WO1990005528A2

WO1990005528A2 - Anti-thrombotic steroids

Info

Publication number: WO1990005528A2
Application number: PCT/US1989/004875
Authority: WO
Inventors: Moses Judah Folkman
Original assignee: Children's Medical Center Corporation
Priority date: 1988-11-01
Filing date: 1989-11-01
Publication date: 1990-05-31
Also published as: WO1990005528A3; JPH03502105A

Abstract

Anti-thrombotic compositions include anti-thrombotic steroids together with potentiators thereof (e.g. heparin or cyclodextrin) or with a thrombolytic substance such as tissue plasminogen activator. Therapy, in which thrombosis in a mammal at risk is prevented or treated, comprises administering an effective amount of a steroid possessing anti-thrombotic activity or a pharmaceutically acceptable salt thereof.

Description

ANTI-THROMBOTIC STEROIDS

Background of the Invention

This invention relates to anti-thrombotic agents, i.e., agents which operate to control or prevent the natural clot-formation process. Control or prevention of detrimental clots is im e.g., for patients at risk for myocardial infarction, stroke, or thrombosis.

Anti-thrombotic agents may or may not have thrombolytic activity -- i.e. the ability to dissolve a clot after it has formed. Streptokinase, urokinase, and tissue plasminogen activator are thought to be

thrombolytic agents.

Summary of the Invention

One aspect of the invention features a method of controlling thrombotic activity in a mammal (particularly a human subject at risk for undesired thrombosis) by administering a therapeutic amount of an anti-thrombotic steroid (or a pharmaceutically acceptable salt thereof) to the mammal.

Heparin and cyclodextrin potentiate the anti- thrombotic effect of anti-thrombotic steroids.

Accordingly, another aspect of the invention features a pharmaceutical composition comprising an effective amount of an anti-thrombotic steroid (or a

pharmaceutically acceptable salt thereof) and a

potentiator such as heparin or cyclodextrin sulfate. The anti-thrombotic agents described herein also can be administered with other agents for controlling

thrombosis, particularly a thrombolytic substance such as tissue plasminogen activator. Description of the Preferred Embodiments

The steroids to be used for the purpose of the invention include anti-thrombotic compounds having a pregnane skeleton (including a norpregnane skeleton), an androstane skeleton, an estrane skeleton, a cholestane skeleton or a cholic acid skeleton, each of said

skeletons being unsubstituted or substituted, and having or not having a double bond therein. Among them,

compounds having a C_18-21 steroid skeleton are preferably used and compounds having an pregnane (preferably 17α-H- pregnane) skeleton, an estrane (preferably 16-alkyl- or 17-deoxy-estrane) skeleton or an androstane (preferably 16-alkyl- or 17-deoxy-androstane) skeleton are more preferably used. Also, compounds having a C_20-21 steroid skeleton such as a pregnane skeleton (C₂₁) or an 18-, 19- or 21-norpregnane skeleton (C₂₀) are used, those having a pregnane or 19-norpregnane skeleton being more preferred. Steroids having a pregnane skeleton are most preferred.

The above skeletons may have 1 to 4 double bonds at any positions where double bonds can be formed, but double bonds are preferably unformed or formed at 1 to 3 positions selected from Δ¹'², Δ⁴'⁵ and Δ⁶'⁷.

The above skeletons may be substituted by a substituent or substituents such as (i) 1 to 6 hydroxyl or mercapto groups, each of said groups being

unsubstituted or substituted, (ii) 1 to 4 oxo groups, (iii) 1 to 4 halogen atoms, (iv) 1 to 3 lower alkyl groups having 1 to 5 carbon atoms which may be

halogenated, (v) 1 or 2 cyano groups, (vi) 1 or 2 amino groups which may be substituted by 1 or 2 lower alkyl groups having 1 to 5 carbon atoms, a lower alkanoyl group having 2 to 5 carbon atoms or a benzoyl group, (vii) 1 or 2 nitro groups, (viii) 1 or 2 cyanomethyl groups, (ix) 1 or 2 carboxyl groups or (x) 1 or 2 qarboxymethyl groups. The hydroxyl and mercapto groups may be attached to any substitutive positions of the above skeletons, but preferable are the positions 3, 16, 19 or/and 21. The substituted hydroxyl and mercapto groups include a methoxy group, a tetrahydropyranyloxy group, a

tetrahydrofuranyloxy group, an alkanoyloxy group having 1 to 20 carbon atoms (e.g. acetyloxy, propionyloxy,

lauroyloxy), an alkenoyloxy group having 2 to 20 carbon atoms, a benzoyloxy group, a phenyl-lower alkanoyloxy group wherein the alkanoyl moiety has 2 to 5 carbon atoms, a phenyl-lower alkenoyloxy group wherein the alkenoyl moiety has 3 to 5 carbon atoms, a

carboxyalkylcarbonyloxy group wherein the alkyl moiety has 1 to 8 carbon atoms, an alkoxycarbonylalkyl- carbonyloxy group wherein the alkoxy moiety has 1 to 5 carbon atoms and the alkyl moiety has 1 to 8 carbon atoms, a carboxyalkenylcarbonyloxy group wherein the alkenyl moiety has 2 to 8 carbon atoms, an

alkoxycarbonylalkenylcarbonyloxy group wherein the alkoxy moiety has 1 to 5 carbon atoms and the alkenyl moiety has 2 to 8 carbon atoms, an alkanesulfonyloxy group, a phosphate group, a sulfate group, a pyranosyloxy or furanosyloxy group derived from a 5- or 6- carbon aldose, ketose, aldoketose, aldonic acid, ketoaldonic acid or aldaric acid, a pyranurono or furanurono group derived from 5- or 6-carbon uronic acid such as a

glucopyranurono group, an alkanoylthio group having 1 to 20 carbon atoms, an alkenoylthio group having 2 to 20 carbon atoms, a benzoylthio group, a phenyl-lower

alkanoylthio group wherein the alkanoyl moiety has 2 to 5 carbon atoms and a phenyl-lower alkenoylthio group wherein the alkenoyl moiety has 3 to 5 carbon atoms. A phenyl moiety of the above substituents having a phenyl moiety may further be substituted by 1 to 3 substituents such as a lower alkyl group having 1 to 5 carbon atoms, a lower alkoxy group having 1 to 5 carbon atoms, a halogen atom, a hydroxyl group, an amino group, a nitro group, a carboxyl group, an alkoxycarboxyl group wherein the alkoxy moiety has 1 to 5 carbon atoms. A carboxyl group of the above substituents having a carboxyl moiety may be cniaternized to form a carboxylato group.

Two of the hydroxyl groups may also combined to form a ketal of the formula:

wherein R¹ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a phenyl group or a phenyl-lower alkyl group wherein the alkyl moiety has 1 to 5 carbon atoms, and R² is an alkoxy group having 1 to 5 carbon atoms, a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a phenyl group or a phenyl-lower alkyl group wherein the alkyl moiety has 1 to 5 carbon atoms, or R¹ and R² combined with each other to form an alkylene group having 4 to 7 carbon atoms.

The oxo groups may be attached to any substitutive positions of the above skeletons, but preferable are the positions 3 and/or 20.

The halogen atoms (preferably fluorine atoms) may be attached to any substitutive positions of the above skeletons, but preferable are the positions 6, 9, 11 and/or 16.

The lower alkyl groups may be attached to any substitutive positions of the above skeletons, but preferable are the positions 2, 6, 7, 16 and/or 17. The lower alkyl groups may be halogenated with 1 to 3 halogen atoms to form a halogenated lower alkyl group such as a trifluoromethyl group. The cyano groups, the unsubstituted or substituted amino groups, the nitro groups, the cyanomethyl groups, the carboxyl groups and the carboxymethyl groups may be attached to any substitutive positions of the above skeletons, but preferable are the positions 16 and/or 17.

Among the steroids, those having a 17α-H-pregnane skeleton (a pregnane skeleton having a hydrogen atom at the position 17α) are preferable. More preferred

steroids are those having a 17α-H-pregnane skeleton which is oxygenated at the positions 3, 20 and 21, e.g. those having a 17α-H-pregnane skeleton which has oxo groups or unsubstituted or substituted hydroxyl groups at each of the positions 3, 20 and 21, and which may have

substituents as mentioned above at any other substitutive positions. Those are preferably unoxygenated at the position 11

The steroids may have several chiral centers in their molecule, and each isomer and a mixture of isomers can be used for the invention. Further, pharmaceutically acceptable salts of the steroids with, for example, an inorganic or organic acid, an alkali metal or an alkaline earth metal may be used.

The above steroids can be prepared according to the methods described in J. Fried and J. A. Edwards, "Organic Reactions in Steroid Chemistry", Vols. l and 2, van Nostrand Reinhold Company, New York, 1972; L. Fieser and M. Fieser, "Steroids", Reinhold Publishing

Corporation, 1959; and N. Applezweig, "Steroid Drugs", McGraw-Hill Book Company, Inc., 1962, or similar methods thereto.

Anti-thrombotic steroids are steroids found to have anti-thrombotic activity according, to the chick membrane assay described below. The steroids

specifically enumerated in Appendix I are examples of steroids that can be evaluated for anti-thrombotic

activity according to that assay.

Another assay for anti-thrombotic activity is as follows: A cotton pellet or a string of natural or synthetic materials is placed in the jugular vein, and thrombin and fibrinogen are locally injected into the jugular vein to produce a jugular vein thrombosis.

Thrombotic agents can be injected via intravenous or other routes and anti-thrombotic activity can be measured by determining the weight of the cotton pellet or string. Otherwise, thrombolysis can be measured by determining solubilized radioactivity using radioactive fibrinogen.

One particular anti-thrombotic steroid is desoxycorticosterone ("DOC"), which has the following structure:

Several other names are sometimes used to designate this compound: deoxycorticosterone; 21-hydroxypregn-4-ene-3, 20-dione; 4-pregnen-21-ol-3, 20-dione; 21- hydroxyprogesterone; 11-deoxycorticosterone; cortexone; and desoxycortone. It is a well known compound and many methods of synthesis reported in the literature. See, The Merck Index (9th Ed.) p. 379.

Desoxycorticosterone is believed to occur naturally as a tetraacetyl-β-D-glucoside (C₃₅H₄₈O₁₂). See Johnson, J. Am. Chem. Soc. 63: 3238 (1941). This and other glycosylated derivatives of desoxycorticosterone having anti-thrombotic activity are suitable for use in the present invention. Other useful desoxycorticosterone derivatives include desoxycorticosterone acetate (or 21- Acetyloxypregn-

4-ene-3,20-dione), which is available under several tradenames. See The Merck Index. cited above.

Anti-thrombotic glucuronides of

desoxycorticosterone are particularly preferred. They can be synthesized by the method of: Hadd, H.E. and Blickenstaff, R. T., Conjugates of Steroid Hormones.

Academic Press, New York, New York (1969); or Hadd et al., J. Steroid Biochem. 18:81-87 (1983).

The anti-thrombotic activity of the steroids of the invention is generally potentiated by heparin

(commerically available dextran sulfate) and heparin fragments. Antithrombotic activity is also potentiated by cyclodextrin sulfate (particularly β-cyclodextrin tetradecasulfate). The antithrombotic compositions discussed above potentiate the thrombolytic activity of tissue plasminogen activator (tPA).

Accordingly, the invention features mixtures having anti-thrombotic quantities of an anti-thrombotic steroid and heparin, cyclodextrin, or tPA. The mixtures are compounded in a suitable physiologically acceptable vehicle and administered, to provide 50-150 μg/μl of the desoxycorticosterone component at the desired site.

Systemic routes of administration include i.v. and oral. The anti-thrombotic desoxycorticosterone glucuronides are water soluble and are absorbed through the

gastrointestinal tract, making them particularly suitable for oral administrations. Moreover, some of these compounds are known to occur naturally in the human body.

Fluorinated analogues of desoxycorticosterone can be prepared by known techniques. See generally,

Bergstrom et al. J. Qrg. Chem. 28:2633-2640 (1963). In the present invention, among the above anti- thrombotic steroids, DOC, tetrahydrocorticosterone and their acetate or glucronide derivatives, 21-acetoxy- 11β, 17α-dihydroxypregne-4,6-dieno-3 , 20- dione, 17β- acetoxy-3α-hydroxy-5β-estrane and 11β, 17β-dihydroxy-6- methylene-17α-(2- hydroxycarboxylethyl)-androst-4-en-3- one-17-lactone are preferable.

The anti-thrombotic steroids, anti-thrombotic potentiators such as heparin and cyclodextrin, and thrombolytic substances such as TPA, which are to be used in accordance with the present invention, have low toxicity.

The dose of the anti-thrombotic steroids depends on the mode of use, purpose of use and other factors.

The effective amount is in a proportion of about 0.5 to 100 mg/kg, preferably about 1 to 30 mg/kg, when used alone, and in a proportion of about 0.5 to 50 mg/kg, preferably about 1 to 20 mg/kg, when used in combination with anti-thrombotic potentiators or thrombolytic

substances.

Anti-thrombotic potentiators such as heparin and cyclodextrin are used in a ratio of about 1/10 to 2 times weight equivalents, preferably about 1/5 to 1/2 time weight equivalent to each weight equivalent of the anti- thrombotic steroids. Thrombolytic substances such as TPA are used in a ratio of about 1/10 to two times weight equivalent, preferably about 1/5 to 1 time weight

equivalent of the anti-thrombotic steroids. The anti- thrombotic potentiators or thrombolytic substances are administered in combination with the anti-thrombotic steroids orally or non-orally. The dose of the anti- thrombotic agent according to the present invention may vary also depending on the kind of anti-thrombotic steroids, anti-thrombotic potentiators or thrombolytic substances employed. Generally, the effective amount of the daily does for a warm-blooded mammals (e.g. mouse, cat, dog, cattle, sheep, goat, rabbit, human) as

expressed in terms of the anti-thrombotic steroids is preferably about 0.5 to 20 mg/kg in a form of injections, about 0.5 to 50 mg/kg in a form of drip infusion

preparations, about 2 to 10 mg/kg in a form of

preparation for percutaneous absorption.

The anti-thrombotic agent according to the present invention which comprises anti-thrombotic steroids or anti-thrombotic potentiators and/or thrombolytic

substances can be formulated for administration by mixing the substance or substances according to an appropriate known pharmaceutical process, using, as desired, one or more pharmaceutically acceptable carriers (including diluents, excipients and the like). It is also possible to make up the respective substances into separate preparations or combine these active substances at the time of use into a single preparation containing them for administration by using a diluent, for instance. It is further possible to administer the above separate

preparations to the same subject either simultaneously or at a certain time interval.

When preparing an agent for injection, as the carrier, there are mentioned distilled water,

physiological saline and human serum albunim-suplemented distilled water or phasiological salins.

As the carrier for an agent for drip infusion preparations, there are mentioned distilled water, physiological saline, dextran sulfate solution.

As the carrier for an agent for precutaneous absorption, several kinds of ointment bases such as glycerin, sodium lauryl sulfate, polyethylene glycol ointment, white wax etc. are usable.

The preparations of the present invention are made up in conventional manners emplying the said carrier. Those steroids with anti-thrombotic activity may be used for prevention and therapy for thromboembolic diseases, cardiac infarction, traumatism, thrombosis associated with extracorporal circulation.

These may be used as powders or as ingredients in therapeutic mixtures for mammals (human, rabbit, dog, cat, rat, mouse etc.) via oral or other routes. When used for prevention or therapy of cardiac infarction, desoxycorticosterone (DOC) can be used at the dose of 0.5-100 mg/kg, favorably 1-30 mg/kg by intravenous administration; 0.15-15 mg/kg. Without wishing to bind myself to any particular theory, it appears that the mechanism of action at issue involves suppression of plasminogen activator inhibitor (P.A.I.), reported by Loskutoff et al. J. Biol. Chem. 256:4142 (1981). This mechanism was supported by data indicating that the DOC inhibits P.A.I., which was determined as follows.

Ethanolic solution of a steroid (100 μg/ml) was added to culture of human umbelic vein endothelial cells (HϋVE), and medium was removed on the next day to determine PAI- 1. PAI-1 was measured by the enzyme-linked immunosorbent assay (ELISA) of Declerck et al. (P. Declerck et al.: Blood: 71, 220 (1988)) as follows. Two murine

monoclonal antibodies raised against human PAI-1 were used as a two-site ELISA assay. Wells of microtiter plates were coated with the first antibody, followed by a sample addition, washing, and the second antibody. The bound immunoglobulins were detected with horseradish peroxidase-conjugated rabbit antimouse IgG. The anti- thrombotic steroids decreased PAI-1 concentrations to less than 50% of the control (no. steroid) level.

The following examples are provided to illustrate the. invention, not to limit it. Examples of Therapeutic Preparations

Preparation Example A

(Injectable preparation)

Steroid:DOC 20 g β-cyclodextrintetradecasulfate 10 g

Lactose 20 g

HPC-L (hydroxypropylcellulose) 10 g

Total 60 g

The above four materials were mixed under aseptic conditions in the above proportions and then dissolved or suspended in distilled water (2000 ml) for injection or physiological saline and, following addition of human serum albumin (HSA) in a concentration of 0.5%. The solution thus obtained was distributed in 2-ml portions into vials under aseptic conditions to give 1000 vials of an anti-thrombotic preparation for injection.

Preparation Example B

(Injectable preparation)

Steroid:DOC 10 g Heparin 2.5 g

Lactose 12.5 g

HPC-L 5 g

Total 30 g

The above four materials were mixed under aseptic conditions in the above proportions and dissolved or suspended in distilled water (2000 ml) for injection or physiological saline and, following addition of human serum akbumin (HSA) in a concentration of 0.5%. The solution thus obtained was distributed in 2-ml portions into vials under aseptic conditions to give 1000 vials of an anti-thrombotic preparation for injection.

Preparation Example C

(Injectable preparation)

Steroid:DOC 20 g

TPA 100 g

Lactose 20 g

HPC-L fhvdroxvprooylcellulose} 20 g

Total 160 g The above four materials were mixed under aseptic conditions in the above proportions and then dissolved or suspended in distilled water (3000 ml) for injection or physiological saline and, following addition of human serum albumin (HSA) in a concentration of 0.5%. The solution thus obtained was distributed in 3-ml portions into vials under aseptic conditions to give 1000 vials of an anti-thrombotic preparation for injection.

Preparation Example D

(Injectable preparation) Steroid:DOC 20 g

Lactose 30 g

HPC-L 10 g

Total 60 g

The above three materials were mixed under aseptic conditions in the above proportions and dissolved or suspended in distilled water (2000 ml) for injection or physiological saline and, following addition of human serum albumin (HSA) in a concentration of 0.5Φ. The solution thus obtained was distributed under aseptic conditions in 1-ml portions into vials to give 1000 vials of an anti-thrombotic preparation for injection.

Preparation Example E

(Oral preparation) (1) Steroid:DOC 15 g

(2) Lactose 135 g

(3) Corn starch 45 g

(4) Magnesium stearate 5 g

Total 200 g The above material (1), (2) and 25 g of (3) were blended, and granulated together with a paste prepared from 10 g of the material (3) and 25 ml of water. 10 g of the material (3) and the material (4) were added to the resulting granules, and the mixture was compressed by a tabletting machine to prepare 1000 tablets of diameter 6 mm each containing 15 mg of the material (1).

ANTI-THROMBOTIC EXAMPLES

Example 1

Tetrahydrodesoxycorticosterone

21-Glucuronide

Tetrahydrodesoxycorticosterone 21-glucuronide (150 μg/10μl) was administered to 9th day chick

chorioallantoic membranes, by known techniques such as the one described in Follaner et al. Nature 297:307 et seq. (1982), and the membranes were evaluated for a hemorrhage of at least 2mm, which was characteristic of a strong positive result. The membranes test was strongly positive for anti-thrombotic activity. Example 2

Tetrahydrodesoxycorticosterone

3-Glucuronide

The procedure of Example 1 was followed using tetrahydrodesoxycorticorterone 3-glucuronide (150

μg/10μl), yielding strong positive results.

Example 3

Tetrahydrodesoxycorticosterone

3. 21-Diglucuronide

The procedure of Example 1 was followed using tetrahydrodesoxycorticorterone 3,21 diglucuronide (150 μg/10μl), yielding strong positive results.

Example 4

Desoxycorticosterone

21-Glucuronide

The procedure of Example 1 was followed using desoxycorticosterone 21-glucuronide (150 μg/μl), yielding positive results in a majority of the membranes tested.

Example 5

Tetrahydro-Desoxycorticosterone

The procedure of Example 1 was followed using tetrahydro-desoxycorticosterone (150 μg/μl), yielding strong positive results in a substantial percentage of the membranes tested. Example 6

Tetrahydro-Desoxycorticosterone

3-Acetate

The procedure of Example 1 was followed using tetrahydro-desoxycorticosterone 3-acetate (15 μg/μl), yielding strong positive results in a substantial percentage of the membranes tested. Example 7

Dihydro-Desoxycorticosterone

21-Ace tate

The procedure of Example 1 was followed using didehydro-desoxycorticosterone 21-acetate, yielding strong positive results in some of the membranes tested.

Examples 8 and 9

Desoxycorticosterone

The procedure of Example 1 was followed with desoxycorticosterone at 150 μg/10μl and at 100 μg/10μl, yielding strong positive results in an increasing percentage of membranes at the higher dosage.

Example 10

Desoxycorticosterone

Plus Heparin

The procedure of Example 1 was followed using desoxycorticosterone (150 μg/10μl) with heparin (50 μg/1μ), yielding strong positive results in a higher percentage of the membranes tested than was the case in Examples 8 and 9.

Examples 11 and 12

Desoxycorticosterone

and tPA

The procedure of Example 1 was used with Desoxycorticosterone (100 μg/10μl) and tPA (Activase™ Genentech, 200 μg/10μl), yielding a substantial

percentage of strong positive results. Reducing the dosage of tPA to 100 μg/10μl reduced, but did not eliminate, the incidence of strong positive results. Example 13

Desoxycorticosterone

and β-Cyclodextrin

The procedure of Example 1 was followed with desoxycorticosterone (100 μg/10μl) and β-cyclodextrin tetradecasulfate (25 μg/10μl). The incidence of strong positive results was significantly higher than with desoxycorticosterone alone (Example 9).

Examples 14-54

The anti-thrombotic activity of each compound listed below was tested in the shell-less chorioallantoic membrane (CAM) assay, generally as described in Taylor and Folkman et al. Nature 297:307 et seq. (1982). The 3- day-chick embryos were removed from their shells and cultured in plastic cups on hammocks of plastic wrap. An ethanolic solution of steroid was mixed with 1%

methylcellulose (1:1) and 10 μl of this mixture at 20- 150 μl of steroid per 10 μl of mixture was dried and placed on the CAM of the embryos.

Bleeding was observed the next day under a stereoscope. In the following table, antithrombotic activity is indicated by the symbol "++", when as little as 50 μg of the steroid in 10 μl mixture shows a strong positive result (a hemorrhage of at least 2mm) . Strong antithrombotic activity is indicated by the symbol "+++" when as little as 20 μg of the steroid in that solution shows a strong positive result. A strong positive result at 150 μg/10μl is shown by the symbol "+".

The steroids are generally described in the following literature and/or are synthesized by the same methods shown in the literature. For example, see:

G. Golo et al., Chem. Pharm. Bull., 21, 1893 (1973); G. Goto et al., Tetrahedron, 30, 2107 (1974); G. Goto et al., Bull. Chem. Soc. Jpn., 50, 186 (1977); G. Goto et al., Chem. Pharm. Bull., 25, 1295 (1977); G. Goto et al., Chem. Parm. Bull., 26, 1718 (1973); X.

Yoshioka et al., Chem. Comm., 1971, 336; K. Yoshioka et al., Chem. Pharm. Bull., 23, 3203 (1975); Y. Yosuoka et al., Yakugaku Zasshi, 103, 1045 (1983).

PREGNANES

Example No. Compound Result

14. 11β, 17α, 21-trihydroxypregne-1,

4-diene-3 , 20-dionel7α, 21-methyl- orthoacetate ++

15, 11β,17α,21-trihydroxypregne-1,

4-diene-3,20-dionel7α,21- acetonide ++

16, 20,21-diacetoxy-11β-hydroxy- 17α,20-epoxy-16α-(1,2- dihydroxy-ethyl)pregne-1,4- dien-3-one ++

17. 21-acetoxy-11β,17α- dihydroxypregne-4,6-dieno- 3,20-dione +++

18. 9α-fluoro-11α,17α,21,22- tetrahydroxy-16α-methylpregne- 1,4-dien-3-one +++

19. 17α,21-diacetoxy-11α- hydroxypregn-4-en-3,20-dione ++ 20. 9α-fluoro-11α,17α,20,21- tetrahydroxy-16α-methylpregne- 1, 4-dien-3-one +++

21. 9α-fluoro-1α-thioaeetyl- 17α,21-dipropionyloxy-11α- hydroxy-16α-methylpregn- 4-en-3-one ++

22. 9α-fluoro-17α,21- dipropionyloxy-11α-acetoxy- 16α-methylpregno-1,4-diene-3, 20-dione ++ 23. 21-acetoxy-llα-hydroxy-16E- nitromethylpregne-1,4-diene- 3,20-dione ++

24. 20,21-diacetoxyy-11α-hydroxy-

16α-vinylpregne-1,4,17(20)- trien-3-one ++

25. 20,21-dihydroxypregne-4-en-3-one +++

ESTRANES

26. 17β-acetoxy-3α-hydroxy-5β- estrane +++ 27. 17β-propionyloxy-18B-ethylestr-

4-en-3-one

28. 17β-hydroxy-16α-propylestr-

4-en-3-one ++

29. 17β-hydroxy-18-vinylestr-4- en-3-one +++ 30. 17β-hydroxy-16α-vinylestr-

4-en-3-one ++

31. 16β, 17β-dihydroxy-3-methoxyestra-

1,3, 5 (10)-triene ++ 32. 16β,17β-dihydroxy-3-methoxy-

16α-ethylestra-1,3,5(10)-triene +++

33. 3-hydroxy-16-ethylestra-1,3,

5 (10),18-tetraene +++

34. 17β-hydroxy-16α-ethylestr- 4-en-3-one +++

35. 3 ,17β-dihydroxy-18β-ethylestra-

1,3,5(10)-triene +++

36. 17β-monosuccinyloxy-3-methoxy-

6,6-dimethylestra-1,35(10)-triene +++ 37. 17β-monosuuccinyloxy-3- methoxyestra-1,3,5(10)-triene ++

38. 16β,17β-dihydroxy-16α- methylestr-4-en-3-one +++

39. 5-chloro-17β-hydroxyestra- 4,5-dien-3-one +++

ANDROSTANES

40. 11β,17β-dihyidroxy-6-methylene- 17α-(2-hydroxycarbonylethyl)- androst-4-en-3-one17-lactone +++

41. 11β-tetrahydrpyranyloxy-3- methoxyandrosta-3,5(6)-dien-17-one ++

42. 3β-acetoxy-7e-hydroxyandrost-4- en-17-one ++

43. 3-methoxyandrosta-3,5(6)-diene +++

44. 3-ethoxyandrosta-3,5(6)-dien-

17-one ++

45. 3α,4α-epoxy-5β- hydroxycarbonylmethylandrostan-

17β-o1 ++

46. 16α,17α-dihydroxy-16β-(1,1- dimethyl-3-hydroxycarbonylethy1)- androsta-4,6-dien-3-one16-lactone ++ 47. androsta-1,4,6-trien-3-one ++

48. 2-formyl-3-methoxyandrosta- 2,4-diene ++

49. 6-ethylidenandrost-4-en-3-one ++

50. 17β-acetoxy-3-methoxyandrosta- 3,5(6)-diens ++

51. 17β-acetoxy-3-methoxy-3- formylandrpsta-3,5(6)-diene ++

52. 6-chloro-l7β-hydroxy-16β- methylandrosta-4,6-dien-3-one ++

53. 17β-hydroxycarbonyl-17α- hydroxyandrost-4-en-3-one +++

54. 17β-hydroxycarbonyl-17α- hydroxyandrosta-1,4-dien-3-one +++

Other embodiments are within the following claims.

Appendix

21-hydroxypregn-4-ene-3,20-dione (11-desoxycorticosterone) 2.-fluoro-21-hydroxypregn-4-ene-3,20-dione

4-chloro-21-hydroxypregn-4-ene-3,20-dione

4-fluoro-21-hydroxypregn-4-ene-3,20-dione

4-iodo-21-hydroxypregn-4-ene-3,20-dione

6α-chloro-21-hydroxypregn-4-ene-3,20-dione

6α-fluoro-21-hydroxypregn-4-ene-3,20-dione

6β-fluoro-21-hydroxypregn-4-ene-3,20-dione

9α-chloro-21-hydroxypregn-4-ene-3,20-dione

9α-broιιo-21-hydroxypregn-4-ene-3,20-dione

9α-fluoro-21-hydroxypregn-4-ene-3,20-dione

11α-chioro-21-hydroxypregn-4-ene-3.20-dione

11α-bromo-21-hydroxypregn-4-ene-3,20-dione

11α-fluoro-21-hydroxypregn-4-ene-3,20-dione

12α-fluoro-21-hydroxypregn-4-ene-3,20-dione

16α-chloro-21-hydroxypregn-4-ene-3,20-dione

16α-fluoro-21-hydroxypregn-4-ene-3,20-dione

17α-fluoro-21-hydroxypregn-4-ene-3,20-dione

19-fluoro-21-hydroxypregn-4-ene-3,20-dione 6α. 9α-difluoro-21-hydroxypregn-4-ene-3. 20-dione

9α. 11α-difluoro-21-hydroxypregn-4-ene-3. 20-dione

6α-broιo-9α-fluoro-21-hydroxypregn-4-ene-3, 20-dione9α -fluoro-21-hydroxy-6--eethylpregn-4-ene-3, 20-dione 21-hydroxy-6α -methylpregn-4-ene-3. 20-dione

21-hydroxy-16α-eethylpregn-4-ene-3. 20-dione 6α, 21-dihydroxypregn-4-ene-3. 20-dione

11 α, 21-dihydroxypregn-4-ene-3.20-dione (corticosterone)6α-fluoro-11α. 21-dihydroxypregn-4-ene-3. 20-dione

9α-fluoro-11α, 21-dihydroxypregn-4-ene-3. 20-dϊone

6α. 9α-di fluoro-11 α. 21-hydroxyρregn-4-ene-3.20-dione 9α-fluoro-6α-methyl-11α, 21-dihydroxyρregn-4-ene-3. 20-dione16α. 21 -dihydroxypregn-4-ene-3, 20-dionee 19. 21 -dihydroxyprcgn-4 ene-3. 20-dione 11 α -acetoxy-21 -hydroxypregn-4-ene-3. 20-dione(cort icosterone 11-acetate ) 11 α -acetox -6α -fluoro-21-hydroxypregn-4-ene-3. 20-dione

11α-acetoxy-6α. 9α-di fluoro-21-hydroxypregn-4-ene-3. 20-dione

11α-acetoxy-6- -broB0-9α -fluoro-21-hydroxypregn-4-ene-3, 20-dione 7α-mercapto-21-hydroxypregn-4-ene-3. 20-dione

7α-acetylthio-21-hydroxyρregn-4-ene-3. 20-dione 6α-cyano-21-hydroxypregn-4-ene-3, 20-dione

16α-cyano-21-hydroxypregn-4-ene-3. 20-dione 6α-amino-21-hydroxypregn-4-ene-3,20-dione

16α-amino-21-hydroxypregn-4-ene-3,20-dione 21-hydroxypregna-1.4-diene-3,20-dione

9α-fluoro-21-hydroxypregna-1,4-diene-3,20-dione

21-hydroxypregna-4.6-diene-3,20-dione

9α-fluoro-21-hydroxypregna-4,6-diene-3,20-dione

21-hydroxypregna-4.9(11)-diene-3,20-dione 21-hydroxypregn-4-ene-3,6.20-trione

21-hydroxyρregn-4-ene-3.11.20-trione 21-hydroxypregna-1,4.6-trien-3,20-dione

9α-fluoro-21-hydroxypregna-1.4.6-trien-3,20-dione 21-hydroxy-3-Bethoxypregna-3,5-dien-20-one

9α-fluoro-21-hydroxy-3-methoxypregna-3.5~dien-20-one 21-acetoxypregn-4-ene-3,20-dione (11-desoxycorticosterone 21-acetate)21-acetoxy-2α-fluoropregn-4-ene-3,20-dione

21-acetoxy-4-fluoropregn-4-ene-3,20-dione

21-acetoxy-6α-fluoroaregn-4-ene-3,20-dione 21-acetoxy-9α-broaopregn-4-ene-3,20-dione

21-acetoxy-9α-fluoropregn-4-ene-3,20-dione

21-acetoxy-11α-fluoropregn-4-ene-3,20-dione

21-acetoxy-19-fluoropregn-4-ene-3,20-dione

21-acetoxy-6α,9α-difluoropregn-4-ene-3,20-dione

21-acetoxy-9α.11α-difluoropregn-4-ene-3,20-dione

21-acetoxy-6α-bromo-9α-fluoropregn-4-ene-3,20-dione

21-acetoxy-9α-fluoro-6α-eethylpregn-4-ene-3,20-dione

21-acetoxy-6α-nethylpregn-4-ene-3,20-dione 21-acetoxy-6α-hydroxypregn-4-ene-3. 20-dione

21-acetoxy-11α-hydroxypregn-4-ene-3,20-dione(corticosterone 21-acetate)21-acetoxy-6α-fluoro-11α-hydroxypregn-4-ene-3,20-dione

21-acetoxy-9α-fluoro-11α-hydroxypregn-4-ene-3,20-dione

21-acetoxy-6α,9α-difluoro-11α-hydroxypregn-4-ene-3,20-dione

21-acetoxy-9α-fluoro-6α-methylpregn-4-ene-3,20-dione

21-acetoxy-16β-hydroxypregn-4-ene-3,20-dione

21-acetoxy-7α-acetylthiopregn-4-ene-3,20-dione 21-acetoxy-6α-cyanopregn-4-ene-3,20-dione

21-acetoxy-6α-aBinopregn-4-ene-3,20-dione

21-acetoxypregna-1,4-diene-3,20-dione

21-acetoxy-9α-fluoropregna-1.4-diene-3,20-dione

21-acetoxypregna-4,6-diene-3,20-dione

21-acetoxy-9α-fluoropregna-4,6-diene-3,20-dione

21-acetoxypregna-4.9(11)-diene-3,20-dione 21-acetoxypregn-4-ene-3.6,20-trione

21-acetoxypregn-4-ene-3.9(11).20-trione 21-acetoxypregna-1,4,6-triene-3,20-dione

21-acetoxy-9α-fiuoropregna-1,4.6-triene-3,20-dione

21-acetoxypregna-1,4,9(11)-triene-3,20-dione 21-acetoxy-3-methoxypregna-3,5-dien-20-one 21-acetoxy-6α-fluoro-3-methoxypregna-3,5'dien-20-one 21-hydroxypregn-4-ene-3,20-dione 21-glucuronide(11-desoxycorticosterone 21-glucuronide)

4-fluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide

6α-fluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide

6β-fluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide

9α-chloro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide

9α-broio-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide

9--fluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide

11α-bronιo-21-hydroxypregn-4-ene-3,20-dione 2l-glucuronide

11α-fluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide

12α-fluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide

16α-fluoro-21-hydroxypregn-4-ene-3,20-dione 21~glucuronide 6α,9f-difluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide

9α.11αdifluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide

6α-bromo-9α-fluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide9α-fluoro-21-hydroxy-6α-aethylpregn-4-ene-3,20-dione 21-glucuronide 21-hydroxy-6α-Bethylpregn-4-ene-3,20-dione 21-glucuronide 11α,21-dihydroxypregn-4-ene-3,20-dione 21-glucuronide (corticosterone 21-glucuronide)

6α-fluoro-11α,21-dihydroxypregn-4-ene-3,20-dione 21-glucuronide9α-fluoro-11α,21-dihydroxypregn-4-ene-3,20-dione 21-glucuronide6α,9α-difluoro-11α,21-hydroxypregn-4-ene-3,20-dione 21-glucuronide9α-fluoro-6α-Bethyl-11α,21-dihydroxypregn-4-ene-3,20-dione 21-glucuro¬nide

11α-acetoxy-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide(corticost¬erone 11-acetate 21-glucuronide)

11α-acetoxy-6α-fluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide11α-acetoxy-6α,9α-difluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucu¬ronide 11α-acetoxy-6α-bromo-9α-fluoro-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide 7α-acetylthio-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide 6α-cyano-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide 21-glucuroni¬de

6α-acetylamino-21-hydroxypregn-4-ene-3,20-dione 21-glucuronide 21-hydroxypregna-1,4-diene-3,20-dione 21-glucuronide

9α-fluoro-21-hydroxypregna-1,4-diene-3,20-dione 21-glucuronide21-hydroxypregna-4.6-diene-3,20-dione 21-glucuronide

9α-fluoro-21-hydroxypregna-4,6-diene-3,20-dione 21-glucuronide21-hydroxypregna-4,9(11)-diene-3,20-dione 21-glucuronide 21-hydroxypregn-4-ene-3,6,20-trione 21-glucuronide

21-hydroxypregn-4-ene-3,11.20-trione 21-glucuronide 21-hydroxypregna-1,4,6-triene-3,20-dione 21-glucuronide

9α-fluoro-21-hydroxypregna-1,4,6-triene-3,20-dione 21-glucuronide 21-hydroxy-3-methoxypregna-3.5-dien-20-one 21-glucuronide

3α,21-dihydroxy-5β-pregnan-20-one

3β.21-dihydroxy-5β-pregnan-20-one

3α,21-dihydroxy-5α-pregnan-20-one

3β.21-dihydroxy-5α-pregnan-20-one

6α-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 6β-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 6α-bromo-3α,21_dihydroxy-5β-pregnan-20-one 9α-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 9α-fluoro-3α,21-dihydroxy-5α-pregnan-20-one 9α-fluoro-3β,21-dihydroxy-5α-pregnan-20-one 9α-fluoro-3β,21-dihydroxy-5β-pregnan-20-one 11α-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 11α-fluoro-3α,21-dihydroxy-5α-pregnan-20-one 11α-fluoro-3β,21-dihydroxy-5α-pregnan-20-one 11α-fluoro-3β,21-dihydroxy-5β-pregnan-20-one 11α-broιao-3α,21-dihydroxy-5β-pregnan-20-one 12α-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 16β-chloro-3α,21-dihydroxy-5β-ρregnan-20-one 16α-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 3α,21-dihydroxy-6α-aethyl-5β-pregnan-20-one 3α,6a,21-trihydroxy-5β-pregnan-20-one3α,6β,21-trihydroxy-5α-pregnan-20-one3α,19,21-trihydroxy-5ββpregnan-20-one 3α,21-dihydroxy-6α-cyano-5p-ppregnan-20-one 3α,21-dihydroxypregn-5(6)-en-20-one

3β,21-dihydroxypregn-5(6)-en-20-one 3α, 11 α, 21 -trihydroxy-5β-pregnan-20-one 3β. 11α, 21-trihydroxy-5β-pregnan-20-one 3α. 11 α, 21-trihydroxy-5α-pregnan-20-one3β, 11α, 21 -trihydroxy-5α-pregnan-20-one 6α-fiuoro-3α,11α,21-trihydroxy-5β-pregnan-20-one

9α-fluoro-3α,11α,21-trihydroxy-5β-pregnan-20-one

9α-fluoro-3α,11α,21-trihydroxy-5α-pregnan-20-one

9α-fluoro-3β,11α,21-trihydroxy-5α-pregnan-20-one

9α-fluoro-3β,11α,21-trihydroxy-5β-pregnan-20-one 3α,21-dihydroxy-5β-pregnane-11,20-dione

3β,21-dihydroxy-5β-pregnane-11,20-dione

3α,21-dihydroxy-5α-pregnane-11,20-dione

3β,21-dihydroxy-5α-pregnane-11.20-dione

6α-fluoro-3α,21-dihydroxy-5β-pregnane-11,20-dione

6β-fluoro-3α,21-dihydroxy-5β-pregnane-11,20-dione

6α-bromo-3α,21-dϊhydroxy-5β-pregnane-11,20-dione

9α-fluoro-3α.21-dihydroxy-5β-pregnane-11,20-dione

9α-fluoro-3α,21-dihydroxy-5α-pregnane-11,20-dione

9α-fluoro-3β,21-dihydroxy-5α-pregnane-11,20-dione

9α-fluoro-3β,21-dihydroxy-5β-pregnane-11,20-dione 3α,21-dιhydroxy-6α-methyl-5β-pregnan-11,20-dione

3α,6a,21-trihydroxy-5β-pregnan-11,20-dione

3β,60,21-trihydroxy-5α-pregnan-11,20-dione 3α,21-dihydroxy-6α-cyano-5β-ppregnan-11,20-dione 3α,21-dihydroxypregn-5(6)-en-11,20-dione

3β,21-dihydroxypregn-5(6)-en-11,20-dione 3α,21-dihydroxy-5β-pregnan-20-one 3α,21-diglucuronide

3β,21-dihydroxy-5β-pregnan-20-one 3β,21-diglucuronide

3α,21-dihydroxy-5α-pregnan-20-one 3α,21-diglucuronide

3β,21-dihydroxy-5α-pregnan-20-one 3β,21-diglucuronide

6α-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 3α,21-diglucuronide6β-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 3α,21-diglucuronide6α-bromo-3α,21-dihydroxy-5β-pregnan-20-one 3α,21-diglucuronide9α-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 3α,21-diglucuronide 9α-fluoro-3α,21-dihydroxy-5α-pregnan-20-one 3α,2l-diglucuronide 9α-fluoro-3β,21-dihydroxy-5α-pregnan-20-one 3β,21-diglucuronide 9α-fluoro-3β,21-dihydroxy-5β-pregnan-20-one β,21-diglucuronide 11α-fluoro-3α,21-dihydroxy-5β-pregnan-20-one3α,21-diglucuronide 11α-fluoro-3α,21-dihydroxy-5α-pregnan-20-one 3α,21-diglucuronide 11α-fluoro-3β,21-dihydroxy-5α-pregnan-20-one3β ,21-diglucuronide 11α-fluoro-3β,21-dihydroxy-5β-pregnan-20-one3β ,21-diglucuronide 12α-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 3α,21-diglucuronide 3α,21-dihydroxy-6e-nethyl-5β-pregnan-20-one 3α,21-diglucuronide 3α,6β,21-trihydroxy-5β-pregnan-20-one 3α.6α,21-triglucuronide 3α,21-dihydroxypregn-5(6)-en-20-one 3α,21-diglucuronide

3β.21-dihydroxypregn-5(6)-en-20-one 3β,21-diglucuronide 3α,11α,21-trihydroxy-5β-pregnan-20-one 3α,21-diglucuronide

3β.11α,21-trihydroxy-5β-pregnan-20-one 3β,21-diglucuronide

3α,11α,21-trihydroxy-5α-pregnan-20-one 3α,21-diglucuronide

3β.11α,21-trihydroxy-5α-pregnan-20-one 3α,21-diglucuronide

6α-fluoro-3α,11α,21-tr hydroxy-5β-pregnan-20-one 3α-,21-diglucuronide 9α-fluoro-3α,11α,21-tr hydroxy-5β-pregnan-20-one 3α,21-diglucuronide 9α-fluoro-3α,11α,21-tr hydroxy-5α-pregnan-20-one 3α,21-diglucuronide9α-fluoro-3β.11α,21-tr hydroxy-5α-pregnan-20-one 3β,21-diglucuronide 9α-fluoro-3β,11α,21-trihydroxy-5β-pregnan-20-one 3β,21-diglucuronide 3α,21-dihydroxy-5β-pregnane-11,20-dione 3α,21-diglucuronide 6α-fluoro-3α,21-dihydroxy-5β-pregnane-11,20-dione 3α,21-diglucuronide9α-fluoro-3α,21-dihydroxy-5β-pregnane-11,20-dione 3α,21-diglucuronide9α-fluoro-3α,21-dihydroxy-5α-pregnane-11,20-dione 3α,21-diglucuronide9α-fluoro-3β,21-dihydroxy-5α-pregnane-11,20-dione 3β.21-diglucuronide9α-fluoro-3β,21-dihydroxy-5β-pregnane-11,20-dione 3β,21-diglucuronide 3α,21-dihydroxy-6α-Bethyl-5β-pregnan-11,20-dione 3α,21-diglucuronide 3α,21-dihydroxypregn-5(6)-en-11,20-dione 3α,21-diglucuronϊde 3β.21-dihydroxypregn-5(6)-en-11,20-dione3β ,21-diglucuronide 3α,21-dihydroxy-5β-pregnan-20-one 3α-glucuronide

3β,21-dihydroxy-5β-pregnan-20-one 3β-giucuronide

3α,21-dihydroxy-5α-pregnan-20-one 3α-glucuronide

3β,21-dihydroxy-5α-pregnan-20-one 3β-glucuronide

6α-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 3α-glucuronide6β-fluoro-3α.21-dihydroxy-5β-pregnan-20-one 3α-glucuronide6α-bromo-3α,21-dihydroxy-50-pregnan-20-one 3α-glucuronide9α-fluoro-3α,21-dihydroxy-50-pregnan-20-one 3α-glucuronide9α-fluoro-3α,21-dihydroxy-5e-pregnan-20-one 3α-glucuronide9α-fluoro-3β,21-dihydroxy-5β-pregnan-20-one 3β-glucuronide9α-fluoro-3β,21-dihydroxy-50-pregnan-20-one 3β-glucuronide11α-fluoro-3α,21-dihydroxy-50-pregnan-20-one 3α-glucuronide11α-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 3α-glucuronide11α-fluoro-3β,21-dihydroxy-5β-pregnan-20-one 3β-glucuronide11α-fluoro-3β,21-dihydroxy-50-pregnan-20-one 3β-glucuronide12β-fluoro-3α,21-dihydroxy-50-pregnan-20-one 3α-glucuronide 3α,21-dihydroxy-6α-methyl-5β-pregnan-20-one 3α-glucuronide 3α,6α,21-trihydroxy-5β-pregnan-20-one 3α-glucuronide 3α,21-dihydroxypregn-5(6)-en-20-one 3α-glucuronide

3β,21-dihydroxypregn-5(6)-en-20-one 3β-glucuronide 3α,11α,21-trihydroxy-50-pregnan-20-one 3α-glucuronide

3β,11α,21-trihydroxy-5β-pregnan-20-one 3β-glucuronide

3α,11α,21-trihydroxy-5β-pregnan-20-one 3α-glucuronide

3β,11α.21-trihydroxy-5β-pregnan-20-one 3α-glucuronide

6α-fluoro-3α,11α,21-trihydroxy-5β-pregnan-20-one 3α-glucuronide9α-fluoro-3α,11α,21-trihydroxy-5β-pregnan-20-one 3α-glucuronide9α-fluoro-3α,11α,21-trihydroxy-5α-pregnan-20-one 3α-glucuronide 9α-fluoro-3β,11α,21-trihydroxy-5α-pregnan-20-one 3β-glucuronide 9α-fluoro-3β,11α,21-trihydroxy-5β-pregnan-20-one 3β-glucuronide 3α,21-dihydroxy-5β-pregnane-11,20-dione 3α-glucuronide 6α-fluoro-3α,21-dihydroxy-5β-pregnane-11,20~dione 3α-glucuronide9α-fluoro-3α,21-dihydroxy-5β-pregnane-11,20-dione 3α-glucuronide9α-fluoro-3α,21-dihydroxy-5α-pregnane-11,20-dione 3α-glucuronide9α-fluoro-3β,21-dihydroxy-5α-pregnane-11.20-dione 3β-glucuronide9α-fluoro-3β,21-dihydroxy-5β-pregnane-11,20-dione 3β-glucuronide 3α,21-dihydroxy-6α-methyl-5β-pregnan-11,20-dione 3α-glucuronide 3α,21-dihydroxypregn-5(6)-en-11,20-dione 3α-glucuronide

3β,21-dihydroxypregn-5(6)-en-11,20-dione 3β-glucuronide

3α,21-dihydroxy-5β-pregnan-20-one 21-glucuronide

3β.21-dihydroxy-5β-pregnan-20-one 21-glucuronide

3α,21-dihydroxy-5α-pregnan-20-one 21-glucuronide

3β,21-dihydroxy-5α-pregnan-20-one 21-glucuronide

6α-fluoro-3α.21-dihydroxy-5β-pregnan-20-one 21-glucuronide6β-fluoro-3α,21-dihydroxy-5β-pregnan-20-one 21-glucuronide6α-bromo-3α,21-dihydroxy-5β-pregnan-20-one 21-glucuronide9α-fluoro-3α,21-dihydroxy-5β-ρregnan-20-one 21-glucuronide9α-fluoro-3α,21-dihydroxy-5α-pregnan-20-one 21-glucuronide9α-fluoro-3β,21-dihydroxy-5α-pregnan-20-one 21-glucuronide9α-fluoro-3β,21-dihydroxy-5β-pregnan-20-one 21-glucuronide11α-fluoro-3α,2I-dihydroxy-5β-pregnan-20-one 21-glucuronide11α-fluoro-3α,21-dihydroxy-5α-pregnan-20-one 21-glucuronide11α-fluoro-3β.21-dihydroxy-5α-pregnan-20-one 21-glucuronide11α-fluoro-3β.21-dihydroxy-5β-pregnan-20-one 21-glucuronide12α-fluoro-3α.21-dihydroxy-5β-pregnan-20-one 21-glucuronide 3α,21-dihydroxy-6α-aethyl-5β-pregnan-20-one 21-glucuronide 3α,6α,21-trihydroxy-50-pregnan-20-one 21-glucuronide 3α,21-dihydroxypregn-5(6)-en-20-one 21-glucuronide

3β.21-dihydroxypregn-5(6)-en-20-one 21-glucuronide 3α,11α,21-trihydroxy-5β-pregnan-20-one 21-glucuronide

3β.11 α,21-trihydroxy-5β-pregnan-20-one 21-glucuronide

3α,11α,21-trihydroxy-5α-pregnan-20-one 21-glucuronide

3β,11α,21-trihydroxy-5α-pregnan-20-one 21-glucuronide

6α-fluoro-3α11 α.21-trihydroxy-5β-pregnan-20-one 21-glucuronide9α-fluoro-3α,11α,21-trihydroxy-5β-pregnan-20-one 21-glucuronide9α-fluoro-3α,11α,21-trihydroxy-5α-pregnan-20-one 21-glucuronide9α-fluoro-3β,11α,21-trihydroxy-5α-pregnan-20-one 21-glucuronide9α-fluoro-3β,11α.21-trihydroxy-5β-pregnan-20-one 21-glucuronide 3α,21-dihydroxy-5β-pregnane-11,20-dione 21-glucuronide 6α-fluoro-3α,21-dihydroxy-50-pregnane-11,20-dione 21-glucuronide 9α-fluoro-3α,21-dihydroxy-50-pregnane-11,20-dione 21-glucuronide 9α-fluoro-3α,21-dihydroxy-5a-pregnane-11,20-dione 21-glucuronide 9α-fluoro-3β,21-dihydroxy-5β-pregnane-11,20-dione 21-glucuronide 9α-fluoro-3β,21-dihydroxy-50-pregnane-11,20-dione 21-glucuronide 3α.21-dihydroxy-6β-Bethyl-5β-pregnane-11,20-dione 21-glucuronide 3α ,21-dihydroxypregn-5(6)-ene-11,20-dione 21-glucuronide

3β ,21-dihydroxypregn-5(6)-ene-11,20-dione 21-glucuronide 3α -acetoxy-21-hydroxy-5β-pregnan-20-one 21-glucuronide

3β-acetoxy-21-hydroxy-5β-pregnan-20-one 21-glucuronide

3α-acetoxy-21-hydroxy-5α-pregnan-20-one 21-glucuronide

3β-acetoxy-21-hydroxy-5α-pregnan-20-one 21-glucuronide

3α-acetoxy-6α-fluoro-21-hydroxy-5β-pregnan-20-one 21-glucuronide3α-acetoxy-6β-fluoro-21-hydroxy-5β-pregnan-20-one 21-glucuronide3α-acetoxy-6α-bromo-21-hydroxy-5β-pregnan-20-one 21-glucuronide3α-acetoxy-9α-fluoro-21-hydroxy-5β-pregnan-20-one 21-glucuronide3α-acetoxy-9α-fluoro-21-hydroxy-5α-pregnan-20-one 21-glucuronide 3β-acetoxy-9α-fluoro-21-hydroxy-5α-pregnan-20-one 21-glucuronide 3β-acetoxy-9α-fluoro-21-hydroxy-5β-pregnan-20-one 21-glucuronide3α-acetoxy-11α-fluoro-21-hydroxy-5β-pregnan-20-one 21-glucuronide3α-acetoxy-11α-fluoro-21-hydroxy-5α-pregnan-20-one 21-glucuronide3β-acetoxy-11α-fluoro-21-hydroxy-5α-pregnan-20-one 21-glucuronide3β-acetoxy-11α-fluoro-21-hydroxy-5β-pregnan-20-one 21-glucuronide3α-acetoxy-12α-fluoro-21-hydroxy-5β-pregnan-20-one 21-glucuronide3α,6α-diacetoxy-21-hydroxy-5β-pregnan-20-one 21-glucuronide 3α-acetoxy-21-hydroxypregn-5(6)-en-20-one 21-glucuronide

3β-acetoxy-21-hydroxypregn-5(6)-en-20-one 21-glucuronide 3α,11α-diacetoxy-21-hydroxy-5β-pregnan-20-one 21-glucuronide 3β,11α-diacetoxy-21-hydroxy-5β-pregnan-20-one 21-glucuronide 3α,11α-diacetoxy-21-hydroxy-5α-pregnan-20-one 21-glucuronide

3α,11α-diacetoxy-21-hydroxy-5α-pregnan-20-one 21-gIucuronide

3α,11α-diacetoxy-6α-fluoro-21-hydroxy-5β-pregnan-20-one 21-glucuronide3α,11α-diacetoxy-9α-fluoro-21-hydroxy-5β-pregnan-20-one 21-glucuronide3α,11α-diacetoxy-9α-fluoro-21-hydroxy-5α-pregnan-20-one 21-glucuronide 3β,11α-diacetoxy-9α-fluoro-21-hydroxy-5α-pregnan-20-one 21-glucuronide 3β,11α-diacetoxy-9α-fluoro-21-hydroxy-5β-pregnan-20-one 21-glucuronide 3α-acetoxy-21-hydroxy-5β-pregnane-11,20-dione 21-glucuronide

3α-acetoxy-6α-fluoro-21-hydroxy-5β-pregnane-11,20-dione 21-gIucuronide 3α-acetoxy-9α-fluoro-21-hydroxy-5β-pregnane-11,20-dione 21-glucuronide 3α-acetoxy-9α-fluoro-21-hydroxy-5α-pregnane-11,20-dione 21-glucuronide3β-acetoxy-9α-fluoro-21-hydroxy-5β-pregnane-11,20-dione 21-glucuronide3β-acetoxy-9α-fluoro-21-hydroxy-5β-pregnane-11,20-dione 21-glucuronide 3α-acetoxy-21-hydroxy-6α-nethyl-5β-pregnane-11,20-dione 21-glucuronide3α-acetoxy-21-hydroxypregn-5(6)-ene-11,20-dione 21-glucuronide 3β-acetoxy-21-hydroxypregn-5(6)-ene-11.20-dione 21-glucuronide3α-acetoxy-21-hydroxy-5β-pregnan-20-one

3β-acetoxy-21-hydroxy-5β-pregnan-20-one

3α-acetoxy-21-hydroxy-5α-pregnan-20-one

3β-acetoxy-21-hydroxy-5α-pregnan-20-one

3α-acetoxy-6α-fluoro-21-hydroxy-5β-pregnan-20-one

3α-acetoxy-6β-broao-21-hydroxy-5β-pregrian-20-one

3α-acetoxy-9α-fluoro-21-hydroxy-5β-pregnan-20-one

3α-acetoxy-9α-fluoro-21-hydroxy-5α-pregnan-20-one

3β-acetoxy-9α-fluoro-21-hydroxy-5α-pregnan-20-one

3β-acetoxy-9α-fluoro-21-hydroxy-5β-pregnan-20-one

3α-acetoxy-11α-fluoro-21-hydroxy-5β-pregnan-20-one

3α-acetoxy-11α-fluoro-21-hydroxy-5α-pregnan-20-one

3β-acetoxy-11α-fluoro-21-hydroxy-5α-pregnan-20-one

3β-acetoxy-11α-fluoro-21-hydroxy-5β-pregnan-20-one 3α-acetoxy-12α-f luoro-21-hydroxy-5β-pregnan-20-one

3α, 6α-diaeetoxy-21-hydroxy-5β-pregnan-20-one

3α -acetoxy-21-hydroxypregn-5(6)-en-20-one

3β-acetoxy-21-hydroxypregn-5(6)-en-20-one

3α,11α-diacetoxy-21-hydroxy-5β-pregnan-20-one

3β,11α-diacetoxy-21-hydroxy-5β-pregnan-20-one

3α,11α-diacetoxy-21-hydroxy-5α-pregnan-20-one

3α,11α-diacetoxy-6α-fluoro-21-hydroxy-5β-pregnan-20-one

3α,11α-diacetoxy-9α-fluoro-21-hydroxy-5α-pregnan-20-one

3β,11α-diacetoxy-9α-fluoro-21-hydroxy-5β-pregnan-20-one

3α-acetoxy-21-hydroxy-50-pregnane-11,20-dione

3α-acetoxy-6α-fluoro-21-hydroxy-5β-pregnane-11,20-dione

3α-acetoxy-9α-fluoro-21-hydroxy-5β-pregnane-11,20-dione

3α-acetoxy-9α-fluoro-21-hydroxy-5α-pregnane-11,20-dione

3β-acetoxy-9α-fluoro-21-hydroxy-5α-pregnane-11,20-dione

3β-acetoxy-9α-fluoro-21-hydroxy-5β-pregnane-11,20-dione

3α-acetoxy-21-hydroxy-6α-Bethyl-5β-pregnane-11,20-dione

3α-acetoxy-21-hydroxypregn-5(6)-ene-11,20-dione

3β-acetoxy-21-hydroxypregn-5(6)-ene-14,20-dione 21-acetoxy-3α-hydroxy-5β-pregnan-20-one3α-glucuronide

21-acetoxy-3β-hydroxy-5β-pregnan-20-one 3β-glucuronide

21-acetoxy-3α-hydroxy-5α-pregnan-20-one 3α-glucuronide

21-acetoxy-3β-hydroxy-5α-pregnan-20-one 3β-glucuronide

21-acetoxy-6α-fluoro-3α-hydroxy-5β-pregnan-20-one 3α-glucuronide21-acetoxy-6β-fluoro-3α-hydroxy-5β-pregnan-20-one 3α-glucuronide21-acetoxy-6α-bromo-3α-hydroxy-5β-pregnan-20-one3α-glucuronide21-acetoxy-9α-fluoro-3α-hydroxy-5β-pregnan-20-one 3α-glucuronide21-acetoxy-9α-fluoro-3α-hydroxy-5α-pregnan-20-one 3α-glucuronide21-acetoxy-9α-fluoro-3β-hydroxy-5α-pregnan-20-one 3β-glucuronide21-acetoxy-9α-fluoro-3β-hydroxy-5β-pregnan-20-one 3β-glucuronide21-acetoxy-11α-fluoro-3α-hydroxy-5β-pregnan-20-one 3α-glucuronide21-acetoxy-11α-fluoro-3α-hydroxy-5α-pregnan-20-one 3α-glucuronide21-acetoxy-11α-fluoro-3β-hydroxy-5α-pregnan-20-one 3β-glucuronide 21-acetoxy-11α-fluoro-3β-hydroxy-5β-pregnan-20-one 3β-glucuronide21-acetoxy-12α-fluoro-3α-hydroxy-5β-pregnan-20-one 3α-glucuronide6α,21-diacetoxy-3α-hydroxy-5β-pregnan-20-one 3α-glucuronide

21-acetoxy-3α-hydroxypregn-5(6)-en-20-one 3α-glucuronide

21-acetoxy-3β-hydroxypregn-5(6)-en-20-one 3β-glucuronide 11α,21-diacetoxy-3α-hydroxy-5β-ρregnan-20-one 3α-glucuronide

11α,21-diacetoxy-3β-hydroxy-5β-pregnan-20-one 3β-glucuronide

11α.21-diacetoxy-3α-hydroxy-5α-pregnan-20-one 3α-glucuronide

11α,21-diacetoxy-3β-hydroxy-5α-pregnan-20-one 3α-glucuronide

11α,21-diacetoxy-6α-fluoro-3α-hydroxy-5β-pregnan-20-one 3α-glucuronide 11α,21-diacetoxy-9α-fluoro-3α-hydroxy-5β-pregnan-20-one 3α-glucuronide 11α,21-diacetoxy-9α-fluoro-3α-hydroxy-5α-pregnan-20-one 3α-glucuronide11α,21-diacetoxy-9α-fluoro-3β-hydroxy-5α-pregnan-20-one 3β-glucuronide 11α,21-diacetoxy-9α-fluoro-3β-hydroxy-5β-pregnan-20-one 3β-glucuronide 21-acetoxy-3α-hydroxy-5β-ρregnane-11,20-dione 3β-glucuronide

21-acetoxy-6α-fluoro-3α-hydroxy-5β-pregnane-11,20-dione 3α-glucuronide21-acetoxy-9α-fluoro-3α-hydroxy-5β-pregnane-11,20-dione 3α-glucuronide21-acetoxy-9α-fluoro-3α-hydroxy-5α-pregnane-11,20-dione 3α-glucuronide21-acetoxy-9α-fluoro-3β-hydroxy-5α-pregnane-11,20-dione 3β-glucuronide21-acetoxy-9α-fluoro-3β-hydroxy-5β-pregnane-11,20-dione 3β-glucuronide 21-acetoxy-3α-hydroxy-6α-methyl-5β-pregnane-11,20-dione 3α-glucuronide21-acetoxy-3α-hydroxypregn-5(6)-ene-11,20-dione 3α-glucuronide

21-acetoxy-3β-hydroxypregn-5(6)-ene-11,20-dione 3β-glucuronide

21 -hydroxy-5β -pregnane-3, 20-dione

21-hydroxy-5α-pregnane-3. 20-dione

6α-fIuoro-21-hydroxy-5β-pregnane-3,20-dione 6β-fluoro-21-hydroxy-5β-pregnane-3,20-dione6α-bromo-21-hydroxy-5β-pregnane-3,20-dione9α-fluoτo-21-hydroxy-5β-pregnane-3,20-dione9α-fluoro-21-hydroxy-5α-pregnane-3,20-dione9α-fluoro-21-hydroxy-5β-pregnane-3,20-dione11α-fluoro-21-hydroxy-5α-pregnane-3,20-dione11α-fluoro-21-hydroxy-5β-pregnane-3,20-dione11α-bromo-21-hydroxy-5β-pregnane-3,20-dione12α-fluoro-21-hydroxy-5β-ρregnane-3,20-dione16β-chloro-21-hydroxy-5β-pregnane-3,20-dione16α-fIuoro-21-hydroxy-5β-ρregnane-3,20-dione 21-hydroxy-6α-methyl-5β-pregnane-3,20-dione 6α,21-dihydroxy-5β-pregnane-3,20-dione

6β,21-dihydroxy-5α-pregnane-3,20-dione

19,21-dihydroxy-5β-pregnane-3,20-dione 21-hydroxy-6α-cyano-5β-ppregnane-3,20-dione 21-hydroxypregn-5(6)-ene-3,20-dione

11α,21-dihydroxy-5β-pregnane-3,20-dione

11α,21-dihydroxy-5α-pregnane-3,20-dione

6α-fluoro-11α,21-dihydroxy-5β-pregnane-3,20-dione9α-fluoro-11α,21-dihydroxy-5β-pregnane-3,20-dione9α-fluoro-11α,21-dihydroxy-5α-pregnane-3,20-dione9α-fluoro-11α,21-dihydroxy-5β-pregnane-3,20-dione 21-hydroxy-5β-ρregnane-3,11,20-trione

21-hydroxy-5α-pregnane-3,11,20-trione 6α-fluoro-21-hydroxy-5β-pregnane-3,11,20-trione

6β-fluoro-21-hydroxy-5β-pregnane-3,11,20-trione

6α-bromo-21-hydroxy-5β-pregnane-3,11,20-trione

9α-fluoro-21-hydroxy-5β-pregnane-3,11,20-trione

9α-fluoro-21-hydroxy-5α-pregnane-3,11,20-trione 21-hydroxy-6α-methyl-5β-pregnane-3,11,20-trione

6α.21-dihydroxy-5β-pregnane-3,11,20-trione

6β.21-dihydroxy-5α-pregnane-3,11,20-trione 21-hydroxy-6α-cyano-5β-pregnane-3,11,20-trione 21-hydroxypregn-5(6)-ene-3,11,20-trione 21-hydroxy-5β-pregnane-3.20-dione 21-glucuronide

21-hydroxy-5α-pregnane-3,20-dione 21-glucuronide

6α-fluoro-21-hydroxy-5β-pregnane-3,20-dione 21-glucuronide 6β-fluoro-21-hydroxy-5β-pregnane-3,20-dione 21-glucuronide 6α-bromo-21-hydroxy-5β-pregnane-3,20-dione 21-glucuronide 9α-fluoro-21-hydroxy-5β-pregnane-3,20-dione 21-glucuronide 9α-fluoro-21-hydroxy-5α-pregnane-3,20-dione 21-glucuronide 9α-fluoro-21-hydroxy-5β-ρregnane-3,20-dione 21-glucuronide 11α-fluoro-21-hydroxy-5α-pregnane-3,20-dione 21-glucuronide 11α-fluoro-21-hydroxy-5β-pregnane-3,20-dione 21-glucuronide 12α-fluoro-21-hydroxy-5β-pregnane-3,20-dione 21-glucuronide 21-hydroxy-6α-Bethyl-5β-pregnane-3,20-dione 21-glucuronide 21-hydroxy-6α-cyano-5β-pregnane-3.20-dione 21-glucuronide 21-hydroxypregn-5(6)-ene-3,20-dione 21-glucuronide 11α,2l-dihydroxy-5β-pregnane-3,20-dione 21-glucuronide

11α,21-dihydroxy-5α-pregnane-3,20-dione 21-glucuronide

6α-fluoro-11α,21-dihydroxy-5β-pregnane-3,20-dione 21-glucuronide 9α-fluoro-11α,21-dihydroxy-5β-pregnane-3,20-dione 21-glucuronide 9α fluoro-11α.21-dihydroxy-5α-pregnane-3.20-dione 21-glucuronide 21-hydroxy-5β-pregnane-3,11,20-trione 21-glucuronide

21-hydroxy-5α-pregnane-3,11,20-trione 21-glucuronide

6α-fluoro-21-hydroxy-5β-pregnane-3,11,20-trione 21-glucuronide9α-fluoro-21-hydroxy-5β-pregnane-3.11,20-trione 21-glucuronide9α-fluoro-21-hydroxy-5α-pregnane-3,11,20-trione 2l-glucuronide 21-hydroxy-6α-methyl-5β-pregnane-3,11,20-trione 21-glucuronide 21-hydroxy-6α-cyano-5β-pregnan-3,11,20-trione 21-glucuronide 21-hydroxypregn-5(6)-ene-3,11,20-trione 21-glucuronide 21-acetoxy-5β-pregnane-3,20-dione

21-acetoxy-5α-pregnane-3,20-dione

21-acetoxy-6α-fluoro-5β-pregnane-3,20-dione

21-acetoxy-6β-fluoro-5β-pregnane-3,20-dione

21-acetoxy-6α-broio-5β-pregnane-3,20-dione

21-acetoxy-9α-fluoro-5β-pregnane-3,20-dione

21-acetoxy-9α-fluoro-5α-pregnane-3,20-dione

21-acetoxy-9α-fluoro-5β-pregnane-3,20-dione

21-acetoxy-11α-fluoro-5α-pregnane-3,20-dione

21-acetoxy-11α-flύoro-5β-pregnane-3.20-dione

21-acetoxy-11α-bromo-5β-pregnane-3.20-dione

21-acetoxy-12α-fluoro-5β-pregnane-3, 20-dione

21-acetoxy-16β-chloro-5β-pregnane-3, 20-dtone

21-acetoxy-16α-fluoro-5β-pregnane-3, 20-dione 21- acetoxy-6α-Bethyl-5β-pregnane-3, 20-dione 21-acetoxy-6α-cyano-5β-pregnane-3, 20-dione 21-acetoxypregn-5(6)-ene-3, 20-dione 11α,21-diacetoxy-5β-pregnane-3.20-dione

11α,21-diacetoxy-5α-pregnane-3.20-dione

21-acetoxy-6α-fluoro-11α-hydroxy-5β-pregnane-3,20-dione 21-acetoxy-9α-fluoro-11α-hydroxy-5β-pregnane-3,20-dione21-acetoxy-9α-fluoro-11α-hydroxy-5α-pregnane-3.20-dione 21-acetoxy-9α-fluoro-11α-hydroxy-5β-ρregnane-3,20-dione 21-acetoxy-5β-pregnane-3.11.20-trione

21-acetoxy-5α-pregnane-3.11.20-trione

21-acetoxy-6α-fluoro-5β-ρregnane-3,11,20-trione

21-acetoxy-6β-fluoro-5β-pregnane-3,11,20-trione

21-acetoxy-6α-bromo-5β-pregnane-3,11,20-trione

21-acetoxy-9α-fluoro-5β-pregnane-3,11,20-trione

21-acetoxy-9α-fluoro-5α-pregnane-3,11,20-trione 21-acetoxy-6α-methyl-5β-pregnane-3.11.20-trione

6α,21-diacetoxy-5β-pregnane-3,11,20-trione

6β,21-diacetoxy-5α-pregnane-3,11,20-trione 21-acetoxy-6α-cyano-5β-pregnane-3,11,20-trione 21-acetoxypregn-5(6)-ene-3,11,20-trione

21 -hydroxy-19-norpregn-4-one-3, 20-dione (11 -desoxy-19-norcorticostero¬ne)

4-f luoro-21-hydroxy-19-norpregn-4-ene-3, 20-dione

6α-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione

9α-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione

11α-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione

6α.9α-difluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione

9α,11α-difluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione

6α-bromo-9α-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione

9α-fluoro-21-hydroxy-6α-Bethyl-19-norpregn-4-ene-3,20-dione

21-hydroxy-6α-Beιhyl-19-norpregn-4-ene-3,20-dione

11α,21-dihydroxy-19-norpregn-4-ene-3,20-dione (19-norcorticosterone) 6α-fluoro-11α,21-dihydroxy-19-norpregn-4-ene-3,20-dione

9α-fluoro-11α,21-dihydroxy-19-norpregn-4-ene-3,20-dione

6α,9α-difluoro-11α.21-hydroxy-19-norpregn-4-ene-3,20-dione

9α-fluoro-6α-Bethyl-11α,21-dihydroxy-19-norpregn-4-ene-3,20-dϊone 11α-acetoxy-21-hydroxy-19-norpregn-4-ene-3.20-dione (19-norcorticoste¬rone 11-acetate)

11α-acetoxy-6α-fluoro-21-hydroxy-19-norpregn-4-ene-3.20-dione

11α-acetoxy-6α,9α-difluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione11α-acetoxy-6α-bromo-9α-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-acetoxy-6α-fluoro-19-norpregn-4-ene-3,20-dione

21-acetoxy-9α-bromo-19-norpregn-4-ene-3,20-dione

21-acetoxy-9α-fluoro-19-norpregn-4-ene-3,20-dione

21-acetoxy-11α-fluoro-19-norpregn-4-ene-3,20-dione

21-acetoxy-19-fluoro-19-norpregn-4-ene-3,20-dione

21-acetoxy-6α, 9α-difluoro-19-norpregn-4-ene-3, 20-dione

2l-acetoxy-9α,11α-difluoro-19-norpregn-4-ene-3, 20-dione

21-acetoxy-6α-broio-9α-fluoro-19-norpregn-4-ene-3, 20-dione

21-acetoxy-9α-fluoro-6β-Bethyl-19-norpregn-4-ene-3, 20-dione

21-acetoxy-6α-methyl-19-norpregn-4-ene-3, 20-dione

21-acetoxy-11α-hydroxy-19-norpregn-4-ene-3. 20-dione (19-norcorticoste¬rone 21-acetate)

21-acetoxy-6α-fluoro-11α-hydroxy-19-norρregn-4-ene-3. 20-dione 21 -acetoxy-9α- fluoro- 11α-hydroxy- 19-norpregn-4 ene-3, 20-dione

21 -acetoxy-6α, 9α-difluoro-11α-hydroxy-19-norpregn-4-ene-3. 20-dione 21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide (11-desoxy-19- norcorticosterone 21-glucuronide)

4-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 6α-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 6β-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 9α-chloro-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 9α-bromo-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 9α-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 11α-bromo-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 11α-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 6α,9α-difluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 9α,11α-difluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 6α-broto-9α-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide

9α-fluoro-21-hydroxy-6α-Bethyl-19-norpregn-4-ene-3,20-dione 21-glucuronide

11α,21-dihydroxy-19-norpregn-4-ene-3.20-dione 21-glucuronide (19-nor-corticosterone 21-glucuronide)

6α-fluoro-11α,21-dihydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 9α-fluoro-11α,21-dihydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide 6α.9α-difluoro-11α,21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuro¬nide

9α-fluoro-6α-iethyl-11α,21-dihydroxy-19-norpregn-4-ene-3.20-dione 21-glucuronide

11α-acetoxy-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glucuronide(corticosterone 11-acetate 21-glucuronide)

11α-acetoxy-6α-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione 21-glu¬curonide

11α-acetoxy-6α,9α-difluoro-21-hydroxy-19-norpregn-4-ene-3.20-dione 2-1-glucuronide 11α-acetoxy-6α-bromo-9α-fluoro-21-hydroxy-19-norpregn-4-ene-3,20-dione

21-glucuronide

3α,21-dihydroxy-5β-19-norpregnan-20 one 21-glucuronide

3β,21-dihydroxy-5β-19-norpregnan-20-one 21-glucuronide

3α,21-dihydroxy-5α-19-norpregnan-20-one 21-glucuronide

3β,21-dihydroxy-5α-19-norpregnan-20-one 21-glucuronide

6α-fluoro-3α,21-dihydroxy-5β-19-norpregnan-20-one 21-glucuronide 6β-fluoro-3α,21-dihydroxy-5β-19-norpregnan-20-one 21-glucuronide 6α-bromo-3α,21-dihydroxy-5β-19-norpregnan-20-one 21-glucuronide 9α-fluoro-3α,21-dihydroxy-5β-19-norpregnan-20-one 21-glucuronide 9α-fluoro-3α,21-dihydroxy-5α-19-norpregnan-20-one 21-glucuronide 9α-fluoro-3β,21-dihydroxy-5α-19-norpregnan-20-one 21-glucuronide 9α-fluoro-3β,21-dihydroxy-5β-19-norpregnan-20-one 21-glucuronide 11α-fluoro-3α,21-dihydroxy-5β-19-norpregnan-20-one 21-glucuronide 11α-fluoro-3α,21-dihydroxy-5α-19-norpregnan-20-one 21-glucuronide 11α-fluoro-3β,21-dihydroxy-5α-19-norpregnan-20-one 21-glucuronide 11α-fluoro-3β.21-dihydroxy-5β-19-norpregnan-20-one 21-glucuronide 12α-fluoro-3α,21-dihydroxy-5β-19-norpregnan-20-one 21-glucuronide 3α,21-dihydroxy-6α-methyl-5β-19-norpregnan-20-one 21-glucuronide 3α.6α,21-trihydroxy-5β-19-norpregnan-20-one 21-glucuronide 3α,21-dihydroxy-19-norpregn-5(6)-en-20-one 21-glucuronide

3β,21-dihydroxy-19-norpregn-5(6)-en-20-one 21-glucuronide 3α,11α,21-trihydroxy-5β-19-norpregnan-20-one 21-glucuronide

3β,11α,21-trihydroxy-5β-19-norpregnan-20-one 21-glucuronide

3α,11α.21-trihydroxy-5α-19-norpregnan-20-one 21-glucuronide

3β,11α,21-trihydroxy-5α-19-norpregnan-20-one 21-glucuronide

6α-fluoro-3α,11α,21-trihydroxy-5β-19-norpregnan-20-one 21-glucuronide9α-fluoro-3α,11α,21-trihydroxy-5β-19-norpregnan-20-one 21-glucuronide9α-fluoro-3α,11α.21-trihydroxy-5α-19-norpregnan-20-one 21-glucuronide9α-fluoro-3β,11α,21-trihydroxy-5α-19-norpregnan-20-one 21-glucuronide9α-fluoro-3β,11α.21-trihydroxy-5β-19-norpregnan-20-one 21-glucuronide 3α,21-dihydroxy-5β-19-norpregnane-11,20-dione 21-glucuronide 6α-fluoro-3α,21-dihydroxy-5β-19-norpregnane-11,20-dione 21-glucuronide 9α-fluoro-3α,21-dihydroxy-5β-19-norpregnane-11,20-dione 21-glucuronide 9α-fluoro-3α,21-dihydroxy-5α-19-norpregnane-11,20-dione 21-glucuronide 9α-fluoro-3β,21-dϊhydroxy-5α-19-norpregnane-11,20-dione 21-glucuronide 9α-fluoro-3β,21-dihydroxy-5β-19-norpregnane-11,20-dione 21-glucuronide

3α,21-dihydroxy-6α-methyl-5β-19-norpregnane-11,20-dione 21-glucuronide

3α,21-dihydroxy-19-norpregn-5(6)-ene-11,20-dione21-glucuronide3β,21-dihydroxy-19-norpregn-5(6)-ene-11, 20-dione 21 -glucuronide 3α-acetoxy-21-hydroxy-5β-19-norpregnan-20-one 21-glucuronide

3β-acetoxy-21-hydroxy-5β-l9-norpregnan-20-one21-glucuronide

3α-acetoxy-21-hydroxy-5α-19-norpregnan-20-one 21-glucuronide

3β-acetoxy-21-hydroxy-5α-19-norpregnan-20-one 21-glucuronide

3α-acetoxy-6α-fluoro-21-hydroxy-5β-19-norρregnan-20-one 21-glucuronide 3α-acetoxy-6β-fluoro-21-hydroxy-5β-19-norpregnan-20-one 21-glucuronide 3α-acetoxy-6α-bromo-21-hydroxy-5β-19-norpregnan-20-one 21-glucuronide3α-acetoxy-9α-fluoro-21-hydroxy-5β-19-norpregnan-20-one 21-glucuronide 3α-acetoxy-9α-fluoro-21-hydroxy-5α-19-norpregnan-20-one 21-glucuronide 3β-acetoxy-9α-fluoro-21-hydroxy-5α-19-norpregnan-20-one 21-glucuronide 3β-acetoxy-9α-fluoro-21-hydroxy-5β-19-norpregnan-20-one 21-glucuronide 3α-acetoxy-11α-fluoro-21-hydroxy-5β-19-norpregnan-20-one 21- glucuronide

3α-acetoxy-11α-fluoro-21-hydroxy-5α-19-norpregnan-20-one 21- glucuronide

3β-acetoxy-11α-fluoro-21-hydroxy-5α-19-norpregnan-20-one 21- glucuronide

30-acetoxy-11α-fluoro-21-hydroxy-5β-19-norpregnan-20-one 21- glucuronide

3α-acetoxy-12α-fluoro-21-hydroxy-5β-19-norpregnan-20-one 21- glucuronide

3α,6α-diacetoxy-21-hydroxy-5β-19-norpregnan-20-one 21-glucuronide 3α-acetoxy-21-hydroxy-19-norpregn-5(6)-en-20-one 21-glucuronide 3β-acetoxy-21-hydroxy-19-norpregn-5(6)-en-20-one 21-glucuronide 3α,11α-diacetoxy-21-hydroxy-5β-19-norpregnan-20-one 21-glucuronide3β,11α-diacetoxy-21-hydroxy-5β-l9-norpregnan-20-one 21-glucuronide 3α,11α-diacetoxy-21-hydroxy-5α-19-norρregnan-20-one 21-glucuronide 3α,11α-diacetoxy-21-hydroxy-5α-19-norpregnan-20-one 21-glucuronide 3α,11α-diacetoxy-6α-fluoro-21-hydroxy-5β-19-norpregnan-20-one 21-glucuronide

3α,11α-diacetoxy-9α-fluoro-21-hydroxy-5β-19-norpregnan-20-one 21-glucuronide

3α,11α-diacetoxy-9α-fluoro-21-hydroxy-5α-19-norpregnan-20-one 21-glucuronide

3β,11α-diacetoxy-9α-fluoro-21-hydroxy-5α-19-norpregnan-20-one 21-glucuronide

30,11α-diacetoxy-9α-fluoro-21-hydroxy-5β-19-norpregnan-20-one 21-glucuronide

3α-acetoxy-21-hydroxy-5β-19-norpregnane-11,20-dione 21-glucuronide 3α-acetoxy-6α-fluoro-21-hydroxy-5β-19-norpregnane-11,20-dione 21-glucuronide

3β-acetoxy-9α-fluoro-21-hydroxy-5β-19-norρregnane-11,20-dione 21-glucuronide

3α-acetoxy-9α-fluoro-21-hydroxy-5α-19-norpregnane-11,20 dione 21-glucu ronide

3β-acetoxy-9α-fluoro-21-hydroxy-5α-19-norpregnane-11.20-dione 21-glucuronide

3β-acetoxy-9α-fluoro-21-hydroxy-5β-19-norpregnane-11,20-dione 21-glucuronide

3α-acetoxy-21-hydroxy-6α-methyl-5β-19-norpregnan-11.20-dione 21-glucuronide

3α-acetoxy-21-hydroxy-19-norpregn-5(6)-ene-11,20-dione 21-glucuronide3β-acetoxy-21-hydroxy-19-norpregn-5(6)-ene-11.20-dione 21-glucuronide3α-acetoxy-21-hydroxy-5β-19-norpregnan-20-one

3β-acetoxy-21-hydroxy-5β-19-norpregnan-20-one

3α-acetoxy-21-hydroxy-5α-19-norpregnan-20-one

3β-acetoxy-21-hydroxy-5α-19-norpregnan-20-one

3α-acetoxy-6α-fluoro-21-hydroxy-5β-19-norpregnan-20-one

3α-acetoxy-6β-fluoro-21-hydroxy-5β-19-norpregnan-20-one

3α-acetoxy-6α-broBθ-21-hydroxy-5β-19-norpregnan-20-one

3α-acetoxy-9α-fluoro-21-hydroxy-5β-19-norpregnan-20-one

3α-acetoxy-9α-fluoro-21-hydroxy-5α-19-norpregnan-20-one

3β-acetoxy-9α-fluoro-21-hydroxy-5α-19-norpregnan-20-one

3β-acetoxy-9α-fluoro-21-hydroxy-5β-19-norpregnan-20-one

3α-acetoxy-11α-fiuoro-21-hydroxy-5β-19-norpregnan-20-one

3α-acetoxy-11α-fluoro-21-hydroxy-5α-19-norpregnan-20-one

3β-acetoxy-11α-fluoro-21-hydroxy-5α-19-norpregnan-20-one

3β-acetoxy-11α-fluoro-21-hydroxy-5β-19-norpregnan-20-one

3α-acetoxy-12β-fluoro-21-hydroxy-5β-19-norpregnan-20-one

3α,6α-diacetoxy-21-hydroxy-5β-19-norpregnan-20-one

3α-acetoxy-21-hydroxy-19-norpregn-5(6)-en-20-one

3β-acetoxy-21-hydroxy-19-norpregn-5(6)-en-20-one

3α,11α-diacetoxy-21-hydroxy-5β-19-norpregnan-20-one

3β,11α-diacetoxy-21-hydroxy-5β-19-norpregnan-20-one

3α,11α-diacetoxy-21-hydroxy-5α-19-norpregnan-20-one

3α,11α-diacetoxy-6α-fluoro-21-hydroxy-5β-19-norpregnan-20-one

3α,11α-diacetoxy-9α-fluoro-21-hydroxy-5β-19-norpregnan-20-one

3α,11α-diacetoxy-9α-fluoro-21-hydroxy-5α-199norpregnan-20-one 3β,11α-diacetoxy-9α-fluoro-21-hydroxy-5α-19-norpregnan-20-one 30.11α-diacetoxy-9α-fluoro-21-hydroxy-5β-19-norpregnan-20-one3α-acetoxy-21-hydroxy-50-19-norpregnane-11,20-dione

3α-acetoxy-6α-fluoro-21-hydroxy-5β-19-norpregnane-11,20-dione3α-acetoxy-9α-fluoro-21-hydroxy-5β-19-norpregnane-11,20-dione3α-acetoxy-9α-fluoro-21-hydroxy-5α-19-norpregnane-11,20-dione3β-acetoxy-9α-fluoro-21-hydroxy-5α-19-norρregnane-11,20-dione3β-acetoxy-9α-fluoro-21-hydroxy-5β-19-norpregnane-11,20-dione3α-acetoxy-21-hydroxy-6α-methyl-5β-19-norpregnan-11,20-dione3α-acetoxy-21-hydroxy-19-norpregn-5(6)-ene-11,20-dione3β-acetoxy-21-hydroxy-19-norpregn-5(6)-ene-11,20-dione

21-acetoxy-3α-hydroxy-5β-19-norpregnan-20-one 3α-glucuronide

21-acetoxy-3β-hydroxy-5β-19-norpregnan-20-one 3β-glucuronide

21-acetoxy-3α-hydroxy-5α-19-norpregnan-20-one 3β-glucuronide

21-acetoxy-3β-hydroxy-5α-19-norpregnan-20-one 3β-glucuronide

21-acetoxy-6α-fluoro-3α-hydroxy-5β-19-norpregnan-20-one 3α-glucuronide 21-acetoxy-6β-fluoro-3α-hydroxy-5β-19-norpregnan-20-one 3a-glucuronide 21-acetoxy-6α-bromo-3α-hydroxy-5β-19-norpregnan-20-one 3α-glucuronide21-acetoxy-9α-fluoro-3β-hydroxy-5β-19-norpregnan-20-one 3α-glucuronide 21-acetoxy-9α-fluoro-3α-hydroxy-5α-19-norpregnan-20-one 3α-glucuronide 21-acetoxy-9α-fluoro-3β-hydroxy-5α-19-norpregnan-20-one 3β-glucuronide 21-acetoxy-9α-fluoro-3β-hydroxy-5β-19-norpregnan-20-one 3β-glucuronide 21-acetoxy-11α-f1uoro-3α-hydroxy-5β-19-norpregnan-20-one 3α-glucuronide

21-acetoxy-11α-fluoro-3α-hydroxy-5α-19-norpregnan-20-one 3α-glucuronide

21-acetoxy-11α-fluoro-3β-hydroxy-5α-19-norpregnan-20-one 3β-glucuronide

21-acetoxy-11 α-fluoro-3β-hydroxy-5β-19-norpregnan-20-one 3β-glucuronide

21-acetoxy-12α-fluoro-3α-hydroxy-5β-19-norpregnan-20-one 3α-glucuronide

6α,21-diacetoxy-3α-hydroxy-5β-19-norpregnan-20-one 3α-glucuronide 21-acetoxy-3α-hydroxy-19-norpregn-5(6)-en-20-one 3α-glucuronide21-acetoxy-3β-hydroxy-19-norpregn-5(6)-en-20-one 3β-glucuronide 11α,21-diacetoxy-3α-hydroxy-5β-19-norpregnan-20-one 3α-glucuronide11α,21-diacetoxy-3β-hydroxy-5β-19-norpregnan-20-one 3β-glucuronide11α,21-diacetoxy-3α-hydroxy-5α-19-norpregnan-20-one 3α-glucuronide 11 α, 21 -diaceloxy-3β-hydroxy-5α - 19-norpregnan-20-one 3α-gl ucuronide 11 α, 21-diacetoxy-6α-f luoro-3α-hydroxy-5β-19-norpregnan-20-one 3α-glucu ronide

11α,21-diacetoxy-9α-fluoro-3α-hydroxy-5β-19-norpregnan-20-one 3α-glucu ronide

11α,21-diacetoxy-9α-fluoro-3α-hydroxy-5α-19-norpregnan-20-one 3α-glucu ronide

11α,21-diacetoxy-9α-fluoro-3β-hydroxy-5α-19-norpregnan-20-one 3β-glucuronide

11 α.21-diacetoxy-9α-fluoro-3β-hydroxy-5β-19-norpregnan-20-one 3β-glucuronide

21-acetoxy-3α-hydroxy-5β-19-norpregnane-11,20-dione 3α-glucuronide 21-acetoxy-6α-fluoro-3α-hydroxy-5β-19-norpregnane-11,20-dione 3α-glucuronide

21-acetoxy-9α-fluoro-3α-hydroxy-5β-19-norpregnane-11,20-dione 3α-glucuronide

21-acetoxy-9α-fluoro-3α-hydroxy-5α-19-norpregnane-11, 20-dione 3α-glucuronide

21-acetoxy-9α-fluoro-3β-hydroxy-5α-19-norpregnane-11,20-dione 3β-glucuronide

21-acetoxy-9α-fluoro-3β-hydroxy-5β-19-norpregnane-11,20-dione 3β-glucuronide

21-acetoxy-3α-hydroxy-6α-methyl-5β-19-norpregnan-11,20-dione 3α-glucuronide

21-acetoxy-3α-hydroxy19-norpregn-5(6)-ene-11,20-dione 3α-glucuronide 21-acetoxy-3β-hydroxy19-norpregn-5(6)-ene-11.20-dione 3β-glucuronide

Claims

Claims 1. A therapeutic composition comprising an antithrombotic amount of a steroid having anti-thrombotic activity in combination with an anti-thrombotic

potentiator or a thrombolytic substance.

2. A composition according to claim 1, wherein said steroid is a steroid having a C_20-21 steroid

skeleton.

3. A composition according to claim 1, wherein said steroid is a steroid having a pregnane skeleton, in which the angular methyl group at the position 10 may be a hydrogen atom.

4. A composition according to claim 1, wherein said steroid is a steroid having a pregnane skeleton.

5. A composition according to claim 1, wherein said steroid is a steroid having a 17α-H-pregnane

skeleton.

6. A composition according to claim 1, wherein said steroid is a steroid having a 17α-H-pregnane

skeleton which is oxygenated at the positions 3, 20 and 21,

7. A composition according to claim 1, wherein said steroid is a steroid having a 21-hydroxy-17α-H- pregnane-20-one structure which is oxygenated at the position 3, said hydroxyl group being unsubstituted or substituted.

8. A composition according to claim 1, wherein said steroid is a steroid having a 3,21-dihydroxy-17α- H- pregnan-20-one or 21-hydroxy-17α-H-pregn-4-ene- 3,20- dione structure, each of said hydroxyl groups being unsubstituted or substituted.

9. A composition according to claim 1, wherein said steroid is a steroid having a 3,21-dihydroxy-17α- H- pregnan-20-one structure, each of said hydroxyl groups being unsubstituted or substituted.

10. A composition according to claim 1, wherein said steroid is a steroid having a 21-hydroxy- 17α-H- pregn-4-ene-3,20-dione structure, said hydroxyl group being unsubstituted or substituted.

11. A composition according to claim 1, wherein said steroid is a steroid having an 11-nonoxygenated 3,21-dihydroxy-17α-H-pregnan-20-one or 11-nonoxygenated 21-hydroxy-17α-H-pregn-4-ene- 3,20-dione structure, each of said hydroxyl groups being unsubstituted or

substituted.

12. A composition according to claim 1, wherein said steroid is a steroid having an ll-nonoxygenated 3,21-dihydroxy-17α-H-pregnan-20-one structure, each of said hydroxyl groups being unsubstituted or substituted.

13. A composition according to claim 1, wherein said steroid is a steroid having an ll-nonoxygenated 21- hydroxy-17α-H-pregn-4-ene-3, 20-dione structure, said hydroxyl group being unsubstituted or substituted.

14. A composition according to claim 1, wherein said steroid is desoxycorticosterone, 3,21- dihydroxypregnan-20-one or a glucuronide thereof.

15. A composition according to claim 1, wherein said steroid is desoxycorticosterone.

16. A composition according to claim 1, wherein said steroid is 3-glucurono-21-hydroxypregnan- 20-one.

17. The composition of claim 1 comprising heparin or cyclodextrin.

18. A composition according to claim 1, wherein said steroid is a steroid having a C_18-21, steroid

skeleton.

19. A composition according to claim 1, wherein said steroid is a steroid having a pregnane skeleton, an estrane skeleton or an androstane skeleton.

20. A composition according to claim 1, wherein said steroid is a steroid having an estrane skeleton.

21. A composition according to claim 1, wherein said steroid is a steroid having an andostane skeleton.

22. A composition according to claim 1, wherein said steroid is a steroid having a 16-alkyl-estrane skeleton.

23. A composition according to claim 1, wherein said steroid is a steroid having a 17-deoxy-estrane skeleton.

24. A composition according to claim 1, wherein said steroid is a steroid having a 16-alkyl-androstane skeleton.

25. A composition according to claim 1, wherein said steroid is a steroid having a 17-deoxy-androstane skeleton.

26. A method for prevention or treatment of thrombosis in a mammal, which comprises administering to said mammal an effective amount of a steroid having antithrombotic acitivty or a pharmaceutically acceptable salt thereof.

27. A method according to claim 26, wherein said steroid is a steroid having a C_20-21 steroid skeleton.

28. A method according to claim 26, wherein said steroid is a steroid having a pregnane skeleton, in which the angular methyl group at the position 10 may be a hydrogen atom.

29. A method according to claim 26, wherein said steroid is a steroid having a pregnane skeleton.

30. A method according to claim 26, wherein said steroid is a steroid having a 17α-H-pregnane skeleton.

31. A method according to claim 26, wherein said steroid is a steroid having a 17α-H-pregnane skeleton which is oxygenated at the positions 3, 20 and 21.

32. A method according to claim 26, wherein said steroid is a steroid having a 21-hydroxy-17α-H- pregnane- 20-one structure which is oxygenated at the position 3, said hydroxyl group being unsubstituted or substituted.

33. A method according to claim 26, wherein said steroid is a steroid having a 3,21-dihydroxy-17o- H- pregnan-20-one or 21-hydroxy-17α-H-pregn-4-ene- 3,20- dione structure, each of said hydroxyl groups being unsubstituted or substituted.

34. A method according to claim 26, wherein said steroid is a steroid having a 3,21-dihydroxy-17α-H- pregnan-20-one structure, each of said hydroxyl groups being unsubstituted or substituted.

35. A method according to claim 26, wherein said steroid is a steroid having a 21-hydroxy- 17α-H-pregn-4- ene-3,20-dione structure, said hydroxyl group being unsubstituted or substituted.

36. A method according to claim 26, wherein said steroid is a steroid having an 11-nonoxygenated 3,21- dihydroxy-17α-H-pregnan-20-one or 11-nonoxygenated 21- hydroxy-17α-H-pregn-4-ene- 3 , 20-dione structure, each of said hydroxyl groups being unsubstituted or substituted.

37. A method according to claim 26, wherein said steroid is a steroid having an 11-nonoxygenated 3,21- dihydroxy-17α-H-pregnan-20-one structure, each of said hydroxyl groups being unsubstituted or substituted.

38. A method according to claim 26, wherein said steroid is a steroid having an 11-nonoxygenated 21- hydroxy-17α-H-pregn-4-ene-3, 20-dione structure, said hydroxyl group being unsubstituted or substituted.

39. A method according to claim 26, wherein said steroid is desoxycorticosterone, 3,21-dihydroxypregnan- 20-one or a glucuronide thereof.

40. A method according to claim 26, wherein said steroid is desoxycorticosterone.

41. A method according to claim 26, wherein said steroid is 3-glucurono-21-hydroxypregnan- 20-one.

42. A method according to claim 26 wherein, said steroid is a steroid having a C_18-21, steroid skeleeton.

43. A method according to claim 26, wherein said steroid is a steroid having a pregnane skeleton, an estrance skeleton or an androstane skeleton.

44. A method according to claim 26, wherein said steroid is a steroid having an estrane skeleton.

45. A method according to claim 26, wherein said steroid is a steroid having an andostane skeleton.

46. A method according to claim 26, wherein said steroid is a steroid having a 16-alkyl-estrane skeleton.

47. A method according to claim 26, wherein said steroid is a steroid having a 17-deoxy-estrane skeleton.

48. A method according to claim 26, wherein said steroid is a steroid having a 16-alkyl-androstane

skeleton.

49. A method according to claim 26, wherein said steroid is a steroid having a 17-deoxy-androstane

skeleton.

50. A pharmaceutical composition for prevention or treatment of thrombosis comprising an effective amount of a steroid possessing anti-thrombotic activity or a pharmaceutically acceptable salt thereof. This application is a continuation-in-part of my earlier co-pending commonly owned U.S. patent application S.N. 265,590 filed November 1, 1988, which is hereby incorporated by reference. This invention was made, at least in part, using funds from the United States

Government, and the Government has certain rights in the invention.