KR20070004149A - 17-ketosteroid compounds - 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. ® KIPO & WIPO 2007

Description

17-ketosteroid compound {17-KETOSTEROID COMPOUNDS}

The present invention relates to 17-ketosteroid compounds, and derivatives, metabolites and precursors of these compounds, optionally in Africa and America, in the treatment of tripanosomosis and malaria, optionally with one or more additional administrations and / or treatments (as described below). And pharmaceutically acceptable salts of any of these compounds (hereinafter collectively referred to as "compounds of the present invention"). The present invention further provides treatment of one or more parasites and / or one or more diseases resulting from such parasites, treatment of one or more mycoplasma and / or one or more diseases resulting from such mycoplasma, and / or It relates to the use of such compounds (and combinations) in the treatment of one or more of the following symptoms or infections: (a) vitiligo, (b) oral candidiasis, (c) aphthaic / herpetic / bacterial Oral ulcers, (d) fungal candida, (e) human papilloma virus, (f) infectious continuous species, (g) squamous oral carcinoma, (h) Kaposi's sarcoma oral lesion, (i) periodontitis, (j) necrotizing gingivitis , (k) oral facial shingles, and (l) rotavirus, in addition, as disclosed in U.S. Patent No. 5,292,725, the entirety of which is incorporated herein by reference (in particular, Column 1, Line 13 to Column 4, Line 25 Disclosure), all signs of infection and so on.

In the case of malaria, human infection is caused by mosquito bites, during which "sporozoite" is introduced into the human blood stream. Sporozoite passes through the bloodstream, finally reaching the parenchymal cells of the liver and penetrating (sporozite may remain in the blood for up to 1 hour).

This preerythrocytic cycle, the first cycle of growth and regeneration, lasts about one week and develops in the liver. This whole blood cell cycle releases thousands of mesozoites, which then turn into blood.

This mesozoid parasites red blood cells. Growth and regeneration occurs in erythrocytes, causing rhythmic fever attacks, and other symptoms increase with the number of parasites in the blood. Among the pathways of the erythrocyte growth cycle, when entering erythrocytes, the parasite is considered to be in the form of a ring with central vacuole. After about six hours, the size of the parasite increases until it almost fills red blood cells, and this fear slowly disappears. Nuclear fission occurs during the last 12 hours of this growth cycle, on average forming about 16 mesozoites. This growth parasite is called a trophic type, and after it begins fission, it is called a fissile.

Malaria parasites feed on hemoglobulin, which uses the protein portion of the molecule, leaves the heme portion, and accumulates to form malaria pigment. The pigment accumulates until the parasite feeds on food, sucks the red blood cell cytoplasm, digestion takes place in food fear, and when the host cell breaks down, it is released into the plasma and the mesozoite is released. Known by EM. Immediately after parasites begin to regenerate in blood fear, sexual form or germ cells begin to appear in red blood cells. Germ cells can survive within a mammalian host for several days, but no longer develop unless they are ingested by a suitable mosquito host. The single nucleus of this germ cell distinguishes it from the fully grown asexual form.

Sleep disease is caused by T. gambiense and T. rhodesiense and is transmitted through tsetse flies (Glosssina) between humans and between animals. In mammalian hosts, this organism resides in the blood but may penetrate other organs that occur in the intercellular space. In a drop of blood, trypanosomes appear fine, causing objects to move.

When a fly flies eats, its toothed snout tears the skin and forms a small amount of bleeding. If trapanosomes are present, the blood drawn from these bleeding areas is inhaled into the digestive tract of the fly. In the first few days after infectious ingestion, tripanosomes are found in the middle intestine. Afterwards, some of them move towards the proventriculus. For successful development, some must move just before the end of the snout where the mouth of the salivary canal is located. Thereafter, they develop through the tube into the salivary glands to infect other mammals. Since they appear at the end of the development cycle, they are called tripanosomes at the end of developmental development. Regeneration occurs at all sites of the fly. The time required for this cycle is 2-3 weeks or longer. Not only are these tripanosomes morphologically modified in the insect host, they are physiologically different from the bloodstream forms.

If a body fly with a mature infector bites a person, tripanosomes at the end of development may be injected with saliva. In the early stages of infection, parasites may be found in the blood. It is a characteristic aspect that many tripanosomes disappear after forming a peak, and this cycle is repeated. Tripanosomes stimulate the host to produce antibodies, which aggregate and dissolve these organisms. Some of these tripanosomes become resistant to antibodies, so that new populations develop various antigen types; They thrive until certain antibodies re-form and destroy them. At the end of this infection, the tripanosome is almost or completely absent from the blood and invades the central nervous system causing sleep disorders.

Tripanosomes can be formed and developed in a wide variety of mammalian species and have been isolated from many African wildlife. In these hosts, this binding appears to be positive and these mammals stay healthy. However, the same tripanosome in humans or human livestock animals shows a very high incidence. Trifanosomia in livestock animals is an urgent problem in many areas of Africa and can not raise livestock because of the presence of somatic flies and wild animals.

Chagas disease (American tripanosomosis) results from T. cruzi. It is infected by vampire insects with Triatomides.

After infection in humans, these parasites immediately exit the blood and settle in tissues, most often the heart, rhabdomyos, or striated muscles. Here they lose their flagella revenge and become round. After that, they multiply and form a cluster of hundreds of cells, altering the muscle fibers. Over time, the colonies begin to disperse, cells grow, develop flagella, respectively, and new tripanosomes enter the circulation. This tripanosome stays in this cycle for several days and then scatters back into the tissue for another regeneration cycle. In chronic infections, almost no blood form can be detected and this tissue condition prevails.

When insects eat blood containing tripanosomes, these tripanosomes primarily form in the middle bowel. In this middle intestine, tripanosomes multiply rapidly and within a few days some form of infection begins to appear in the feces via the posterior bowel. Unlike African tripanosomes, in which the form of infection is located in the front of the factor and injected into humans through inoculation, the form of infection of tripanosoma croge is located at the posterior end of the factor and infected by contamination. Triatomid insects ingest a large amount of blood relative to their weight, and the ingested blood is concentrated by secreting fluid while the insect eats. In this way infectious tripanosomes accumulate in the skin of the host. The tripanosome cannot penetrate unbreakable skin, but it can also get an exit through a crack wound. Because these insects are nocturnal and feed in the excretory area, the tripanosome is usually contaminated by the eyes, mouth or nose and penetrates the mucous membranes.

Tripanosoma cruising is developed in several species of insects, all of which act as hosts. If ten insects are eaten by an infected person, perhaps all ten of them will be infected. Usually diagnostics are used in laboratory or "clean" insects.

Tripanosoma cruising is found in chimneys and reddish inbsects and in a wide variety of wildlife in Central and South America and some southern parts of the USA. Human infections are rare in the USA, but infection rates in humans can be as high as 20 percent in Central and South America. Some 35 million people are at risk of infection. Infection can spread from human to human or from animal to human. Cattle dogs and cats in rural areas become carriers. Dogs that are effective against African tripanosomes have no effect on human infection by tripanosoma cruising, and no therapeutic drug has yet been found to eradicate the parasites.

Many steroidal compounds and uses thereof are disclosed. See, for example, US Patent Publications 4956355, 5859000, 4268441, 4666898, 5837269, 5827841, 5811418, 5824313, 5686438, 5635496, 5587369, 5583126, 5562910, 5532230, 5518725, 5736537, 5843932, 5837700, 5824671, 5807849, 579877 , 5728688, 5610150, 5593981, 5372996, 5110810, 5807848, 5707983, 5641766, 5585371, 5506223, 5424463, 5296481, 5292730, 5776921, 5641768, 5559107, 5478566, 5471042, 5407684, 5387583, 5277907, 5206008, 5077284, 51621 , 5527789, 5756482, 5709878, 5804576, 5744462, 5714481, 5700793, 5696106, 5656621, 5175154, 5157031, 5028631, 5001119, 4898694, 5824668, 5710143, 5795880, 5527788, 5591736, 5861390 and PCT Patent Publication WO 98/05338, WO 95/21617, WO 98/50040, WO 98/50041 and WO 97/48367, all of which are incorporated herein by reference.

A number of flavonoids, methods of obtaining them and their use are disclosed. For example, J.A. Manthey and BSBuslig, editors, Flavonoids in the living system, Advances in experimental medicine and biology, volume 439, Plenum Press, New York, 1998, Chapter 15 (pp. 191-225), Chapter 16 (pp. 227-235) And Chapter 17 (pp. 237-247), all of which are incorporated herein by reference.

An object of the present invention is a 17-ketosteroid compound, and derivatives thereof, which can be used to treat malaria, African tripanosoma and American tripanosoma, or to reduce or alleviate one or more symptoms associated with tripanosoma and plasmodium infections, To provide metabolites, precursors, pharmaceutically acceptable salts.

Summary of the Invention

According to one aspect of the present invention, the tripanosome parasite, such as a malaria parasite, is now a compound of Formula 1 (or a pharmaceutically acceptable salt thereof), and salts, stereoisomers, regioisomers, metabolites, homologues thereof It has been found that it can be treated with precursors, hydrates, tautomers, ionized forms and solvent compounds.

[Formula 1]

In the formula,

Q ₁ is -C (R ₁ ) ₂ -or -C (O)-;

Q ₂ is —C (R ₁ ) ₂ —, —C (R ₁ ) (Y) —, —C (Y) — or —CH ₂ —CH ₂ —;

Q ₃ is -H or -C (R ₁ ) _3- ;

Q ₄ is -C (R ₁ ) _2- , -C (O)-, hydroxyvinylidene (-CH (CH = CHOH)-) or methyl methylene (-CH (CH ₃ )-);

Q ₅ is -C (R ₁ ) ₂ -or -C (O)-;

X and Y are -OH, -H, lower alkyl (eg, C _1-6 alkyl), -OC (O) -R ₅ , -C (O) -OR ₅ , halogen (ie -F, -Cl) , -Br or -I) or = O;

Each R ₁ is independently —H, —F, —Cl, —Br, —I, —OH, C _1-6 alkoxy, or C _1-6 alkyl;

R ₂ is independently —H, —OH, —F, —Cl, —Br, —I, C _1-6 alkyl, C _1-6 alkoxy, —OR ₃ , ester (eg, —OC (O) —R ₄ or -C (O) -OR ₄ ), thioester (eg -OC (S) -R ₄ or -C (S) -OR ₄ ), thioacetal (eg -SC (O) -R ₄ or -C (O) -SR ₄ ), sulfate esters (eg -OS (O) (O) -OR ₄ ), sulfonate esters (eg -OS (O) -OR ₄ ) or carbamate (eg- OC (O) —NH—R ₄ or —NH—C (O) —OR ₄ ), or R ₂ is ═O with R ₁ bonded to the same carbon atom;

R ₃ is -S (O) (O) -OM, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ , -P (O) (O) -O-CH ₂ -CH (OC (O) -R ₇ ) -CH ₂ -OC (O) -R ₇ , or a glucuronide group having the formula A:

[Formula A]

R ₃ is C _1-18 alkyl, C _2-18 alkenyl, C _2-18 alkynyl, C _1-18 ester, or C _1-18 thioester, said C _1-18 or C _2-18 Any of the substituents may be substituted with one or more hydrogen atoms each selected from one or more selected from -OR ^PR (including -OH), -NHR ^PR (including -NH ₂ ) or -SR ^PR (including -SH), or R ₃ is C _1-18 fatty acid, C _2-10 alkynyl, (J) _n -phenyl-C _1-5 -alkynyl or (J) _n -phenyl-C _2-5 -alkenyl;

R ₄ is H, a protecting group, optionally substituted C _1-18 alkyl, optionally substituted C _1-18 alkenyl, optionally substituted C _1-18 alkynyl, optionally substituted aryl, optionally substituted aryl-C _1-6 Alkyl, optionally substituted aryl-C _2-6 alkenyl, optionally substituted aryl-C _2-6 alkynyl, optionally substituted heterocycle-C _1-6 alkyl, optionally substituted C _2-6 alkenyl-hetero cycle , Optionally substituted C _2-6 alkynyl-heterocycle or optionally substituted heterocycle, any one of the above substituents optionally having one, two, three, four, five or more carbon or hydrogen atoms —O—, —S—, NR ^PR -(With -NH-), -NH-C (O)-, -OR ^PR (with -OH), -NHR ^PR (with -NH ₂ ), -SR ^PR (with -SH), = O, = S , May be substituted with one or more selected from the groups — = N—OH, —CN, —NO, —F, —Cl, —Br, or —I, or an atom;

Each R ₅ is independently straight or branched C _1-14 alkyl;

Each R ₆ is independently straight or branched C _1-14 alkyl;

Each R ₇ is independently straight or branched C _1-14 alkyl or a glucuronide group of formula A above;

Each R ^PR is independently —H or each selected protecting group;

n is 0, 1, 2 or 3;

Each J is independently -F, -Cl, -Br, -I, C _1-4 alkyl, C _1-4 alkenyl, C _1-4 alkoxy, carboxy, nitro, sulfate, sulfonyl, C _1-6 Carboxy ester or C _1-6 sulphate ester;

M is hydrogen, sodium, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ , -P (O) (O) -O-CH ₂ -CH (OC (O) -R ₇ ) -CH ₂ -OC (O) -R ₇ or a glucuronide group of Formula A;

In Chemical Formula 1, the dotted line represents an arbitrary double bond, provided that there is no double bond at both 4-5 and 5-6 positions, and in the case where the double bond exists, 1-, 2-, 4-, 5- , At the 6- or 17 position, one or more R ₁ groups bonded to the carbon atom are tetravalent. Hereinafter, the compound of formula 1 is collectively referred to as "invented compound" or "compound of the present invention".

Additionally, as noted above, the present invention relates to treating sleep sickness and treating Chaga disease by administering one or more of the compounds of the present invention. In addition, the present invention relates to the treatment of one or more parasites and / or one or more diseases resulting from such parasites, the treatment of one or more mycoplasma and / or one or more diseases resulting from such mycoplasma, And / or the use of a compound of the invention in the treatment of one or more of the following symptoms or infections: (a) vitiligo, (b) oral candidiasis, (c) aphthaic / herpetic / Bacterial oral ulcers, (d) fungal candida, (e) human papillomavirus, (f) infectious continuous species, (g) squamous oral carcinoma, (h) Kaposi's sarcoma oral lesion, (i) periodontitis, (j) necrosis Sexual gingivitis, (k) oral facial shingles, and (l) rotaviruses, as well as US Patent No. 5,292,725, the entirety of which is incorporated herein by reference (in particular, column 1, lines 13 to column) 4, la Disclosure of phosphorus 25) All other symptoms and infectious diseases.

Accordingly, the present invention provides a therapeutically effective amount of a compound (or pharmaceutically acceptable salt thereof) having the structure of Formula 1 (as described above), and derivatives, metabolites and precursors thereof, as described herein. Provided are methods for treating these parasitic infections, which consist of administering to a host.

The present invention further relates to a method for treating any abnormal condition as described in the text by administering a compound that inhibits glucose-6phosphate dehydrogenase.

Another embodiment of the present invention provides a subject to be treated with a compound of the formula 2A or 2B and salts, stereoisomers, regioisomers, metabolites, homologues, hydrates, tautomers, ionized forms, and solvent compounds thereof Methods of treating or inhibiting tripanosomes or Plasmodium infections, which consist of simultaneous or successive administrations, include:

[Formula 2A]

[Formula 2B]

Wherein, if a double bond or a single bond is present in the dashed line and a double bond is present, (i) an optionally substituted phenyl ring is present at the 2- or 3-position and R ₈ attached to this carbon atom is present And (ii) there is no one R ₈ in the adjacent 2- or 3- position;

X ₁ is —O— or —C (R ₈ ) ₂ —;

X ₂ is -CO- or -C (R ₁₁ ) _2- ;

Each R ₈ may independently form a substituent of —H, —OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glocuronide, C _1-25 fatty acid, or a compound of Formula 2A or 2B The residue of the compound of formula 2A or 2B wherein the hydrogen atom has been removed, -CH ₂ CH = C (CH ₃ ) ₂ , glucoside, a substituent having the structure of formula B or C:

[Formula B]

[Formula C]

R ₁₀ is C _1-6 alkyl, C _1-6 alkoxy, neohesperidoside, apiglucoside, lutinoside, glucoside, galactoside, rhamnoside, arabinoside, or the stereoisomer of any of these substituents , Hydrate, homologue, derivative, or metabolite, any of which optionally represents one or more hydrogen atoms each -OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glucuronide or C _1-25 fatty acid Or R ₁₀ is —H, —OH or halogen;

Each R ₁₁ is independently —H, —OH, halogen, C _1-6 alkyl, C _1-6 alkoxy, glucuronide, C _1-25 fatty acid, or both R ₁₁ together form ═O .

Unless otherwise stated in the context as used in the text, the following terms have the meanings as defined herein.

"Patient" or "treatment subject" means a human or animal. Usually animals are vertebrates such as primates, rodents, livestock or wildlife. Primates include chimpanzee cynomorgus monkeys, spider monkeys, and macaques, such as the rhesus monkey. Rodents include mice, rats, marmots, ferrets, rabbits and hamsters. Livestock and wildlife include cattle, horses, pigs, deer, bison, buffalo, domestic cats such as breeding cats, canine animals such as dogs, birds such as chickens, emu, ostrich, fish such as trout, catfish and salmon do. The patient or subject to be treated includes any subset as described above, but excludes one or more species or groups, such as humans, primates or rodents.

"Alkyl" in the text refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 in the form of CH ₂ primary, secondary, tertiary, cyclic or mixed structure, unless otherwise specified. , C ₁ -C ₁₈ hydrocarbon containing 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms. Examples thereof include -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) CH ₂ CH ₃ , -C (CH ₃ ) ₃ , -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH ₂ CH ₃ , -CH (CH ₂ CH ₃ ) ₂ , -C (CH ₃ ) ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ C (CH ₃ ) ₃ , -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₂ CH ₃ ) ( CH ₂ CH ₂ CH ₃ ), -C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ , -CH (CH ₃ ) CH ₂ CH (CH ₃₎ ) ₂ , -C (CH ₃ ) (CH ₂ CH ₃ ) ₂ , -CH (CH ₂ CH ₃ ) CH (CH ₃ ) ₂ , -C (CH ₃ ) ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) C (CH ₃ ) ₃ , cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclobutylmethyl, 1-cyclopropyl-1-ethyl, 2-cyclopropyl-1-ethyl, cyclohexyl, cyclopentyl Methyl, 1-cyclobutyl-1-ethyl, 2-cyclobutyl-1-ethyl, 1-cyclopropyl-1-propyl, 2-cyclopropyl-1-propyl, 3-cyclopropyl-1-prop , There may be mentioned 2-cyclopropyl-2-propyl, and 1-cyclopropyl-2-propyl.

As used herein, "alkenyl" means 1, 2, 3, 4, 5, 6, 7, 8, 9, in the form of primary, secondary, tertiary, cyclic or mixed structures, unless otherwise specified. C ₂ -C ₁₈ hydrocarbons containing 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms and containing 1, 2, 3 or more double bonds between adjacent carbon atoms. Examples thereof include -CH = CH ₂ , -CH = CHCH ₃ , -CH ₂ CH = CH ₂ , -C (= CH ₂ ) (CH ₃ ), -CH = CHCH ₂ CH ₃ , -CH ₂ CH = CHCH ₃ , -CH ₂ CH ₂ CH = CH ₂ , -CH = C (CH ₃ ) ₂ , -CH ₂ C (= CH ₂ ) (CH ₃ ), -C (= CH ₂ ) CH ₂ CH ₃ , -C ( CH ₃ ) = CHCH ₃ , -CH (CH ₃ ) CH = CH ₂ , -C = CHCH ₂ CH ₂ CH ₃ , -CHCH = CHCH ₂ CH ₃ , -CHCH ₂ CH = CHCH ₃ , -CHCH ₂ CH ₂ CH = CH ₂ , -C (= CH ₂ ) CH ₂ CH ₂ CH ₃ , -C (CH ₃ ) = CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) CH = CHCH ₃ , -CH (CH ₃ ) CH ₂ CH = CH ₂ , -CH ₂ CH = C (CH ₃ ) ₂ , 1-cycloprop-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex -1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl are mentioned.

In the text, "alkynyl", unless otherwise specified, in the form of primary, secondary, tertiary, cyclic or mixed structures 1, 2, 3, 4, 5, 6, 7, 8, 9, C ₂ -C ₁₈ hydrocarbons containing 10, 11, 12, 13, 14, 15, 16, 17 or 18 carbon atoms and containing 1, 2, 3 or more triple bonds between adjacent carbon atoms. Examples thereof include -CCH, -CCCH ₃ , -CH ₂ CCH, -CCCH ₂ CH ₃ , -CH ₂ CCCH ₃ , -CH ₂ CH ₂ CCH, -CH (CH ₃ ) CCH, -CCCH ₂ CH ₂ CH ₃ , -CH ₂ CCCH ₂ CH ₃ , -CH ₂ CH ₂ CCCH ₃ , and -CH ₂ CH ₂ CH ₂ CCH.

"Halogen" or "halo" means fluorine (-F), chlorine (-Cl), bromine (-Br) or iodine (-I), where one or more halogens are mentioned (e.g. Halogen), and each halogen is independently selected.

"Steroid nucleus" means four fused rings having the structure of Formula 1.

"PEG" means an ethylene glycol polymer containing about 20 to about 2000000 linked monomers, typically about 50-1000, usually about 100-300 linked monomers. Polyethylene glycols include PEGs containing various numbers of linked monomers, such as PEG20, PEG30, PEG40, PEG60, PEG80, PEG100, PEG115, PEG200, PEG300, PEG400, PEG500, PEG600, PEG1000, PEG1500, PEG2000, PEG3350, PEG4000, PEG4600, PEG5000, PEG6000, PEG8000, PEG11000, PEG12000, PEG2000000, and any mixtures thereof.

"Excipient" or "carrier" means an ingredient or element that is acceptable in view of being suitable for other compositions or combinations as described herein and that is not severely harmful to the patient or animal to which the combination is administered. Excipients and carriers in the body include benzyl benzoate, cottonseed oil, N, N-dimethylacetamide, C _1-12 alcohols (such as ethanol), glycerol, peanut oil, PEG, vitamin E, poppy seed oil, propylene glycol, safflower seed Liquids including oils, sesame oil, soybean oil, and vegetable oils. As siblings in the text, solvents such as chloroform, dioxane or DMSO may be excluded. Excipients typically include one or more components used in the field of pharmaceutical formulations, such as fillers, binders, disintegrants and lubricants.

Unless otherwise specified, the expressions referring to "compound (s) of formula 1", "compound of the present invention", "compound 2A or 2B", "plasma concentration increasing compound", and the like, may be one or more formula (1) By a composition or method, typically 1, 2, 3, or 4, usually 1, where a compound of Formula 2A or 2B is present, such as a method of treating tripanosome infection as described in the text.

By "alcohol" is meant herein an alcohol comprising an excipient and containing one or more hydrogen atoms as one or more hydroxyl groups, usually one, two or three substituted C _1-12 alkyl groups. Alcohols include, for example, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, s-butanol, t-butanol, n-pentanol, i-pentanol, n-hexanol, cyclohexanol, n-heptanol, n-octanol, n-nonanol, n-decanol, and benzyl alcohol. The carbon atoms in the alcohols may be straight chain, branched or cyclic. Alcohols include any subset of bar as described above, such as C _2-4 alcohols (containing 2, 3 or 4 carbon atoms).

"Ester" means a substituent comprising a -C (O) -O- structure. Typically, esters in the text refer to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms (eg, O, S, N, respectively). , P, Si), wherein the organic substituent is R ² of the steroid nucleus of the formula (1) through the structure -C (O) -O-, for example, the organic substituent -C (O) -O- steroid or organic Substituents -OC (O)-are bound together with steroids. These organic substituents are usually one or more of any of the organic functional groups as described above, such as C _1-20 alkyl groups, C _2-20 alkenyl groups, C _2-20 alkynyl groups, aryl groups, C _2-9 heterocycles, or And substituted derivatives of any of these, including one, two, three, four or more substituents, each substituent being selected independently. Typical substituents for hydrogen or carbon atoms in this organic functional group include one, two, three, four or more, usually one, two or three -O-, -S-, -NR ^PR- (including -NH-), -C (O)-, = O, = S, -N (R ^PR ) ₂ (with -NH ₂ ), C (O) OR ^PR (with -C (O) OH), -OC (O) R ^PR (With -OC (O) -H), -OR ^PR (with -OH), -SR ^PR (with -SH), -NO ₂ , -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, -OPO ₃ (R ^PR ) ₂ , -OSO ₃ H ₂ or halogen substituents or atoms, wherein each R ^PR is -H, each selected protecting group Or two R ^PR together form a protecting group, and A8 is C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-4 alkyl-aryl (eg, benzyl), aryl ( Phenyl) or a C _0-4 alkyl-C _2-9 heterocycle. Substituents are each independently selected. Organic substituents are defined by the R ₄ variable. Organic substituents explicitly exclude unstable substituents such as -OO- except that such unstable substituents are a type of retention step that can be used to prepare compounds having sufficient chemical stability for one or more uses as in the text. And exclude such unstable substituents. Substituents as described above are typically substituents that can be used to replace one or more carbon atoms, such as -O- or -C (O)-, or substituents that can be used to replace one or more hydrogen atoms, such as Halogen, -NH ₂ or -OH and the like.

"Thioester" means a substituent comprising a -C (S) -O-structure. Typically, thioesters in the text refer to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms (eg, O, S, N, P, Si), wherein the organic substituent is attached to R ² of the steroid nucleus of the formula (1) via a -C (S) -O- structure, for example, an organic substituent -C (S) -O- steroid or Organic substituent -OC (S)-is bound together with steroids. These organic substituents are usually one or more of any of the organic functional groups as described above, such as C _1-20 alkyl groups, C _2-20 alkenyl groups, C _2-20 alkynyl groups, aryl groups, C _2-9 heterocycles, or And substituted derivatives of any of these, including one, two, three, four or more substituents, each substituent being selected independently. Typical substituents for hydrogen or carbon atoms in this organic functional group include one, two, three, four or more, usually one, two or three -O-, -S-, -NR ^PR- (including -NH-) , -C (O)-, = O, = S, -N (R ^PR ) ₂ (with -NH ₂ ), C (O) OR ^PR (with -C (O) OH), -OC (O) R ^PR (with -OC (O) -H), -OR ^PR (with -OH), -SR ^PR (with -SH), -NO ₂ , -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, -OPO ₃ (R ^PR ) ₂ , -OSO ₃ H ₂ or halogen substituents or atoms are included, wherein each R ^PR is -H, each selected Is a protecting group, or two R ^PRs together form a protecting group, and A8 is C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-4 alkyl-aryl (eg, benzyl), aryl (Eg, phenyl) or a C _0-4 alkyl-C _2-9 heterocycle. Substituents are each independently selected. Organic substituents are defined by the R ₄ variable. Organic substituents clearly exclude unstable substituents such as -OO-, except that such unstable substituents are a type of retention step that can be used to prepare compounds having sufficient chemical stability for one or more uses as in the text. And exclude such unstable substituents. Substituents as described above are typically substituents that can be used to replace one or more carbon atoms, such as -O- or -C (O)-, or substituents that can be used to replace one or more hydrogen atoms, such as Halogen, -NH ₂ or -OH and the like.

"Tioacetal" means a substituent comprising a -C (O) -S- structure. Typically, thioacetal in the text refers to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms (eg, O, S, N, P, Si), wherein the organic substituent is, for example, an organic substituent -C (O) -S steroid or an organic substituent to R ² of the steroid nucleus of the formula (1) through the structure -C (O) -S- Bound like SC (O) -steroids. This organic substituent is as having described in the part regarding thioester.

A "carbamate" refers to an ester, comprising a -C (O) -NR- structure, wherein each R ^PR is -H, an organic substituent as described in the section on the selected protecting group or ester, respectively. It means an organic substituent as described in. Typically, the term carbamate in the text refers to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms (eg, O, S, N, P, Si), wherein the organic substituent is -OC (O) -NR ^PR -to the R ² of the steroid nucleus of Formula 1, for example, the organic substituent -NR ^PR -C (O)- O-steroids or organic substituents -OC (O) -NR ^PR -are bound together. This organic substituent is as having described in the part regarding thioester.

"Sulfate ester" means a substituent comprising a structure -OS (O) (O) -O-. Typically, the term sulfate ester in the text refers to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms (eg, O, S, N, P, and Si), wherein the organic substituent is attached to R ² of the steroid nucleus of Formula 1 through the structure -O- S (O) (O) -O-, for example, the organic substituent -OS (O) Combined with (O) -O- steroids. This organic substituent is as having described in the part regarding thioester.

"Sulfite ester" means a substituent comprising a -OS (O) -O- structure. Typically, sulfite esters in the text refer to organic substituents containing about 1-50 carbon atoms (eg, about 2-12 carbon atoms) and 0 to about 10 selected heteroatoms each (eg, O, S). , N, P, Si), wherein the organic substituent is attached to R ² of the steroid nucleus of the general formula (I) through -OS (O) -O- structure, for example, the organic substituent -OS (O) -O-steroid Combined as This organic substituent is as having described in the part regarding thioester.

Compositions herein include salts of compounds of Formulas 1 and 2 above, including optionally non-ionizable substituents or polar substituents. As used herein, the term "salt" includes complexes containing substituents of relative charge. Ionizable substituents include NH ₂ and —OS (O) (O) —OH substituents in r, and polar substituents include —OH. Salts include, for example, pharmaceutically acceptable salts comprising uncharged substituents or monovalent cation substituents or monovalent anion substituents. Salts include compounds derived by combination of suitable anions such as inorganic acids. Suitable acids include those with sufficient acidity to form stable salts, preferably acids with low toxicity. Examples include basic centers that may be present in compounds of Formulas 1, 2A or 2B, typically acid additions that add certain inorganic acids, such as HF, HCl, HBr, HI, H ₂ SO ₄ , H ₃ PO ₄ , to amines. It is also possible to form the salts of the present invention from the reaction. Alternatively, certain organic acids such as organic sulfonic acids and organic carboxylic acids may be used in the same manner. Examples of organic sulfonic acids are C _6-16 aryl sulfonic acids, C _6-16 heteroaryl sulfonic acids and C _1-16 alkyl sulfonic acids such as phenyl, α-naphthyl, β-naphthyl, (S) -camphor , Methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pentyl and hexyl sulfonic acid and the like. Examples of organic carboxylic acids include C _1-16 alkyl, C _6-16 aryl carboxylic acid and C _4-16 heteroaryl carboxylic acid, such as acetic acid, glycolic acid, lactic acid pyruvic acid malonic acid, glutaric acid, tartaric acid, Citric acid, fumaric acid, succinic acid, malic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid and phenoxybenzoic acid. Salts also include salts of one or more amino acids and compounds of the invention. Although amino acids typically include a basic or acidic group such as lysine, argin, or glutamic acid, or a side chain having a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine, Amino acids are suitable, in particular natural amino acids found as protein components. Salts are usually biologically compatible or pharmaceutically acceptable, nontoxic, and especially those having mammalian cells. Biologically toxic salts are generally used as synthetic intermediates for preparing other inventive compounds.

Neohesperidoside, rutinoside and glucoside groups each have the following structure:

*

Wherein each optionally one or more hydrogen atom is a hydroxy group, is optionally substituted by halogen, C _1-6 alkyl, C _1- 6 alkoxy, a C _1-25 fatty acid or glucuronic arsenide.

Heterocycle . "Heterocycle" or "heterocyclic" includes, but is not limited to, a heterocycle as disclosed in Paquette, Leo A .: "Principles of Modern Heterocyclic Chemistry" (WA Benjamin, New York, 1968), in particular Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19 and 28; And J. Am. Chem. Soc. 1960, 82: 5566; And US Patent 5763483, all of which are incorporated herein by reference.

Examples of heterocycles include pyridyl, thiazoyl, tetrahydrothiophenyl, sulfur oxygen substituted tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofu Ranil, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benziindazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidoneyl, pyrrolinyl , Tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azosinyl, triazinyl, 6H-1,2,5-thiadiazinyl , 2H, 6H-1,5,2-dithiazinyl, thienyl, thiaandrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatiinyl, 2H-pyrrolyl, isothiazolyl , Isoxazolyl, pyrazinyl, pyridazinyl, indolinyl, isoindoli, 3H-indolyl, 1H-indazolyl, purinyl, 4 H-quinolininyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnaolinyl, putridinyl, 4aH-carbazolyl, carbazolyl, b-carbolinyl, phenandrodinyl, Acridinyl, pyrimidinyl, phenandrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromenyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, Pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisooxazolyl, oxindolinyl, benzoxazolinyl, and istinoyl It may include, but is not limited to.

The carbon-bonded heterocycle is at position 2, 3, 4, 5 or 6 of pyridine, at position 3, 4, 5, or 6 of pyridazine, at position 2, 4, 5 or 6 of pyrimidine, In position 2, 3, 4, or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole, in position 2, 4 or 5 of oxazole, imidazole or thiazole At position 3, 4 or 5 of oxazole, pyrazole or isothiazole, at position 2 or 3 of aziridine, at position 2, 3 or 4 of azetidine, 2, 3, 4, 5 of quinoline , 6, 7, or 8 position, is coupled to the 1, 3, 4, 5, 6, 7 or 8 position of isoquinoline, but is not limited thereto.

Nitrogen conjugation heterocycles include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrrolidine, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyra In position 1 of sol, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indolin, 1H-indazole, in position 2 of isoindole or isoindolin, For example, the binding to carbazole or 9-position of β-carboline at position 4 of the polyline is not limited thereto. Typically, nitrogen-bonded heterocycles include 1-aziridyl, 1-azededyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

"Heteroaryl" means one, two, three or more heteroatoms, usually oxygen (-O-), nitrogen (-NX-) or sulfur (-S-), where X is -H, a protecting group or C _{1 -6} alkyl, which is usually -H, and means an aromatic ring or two or more fused rings comprising one or more aromatic rings. Examples include those described in the section on heterocycles.

Protector . Examples of the various substituents that the compounds of Formula 1, 2A or 2B may include include substituted alkyl groups, substituted alkenyl groups, esters or substituted heterocycles, and the like, and these may include one or more reactors such as hydroxy groups or thiols. It may include. Intermediates used to prepare the compounds of Formula 1 or Formula 2A or 2B may be substituted with protecting groups as is well known in the art. Bicyclic and cyclic protecting groups and their deprotecting reactions are described in "Protective Groups in Organic Chemistry", Theodora W. Greene (Jphn Wiley & Sons, Inc., New York, 191, ISBM 0-471-62301-6) Greene ". In the context of the present invention these protecting groups are substituents that can be removed from the molecule of the present invention without non-thermally changing the oxidation / reduction index or covalent structure of the rest of the molecule of the present invention. For example, a protecting group bound to a -OX or -NHX group, -X, can be eliminated without affecting other covalent bonds in the molecule and forming -OH or -NH ₂ , respectively. At this time, if necessary, one or more protecting groups can be removed simultaneously or continuously. In the compounds of the present invention comprising one or more protecting groups, the protecting groups may be the same or different.

Although protecting group substituted intermediates are also included within the scope of the present invention, protecting groups are intended to be removed by known methods. Removal of the protecting group can be straightforward or difficult depending on the associated lowering properties and economics. Generally, during the synthesis of Formula 1, a protecting group will be used as an cyclic amine group or carboxyl group. In most therapeutic uses, the amine groups must be deprotected. Protecting groups are typically used to prevent covalent modification of functional groups sensitive to reactions such as alkylation or acylation reactions. In general, protecting groups are removed by, for example, hydrolysis, removal reactions or amine decomposition reactions. Thus, simple functional considerations will be sufficient as a guide to selecting reversible or irreversible protecting groups at a given position on the compounds of the present invention. Appropriate protectors and the criteria for selecting them are listed in T.W. Greene and P.G.M. Wuts, Eds. "Protective Groups in Organic Synthesis" 2nd edition, pps. Of Wiley Press. 10-142, 143-174, 175-223, 224-276, 277-308, 309-405, and 406-454, which are incorporated herein by reference.

Determination of whether a functional group is a protecting group is carried out in conventional manner, for example by Kocienski, Philip J .; "Portecting Groups" (Georg thieme Verlag Shuttgart, New York, 1994) (hereinafter referred to as "Kocienski"), Section 1.1, page 2 and Greene Chapter 1, pages 1-9; And US Patent Publication 5763483, which are incorporated herein by reference. In particular, 90% of the protecting groups are removed in the deprotection reaction based on the molar ratio, and changes carried out to the covalent structure or oxidation / reduction state other than that produced by removal of the protecting groups result in the deprotected production of the present invention. If it is 50%, preferably 25%, more preferably 10% or less of the molecule, the functional group is a protecting group. If multiple protecting groups of the same type are present in the molecule, the molar ratio when all functional groups of that type are removed is calculated. If different types of multiple protecting groups are present in the molecule, each type of protecting group is treated with each or the other, depending on which one is also associated with another type containing deprotection reaction conditions for one type. (By measuring the molar ratio). In one example of the invention, based on the molar ratio measured by conventional techniques, 90% of the protecting groups are removed by conventional deprotection reactions and covalently bonded structures or oxidation other than those produced by removal of the protecting groups The functional group becomes a protecting group when an irreversible change to the / reduced state is carried out at 50%, preferably 25%, more preferably 10% or less of the deprotecting product of the invention. Irreversible changes are other than those resulting from chemical reactions (aqueous hydrolysis, acid / base neutralization or conventional separation, identification or purification methods) to regenerate the covalent structure or oxidation / reduction state of the deprotected molecules of the invention. Need).

Protectors are also described in general conceptual terms and in strategic terms for each use, Kocienski, Phili J .; Expected in detail in the "Protecting Group" (Georg Thieme Verlag Stuttgart, New York, 1994), which is a reference of the present invention. In particular, Chapter 1, protecting groups; Overview, pp. 1-20, Chapter 2, Hydroxy protecting groups, pages 21-94, Chapter 3 Diol protecting groups, pages 95-117, Chapter 4, Carboxyl protecting groups, pages 118-154, Chapter 5, Carbonyl protecting groups , 155-184, Chapter 6, amino protecting groups, pages 185-243, Chapter 7, Epilogue, pages 244-252 and the index, pages 253-260, are specifically incorporated by reference. More specifically, section 2.3 silyl ether, 2.4 alkyl ether, 2.5 alkoxyalkyl ether (acetal), 2.6 reviews (hydroxy and thiol protecting groups), 3.2 acetal, 3.3 silylene derivatives, 3.4 1,1,3,3-tetraiso Propyldisiloxanenilidene derivatives, 3.5 reviews (diol protecting groups), 4.2 esters, 4.3 2,6,7-trioxabicyclo [2.2.2] octane [OBO] and other ortho esters, 4.4 oxazolines, 4.5 reviews ( Carboxyl protecting group), 5.2 O, O-acetal, 5.3 S, S-acetal, 5.4 O, S-acetal, 5.5 reviews (carbonyl protecting group), 6.2 N-acyl derivatives, 6.3 N-sulfonyl derivatives, 6.4 N- Sulphenyl derivatives, 6.5 N-alkyl derivatives, 6.6 N-silyl derivatives, 6.7 imine derivatives, and 6.8 reviews (amino protecting groups) are described in detail in which the protecting group substitution reaction / deprotection group substitution reaction of the required functional groups is discussed. It becomes the literature. In addition, the tables of "Index for Major Protectors" on the inside and opposite sides of the front cover, "abbreviations" on page xiv, and "reagents and solvents" on page xv, respectively, are incorporated herein by reference in their entirety. It becomes the literature.

Typical hydroxy protecting groups are described on pages 14-118 of Greene, ether (methyl); Substituted methyl ether (methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, Guoacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) Methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4- Methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiothioranil, S, S-dioxido, 1-[(2-chloro-4-methyl) phenyl] -4-methoxypiperidine-4- 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl -4,7-methanobenzofuran-2-yl); Substituted ethyl ether (1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy 2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2 , 4-dinitrophenyl, benzyl); Chihoned 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-methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri (p-methoxyphenyl) methyl, 4- (4'-bromophenacyloxy) phenyldi Phenylmethyl, 4,4 ', 4 "-tris (levulinoyloxyphenyl) methyl, 4,4', 4" -tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis ( 4 ', 4 "-dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1'-phenylmethyl, 9-anthryl, 9- (9-phenyl) xanthenyl, 9- ( 9-vslf-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl, S, S-dioxido); silyl ether (trimethylsilyl, triethylsilyl, triisopropyl Silyl, dimethylisopropyl Reyl, diethylisopropylsilyl, dimethyltexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, t-butyldiyl Phenylsilyl, tribenzylsilyl, tri-p-) xylylsilyl, triphenylsilyl, diphenylmethylsilyl, t-butylmethoxyphenylsilyl); ester (formate, benzoylformate, acetate, chloroacetate, dichloroacetate , Trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-poly-phenylacetate, 3-phenylpropionate, 4-oxopentano Ate (levulinate), 4,4- (ethylenedithio) pentanoate, pivaloate, adamantatoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (meth Toate)); carbonate (methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- ( Phenylsulfonyl) ethyl, 2- (triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3.4-dimethoxybenzyl, o-nitrobenzyl, p- Nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, methyl dithiocarbonate); Functional groups with assisted cleavage (2-iodobenzoate, 4-azidobutylate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formyl benzene Sulfonate, 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-tetramethylbutyl) phenoxyacetate, 2,4- Bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E) -2-methyl-2-butenenoate (tigloate), o- (methoxy Carbonyl) benzoate, p-poly-benzoate, α-naphtholate, nitrate, alkyl N, N, N ', N'-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethyl Phosphinothioyl, 2,4-dinitrophenylsulfenate); And sulfonates (sulfates, methanesulfonates (mesylate), benzylsulfonates, tosylate).

More typically, hydroxy protecting groups include substituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, and even more typically, trialkylsilyl ethers, tosylates and acetates.

Typical 1,2- and 1, -diol protecting groups are described on pages 118-142 of Greene and include cyclic acetals and ketals (methylene, ethylene, 1-t-butylethylidene, 1-phenylethylidene, (4 -Methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxy Benzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, 2-nitrobenzylidene); Cyclo ortho esters (methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,2-dimethoxyethylidene, alpha-methoxybenzylidene, 1- (N, N-dimethylamino) ethylidene derivative, alpha- (N, N-dimethylamino) benzylidene derivative, 2-oxacyclopentylidene); And silyl derivatives (di-t-butylsilyl group, 1,3- (1,1,3,3-tetraisopropyldisiloxanylidene) derivative, tetra-t-butoxydisiloxane-1,3-diyl Den derivatives, cyclic carbonates, cyclic boronates, ethyl boronates, phenyl boronates).

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

Typical amine protecting groups are disclosed on pages 315-385 of Greene, carbamate (methyl and ethyl, 9-fluorenylmethyl, 9 (2-sulfo) fluoroenylmethyl, 9- (2,7-dibromo) ) Fluorenylmethyl, 2,7-di-t-butyl- [9- (10,10-dioxo-10,10,10,10-tethahydrothiooxanthyl)]-methyl, 4-methoxy Phenacyl); Substituted ethyl (2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 2- (1-adamantyl) -1-methylethyl, 1,1-methyl-2-haloethyl , 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- ( 3,5-di-t-butylphenyl) -1-methylethyl, 2- (2'- and 4'-pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) ethyl, t- Butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamil, 4-nitrocinnamil, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-meth Oxybenzyl, p-nitrobenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); Functional groups having secondary cleavage (2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithiayl)] methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (di Hydroxyboryl) benzyl, 5-benzisooxazolylmethyl, 2- (trifluoromethyl) -6-chloromonylmethyl); Functional groups capable of photolytic decomposition (m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl (o-nitrophenyl) methyl); Urea-type derivatives (phenothiazinyl- (10) -carbonyl derivatives, N'-p-toluenesulfonylaminocarbonyl, N'-phenylaminothiocarbonyl); Mixed carbamate (t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2 Dimethoxycarbonylvinyl, o- (N, N-dimethylcarboxamido) benzyl, 1, -dimethyl-3- (N, N-dimethylcarboxamido) propyl, 1,1-dimethylpropynyl, di ( 2-pyridyl) methyl, 2-furanylmethyl, 2-iodineethyl, isobornyl, isobutyl, isonicotyl, p- (p'-methoxyphenylazo) benzyl, 1-methylcyclobutyl, 1- Methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1- (3,5-dimethoxyphenyl) ethyl, 1-methyl-1- (p-phenylazophenyl) ethyl, 1-methyl -1-phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2,4,6-tri-t-butylphenyl, 4- (trimethylammonium) benzyl , 2,4,6-trimethylbenzyl); Amides (N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trofluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picorynoyl, N-3 -Pyridylcarboxamide, N-qswhdlfvpslfdkffkslf derivative, N-benzoyl, Np-phenylbenzoyl); Amides with secondary cleavage (No-nitrophenylacetyl, No-nitrophenoxyacetyl, N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) propy O'Neill, 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-nitrobutyl, No-nitrocinnamoyl, N-acetylmethionine derivative, No-nitrobenzoyl, No- (benzoyloxymethyl) benzoyl, 4 , 5-diphenyl-3-oxazolin-2-one); Cyclic imide derivatives (N-phthalilicin, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4- Tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,35-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5 Triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridonyl); N-alkyl and N-aryl amines (N-methyl, N-allyl, N- [2- (trimethylsilyl) ethoxy] methyl, N-3-acetoxypropyl, N- (1-isopropyl-4-nitro -2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di (4-methoxyphenyl) methyl, N-5-dibenzosubbeli, N-triphenylmethyl, N- (4-methoxyphenyl) diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, N-2-phycoylamine N'-oxide); Imine derivatives (N-1,1-dimethylthiomethylene, N-benzylidene, Np-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl) mesityl] methylene, N, (N ' , N'-dimethylaminomethylene, N, N'-isopropylidene, Np-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene, N- (5-chloro-2-hydroxy Phenyl) phenylmethylene, N-cyclohexylidene); enamine derivatives (N- (5,5-dimethyl-3-oxo-1-cyclohexenyl); N-metal derivatives (N-borane derivatives, N-di Phenylboronic acid derivatives, N- [phenyl (pentacarbonylchrome- or -tungsten)] carbenyl, N-copper or N-zinc chelate), NN derivatives (N-nitro, N-nitroso, N-oxide); NP-derivatives (N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl); Si derivatives; NS derivatives; N-sulphenyl derivatives (N-benzenesulphenyl, No-nitrobenzenesulphenyl, N-2,4-dinitrobenzenesulphenyl, N-pen Tachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulphenyl, N-triphenylmethylsulphenyl, N-3-nitropyridinesulphenyl) and N-sulfonyl derivatives (Np-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-tetramethyl-4-methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2,4 , 6-trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulphur Ponyl, N-beta-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N-4- (4 ', 8'-dimethoxynaphthylmethyl) benzenesulfonyl, N-benzylsulfonyl, N-tri Fluoromethylsulfonyl, N-peacylsulfonyl).

More typically, amino protecting groups include carbamates and amides, and even more typically include n-acetyl groups.

Stereoisomer . Formula 1 and Formula 2A or 2B compounds include predominant or purified optical isomers at any or all asymmetric atoms as can be seen from the structural formula. Both racemic mixtures and diastereomeric mixtures, and individual optical isomers, can be synthesized or purified so that they are substantially free of enantiomers or diastereomeric partners, all of which are included within the scope of the present invention. In the compounds of the invention, chiral centers can be found, for example, in R ¹ , R ² or R ⁴ .

In the text, one or more of the following methods may be used to prepare enantiomers with predominant or pure isomers. This method is described in roughly its preferred order, ie generally using stereospecific synthesis from chiral precursors followed by chromatographic separation and spontaneous determination.

 Stereospecific synthesis is as described in the Examples. These types of methods are conveniently used where appropriate chiral starting materials are available and the reaction steps are chosen such that they do not result in undesirable racemization reactions at the chiral site. One advantage of stereospecific synthesis is that it does not produce undesirable enantiomers that lower the overall synthetic yield since it must be removed from the final product. In general, those skilled in the art will know by certain synthesis which starting materials and reaction conditions should be used to obtain the preferred enantiomers with the predominant or pure isomers.

If a suitable stereospecific synthesis method is not empirically designed or determined through routine experimentation, one skilled in the art will be able to switch to another method. One commonly used method is the chromatographic separation of enantiomers on chiral chromatography resins. This resin is commonly referred to as a Pirkle column and packed in a commercially available column. This column contains a chiral rectified phase. The racemics were placed in solution and loaded on a column and then separated by HPLC. See, eg, Proceedings Chromatogrphic Society-International Symposium on Chiral Separations, Sept. 3-4, 1987, which is incorporated herein by reference. Examples of chiral columns that can be used for blocking for appropriate separation techniques include Diacel Chriacel OD, Regis Pirkle Covalent D-phenylglycine, Regis Pirkle Type 1A, Astec Cyclobond II, Astec Cyclobond III, Serva Chiral D-DL = Daltosil 100, Bakerbond DNBLeu, Sumipax OA-1000, Merck cellulose triacetate column, Astec Cyclobond I-Beta, or Regis Pirkle Covalent D-Naphthylalanine. Not all of these columns are effective for all racemic mixtures. However, one skilled in the art will appreciate that some amount of conventional screening may be required to select the most effective rectified phase. When using such a column, it is preferable to use an example of the compound of the present invention where the charge is not neutralized, for example, acidic functionalities such as carboxyl groups are not esterified or amidated.

Another method involves converting the enantiomers in the mixture to diastereomers with chiral auxiliaries and then separating the conjugates by normal column chromatography. This method is particularly well suited when the example comprises free hydroxy groups which can form salts or covalently bond with chiral auxiliaries. Chirally pure amino acids, organic acids or organic sulfonic acids are all worth investigating as chiral auxiliaries, all of which are well known in the art. Salts with these auxiliaries may be formed or they may be covalently (irreversibly) functional groups.

Enzyme separation is another method of significant value. In these methods, after preparing covalent derivatives of enantiomers, generally lower alkyl esters, in a racemic mixture, the derivatives are subjected to enzymatic degradation reactions, generally hydrolysis reactions. For this method to be successful, enzymes must be screened for steric-specific degradation reactions, and therefore usually several enzymes need to be routinely screened. If the ester is to be degraded, it is selected from the group consisting of esterases, phosphatases, and lipases, and the activity for this derivative is detected. Typical esterases are obtained from liver, pancreas or other animal organs and include pig liver esterases.

If the enantiomeric mixture is to be separated from the melt or solution as agglomerates, ie a mixture of pure enantiomeric crystals, these crystals can be physically separated, thereby producing an enantiomerically superior formulation. However, this method is not practically available in high volume formulations and has limited value for pure racemic compounds.

Asymmetric synthesis is another technique for achieving the preponderance of the enantiomers. For example, the chiral protecting group reacts with the functional group to be substituted for the protecting group and the reaction mixture is in equilibrium. If this reaction is enantiomer specific, the product will be enantiomeric dominant.

Further instructions in the separation of enantiomeric mixtures are described, for example, in "Enatiomers, Racemates, and resilutions", Jean Jacques, Andre Collet, and Samuel H. Wilen (Krieger Publishing Company, Malabar, FL, 1991, ISBN 0-89464-618-4 ): Part 2, Separation of Enantiomeric Mixtures, pp. 217-435; More specifically, section 4, Separation by Direct Crystallization, pp. 217-251, Section 5, Formation and Separation of Diastereoisomers, pp. 251-369, Section 6, Crystallization-Induced Asymmetric Rice, pp. 369-378, And Section 7, Laboratory Aspects and Techniques of Separation, pp. 378-435, more specifically, Section 5.1.4, Separation of Alcohols, Conversion of Alcohols to Salt-Forming Derivatives, pp. 263-266, Section 5.2.3 , Covalent derivatives of alcohols, thiols and phenols, p. 332-335, section 5.1.1, acid separation, p. 257-259, section 5.1.2, base separation p. 259-260, section 5.1.3, amino acid separation 261 Page 263, section 5.2.1, covalent derivatives of acids, page 329, section 5.2.2, covalent derivatives of amines, pages 330-331, section 5.2.4, covalent derivatives of aldehydes, ketones and sulfoxides 335-339 , Section 5.2.7, Chromatographic Aspects of Covalent Diastereoisomers, pages 348-354, but are not limited to, all of which Reference is made to the invention.

Specific examples include compositions that are produced temporarily when performing a method step or operation. For example, when contacting a compound of Formula 1 with an excipient such as water, cyclodextrin, PEG, alcohol, propylene glycol, benzyl alcohol or benzyl benzoate, the composition may be added before adding one component with another Non-uniform mixtures. As the components contact, the uniformity of the mixture increases and the ratio of components to each other approaches the desired value. Thus, some compositions as disclosed herein optionally contain less than about 3% w / w water, such as less than 0.5% w / w, and include such as 16a-bromoepiandrosterone and one or more excipients. It may contain about 0.0001-99% w / w of the compound of formula (1). These temporary compositions are intermediates that may arise in the process of preparing the present qkfaudd compositions or combinations, which are included in the examples of the present invention to the patentable scope.

Compound of Formula 1 . The compound of formula 1 or “compound of the present invention” is useful for treating or preventing such an infection with one or more tripanosome parasites.

Preferred compounds of formula (I) have R ₂ groups bonded to the steroid ring generally having a β-array structure, two R ₁ are bonded to Q ₂ , and X is a double bond oxygen group (═O). Typically, one R ₁ bonded to Q ₂ is hydrogen of the β-array structure, the remaining R ₁ bonded to Q ₂ is hydrogen or halogen, usually bromine, of the α-array structure and the double bond is 5-6 times Exists at the location. Such preferred compounds include dehydroepiandrosterone ("DHEA") and 16α-bromodehydroepiandrosterone ("Br-DHEA").

Another preferred compound of formula (I) has a double bond at positions 5-6, X is = O, Q ₂ is -CH ₂ -or -CHBr-, and R ₂ is -H-, -S (O) ( O) -OH, -S (O) (O) -ONa, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ (wherein R ₆ is each C _1-14 linear or branched alkyl), -P (O) (O) -O-CH ₂ -CH (OC (O) R ₇ ) -CH ₂ -OC ( O) -R ₇ , wherein R ₇ is a glucuronide group or a C _1-14 linear or branched alkyl, respectively, or a 17-ketosteroid of Formula 1 wherein R ₂ is a glucuronide group do. As another preferable compound, the compound which has following General formula 20-43 is mentioned.

In the formula of each general structure 20-43,

Q ₃ and Q ₆ are each —C (R ₁ ) ₃ —, wherein each R ₁ is independently selected;

X and Y are -OH, -H, lower alkyl (eg, C _1-6 alkyl), -OC (O) -R ₅ , -C (O) -OR ₅ , halogen, or X and Y are the same Together with R _{1 at the} position independently form a ketone (═O);

Each R ₁ is independently selected and as described above;

R ₂ and R ₅ are as described above.

In some examples, the compound of Formula 1 has a structure of Formula 20-43, wherein the R ₁ groups of 2, 3, 4, 5, or 6 are each -OH, halogen, or alkoxy, and the remaining R ₁ are all hydrogen; R ₂ is —OH, ester, thioester or carbamate, or R ₂ together with R ₁ in the 3-position form ═O; Y is -H, -OH, halogen or -OC (O) -R ₅ , or Y forms = O with R ₁ at the 16-position; X is —OH or —OC (O) —R ₅ , or X together with R ₁ at the 17-position forms ═O and Q and Q are —CH ₃ or —CH ₂ OH, respectively. Examples of this include compounds of the general formula 20-43 wherein two OHs are present at 3-, 16- or 17- dentures.

Preferred examples of the present invention include compounds having the formula

[Formula 44]

Wherein Y is hydrogen or bromine, R ₄₄ is -H, -S (O) (O) -OH, -S (O) (O) -ONa, -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) -R ₆ , -P (O) (O) -O-CH ₂ -CH (OC (O) -R ₇ ) -CH ₂ -OC (O) -R ₇ , or a glucuronide group of the formula (A). In another preferred embodiment, both of Y and R ₄₄ in Formula 44 are hydrogen. Particularly preferred compounds are dehydroepiandrosterone (Y and R ₄₄ in formula ₄₄ are both hydrogen and have a double bond in positions 5-6). In another example, the compound is epiandrosterone (Y and R ₄₄ in formula ₄₄ are hydrogen and there are no double bonds in positions 5-6). 16-haloepiandrosterones having F, Cl, Br or I at the 16 position, such as 16α-bromoepiandrosterone, may also be used as antiviral agents. Other preferred compounds are (i) 16a-bromodehydroepiandrosterone, (ii) dehydroepiandrosterone-3-sulfate (wherein Y is -H and R ₄₄ is -S (O) (O) -OM And both are hydrogen and the double complex is at position 5-6) (iii) 5β-androstan-3β-ol-17one. Relevant examples consisting of compounds associated with compounds of Formula 44 include -OH, -Br, -Cl, -F, -I, wherein 1, 2, 3, 4, 5 or 6 hydrogen atoms each attached to the steroid nucleus are selected. It consists of a compound of formula 44 substituted with -OCH ₃ or -OC ₂ H ₅ atom or atom group.

In another embodiment, the 17-ketosteroid of Chemical Formula 1 may be represented by: in Formula 44, R ₄₄ is -S (O) (O) -O-CH ₂ -CH (OC (O) -R ₆ ) -CH ₂ -OC (O) —R ₆ , —P (O) (O) —O—CH ₂ —CH (OC (O) —R ₇ ) —CH ₂ —O—C (O) —R ₇ , or glucuro of Formula A A dehydro-epiandrosterone in which it is a ide group, Y is hydrogen and 5-6 double bonds are present. In other compounds of formula 44, Y is hydrogen, double bond is present at 5-6 and R ₄₄ is hexyl sulfate, dodecyl sulfate, octadecyl sulfate, octadecyl sulfate, O-dihexadecylglycerol sulfate, hexadecane sulfonate di Conjugates of dehydroepiandrosterone, which is an octadecanenoylglycerol phosphate or O-hexadecylglycerol phosphate.

In another preferred embodiment of the present invention, the steroid of Formula 1 is a compound of Formula 45:

[Formula 45]

Wherein R ₅₀ is -H, -OH or = O; R ₅₁ is -Br, -Cl, -F or -I; R ₅₂ is -OH or = O; R ₄₉ is -H, -OH or -OR ₅₃ ; R ₅₃ is C _1-18 alkyl, C _2-18 alkenyl, C _2-18 alkynyl, C _1-18 ester, C _1-18 thioester, wherein the C _1-18 or C _2-18 substituent Any one of at least one hydrogen atom may be substituted with at least one selected from the group —O—, —S—, —OH, —NH ₂ , —SH═O), or R ₅₃ is thioacetal, sulfate ester, Sulfonate esters, carbamates or thioesters. In a preferred embodiment, R ₄₉ is —OC (O) —CH ₂ —CH ₂ —CH (R ₅₄ ) —CH (R ₅₅ ) —CH ₂ R ₅₆ , wherein R ₅₄ is —NH, —OH, — SH, -O-PO ₃ , -SO ₃ or -OSO ₃ ; R ₅₅ is —H, —NH ₂ , —OH, —SH, —O—PO ₃ , —SO ₃ or —OSO ₃ ; R ₅₆ is C _1-18 alkyl, C _2-18 alkenyl, C _2-18 alkynyl, C _1-18 ester, C _1-18 thioester, wherein the C _1-18 or C _2-18 substituent In any of these, one or more hydrogen atoms can be substituted with one or more selected from -OH, -NH ₂ , or -SH groups, respectively, and become precursors, metabolites and homologues thereof. Relevant examples of compounds of formula 44 include -OH, -Br, -Cl, -F, -I, -OCH ₃ or-each selected from 1, 2, 3, 4, 5 or 6 hydrogen atoms attached to the steroid nucleus, respectively. It consists of a compound of formula 45 substituted with an OC ₂ H ₅ atom or atom group.

In another preferred embodiment, Formula 1 compound has Formula 1B or 1C:

[Formula 1B]

[Formula 1C]

Wherein R ₁ is —H, —OH, halogen, —CHCH ₂ , —CHCHCH ₃ , —CCH, —CCCH ₃ , or there are no other substituents attached to the same carbon atom, and R ₁ is ═O; R ₂ is —H, —OH, halogen, C _1-18 alkoxy, —SC (O) — (CH ₂ ) _m -R ₄ , -C (O) -S- (CH ₂ ) _m -R ₄ ,- OS (O) (O)-(CH ₂ ) _m -R ₄ , -OS (O) (O) -O- (CH ₂ ) _m -R ₄ , -OC (O) -NH- (CH ₂ ) _m -R ₄ , -NH-C (O) -O- (CH ₂ ) _m -R ₄ , -OC (S)-(CH ₂ ) _m -R ₄ , -C (S) -O- (CH ₂ ) _m- R ₄ , -OC (O)-(CH ₂ ) _m -R ₄ , or -C (S) -O- (CH ₂ ) _m -R ₄ ; R ₄ is —H, —CH ₃ , —C ₂ H ₅ , —C ₃ H ₇ , —C ₂ H ₄ OH, —C ₃ H ₅ OH, —CH ₂ —CH ₂ —O—CH ₃ , —CH ₂ -CH ₂ -O-CH ₂ -CH ₃ , -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ OH, C _3-6 alkenyl group, C _3-6 alkynyl group, benzyl or phenyl, wherein Phenyl or benzyl groups may be optionally substituted with 1, 2, or 4 selected halogen, C _1-4 alkoxy, —OH, —SH, —O— or —NH— groups; Q ₃ and Q ₆ are each -H, -CH ₃ or -CH ₂ OH; Q ₂ is —C (R ₁ ) ₂ — or —CH ₂ —CH ₂ —. In this example, Q ₃ and Q ₆ usually all have a β-array structure, typically —CH ₃ , and Q ₂ is usually a-array structure with —CH ₂ —, —C (with a Br, I or OH group). O)-, -CH (Br)-, -CH (I)-, or -CH (OH)-, or Q ₂ consists of = O, and in the 7-position R ₁ is -H,- OH or = O. A related example consisting of the above formula 44 and related compounds is selected from -OH, -Br, -Cl, -F, -I, -OCH ₃ or 1, 2, 3, 4, 5 or 6 hydrogen atoms respectively attached to the steroid nucleus or -OC ₂ H ₅ consisting of compounds of Formula 1A or 1B substituted with atoms or groups of atoms.

The compound of Formula 1 may be derived in crystalline or polymorphic form.

Metabolites . In vivo metabolites of the compounds of the present invention are also included within the scope of the present invention to the extent that such products are novel and not obvious from the prior art. Such products can be derived, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. of the compound of formula 1 administered. Accordingly, the present invention includes novel non-magnetic compounds produced by the method comprising contacting a compound of the invention with a subject, such as a human, rodent or primate, for a period sufficient to produce a product of its acid. Such products are typically identified by making radiolabeled (eg, C ¹⁴ or H ³ ) compounds of the compounds of the present invention, which are detectable doses (eg, about 0.5 mg / mg) in rats, mice, guinea pigs, primates or humans. parenteral or oral administration of at least kg) allow sufficient time for metabolism to occur (typically from about 30 seconds to about 30 hours) to identify its conversion product from urine, blood or other biological sample. These products are labeled and easily identified (the rest are identified using antibodies capable of binding epitopes that live in metabolites). This metabolite structure is measured by conversion and is determined by HPLC, MS or NMR analysis. In general, the analysis of metabolites is performed in the same manner as metabolic studies of conventional drugs well known to those skilled in the art. The conversion product is useful for diagnostic assessment of therapeutic administration of a compound of the invention, even if it does not have therapeutic activity on its own, unless otherwise found in vivo.

Specific examples of the compound of Formula 1 are as follows.

Group 1 . Illustrative examples include compounds of Formula 1 referred to in Table B based on the designation of compound structures as defined in Table A below. Each compound referred to in Table B below is depicted as a compound of Formula 4 below.

[Formula 4]

In the formula, both Q ₃ and Q ₆ are —CH ₃ , Q ₄ is —CH ₂ —, and R ₂ , R ₁ A, and Y and X have a structure as shown in the following Table A. Compounds defined according to Tables A and B are referred to as "Group 1" compounds.

Compounds defined in Table B are formulated using the following chemical formulas as indicated in Table A, using the following compound name arrangements, R ₂ . R ₁ AYXR _{2. According} to R ₁ A and the numbers assigned to Y and X. As shown in Formula 4, R ₂ is in the 3β-position, hydrogen fills the rest of the valence, or R ₂ is a double bond to 16 carbons, R ₁ A is an R ₁ group in the 7b-position, or R ₁ A is a R ₁ group double bonded to 7 carbons, Y is at 16α-position, hydrogen fills the rest of the valence, or R ₂ is double bond to 16 carbons, X is at 17β-position, and hydrogen is remaining To fill the valence, or X double bonds to 17 carbons. When R ₂ , R ₁ A, Y or X are divalent substituents such as ═O, there is no hydrogen at that position. Thus, Group 1 compounds defined as 1.2.1.1. Have β-hydroxy groups bonded to carbon in 3- and 7-positions (variable substituents R ₂ and R ₁ A, respectively) and α-bromine bonded to carbon 16 (Variable substituent y) and the structure of Formula 4 having oxygen (= O) (variable substituent X) double-bonded at the position 17, and has the following structural formula.

TABLE A

TABLE B

TABLE B-1

TABLE B-2

Table B-3

TABLE B-4

Table B-5

Table B-6

TABLE B-7

TABLE B-8

Table B-9

Table B-10

TABLE B-11

TABLE B-12

Table B-13

TABLE B-14

Table B-15

TABLE B-16

Table B-17

Table B-18

Table B-19

Table B-20

Table B-21

Table B-22

Table B-23

Table B-24

TABLE B-25

Further examples of compounds of Formula 1 include groups as described below.

Group 2. Group 2 compounds are as defined in Table B above, ie, R ₂ , R ₁ A, Y and X substituents are as defined in Table A above, but without 5-6 double bonds and in the 5-position It is bonded to the steroid nucleus as shown in the following formula (5), which is the same as in formula (4) except that hydrogen is present in the α-array structure.

[Formula 5]

Therefore, the group 2 compound defined as 1.2.1.1 has the following structural formula.

Group 3. Group 3 compounds are as defined in Table B above, ie, R ₂ , R ₁ A, Y and X substituents are as defined in Table A above, but without 5-6 double bonds and in the 5-position It is bonded to the steroid nucleus as shown in the following formula (6), except that hydrogen is present in the β-array structure.

[Formula 6]

Thus, Group 3 compounds defined as 1.2.1.1 have the following structural formula.

Group 4. Group 4 compounds are as defined in Table B above, that is, except that R ₂ , R ₁ A, Y and X substituents are as defined in Table A above, but Q ₃ is -CH ₂ OH. Is bound to the steroid nucleus as shown in the following formula (7), the same as formula (4).

[Formula 7]

Thus, Group 4 compounds defined as 1.2.1.1 have the following structural formula.

Group 5. Group 5 compounds are as defined in Table B above, that is, while the R ₂ , R ₁ A, Y and X substituents are as defined in Table A above, there are no 5-6 double bonds and the 5-position It is bonded to the steroid nucleus as shown in the following formula (8), which is identical to formula (4) except that hydrogen is present in the α-array structure and Q ₃ is —CH ₂ OH.

[Formula 8]

Therefore, the group 5 compound defined as 1.2.1.1 has the following structural formula.

Group 6. Group 6 compounds are as defined in Groups 1-5, except that Q in Formulas 4-8 is -CH ₂ OH instead of methyl. In group 6, there are five subgroups of group 6 compounds. The first subgroup, subgroup 6-1, has the same steroid nucleus with substituents as defined in group 1 compounds above, and the second subgroup, subgroup 6-2, as defined in group 2 compounds above Have the same steroid nucleus with substituents. Subgroups 6-3 to 6-5 each have the same steroid nucleus with substituents as defined in groups 3 to 5 above. Thus, for example, a subgroup 6-1 compound defined as 1.2.1.1. Has the structure

The compound of subgroup 6-2, defined as 1.2.1.1., Has the following structural formula:

Group 7. Group 7 compounds are as defined in Groups 1-5 except that the Y group of Formula 4-8 has a β-array structure in place of the α-array structure. Group 7 consists of five subgroups, and these compounds are basically as described for the Group 6 compound above except that the Y group has a β-array structure.

Group 8. Group 8 compounds are as defined in Groups 1-5, except that the X group of Formula 4-8 has an α-array structure instead of the β-array structure. Group 7 consists of five subgroups, and these compounds are basically as described for the Group 6 compounds above except that the X group has an α-array structure.

Group 9. Group 9 compounds are as defined in Groups 1-5, except that the R ₂ groups of Formula 4-8 have an α-configuration structure instead of the β-configuration structure. Group 7 consists of five subgroups, and these compounds are basically as described for the Group 6 compounds except that the R ₂ groups have an α-array structure.

Group 10. Group 10 compounds are as defined in Groups 1-9, except that R ₂ substituents 1-10 in Table A above are replaced with the following substituents.

Group 10 consists of compounds of 25 subgroups. The first subgroup 10-1 has the same steroid nucleus with substituents as defined in Group 1 above, except that the R ₂ substituents or atom groups as described above replaced those in Table A above. Subgroup 10-1 compound, defined as 1.2.1.1, has the structure

The subgroup 10-2 compound, defined as 1.2.1.1, has the structure

Subgroup 10-6-1 compound, defined as 1.2.1.1, has the structure

The subgroup 10-6-2 compound defined as 1.2.1.1 has the following structure.

Group 11. Group 11 compounds are as defined in Groups 1-9, except that R ₂ substituents 1-10 in Table A above are replaced with the following substituents.

Group 12. Group 12 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 13. Group 13 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 14. Group 14 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 15. Group 15 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 16. Group 16 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 17. Group 17 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 18. Group 18 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 19. Group 19 compounds are as defined in Groups 1-9, except that R ₂ substituents 1 to 10 in Table A above were replaced with the following substituents.

Group 20. Group 20 compounds are as defined in Groups 1-9, except that R ₂ substituents 1-10 in Table A were replaced with the following substituents.

Group 21. Group 21 compounds are as defined in Groups 1-9, except that R ₂ substituents 1-10 in Table A were replaced with the following substituents.

Accordingly, the group 21-1 compound defined as 1.2.1.1 has the structure

A group 21-2 compound defined as 1.2.1.1 has the structure

A group 21-3 compound defined as 1.2.1.1 has the structure

Subgroup 21-4 compound, defined as 1.2.1.1, has the structure

A group 21-6-1 compound defined as 1.2.1.1 has the structure

A group 21-6-2 compound defined as 1.2.1.1 has the structure

The subgroup 21-6-3 compound, defined as 1.2.1.1, has the structure

G12 in group 21 contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, each having an selected O, S, N, P or Si atom Substituent, provided that only one Si or P is present if Si or P warmer is present, wherein the organic substituent is optionally C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, aryl , A C _2-9 heterocycle or a substituted derivative of any of these, including 1, 2, 3, 4 or more substituents, wherein each substituent is independently selected and is selected from -O-, -S-, NR ^PR- (With -NH-), -C (O)-, = O, = S, -N (R ^PR ) ₂ (with -NH ₂ ), -C (O) OR ^PR (with -C (O) OH) , -OC (O) R ^PR (with -OC (O) -H), -OR ^PR (with -OH), -SR ^PR (with -SH), -NO ₂ , -CN, -NHC (O)- , -C (O) NH-, -OC (O)-, -C (O) O-, -O-A8, -S-A8, -C (O) -A8, -C (O) O-A8 , = N-, -N =, = N-OH, -OPO ₃ (R ^PR ) ₂ , -OSO ₃ H ₂ and halogen substituents or atoms, each R ^PR is -H, each selected protecting group, Or two R ^PR together form a protecting group and A 8 is C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-4 alkyl-aryl (eg benzyl), aryl (eg , Phenyl) or a C _1-4 alkyl-C _2-9 heterocycle. G12 substituents include -CH ₃ , -C ₂ H ₅ , -C ₃ H ₇ , -C ₄ H ₉ , -C ₆ H ₁₃ , -CH ₂ -C ₆ H ₆ , -C ₂ H ₄ -C ₆ H ₅ , -C ₃ H ₆ -C ₆ H ₅ , -C ₆ H ₅ , -CH ₂ -heterocycle, -CH ₂ -CH ₂ -heterocycle and heterocycle, these include -O-, -S-, -F, -Cl, -Br, -I, -NH-, = O, -CN, -OCH ₃ , -OC ₂ H ₅ , -OC ₄ H ₉ , -NO ₂ , -NH ₂ , -COOH or- It may be substituted with one, two, three or more each selected from the group NH-C (O)-.

Other examples include the use of any of the above Formula 4 compound classes defined as any of the above Formula 4 compounds, or any of the groups as described above, for any therapeutic use or other use as described herein. (I) R ₂ has an α-array structure, (ii) Q ₄ is —CH (halogen) —, (iii) X has an α-array structure, and —H at 17 position is β -Has an array structure, (iv) Y has a β-array structure, -H at the 16-position has an α-array structure, or (v) R ₁ A has an α-array structure and 7- The use of the compound of formula (4) or the like in any definition for any of these applications, where -H in position has a β-array structure, is included.

Specific examples include compounds of Formula 1 (eg, Formula 4), wherein R ₄ is optionally substituted C _1-8 alkyl, optionally substituted C _2-8 alkenyl, optionally substituted C _2-8 alkynyl , Optionally substituted aryl, optionally substituted heterocycle, optionally substituted C _1-8 alkyl-aryl, optionally substituted C _1-8 alkyl-heterocycle or optionally substituted -CH ₂ -C _1-8 organic substituent, wherein , Organic substituents as described in the section on esters), any one of which is independently 1, 2, 3, 4, 5, or 6 or more -O-, -S-, -NH-, -NH-C (O)-(ie -NH-C (O)-or -C (O) -NH-), = O, = NOH, -NO ₂ , -CN, -F, -Cl,- It may be substituted with Br, -I, -OH, -SH, or -NH ₂ . Such R ₄ substituents include -CH ₂ -C _1-6 optionally substituted alkyl, -CH ₂ -C _2-6 optionally substituted alkenyl, -CH ₂ -C _1-6 optionally substituted aryl, and -CH ₂ -C _2-9 optionally substituted phenerocycles are included.

Plasma concentration-increasing compounds . One aspect of the invention consists in administering an effective amount of a plasma concentration-increasing compound, such as the compound of formula 2A or 2B, in combination with a compound of formula 1 to treat or inhibit one or more tripanosome infections in the subject to be treated. In addition to the above formula (2A) or (2B), plasma concentration-increasing compounds include barbakinin A, didiamine (isosacuranetin-7-rutinoside or neophonyrine), flavanomarine (isoocyanin-7- Glucoside), flavanone azine, flavanone diacetylhydrazone, flavanone hydrazone, silybin having the structure

Silylcristine having the following structure,

Isosilyl bean having the structure

Silanelin having the following structure, and

Compounds having the following formula E are included.

[Formula E]

Collectively these compounds and the above formulas 2A and 2B are referred to as "plasma concentration-increasing compounds".

The compounds of Formulas 2A and 2B include a number of natural and synthetic flavonoids, including any flavones, flavans, and iso analogs thereof. It is known that the inclusion of the compounds of Formulas 2A and 2B in a composition containing the Formula 1 compound enhances the systematic biocompatibility of the formulation containing the Formula 1 compound. Increased plasma concentrations of the compound of formula 1 can be obtained by containing the compound of formula 2A or 2b, such as naringin or naringinin. The above Formula 2A or 2B compound does not necessarily have to be included in the formulation containing the above Formula 1 compound. Formula 2A or 2B may also be administered, for example, about 1-4 hours before, preferably, before, or after the compound of Formula 1 is administered. In such instances, an oral or parenteral combination containing the Formula 1 compound and Formula 2A or 2B compound will be administered.

Plasma concentration-promoting compounds include compounds of the general formula

In the formula,

R ₈ at the 6-position is -H, -OH, -F, -Cl, -Br, -I, -C _1-6 alkyl, -C _1-6 alkoxy, glucuronide, C _1-25 fatty acid , Glucoside, —CH ₂ CH═C (CH ₃ ) ₂ or a substituent having Formula B above;

R ₈ in the 8-position is -H, -OH, -F, -Cl, -Br, -I, -C _1-6 alkyl, -C _1-6 alkoxy, glucuronide, C _1-25 fatty acid , A glucoside, —CH ₂ CH═C (CH ₃ ) ₂ or a residue of the above formula 50-65 compound which removes hydrogen to form the above formula 50-65 substituent;

R ₈ A is -H, -OH, -F, -Cl, -Br, -I, -C _1-6 alkyl, -C _1-6 alkoxy, glucuronide, C _1-25 fatty acid, glucoside, -CH ₂ CH = C (CH ₃ ) ₂ or a substituent having the formula (C) above;

R ₈ at the 6-position is -H, -OH, -F, -Cl, -Br, -I, -C _1-6 alkyl, -C _1-6 alkoxy, glucuronide, C _1-25 fatty acid , Glucoside, —CH ₂ CH═C (CH ₃ ) ₂ or a substituent having Formula B above;

The other R ₈ is —H, —OH, —F, —Cl, —Br, —I, —C _1-6 alkyl, —C _1-6 alkoxy, glucuronide, C _1-25 fatty acid, or — CH ₂ CH═C (CH ₃ ) ₂ ;

R ₁₀ is (i) —OH or —F, —Cl, —Br, —I, —C _1-6 alkyl, —C _1-6 alkoxy, neoesperidoside, apioglucoside, lutinoside, glucoside , Galactoside, rhamnoside, arabinoside or a stereoisomer, hydrate, homologue, derivative or metabolite of any of these substituents, wherein any one or more of the hydrogen atoms is optionally -OH, -F, -Cl, May be substituted with —Br, —I, —C _1-6 alkyl, —C _1-6 alkoxy, glucuronide, C _1-25 fatty acid, and (ii) R ₁₀ is barbaminamine A, didamine, flava Nomarane, flavanone azine, flavanone diacetylhydrazone, flavanone hydrazone, silylbin, silylcristine, isosilylbin, siladrin, stereoisomers, hydrates of the compounds of formula E or any of these substituents , Homologues, derivatives or metabolites.

Additional therapeutic example. According to another preferred aspect of the present invention, a combination therapy comprising at least one compound of the present invention is administered simultaneously or consecutively with one or more macrophage stimulating factors (optionally additional co-administered one or more plasma concentration increasing compounds). A method of treating one or more symptoms as described above, such as tripanosome infection, and the like, is provided. Macrophage stimulating factors are well known to those skilled in the art and include GM-CSF (see, e.g., Callad et al., The Cytokine Facts Book, Academic Press, 1994, p. 139, which is incorporated herein by reference). Examples include leukin-4 (available as "Leukine" by Immunex and "Prokine" by Schering Plow).

While not wishing to be based on any theory, it is known that compounds that inhibit glucose-6-phosphate dehydrogenase have surprising effectiveness against malaria. Accordingly, the present invention also provides for the treatment of any symptom as described herein in a combination therapy with any compound as described herein that will optionally be suitable for use in any other compound or combination of the invention. , In particular, relates to the administration of glucose-6-phosphate dehydrogenase inhibitors in the treatment of malaria. One of ordinary skill in the art would be well aware of the inhibitors of glucose-6-phosphate dehydrogenase and would readily be able to distinguish other agents that exhibit this inhibition.

In another preferred aspect of the invention, in order to promote the destruction of parasitic infected erythrocytes, the compounds of the invention are administered with one or more oxidants (optionally together with the addition of plasma concentration enhancing compounds and / or macrophage stimulating factors). In addition, the patient is given oxygen to increase oxidative steroids in the plasma.

The components of any of the above combination treatments in the body may be administered simultaneously (in complex combinations), substantially simultaneously (eg, at intervals of minutes or hours of administration of each compound) or continuously, eg, several days It may be administered at intervals or at least one week apart. For example, the compounds of the present invention and plasma concentration enhancing compounds (and / or macrophage stimulating factors) may be administered together or substantially simultaneously, eg, each compound may be administered at intervals of several minutes or hours, or continuously For example, it may be administered at intervals of several days or more than one week (optionally oxidant administration or oxygen supply may be performed simultaneously or sequentially). All such modifications in the administration of combination therapy are included within the scope of the present invention. The present invention also encompasses pharmaceutical combinations comprising any combination as described herein.

The invention also relates to malaria, African tripanosomosis, American tripanosomosis, and one or more parasites and / or one or more diseases caused by such parasites, one or more mycoplasma and / or one or more diseases resulting from such mycoplasma. In the manufacture of a medicament for use in the treatment of, and / or for the treatment of one or more of the following symptoms or infections, the use of the combination as described in the text: (a) vitiligo, (b) oral candidiasis (c) aphthaic / herpetic / bacterial oral ulcers, (d) fungal candida, (e) human papillomavirus, (f) infectious continuous species, (g) squamous oral carcinoma, (h) Kaposi's sarcoma oral lesion , (i) periodontitis, (j) necrotizing gingivitis, (k) oral facial shingles, and (l) rotavirus, in addition, the U.S. Patent to which the entirety is incorporated herein by reference All other symptoms and infections as disclosed in US Pat. No. 5,292,725.

The invention also relates to the use of the compounds of the invention in the manufacture of a therapeutic medicament as described herein.

The present invention also relates to administering a compound of the present invention to provide prophylactic treatment of liver parasites such as tripanosome parasites.

Article of manufacture . The invention also relates to articles of manufacture, such as packing materials, at least one or more unit-dosers of a compound of the invention (along with one or more unit-dosers of a compound that can optionally be administered in a combination therapy) and the compounds described herein An article of manufacture consisting of a label or package insert indicating that it can be used in such a manner is provided.

In one example, the article of manufacture indicates that a packing material, 17-ketosteroid compound (Formula 1 compound) and 17-ketosteroid compound (Formula 1 compound) of at least one or more unit dosage forms can be used in the manner as described herein. It consists of a label or package insert. The packing material may be prepared from one or more common known materials, such as foams, cardboard, fiberboard, polystyrene, and polypropylene, and has a suitable size to include the compounds involved in the packing material. The label or package insert may be a tag or label affixed to the packing material, or a label printed on the packing material, or a label contained within the packing material. This label will specify that 17-ketosteroids can be used in therapy as described in the text, eg, in combination with plasma concentration-increasing compounds and / or macrophage-stimulating factors. Iravel may also specify that the compound has been approved for medicinal or veterinary use in accordance with this method by a secretariat such as the US Food and Drug Administration (FDA). The label may also include additional components such as plasma concentration increasing compounds or macrophage stimulating factors in at least one or more unit doses.

Formulation and Administration Methods. Dosages for individual patients will depend on factors such as the patient's overall health, dosage and route and method, and the severity of the side effects, if any. Appropriate dosages are determined by the clinician using factors as are well known in the art. In general, administration begins with an amount that is less than the proper dosage and then incrementally increases until a desired or proper effect is achieved. The dosage of the compound of the present invention is appropriately determined depending on the individual case in consideration of the degree of symptoms, the age and sex of the patient, and the like. In the treatment period, the clinician decides whether to increase the dose, decrease the dose, stop the treatment, start the treatment or change the treatment, and determine the point of inhibition that provides the therapeutic benefit. The patient should be observed

The therapeutically effective dosage of a particular compound will vary slightly from compound to compound and from patient to patient. As a general suggestion, dosages in the range of about 0.1 to 500 mg / kg will have therapeutic efficacy. Typically dosages in the range of about 0.5 mg / kg to about 500 mg / kg will be used. The compound of formula 1 will typically comprise about 10 to 750 mg, usually about 20 to about 400 mg, in a single dose, E may be administered in two or more subdoses. Such dosages or subdoses may be administered to one or more sites or by one or more routes of administration. The duration of treatment is usually once a day for a period of time sufficient for the patient to feel no symptoms or to significantly reduce symptoms. Depending on the severity of the infection of the individual patient, it lasts for days, weeks or more.

In the frequency and duration of treatment, the average physician will be able to observe the patient's symptoms and make adequate decisions about stopping, pausing and resuming treatment.

The dosage used in the present invention is appropriately determined depending on the individual case in consideration of the sex, age, symptoms, etc. of the patient. In addition, it is known to the clinician in this field that it is within the knowledge category to determine the appropriate dosage based on the above and other factors.

According to the method of the invention, the compounds of the invention can be administered orally, intramuscularly (IM), intravenously (IV), subcutaneously (SC), and intravenous administration is particularly desirable. Although other routes of administration may be used, it has been found that intravenous administration provides surprising efficacy. For oral administration, the use of plasma concentration-enhancing compounds may become very important. The compounds or salts of the invention may also be administered intravenously or intramuscularly as liposome suspensions. Administration may also consist of a cyclodextrin combination (provided by oral, SC, IN or IM). Thus, the compounds of the present invention and their pharmaceutically or physiologically acceptable salts can be administered by any suitable route depending on the condition to be treated, such as oral, rectal, intranasal, topical (eye drops, mouthwashes, sublingual agents). Vaginal administration, parenteral (including subcutaneous, intramuscular, intravenous, intraperitoneal, transdermal, intramedullary, epidural injections) and aerosol by respiratory system. In general, the compounds of the present invention may be parenterally administered, orally administered or topically administered. If oral administration does not provide sufficient bioavailability, it may be administered by other routes as described above.

Specific examples include formulations consisting of liposomes or lipid complexes containing a compound of formula (I). Such formulations are prepared according to known methods, for example, according to US Pat. Nos. 4427649, 5043165, 5714163, 5744158, 5783211, 5795589, 5795987, 5798348, 5811118, 5820848, 5834016 and 5882678, all of which are incorporated by reference herein. do. Liposomes may optionally contain additional therapeutic or other agent (s), such as a compound of Formula 2A or 2B. Liposomes can be delivered to the patient via any standard route, such as oral, aerosol or parenteral (eg SC, IV, IM).

Most generally, pharmaceutical compositions useful in the present invention will contain a compound of formula 1, a pharmaceutically acceptable salt thereof, in any pharmaceutically acceptable carrier. If a solution is desired, water is selected as the carrier for the water-soluble compound or salt. In another example, organic excipients such as glycerol, ethanol, propylene glycol, polyethylene glycol, DMSO, DMSO ₂ , vegetable oils, mineral oils, ethanol, benzyl benzoate or mixtures thereof may be suitable. In general, any solution should be sterilized in a suitable manner, preferably filtration through a 0.22 micron filter. Compositions useful for practicing the present invention may be provided in the form of vials, ampoules, and the like.

In some examples, the compound of Formula 1 present in the composition or used in the methods as described herein is completely dissolved in the non-aqueous excipient. However, in some examples, for example, in temporary compositions or in some combinations, the compound of formula 1 may be partially dissolved and the remainder present as a solid to form colloids or suspensions. In a related example, the compound of formula 1 is incompletely dissolved and exists as a suspension or gel.

In addition to the compound of formula 1, or a salt thereof, the pharmaceutical composition may contain other additives such as pH adjusting additives, in particular agents such as acids, bases, buffers, including sodium lactate, sodium acetate and sodium gluconate. It may be. In addition such compositions may contain microbiological preservatives such as methylparaben, propylparaben, benzyl alcohol and benzyl benzoate. If a multi-use vial is provided, the pharmaceutical composition must also contain such microbial preservatives. Of course, this formulation may be lyophilized using known techniques in the art.

In the practice of the method of the present invention for treating malaria with the compound of formula (I) or a pharmaceutically acceptable salt thereof, it has been found to have an excellent effect on other of certain compounds.

This combination includes those suitable for the route of administration as described above. This combination may conveniently be presented in unit dosage form or may be prepared by any method well known in the art of pharmacy. Techniques, excipients and combinations are generally described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA 185, 17 edition, Nema et al., PDA J. Pharm. Sci. Tech. 197 51: 166-171, both of which are incorporated herein by reference. Methods of preparing the inventive combinations include mixing a compound of Formula 1 with one or more excipients or carriers. Generally, the formulation is prepared by uniformly and intimately mixing the compound of formula 1 with a liquid excipient or a finely divided solid excipient, followed by molding the product as the case may be.

Formulations of the present invention suitable for oral administration are in discrete form, such as capsules, cachets, or tablets, each containing an amount of Formula 1 or Formula 2A or 2B, as a powder or granules; As a solution or suspension of an aqueous or non-aqueous solution; Or as a liquid emulsion of oily water phase or a water-based emulsion of a water layer in oil. The compound of formula 1 or formula 2A or 2B may also be provided as a pill, soft or paste.

Tablets may be made by compression or molding, optionally with one or more excipients. Compressed tablets may be prepared by compressing the above formula (1) or (2A) or (2B) compound in a fluidless form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant and then compressed in a suitable apparatus. Can be. Molded tablets may be prepared by molding in a suitable apparatus a mixture of the powdered compounds moistened with an inert liquid diluent. Tablets may be optionally coated or graduated and may be formulated to control or delay the release of contained Formula 1 or Formula 2A or 2B compounds.

The oil phase of the emulsion of the invention can be prepared from known ingredients by the known art. Although this oil phase may contain only emulsifiers (otherwise known as emulsifiers), it is preferred to contain at least one emulsifier and a mixture of fats or oils or both fats and oils. Preferably, a hydrophilic emulsifier can be included with the hydrophobic emulsifier to act as a stabilizer. It is also desirable to contain both oils and fats. In addition, the emulsifier (s), with or without stabilizer, constitutes an emulsifying wax, and together with oils and fats, the wax constitutes an emulsifying ointment base material that forms an oil phase dispersed phase of the cream formulation. . Suitable emulsifiers and emulsion stabilizers for use in formulations containing Formula 1 or Formula 2A or 2B compounds include Tween ^® 60, Span ^® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium Lauryl sulfate.

Formulations suitable for oral administration include tablets (lozenges) containing a compound of Formula 1 or Formula 2A or 2B in an aromatic base, generally in sucrose and acacia or tragacanth; Pastllers containing a compound of Formula 1 or Formula 2A or 2B in an inert base such as gelatin and glycerin, or sucrose and acacia.

Formulations for rectal administration may be provided as suppositories of suitable bases such as cocoa butter or salicylate.

Formulations suitable for inhalation or intranasal administration can have particle sizes on the order of, for example, 0.01 to 200 microns (0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 5, 30 microns, 35 microns, etc.). Increasing to include various particle sizes in the range between 0.01 and 500 microns), by inhalation through the nasal route, or through inhalation through the bronchus or alveolar sac. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered in conjunction with other therapeutic agents such as compounds used to treat or prevent tripanosome infections. Inhalation therapy is easily administered with a metered dose inhaler.

Formulations suitable for intravaginal administration may be provided as pessaries, tampons, creams, gels, pastes, foams, spray formulations containing excipients or carriers such as those well known in the art, in addition to compounds of formula (I).

Formulations suitable for parenteral administration are sterile and comprise aqueous and non-aqueous injectable solutions comprising antioxidants, buffers, bacteriostatic agents and solute components providing the isotonic formulation with the blood of treatment; Water-soluble and non-aqueous sterile suspensions, which may include suspending agents and concentration increasing agents. This formulation may be provided in unit dose or multi-dose containers, eg in ampoules and vials sealed with a rubber stopper, and freeze-drying (freeze-drying) which requires only a sterile liquid carrier, such as water for injection, immediately prior to use. It can also be stored in a closed state. Instant injection water and suspensions may also be prepared from sterile powders, granules and tablets as described above. The unit dosage combination will typically contain the compound of Formula 1 or Formula 2A or 2B above in a daily dosage or unit daily sub-dose, or appropriate fraction thereof, as described above.

In some embodiments, the compound of Formula 1 will be administered according to intermittent criteria. In this example, at least one day (at least 24 hours) after administration of the compound of Formula 1, such as about 5-500 mg (typically 50-400 mg) of Formula 1 compound, is administered for at least one day ), Optionally at least one or more daily doses, such as about 50-500 mg, may be administered. Intermittent dosing regimens may be administered on a weekly basis (1, 2, 3 or 4 daily), for example, Monday, Wednesday and Friday for at least about 1, 2, 3, 4, 6, 8 weeks or more. , Or after administration on Tuesday, Thursday, and Saturday, without administration for a period of at least about 2, 3, 4, 5, 30, 45, 60, 90 days, and then optionally about 1, 2, 3, 4, 6 It may be administered on Mondays, Wednesdays and Fridays for more than eight weeks. The weekly administration method consists of administering a compound of Formula 1 to a patient 1, 2, 3, 4 or 5 times weekly for at least 1, 2, 3, 4 weeks. In a related example, the administration consists of administering to the patient daily for at least 2, 3, 4, 5, 6, 7 days, followed by about 1, 2, 3, 4, 5, 7, 14, 30, 45 After having spent at least 60, 90 days, optionally another route may be administered daily. These examples may further include treatment with a compound of Formula 2A or 2B or another therapy as described herein.

To the extent not yet indicated, those skilled in the art will appreciate that any of the various specific examples described and illustrated in the text may further be modified to incorporate the features indicated in any of the other examples described herein. There will be.

Treatment regimen . In therapeutic applications, a composition as described herein will typically contain one or more compounds of Formula 1, and will utilize such compositions in a manner as described herein, with one or more such compounds, usually one Will include. Although the compounds of the present invention may be administered as pure compounds, they are preferably provided as a pharmaceutical combination. Formulations of the present invention may comprise at least one compound of Formula 1 and one or more acceptable carriers or excipients, and any other therapeutic agents, such as Formula 2A or 2B compound (s), chloroquine, chloroquine homologs, macrophage stimulating factor (s) and And / or contains oxidant (s). One or more carriers or excipients are not harmful to the patient and must be "acceptable" in the sense of being suitable for other formulation ingredients.

In another example, the dosage form of the compound of Formula 1 may be administered at a relatively high introductory dose, such as about 150-750 mg per day or about 150-750 mg per day using an intermittent dosing cycle, followed by a lower maintenance dose, such as , About 50-250 mg per day or about 50-250 mg per day on an intermittent dosing cycle. In these examples it may further include a treatment with a compound of Formula 2A or 2B or another treatment as described in the text.

Parenteral formulations may contain cyclodextrins such as α-cyclodextrin, α, β-cyclodextrin (eg β-hydroxypropylcyclodextrin) or C1-6-cyclodextrin and are typically used as water soluble formulations. May optionally include one or more buffers, salts (NaCl, etc.), such as to provide an isotonic solution, and may include bacteriostatic agents or other excipients known in the art. For example, a concentration of about 5-25 mg / mL, typically about 10-20 mg / mL. Parenteral formulations containing the compound of Formula 1 and one or more excipients may be administered to a patient, eg, diluted with sterile saline. Parenteral formulations are typically administered to patients, such as humans, eg, by intravenous, topical or oral route. For non-aqueous formulations, one or more solvents may be used, such as propylene glycol, PEG such as PEG 300 or PEG 400, ethanol and benzyl benzoate. Typical water soluble and non-aqueous formulations will contain about 5 to 400 mg / mL of Formula 1 compound, usually about 10 to 200 mg / mL. Such parenteral combinations may be delivered orally or via intramuscular, intravenous or subcutaneous injection.

In preparing a composition containing the compound of Formula 1, the compound of Formula 1 may be optionally ground or granulated before or after contacting the compound of Formula 1 with one or more excipients to produce a desired particle size. For example, a compound of formula 1, such as 16α-bromoepiandrosterone, may be ground to obtain an average particle size (or about 0.5-25 uM or about 1-10 uM (eg, about 2,5 or 10 uM average particle size or diameter) (or Diameter) can be contacted with the ground compound of Formula 1 and liquid or solid excipients. The ground compound of Formula 1 may dissolve or suspend the compound of Formula 1 in one or more liquid excipients (eg, PEG, propylene glycol, or benzyl benzoate, such as PEG 300), or the ground compound in one or more solid excipients. (E.g., fillers, binders or lubricants) is useful for uniformly dispersing the medicinal material.

Compositions and combinations in the body are useful for treating or alleviating one or more of the symptoms associated with an infection or infection as described herein. The compositions and combinations may also be used to treat one or more symptoms associated with retroviral infections, such as HIV1 or HIV2 infections in humans. As described herein, "reduction of one or more related symptoms" refers to the reduction of the number of infectious agents or the copying of an infectious agent in the subject or combination of these compounds or combinations, It can be used to alleviate one or more of the symptoms caused by or associated with (eg, decreased fever, decreased duration or level of pain, or significantly reduced or eliminated lethargy or fatigue).

In addition to the components specifically mentioned above, the inventive formulations may include other agents customary in the art, which are relevant to the type of the formulation, for example, those suitable for oral administration may include perfumes or pigments. have.

The present invention further provides a veterinary composition containing at least one compound of Formula 1 or Formula 2A or 2B and at least one veterinary carrier. In addition, the compound of Formula 1 may be included in animal feed or water. Excipients for veterinary use include, for example, small amounts of compounds such as chloroform, which are generally not suitable for human use.

Veterinary carriers are substances useful for the purpose of administering the composition to cats, dogs, horses, mice, rats, hamsters, rabbits, and other animals, and are inert or acceptable in the veterinary arts, Suitable solid, liquid or gaseous materials for 2B. These veterinary compositions can be administered by oral administration, parenteral administration or any other desired route, such as those described in the text.

Specific examples of the compound of Formula 1 include or exclude a subset of compounds within the definition of Formula 1, provided that at least one compound remains. For example, a subset of the general formula (1) compounds that are generally preferred and usually included are, for example, water-soluble or water-insoluble formulations containing 16α-bromoepiandrosterone. A subset compound or usage that is optionally excluded from the compound of Formula 1 or its use in the claims or any specific example of the text, includes, for example, the use of one or more compounds described in one or more prior art references or publications. To the extent that the disclosed compounds or uses provide claims or examples that are not patentable due to novel, self-evident and / or inventive step reasons.

In another example, the compound of Formula 1 may be combined with an oligonucleotide or oligonucleotide analog to be used to deliver an oligonucleotide or analog to a cell. Typically the compound of Formula 1 will bind to the steroid nucleus via terminal hydroxyl groups at the 5 ', 3' or 2 'position of the oligonucleotide. Oligonucleotides and homologues of oligonucleotides are known and described, for example, in US Patent Publications 4725677, 4973679, 4997927, 4415732, 4458066, 5047524, 4959463, 5212295, 5386023, 5489677, 5594121, 5614622, 5624621; And PCT patent publications WO 92/07864, WO 96/29337, WO 97/14706, WO 97/14709. WO 97/31009. WO 98/04585 and WO 98/04575, all of which are incorporated herein by reference.

Synthesis method . In general, the compounds used in the present invention can be synthesized in a manner well known to those skilled in the art. Thus, the methods used for the synthesis of most of these compounds need not be described in great detail.

Formula 1 compounds containing thioacetal groups, sulfate esters, sulfite esters, carbamate or thioester groups in R ₂ (3-position) were prepared substantially according to methods known in the art. Suitable protecting group substituted intermediates can be used as specified. See, eg, US Patent Publication 5198432; European Patent Publication EP 576915; C. Chrostoana et al., J. Chem. Soc. Che. Coommun. 1991 vol 22, C. Christiana et al., J. Chem. Soc., Chem. Commun. 1991 19 : 1403-1405, hN Abramson et al., J. Pharm. Sci. 1977 66: 602-603, EJ Corey et al., J. Am. Chem. Soc. 1996 118: 8765-8766, AGM Barrett et al., J. Org. Chem. 1989 54: 227, DHR Barton et al., J. Chem. Soc. Perkin Trans. I 1976 19: 2112-2116, DHR Barton et al., J. Chem. Soc. Perkin Trans. I 1975 16: 1574-1585, and WT Smith et al., Trans. Kentucky Acad. Sci. 1984 45: 76-77, all of which are incorporated herein by reference.

Examples listed . One aspect of the invention includes the examples listed below, which further illustrate the invention and its preferred aspects or related subject matter.

1. A method of treating malaria or tripanosomosis in a patient in need of treatment comprising administering to a patient in need thereof an effective amount of at least one compound selected from the group consisting of the compounds of the invention.

2. The method of example 1, further comprising administering at least one plasma concentration-enhancing compound to said patient.

3. In a second example, a method of simultaneously administering at least one of the compounds of the present invention and at least one of said plasma concentration enhancing compounds.

4. In a second example, a method of continuously administering at least one compound of the invention and at least one plasma concentration enhancing compound.

5. The method of example 2, wherein at least one of said plasma concentration enhancing compounds is naringin and / or naringenin.

6. The method of any one of 1-5, further comprising administering at least one macrophage stimulating factor to said patient.

7. The method of any one of paragraphs 1-6, further comprising performing at least one oxidant administration and / or oxygenation to said patient.

8. The method of any one of paragraphs 1-7, wherein the patient is a mammal.

9. The method of example 8, wherein the patient is a human.

10. The method of any one of paragraphs 1-9, wherein said administration is via injection.

11. The method of any one of paragraphs 1-9, wherein said administration is via infusion.

12. The method of any one of 1-9, wherein the administration is via intravenous injection.

13. The method of example 1, wherein the at least one compound is selected from the group consisting of compounds of Formula 1 and R ₁₇ is not a hydroxy group.

14. The method in a first example, the at least one compound selected from the group consisting of compounds of the formula 1, Q ₂ is other than CH _2.

15. The method of the first example, wherein the double bond is absent.

16. The method of first example, wherein the at least one compound is selected from the group consisting of compounds of Formula 1 and Q ₂ is halogen.

17. The method of example 1, wherein the at least one compound is not DHEA.

18. A method of treating sleep sickness in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound of the present invention.

19. The method of example 18, further comprising administering at least one plasma concentration-enhancing compound to said patient.

20. The method of example 19, wherein at least one of the compounds of the present invention and at least one of the plasma concentration enhancing compounds are administered simultaneously.

21. The method of embodiment 19, wherein the at least one compound of the present invention and the at least one plasma concentration enhancing compound are administered continuously.

22. The method of example 19, wherein at least one of said plasma concentration enhancing compounds is naringin and / or naringenin.

23. The method of any one of clauses 18-22, further comprising administering at least one macrophage stimulating factor to the patient.

24. The method of any one of clauses 18-23, further comprising performing at least one oxidant administration and / or oxygenation to said patient.

25. The method of any one of clauses 18-24, wherein the patient is a mammal.

26. The method of example 25, wherein the patient is a human.

27. The method of any one of 18-26, wherein the administration is via injection.

28. The method of any one of clauses 18-26, wherein said administration is via infusion.

29. The method of any one of 18-26, wherein the administering is via intravenous injection.

30. A method for treating Shaga's disease in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound of the present invention.

31. The method of example 30, further comprising administering at least one plasma concentration-enhancing compound to said patient.

32. The method of example 31, wherein at least one of the compounds of the present invention and at least one of the plasma concentration enhancing compounds are administered simultaneously.

33. The method of example 31, wherein continuously administering at least one of the compounds of the present invention and at least one of the plasma concentration enhancing compounds.

34. The method of example 31, wherein at least one of said plasma concentration enhancing compounds is naringin and / or naringenin.

35. The method of any one of items 30-34, further comprising administering at least one macrophage stimulating factor to said patient.

36. The method of any one of paragraphs 30-35, further comprising performing at least one oxidant administration and / or oxygenation to said patient.

37. The method of any one of items 30-36, wherein the patient is a mammal.

38. The method of example 37, wherein the patient is a human.

39. The method of any one of 30-38, wherein said administering is via injection.

40. The method of any one of items 30-38, wherein said administering is via infusion.

41. The method of any one of 30-38, wherein the administering is via intravenous infusion.

42. One or more parasites and / or one or more diseases resulting from such parasites, one or more mycoplasmas, and / or comprising administering an effective amount of a compound of the invention to a patient in need thereof. One or more diseases resulting from such mycoplasma, and / or a method of treating one or more of the following symptoms or infections: (a) vitiligo, (b) oral candidiasis, (c) aphthaic / her Percutaneous / bacterial oral ulcers, (d) fungal candida, (e) human papilloma virus, (f) infectious continuous species, (g) squamous oral carcinoma, (h) Kaposi's sarcoma oral lesion, (i) periodontitis, (j ) Necrotic gingivitis, (k) oral facial shingles, and (l) rotavirus.

43. The method of example 42, further comprising administering at least one or more plasma concentration-enhancing compounds to said patient.

44. The method of example 43, wherein at least one of the compounds of the present invention and at least one of the plasma concentration enhancing compounds are administered simultaneously.

45. The method of example 43, wherein continuously administering at least one of the compounds of the present invention and at least one of the plasma concentration enhancing compounds.

46. The method of example 43, wherein at least one of said plasma concentration enhancing compounds is naringin and / or naringenin.

47. The method of any one of 42-46, further comprising administering at least one macrophage stimulating factor to said patient.

48. The method of any one of 42-47, further comprising administering one or more oxidants and / or oxygenation to the patient.

49. The method of any one of paragraphs 42-48, wherein the patient is a mammal.

* 50. 49. The method of claim 49, wherein the patient is a human.

51. The method of any one of paragraphs 42-50, wherein said administration is via injection.

52. The method of any one of paragraphs 42-50, wherein said administering is via infusion.

53. The method of any one of paragraphs 42-50, wherein said administering is via intravenous infusion.

54. A composition containing at least one compound of the invention and at least one plasma concentration-enhancing compound.

55. The composition of example 54, further comprising at least one macrophage stimulating factor.

56. The composition of example 54 or 55, further comprising an oxidizing agent.

57. A composition containing at least one compound of the invention and at least one macrophage stimulating factor.

58. The composition of example 57, further comprising at least one or more oxidizing agents.

59. A composition containing at least one compound of the invention and at least one oxidant.

60. A kit consisting of unit doses of at least one compound of the invention and unit doses of at least one plasma concentration-enhancing compound.

61. The kit of example 60, further comprising a unit dose of at least one macrophage stimulating factor.

62. The kit of examples 60 or 61, further comprising a unit dose of an oxidant.

63. A kit comprising a unit dose of at least one compound of the invention and a unit dose of at least one macrophage stimulating factor.

* 64. The kit of claim 63 further comprising a unit dose of at least one oxidant.

65. A kit consisting of unit dosages of at least one compound of the invention and unit dosages of at least one oxidant.

66. The method, composition or kit of any one of clauses 1-64, wherein the compound of the present invention is a compound of Formula 1 or a metabolite thereof.

67. The method of embodiment 66, wherein the compound of formula 1 is a compound defined by compound group 1-21, or any compound of formula 1 (eg, formula 4) or the kind described or referred to herein, or a metabolite thereof.

68. A composition containing 16α-bromoepiandrosterone and 2, 3, 4, or 5 excipients selected from polyethylene glycol, dehydrated ethanol, benzyl benzoate, benzyl alcohol, and propylene glycol, wherein about 3% v / v A composition containing less than, or less than about 1% v / v, or less than about 0.5% v / v or less than about 0.1% v / v.

69. In an example 68, the composition comprises (i) 16α-bromoepiandrosterone at a concentration of about 45-55 mg / mL, (ii) 20-30% v / v polyethylene glycol 300, polyethylene glycol 400 or polyethylene glycol A composition containing 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. In an example 69, the composition comprises 16α-bromoepiandrosterone at a concentration of 50 mg / mL, about 25% v / v polyethylene glycol 300, about 12.5% v / v dehydrated ethyl alcohol, about 5% v / v A composition containing benzyl benzoate, about 57.5% v / v propylene glycol and less than about 0.5% v / v water.

71. In an example 68, the composition comprises 16α-bromoepiandrosterone at a concentration of 50-105 mg / mL, about 27-33% w / w benzyl benzoate, about 27-33% w / w polyethylene glycol 300, A composition containing about 25-30% w / w propylene glycol and about 1-3% w / w benzyl alcohol.

72. In one example 71, wherein the composition is 100 mg / mL of 16α-bromoepiandrosterone, about 30.4% w / w benzyl benzoate, about 30.7% w / w polyethylene glycol 300, about 28% w / w A composition containing propylene glycol and about 1.9% w / w benzyl alcohol.

73. Tripanosoma cruji, tripanosoma, bruisei, tripanosoma gambiens, tripanosoma rodides, pripanosoma bruises rodyceens, tropic flies, trifle filaments, sils flies, ovals flies, or Plasmodium Bergei berghei), mycoplasma fermentans, mycoplasma genitalium or mycoplasma pneumoniae, for use in the manufacture of a medicament for the treatment of infections caused by one or more of the patients' tripanosoma or plasmodium parasites or mycoplasma bacteria. Use of the compound of formula (I).

74. The use of embodiment 73, wherein the compound of formula 1 is a compound defined as compound group 1-21 or a metabolite thereof.

75. An effective amount of a composition according to any one of items 68-71 is administered to a patient with or susceptible to tripanosoma, plasmodium or mycoplasma infection, the composition optionally comprising 16α-bromoepiandrosterone. And a pharmaceutically acceptable excipient thereof.

76. Reduce or reduce one or more symptoms associated with Tripanosoma, Plasmodium or Mycoplasma infection in a patient, comprising administering an effective amount of a compound of Formula 1 to a patient, or in a patient infected with Tripanosoma, Plasmodium, or Mycoplasma To reduce replication of tripanosoma, plasmamodium or mycoplasma.

77. In an example 76, wherein the compound of formula 1 is a compound as defined herein in the claims or a compound as defined herein or a compound within this class, such as a compound of this class or a compound as defined in claim 1-21; Or the compound of Formula 1 is present in a composition containing one or more pharmaceutical excipients, such as in any combination as described or disclosed herein.

78. A compound of Formula 1 above and at least one of which is a compound as defined herein or a compound within this class, such as a compound as defined in the claims or compounds group 1-21 as originally filed or a compound of this kind At least one excipient and a local anesthetic, wherein said local anesthetic is optionally selected from procaine, benzocaine and lidocaine.

79. A product produced by a process of contacting a compound of Formula 1, such as, for example, any compound defined by compound group 1-21 and a first excipient with a second excipient, wherein the product optionally further contains a local anesthetic; The local anesthetic is optionally a product selected from procaine, benzocaine and lidocaine.

80. A product produced by a process of contacting a compound of Formula 1, such as any compound defined by Compound Group 1-21 and a first non-aqueous liquid excipient, with a second non-aqueous liquid excipient, wherein the product is about 3% v optionally containing less than / v, or less than about 1% v / v, or less than about 0.5% v / v or less than about 0.1% v / v, wherein said first or second water-insoluble liquid excipient The above dimethyl sulfoxide, chloroform, dioxane, vegetable oil and olive oil are excluded, the product optionally further contains a local anesthetic, and the local anesthetic is optionally selected from procaine, benzocaine and lidocaine.

81. An effective amount of the composition of Example 78 or product 79 or 80 of an example is administered to a patient with an abnormal disease or infection as described herein, such as malaria, African tripanosomosis or Chagall disease, thereby A method of alleviating, eliminating, treating, enhancing or alleviating an infectious disease or abnormal disease or symptom thereof.

82. The method of example 81, wherein the compound of formula 1 is 16α-haloepiandrosterone or 16α-halidehydroepiandrosterone.

Example

The following examples further illustrate the invention and should not be construed as limiting the reaction thereto.

Example 1.16 α-bromoepiandrosterone Formulation 1.

Two non-aqueous formulations were prepared with 50 mg / mL concentration of 16a-bromoepiandrosterone ("BrEA") in 25% polyethylene glycol 300, 12.5% dehydrated ethyl alcohol, 5% benzyl benzoate, and 57.5% propylene glycol as follows: It was prepared as, hereinafter referred to as "compound 1". BrEA was purchased from Procyte, Inc. The remaining excipients are:

Excipient Detail Supplier Lot No. Final product concentration Propylene glycol USP Arco Chemical HOC-61220-01104 57.5% (v: v) Polyethylene Glycol 300 NF Union Carbide 695752 25% (v: v) Dehydrated Alcohol (ethanol) USP McComickDistilling 97K10 12.5% (v: v) Benzyl benzoate USP Spectrum Pharmaceuticals MG025 5% (v: v)

After suspending BrEA in polyethylene glycol 300, propylene glycol, benzyl benzoate and dehydrating alcohol are added to form a solution to prepare a formulation which is diluted with further propylene glycol to the final desired volume. This process is as follows.

A predetermined amount of polyethylene glycol 300 was added to the compounding vessel. Thereafter, a mixture was added, and a predetermined amount of BrEA was added to this vessel and mixed for at least 5 minutes to form a soft creamy liquid. Porphylene glycol was added to this vessel and at least 5 minutes were mixed to produce a homogeneous suspension. An amount of benzyl benzoate was added to this vessel and mixed for approximately 5 minutes to form a clear liquid suspension. Dehydrated alcohol was added to this vessel and mixed for approximately 5 minutes to yield a clear colorless solution. Propylene glycol was then added to produce the desired final blend and mixed for about 5 minutes. The drug solution was transferred in succession to the concentration-dilution device through two 0.2 μm polyvinylidene fluoride filters prior to dilution. The vials were crimp sealed after capping with Teflon-coated, butyl-rubber stoppers.

The substances used in this potion bottle are:

matter Source Product code Detailed mention Vials Wheaton 2702-B51BA Tubing vial, 2 mL / 13 mm, glass, type 1 brown bottle Stopper omniflex V9239 FM257 / 2 13 mm, teflon coated, butyl rubber stopper Sealant West 4107 Flip sealant, 13 mmm, mist gray bridge

Example 2. BrEA Blend 2.

Benzyl Benzoate (USP) 30.4 $ w / w, Polyethylene Glycol 300 (NF) 30.7% w / w, Propylene Glycol (USP), qs, about 28% w / w and Benzyl Alcohol (NF) 1.9% w / A formulation containing 100 mg / mL of BrEA, 10% w / w in w was prepared as follows, hereinafter referred to as "Formulation 2". A predetermined amount of BrEA (1.0 kg) was suspended in a mixing vessel with PEG 300 (about 3.0 L) and mixed for at least about 5 minutes at room temperature to produce a soft creamy liquid. Thereafter, the required amount of propylene glycol (about 1.5 L) was added and mixing continued for at least 5 minutes to produce a homogeneous suspension. Thereafter, benzyl benzoate (about 3.0 L) was added and the material in the vessel was mixed for about 5 minutes to produce a clear suspension. Thereafter, benzyl alcohol (about 200 mL) was added and mixing continued for about 5 minutes to yield a clear colorless solution. Thereafter, propylene glycol was added to achieve the final desired compounding volume (about 1.5 L) and mixing continued for about 5 minutes. This drug solution was transferred to a concentration-dilution device and divided into 1.2 mL per vial (2 mL, glass, type 1 brown vial). This blend was filtered under nitrogen pressurization (about 3 atm) continuously through two 0.2 μm polyvinylidene fluoride filters. These vials were capped using a Teflon-coated butyl rubber stopper, followed by crimp sealing essentially as in Example 1 above. This vial was stored in a low temperature dark room (2-8 ° C.).

Example 3. Test tube test .

For antimalarial testing, micro-titer plates were used. Drug concentrations were prepared in pMol / well according to WHO criteria (WHO, 1990). Test compounds were dissolved in 15% DMSO in sterile RPMI1640. Both chloroquine sensitive (WS / 97) and resistant (MN / 97) isolates were used throughout the experiment.

A. Schizont Inhibition Evaluation : Various concentrations of test compound were pre-administered to micro-titer plates. 50 μl of parasitic red blood cell suspension (0.2 mL erythrocytes + 0.3 mL serum + 4-5 mL RPMI-1640) in sterile RPMI-1640 was suspended in microtiter wells containing various concentrations of drug. Three reads were performed for each concentration.

B. ³ H-Hypoxanthine Consolidation Assessment : The test was performed according to the method of Desjardins et al., 1979. After incubating 30 hr at 37 ° C., some microtiter plates from the SchiZant inhibition evaluation of another triple wells were pulsed with ³ H-hypoxanthine overnight. The cell suspension was washed twice with a Millipore filter on a Millipore glass fiber filter. Filter discs were calculated for DPM by Beckman LS6000 β-scintillation counter. The activity of this drug was measured by plotting the DPM against the concentration of the drug.

In vitro Activity of Compounds against Chloroquine Sensitive T996 / 86 Tropical Fever Protozoa Concentration (uM) DHEA (% inhibition) Bromine-epiandrosterone (% inhibition) Ethienoic acid methyl ester (% inhibition) Ethian acid methyl ester (% inhibition) 30 65.5 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 47.1 IC ₅₀ 19.0 uM 7.5 uM 19.5 uM 17.5 uM 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 IC ₅₀ 9.0 nM

In vitro activity of 16-chloro-epiandrosterone and DHEA-Br against chloroquine sensitive T996.86 and chloroquine resistant KI P. falciparum was as follows.

T996.86 KI 16-chloroepiandrosterone IC ₅₀ -9.25 pgmL ^-1 ~ 9.25 μgmL ^-1 DHEA-Br IC ₅₀ -25.0 pgmL ^-1 ~ 25.0 μgmL ^-1

Example 4 4-day in vivo test protocol for Plasmodium berghei .

4-day inhibition tests were used extensively because they could be run for one week. This test consisted of inoculation of parasite-treated red blood cells on the first day of the experiment, followed by injection of test compounds and repeated administrations of D + 1, D + 2 and D + 3. On D + 4 (Friday), blood films were taken to estimate parasitemia or by scoring parasite numbers on predetermined units (eg, 1-5). The basic method using this four-day test is described by Peters (1970).

<Protocol>

1. 5 female TO mice per test group

2. Parasites ( P. berghei HP15 ANKA) were collected in heparinized syringes by cardiac puncture from feeder mice with 30 +% parasiticemia.

3. Blood was diluted in diluent to a final concentration of 1% parasitemia or 1 × 10 ⁷ infected erythrocytes per 0.2 mL infection suspension.

4. Each mouse was inoculated intravenously to form a more uniform infection rate than the intraperitoneal administration of parasites.

5. Test compounds were prepared at a dose of 100 mg / kg in (16.7% DMSO + 83.3% Celacol).

6. Test compounds were administered intraperitoneally 2 hours after parasite inoculation.

7. These compounds were administered once daily, starting on day D ₀ and continuing on days D + 1, D + 2 and D + 3.

8. Blood films were prepared with tail blood on D + 4 days, settled with 100% methanol and stained with 10% Giemsa.

9. Parasitemia was scored in 0-5 units, 5 being equivalent to control.

Experimental Protocol

Five female mice / group (strain TO) were used to deliver an inoculum consisting of 1% parasitemia or 1 × 10 ⁷ parasites / mL, 0.2 mL / mouse via intravenous injection. Drug administration was initiated 2 hours after inoculation on Day 1 and continued for 3 days. Blood films were prepared on day 5 from all 20 mice and parasiticemia was measured. The result is as follows.

compound process Parasiticemia score (0-5) Bromine-epiandrosterone 100mg / kg × 4 days ip ^* One Ethienoic acid 100 mg / kg × 4 days i.p. 2 DHEA 100 mg / kg × 4 days i.p. One Chloroquine 100 mg / kg × 4 days i.p. One Control N / A 5 ^* Ip = intraperitoneal injection

Example 5 Intermediate In vivo Malaria Study.

Default protocol :

1. Mice were infected with 1% parasiticemia via IV injection using a solution containing 1 × 10 ⁷ red blood cells / mL.

2. After 2 hours the drug is preferably in I.V. Administration was by injection.

3. Drug bromine-Epiandrosterone (Epi-Br) was administered once daily for 4 days (0.2 mL I.V. or S.C.).

4. After the experiment, the tail was excised to collect blood.

Experimental results :

Day 0

T = 0 infected mice with Plasmodium parasite (P. berghei). Parasite heart

Harvest from mouse blood and do not use mice with 0.2 mL blood.

Infected with 14% parasiticemia per cow.

I.V.

T = 2 hour primary dose: 100 mg / kg I.V. Or S.C.

T = 4 days 100 mg / kg I.V. Or S.C. Dosing daily in dosage

T = 2/5 lethality in 7 days untreated control

S.C. 3/5 fatality in the military

T = 1/3 lethality in 8 days untreated control

On day 30, I.V. There was no mortality among the groups administered the drug, but all control animals died on day 10. S.C. All animals treated by the delivery method died on day 11.

Example 6. Mouse In Vitro and In Vivo Studies.

Parasites (tropical protozoa, chloroquine sensitive strain WT chloroquine resistant strain Dd2) levels were adjusted to 1% and hemocrete to 7% in medium in an in vitro protocol. Using a 96 well plate, 100 μl of drug and 50 μl of parasite mixed in the medium were added to each well, and this process was repeated three times. The plate was placed in a chamber containing a physiological gas mixture and incubated at 37 ° C. The medium / drug mixture was changed at 24, 48 and 72 hours. On day 5 (96 hours) slides of each well were prepared, stained with gilt and 500 erythrocytes counted for each slide. Three replicates were averaged and data presented as percent inhibition.

In an in vivo protocol, Lewis rats of 80-85 g body weight were administered a standard IP injection of Plasmodium berghei. Thereafter, rats were injected intravenously after 2 hours with one of the treatments listed in the following table, returned to the cages and fed to standard laboratory feed and water freely. After 24, 48 and 72 hours of primary treatment, animals were weighed and treated again, and allowed to feed and water freely after being returned to the cage. After 5, 11 and 28 days post inoculation, the animals were weighed again and blood was collected using 26-gauge needles. Hemocrete was measured and blood smears were prepared for each rat. Blood smears were then stained with Gemsia and the level of parasitemia (defined as percent erythrocytes with parasites) was measured. Animals were sent back to their cages, twice daily to monitor for disease progression, defined as loss of 20% of their original body weight for the entire 28 days and called lethargy or drug side effects. Animals were euthanized if disease progression or drug reactions appeared.

 The PPB2 blend contained a sterile solution containing 15 mg / mL of 16α-bromo epiandrosterone in 45% β-cyclodextrin and 0.9% physiological saline.

Group 1 Group 2 Group 3 Group 4 Control 0.9% saline Chloroquine Control 40 mg / kg PPB2 Low Dose (LD) 30 mg / kg PPB2 High Dose (HD) 60 mg / kg

Intravenous injections were given on days 0, 1, 2 and 3 and the results are as follows. These results show that in vivo treatment with the combination containing 16α-bromoepiandrosterone reduces parasitemia to a level comparable to that seen from the chloroquine (“Clq”) control.

Example 7. Clinical Study of the Human Body.

Drug treatment responses were graded according to World Health Organization criteria (WHO 1973). Evaluation of treatment response was measured using parasites and heat removal time. Parasite removal was expressed as three indices: the time at which the parasite number reached 50% of the pre-treatment (baseline) index (PC ₅₀ ), the time to reach 90% of the baseline index (PC ₉₀ ), and the time below the microscopic measurement level ( Parasite removal time: PCT -parasite clearance time (White and Krishna 1989l White et al. 1992). Heat removal time refers to the time from administration of the drug until the oral or rectal temperature drops below 37.2 ° C. and lasts longer than 48 h.

There will be complete elimination of peripheral parasiticemia from two patients before, after 4, 6, 8, 12, 18, 20, 24, 30 and 36 h, or at 4 or 6 hour intervals after treatment. Venous blood (5 mL) was collected until. Blood was aseptically collected and transferred to a 10 mL syringe containing 2 mL of acid citrate dextrose (ACD) for in vitro culture. Prior to incubation, the plasma and erythrocytes were separated and washed twice. Parasites were cultured by modifying standard in vitro culture techniques (Trager and Jensen 1976; Oduola et al. 192). Samples were suspended and rotated in sterile centrifuge tubes within 10 minutes of collection. Supernatant plasma was stored and packed cells were washed twice with culture medium (wash medium, RPMI 1640 medium, 25 mM HEPES buffer and 25 mmol / L NaOH). The leukocyte layer was removed via vacuum aspiration. Each blood sample was subjected to 1:10 fold dilution with complete wash medium [CMP (wash medium with 10% human plasma)]. One milliliter of each sample was transferred to two wells of 24 well micro culture plates. Cultures were incubated at 37 ° C. under an atmosphere of 5% CO ₂ , 5% O ₂ and 90% N ₂ premixed gas. The culture medium was changed daily, and a thin blood smear was prepared for the microscope 24 h after the culture, and the culture was terminated after 48 h. If the percentage of parasite treated erythrocytes exceeded 2%, the culture samples were diluted with non-parasite treated washed type A Rh-positive erythrocytes.

Microscopy under a microscope . During in vivo studies, thin and thick blood films were fixed with dehydrated methanol (100%) and heat, respectively, and stained for 20 minutes with 10% laver. Parasitemia was quantified in thin films by measuring 2000 erythrocytes in clean adjacent fields and measuring the parasite treatment rate. In thick films, parasitemia was quantified by counting parasites against leukocytes. If no parasites were found after examination of 200 microscopic fills of thick smear, the film was judged negative. In in vitro and ex vivo studies, pretreatment of thin and thick smears was ringed by Jiang's method (Jiang et al, 1982; Silanmut and White 1993; Li et al, 1994) as modified by Li et al. Ratings were taken for the states. Approximately 5000 erythrocytes were acidified 24 h and 48 h after incubating the blood obtained at each time point in a clean contiguous field, and the maturity to microrings, small rings, macrocycles, dyed trophic and dividing bodies was graded. . Functional viability was assessed as a percentage of asexual ring form that could develop into dyed trophic or dividing bodies after 24-48 h of in vitro culture (Qatkins et al. 1993).

Acid side of the factors . Patients infected with acute symptomatic severe non-cerebral pure tropic filamentous malaria have oral fluid rejection, have a body temperature of 39 ° C. or higher, have parasite levels of 5000 or more per microliter of blood, have asexual parasitic hyperemia, and antimalarial drugs A negative urine test was shown. They were injected intravenously every 25 hours with bromine epiandrosterone (16α-bromoepiandrosterone) suspended in 45% beta cyclodextrin in saline at a concentration of 25 mg / mL. This dosing was continued for 4 days Parasitic quantification and clinical tests were performed for 73 hours once every 6 hours, measurements of these factors were performed daily until day 7, and then at 14 days.

Blood films were stained with gold and parasitic quantification was performed by evaluating 2000 parasites for leukocytes in thick films and measuring the percentage of infected red blood cells in thin films. Half of the drug treatments were graded according to WHO criteria. Evaluation of treatment response was performed using parasite and heat elimination times. Parasite elimination is represented by three indices: the time when parasite numbers fall to 50% of the pre-treatment index (baseline) (PC ₅₀ ), the time to fall to 90% of baseline (PC ₉₀ ), and below the level of microscopy Fall time (parasite removal time: PCT).

The heat removal time was referred to as the time at which the oral / rectal temperature dropped below 37.2 ° C. from the drug administration and lasted more than 48 hours.

I.V. Bromine Epiandrosterone Malaria Patient Test Patient A Patient B Heat removal time (H) 12 hrs 18 hrs Parasite Removal Time (H) 50% removal time 18 hrs 24 hrs 90% removal time 24 hrs 48 hrs 100% removal time 48 hrs 64 hrs

Result . The response consisted of parasite removal in both patients, ie at 14 days the clearance was 100%.

Example 8. Cell Research In Vitro .

The effect of bromine epiandrosterone (EPI, 16α-bromoepiandrosterone) on pentosephosphate shunt (PPS) activity in normal human RBCs was detected using whole cells. Since glucose-6-phosphate dehydrogenase ("G6PD") is the limiting enzyme of PPS, PPS flux measurements reflect better G6PD activity in the whole cell compared to G6PD activity measurements in cell lysates. Known. G6PD activity measured in cell lysates is typically about 1100-fold greater than PPS flow rate in the total remaining unstimulated RBC (G6PD activity in cell lysate: 165; PPS flow rate 0.142 micormoles / hour / mL RBC). PPS flow rate and G6PD activity in the total RBC depend on the number of urea factors (NADPH, NAD and ATP concentrations, and intracellular pH), which remain constant if performed in lysate and will vary over the entire RBC. It may be. The level of G6PD activity in cells is considerably above normal basal requirements, and inhibition of stagnant G6PD activity has little or no effect on PPS flow rate in the whole cell. For example, the RBC of the Mediterranean G6PD variant with about 1-3 percent residual activity relative to the settlement individual does not reduce the basal PPS flow rate, but the depleted flow rate is reduced when the flow rate through the PPS is stimulated by the methylene blue additive. appear. A series of experiments were performed using varying amounts of EPI and PPS flow rates were measured in unstimulated basal RBC and in methylene-blue (MB) -stimulated RBC.

The following data shows the PPS flow rate (micromoles / hour / mL RBC) in basic, unstimulated, and MB-stimulated normal RBCs. PPS flow rates were measured immediately without further incubation and without further cleaning steps by feeding various concentrations of EPI (0.3, 3.5 and 7 micormolar, final) to a suspension of washed RBCs suspended in RPMI, pH 7.4 with 10% hemocrete. The minimum inhibition of MB-stimulated PPS flow rate was observed with an EPI of 7 uM.

PPS flow rate Control, Unstimulated RBC 230 DMSO Control, Unstimulated RBC 270 DMSO Control, MB Stimulated RBC 5090 0.3 uM EPI, non-stimulated 250 0.3 uM EPI, MB stimulated 5000 3.5 uM EPI, non-stimulated 270 3.5 uM EPI, MB stimulated 4950 7 uM EPI, non-stimulated 295 7 uM EPI, MB stimulated 4660

The following data shows the average of three experiments in which basal, unstimulated and MB-stimulated PPS (micromoles / hour / mL RBCs) are measured within normal RBCs. In these experiments, various concentrations of EPI (˜0.8, 8 and 80 micromolar, final) were given to a suspension of washed RBCs suspended in RPMI at pH 7.4 with 10% hematocrit. After 90 minutes of incubation at 37 ° C. without EPI, the PPS flow rate was measured. These results indicated that MB-stimulated PPS flow rate was dose dependently suppressed. 10% was inhibited at 8 uM (p = 0.006 vs control + DMSO) and 25% at 80 uM (p = 0.002 vs control + DMSO).

PPS flow rate Control, Unstimulated RBC 430 Control, MB stimulated RBC 5410 DMSO Control, Unstimulated RBC 480 DMSO Control, MB Stimulated RBC 4890 0.8 uM EPI, non-stimulated 410 0.8 uM EPI, MB stimulated 4930 8 uM EPI, non-stimulated 450 8 uM EPI, MB stimulated 4430 80 uM EPI, non-stimulated 450 80 uM EPI, MB Stimulated 3660

Example 9 Inhibition of Parasite Growth.

The effect of EPI (16α-bromo-epiandrosterone) on parasite (tropical protozoan) growth was shown. EPI showed activity at a concentration of 1 uM.

Parasiticemia after treatment time 0 24 hrs 48 hrs 72 hrs Control + DMSO 5% 5.40% 3.10% 5.20% Epi 1 uM 5% 5.70% 5.50% 1.60% Epi 10 uM 5% 5.60% 0.90% 0 Epi 100 uM 5% 0 0 0 Epi 500 uM 5% 0 0 0 Control + DMSO 2% 8.80% 11% Epi 50 nM 2% 9.90% 9.20% 8.30% Epi 1 uM 2% 5.80% 6.10% 2.10% Epi 2.5 uM 2% 7.30% 5.80% 3.20% Epi 5 uM 2% 5.40% 6% 1.80% Epi 10 uM 2% 4.20% 3% 0 Epi 50 uM 2% 0 0 0

Parasitic hyperemia was measured according to standard methods (microscopic examination over 500 cells, staining with Diff-Quick ™ (Baxter)). Parasites were incubated under standard conditions in RPMI-1640 provided Hepes / glucose (10 mM), glutamine (0.3 g / L) and 10% human plasma. Hematocrit was 1%.

Example 10. Promotion of Phagocytosis.

Plasmodium parasite EPI (16α-bromo-epiandrosterone) performance on phagocytosis of infected RBCs was detected using adherent human monocytes. Parasitemia levels were about 8-10%, and human mononuclear cells were obtained from the leukocyte layer of blood as follows. Peripheral blood mononuclear cells were isolated from discarded platelet-removed leukocytoma layer discarded from blood samples of healthy adult male and female volunteers. The isolated cells were washed once with lukewarm PBS (PSB-G) fed with 10 mM glucose and 5 in ice-cooled RPMI 1640 medium, pH 7.4 (RMBH) fed with 23 mM NaHCO and 25 mM Hepes. Resuspend at 10 cells / mL. Dynabeads M450 Pan B and Pan T (Dynal) were added to the cells at 4 ° C. in a 4: 1 ratio for 20 minutes. B-lymphocytes and T-lymphocytes were removed as specified in the manufacturer. The remaining mononuclear cells were washed twice with RMBH and resuspended in AIM V cell culture medium (Gibco) at 1 × 10 ⁶ cells / mL. The mononuclear cell layers were collected, washed with PBS-G at 37 ° C., and resuspended in AIM V medium at 1 × 10 ⁶ cells / mL. Purified cells were> 90% as assessed by CD14 expression.

Phagocytosis (PE) of phagocytized phagocytic RBCs was determined as follows. Phagocytosis of fresh-blood phagocytized PE is initiated by mixing 10 PE / monocytes. The suspension enhances contact between PE and monocytes through simple centrifugation (at room temperature for 5 seconds at 150 × g). Cells are stored in suspension in 5 × 10 cells / gmL AIM V medium in a 6 cm diameter terpon bottomed dish (Heraeus) in a 37 ° C. wet incubator for the entire incubation period to prevent mononuclear cell adhesion after centrifugation. It was. On average, at least 90% of monocytes phagocytized by microscopic examination. Control cells were placed under the same conditions without phagocytosis. Quantitative evaluation of phagocytosis was performed by bioluminescence as described above (E. Schwarzer, et al., Br. J. Haematol. 1994 88 : 740-745).

Erythrocyte treatment and parasite culture are as follows. Red blood cells were isolated (RBC) using fresh blood (Rh +). The washed RBCs were infected at the cleavage / nutrition parasite stage (Palo Alto strain, mycoplasma-free). Step Specific parasites were isolated by Percoll-mannitol method. Briefly, normal fissile-stage parasited E (SPE) isolated on percol-mannitol gradient (parasitic> 955 SPE) was grown to growth medium (25 mmol / L Hepes, 20 mmol / L Glucose, 2 mmol / L). Co-culture was initiated at selected Hematocrit Index by mixing with E suspended in glutamine, 24 mmol / L NaHCO ₃ , 32 mg / L gentamycin and RPMI 1640 medium, pH 7.30) containing 10% AB or A human serum. Inoculum parasitemia was adjusted to 20% normal SPE for purification of ring parasite treated RBC (RPE) and 5% normal SPE for purification of trophic-stage parasite treated E (TPE). At 14-18 hours after inoculation, the parasites become ring-stage in the first cycle, and after 34-33 hours, the parasites are trophic-stage during the first cycle and 40-44 hours after inoculation The parasites then became the meristem-stage during the first cycle. RPE, TPE and SPE were separated on percol-mannitol gradient. Parasiticemia is usually 8-10% RPE and> 95% TPE. Nonparasitic and parasitic RBCs were electrically estimated. RPE ,. To assess the relative contribution of TPE and SPE and total parasitemia, slides were prepared from the cultures at designated times, stained with Diff-Quick parasite stain, and 400-1000 cells microscopically detected.

EPI or its effects in parasited RBCs were detected using various concentrations of EPI such as 0.5 uM, 1 uM, 10 uM, 25 uM and 50 uM. Nutritional-parasite treated RBCs, meristem-parasite treated RBCs, or ring-parasite treated RBCs were detected as described above.

Example 11. Human Clinical Trial.

A clinical trial protocol was established with approximately 15-20 patients. For state I or I / II, patients are infected to a less severe degree with one or more tropical fever protozoa, and they have had some symptoms (less than about 8-10% RBC parasitemia). Prior to treatment, patients were optionally tested for HIV, HCV, TB and Cryptosporidium infections. For one or more co-infected patients, standard treatments for co-infection have been provided. Patients received hospital treatment for a week. Two, more than three administration groups, such as 25, 50 or 100 mg / day 3, 4 or of the week in which 16α-bromoepiandrosterone (BrEA) or its esters are administered to a patient parenterally, such as intramuscular or intravenous Administration was on day 5. Administration is in an intermittent cycle or in successive days, such as two, three or four administrations in an amount administered once every other day. Formulations containing BrEA are as described herein, for example the formulations of Examples 1 or 2. On days 5-7, if parasitemia was reduced by about 50%, the patient was given a standard mefloquine of malaria. For parasitemia, pharmacokinetics, plasma cytokines (eg, IL-2, IL-4, IL-10, IGF1, γIFN, GM-GSF), and cells for the week of treatment and for at least 1, 2 or 3 weeks later Blood samples were taken periodically for evaluation of cytokines (eg, IL-2, IL-4, IL-10, IGF1, γIFN, GM-CSF). Patients are optionally retreated using the same or similar protocol as used in the initial dosing protocol about 2-12 weeks after the start of dosing.

Even if not yet described, one of ordinary skill in the art will recognize that any one of the various specific examples described and illustrated in the text can be further modified by incorporating the features as set forth in the remainder of these specific examples. .

The foregoing detailed description has been provided to better understand the present invention, and a person of ordinary skill in the art may limit the present invention to the present invention, since some modifications may be made without departing from the spirit and scope of the present invention. Not to sleep.

According to the present invention a 17-ketosteroid compound has been provided.

Claims (4)

Compounds having the formula:

,

,

or

In the formula, The dotted line represents any double bond, hydrogen may be present at position 5, Q ₄ is -CH (halogen)-and the halogen is -F, -Cl, Br or I; R ₂ is -OH; R ₁ A is —H, —OH or ═O; Q ₃ is -H, -CH ₃ -or -CH ₂ OH; X is -OH, -OC (O) CH ₃ , -OC (O) CH ₂ CH ₃ or -OC (O) CH ₂ CH ₂ CH ₃ ; Y is —Br, —Cl, —I, —F, —OH, —OC (O) CH ₃ , —OC (O) CH ₂ CH ₃ or —OC (O) CH ₂ CH ₂ CH ₃ . The compound of claim 1, wherein R ₁ A, X and Y are —OH. The compound of claim 2, wherein Q ₃ is CH ₃ . The compound of claim 2, wherein Q ₃ is H. ₄ .