WO1997041867A1 - Use of steroid compounds to prevent non-cancerous tissue growth - Google Patents

Abstract

Compounds for use in preventing non-cancerous tissue growth are disclosed. Pharmaceutical compositions of the compounds and methods for their use in preventing non-cancerous tissue growth are disclosed.

Description

IN THE UNTIED STATES PATENT AND TRADEMARK CΦΪΪCE

USE OF STEROID COMPOUNDS TO PREVENT NON-CANCEROUS TISSUE GROWTH

Priority is claimed from the provisional application, U.S. Patent Application Serial No. 60/019060, filed May 9, 1996.

Field of the Invention

This invention relates to compounds and their use in methods and compositions for preventing and treating diseases in mammals, particularly humans, in which non-cancerous tissue growth plays a pathogenic role.

Description of Related Art

Steroids functioning to inhibit angiogenesis in the presence of heparin or specific heparin fragments are disclosed in Crum, et al., A New Class of Steroids Inhibits

Angiogenesis In The Presence of Heparin or Heparin Fragment, Science, 230, pp. 1375- 1378 (December 20, 1985). The authors refer to such steroids as "angiostatic" steroids. Included in the new class of steroids found to be angiostatic are cortisol, cortexolone, and several dihydro and tetrahydro derivatives. In a follow up study directed to testing a hypothesis as to the mechanism by which the steroids inhibit angiogenesis, it was shown that heparin/angiostatic steroid compositions caused dissolution of the basement membrane scaffolding to which anchorage dependent endothelia are attached resulting in capillary involution; see, Ingber, et al. A Possible Mechanism for Inhibition of Angiogenesis by Angiostatic Steroids: Induction of Capillary Basement Membrane Dissolution, Endocrinology 119, pp. 1768-1775 (1986).

A group of tetrahydro angiostatic steroids useful in inhibiting angiogenesis is disclosed in International Patent Application WO 87/02672 (Aristoff et al.). The compounds are disclosed for use in treating head trauma, spinal trauma, septic or traumatic shock, stroke, and hemorrhagic shock. In addition, the patent discusses the utility of these compounds in embryo implantation and in the treatment of cancer, arthritis, and arteriosclerosis. Some of the steroids disclosed in Aristoff, et al. are disclosed in U.S. Patent No. 4,771,042 in combination with heparin or a heparin fragment for inhibiting angiogenesis in a warm blooded animal.

Compositions of hydrocortisone, "tetrahydrocortisol-S," and U-72,745G, each in combination with a beta cyclodextrin, have been shown to inhibit corneal neovascularization: Li, et al., Angiostatic Steroids Potentiated by Sulphated Cyclodextrin Inhibit Corneal Neovascularization, Investigative Ophthalmology and Visual Science, Vol. 32, No. 11, pp. 2898-2905 (October, 1-991). The steroids alone reduce neovascularization somewhat but are not effective alone in effecting regression of neovascularization.

Some of the compounds of the present invention are disclosed in commonly owned patent application WO 93/10141, for controlling neovascularization and ocular hypertension.

Currently, glucocorticoids or surgical removal of tissue growth are used to try and control disease states associated with scar formation and non-cancerous tissue growth. However, neither approach has proved very effective and there is a need for methods to treat persons with such disease states. The use of the compounds of the present invention fill this need. Summary of the Invention

This invention is directed to compounds useful for treating persons with diseases in which non-cancerous tissue growth, including scar formation, plays a pathogenic role. In particular, the compounds are useful for treating pterygium (primary and recurrent), glaucoma filtration bleb failure, hyperkeratosis, cheloid formation, polyp formation and wound healing conditions with excessive scar formation.

The invention encompasses methods for controlling these diseases through the systemic or local administration of the compositions of the compounds disclosed herein.

Detailed Description of Prefetrcd Embodiments

The compounds of the present invention have the following formula:

Structure [A] Structure^]

wherein R, is H, β-CH₃ or β-QH,;

R₂ is F, CcrC,, double bond, C₉-C_n epoxy, H or -Cl;

R₃ is H, OR₂₆, OC(=0)R₂₇, halogen, Q-C,, double bond, Q-C,, epoxy, O, -OH, -O- alkyl(C,-C₁₂), -OC(=0)alkyl(C,-C₁₂), -OC(=0)ARYL, -OC(K))N(R)₂ or -OC(=θpR₇, wherein ARYL is furyl, thienyl, pyrrolyl, or pyridyl and each of said moieties is optionally substituted with one or two (C,-C₄)alkyl groups, or ARYL is -(CH₂)_rphenyl wherein f is 0 to 2 and the phenyl ring is optionally substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, alkyl(C,-C₃), alkoxy(C,-C₃), thioalkoxy-(C_rC₃), C1₃C-, F₃C-, -

NH₂ and -NHCOCH₃ and R is hydrogen, alkyl (C,-C₄), or phenyl and each R can be the same or different, and R₇ is ARYL as herein defined, or aIkyl(C]-C₁₂);

R, is H, CH₃, Cl or F; Rs is H, OH, F, Cl, Br, CH₃, phenyl, vinyl or allyl;

R* is H or CH₃;

Rt, is CH₂CH₂OR₂₆, CH₂CH₂0C(=O)R₂₇, H, OH, CH₃, F, =CH₂, CH₂C(O)0R_2s, OR₂₆,

0(C=0)R₂₇, or 0(C=0)CH₂(C=0)OR₂₆;

R,₀ is -C≡CH, -CH=CH₂, CH₂OH, halogen, CN, N₃, OR₂₆, 0C(=O)R₂₇, H, OH, CH₃ or R₁₀ forms a second bond between positions C-16 and C-17;

R,₂ is H or forms a double bond with R, or R,₄;

R₁₃ is halogen, OR₂₆, OC(0)R₂₇, NH₂, NHR₂₆, NHC(0)R₂₇, N(R₂₆)₂, NC(=0)R₂₇, N₃, R

-OH O, -0-P(=0)(OH)₂, or -0-C(<))-(CH₂)₍COOH where t is an integer from 2 to 6;

R₁₄ is H or forms a double bond with R₁₂; R₁₅ is H, =0 or -OH;

R₂₃ is -OH,

-OP(0)-(OH)₂, -0-C(=0)-(CH₂)_tCOOH or with R_]0 forms a cyclic phosphate wherein t is an integer from 2 to 6; and R,, is -Y-(CH₂)_n-X-(CH₂)_m-S0₃H,

-Y-(CH₂)_p-X-(CH₂)_q-NR₁₆R₁₇ or -Z(CH₂)_rQ, wherein Y is a bond or -O-; Y is a bond, -0-, or -S-; each of X and X is a bond,- CON(R₁₈)-, -N(R₁₈)CO-, -0-, -S-, -S(0>, or -S(0₂)-; R₁₈ is hydrogen or alkyl (C,-C₄); each of R,₆ and R₎₇ is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R₁₆ and R_I7 taken together with the nitrogen atom to which each is attached forms a monocyclic heterocycle selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N(lower)alkyl-piperazino wherein alkyl has from 1 to 4 carbon atoms; n is an integer of from 4 to 9; m is an integer of from

1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5;

Z is a bond or -O-; r is an integer of from 2 to 9; and Q is one of the following:

(1) -R₁₉-CH₂COOH wherein R₁₉ is -S-, -S(O)-, -S(0)r, -SO^R )-, or N(R_2ϋ) SO^; and R₂₀ is hydrogen or lower alkyl-(C_rC₄); with the proviso that the total number of carbon atoms in R₂₀ and (CH₂)_r is not greater than 10; or

(2) -CO-COOH; or

(3)

is H, CH₃, -CH₂COOH, - CH₂CH₂COOH, -CH₂OH, -CH₂SH, -CH₂CH₂SCH₃, or -CH₂Ph-OH wherein Ph-OH is p-hydroxyphenyl; or R₂₁ is CH₃ and R^ is H; or R₂₁ and R^ taken together are -CH₂CH₂CH₂-; or

taken together is -NHCH₂CONHCH₂COOH; and pharmaceutically acceptable salts thereof; with the proviso that except for the compound wherein R, is -CH₃, R₂ and R₃ taken together form a double bond between positions 9 and 11, R₄ and R , are hydrogen, R₁₂ and R₎₄ taken together form a double bond between positions 4 and 5, R_$ is oc-F, Rg is β-CH₃, R₁₀ is OG-OH, R₁₃ and R₁₅ are =0 and R_B is -OP(0)-(OH)₂, R_I3 is =0 only when R with R₁₀ forms the above described cyclic phosphate. R₂₄ = C, Q-C_j double bond, O; R₂₅ = CCR.sJCHrll_B, OH, OR₂₆, OC(=0)R₂₇, R₂₆, COOH, C(=0)OR₂₆,

CHOHCH.OH, CHOHCH₂OR₂₆, CHOHCH₂OC(0)R₂₇, CH₂CH₂OH, CH₂CH₂OR₂₆, CH₂CH₂0C(=O)R₂₇, CH₂CN, CH₂N₃, CH₂NH₂,

CH.NHR , CH₂N(R₂₆)₂, CH₂OH, CH₂OR₂₆, CH₂0(CO)R₂₇, CH₂0(P=0)(OH)₂,

CH₂0(P=O)(0R₂₆)₂, CH₂SH, CH₂S-R₂₆, CH₂SC(=C)R₂₇,

CH₂NC(=0)R₂₇, C(O)CHR₂₈0R₂₆, C(=0)CHR_2gC(=0)R₂₇ or R_]0 and

R₂₅ taken together may be =C(R₂₈)₂, that is, an optionally alkyl substituted methylene group; wherein R₂₆ = C,-C₆ (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl); R₂₇ = R₂₆ + OR₂₆; R_2g = H, C1-C6 (alkyl, branched alkyl, cycloalkyl).

Unless specified otherwise, all substituent groups attached to the cyclopentanophenanthrene moiety of Structures [A] and [B] may be in either the alpha or beta position. Additionally, the above structures include all pharmaceutically acceptable salts of the compounds. Preferred compounds are:

1-Nor-5β-pregnan-3oςl7oς20-triol- -acetate

1-Nor-5β-pregnan-3oς 17β,20-triol 20-Acetamido-21-nor-5β-pregnan- 3oςl7oodiol-3-acetate

β-Azido-5β-pregnan-l 1^17oς21-triol- 17oc-Ethyny l-5( 10)-estren- 0-one-21 -acetate 17β-ol-3-one

1 -Nor-5oc-pregnan-3oς 17β,20-triol 21 oo-Methyl-5^-pregnan-3oς 11 ft 17oς 2 l-tetrol-20-one-21 -methyl ether

7oc-Ethynyl- 1 ,3,5( 10)-estratrien- 4,9( 11 >Pregnadien- 17oς21 -diol-3,20- ,17β-diol dione-21 -acetate

4,9( 11 >Pregnadien- 17oς21 - diol-3,20-dione

Most preferred compounds are:

4,9(1 1 >Pregnadien- 17oς21 -diol-3,20-dione-21 -acetate

4,9( 1 1 >Pregnadien- 17oς21 -diol-3,20-dione

21 -Nor-5β-pregn- 17(20)-en-3oς 16-diol-3-acetate- 16-(0-methyl)malonate

21 -Nor-5β-pregnan-3oς 17oς20-triol-3-acetate

21 -Nor-5oG-pregnan-3oς 17oς20-triol-3-phosphate

4-Androstcn-3-one-17β-carboxylic acid

The compounds of the present invention are useful in preventing and treating persons with diseases in which non-cancerous tissue growth plays a pathogenic role. In particular, the compounds are useful in treating persons suffering from pterygium (primary and recurrent), glaucoma filtration bleb failure, hyperkeratosis, cheloid formation, polyp formation, and post-surgical wound healing conditions with excessive scar formation, such as burns and cuts, including surgical cuts.

The compounds of the present invention may be incorporated in various formulations for delivery. The type of formulation (topical or systemic) will depend on the site of disease and its severity. For administration to the eye, topical formulations can be used and can include ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, buffers, sodium chloride, and water to form aqueous sterile ophthalmic solutions and suspensions. In order to prepare sterile ophthalmic ointment formulations, a compound is combined with a preservative in an appropriate vehicle, such as mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations comprising the compounds of the present invention can be prepared by suspending a compound in a hydrophilic base prepared from a combination of, for example, Carbachol-974P (a carboxy vinyl polymer available from the BF Goodrich Company) according to published formulations for analogous ophthalmic preparations. Preservatives and antimicrobial agents may also be incorporated in such gel formulations. Systemic formulations can also be used, for example, orally ingested tablets, suppositories, transdermal patches, and formulations for intraocular injection.

The specific type of formulation selected will depend on various factors, such as the compound or its salt being used, the dosage frequency, and the disease being treated. Topical aqueous solutions, suspensions, ointments, creams and gels are the preferred dosage forms for the treatment of pterygium, hyperkeratosis, and cheloid and polyp formation. Topical ophthalmic formulations are suitable for preventing glaucoma filtration bleb failure or scar formation associated with ophthalmic surgery. The compound will normally be contained in these formulations in an amount from about 0.01 to about 10.0 weight/percent. Preferable concentrations range from about 0.1 to about 5.0 weight/percent. Thus, for topical administration, these formulations are delivered to the disease site one to six times a day, depending on the routine discretion of the skilled clinician. Systemic administration, for example, in the form of tablets or suppositories is useful for the treatment of polyp formation. Tablets containing 10-1000 mg of a compound can be taken 2-3 times per day depending on the discretion of the skilled clinician.

The following examples illustrate formulations of the present invention, but are in no way limiting. Example 1

Topical 1 ocular suspension

Ingredient Amount rwt.%ϊ

Compound 0.01 - 5.0

Tyloxapol 0.01 to 0.05

HPMC 0.5

Benzalkonium chloride 0.01

Sodium chloride 0.8

Edetate Disodium 0.01

NaOH/HCl q.s. pH 7.4

Purified Water q.s. 100 mL

The formulation is prepared by first placing a portion of the purified water into a beaker and heating to 90°C. The hydroxypropylmethylcellulose (HPMC) is then added to the heated water and mixed by means of vigorous vortex stirring until all of the HPMC is dispersed. The resulting mixture is then allowed to cool while undergoing mixing in order to hydrate the HPMC. The resulting solution is then sterilized by means of autoclaving in a vessel having a liquid inlet and a hydrophobic, sterile air vent filter.

The sodium chloride and the edetate disodium are then added to a second portion of the purified water and dissolved. The benzalkonium chloride is then added to the solution, and the pH of the solution is adjusted to 7.4 with 0.1M NaOH/HCl. The solution is then sterilized by means of filtration.

The Compound, 4,9(1 l)-Pregnadien-17oς21-diol-3,20-dione-21 -acetate, is sterilized by either dry heat or ethylene oxide. If ethylene oxide sterilization is selected, aeration for at least 72 hours at 50°C is necessary. The sterilized Compound is weighed aseptically and placed into a pressurized ballmill container. The tyloxapol, in sterilized aqueous solution form, is then added to the ballmill container. Sterilized glass balls are then added to the container and the contents of the container are milled aseptically at 225 rpm for 16 hours, or until all particles are in the range of approximately 5 microns.

Under aseptic conditions, the micronized drug suspension formed by means of the preceding step is then poured into the HPMC solution with mixing. The ballmill container and balls contained therein are then rinsed with a portion of the solution containing the sodium chloride, the edetate disodium and benzalkonium chloride. The rinse is then added aseptically to the HPMC solution. The final volume of the solution is then adjusted with purified water and, if necessary, the pH of the solution is adjusted to pH 7.4 with NaOH/HCl. The formulation will be given topically, in a therapeutically effective amount. In this instance, the phrase "therapeutically effective amount" means an amount which is sufficient to substantially prevent or reverse any ocular neovascularization. The dosage regimen used will depend on the nature of the neovascularization, as well as various other factors such as the patient's age, sex, weight, and medical history.

Example 2

Tablet: 10-1000 mg of a compound of the present invention with inactive ingredients such as starch, lactose and magnesium stearate can be formulated according to procedures known to those skilled in the art of tablet formulation.

Example 3

FORMULATION FOR STERILE INTTMOCULAR INJECΗON

each mL contains:

4,9(1 l>Pregnadien-17oς21-diol-3,20-dione-21-acetate 10-100 mg

Sodium Chloride 7.14 mg

Potassium Chloride 0.38 mg

Calcium chloride dihydrate 0.154 mg Magnesium chloride hexahydrate 0.2 mg

Dried sodium phosphate 0.42 mg

Sodium bicarbonate 2.1 mg

Dextrose 0.92 mg Hydrochloric acid or sodium hydroxide to adjust pH to approximately 7.2

Water for injection

Example 4

FORMULATION FOR TOPICAL OCULAR SOLUTION

21 -Nor-5oG-pregnan-3oς 17oc-20-triol 1.0% -3-phosphate Benzalkonium chloride 0.01%

HPMC 0.5%

Sodium chloride 0.8%

Sodium phosphate 0.28%

Edetate disodium 0.01% NaOH/HCl q.s. pH 7.2

Purified Water q.s. 100 mL Example 5

FORMULATION FOR TOPICAL DERMATOLOGICAL USE

Cream: 4,9(1 l)-Pregnadien-17α,21-diol-3-20-dione 1 mg/g in cream base of purified water, emulsifying wax, propylene glycol, stearic acid, isopropyl palmitate, synthetic beeswax, polysorbate 60, potassium sorbate, sorbic acid, propyl gallate, citric acid, and sodium hydroxide

Ointment: 1 mg/g of a compound of the present invention in base of mineral oil and polyethylene

Example 6

FORMULATION FOR SUPPOSITORY

10-500 mg of a compound of the present invention with the following inactive ingredients: glycerin, butylated hydroxytoluene, butylated hydroxyanisole, edetic aςid, polyethylene glycol, and sodium chloride

Claims

We qajm:

1. A composition for treating diseases in mammals in which non-cancerous tissue growth plays a pathogenic role, comprising a therapeutically effective amount of a compound of the following formula:

Structure [A] Structure^]

wherein R, is H, β-CH₃ or ft-Cft;

R₂ is F, C₉-C₁₁ double bond, Q-C,, epoxy, H or -Cl;

R₃ is H, OR^, OC(=0)R₂₇, halogen, Q-C,, double bond, (VC,, epoxy, O, -OH, -O- alkyl(C,-C₁₂), -0C(=O)alkyl(C_rC₁₂), -0C(=O)ARYL, -OC(=0)N(R)₂ or -OC(=0)OR₇, wherein ARYL is furyl, thienyl, pyrrolyl, or pyridyl and each of said moieties is optionally substituted with one or two (C,-C₄)alkyl groups, or ARYL is -(CH₂)_rphenyl wherein f is 0 to 2 and the phenyl ring is optionally substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, alkyl(C_rC₃), alkoxy^-Q), thioalkoxy^Q-Q), C1₃C-, F₃C-, -

NH₂ and -NHCOCH, and R is hydrogen, alkyl (C,-C₄), or phenyl and each R can be the same or different, and R₇ is ARYL as herein defined, or alkyl(C_rC₁₂);

R, is H, CH₃, Cl or F;

Rs is H, OH, F, Cl, Br, CH₃, phenyl, vinyl or allyl;

Rs is H or CH₃;

R, is CH₂CH₂OR₂₆, CH₂CH₂OC(=0)R₂₇, H, OH, CH₃, F, =CH₂, or CH₂C(=0)OR_2g, OR₂₆,

0(C=O)R₂₇, or 0(CK))CH₂(C=0)OR₂₆;

R_]0 is -C^CH, -CH=CH₂, CH₂OH, halogen, CN, N₃, OR₂₆, OC(=0)R₂₇, H, OH, CH₃ or R,₀ forms a second bond between positions C-16 and C-17;

R,₂ is H or forms a double bond with R, or R,₄;

R₁₃ is halogen, OR₂₆, 0C(O)R₂₇, NH₂, NHR^, NHC(=0)R₂₇, N(R₂₆)₂, NC(=0)R₂₇, N₃, H,

-OH, =0, -0-P(=0)(OH)₂, or -0-C(=0)-(CH₂)_tCOOH where t is an integer from 2 to 6; R,₄ is H or forms a double bond with R₁₂; R₁₅ is H, =0 or -OH;

R_M is -OH, 0-C(0>R,„ -OP(0)-(OH)₂, -0-C(=0)-(CH₂)_!COOH or with R,₀ forms a cyclic phosphate wherein t is an integer from 2 to 6; and R_u is -Y-(CH₂)_π-X-(CH₂)_m-S0₃H, -Y-(CH₂)_p-X-(CH₂)_q-NR₁₆R₁₇ or -Z(CH₂)_rQ, wherein Y is a bond or -0-; Y is a bond, -0-, or -S-; each of X and X is a bond,-

CON(R₁₈)-, -N(R,₈)Cα, -0-, -S-, -S(O)-, or -S(0₂>; R₁₈ is hydrogen or alkyl (C,-C₄); each of R_l6 and R,₇ is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R,₆ and R,₇ taken together with the nitrogen atom to which each is attached forms a monocyclic heterocycle selected from pyrrolidino, piperidino, morpholino, thiomoφholino, piperazino or N(lower)alkyl-piperazino wherein alkyl has from 1 to 4 carbon atoms; n is an integer of from 4 to 9; m is an integer of from

1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5;

Z is a bond or -0-; r is an integer of from 2 to 9; and Q is one of the following:

(1) -R₁₉-CH₂COOH wherein R,₉ is -S-, -S(O)-, -S(0)₂-, -SO₂N(R₂₀>, or N(R₂₀) S0₂-; and R₂₀ is hydrogen or lower alkyKQ-Q); with the proviso that the total number of carbon atoms in R₂₀ and (CH₂)_r is not greater than 10; or

(2) -CO-COOH; or

(3) CON(R₂,)CH(R₂₂)COOH wherein R₂, is H and R_Ώ is H, CH₃, -CH₂COOH, - CH₂CH₂COOH, -CH₂OH, -CH₂SFI, -CH₂CH₂SCH₃, or -CH₂Ph-OH wherein Ph-OH is p-hydroxyphenyl; or R_2I is CH₃ and R^ is H; or R₂₁ and R^ taken together are -CH₂CH₂CH₂-; or -N(R₂,)CH(R₂₂)COOH taken together is -NHCH₂CONHCH₂COOH; and pharmaceutically acceptable salts thereof; with the proviso that except for the compound wherein R, is -CH₃, R₂ and R₃ taken together form a double bond between positions 9 and 11, 1^, and R_$ are hydrogen, R,₂ and

R,₄ taken together form a double bond between positions 4 and 5, R^ is -F, R_g is -CH₃, R,₀ is -OH, R₁₃ and R₁₅ are =0 and R₂₃ is -OP(0>(OH)₂, R₁₃ is =0 only when R^ with

R₁₀ forms the above described cyclic phosphate;

R₂₄ = C, Q-Q double bond, O;

R₂₅ = OR^CH^, OH, OR,,, 0C(O)R₂₇, Raj, COOH, C(O)0R₂₆, CHOHCH₂OH, CHOHCH₂OR₂₆, CHOHCH₂OC(=0)R₂₇, CH₂CH₂OH,

CH₂CH₂OR₂₆, CH₂CH₂OC(=0)R₂₇, CH₂CN, CH₂N₃, CH₂NH₂, CH₂NHR₂₆, CH₂N(R₂₆)₂, CH₂OH, CH₂OR₂₆, CH₂0(C=O)R₂₇, CH₂0(P=O)(0H)₂, CH₂0(P=O)(0R₂₆)₂, CH₂SH, CH₂S-R₂₆, CH₂SC(=0)R₂₇, CH₂NC(=C)R₂₇, C(=0)CHR₂₈OR₂₆, C(O)CHR₂₈C(=0)R₂₇ or R,₀ and R₂₅ taken together may be =C(R₂₈)₂, that is, an optionally alkyl substituted methylene group; wherein R₂₆ = C,-C₆ (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl); R₂₇ = R₂₆

+ OR₂₆; R₂₈ = H, C1-C6 (alkyl, branched alkyl, cycloalkyl);

2. The composition of Claim 1 wherein the compound is selected from the group consisting of 21 -Nor-5β-pregnan-3oς 17oς20-triol; 2 l-Nor-5β-pregn- 17(20)en-3oς 16-diol-3- acetate- 16-(0-methyl)malonate; 21 -Nor-5β-pregnan-3oς 17oς20-triol-3-acetate; 21 -Nor-5<x- pregnan-3oςl7oς20-triol-3 phosphate; 4-Androsten-3-one-17β-carboxylic acid; 21-Nor-5β- pregn- 17(20)en-3oς 16-diol; 21 -Nor-5β-ρregnan-3oς 17β20-triol; 20-Acetamido-21 -nor-5β- pregnan-3oς 17oc-diol-3-acetate; 3β-Azido-5β-pregnan- 11 β, 17oς21 -triol-20-one-21 -acetate; 17oc-Ethynyl-5( 10)-estren- 17β-ol-3-onς; 21 -Nor-5oc-pregnan-3oς 17β20-triol; 21 oc-Methyl- 5β-pregnan-3oς 11 β, 17oς 21 -tetrol-20-one-21 -methyl ether; 17oc-Ethynyl- 1,3,5(10)- estratrien-3,17β-diol; 4,9(1 l)-Pregnadien-17oς21-diol-3,20-dione-21-acetate; and 4,9(11)- Pregnadien- 17oς21 -diol-3,20-dione.

3. The composition of Claim 2 wherein the compound is 4,9(1 l)-Pregnadien-17oς21- diol-3,20-dione-21 -acetate.

4. The composition of Claim 1 wherein the compound concentration is 0.01 - 10.0 Wt.%.

5. The composition of Claim 4 wherein the concentration is 0.1 - 5.0 wt.%.

6. A method for treating diseases in mammals in which non-cancerous tissue growth plays a pathogenic role, which comprises: administering a therapeutically effective amount of the composition of Claim 1.

7. The method of Claim 6 wherein the compound is selected from the group consisting of 21-Nor-5β-pregnan-3oςl7oς20-triol; 21-Nor-5β-ρregn-17(20)en-3oςl6-diol-3- acetate- 16-(0-methyl)malonate; 21 -Nor-5β-pregnan-3 °ς 17oς20-triol-3-acetate; 21 -Nor-5oc- pregnan-3oςl7oς20-triol-3 phosphate; 4-Androsten-3-one-17β-carboxylic acid, 21-Nor-5β- pregn- 17(20)en-3oς 16-diol; 21 -Nor-5 β-pregnan-3oς 17β,20-triol; 20-Acetamido-21 -nor-5β- pregnan-3oςl7oG-diol-3-acetate; 3β-Azido-5β-pregnan-l lβ,17oς21-triol-20-one-21 -acetate; 17o&Ethynyl-5(l 0)-estren-l 7β-ol-3-one; 2 l-Nor-5o^pregnan-3oς 17ft20-triol; 21 ooMethyl- 5β-pregnan-3oς 11 β, 17oς 21 -tetrol-20-one-21 -methyl ether; 17ocEthynyl- 1,3,5(10), 4,9( 11 )- Pregnadien-17oς21-diol-3,20-dione-21-acetate; and 4,9(1 l)-Pregnadien-17oς21-diol-3,20- dione-estratrien-3, 17β-diol.

8. The method of Claim 7 wherein the compound is 4,9(11)-Pregnadien- 17oς21-diol- 3,20-dione-21 -acetate.

9. The method of Claim 6 wherein the non-cancerous tissue growth is selected from the group consisting of pterygium, glaucoma filtration bleb failure, hyperkeratosis, cheloid formation, polyp formation, and wound healing conditions.

10. The method of Claim 6 wherein the compound concentration is 0.01 - 10 wt.%.

11. The method of Claim 10 wherein the compound concentration is 0.1 to 5.0 wt.%.

12. The method of Claim 6 wherein the composition is administered topically to the disease site.

13. The method of Claim 6 wherein the composition is administered systemically.