.6.7.9, 10.6.7.10, 10.6.8.1, 10.6.8.2, 10.6.8.3, 10.6.8.4, 10.6.8.5, 10.6.8.6, 10.6.8.7, 10.6.8.8, 10.6.8.9, 10.6.8.10, 10.6.9.1, 10.6.9.2, 10.6.9.3, 10.6.9.4, 10.6.9.5, 10.6.9.6, 10.6.9.7, 10.6.9.8, 10.6.9.9, 10.6.9.10, 10.6.10.1, 10.6.10.2, 10.6.10.3, 10.6.10.4, 10.6.10.5, 10.6.10.6, 10.6.10.7, 10.6.10.8, 10.6.10.9, 10.6.10.10, 10.7.1.1, 10.7.1.2, 10.7.1.3, 10.7.1.4, 10.7.1.5, 10.7.1.6, 10.7.1.7, 5 10.7.1.8, 10.7.1.9, 10.7.1.10, 10.7.2.1, 10.7.2.2, 10.7.2.3, 10.7.2.4, 10.7.2.5, 10.7.2.6, 10.7.2.7, 10.7.2.8, 10.7.2.9, 10.7.2.10, 10.7.3.1, 10.7.3.2, 10.7.3.3, 10.7.3.4, 10.7.3.5, 10.7.3.6, 10.7.3.7, 10.7.3.8, 10.7.3.9, 10.7.3.10, 10.7.4.1, 10.7.4.2, 10.7.4.3, 10.7.4.4, 10.7.4.5, 10.7.4.6, 10.7.4.7, 10.7.4.8, 10.7.4.9, 10.7.4.10, 10.7.5.1, 10.7.5.2, 10.7.5.3, 10.7.5.4, 10.7.5.5, 10.7.5.6, 10.7.5.7, 10.7.5.8, 10.7.5.9, 10.7.5.10, 10.7.6.1, 10.7.6.2, 10.7.6.3, 10.7.6.4, 10.7.6.5, 10.7.6.6, 10.7.6.7, 10 10.7.6.8, 10.7.6.9, 10.7.6.10, 10.7.7.1, 10.7.7.2, 10.7.7.3, 10.7.7.4, 10.7.7.5, 10.7.7.6, 10.7.7.7, 10.7.7.8, 10.7.7.9, 10.7.7.10, 10.7.8.1, 10.7.8.2, 10.7.8.3, 10.7.8.4, 10.7.8.5, 10.7.8.6, 10.7.8.7, 10.7.8.8, 10.7.8.9, 10.7.8.10, 10.7.9.1, 10.7.9.2, 10.7.9.3, 10.7.9.4, 10.7.9.5, 10.7.9.6, 10τ7.9.7, 10.7.9.8, 10.7.9.9, 10.7.9.10, 10.7.10.1, 10.7.10.2, 10.7.10.3, 10.7.10.4, 10.7.10.5, 10.7.10.6, 10.7.10.7, 10.7.10.8, 10.7.10.9, 10.7.10.10, 10.8.1.1, 10.8.1.2, 10.8.1.3, 10.8.1.4, 10.8.1.5, 10.8.1.6, 15 10.8.1.7, 10.8.1.8, 10.8.1.9, 10.8.1.10, 10.8.2.1, 10.8.2.2, 10.8.2.3, 10.8.2.4, 10.8.2.5, 10.8.2.6, 10.8.2.7, 10.8.2.8, 10.8.2.9, 10.8.2.10, 10.8.3.1, 10.8.3.2, 10.8.3.3, 10.8.3.4, 10.8.3.5, 10.8.3.6, 10.8.3.7, 10.8.3.8, 10.8.3.9, 10.8.3.10, 10.8.4.1, 10.8.4.2, 10.8.4.3, 10.8.4.4, 10.8.4.5, 10.8.4.6, 10.8.4.7, 10.8.4.8, 10.8.4.9, 10.8.4.10, 10.8.5.1, 10.8.5.2, 10.8.5.3, 10.8.5.4, 10.8.5.5, 10.8.5.6, 10.8.5.7, 10.8.5.8, 10.8.5.9, 10.8.5.10, 10.8.6.1, 10.8.6.2, 10.8.6.3, 10.8.6.4, 10.8.6.5, 10.8.6.6, 20 10.8.6.7, 10.8.6.8, 10.8.6.9, 10.8.6.10, 10.8.7.1, 10.8.7.2, 10.8.7.3, 10.8.7.4, 10.8.7.5, 10.8.7.6, 10.8.7.7, 10.8.7.8, 10.8.7.9, 10.8.7.10, 10.8.8.1, 10.8.8.2, 10.8.8.3, 10.8.8.4, 10.8.8.5, 10.8.8.6, 10.8.8.7, 10.8.8.8, 10.8.8.9, 10.8.8.10, 10.8.9.1, 10.8.9.2, 10.8.9.3, 10.8.9.4, 10.8.9.5, 10.8.9.6, 10.8.9.7, 10.8.9.8, 10.8.9.9, 10.8.9.10, 10.8.10.1, 10.8.10.2, 10.8.10.3, 10.8.10.4, 10.8.10.5, 10.8.10.6, 10.8.10.7, 10.8.10.8, 10.8.10.9, 10.8.10.10, 10.9.1.1, 10.9.1.2, 10.9.1.3, 10.9.1.4, 25 10.9.1.5, 10.9.1.6, 10.9.1.7, 10.9.1.8, 10.9.1.9, 10.9.1.10, 10.9.2.1, 10.9.2.2, 10.9.2.3, 10.9.2.4, 10.9.2.5, 10.9.2.6, 10.9.2.7, 10.9.2.8, 10.9.2.9, 10.9.2.10, 10.9.3.1, 10.9.3.2, 10.9.3.3, 10.9.3.4, 10.9.3.5, 10.9.3.6, 10.9.3.7, 10.9.3.8, 10.9.3.9, 10.9.3.10, 10.9.4.1, 10.9.4.2, 10.9.4.3, 10.9.4.4, 10.9.4.5, 10.9.4.6, 10.9.4.7, 10.9.4.8, 10.9.4.9, 10.9.4.10, 10.9.5.1, 10.9.5.2, 10.9.5.3, 10.9.5.4,' 10.9.5.5, 10.9.5.6, 10.9.5.7, 10.9.5.8, 10.9.5.9, 10.9.5.10, 10.9.6.1, 10.9.6.2, 10.9.6.3, 10.9.6.4, 30 10.9.6.5, 10.9.6.6, 10.9.6.7, 10.9.6.8, 10.9.6.9, 10.9.6.10, 10.9.7.1, 10.9.7.2, 10.9.7.3, 10.9.7.4, 10.9.7.5, 10.9.7.6, 10.9.7.7, 10.9.7.8, 10.9.7.9, 10.9.7.10, 10.9.8.1, 10.9.8.2, 10.9.8.3, 10.9.8.4, 10.9.8.5, 10.9.8.6, 10.9.8.7, 10.9.8.8, 10.9.8.9, 10.9.8.10, 10.9.9.1, 10.9.9.2, 10.9.9.3, 10.9.9.4, 10.9.9.5, 10.9.9.6, 10.9.9.7, 10.9.9.8, 10.9.9.9, 10.9.9.10, 10.9.10.1, 10.9.10.2, 10.9.10.3, 10.9.10.4, 10.9.10.5, 10.9.10.6, 10.9.10.7, 10.9.10.8, 10.9.10.9, 10.9.10.10, 10.10.1.1, 10.10.1.2, 10.10.1.3, 35 .10.10.1.4, 10.10.1.5, 10.10.1.6, 10.10.1.7, 10.10.1.8, 10.10.1.9, 10.10.1.10, 10.10.2.1, 10.10.2.2, 55 11715 10.10.2.3, 10.10.2.4, 10.10.2.5, 10.10.2.6, 10.10.2.7, 10.10.2.8, 10.10.2.9, 10.10.2.10, 10.10.3.1, 10.10.3.2, 10.10.3.3, 10.10.3.4, 10.10.3.5, 10.10.3.6, 10.10.3.7, 10.10.3.8, 10.10.3.9, 10.10.3.10, 10.10.4.1, 10.10.4.2, 10.10.4.3, 10.10.4.4, 10.10.4.5, 10.10.4.6, 10.10.4.7, 10.10.4.8, 10.10.4.9, 10.10.4.10, 10.10.5.1, 10.10.5.2, 10.10.5.3, 10.10.5.4, ίθ.10.5.5, 10.10.5.6, 10.10.5.7, 10.10.5.8, 5 10.10.5.9, 10.10.5.10, 10.10.6.1, 10.10.6.2, 10.10.6.3, 10.10.6.4, 10.10.6.5, 10.10.6.6, 10.10.6.7, 10.10.6.8, 10.10.6.9, 10.10.6.10, 10.10.7.1, 10.10.7.2, 10.10.7.3, 10.10.7.4, 10.10.7.5, 10.10.7.6, 10.10.7.7, 10.10.7.8, 10.10.7.9, 10.10.7.10, 10.10.8.1, 10.10.8.2, 10.10.8.3, 10.10.8.4, 10.10.8.5, 10.10.8.6, 10.10.8.7, 10.10.8.8, 10.10.8.9, 10.10.8.10, 10.10.9.1, 10.10.9.2, 10.10.9.3, 10.10.9.4, 10.10.9.5, 10.10.9.6, 10.10.9.7, 10.10.9.8, 10.10.9.9, 10.10.9.10, 10.10.10.1, 10.10.10.2, 10 10.10.10.3, 10.10.10.4' 10.10.10.5. 10.10.10.6, 10,10,10.7, 10,10,10,8, 10.10,10,9, 10.10.10.10 15

Additîonal exemplary formula 1 compound groups include the following groups asdisclosed below.

Group 2. Group 2 compounds are as named in Table B, i.e., R2, R] A, Y and Xsubstituents are as defined in Table A, but they are bonded to the steroid nucléus shown in formula5, which is the same as the formula 4 steroid nucléus, except that the 5-6 double bond is absent andhydrogen is présent at the 5-position in the α-conf guration

20

Thus, the group 2 compound named 1.2.1.1 has the structure

Group 3. Group 3 compounds are as named in Table B, i.e., R2, RjA, Y and X substituents are as defined in Table A, but they are bonded to the steroid nucléus shown in formula

56 11715 6, which is the same as the formula 4 steroid nucléus, except that the 5-6 double bond is absent andhydrogen is présent at the 5-position in the β-confîguration

10

Group 4. Group 4 compounds are as named in Table B, i.e., R-2, RjA, Y and Xsùbstituents are as defined in Table A, but they are bonded to the steroid nucléus shown in formula7, which is the same as the formula 4 steroid nucléus, except that Q3 is “CH2OH

57 11715

Group 5. Group 2 compounds are as named in Table B, i.e., Ro, Rj A, Y and Xsubstituents are as defined in Table A, but they are bonded to the steroid nucléus Shown in formula8, which is the same as the formula 4 steroid nucléus, except that the 5-6 double bond is absent andhydrogen is présent at the 5-position in the α-confîguration and Q3 is -CH2OH

10 15

Group 6. Group 6 compounds are as named in groups 1-5, except that Qg in formulas 4-8is -CH2OH instead of methyl. In group 6, there are 5 subgroups of group 6 compounds. The fïrstsubgroup, subgroup 6-1, has the same steroid nucléus with the substituents as defined for group Icompounds while the second, subgroup 6-2, has the same steroid nucléus with the substituents asdefined for group 2 compounds. Subgroups 6-3 through 6-5 hâve the same steroid nucléus with thesubstituents as defined for group 3 through 5 respectively. Thus, for example, the subgroup 6-1compound named 1.2.1.1 has the structure

5* 10 15 20 25 30

Group 7. Group 7 compounds are as named in groups 1-5, except that the Y moiety informulas 4-8 is in the β-configuration instead of in the α-configuration. Group 7 comprises 5subgroups, wherein the compounds are named essentially as described for group 6 compounds,except that the Y group is in the β-configuration.

Group 8. Group 8 compounds are as named in groups 1-5, except that the X moiety informulas 4-8 is in the α-configuration instead of in the β-configuration. Group 8 comprises 5subgroups, wherein the compounds are named essentially as described for group 6 compounds,except that the X group is in the a-configuration.

Group 9. Group 9 compounds are as named in groups 1-5, except that the R2 moiety informulas 4-8 is in the α-configuration instead of in the β-configuration. Group 9 comprises 5subgroups, wherein the compounds are named essentially as described for group 6 compounds,except that the R2 group is in the a-configuration.

Group 10. Group 10 compounds are as named in groups 1-9, except that R2 moieties 1through 10 in Table A are replaced with the following moieties. 1 -S-C(O)-CH3 2 -S-C(O)-CH2-C6H5 3 -0-S(0)-0-CH3 4 -O-S(O)-O-CH2-C6H5 5 -O-S(O)(O)-O-CH3 6 -O-S(O)(O)-O-CH2-C6H5 7 -O-C(O)-NH-CH3 8 -O-C(O)-NH-C6H5 9 -O-C(S)-CH3 10 -O-C(S)-CH2-CgH5

Group 10 comprises 25 subgroups of compounds. The first, subgroup 10-1, has the samesteroid nucléus with substituents as defined for group 1, except that the R 2 moieties or groupslisted replace those in Table A above. The subgroup 10-1 compound named 1.2.1.1 has thestructure

59 11715

thesubgroup 10-6-1 compound named 1.2.1 1 has the structure

and the subgroup 10-6-2 compound named 1.2, 1 has the structure

10 Group 11. Group 11 compounds are as named in groups 1-9, except that R/j moieties 1 through 1 0 in Table A are replaced with the following moieties. 60 11715 1 -S-C(O)-CH2CH2-O-CH2CH3 2 -S-C(O)-CH2-C6H4OCH3 3 -O-S(O)-O-CH2CH2-O-CH2CH3 4 -O-S(O)-O-CH2-C6H4OCH3 5 5 -O-S(O)(O)-O-CH2CH2-O-CH2CH3 6 -0-S(O)(O)-O-CH2-C6H40CH3 7 -O-C(O)-NH-CH2CH2-O-CH2CH3 8 -O-C(O)-NH-C6H4OCH3 9 -O-C(S)-GH2CH2-O-CH2CH3 10 10 -O-C(S)-CH2-C6H4OCH3

Group 12. Group 12 compounds are as named in groups 1-9, except that R2 moieties 1 through 10 in Table A are replaced with the following moieties.

1 -S-C(O)-CH2CH2-0-CH2C(0)0H

2 -S-C(O)-CH2-C<5H4F

15 3 -0-S(0)-0-CH2CH2-0-CH2C(0)OH

4 -O-S(O)-O-CH2-C6H4F

5 -0-S(0)(0)-0-CH2CH2-0-CH2C(0)OH

6 -0-S(0)(0)-0-CH2-CôH4F

7 -0-C(O)-NH-CH2CH2-0-CH2C(0)0H

20 8 -O-CfOJ-NH-CgHztF

9 -O-C(S)-CH2CH2-O-CH2C(O)OH

10 -O-C(S)-CH2-C6H4F

Group 13. Group 13 compounds are as named in groups 1-9, except that R2 moieties 1through 1 0 in Table A are replaced with the following moieties.

25 1 -S-C(O)-CH2CH2-0-CH2CH20H 2 -S-C(O)-CH2-C6H4CH3

3 -O-S(O)-O-CH2CH2-O-CH2CH2OH 4 -O-S(O)-O-CH2-C6H4CH3

5 -0-S(0)(0)-0-CH2CH2-0-CH2CH20H 30 6 -O-S(O)(O)-O-CH2-C6H4CH3

7 -O-C(O)-NH-CH2CH2-O-CH2CH2OH 8 -O-C(O)-NH-C6H4CH3

9 -O-C(S)-CH2CH2-O-CH2CH2OH 10 -O-C(S)-CH2-C6H4CH3 61 11 117 1 5

Group 14. Group 14 compounds are as named in groups 1-9, exceptthat R2 moieties 1 through 10 in Table A are replaced with the following moieties.

1 -S-C(O)-CH2CH2-O-CH2CH2ORPR

2 -S-C(O)-CH2-C6H4ORPR

5 3 -0-S(0)-0-CH2CH2-0-CH2CH2ORPR

4 -O-S(O)-O-CH2-C6H4ORPR

5 -O-S(O)(O)-O-CH2CH2-O-CH2CH2ORPR

6 -O-S(O)(O)-O-CH2-C6H4ORPR

7 -o-cco)-nh-ch2ch2-o-ch2ch2orPR

10 8 -O-C(O)-NH-C6H4ORPR

9 -o-c(S)-ch2ch2-o-ch2ch2orpR

10 -O-C(S)-CH2-C6H4ORPR

Group 15. Group 15 compounds are as named in groups 1-9, except that R2 moieties 1through 10 in Table A are replaced with the following moieties. 15 i -s-c(O)-ch2ch2-0-ch2ch2nhrpr 2 -S-C(O)-CH2-C6H3(ORPR)2

3 -O-S(O)-O-CH2CH2-O-CH2CH2NHRPR 4 -o-s(O)-o-ch2-c6h3(orpR)2

5 -O-S(O)(O)-O-CH2CH2-0-CH2CH2NHRPR 20 6 -0-S(0)(0)-0-CH2-C6H3(ORPR)2

7 -o-C(O)-nh-ch2ch2-o-ch2ch2nhrPR 8 -O-C(O)-NH-C6H3(ORPR)2

9 -O-C(S)-CH2CH2-O-CH2CH2NHRPR 10 -û-C(S)-CH2-C6H3(ORPR)2

Group 16. Group 16 compounds are as named in groups 1-9, except that R2 moieties 1 through 10 in Table A are replaced with the following moieties. 1 -S-C(O)-(CH2)0-6-CH3 2 -S-C(O)-CH2-C6H5 3 -O-S(O)-O-(CH2)0-6'CH3 30 4 -O-S(O)-O-CH2-C6H5 5 -O-S(O)(O)-O-(CH2)0-6-CH3 6 -O-S(O)(O)-O-CH2-C6H5 7 -O-C(O)-NH-(CH2)0-6-Ch3 8 -O-C(O)-NH-(CH2)0_6-C6H5 35 9 -O-C(S)-(CH2)0-6-CH3 62 11715 10 -0-C(S)-CH2-CôH5

Group 17. Group 17 compounds are as named in groups 1-9, except that R2 moieties 1through 10 in Table A are replaced with the following.moieties.

1 -S-C(O)-CH2CH2-(O-CH2CH2)i_50-H 5 2 -S-C(O)-CH2-C6H4OCH3

3 -O-S(O)-O-CH2CH2-(O-CH2CH2)i.50-H 4 -0-S(0)-0-CH2-C6H4OCH3

5 -O-S(O)(O)-O-CH2CH2-(O-CH2CH2)i-50-H 6 -0-S(0)(0)-0-CH2-C6H40CH3

10 7 -O-C(O)-NH-CH2CH2-(O-CH2CH2)1_50-H 8 -O-C(O)-NH-C6H40CH3

9 -O-C(S)-CH2CH2-(O-CH2CH2)1.50-H 10 -O-C(S)-CH2-C6H4OCH3 15

Group 18. Group 18 compounds are as named in groups 1-9, except that R2 moieties 1through 1 0 in Table A are replaced with the following moieties.

1 -0-C(0)-CH2CH2-(0-CH2CH2) 1.50-H 2 -O-C(O)-CH2-C6H4OCH3 3 -0-C(0)-(CH2)o-6-CH3 4 -0-C(0)-CH2-C6H4N02

20 5 -0-C(0)-CH2CH2-(0-CH2CH2) 1.50-H 6 -O-C(O)-CH2-C6H5 7 -0-C(0)-CH2CH2-0-CH2CH3 8 -0-C(0)-C6H5 9 -O-C(O)-CH2CH2-S-CH2CH3

25 10 -O-C(O)-CH2-C6H4F

Group 19. Group 19 compounds are as named in groups 1-9, except that R2 moieties 1through 10 in Table A are replaced with the following moieties.

1 -O-CH2CH2-(O-CH2CH2)i.50-H 2 -O-CH2-C6H4OCH3 30 3 -O-(CH2)0-6-CH3 4 -O-CH2-C6H4NO2

5 -O-CH2CH2-(O-CH2CH2)i-50-H 6 -O-CH2-C6H5 7 -O-CH2CH2-O-CH2CH3 35 8 -O-C6H5 63 • 117 1 5 9 -O-CH2CH2-S-CH2CH3

10 -O-CH2-C6H4F

Group 20. Group 20 compounds are as named in groups 1-9, except that R2 moieties 1through 10 in Table A are replaced with the following moieties.

5 1 -C(O)-O-CH2CH2-(O-CH2CH2)i-50-H 2 -C(O)-O-CH2-C6H4OCH3 3 -C(0)-0-(CH2)o-6-CH3 4 -C(O)-O-CH2-C6H4NO2

5 -C(O)-O-CH2CH2-(O-CH2CH2)i.50-H 10 6 -C(O)-O-CH2-CgH5 7 -C(O)-O-CH2CH2-O-CH2CH3 8 -C(O)-O-CgH5 9 -C(O)-O-CH2CH2-S-CH2CH3

10 -C(O)-O-CH2-C6H4F 15 Group 21. Group 21 compounds are as named in groups 1-9, except that R2 moieties 1 through 10 in Table A are replaced with the following moieties. 1 -C(O)-O-G12 (G 12 is defined below) 2 -0-C(0)-G12 3 -C(O)-S-G12 20 4 -S-C(O)-G12 5 -C(S)-O-G12 6 -O-C(S)-G12 7 -O-C(O)-NH-G12 8 -NH-C(O)-O-G12 25 9 -C(O)-O-CH2-G12 10 -O-C(O)-CH2-G12

Thus, the group21-l compound named 1.2.1.1 has the structure

64

the group 21 -6-2 compound named 1.2.1.1 has the structure

65 11715 ο ch2oh G12

and the group 21-6-3 compound named 1.2.1.1 has the structure G12

10 15 G12 in Group 21 is an organic moiety comprising 1,2, 3, 4, 5, 6, 7, 8, 9 10, 11 or 12carbon atoms and 0, 1,2, 3, 4, 5, 6, 7 or 8 independently selected O, S, N, P, or Si atoms, but, if aSi or P atom is présent, only one Si or P is présent, wherein the organic moiety is optionallyselected from Cj-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, aryl, a C2.9 heterocycle or a substituteddérivative of any of these comprising 1,2, 3, 4 or more substituents, wherein each substituent isindependently chosen and is selected from -O-, -S-, -NRPP- (including -NH-), -C(O)-, =O, =S, -N(RPR)2 (including -NH2), -C(O)ORPR (including -C(O)OH), -OC(O)RPR (including -O-C(O)-H), -ORpR (including -OH), -SRPR (including -SH), -NO2, -CN, -NHC(O)-, -C(O)NH-, -OC(O)-,-C(O)O-, -O-A8, -S-A8, -C(O)-A8, -OC(O)-A8, -C(O)O-A8, =N-, -N=, =N-OH, -OPO3(RPR)2, -OSO3H2 and halogen moieties or atoms, where each Rpp- is -H, an independently selectedprotecting group or both RPR together comprise a protecting group, and A8 is Cj.g alkyl, C2-8alkenyl, C2-8 alkynyl, C]_4 alkyl-aryl (e.g., benzyl), aryl (e.g. phenyl) or Cj_4 aIkyl-C2-9heterocycle. G12 moieties include -CH3, -C2H5, -C3H7, -C4H9, -CgH^, -CH2O5H5, -C2H4-C6H5, -C3H6~C6H5, -C5H5, -CH2-heterocycle, -CH2-CH2-heterocycle and a heterocycle, and ofwhich are substituted with one, two, three or more independently selected -O-, -S-, -F, -CI, -Br, -I,-NH-, =0, -CN, -OCH3, -OC2H5, -OC4H9, -NO2, -NH2i -COOH, or-NH-C(O)- moieties.

Other embodiments include the use of any formula 4 compound or genus of formula 4compounds that are named in any ofthe foregoing groups for any of the therapeutic or otherapplications described herein. This includes the use of any named formula 4 compound or genusfor any of those applications wherein (i) Ri is in the α-configuration, (ii) Q4 is -CH(halogen)-, (iii)

20 66 11715 X is in the c-configuration and the -H at the 17-position is in the β-configuratïon, (iv) Y is in theβ-configuration and the -H at the 16-position is in the α-confïguration or (v) Rj À is in the a-configuration and the -H at the 7-position is in the β-conFiguration.

Embodiments also include formula 1 compounds (e.g., formula 4 compounds) wherein R45 is optionally substituted Ci_8 alkyl, optionally substituted C2-8 alkenyl, optionally substituted C2-8 alkynyl, optionally substituted aryl, optionally substituted heterocycle, optionally substituted Cj. 8 alkyl-aryl, optionally substituted C]_g alkyl-heterocycle or optionally substituted -CH2-C[_gorganic moiety (where the organic moiety is as described for esters), wherein any of the foregoingare independently substitued with 1, 2, 3, 4, 5 or 6 or more -O-, -S-, -NH-, -NH-C(O)- (i.e., -NH- 10 C(O)- or -C(O)-NH-), =0, =NOH, -NO2> -CN, -F, -Cl, -Br, -I, -OH, -SH, or -NH2. Such R4 moieties include -CH2-Ci.6 optionally substituted alkyl, -CH2-C2-6 optionally substitutedalkenyl, -CH2-Ci_6 -optionally substituted aryl and -CH2-C2-9 optionally substituteddieterocycle.

Plasma concentration-enhancing compounds. An aspect of the invention comprisesadministering an effective amount of a plasma concentration-enhancing compound, e.g., a 15 compound of formula 2A or 2B compound with a formula 1 compound to facilitate preventing ortreating one or more Trypanosome infections in a subject. In addition to the formula 2A or 2Bcompounds, the plasma concentration-enhancing compounds include bavachinin A, dïdymin(isosakuranetin-7-rutinoside or neoponcirin), flavanomarein (isookanine-7-glucoside), flavanoneazine, flavanone diacetylhydrazone, flavanone hydrazone, silybin, which has the structure

OH

isosilybin, which has the structure 67 11715 10

5 and a compound having the structure (E)OH

OH O (E).

Collectively, these compounds and the formula 2A and 2B compounds are referred to as the“plasma concentration-enhancing compounds”.

The formula 2A and 2B compounds encompass a number of natural and syntheticflavonoids, including certain flavones, flavans, and their iso analogs. The présence of a formula2A or 2B compound in compositions comprising a formula 1 compound has been found to enhancethe systemic bioavailability of formulations that comprise a formula 1 compound. The presence ofa formula 2A or 2B compound, e.g., naringin or naringenin, results in enhanced plasmaconcentrations of the formula 1 compound. The formula 2A or 2B compound need not be présentin a formulation that contams a formula 1 compound. The formula 2A or 2B can also beadministered, e.g., about 1-4 hours, before or after, preferably before, the formula 1 compound is 68 administered. In these embodiments, one wiII administer an oral or parentéral formulation that contains a formula 1 compound and a formula 2A or 2B compound.

The plasma concentration-enhancing compounds include compounds of formulas 50-65 J 17 ι 5

69 11715

70 117 1 5 *β Rb ββ

Rfl R8 Rb

64 65 wherein

Rg at the 6-position independently are -H, -OH, -F, -Cl, -Br, -I, Ci_6 alkyl, Ci_g alkoxy,glucuronide, a Ci_25 fattY ac‘d, glucoside, -CH2CH=C(CH3)2 or a group having the structure (B);

Rg at the 8-position independently are -H, -OH, -F, -CI, -Br, -I, alkyl, alkoxy,glucuronide, a Cj_25 fatty acid, glucoside, -CH2CH=C(CH3)2 or the residue of a formula 50-65compound where a hydrogen atom is removed to form the formula 50-65 radical;

RgA independently are -H,-OH, -F, -Cl, -Br, -I, Çi.g alkyl, Cj.6 alkoxy, glucuronide, aCl-25 fatty acid, glucoside, -CH2CH=C(CH3)2 or a group having the structure (C); the remaining Rg independently are -H, -OH, -F, -Cl, -Br, -I, Ci_6 alkyl, Cj-g alkoxy,glucuronide, a Cj.25 fatty acid or -CH2-CH=C(CH3)2; and

RlO (*) *s -OH or-F, -Cl, -Br, -I, C].g alkyl, Cj.g alkoxy, neohesperidoside,apioglucoside, rutinoside, glucoside, galactoside, rhamnoside, arabinoside, or a stereoisomer,hydrate, analog, dérivative or métabolite of any of these moieties, any of which are optionallyindependently substituted at one or more hydrogen atoms with -OH, -F, -Cl, -Br, -I, Cj_6 alkyl,C]_6 alkoxy, glucuronide or a Cj.25 fatty acid, or (ii) Rjq is the radical of bavachinin A, didymin,flavanomarein, flavanone azine, flavanone diacetylhydrazone, flavanone hydrazone, silybin,silychristin, is csilybin, silandrin, a moiety of structure (E) or a stereoisomer, hydrate, analog,dérivative or métabolite of any of these moieties.

Additional therapeutic embodiments. In accordance with another preferred aspect of theprésent invention, there is provided a method of treatment of one or more of the conditionsdescribed above, e.g., a Trypanosome infection, comprising administering a combination therapyincluding one or more of the compounds of the présent invention administered simultaneously orsequentially with one or more macrophage stimulating factor (and optionally furtherco-administering one or more plasma concentration-enhancing compounds). Macrophagestimulating factors are well known to those of skill in the art, examples including GM-CSF (see,e.g., Callard et al., The Cytokine Facts Book, Academie Press, 1994, p. 139, which is incorporatedherein) and Interleukin-4 (sold by Immunex as "Leukine1.1 and by Schering Plough as "Prokine"). » 71 11715 10 15 20 25 30 35

While not wishing to be bound by any theory, it is believed that compounds that inhîbitglucose-6-phosphate dehydrogenase are surprisingly effective against malaria. Accordingly, theprésent invention also relates to the administration of a glucose-6-phosphate dehydrogenaseinhibitor in the treatment of any of the conditions described herein, particularly in the treatment ofmalaria, optionally in a combination therapy with any other compounds of the présent invention orany of the compounds described herein as being suitable for use in a combination therapy. Thoseofskill in the art are readily familiarwith inhibitors of glucose-6-phosphate dehydrogenase, andcan readily identify other material, which exhibits such inhibition.

In another preferred aspect of the présent invention, to enhance destruction of parasiteinfected érythrocytes, the compounds of the présent invention can be coadministered with one ormore oxidation agent (optionally further together with a plasma concentration-enhancingcompound and/or a macrophage stimulating factor), or the patient may be given oxygeiT ventilationto increase oxidative steroids in the plasma.

The components of any ofthe combination thérapies disclosed herein can be administeredsimultaneousty (in a combination formulation), essentially simultaneously (e.g., administration ofeach compound a few minutes or a few hours apart), or can be administered sequentially, e.g.,several days apart, or more than a week apart. For example, a compound of the présent inventionand a plasma-concentration-enhancing compound (and/or a macrophage stimulating factor) can beadministered together, or essentially simultaneously, e.g., administration of each compound a fewminutes or a few hours apart, or can be administered sequentially, e.g., several days apart, or morethan a week apart (optionally together with simultaneous or sequential administration of oxidatingagent or oxygen ventilation). Ail such variations in administration of the combination therapy areencompassed within the scope of the invention.

The invention also includes pharmaceutical formulations containing any such combinationas described herein.

The invention also includes the use of combinations of compounds as disclosed herein inthe manufacture of a médicament for use in the treatment of a condition selected from malaria,African Trypanosomiasis, American Trypanosomiasis, as well as one or more kind of parasitesand/or one or more diseases caused by such parasites, against one or more kind of Mycoplasmaand/or one or more diseases caused by such Mycoplasmas and/or against one or more ofthefollowing indications or infections: (a) hairy Leukopiakia, (b) oral candidosis, (c) mouthulcerations-aphthous/ herpetic/bacterial, (d) fungal candida, (e) human papilloma virus, (f)molluscum contagiosum, (g) squamous oral carcinoma, (h) Kaposi's sarcoma oral lésions, (ï)periodontitis, G) necrotizing gingivitis, (k) orafacial herpès zoster, and (1) rotaviruses, as well as ailother indications and infections disclosed in U.S. Patent-No. 5,292,725.

72 11715

The présent invention is also directed to the use of compounds of the présent invention inthe manufacture of a médicament for treatment as described herein.

The présent invention is aiso directed to administering of compounds of the présentinvention to provide a prophylactic treatment of a patient against liver parasites, e.g., Trypanosome 5 parasites.

Articles of manufacture. The présent invention also provides articles of manufacturecomprising, for example, packaging material, at least one unit-dosage of a compound of the présentinvention (optionally together with one or more unit-dosage of a compound winch can beadministered in a combination therapy) and a label or package insert indicating that the compound 10 can be used in a method disclosed herein.

In one embodiment, an article of manufacture comprises packaging material, at least oneunit dose of a 17-ketosteroid compound (a formula 1 compound) and a label or package insertindicating that the 17-ketosteroid compound (a formula 1 compound) can be used in a method asdescribed herein. The packaging material can be made from one or more generally known 15 materials, e.g., foam, cardboard, fiberboard, polystyrène and polypropylene, and is of a size suitable to contain the compound(s) accompanying the packaging material. A label or packageinsert can be a tag or label secured to the packaging material, a label printed on the packagingmaterial or a label inserted within the packaging material. The label indicates that the17-ketosteroid can be used in a therapy as disclosed herein, e.g., in combination with a plasma 20 concentration-enhancing compound and/or a macrophage-stimulating factor. The label can alsoindicate that the compound(s) hâve received approval from an official agency, for example, theU.S. Food and Drug Administration, for medical or veterinary use according to the method. Thelabel may also indicate suitable administration routes, dosage regimen, and the like. If desired, thearticle may contain additional components such as at least one unit dose of a plasma 25 concentration-enhancing compound or the macrophage-stimulating factor.

Methods of administration and formulations. The dosage for a particular patient will vary depending on factors such as the overall health of the patient, the method, route and dose ofadministration and the severity of side effects (if any). Détermination of the appropriate dose ismade by the clinician using parameters known in the art. Generally, the dose begins with an 30 amount somewhat less tlian the optimum dose and Jt is increased by small incréments thereafteruntil the desired or optimum effect is achieved. The dosage of the compounds of the invention issuitably determined depending on the individual cases taking symptoms, âge and sex of the subjectand the like into considération. With respect to the duration of treatment, it is typical for skilledclinicians to monitor patients in order to détermine when inhibition is providing therapeutic . 73 11715 benefit, and to détermine whetherto increase dosage, decrease dosage, discontinue therapy, résumétherapy or alter therapy.

The therapeutically effective dosage of any spécifie compound wi 11 vary somewhat from compound to compound and patient to patient. As a general proposition, a dosage in the range of 5 from about 0.1 to about 500 mg/kg will hâve therapeutic efficacy. Typically, a dosage in the range of from about 0.5 mg/kg to about 500 mg/kg will be employed. A daily dosage of a formula 1compound will typically comprise about 10 to about 750 mg, usually about 20 to about 400 mg,which may be administered as a single dose or as two or more subdoses. Such doses or subdoses may be administered at one or more sites or by one or more than one route of administration. The10 duration for the treatment is usually once per day for a sufficient length of time for the patient to become asymptomatic, or for symptoms to abate noticeably. Depending upon the severity of theinfection in the individual patient, thîs may last several days, weeks, or longer.

With regard to the frequency and duration of treatment, it is well known that it is withinthe skill of the ordinary physician to monitor a patient's condition and to make appropriate 15 decisions with regard to discontinuing, interrupting and resuming treatments.

The dosages used in accordance with the invention are suitably determined depending on the individual cases taking symptoms, âge and sex of the subject and the like into considération. Inaddition, it lis well known that it is within the skill of ordinary artisans to détermine suitabledosages based on the above and other factors. 20 In accordance with the présent method, a compound of the présent invention may be administered orally, intramuscularly (IM), intravenously (IV), or subcutaneously (SC), withintravenous administration being especially preferred. Although other routes of administration canbe used, it has been, found that intravenous administration provides surprising effectiveness. Fororal administration, the use of a plasma concentration-enhancing compound may be of great 25 importance. Alternatively, the compound or sait may also be administered intravenously orintramuscularly as a liposomal suspension. The administration may also be in a cyclodextrinformulation (given orally, SC, IV or IM). Compounds of the invention and their pharmaceuticallyor physiologically, acceptable salts, are thus administered by any route suitable to the condition tobe treated, including oral, rectal, nasal, topical (including ocular, buccal or sublingual), vaginal, 30 parentéral (including subeutaneous, intramuscular, intravenous, intraperitoneal, intradermal, intrathecal, intradural and épidural) and pulmonary by aérosol. Generally, the compounds of theinvention are administered parenteraliy, orally or topically. If an embodiment is not sufficientlyorally bioavailable it can be administered by the other routes noted above.

Embodiments include formulations that comprise a liposome or lipid complex that 35 comprises a formula 1 compound. Such formulations aFe prepared according to known methods, 1 74 11715 10 15 20 25 30 35 e.g., U.S. patents 4427649, 5043165, 5714163, 5744158, 5783211, 5795589, 5795987, 5798348,5811118, 5820848, 5834016 and 5882678, ail of which are incorporated herein bÿ reference. Theliposomes may optionally comprise an additional therapeutic or other agent(s), e.g., a compound offormula 2A or 2B. The liposomes can be delivered to a subject by any standard route, e.g., oral,aérosol or parentéral (e.g., SC, IV, IM).

Most often, the pharmaceutical compositions useful in the présent invention will comprisea compound of Formula 1, or a pharmaceutically acceptable saltthereof, in any pharmaceuticallyacceptable carrier. If a solution is desired, water is the carrier of choice with respect towater-soluble compounds or salts. In other embodiments, an organic vehicle, such as glycerol,éthanol, propylene glycol, polyethylene glycol, DMSO, DMSO2, vegetable, minerai oils. éthanol,benzyl benzoate, or mixtures thereof, may be suitable. In general, the solutions in any instanceshould be sterilized in a suitable manner, preferably by filtration through a 0.22 microrffilter. Thecompositions useful in the practice of the présent invention may be provided in the form of vials,ampoules, and the like.

In some embodiments, the formula 1 compound that is présent in the compositions or thatis used in the methods disclosed herein is completely dissolved in non-aqueous excipients.However, in some embodiments, e.g., transient compositions or some formulations, the formula 1compound is partially dissolved while the remaining portion is présent as a solid, which can be asuspension or a colloid. In related embodiments, the formula 1 compound is incompletely 'dissolved and is présent as a suspension or gel.

In addition to compounds of formula 1, or their salts, the pharmaceutical compositionsmay contain other additives, such as pH adjusting additives, in particular, agents such as acids,bases, or buffers, including sodium lactate, sodium acetate, and sodium gluconate. Further, suchcompositions may contain microbial preservatives, such as methylparaben, propylparaben, benzylalcohol and benzyl benzoate. If a multiple use vial is supplied, the pharmaceutical compositionshould likewise include such a microbial preservative. The formulations may be, of course,lyophilized, using techniques well known in the art.

It has been found that with respect to the practice of the method of the présent invention,treating malaria with a compound of formula 1, or a pharmaceutically acceptable sait thereof,certain compounds appear to possess superior efficacy to others.

The formulations include those suitable for the foregoing administration routes. Theformulations may conveniently be presented in unit dosage form and may be prepared by any ofthe methods well known in the art of pharmacy. Techniques, excipients and formulations generallyare found in, e.g., Reminglon's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA 1985, 1 édition, Nema et al., PDA J. Pharm. Sci. Tech. 1997 51:166-171, both of which are

75 11715 incorporated herein by reference. Methods to make invention formulations include the step ofbringing into association a formula l compound with one or more excipients or carriers. Ingeneral, the formulations are prepared by uniformly and intimately bringing into association theformula 1 compound with liquid excipients or fînely divided solid excipients or both, and then, if 5 appropriate, shaping the product.

Formulations of the présent invention suîtable for oral administration may be presented asdiscrète units such as capsules, cachets or tablets each containing a predetermined amount of theformula 1 or formula 2A or 2B compound; as a powder or granules; as solution or a suspension inan aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid émulsion or a water-in-oil 10 liquid émulsion. The formula 1 or formula 2A or 2B compound may also be presented as a bolus,electuary or paste. A tablet may be made by compression or molding, optionally with one or morerexcipients.Compressed tablets may be prepared by compressing in a suitable machine the formula 1 orformula 2A or 2B compound in a free-flowing form such as a powder or granules, optionally 15 mixed with a binder, lubricant, ïnert diluent, preservative, surface active or dispersing agent.Molded tablets may be made by moulding in a suitable machine a mixture of the powderedcompound moistened with an inert liquid diluent. The tablets may optionally be coated or scoredand may be formulated so as to provide slow or controlled release of the formula 1 or formula 2Aor 2B compound therein. 20 The oily phase ofthe émulsions ofthis invention may be constituted from known ingrédients in a known manner. While the phase may comprise merely an emulsifier (otherwiseknown as an emulgent), it desirably comprises a mixture of at ieast one emulsifier with a fat or anoil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with alipophilie emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat. 25 Together, the emulsifier(s) with or without stabilizer(s) make up the emulsifying wax, and the waxtogether with the oil and fat make up the emulsifying ointment base which forms the oily dispersedphase of the cream formulations. Emulgents and émulsion stabilizers suitable for use informulations comprising a formula 1 or a formula 2A or 2B compound include Tween® 60, Span®80, cetostearyl alcohol, benzyl alcoho), myristyl alcohol, glyceryl mono-stearate and sodium lauryl 30 sulfate.

Formulations suitable for buccal administration include lozenges comprising a formula 1or formula 2A or 2B compound in a flavored basis, usually sucrose and acacia or tragacanth;pastilles comprising the formula 1 or formula 2A or 2B compound in an inert basis such as gelatinand glycerin, or sucrose and acacia.

76 .11715

Formulations for rectal administration may be presented as a suppository with a suitablebase corriprising for example cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration wi 11 hâve a particle sizefor example in the range of 0.01 to 200 microns (including particle sizes in a range between 0.01and 500 microns in incréments of 0.1 microns such as 0.1, 0.2, 0.3, 0.4, 0.5, 1,2, 5, 30 microns, 35microns, etc.), which is administered by inhalation through the nasal passage or by inhalationthrough the mouth so as to reach the various bronchi or alveolar sacs. Formulations suitable foraérosol or dry powder administration may be prepared according to conventional methods and maybe delivered with other therapeutic agents such as compounds heretofore used in the treatment orprophylaxis of Trypanosome infections. Inhalation therapy is readtiy administered by metereddose inhalers.

Formulations suitable for vaginal administration may be presented as pessariesftampons,creams, gels, pastes, foams or spray formulations containing in addition to the formula 1compound such carriers or excipients as are known in the art to be appropriate.

Formulations suitable for parentéral administration are stérile and include aqueous andnon-aqueous injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutéswhich render the formulation isotonie with the blood of the intended récipient; and aqueous andnon-aqueous stérile suspensions which may include suspending agents and thickening agents. Theformulations may be presented in unit-dose or multi-dose containers, for example sealed ampoulesand vials with elastomeric stoppers, and may be stored in a freeze-dried (lyophiiized) conditionrequiring oniy the addition of the stérile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions and suspensions may be preparedfrom stérile powders, granules and tablets of the kind previously described. Unit dosageformulations will typically contain a daiiy dose or unit daily sub-dose, as recited above, or anappropriate fraction thereof, of a formula 1 or formula 2A or 2B compound.

In some embodiments, the formula 1 compounds will be administered on an intermittentbasis. In these embodiments, the formula 1 compound, e.g., a dose that comprises about 5-500 mgof a formula 1 compound (typically about 50-400 mg), is administered to a subject for at least oneday, foilowed by no dosing for at least one day (at least 24 hours), optionally followed by at leastone more daiiy dose of, e.g., about 50-500 mg. Intermittent dosing methods may comprise dosing(1, 2, 3 or 4 doses per week) based on a weekly schedule, e.g., dosing on Monday, Wednesday andFriday, or on Tuesday, Thursday Saturday for about 1, 2, 3, 4, 6, 8 or more weeks, followed byperiods of about 2, 3, 4, 5, 30, 45, 60, 90 or more days with no dosing, optionally followed bydosing again on Monday, Wednesday and Friday for about 1,2, 3, 4, 6, 8 or more weeks. Weeklydosing methods may comprise administration of the formula 1 compound to a subject 1, 2, 3, 4 or 5 77 10 15 20 25 30 35 1171b times per week for 1,2, 3, 4, or more weeks.. In related embodiments, dosing may be administeredto a subject tiaily for 2, 3, 4, 5, 6, 7 or more days, followed by a period of about Γ, 2, 3, 4, 5, 7, 14,30, 45 60, 90 or more days, optionally followed by another course of daily dosing. Theseembodiments may further comprise treatment with a formula 2A or 2B compound or anothertreatment as described herein.

To the extent not already indicated, it will be understood by those of ordinary skill in theart that any one of the various spécifie embodiments herein described and illustrated may befurther modified to incorporate features shown in any of the other embodiments disclosed herein.

Therapeutic applications. For therapeutic applications, the compositions disclosed hereinwill typically comprise one or more compounds of formula 1, and, the methods disclosed hereinwill utilize such compositions, which will contain one, two or more of such compounds, usuallyone. While it is possible for the compounds of the invention to be administered as pure-compoundsit is préférable to présent them as pharmaceutical formulations. The formulations of the présentinvention comprise at least one formula 1 compound together with one or more acceptable carriersor excipients and optionally other therapeutic agents, e.g., a formula 2A or 2B compound(s),chloroquine, a chlroquine analog, a macrophage stimulating factor(s) and/or an oxidation agent(s).The one or more carriers or excipients must be "acceptable" in the sense of being compatible withthe other ingrédients of the formulation and not deleterious to the patient.

In other embodiments, a dosing regimen for a formula 1 compound will comprise the useof a relatively high induction dose, e.g., about 150-750 mg per day or about 150-750 mg per dayusing an intermittent dosing schedule (such as described herein), followed by lower maintenancedosing, e.g., about 50-250 mg per day or about 50-250 mg per day on an intermittent dosingschedule. These embodiments may further comprise treatment with a formula 2A or 2B compoundor another treatment as described herein.

Parentéral formulations may comprise a cyclodextrin, e.g., an oc-cyclodextrin, a β-cyclodextrin (e.g., β-hydroxypropylcyclodextrin) or a γ-cyclodextrin, which are typically employedin aqueous formulations, which optionally comprise one or more of a buffer, a sait (NaCl, etc.) to,e.g., render the solution isotonie, a bacteriostat or other excipients as known in the art and aformula 1 compound at a concentration of, e.g., about 5-25 mg/mL, typically about 10-20 mg/mL.Parentéral formulations that comprise a formula 1 compound and one or more excipients may bediluted into, e.g., stérile saline and infeused into a subject. Parentéral formulations are typicallyadministered by, e.g., intravenous, topical or oral delivery to a subject such as a human. For non-aqueous formulations, one or more solvents such as propylene glycol, a PEG, e.g., PEG 300 orPEG 400, éthanol, and benzyl benzoate may be employed. Typical aqueous and non-aqueousformulations will contain about 5 to about 400 mg/mL of a formula 1 compound, usually about 10

78 117 1 5 to about 200 mg/mL. Such parentéral formulations mav be delivered orally, or by intramuscular,intravenous or subcutaneous injection.

In preparing compositions that comprise a formula 1 compound (and optionally one ormore excipients), one may optionally mi 11 or otherwise granulate the compound to obtain a desired 5 particle size, before or after the formula 1 compound is contacted with one or more excipients. Forexample, one may mill a formula 1 compound such as 16a-bromoepiandrosterone, to obtain anaverage particle size (or diameter) of about 0.5-25 pM or about 1-10 μΜ (e.g., about 2, 5 or 10 pMaverage particle size or diameter) before contacting the milled formula 1 compound with a liquidor solid excipient. Milled formula 1 compound is useful to facilitate dissolution or suspension of 10 the formula 1 compound in one or more liquid excipients (e.g., a PEG such as PEG 300, propyleneglycoi or benzyl benzoate) or to facilitate uniformly distributing drug substance when the milledcompound is contacted with one or more solid excipients (e.g., a filler, a binder or a lubricant).

The compositions and formulations disclosed herein are useful in the treatment of, orameliorate one or more symptoms associated with, the conditions or infections disclosed herein. 15 These compositions and formulations may also be used to treat, or ameliorate one or more symptoms associated with, a retroviral infection such as a HIV1 or HIV2 infection in humans. Asused herein, phrases such as “amelioration of one or more symptoms associated with” means thatsuch compounds or formulations may be used to reduce réplication of an infectious agent or toreduce the number of infectious agents that are présent in a subject or to ameliorate one or more 20 symptoms associated with, or caused by, the condition or infection (e.g., reduced fever, a shortenedduration of, or reduced level of, pain, or a noticeable réduction of or élimination of diarrhea orfatigue).

In addition to the ingrédients particularly mentioned above the formulations of thisinvention may include other agents conventional in the art having regard to the type of formulation 25 in question, for example those suitable for oral administration may include flavoring or colorïngagents.

The présent invention further provides veterinary compositions comprising at least oneformula 1 or formula 2A or 2B compound together with a veterinary carrier therefor. Also, theformula 1 compound may be présent in the animal’s feed or water. Excipients for veterinary 30 applications may include compounds, e.g., small amounts of chloroform, that may not be generallysuitable for human use.

Veterinary carriers are materials useful for the purpose of administering the composition tocats, dogs, horses, mice, rats, hamsters, rabbits and other animais and may be solid, liquid orgaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible

79 ; 11715 with the formula 1 or formula 2A or 2B compound. These veterinary compositions may beadministered orally, parenterally or by any other desired route, e.g., as described herein.

Embodiments of formula 1 compounds include or exclude any subset of compounds withinthe définition of formula 1, provided that at least one compound remains. For example, a subset of 5 formula 1 compounds that are generally preferred and are usually included, for example are aqueous or nonaqueous formulations comprising 16a-bromoepiandrosterone. A subset compoundsor applications for compounds that are optionally excluded from formula 1 compounds or theiruses in any embodiment or claim herein comprises, e.g., the use of one or more compounds (ortheir use) that are disclosed in one or more prior art references or publications, to the extent that 10 the disclosed compounds or uses renders any claim or embodiment unpatentable for novelty,obviousness and/or inventive step reasons.

In other embodiments, a formula 1 compound may be linked to an oligonucleotide or anoligonucleotide analog to facilitate delivery of the oligonucleotide or analog into cells. Typicallythe formula 1 compound wi 11 be linked to the steroid nucléus through a terminal hydroxyl group at

15 a 5’, 3’ or 2’ position of the oligonucleotide. Oligonucleotides and analogs of oligonucleotides areknown and hâve been described, e.g., U.S. patents 4725677, 4973679, 4997927, 4415732,4458066, 5047524, 4959463, 5212295, 5386023, 5489677, 5594121, 5614622, 5624621; and PCTpublication Nos. WO 92/07864, WO 96/29337, WO 97/14706, WO 97/14709, WO 97/31009, WO 98/04585 and WO 98/04575 ail ofwhich are incorporated herein by reference. 20 Svnthesis methods. In general, the compounds employed in the présent invention in general may be synthesized in manners known and readily understood by those skilled in the art.Therefore, there is no need to explain in great detail the methodology used for the synthesis ofmost such compounds.

Formula 1 compounds that comprise a thioaceral moiety, sulfate ester, sulfite ester, 25 carbamate or thioester moiety at R2 (the 3-position) are prepared essentially according to methodsknown in the art. Suitably protected intermediates will be used as is apparent. See, for example, U.S. patent 5198432; European patent publications EP 576915 and EP 576914; C. Christiana et al.,J. Chem. Soc. Chem. Commun. 1991 vol 22, C. Christiana et al., J. Chem. Soc. Chem. Commun.1991 19:1403-1405. H.N. Abramson et al., J. Pharm. Sci. 1977 66:602-603, E.J. Corey et al., J. 30 Am. Chem. Soc. 1996 118:8765-8766. A.G.M. Barrett et al., J. Org. Chem. 1989 54:227. D.H.R.Barton et al., J. Chem. Soc. Perkin Trans. 1 1976 19:2112-2116, D.H.R. Barton et al., J. Chem.

Soc. Perkin Trans. 1 1975 16:1574-1585 and W.T. Smith étal., Trans. Kentucky Acad. Sci. 198445:76-77, ail of which are incorporated herein by reference.

Enumerated embodiments. Aspects of the invention include the following enumerated 35 embodiments, which further illustrate the invention and preferred aspects thereof or related subjectmatter.

80 117 1 5 5 10 15 20 25 30 1. A method of treating malaria or Trypanosomiasis in a patient in need of such treatment,comprising administering to said patient an effective amount of at least one comp'ound selectedfrom the group consisting of the compounds of the présent invention. 2. A method as recited in embodiment 1, further comprising administering to said patientat least one plasma concentration-enhancing compound. 3. A method as recited in embodiment 2, wherein said at least one compound of the présentinvention and said at least one plasma concentration enhancing compound are administeredsimultaneously. 4. A method as recited in embodiment 2, wherein said at least one compound of the présentinvention and said at least one plasma concentration-enhancing compound are administeredsequentially. 5. A method as recited in embodiment 2, wherein said plasma concentration-enhancingcompound is naringin and/or naringenin. 6. A method as recited in any one of embodiments l - 5, further comprising administeringto said patient at least one macrophage stimulating factor. 7. A method as recited in any one of embodiments 1 - 6, further comprising administeringto said patient one or more oxidation agent and/or oxygen ventilation. 8. A method as recited in any one of embodiments 1 - 7, wherein said patient is a mammal. 9. A method as recited in embodiment 8, wherein said patient is a human. 10. A method as recited in any one of embodiments 1 - 9, wherein said administering is byinjection. 1 1. A method as recited in any one of embodiments 1 - 9, wherein said administering is byinfusion. 12. A method as recited in any one of embodiments 1 - 9, wherein said administering is byintravenous injection. 13. A method as recited in embodiment 1, wherein said at least one compound is selectedfrom the group consisting of compounds of formula 1, wherein R] 7 is not hydroxy. 14. A method as recited in embodiment 1, wherein said at least one compound is selectedfrom the group consisting of compounds of Formula 1, wherein Q2 is not CH2. 15. A method as recited in embodiment 1, wherein said double bond is not présent. 16. A method as recited in embodiment 1, wherein said at least one compound is selectedfrom the group consisting of compounds of Formula 1, w'herein Q2 is a halogen. 17. A method as recited in embodiment I, wherein said at least one compound is not DHEA.

81 5 10 15 20 25 30 T171 5 18. A method of treating sleeping sickness in a patient in need of such treatment,comprising administering to said patient an effective amount of a compound of th'e présentinvention. 19. A method as recited in embodiment 18, further comprising administering to saidpatient at least one plasma concentration-enhancing compound. 20. A method as recited in embodiment 19, wherein said at least one compound of theprésent invention and said at least one plasma concentration-enhancing compound are administeredsimultaneouslÿ. 21. A method as recited in embodiment 19, wherein said at least one compound of the 70présent invention and said at least one plasma concentration-enhancing compound are administeredsequentially. 22. A method as recited in embodiment 19, wherein said plasma concentration-enhancingcompound is naringin and/or naringenin. 23. A method as recited in any one of embodiments 18 - 22, further comprisingadministering to said patient at least one macrophage stimulating factor. 24. A method as recited in any one of embodiments 18 - 23, further comprisingadministering to said patient one or more oxidation agent and/or oxygen ventilation. 25. A method as recited in any one of embodiments 18 - 24, wherein said patient is amammal. 26. A method as recited in embodiment 25, wherein said patient is a human. 27. A method as recited in any one of embodiments 18 - 26, wherein said administering isby injection. 28. A method as recited in any one of embodiments 18 - 26, wherein said administering îsby infusion. 29. A method as recited in any one of embodiments 18-26, wherein said administering isby intravenous injection. 30. A method of treating Chagas disease in a patient in need of such treatment, comprisingadministering to said patient an effective amount of a compound of the présent invention. 31. A method as recited in embodiment 30, further comprising administering to saidpatient at least one plasma concentration-enhancing compound. 32. A method as recited in embodiment 31, wherein said at least one compound of the 71présent invention and said at least one plasma concentration-enhancing compound are administeredsimultaneouslÿ. \ 82 11715 5 10 15 20 25 30 33. A method as recited in embodiment 31, wherein said at least one compound of theprésent invention and said at ieast one plasma concentration-enhancing compound are administeredsequentially. 34. A method as recited in embodiment 31, wherein said piasma concentration-enhancingcompound is naringin and/or naringenin. 35. A method as recited in any one of embodiments 30 - 34, further comprisingadministering to said patient at least one macrophage stimulating factor. 36. A method as recited in any one of embodiments 30 - 35, further comprisingadministering to said patient one or more oxidation agent and/or oxygen ventilation. 37. A method as recited in any one of embodiments 30 - 36, wherein said patient is amammal, 38. A method as recited in embodiment 37, wherein said patient is a human. 39. A method as recited in any one of embodiments 30 - 38, wherein said administering isby injection. 40. A method as recited in any one of embodiments 30 - 38, wherein said administering isby infusion. 41. A method as recited in any one of embodiments 30 - 38, wherein said administering isby intravenous injection. 42. A method of treating one or more kind of parasites and/or one or more diseases causedby such parasites, against one or more kind of Mycoplasma and/or one or more diseases caused bysuch Mycoplasmas and/or against one or more of the following indications or infections: (a) hairyLeukoplakia, (b) oral candidosis, (c) mouth ulcérations (aphthous/herpetic/bacterial), (d) fungalcandida, (e) human papilloma virus, (f) molluscum contagiosum, (g) squamous oral carcinoma, (h)Kaposi's sarcoma oral lésions, (i) periodontitis, (j) necrotizing gingivitis, (k) orafacial herpeszoster, and (I) rotaviruses in a patient in need of such treatment, comprising administering to saidpatient an effective amount of a compound of the présent invention. 43. A method as recited in embodiment 42, further comprising administering to saidpatient at least one plasma concentration-enhancing compound. 44. A method as recited in embodiment 43, wherein said at least one compound of theprésent invention and said at least one plasma concentration-enhancing compound are administeredsimultaneously. 45. A method as recited in embodiment 43, wherein said at least one compound of theprésent invention and said at least one plasma concentration-enhancing compound are administered sequentially. \ \λζ- 83 11715 5 10 15 20 25 30 35 46. A method as recited in embodiment 43, wherein said plasma concentration-enhancingcompound is naringin and/or naringenin. 47. A method as recited in any one of embodiments 42 - 46, further comprisingadministering to said patient at least one macrophage stimulating factor. · 48. A method as recited in any one of embodiments 42 - 47, further comprisingadministering to said patient one or more oxidation agent and/or oxygen ventilation. 49. A method as recited in any one of embodiments 42 - 48, wherein said patient is amammal. 50. A method as recited in embodiment 49, wherein said patient is a human. 51. A method as recited in any one of embodiments 42 - 50, wherein said administering isby injection. 52. A method as recited in any one of embodiments 42 - 50, wherein said administering isby infusion. 53. A method as recited in any one of embodiments 42 - 50, wherein said administering isby intravenous injection. 54. A composition comprising at least one of the compounds of the présent invention, andat least one plasma concentration-enhancing compound. 55. A composition as recited in embodiment 54, further comprising at least onemacrophage stimulating factor. 56. A composition as recited in embodiment 54 or 55, further comprising an oxidation agent. 57. A composition comprising at least one of the compounds of the présent invention, andat least one macrophage stimulating factor. 58. A composition as recited in embodiment 57, further comprising at least one oxidation agent. 59. A composition comprising at least one of the compounds of the présent invention, andat least one an oxidation agent. 60. A kit comprising unit dosages of at least one of the compounds of the présentinvention, and unit dosages of at least one plasma concentration-enhancing compound, 61. A kit as recited in embodiment 60, further comprising unit dosages of at least onemacrophage stimulating factor. 62. A kit as recited in embodiment 60 or 61, further comprising unit dosages of anoxidation agent. 63. A kit comprising unit dosages of at least one of the compounds of the présentinvention, and unit dosages of at least one macrophage stimulating factor.

84 11715 5 64. A kit as recited in embodiment 63, further comprising unit dosages of at least one oxidation agent. 65. A kit comprising unit dosages of at least one of the compounds of the présent invention, and unit dosages of at least one oxidation agent. 66. The method, composition or kit of any of embodiments 1-65 wherein the compound of the invention is a formula 1 compound or a métabolite thereof. 67. The method of embodiment 66 wherein the formula 1 compound is a compound named in compound groups 1-21, or in any formula 1 (e.g., any formula 4) compound or genus disclosedor named herein, or a métabolite of any of these. 10 68. A composition comprising 16a-bromoepiandrosterone, and 2, 3, 4 or 5 excipients selected from polyethylene glycol, dehydrated éthanol, benzyl benzoate, benzyl alcohol andpropylene glycol, wherein the composition comprises less than about 3% v/v, or less then about1% v/v, or less than about 0.5% v/v of water, or less than about 0.1% v/v of water. 69. The composition of embodiment 68 wherein the composition comprises (i) 16a- 15 bromoepiandrosterone at a concentration of about 45-55 mg/mL, (ii) 20-30% v/v polyethylene glycol 300, polyethylene glycol 400 or a mixture of polyethylene glycol 300 and 400, (iii) 10-15%v/v dehydrated ethyl alcohol, 2.5-7.5% v/v benzyl benzoate, and (iv) 55-60% v/v propylene glycol. 70. The composition of embodiment 69 wherein the composition comprises 16a-bromoepiandrosterone at a concentration of about 50 mg/mL, about 25% v/v polyethylene glycol 20 300, about 12.5% v/v dehydrated ethyl alcohol, about 5% v/v benzyl benzoate, about 57.5% v/v propylene glycol and less than about 0.5% v/v water. 71. The composition of embodiment 68 wherein the composition comprises 16a-bromoepiandrosterone at a concentration of about 50-105 mg/mL, about 27-33% w/w benzylbenzoate, about 27-33% w/w polyethylene glycol 300, about 25-30% w/w propylene glycol and 25 about 1-3% w/w benzyl alcohol. 72. The composition of embodiment 71 wherein the composition comprises 16a-bromoepiandrosterone at a concentration of about 100 mg/mL (about 10% w/w), about 30.4% w/wbenzyl benzoate, about 30.7% w/w polyethylene glycol 300, about 28% w/w propylene glycol andbenzyl alcohol about 1.9% w/w. 30 73. The use of a formula 1 compound for making a médicament for the treatment of an infection caused by one or more Trypanosoma or Plasmodium parasites or a Mycoplasmabacterium in a subject, including one or more of Trypanosoma cruzi, Trypanosoma brucei,Trypanosoma gambiense, Trypanosoma rhodesiense, Trypanosoma brucei rhodesiense,Plasmodium falciparum. Plasmodium vivax, Plasmodium malariae, Plasmodium ovale or 35 Plasmodium berghei, Mycoplasma fermentons^ Mycoplasma genitalium or Mycoplasma pneumoniae. y 85 11715 74. The use of embodiment 73 wherein the formula 1 compound is a compound named incompound groups 1-21, or a métabolite thereof. 75. A method comprising administering an effective amount of a composition of any ofembodiments 68-71 to a subject having, or susceptible to, a Trypanosoma, a Plasmodium or a 5 Mycoplasma infection wherein the composition optionally comprises 16ct-bromoepiandrosteroneand a pharmaceutically acceptable excipient. 76. A method to ameliorate or reduce one or more symptoms associated with aTrypanosoma, a Plasmodium or a Mycoplasma infection in a subject, or to reduce réplication of aTrypanosoma, a Plasmodium or a Mycoplasma in a subject infected with a Trypanosoma, a 10 Plasmodium or a Mycoplasma, comprising administering to the subject an effective amount of acompound of formula 1. 77. The method of embodiment 76 wherein the formula 1 compound is a compound orwithin a genus of compounds as disclosed herein, e.g., a compound or genus named in compoundgroups 1-21 or in the claims as originally filed, or the formula 1 compound is présent in a 15 composition comprising one or more pharmaceutical excipients, e.g., any of the formulationsdisclosed or described herein. 78. A composition comprising a formula 1 compound wherein the formula 1 compound isa compound or within a genus of compounds as disclosed herein, e.g., a compound or genus namedin compound groups 1-21 or in the claims as originally filed, and at least one excipient and a local 20 anesthetic, wherein the local anaesthetic is optionally selected from procaine, benzocaine andlidocaine. 79. A product produced by the process of contacting a compound of formula 1, e.g., anycompound named in compound groups 1-21, and a first excipient with a second excipient whereinthe product optionally further comprises a local anesthetic, wherein the local anaesthetic is 25 optionally selected from procaine, benzocaine and lidocaine. 80. A product produced by the process of contacting a compound of formula 1, e.g., anycompound named in compound groups 1-21, and a first nonaqueous liquid excipient with a secondnonaqueous liquid excipient wherein the product comprises less than about 3% w/w water, or lessthan about 0.5% w/w water, or less than about 0.1% w/w water, and wherein the first or the second 30 nonaqueous liquid excipient optionally excludes one or more of dimethylsulfoxide, chloroform, dioxane, a vegetable oil and olive oi 1, and wherein the product optionally further comprises a localanesthetic, wherein the local anaesthetic is optionally selected from procaine, benzocaine andlidocaine. 81. A method comprising administering an effective amount of the composition of 35 embodiment 78 or the product of embodiments 79 or 80 to a subject having an infection or condition described herein, e.g., Malaria, African Trypanosomiasis or Chagas disease, whereby theinfection or'condition, or a symptom thereof, is eliminated, reduced, treated, improved orameliorated. 86 11715 82. The method ofembodiment 81 wherein the formula 1 compound is 16a-haloepiandrosterone or 16a-halodehydroepiandrosterone.

EXAMPLES

The following examples further illustrate the invention and are not to be construed as5 limiting the invention.

Example 1. 16a-Bromoepiandrosterone formulation 1. Two lots of a non-aqueousformulation was made at a 16a-bromoepiandrosterone (“BrEA”) concentration of 50 mg/mL in25% polyethylene glycol 300, 12.5% dehydrated ethvl alcohol, 5% benzyl benzoate, and 57.5%propylene glycol, hereafter “formulation 1", as follows. BrEA was obtained from Procyte, Inc. 10 The remaining excipients are shown below.

Excipient Propylene glycol Specifica-tion USP Supplier Lot No. Arco Chemical HOC-61220-01104 Final ProductConcentration57.5% (v:v) Polyethyleneglycol 300 NF Union Carbide 695752 25% (v:v) Dehydrated alcohol(éthanol) USP McCormick Distilling97K.10 12.5% (v:v) Benzyl benzoate USP Spectrum Pharmaceuticals MG025 5% (v:v)

The formulation was prepared by suspending BrEA in polyethylene glycol 300, andsequentially adding propylene glycol, benzyl benzoate, and dehydrated ethyl alcohol to form asolution, which was diiuted to the final desired volume with additional propylene glycol. The 15 procedure is described below.

The calculated amount of polyethylene glycol 300 was added to a compounding vessel.Then, while mixing, the calculated amount of BrEA was added to the vessel, and mixed for at least5 minutes to form a smooth, creamy liquid. Propylene glycol was added to the vessel, and mixedfor a minimum of 5 minutes to form a uniform suspension. The calculated amount of benzyl 20 benzoate is added to the vessel, and mixed for approximately 5 minutes to form a translucent liquidsuspension. Dehydrated alcohol was added to the vessel, and mixed for approximately 5 minutesto form a clear, colorless solution. Propylene glycol was then added to achieve the desired finalformulation, and mixed for approximately 5 minutes. The drug solution was transferred to avolume-dispensing device set to deliver 1.2 mL per vial. Under nitrogen pressure, the solution was 25 filtered through two 0.2 pm polyvinylidene fluoride f lters in sériés before dispensing. The vialswere capped with Teflon-coated, butyl-rubber stoppers and crimp sealed.

Materials used in the product vials are 1 isted below. 87 •117 1 5

Material Vial Source Wheaton Product Code2702-B51BA Description Tubing vial, 2 mL/I3 mm,glass, type 1 amber Stopper Omniflex V9239 FM257/2 13 mm, Teflon coated, butylrubber stopper Seal West 4107 Flip seal, 13 mm, mist gray bridgé

Exemple 2. BrEA formulation 2. A formulation containing 100 mg/mL of BrEA, 10%w/w, in oenzyl benzoate (USP) 30.4% w/w, polyethylene glycol 300 (NF) 30.7% w/w, propyleneglycol (USP), qs, about 28% w/w and benzyl alcohol (NF) 1.9% w/w, hereafiter “formulation 2”, 5 was prepared as follows. A desired amount of BrEA (1.0 kg) was suspended in PEG 300 (about3.0 L) in a compounding vessel and mixed forât least 5 minutes at room température tO form asmooth creamy liquid. The needed amount of propylene glycol (about 1.5 L) was then added andmixing was continued for at least 5 minutes to form a uniform suspension. Benzyl benzoate (about3.0 L) was then added and the vessel contents were mixed for about 5minutes to form a translucent 10 suspension. Benzyl alcohol (about 200 mL) was then added and the mixing was continued for about 5 minutes to form a clear, colorless solution. Propylene glycol was then added to achieve thedesired final formulation volume (about 1.5 L) and mixing was continued for about 5 minutes. Thedrug solution was transferred to a volume-dispensing device, which was set to deliver 1.2 mLpervial (2 mL, glass, type 1 amber vials). The formulation was filtered under nitrogen pressure (about 15 3 atm) through two 0.2 pm polyvinylidine fluoride filters in sériés. The vials were capped using

Teflon-coated, butyl rubber stoppers and then crimp sealed essentially as described in example 1.

The vials were stored in the dark at reduced température (about 2-8°C).

Example 3. In vitro testing. For in vitro antimalarial testing, micro-titer plates wereused. The concentration of drugs were prepared as pMol/well according to WHO standard 20 procedures (WHO, 1990). The test compound was dissolved in 15% DMSO in stérile RPM11640.Both chloroquine sensitive (WS/97) and résistant (MN/97) isolâtes were used throughout theexperiments. A'. Schizont inhibition assay: The micro-titer plates were predosed with variousconcentrations of the test compound. 50 pL of parasitised érythrocyte suspension in RPMI-1640 25 (0.2 mL érythrocyte + 0.3 mL sérum + 4-5 ml RPMI-1640) were dispensed in microtiter wells that contained various concentrations of drug. Triplicate readings were made for each concentration. B. ^H-Hypoxanthine incorporation assav: The testing was carried out according to the procedure of Desjardins et al.. 1979. After 30 hr culture at 37 degrees C, the same microtiter plates from schizont inhibition assays with another triplicate wells were pulsed with H-hypoxanthine for | 88 11715 ovemight. The cell suspensions were washed twice on millipore glass fîber filter with Milliporefilter apparatus. The filter dises were counted for DPM by a Beckman LS60Q0 β-scintillationcounter. The activity of the drug was measured by plotting DPM against concentration of drug.

Activity of compounds against Chloroquine sensitive T996/86 P. falciparum in vitro.

Concentra-tion (μΜ) DHEA (% Inhibition) Bromine-Epiandrosterone(% Inhibition) Etienic AcidMethyl Ester(% Inhibition) Etianic AcidMethyl Ester(% Inhibition) 30 65.6 98 60 61.5 15 44 60.1 45.7 47.4 7.5 38.3 50 40.9 45.3 3.25 37.2 43.7 46 41.4 1.875 23.2 40.9 41 43.4 0.938 37.2 31.8 43.3 "47. Γ-" 1C5O 19.0 μΜ 7. 5 μΜ 19.5 μΜ 17.5 μΜ

Concentration (nM)Chloroquine % Inhibition Chloroquine 200 95.9 100 94.6 50 97.3 25 94.5 12.5 86.8 6.25 27.2 ic50 9.0 nM

The activity of 16-chIoro-epiandrosterone and DHEA-Br against chloroquine sensitiveT996.86 and chloroquine résistant I<J P. falciparum in vitro is shown below. 10 T996.86 Kl 16-chloroepiandrosterone IC50 -9.25pgmL"i -9.25 pgmL-l DHEA-Br IC50 -25.0 pgmL"' -25.0 pgmL'i

Example 4. Four-day in vivo test protocol for P. berghei. The 4-day suppressive testlias been widely used since it can be performed with a 1 -week period. The test consists of the 15 inoculation of parasitised érythrocytes on Monday, the first day of the experiment (Do), followedby an injection of the test compound, which is repeatedly administered on D+l, D+2, D+3. On

D+4 (Friday), blood films are taken and antimalarial activity is assessed either by calculating I \Azx_- 89 11715 10 15 20 25 30 parasitaemias, or by scoring parasite numbers on a predetermined scale (i.e., 1-5). Peters (1970)described a basic procedure using this 4-day test.

PROTOCOL 1 . 5 female TO mice per test group. 2. Parasites (P. berghei HP 15 ANKA) were collected by cardiac puncture in a heparinised syringe from a donor mouse harboring a 30+% parasitaemia. 3. Blood was diluted with diluting agent (50% HIFCS+50% stérile PBS) to a finalconcentration of 1% parasitaemia or 1X10^ infected érythrocytes per 0.2 mL infectïngsuspension. 4. Each mouse was inoculated intravenously, producing a more uniform infection rate than anintraperitoneal administration of parasites. 5. Test compounds were prepared at doses of 100 mg/kg in (16.7% DMSO + 83.¾¾

Celacol). 6. Test compounds were administered intraperitoneally 2 hours after parasite inoculation. 7. The compounds were administered once a day starting on Do, and continued onD+l, D+2 and D+3. 8. Blood films were made from tail blood on D+4, fixed with 100% methanol and stained with 10% Giemsa. 9. Parasitaemias were scoréd on a scale of 0-5, where a 5 would be equal to the control. EXPERIMENTAL PROTOCOL: 5 female mice/group (strain TO) were used and an inoculum consisting of 1 %parasitaemia or lxl0? parasites/mL, 0.2 mL/mouse was delivered by intravenous injection. Drugadministration commenced 2 hours after inoculation on Day 1 and continued for 3 days. Bloodfilms from ali 20 mice were made on Day 5 and parasitaemias were assessed. The results areshown below.

Compound_Treatment_Parasitaemia Score (0 - 5)

Bromine-Epiandrosterone lOOmg/kg x 4 days i.p.* * 1

Etienic A.cid 1 OOmg/kg x 4 days. i.p. 2 DHEA lOOmg/kg x 4 days i.p. 1

Chloroquine 3 mg/kg x 4 days i.p. 1 control N/A 5 * i.p. = intraperitoneal injection

90 11715 ΙΟ 20 25 30

Example 5. Intérim in vivo malaria study.

Basic Protocol: 1. Infect mouse to 1% parasitemia using a solution containing 1x10? erythrocytes/mLby I.V. injection. 2. Two hours later give drug preferably by I.V. injection. 3. Drug Bromine-Epiandrosterone (Ερί-Br) given (0.2 mL I.V. or S.C.) once a day for 4days. 4. Tail snips to obtain blood after study.

Experimental results:

Day 0 T = 0 Mice were infected with P. berghei. Parasites were harvested from cardiac mouse blood, and mice were infected using 0.2 ml of blood with 14% parasitaemia pep> mouse 15 I.V. T = 2 hours First dose given: 100 mg/kg I.V. or S.C T=4days Daily doses of 100 mg/kg I.V. or S.C. T = 7 days 2/5 dead in the untreated control group3/5 dead in the S.C. group. T = 8 days 1/3 dead in the untreated control group.

No deaths occurred in the group receiving I.V. drug at day 30, but ail control animais weredead by day 10. Ail animais treated by S.C. delivery were dead by Day 11.

Example 6. Mouse ht vitro and in vivo study. In the in vitro protocol the parasite{Plasmodium falciparum, chloroquine sensitive strain WT and chloroquine resistanr strain Dd2)level is adjusted to 1% and the hemocrit is adjusted 7% with medium. Using a 96 well plate, 50pL of parasite and 100 pL of drug mixed with media are added to each well and the procedure isdone in triplicate. The plate is placed in a chamber containing a physiological gas mixture andincubated at 3 7°C. The media/drug mixture is changed at 24, 48 and 72 hours. On day 5 (96hours) slides of each well are made, stained with Gemsia and 500 red blood cells are counted foreach slide. The triplicates are averaged and data are reported in percent inhibition.

In the in vivo protocol, Lewis rats weighing 80-85 grams were given a standardized IPinjection of parasite {Plasmodium berghei}. Rats were then intravenously injected 2 hours laterwith one of the treatments described in the table below, returned to their housing, fed standard labchow and allowed free access to water. Animais were weighed and treated again 24, 48, and 72hours after the First treatment and again returned to their housing and they were allowed free accessto food and water. The animais were weighed again and then bled using a 26-gauge needle on day5, 1 1 and 28 post inoculation. Hemocrits were measured and blood smears are prepared for each Λ 35 91 11715 rat. The blood smears were then stained using Gemsia and the level of parasitemia (defined as thepercent of red cells with parasites) were determined. Animais were again retume'd to theïr housingand observed twice daily for evidence of progressive disease, defined as iistlessness and or adversedrug reaction, which is defined as a loss of20% of original body weight, for a total of 28 days. If 5 either progressive disease or drug reaction is noted, the animais are euthanized.

The PPB2 formulation comprised a stérile solution contajning 15 mg/mL of 16a- bromoepiandrosterone in 45% β-cyclodextrin and 0.9% saline.

Group l Group 2 Group 3 Group 4 Control 0.9% Chloroquine Control PPB2 Low Dose PPB2 High Dose saline 40mg/kg (LD) 30 mg/kg (HD) 60 mg/kg

The intravenous injections were given on days 0, 1, 2 and 3 and the results are Shown10 below. The results showed that treatment in vivo with a formulation comprising 16a- bromoepiandrosterone reduced parasitemia to a level comparable to that seen with the chloroquine(“Clq”) control. PPB2 In Vivo Run#1 Day 4

Saline Glq LD PPB2 HD PPB2

92 11715 PPB2 In Vivo Run #1 (Day 11 ) 45 40

Saline Clq LD PPB2 HD PPB2

Example 7. Human clinical study. Response to drug treatment was graded as per WorldHealth Organization criteria (WHO 1973). Evaluation of therapeutic response was determined 5 usïng the parasitic and fever clearance times. Parasite clearance was expressed as three indices; thetime for the parasite count to fall by 50% of the pre-treatment (baseline) value (PC50); to fall by 90% of the baseline value (PC90) and to fall below the level of microscopie détection (parasiteclearance time PCT) (White and Krishna 1989; White et al. 1992). The fever clearance time wasdefined as the time front drug administration till the oral or rectal température fell to or below 10 37.2° C and remained so for at least 48 h.

Venous blood (5mL) was obtained from two patients before treatment and at 4, 6, 8, 12, 18, 20, 24, 30 and 36 h after treatment or at 4 or 6-hourly intervals after treatment until there wascomplété clearance of peripheral parasitemia. Blood was collected aseptically and transferred to 10mL syringes containing 2 mL of acid citrate dextrose (ACD) for in vitro culture. Prior to

1 5 incubation, the plasma was separated from the red blood cells and the red blood cells were washedtwice. Parasites were cultured by modification of standard in vitro culture techniques (Trager andJensen 1976; Oduola et at. 1992). Samples were dispensed into stérile centrifuge cubes within 10min of collection and spun down. The supematant plasma was stored while the packed cells werewashed twice with culture medium (washing medium, RPM1 1640 medium, containing 25 mM 20 HEPES buffer and 25 mmol/L NaOH). The buffÿ coat was removed by vacuum aspiration. A 1:10fold dilution was done for each blood sample with complété washing medium [CMP (washingmedium supplemented with 10 % human plasma)]. One milliliter each of the sample was » 93 11715 transferred into 2 weils of a 24 well micro culture plate. Cultures were incubated at 37 degrees C inan atmosphère of 5% CO2, 5% O2 and 90% N2 premixed gas. The culture medium was changeddaily and thin blood smears were prepared for microscopy at 24 and 48 h after the culture has beenset up. The culture samples were diluted with unparasitized washed type A Rh-positive red blood 5 cells if the proportion of parasitized red blood cells was more than 2%.

Microscopy. During the in vivo study, thin and thick blood films were fixed withdehydrated methanol (100%) and heat, respectively, were stained with 10% Giemsa for 20 min.Parasitemia was quantified in thin films by counting 2000 red blood cells in clear contiguous fieldsand fïnding the proportion that was parasitized. In thick Films, parasitemia was quantified by 10 counting parasites against leukocytes. A film was declared négative if no parasites were found afterexamination of 200 microscope fields of a thick smear. During in vitro and ex vivo study,pretreatmentthin and thick smears were, graded for ring stages by the method of Jiang as modifiedby Li et al. (Jiang et al, 1982; Silamutand White 1993; Li étal, 1994). Approximately 5000érythrocytes were counted in clear contiguous fields 24 and 48 h after incubation of blood obtained 15 at each time point and graded for maturity into tiny rings, small rings, large rings, pigmented trophozoites and schizonts. Functional viability was estimated as the percentage of asexual ringforms capable of maturing to pigmented trophozoites or schizonts after 24-48 h of in vitro culture(Watkins et al. 1993).

Calculations of parameters. The Patients presented with acute symptomatic severe 20 non-cerebral pure P. Falciparum malaria, they had oral fluid intolérance and had body températuresgreater than 39 degrees C, greater than 5000 parasites per micro liter of blood and asexualparasitemia and they had a négative urine test for antimalarial drugs. They were administered 25mL intravenously every four hours with bromine epiandrosterone (16a-bromoepiandrosterone)suspended in 45% beta cyclodextrin in saline at a concentration of 25 mg/mL. This regimen was 25 continued for four days. Parasitemia quantification and clinical examination were done once every6 hours for the first 72 hours, followed by daily assessment of the parameters up to day 7 (168 hrs)and thereafter on day 14.

The blood films were Giemsa-stained and parasitemia quantification was done in thickfilms by counting 2000 parasites against leukocytes, and the thin films by fïnding the proportion of30 infected red blood cells. Response to drug treatment was graded according to WHO criteria.

Evaluation of therapeutic response was done using the parasitic and fever clearance times. Parasiteclearance was expressed as three indices: The time for the parasite count to fall by 50% of thepre-treatment (baseline) value (PCgo);t0 fall by 90% of the baseline value (PC90); and to fallbelow the level of microscopie détection (parasite clearance time) PCT.

94 11715

The fever clearance time was defined as the time from drug administration until theoral/rectal température fell to below 37.2 degrees C and remained so for greater th'an 48 hours. I.V. Bromine Epiandrosterone Malaria Patient Trial

Patient A Patient B Fever clearance time (H) 12 hrs 18 hrs Parasite clearance times (H) Time to 50% clearance 18 hrs 24 hrs Time to 90% clearance 24 hrs 48 hrs Time to 100% clearance 48 hrs 64 hrs 10 Results. The response consisted of parasite clearance in both patients, i.e., the clearance rate at day 14 was 100%.

Example 8. Cellular studies in vitro. The effect of Bromine Epiandrosterone{EPI, 16a-bromoepiandrosterone) on pentosephosphate shunt (PPS) activity in normal human RBC wasexamined using whole cells. Since gIucose-6-phosphate dehydrogenase (“G6PD”) is the limiting 15 enzyme of the PPS, PPS flux measurement is considered to better reflect G6PD activity in the whole cell compared to G6PD activity measurement in a cell lysate. G6PD activity measured in acell lysate is typically about 1 100-foId higherthan the PPS flux in whole resting unstimulated RBC(G6PD activity in cell lysate: 165; PPS flux 0.142 micromoles/hour/ml RBC). PPS flux and G6PDactivity in the whole RBC dépends on a number of factors (the concentration of NADPH, NAD,

20 and ATP, and intracellular pH), which are kept constant if the measurement is performed in thelysate and may vary in the whole RBC. Levels of G6PD activity in cells is considerably abovenormal basal needs and inhibition of overall G6PD activity might hâve no or minor conséquenceon PPS flux in the whole cell. For example, RBC with the Mediterranean G6PD mutant with about1-3 percent residual activity compared with normal individuals hâve no impairment in basal PPS 25 flux, but show impaired flux when flux through PPS is stimulated by methylene blue addition. Asériés of experiments were perfromed using varying amounts of EPI and PPS flux was measured inunstimulated basal RBC and in methylene-blue (MB)-stimulated RBC.

The data below shows PPS flux (micromoles/hour/ml RBC) in basal unstimulated, andMB-stimulated normal RBC. Different concentrations of EPI (0.3, 3.5 and 7 micromolar, final)

30 were supplemented to suspensions of washed RBC suspended in RPMI, pH 7.4 at 10% hematocrit,whereby PPS flux was immediately measured without further incubation and without furtherwashings. A minor inhibition of MB-stimulated PPS flux wasobserved with EPI at 7 μΜ. I 95 11715 PPS Flux control, unstimulated RBC 230 DMSO control, unstimulated RBC 270 5 DMSO control, MB stimulated RBC 5090 0.3 μΜ EPI, unstimulated 250 0.3 μΜ EPI, MB stimulated 5000 3.5 μΜ EPI, unstimulated 270 3.5 μΜ EPI, MB stimulated 4950 10 7 μΜ EPI, unstimulated 295 7 μΜ EPI, MB stimulated 4660

The data below shows average values of 3 experiments, where basal, unstimulated, andMB-stimulated PPS flux (micromoles/hour/ml RBC) was measured in normal RBC. In these 15 experiments, different concentrations of EPI ~0.8, 8 and 80 micromolar, final) were supplementedto suspensions of washed RBC suspended in RPMI, pH 7.4 at 10% hematocrit. After a 90-minincubation at 37° C with and without EPI, PPS flux was measured, The results showed adose-dependent inhibition of MB-stimulated PPS flux. Inhibition was 10% at 8 micromolar(p=0.006 vs control+DMSO) and 25% at 80 micromolar (p=0.002 vs control+DMSO). 20 ;PPS flux control, unstimulated RBC 430 control, MB stimulated RBC 5410 DMSO control, unstimulated RBC 480 25 DMSO control, MB stimulated RBC 4890 0.8 μΜ EPI, unstimulated 410 0.8 μΜ EPI, MB stimulated 4930 8 μΜ EPI, unstimulated 450 8 μΜ EPI, MB stimulated 4430 30 80 μΜ EPI, unstimulated 450 80 μΜ EPI, MB stimulated 3660

Example 9. Inhibition of parasite growth, The effect of EPI (16a-bromo-epiandrosterone) on parasite (Plasmodium falciparum) growth was shown. EPI was active at a

35. concentration of 1 μΜ. V 96 11 715

Parasitemia after treatment

Time 0 24hrs 48hrs72hrs control + DMSO 5% 5.40% 3.10% 5.20% 5 Epi 1 μΜ 5% 5.70% 5,50% 1,60% Epi 10 μΜ 5% 5,60% 0.90% o Epi Î00 μΜ 5% 0 0 0 Epi 500 μΜ 5% 0 0 0 10 control + DMSO 2% 8.80% 1 1% 8% Epi 50 nM 2% 9.90% . 9.20% 8.30% Epi 1 μΜ 2% 5.80% 6.10% 2.10% Epi 2.5 μΜ 2% 7.30% 5.80% 3.20% Epi 5 μΜ 2% 5.40% 6% 1.80% 15 Epi 10 μΜ 2% 4.20% 3% 0 Epi 50 μΜ 2% 0 0 . 0

Parasitemias were determined by standard methods (microscopie inspection of at least 500cells, stained with Diff-QuickTM (Baxter). Parasites were cultured under standard conditions in 20 RPMI-1640 supplemented with Hepes/Glucose (10 mM), glutamine (0.3 g/liter) and 10% humanplasma. The hematocrit was 1%.

Example 10. Stimulation of phagocytosis. The capacity of EPI (16cx-bromo-epiandrosterone) to influence phagocytosis of Plasmodium parasite infected RBC is examinedusing adhèrent human monocytes. The parasitemia level is about 8-10% and human monocytes are25 obtained from buffy coats from blood as follows. Peripheral blood mononuclear cells are separated from freshly collected platelet-poor buffy coats discarded from blood samples ofheafthyadult donors of both sexes. Separated cells are washed once with luke-warm PBS supplementedwith 10 mM glucose (PBS-G) and resuspended at 5 x 10^ cells/mL in ice-cold RPMI 1640 mediumsupplemented with 23 mM NaHCÛ3 and 25 mM Hepes, pH 7.4 (RMBH). Dynabeads M450 Pan B30 and Pan T (Dynal) are added to cells in a 4:1 ratio for 20 min at 4°C. B-lymphocytes and T-lymphocytes are removed as specified by the manufacturer. The remaining monocytes arewashed 2 times in RMBH, resuspended in AIM V cell culture medium (Gibco) at 1 x 10^ cell/mL.The monocyte layer is collected, washed with PBS-G at 37°C and resuspended in AIM V mediumat 1 x lO^cells/mL. Purified cells are >90% monocytes as assessed by CD14 expression.

97 11715

Phagocytosis of opsonized parasitized RBC (PE) is determined as follows. Phagocytosisof fresh-serum opsonized PE is initiated by mixing 10 PE/monocyte, Suspensions"are brieflycentrifuged (150 x g for 5 sec at room température) to improve contact between PE and monocytes.To avoid attachement of monocytes after centrifugation and during the whole incubation period, 5 cells are kept in suspension at 5 x 10^ cells/5 mL AIM V medium in 6 cm diameter teflon bottom dishes(Heraeus) in a humidified incubator (95% air, 5% CO2) at 37°C. On average, at least 90%of the monocytes phagocytose PE, as assessed by microscopie inspection. Control cells are keptunder similar conditions without phagocytosis. Quantitative assessment of phagocytosis is 10 performed by a previously described bioluminescence method (E. Schwarzer, et al., Br. J.Haematol. 1994 88:740-745).

Erythrocyte treatments and parasite cultures are as follows. Fresh blood (Rh+)5S used toisolate érythrocytes (RBC). Washed RBC are infected with schizont/trophozoite parasite stages(Palo Alto strain, mycoplasma-free). Stage spécifie parasites are isolated by the Percoll-mannitol 15 method. Briefly, normal schizont-stage parasitized E (SPE) separated on Percoll-mannitol

gradient (parasitemia > 95% SPE) are mixed with E suspended in growth medium (RPMI 1640medium containing 25 mmol/L Hepes, 20 mmol/L glucose, 2 mmol/L glutamine, 24 mmoI/LNaHCOj, 32 mg/L gentamicin and 10% AB or A human sérum, pH 7.30) to start synchronouscultures at selected hematocrit values. The inoculum parasitemia is adjusted to 20% normal SPE 20 for isolation of ring parasitized RBC (RPE) and to 5% normal SPE for isolation of trophozoite-stage parasitized E (TPE). At 14-18 hours after inoculum parasites are at ring-stage inthe First cycle; at 34-33 hours, parasites are at trophozoite-stage in the First cycle; and at 40-44hours after inoculum parasites are at schizont-stage in the first cycle. RPE, TPE and SPE areseparated on Percoll-mannitol gradients. The parasitemia is usually 8-10¾ RPE, and >95% TPE. 25 Nonparasitized and parasitized RBC are counted electronically. To assess total parasitemia andrelative contribution of RPE, TPE and SPE, slides are prepared from cultures at indicated times,stained with Diff-QuikTM parasite stain and 400-1000 cells are examined microscopically.

The effect or EPI in parasitized RBC is examined using varions concentrations of EPI, e.g., 0.5 μΜ, 1 μΜ, 10 μΜ, 25 μΜ and 50 μΜ. Trophozoite-parasitized RBC, schizont-parasitized30 RBC or ring-parasitized RBC are examined as described.

Example 11. Human clinical trial. The clinical trial protocol that incorporâtes about 15- 20 patients is established. For a phase 1 or I/II trial, the patients are mildly infected with one ormore Plasmodium parasites and they are mildly symptomatic (less than about 8-10% parasitemiaof RBC). Before treatment, the patients are optionally tested for infection with HIV, HCV, TB,

35. and Cryptosporidium. Patients with one or more co-infections are given standard care for the I 98 11715 coinfection. The patients are hospitalized for treatment tor one week. 1 wo or more dose groups,e.g., 25, 50 or 100 mg/day of ] 6a-bromoepiandrosterone (BrEA), or an ester thereof, administeredparenterally, e.g., by intramuscular or intravenous injection, on 3, 4 or 5 days of the week whenpatients are dosed. Dosing is on consecutive days or on an intermittent schedule, e.g., 2, 3 or 45 doses with one dose administrered every other day. The formulation containing BrEA is asdescribed herein, e.g., the formulation of example 1 or 2. At day 5-7, if less than about 50%réduction in parasitemia is observed, the patients are given standard care for malaria (mefloquine).During the week of treatment and for 1,2 3, or more weeks theerafter, blood samples are takenperiodicaliy for évaluation of parasitemia, pharmacokinetics, plasma cytokines (e.g., IL-2, IL-4, 10 IL-10, IGF1, ylFN, GM-CSF), and intracellular cytokines (e.g., IL-2, IL-4, IL-10, IGF1, ylFN, GM-CSF). The patients are optionally treated again at about 2 to 12 weeks after the initial dosing,using the same or a similar protocol as that used in the initial dosing protocol. -

To the extent not already indicated, it will be understood by those of ordinary skill in theart that any one of the various spécifie embodiments herein described and illustrated may be15 further modified to incorporate features shown in other of the spécifie embodiments.

The foregoing detailed description has been provided for a better understanding of theinvention only and no unnecessary limitation should be understood therefrom as somemodifications will be apparent to those skilled in the art without deviating from the spirit and scopeof the appended daims. 20

99

Claims (26)

11 7.15 CLAIMS What is ciaimed is: 1 · The use of a compound having formula I,

wherein Ql is -C(Ri)2- or -C(O)-; Q2Îs-C(Ri)2-,-C(R1)(Y)-,-C(Y)-or-CH2-CH2-; ' * Q3 is -H or-C(Rj)3-; Q4 is -C(Ri)2-, -C(O)-, hydroxyvinylidine or methyl methylene; Q5 is-CCR!)2-or-C(O)-; X and Y independently are -OH, -H, lower alkyl, -O-C(O)-R5, -C(O)-OR5, halogen or =O; each Ri independently is -H, halogen, -OH, alkoxy, or Cialkyl; R2 is -H, -OH, halogen, C].g alkyl, C].6 alkoxy, -OR3, an ester, a thioester, a thioacetal, a sulfate ester, a sulfonate ester or a carbamate or R2, together with the R] that is bonded to the samecarbon atom is =O; R3 is -S(O)(O)-OM, -S(0)(0)-0-CH2-CH(0-C(0)-R6)-CH2-0-C(0)-R6,-P(O)(O)-O-CH2-CH(O-C(O)-R7)-CH2-O-C(O)-R7, a glucuronide group of structure (A)

or R3 is Ομ] 8 alkyl, C2-18 alkenyl, C2-i8 alkynyl, a Cm g ester or a C μ ! g thioester, where anyof the foregoing Ci_i8 or c2-18 moieties are optionally substituted at one or more hydrogen atomswith one or more independently selected -OR^P-, -NHRPP·, or-SRPP·, groups, or R3 is a Cj_j g 100 11715 wo ·. /f fatty acid, C2-IO alkynyï, (J)n-phenyl-C 1.5-aIkyl, (J)n-phenyl-C2-5-alkenyl;each R5 independently is straight or branched C ]. 14 aikyl;each Rg independently is Ci-14 straight or branched aikyl; and e3ch R7 independently is C μ 14 straight or branched aikyl or a glucuronide group of5 structure (A); each RPR independently is -H or an independently selected protecting group;n is 0, 1, 2 or 3; each J independently is halogen, Cj_4 aikyl, C2-4 alkenyl, Cj_4 alkoxy, carboxy, nitro,sulfate, sulfonyl, a carboxyl ester or a Cj.ô sulfate ester; 10 M is hydrogen, sodium, -S(O)(O)-O-CH2-CH(O-C(O)-Rô)-CH'2-C)-C(O)-R6, -P(O)(O)-O- CH2-CH(O-C(O)-R7)-CH2-O-C(O)-R.7 or a glucuronide group of structure (A); and the dotted lines represent an optiona! double bond, provided that there are not double bonds at both the 4-5 and 5-6 positions and provided that when a double bond is présent, zéro or 1Rj group is bonded to carbon atoms at the 1-, 2-, 4-, 5-, 6- or 17- positions so that these carbon 15 atoms are tetravalent; and the salts, stereoisomers, positional isomers, métabolites, analogs, precursors, hydrates,tautomers, ionized forms and solvatés thereof, in a method of making a médicament for use in a methodof treating or preventing Trypanosoma or Plasmodium infection, or to ameliorate one or more symptomsassociated with a Trypanosoma or Plasmodium infection, in a subject suffering from or subject to aTrypanosoma or Plasmodium infection.

2. The use of claim 1 wherein the Trypanosoma or Plasmodium infection is aTrypanosoma cruzi, Trypanosoma brucei, Trypanosoma gambiense, Trypanosoma rhodesiense, Trypanosoma brucei rhodesiense. Plasmodium falciparum, Plasmodium vivax. Plasmodium malariae, Plasmodium ovale or a Plasmodium berghei infection.

3. The use of claim 2 wherein the formula 1 compound is one or more compounds selected-5 from compound groups 1-21.

4. The use of claim 2 wherein the Trypanosoma or Plasmodium infection is aTrypanosoma cru:i infection.

5. The use of claim 4 wherein the formula I compound is one or more compounds selectedfrom compound groups I -21.

6. The use of claim 2 wherein the Trypanosoma or Plasmodium infection is a Plasmodiumberghei or a Plasmodium falciparum infection.

7. The use of claim 5 wherein the subject is a human or a primate.

8. The use of claim 7 wherein the formula 1 compound is one or more compounds selectedfrom compound groups 1-21. 101 11715

9. The use ofciaim 8 wherein the formula 1 compound is 16a-bromo-3p-hydroxy-5ct-androstan-17-one or 16a-bromodehydroepiandrosterone.

10. The use of claim l wherein the subject is coinfected with a retrovirus.

11. The use of ciaim 10 wherein the subject is a human and the retrovirus is H1V1 or HIV2.

12. The use of claim 1 wherein the formula 1 compound has the formula IB or 1C

10 15 20 25 wherein, each Rj independently is -H, -OH, a halogen, -CHCH2, -CHCHCH3, -CCH, -CCCH3, or,the other moiety thaï is bonded to the same carbon atom is absent and Rj is =0; R2 is -O-C(O)-R4, -S-C(O)-R4, -O-S(O)(O)-R4, -0-S(0)(0)-OR4, -O-C(O)-NHR4, or -O- c(S)-R4; R_4 is -H, a protecting group, optionally substiruted C1 _ 1 g alkyl, optionally substituted Cj.[g alkenyl, optionally substituted C|.}g alkynyl, optionally substituted aryl, optionally substitutedaryl-Ci_g alkyl, optionally substituted aryI-C2-6 alkenyl, optionally substituted aryl-C2-6 alkynyl,optionally substituted heterocycle-Ci_6 alkyl, optionally substituted C2-6 alkenyl-heterocycle,optionally substituted C2-6 alkynyl-heterocycle or an optionally substituted heterocycle, where anyof the foregoing moieties are optionally substituted at one, two, three, four, fîve or more carbon orhydrogen atoms with one or more independently selected -O-, -S-, -NR^^-, -OR^^·, -NHRPR, -SrPR, =O, =S, -CN, -NO2, -F, -CI, -Br or -I groups or atoms; and each RPR independently is -H or an independently selected protecting group; Q2 is -C(Ri)2-; and Q3 and Qg independently are -H, -CH3 or -CH2OH.

13. The use ofciaim 12 wherein Q3 and Qô are both -CHj in the β-configuration; .and Q2 is -CHo-, -C(O)-, -CH(Br)-, -CH(I)-, or-CH(OH)- with the Br, I or OH moieties in theα-configuration, or Q2, together with the hydrogen atom that is bonded to the same carbon atomcomprises -C(O)- or -CH2-CH2-; and Rj at the 7-pusition is -H, -OH or, when taken with the hydrogen atom that is Bonded tothe same carbon atom, R| is =0. 102 117 15

14. The use of claim I wherein the formula 1 compound has the formula l A

•wherein, R2 is -OH, halogen, Cj.g alkoxy, -OR3, a Ci_ 1 g fatty acid, Cj. 1 0 alkynyl, (J)n-phenyl-5 C}_5-alkyl, (J)n-phenyl-Ci_5-alkenyl, an ester optionally selected from -O-C(O)-(CH2)m-R4 and - C(O)-O-(CH2)m-R4. or R2 is -S-C(O)-(CH2)m-R4, -C(O)-S-(CH2)m-R4, -O-S(O)(O)-(CH2)m-. R4, -0-S(0)(0)-0-(CH2)m-R4, -O-C(O)-NH-(CH2)m-R4. -NH-C(O)-O-(CH2)m-R4.*O-C(S)- (cH2)m-R4> -C(S)-O-(CH2)m-R4, -O-C(O)-(CH2)m-R4 or -C(O)-O-(CH2)m-R4, or R2, togetherwith the Rj that is bonded to the same carbon atom is =O; 10 R4 is -H, a protecting group, optionally substituted C j. j 8 alkyl, optionally substituted C2- jg alkenyl, optionally substituted C2_]g alkynyl, optionally substituted aryl, optionally substitutedaryl-Cj_6 alkyl, optionally substituted aryl-Cg-g alkenyl, optionally substituted aryl-C2-6 alkynyl,optionally substituted heterocycle-C alkyl, optionally substituted C2-6 aikenyl-heterocycle,optionally substituted C2_g alkynyl-heterocycle or an optionally substituted heterocycle, where any 15 of the foregoing moieties are optionally substituted at one, two, three, four, fïve or more carbon orhydrogen atoms with one or more independently selected -O-, -S-, -NR^R-, -ORPR, -NHRPR, -SRPR, =O, =S, -CN, -NO2, -F, -Cl, -Br or -I groups or atoms; each RPR independently is -H or an independently selected protecting group;m is 0, 1, 2 or 3; and 20 the dotted line is an optional double bond.

15. The use of claim 1 wherein the formula I compound has the formula 45

wherein, R50 is -H, -OH or =O; 25 - R5 ] is-Br,-Ci,-F,-I or-OH; R$2 is -OH or, R52, together with the -H bonded to the same position, is =O; 103 η 7J 5 w< R49is -h, -oh, or -OR53; R53 is Cl. 18 aikyl, C2-I8 alkenyl, C2-I8 aikynyl, a Cm g ester, a Cmg‘thioester,wherein any of the foregoïng Cm8 or ^2-18 gr0UPs ’s substituted at one or more hydrogen orcarbon atoms with one or more independentiy selected -O-, -S-, -OH, -NH2, -SH or =O groups or 5 R53 ïs a thioacetal, a sulfate ester, a sulfonate ester, a carbamate or a thioester, and the dotted line is an optional double bond.

16. The use of claim 15 wherein R4Q is -O-C(O)-CH2-CH2-CH(R;4)-CH(R.55)- CH2R56 wherein R54 is -NH2, -OH, -SH, -O-PO3, -SO3 or -OSO3; R55 is -H, -NH2, -OH, -SH, -O-PO3, -SO3 or-OS03; and R55 is CmS aikyl, C2-I8 alkenyl, C2-I8 alkynyl, a Ci_jg ester or a 10 Ci-18 thioester, wherein any of the foregoïng Cm 8 or C2-I8 groups is substituted at one or more hydrogen atoms with one or more independentiy selected -OH, -NH2, -SH or =0 groups.

17. The use of claim I wherein the formula 1 compound has the formula 44

wherein, 15 Y is hydrogen or a halogen; R44 is -H, -S(O)(O)-OH, -S(O)(O)-ONa, -S(0)(0)-0-CH2-CH(0-C(0)-R6)-CH2-0-C(0)-Rg, -P(0)(0)-0-CH2-CH(0-C(0)-R7)-CH2-0-C(0)-R7 or a glucuronide group of structure (A);and the dotted line is an optional double bond.

18. The use of claim 17 wherein the formula 44 compound is déhydroépiandrostérone, epiandrosterone, I6a.-bromoepiandrosterone, 16a-bromodehydroepiandrosterone, dehydroepiandrosterone-3-sulfate or 5|3-androstan-3{3-ol-17-one.

19. The use of a composition comprising I6a-bromoepiandrosterone, and 2, 3, 4 or 5excipients selected from polyethylene glycol, dehydrated éthanol, benzyl benzoate, benzyl alcohol and 25 propylene glycol, wherein the composition optionally comprises less than about 3% v/v, or less than about I % v/v, or less than about 0.5% v/v of water, or less than about 0.1 % v/v of water in a method ofmaking a médicament for use in a method of treating or preventing a Trypanosoma or Plasmodium orMycoplasma infection, or to ameliorate one or more symptoms associated with a Trypanosoma, Plasmodium or Mycoplasma infection, in a subject suffering from or subject to a Trypanosoma, Plasmodium or Mycoplasma infection. 104 11 7 15 vt •''Ή 10

20. The use of claim 19 wherein the composition comprises 16a-bromoepiandrosterone at aconcentration of about 45-55 mg/mL, 20-30% v/v polyethylene glycol 300, polyethylene glycol 400 or amixture of polyethylene glycol 300 and 400, 10-15% v/v dehydrated ethyl alcohol, 2.5-7.5% v/v benzylbenzoate, and 55-60% v/v propylene glycol.

21. The use of claim 20 wherein the composition comprises 16a-bromoepiandrosterone at aconcentration of about 50 mg/mL, about 25% v/v polyethylene glycol 300, about 12.5% v/v dehydratedethyl alcohol, about 5% v/v benzyl benzoate, about 57.5% v/v propylene glycol and less than about 0.5%v/v water.

22. The use of claim 19 wherein the composition comprises 16a-bromoepiandrosterone at aconcentration of about 85-105 mg/mL, about 27-33% w/w benzyl benzoate, about 27-33% w/wpolyethylene glycol 300, about 25-30% w/w propylene glycol and about 1-3% w/w benzyl alcohol.

23. The use of claim 22 wherein the composition comprises 16a-bromoepiandrosterone at aconcentration of about 100 mg/mL, about 30.4% w/w benzyl benzote, about 30.7% w/w polyethyleneglycol 300, about 28% w/w propylene glycol and about 1.9% w/w benzyl alcohol. 24. 15 20 25

30 wherein Ql is -C(R[)2- or -C(O)-; Q2 is-C(R1)2-, -C(Ri)(Y)-,-C(Y)- or -CH2-CH2-; ,· ' ' Q3 is -H or -C(Rj)3-; Q4 is -C(Ri)2-, -C(O)-, hydroxyvinylidine or methyl methylene; Q5 is -C(Ri)2- °r -C(O)-; X and Y independently are -OH, -H, lower alkyl, -O-C(O)-Rs, -C(O)-OR5, haiogen or =O; each Rj independently is -H, haiogen, -OH, Cj.g alkoxy, or Ci.g alkyl; R2.is -H, -OH, haiogen, Cj.g alkyl, Ci.g alkoxy, -OR3, an ester, a thioester, a thioàcetal, a sulfate ester, a sulfonate ester or a carbamate or R2, together with the R] that is bonded to the samecarbon atom is =O; 105 11715 R 3 is -S(O)(O)-OM, -S(0)(0)-0-CH2-CH(0-C(0)~R6)-CH2-0-C(0)-R6,-P(O)(O)-O-CH2-CH(O-C(O)-R7)-CH2-O-C(O)-R7, a glucuronide group of structure (A)

or R3 is Cm 8 aikyl, C2-18 aikenyl, C2.j8 alkynyl, a 8 ester or a g thioester, where any5 of the foregoing Cl-18 or C2-I8 moieties are optionally substituted at one or more hydrogen atoms with one or more independently seiected -ORPR, -NHRPR, or -SRPR·, groups, or R3 is a C 3fatty acid, C2-1Q alkynyl, <J)n-phenyl-C 1.5-alkyl, (J)n-phenyi-C2-5-alkenyl; « each R5 independently is straight or branched C j. ] 4 aikyl; each Rg independently is C I_14 straight or branched aikyl; and 10 each R7 independently is C1 _ ] 4 straight or branched aikyl or a glucuronide group of structure (A); each RPR independently is -H or an independently seiected protecting group;n is 0, 1, 2 or 3; each J independently is halogen, Cj_4 aikyl, C2-4 aikenyl, C1.4 alkoxy, carboxy, nitro, 15 sulfate, sulfonyl, a C].g carboxyl ester or a Cj.g sulfate ester; M is hydrogen, sodium, -S(0)(0)-0-CH2-CH(0-C(0)-R,5)-CH2-0-C(0)-Rg, -P(O)(O)-O-CH2-CH(O-C(O)-R7)-CH2-O-C(O)-R7 or a glucuronide group of structure (A); and the dotted lines represent an optional double bond, provided that there are not doublebonds at both the 4-5 and 5-6 positions and provided that when a double bond is présent, zéro or 1 20 Rj group is bonded to carbon atoms at the 1-, 2-, 4-, 5-, 6- or 17- positions so that these carbonatoms are tetravalent; and the salts, stereoisomers, positional isomers, métabolites, analogs, precursors, hydrates,tautomers, ionized forms and solvatés thereof, for intermittent administration to a subject having a retroviral infrection. or for amelioration of22 one or more symptoins associated with a Retroviral infection in a subject.

25. The use according to claim 24 wherein the retroviral infection is an H1V-1 or H1V-2infection and the subject is a human.

26. The use according to claim 25 wherein the formulai compound is one or morecompounds seiected from compound groups 1-21.

27. The use according to claim 25 wherein the formula 1 compound is 16a-bromo-3P-hydroxy-5cx-androstan-17-one, 3p-hydroxy-7-oxo-5a-androstan-17-one, 3p, 17P-dihydroxyaridrost-5-ene, 3p,7p,17P-trihydroxyandrost-5-ene, 3P,7a,17P-trihydroxyandrost-5-ene or 16a- bromodehydroepiandrosterone. 106