MXPA00005276A - Angiostatic agents and compositions for controlling ocular hypertension - Google Patents

Abstract

Compositions of angiostatic agents for treating GLC1A glaucoma and methods for their use are disclosed.

Description

ANGIOESTATIC AGENTS AND COMPOSITIONS FOR CONTROLLING EYE HYPERTENSION This is a continuation-in-part of an application entitled "Angiostatic Steroids and Methods and Compositions for Controlling Ocular Hypertension" (Angioesthetic Steroids and Methods and Compositions to Control Ocular Hypertension) presented in December 15, 1997, which is a continuation of the US patent application Serial No. 08 / 643,387 filed on May 6, 1996 (granted December 16, 1997, Patent No. 5,698,545) which is a continuation of the patent application of the E.TJ.A. Serial No. 08 / 349,342 filed on December 2, 1994, which is a continuation of the US patent. No. 5,371,078, issued December 6, 1994, which is a continuation-in-part of the U.S. patent application. Serial No. 07 / 559,123 filed July 27, 1990, which in turn is a continuation-in-part of the U.S. patent application. Serial No. 07 / 419,226 filed October 10, 1989, which is a continuation of the U.S. patent application. Serial No. 07 / 264,918 filed on October 31, 1988 (U.S. Patent No. 4,876,250). Background of the Invention Field of Invention This invention is directed to the use of angiostatic agents to treat glaucoma or ocular hypertension resulting from altered expression of the GLC1A gene (below Iq glaucoma or GLC1A) in an individual. Description of Related Art Glaucomas are a heterogeneous group of optic neuropathies characterized by the coping of the optic nerve head, thinning of the retinal nerve fiber layer due to loss of retinal ganglion cells and specific pathognomonic changes in visual fields. Elevated intraocular pressure (IOP) is a very important risk factor for the development of most common forms of glaucoma (Sommer A, et al., "Relationship Between Intraocular Pressure and Primary Open Angle Glaucoma Among White and Black Americans"). Relationship Between Intraocular Pressure and Primary Open-angle Glaucoma Among White and Black Americans) Arch. Ophthalmol., 109: 1090-1095 (1991)). A family history of glaucoma is also an important risk factor for the development of glaucoma. It appears that a significant portion of glaucoma is inherited (or at least the risk of developing glaucoma is inherited) although it is often difficult to establish clear patterns of inheritance for most glaucoma due to the onset of advanced disease in life, and in the slowly progressive clinical manifestations of the disease. Despite these problems, a number of families with heritable forms of glaucoma have been identified and these families have been used to map a variety of glaucoma genes (Sheffield, et al. "Genetic Linkage of Familial Open Angle Glaucoma to Chromosome Iq21-q31"(Genetic Link of Family Open Angle Glaucoma to Chromosome Iq21-q31), Nature Genetics, 4: 47-50 (1993), Sarfarazi et al. Assignment of a Locus (GLC3A) for Primary Congenital Glaucoma (Buphthalmols) to 2p21 and Evidence for Genetic Heterogeneity "(Assignment of a Site (GLC3A) for Primary Congenital Glaucoma (Buphthalmos) at 2p21 and Evidence for Genetic Heterogeneity), Genomics, 30: 171-177 (1995), Akarsu, and collaborators" A Second Locus (GLC3B ) for Primary Congenital Glaucoma (Buphthalmos) Maps to the lp36 Region "(A Second Site (GLC3B) for Maps of Primary Congenital Glaucoma (Buphthalmos) to Region lp36), Human Molecular Genetics, 5 (8): 1199-1203 (1996 ); Stoilova and collaborators, "Localization of a Locus (GLC1B) for Adult-Onset Primary Open Angle Glaucoma to the 2nd Region" (Location of a Site (GLC1B) for Primary Open Angle Glaucoma of Adults to Region 2cen-ql3 ), Genomics, 36: 142-150 (1996); Wirtz et al., "Mapping a Gene for Adult-Onset Primary Open-Angle Glaucoma to Chromosome 3q" (Mapping of a Primary Open-Ended Glaucoma Gene in Adults to Chromosome 3q), Am. J. Hum. Genet., 60: 296-304 (1997); Andersen, et al., "A Gene Responsible for the Pigment Dispersion Syndrome Maps to Chromosome 7q35-q36" (A Responsible Gene for Pigment Dispersion Syndrome Maps to Chromosome 7q35-q36), Arch. Ophthalmol. 115: 384-388 (1997). The first mapped glaucoma gene (GLC1A) was in a large family with autosomal dominant inherited juvenile glaucoma (JG = Juvenile Glaucoma). This disease is characterized by an early onset of the disease (close to 20 years of age at ventricular), relatively high IOPs and general resistance to therapy for conventional pharmacological IOP reduction. The GLC1A gene was mapped by positional cloning and chromosome binding analysis Iq22-q25 (Sheffield et al., Id.), And a number of other groups have confirmed the lq location of this juvenile glaucoma gene (Richards, et al., "Mapping of a Gene for Autosomal Dominant Juvenile-Onset Open-Angle Glaucoma to Chromosome Iq "(Mapping of a Genome for Autosomal Dominant Juvenile Home of Open Angle Glaucoma to Chromosome lq), Am. J. Hum. Genet., 54: 62-70 (1994); Morissette, et al.," A Common Gene for Juvenile and Adult-Onset Primary Open-Angle Glaucoma Confined on Chromosome lq "(A Common Gen for Juvenile and Adult Start of Open Angle Glaucoma Primary Confined on Chromosome lq), Am. J. Hum. Genet., 56: 1431-1442 (1995); Wiggs, et al., "Genetic Linkage of Autosomal Dominant Juvenile Glaucoma to Iq21-q31 in Three Affected Pedigrees" (Genetic Link of Autosomal Dominant Juvenile Glaucoma to Iq21-q31 in Three Affected Pedigrees), Genomics, 21: 299- 303 (1994); Meyer et al. "Age-Dependent Penetrance and Mapping of t I Locus for Juvenile and Early-Onset Open-Angle Glaucoma on Chromosome lq (GLC1A) in a Frenen Family "(Site Age-Dependent Mapping and Penetration for Juvenile and Early Open-Ended Glaucoma Start on Iq Chromosome (GLC1A) in a French Family), Hum. Genet., 98: 567-571 (1996); Graff, et al. "Confirmation of Linkage to la21-31 in a Danish Autosomal Dominant Juvenile-Onset Glaucoma Family and Evidence of Genetic Heterogeneity" (Link Confirmation to lq21-31 in an Autosomal Dominant Juvenile Home of Glaucoma in Danish Family and Evidence from Genetic Heterogeneity), Hum. Genet., 96: 285-289 (1995). Glaucoma due to the GLC1A gene is often referred to as glaucoma lq. The GLC1A gene is identified to encode a 57 kD protein expressed in the trabecular network (TM) (Stone, et al., "Identification of a Gene That Causes Primary Open Angle Glaucoma" (Identification of a Primary Open Angle Glaucoma Generator ), Science, 275: 668-670 (1997) The expression of the GLC1A gene and the encoded protein TM is up-regulated by glucocorticoids (Polansky, et al., "Eicosanoid Production and Glucocorticoid Regulatory Mechanisms in Cultured Human Trabecular Meshwork Cells"). (Production of Eicosanoid and Glucocorticoid Regulatory Mechanism in Cells of the Trabecular Mesh Network in Cultured Human), The Ocular Effects of Prostaglandins and Other Eicosanoids (The Ocular Effects of Prostaglandins and Other Eicosanosides), pp. 113-138 (1989); Polansky, et al., "In Vitro Correlates of Glucocorticoid Effects on Intraocular Pressure" (In Vitro Correlations of Glucocorticoid Effects in Ocular Pressure ), Glaucoma Update IV (1991); and Polansky, and collaborators, "Cellular Pharmacology and Molecular Biology of the Trabecular Meshwork Inducible Glucocorticoid Response Gene Product " (Cellular Pharmacology and Molecular Biology of the Product Glucocorticoid Response Inducible by Trabecular Mesh), Ophthalmologica, 211: 126-139 (1997)). This TM protein is also known as (trabecular mesh-inducible glucocorticoid response) (TIGR = Trabecular Mesh Inducible Glucocorticoid Response) (Polansky, Id). The glucocorticoid induction of this TM protein has been suggested to be involved in the generation of glaucoma and ocular hypertension induced by glucocorticoid (Polansky, Id.). The GLC1A gene is expressed in other ocular tissues such as the ciliary epithelium (Ortego et al., "Cloning and Characterization of Subtracted cDNAs from a Human Ciliary Body Library Encoding TIGR, to Protein Involved in Juvenile Open Angle Glaucoma with Homology to Myosin and Olfactomedin "(Cloning and Characterization of cDNAs Subtracted from a Human Ciliary Body Library Encoding TIGR, a Protein Involved in Juvenile Open Angle Glaucoma with Homology to Myosin and Olfactomedin), FEBS Letters, 413: 349-353 (1997) and the Retina (Kubota et al., "A Novel Myosin-like Protein (Myocilin) Expressed in the Connecting Cilium of the Photoreceptor; Molecular Cloning, Tissue Expression, and Chromosomal Mapping "(A Novel Myosin-like Protein (Miocillin) Expressed in the Cylindrical Connector of the Photoreceptor: Molecular Cloning, Tissue Expression, and Chromosomal Mapping), Genomics, 41: 360-369 ((1997)) The gene is referred to by several names including GLC1A (Sheffield, above; Sunden, et al., "Fine Mapping of the Autosomal Dominant Juvenile Open Angle Glaucoma (GLC1A) Region and Evaluation of Candidate Genes" (Fine Mapping of the Glaucoma Region of Juvenile Autosomal Dominant Open Angle (GLC1A) and Candidate Genes Evaluation), Genome Research, 6: 862-869 (1996), Stone, et al., Above), TIGR (Polansky above: Ortego, above), and myocillin (Kubota, above) GLC1A mutations are not only responsible for juvenile glaucoma, but a significant subset of primary open angle glaucoma of adult onset (Stone, et al., above, Adam, et al., "Recurrent Mutations. in a Single Exon Encoding the Evolutionarily Conserved Olfactomedin-Homology Domain of TIGR in Familial Open-Angle Glaucoma "(Recurrent Mutations in a Single Exon that Codifies the Homology Domain of Olfactomedin Evolutionary Conserved TIGR in a Family Open Angle Glaucoma), Human Molecular Genetics, 6 (12): 2091-2097 (1997)). The glaucoma gene lq (GLC1A, TIGR) is the subject of the U.S. patent. No. 5,606,043, Nguyen et al., Issued on February 25, 1997. Glucocorticoids have been associated with the development of ocular hypertension and primary open-angle glaucoma (Kass, et al., "Corticosteroid-Induced Glaucoma" (Glaucoma Induced by Corticosteroid), In Ritch, R., Shields, MB, Krupin, T. (eds.) The Glaucomas (The Glaucoma), The CV Mosby Company, St. Louis, MO, pp. 1161-1168 (1989); DeSantis, and collaborators, "Dexamethasone-Induction of Ocular Hypertension in the Primate", (ARVO Abstracts, Invest. Ophthalmol, Vis. Sci., 31 (Suppl.): 99 (1990), Knepper, "Dexamethasone-Induction of Ocular Hypertension in the Primate." , et al., "Intraocular Pressure and Glycosaminoglycan Distribution in the Rabbit Eye: Effect of Age and Dexamethasone" (Distribution of Glycosaminoglycan and Intraocular Pressure in the Rabbit Eye: Effect of Age and Dexamethasone), Exp. Eye Res., 27: 567 -575 (1978); Francois, et al., "Ultrastructural and Mo rphometric Study of Corticosteroid Glaucoma in Rabbits "(Ultrastructural and Morphometric Study of Corticosteroid Glaucoma in Rabbits), Ophthalic Res., 16: 168-178 (1984); Lorenzetti, 0. J., "Effects of Coricosteroids on Ocular Dynamics in Rabbits" (Effects of Corticosteroids on Eye Dynamics in Rabbits), J. Pharmacol. Exp. Therap., 175: 763-772 (1970); and Zhan, et al., "Steroid Glaucoma: Corticosteroid-Induced Ocular Hypertension in Cats" (Steroid Glaucoma: Ocular Hypertension Induced by Corticosteroid in Cats), Exp. Eye Res., 54: 211-218 (1992)). Glaucoma patients with higher levels of endogenous glucocorticoid, cortisol (Rozsival, et al., "Aqueous") have also been reported.

Humour and Plasma Cortisol Levéis in Glaucoma and Cataract Patients "(Plasma Cortisol Levels and Aqueous Humor in Patients with Glaucoma and Cataracts), Current Eye Research, 1: 391-396 (1981), Ray, et al.," Plasma Cortisol in Glaucoma "(Plasma Cortisol in Glaucoma), Ann Ophthalmol., 9: 1151-1154 (1977), and Schwartz, et al.," Increased Plasma Free Cortisol in Ocular Hypertension and Open Angle Glaucoma "(Plasma-Free Cortisol Increased in Ocular Hypertension and Open Angle Glaucoma), Arch. Ophthalmol., 105: 1060-1065 (1987).) It is known that trabecular mesh cells have glucocorticoid receptors and that the binding of glucocorticoid with these receptors causes a change in expression of trabecular meshwork cell gene.Manifestations known for this change include a rearrangement of the cytoskeleton (Wilson, et al., "Dexamethasone Induced Ultrastructural Changes in Cultured Human Trabecular Meshwork Cells". estru.cturales Induced by Dexamethasone in Human Trabecular Mesh Cells Cultivated), Cur. Eye Res., 12: 783-793 (1993), and Clark, et al., "Glucocorticoid-Induced Formation of Cross-Linked Actin Networks in Cultured Human Trabecular Meshwork Cells " (Glucocorticoid Induced Formation of Actin Networks Interlaced in Human Trabecular Mesh Cells Cultivated), Invest. Ophthalmol. Vis. Sci., 35: 281-294 (1994)) and increased deposition of extracellular matrix material in trabecular mesh cells. As a result, the trabecular meshwork is "plugged" and unable to perform its most critical functions, that is to serve as a gate for the flow of aqueous humor from the anterior chamber of the eye. When the flow of aqueous humor out of the eye is reduced by the trabecular meshwork, the intraocular pressure of the eye is increased. If this state of elevated intraocular pressure is maintained or occurs frequently, the head of the optic nerve can be damaged resulting in loss of visual field. Loss of visual field is the distinctive symptom associated with glaucoma. Endogenous glucocorticoids may be responsible for producing changes in the trabecular network that lead to ocular hypertension and glaucoma. In summary, the GLC1A gene product can lead to the development of ocular hypertension and glaucoma in one of two ways: (1) mutations in GLC1A are responsible for the majorities of juvenile glaucoma forms and a subset of POAGs of adult onset or (2) exposure of some individuals to glucocorticoids leads to increased expression of GLC1A in TM, which causes resistance to increased outflow of aqueous humor and the development of ocular hypertension. The precise mechanism (s) responsible for the effects of GLClA in IOP are currently unknown.

Steroids that work to inhibit angiogenesis in the presence of heparin or specific heparin fragments are described in Crum, et al., "A New Class of Steroids Inhibits Angiogenesis in the Presence of Heparin or a Heparin Fragment" (A New Class of Steroids Inhibits Angiogenesis in the Presence of Heparin or a Fragment of Heparin), Science, 230: 1375-1378 (December 20, 1985). The authors refer to these steroids as "angioesthetic" steroids. Included within the new class of steroids that are angiostatic are dihydro and tetrahydro metabolites of cortisol and cortexolone. In a follow-up study aimed at testing a hypothesis regarding the mechanism by which steroids inhibit angiogenesis, it was shown that angioesthetic steroid / heparin compositions cause dissolution of the basement membrane structure, to which the dependent endotheliums are connected of anchorage, resulting in capillary involution; see, Ingber, and collaborators, "A Possible Mechanism for Inhibition of Angiogenesis by Angiostatic Steroids: Induction of Capillary Basement Membrane Dissolution" (A Possible Mechanism for Inhibition of Angiogenesis by Angioesthetic Steroids: Induction of Basal Capillary Membrane Dissolution), Endocrinology (Endocrinology) ), 119: 1768-1775 (1986).

A group of tetrahydro steroids useful for inhibiting angiogenesis is described in International Patent Application No. PCT / US86 / 02189, Aristoff, et al., (The Upjohn Company). The compounds are described for use in treating head trauma, spinal trauma, septic or traumatic shock, attack and hemorrhage shock. In addition, the patent application discusses the utility of these compounds in embryo implants and the treatment of cancer, arthritis and arteriosclerosis. The compounds are not described for ophthalmic use. Tetrahydrocortisol (THF) has been described for its use to reduce intraocular pressure (IOP = IntraOcular Pressure) of rabbits made hypertensive with only dexamethasone, or with dexamethasone / 5-beta-dihydrocortisol; see South, and collaborators, "Intraocular Hypotensive Effect of a Topically Applied Cortisol Metabolite: 3-alpha, 5-beta-tetrahydrocortisol" (Intraocular Hypotensive Effect of a Metabolite Cortisol Applied Topically: 3 -alpha, 5-beta-tetrahydrocortisol), Investigative Ophthalmology and Visual Science, 2B (May, 1987). The authors suggest that THF may be useful as an anti-glaucoma agent. In the patent of the U.S.A. No. 4,863,912, issued to Southren et al., On September 5, 1989, describe pharmaceutical compositions containing THF and a method for using these compositions to control intraocular pressure. THF has been described as an angiostatic steroid in Folkman, and collaborators, "Angiostatic Steroids" (Angioesthetic Steroids), Ann. Surg. , 206 (3) (1987) where it is suggested that angiostatic steroids may have potential use for diseases dominated by abnormal neovascularization, including diabetic retinopathy, neovascular glaucoma and retrolental fibroplasia. COMPENDIUM OF THE INVENTION Angioesthetic steroids and their pharmaceutical formulations are useful for treating GLC1A glaucoma. The invention is also directed to methods for controlling GLC1A glaucoma using angiostatic steroids. DETAILED DESCRIPTION OF PREFERRED MODALITIES Agents that alter the expression of GLC1A in the glaucomatous eye are expected to reduce IOP and thus prevent or inhibit glaucomatous optic neuropathy that is targeted by elevated IOP. Glucocorticoids improve GLC1A expression in TM of certain individuals. There have been several reports of elevated levels of natural glucocorticoid cortisol in the aqueous humor and plasma of glaucoma patients (Schwartz, et al., Above, Rozsival, et al., Supra). In addition, certain GLC1A mutations may alter GLC1A expression in the TM tissue of glaucoma patients lq. Unexpectedly, it has been discovered that angiostatic agents inhibit the expression of GLC1A in cultured human TM cells and reduce elevated IOP in certain models of ocular hypertensive animals. The compounds in this manner prevent the expression of GLC1A and the subsequent development of ocular hypertension. The development of blood vessels for the purpose of supporting viable tissue is known as angiogenesis. Agents that inhibit angiogenesis are known by a variety of terms such as angiostatic, angiolytic or angiotropic agents. For purposes of this specification, the term "angioesthetic agent" means compounds that can be used to inhibit angiogenesis. Specific angiostatic agents of the present invention are steroids or steroid metabolites. For the present purposes, the term "angiostatic steroids" means steroids and steroid metabolites that inhibit angiogenesis. The present invention is based on the finding that angiostatic steroids can be used for the control of ocular hypertension. In particular, the agents can be used for the treatment of glaucoma GLC1A. Preferred angiostatic steroids of the present invention have the following formula: Structure [A] Structure [B] where Rx is H, ß-CH3 or ß-C2H5; R2 is F, double bond C9-C1: L, epoxy C9-Cu, H or Cl; R3 is H, OR26, OC (= 0) R27, halogen, C9-Cn double bond, Cg-CQ epoxy, = 0, -OH, -O-alkyl (C! -C12), -OC (= 0) alkyl (Ci-Cia) # -OC (= 0) ARILO, -OC (= 0) N (R) 2 or -0C (= 0) 0R7, where ARILO is furyl, thienyl, pyrrolyl, or pyridyl and each of the portions is optionally substituted with one or two alkyl groups (with 1 to 4 carbon atoms), or ARILO is - (CH2) f-phenyl where f is 0 to 2 and the phenyl ring is optionally substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, alkyl (1 to 3 carbon atoms), alkoxy (1 to 3 carbon atoms), thioalkoxy- (1 to 3 carbon atoms), C13C-, F3C-, - NH2 and -NHC0CH3 and R is hydrogen, alkyl (1 to 4 carbon atoms), or phenyl and each R may be the same or different and R7 is ARIL as defined herein, or alkyl (1 to 12 carbon atoms); R4 is H, CH3, Cl or F; R5 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; R6 is H or CH3; Rg is CH2CH20R26, CH2CH20C (= 0) R27, H, OH, CH3, F, = CH2, CH2C (= 0) OR26, OR26, 0 (C = 0) R27 or 0 (C = 0) CH2 (C = 0) OR26 R10 is -C = CH, -CH = CH2, halogen, CN, N3, OR26, OC (= 0) R27, H, OH, CH3 or R10 forms a second bond between positions C-16 and C-17; R12 is H or forms a double bond with Rx or R14; R13 is halogen, OR26, OC (= 0) R27, NH2, NHR26, NHC (= 0) R27, N (R26) 2, NC (= 0) R27, N (R26) 2, NC (= 0) R27, N3, H, -OH, = 0, 0-P (= 0) (OH) 2, or - 0-C (= 0) - (CH2) tCOOH wherein t is an integer from 2 to 6; R14 is H or forms a double bond with R12; R15 is H, = 0 or -OH; and R23 with R10 forms a cyclic phosphate; wherein R9 and R15 have the meanings given above; or wherein R23 is -OH, 0-C (= 0) -Rn, -OP (O) - (OH) 2, or -O-C (-O) - (CH2) tC00H wherein t is an integer from 2 to 6; and Ru is -Y- (CH2) nX- (CH2) ra -S03H, -Y'- (CH2) p -X '- (CH2) q-NR16R17 or -Z (CH2) rQ, where Y is a bond or -0-; Y1 is a link, -O-, or -S-; each of X and X1 is a bond, -CON (R18) -, N (R18) CO-, -O-, -S-, -S (0) -, or -S (02) -; R18 is hydrogen or alkyl (^ -04); each of R16 and R17 is a lower alkyl group of 1 to 4 carbon atoms optionally substituted with a hydroxyl or R16 and R17 together with the nitrogen atom to which each is connected, to form 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 from 4 to 9; m is an integer from 1 to 5; p is an integer from 2 to 9; q is an integer from 1 to 5; Z is a bond or -O-; r is an integer from 2 to 9; and Q is one of the following: (1) -R19-CH2C00H wherein R19 is -S-, -S (0) -, -S (0) 2-, -SO2N (R20) -, or N (R20) SO2-; and R20 is hydrogen or lower alkyl- (1 to 4 carbon atoms); 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 (R21) CH (R22) COOH wherein R21 is H and R22 is H, CH3, -CH2COOH, -CH2CH2COOH, -CH20H, -CH2SH, -CH2CH2SCH3, or -CH2Ph-OH wherein Ph-OH is p-hydroxy-enyl; or R21 is CH3 and R22 is H; or R21 and R2 together are -CH2CH2CH2-; or -N (R21) CH (R22) COOH together are -NHCH2CONHCH2COOH; and their pharmaceutically acceptable salts; with the proviso that if R23 is a phosphate, it must form a cyclic phosphate, with R10 when R13 is = 0, except for the compound where Rx is β-CH3, R2 and R3 together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, R12 and R14 together form a double bond between positions 4 and 5, R5 is «-F, R9 is β-CH3, R10 is« -0H, R13 and R15 are = O and R23 is -0P (0) - (OH) 2. R 2.4 C, double bond C1-C2, 0; R25 = C (R15) CH2-R23, OH, OR26, OC (= 0) R27, R26, COOH, C (= 0) OR26, CHOHCH2OH, CHOHCH2OR26, CH0HCH20C (= 0) R27, CH2CH2OH, CH2CH2OR26, CH2CH2OC (= 0) R27, CH2CN, CH2N3, CH2NH2, CH2NHR26, CH2N (R26) 2, CH20H, CH2OR26, CH20 (C = 0) R27, CH20 (P = 0) (OH) 2, CH20 (P = 0) (0R26) 2, CH2SH, CH2S-R26, CH2SC (= 0) R27, CH2NC (= 0) R27, C (= 0) CHR280H, C (= 0) CHR28OR26, C (= 0) CHR28OC (= 0) R27 or R10 and R25 together can be = C (R28 2, this is an optionally substituted alkyl methylene group; wherein R26 = (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl) with 1 to 6 carbon atoms; = R 2-6 OR 2.6 i R ^ 2.8 H, (alkyl, branched alkyl, cycloalkyl) with 1 to 6 carbon atoms.

Unless otherwise specified, all substituent groups connected to the cyclopentane-phenanthrene moiety of Structures [A] and [B] may already be in the alpha or beta position. Additionally, the above structures include all pharmaceutically acceptable salts of angiostatic steroids. Preferred angiostatic steroids are: 21-METHYL-5β-PREGNAN-3, 11β, 17, 21-TETROL-20-ONA-21-METHYL ETHER 3β-AZIDO-5β-PREGNAN-11β, 17, 21-TRIOL-20-ONA-21-ACETATE 3ß-ACETAMID0-5β-PREGNAN-5ß-PREGNAN-11β-, 17, 21-TRIOL-11β-17, 21-TRIOL-20-ONA-20-ONA 21-ACETATE 17- ((4 -FLUORO) TIOF ENOXY) METHYL-L, 3,5-ESTRATRIEN-3,17-DIOL -AZIDO-21-NOR-5ß-PREGNAN-3a, 17 -DIOL 20- (CARBETOXIMETHYL) TIO-21-NOR-5β- PREGNAN-3 -17a-DIOL - (4-FLUOROFENIL) TIO-21-NOR-20-ACETAMIDO-21-NOR-5ß-PREGNAN-3a, 17a-DIOL PREGNAN-3a-5β-17a-DIOL-3-ACETATE 6a- (2-HYDROXYTHYL) -17β-METHYL- 20-CYANO-21-NOR-5β-β-ANDROSTAN-3, 17 -DIOL PREGNAN-3a, 17 -DIOL H 7a-METHYL-5β-ANDROSTAN-21-NOR-5β-PREGN-17 (20) -EN-3a-OL, 17β-DIOL 1-NOR-5β-PREGN-17 (20) -EN- 21-NOR-5β-PREGN-17 (20) -IN-a-OL-3 -ACETATE 3a-OL-16-ACCIDENTAL-3-ACETATE ACID 1-NOR-5β-PREGNAN-3, lia, 21-NOR-5β-PREGNAN-3, 17a, 0 -TRIOL 20 -TRIOL-3 -ACETATE 4.9 (11) -PREGN / ADIEN-17 ° < , 21- 4, 9 (11) -PREGNADIEN-17 «, 21-DIOL-3,20-DIONA-21-ACETATE DIOL-3, 20-DIONA The most preferred compounds are 21-methyl-5β-pregnan-3 ° < , llß, 17 «, 21-tetrol 20-one-21-methyl ether; 3β-azido-21-acetoxy-5β-pregnan-llβ, 178-diol-2-one; 3β-acetamido-21-acetoxy-5β-pregnan-llβ, 178-diol-20-one; and 5β-pregnan-llβ, 17", 21-triol-20-one. The most preferred compounds are 4, 9 (11) -pregnadien-17", 21-diol-3,20-dione-21-acetate and 4,9 (11) -pregnadien-17 < *, 21-diol-3, 20-dione. The angiostatic steroids of the present invention can be incorporated into various formulations to be delivered to the eye. For example, topical formulations may be employed and may include ophthalmologically acceptable preservatives, surfactants, viscosity improvers, buffers, sodium chloride and water to form sterile aqueous solutions and ophthalmic suspensions. In order to prepare sterile ophthalmic ointment formulations, an angiostatic steroid is combined with a preservative in an appropriate vehicle, such as mineral oil, liquid lanolin or white petrolatum. Sterile ophthalmic gel formulations comprising the angiostatic steroids of the present invention can be prepared by suspending an angiostatic steroid in a hydrophilic base prepared from a combination of for example Carbopol-940 (a carboxyvinyl polymer available from BF Goodrich Company) of according to published formulations for analogous ophthalmic preparations. Preservatives and tonicity agents can also be incorporated in these gel formulations. The specific type of formulations selected depends on various factors, such as the angiostatic steroid or its salt used and the frequency of dosing. Aqueous solutions, suspensions, ointments and ophthalmic gels are the preferred dosage formulas. The angiostatic steroid will normally be contained in these formulations in an amount from about 0.005 to about 5.0 percent (% by weight). The preferable range of concentrations is from about 0.05 to about 2.0% by weight. Thus, for topical administration, these formulations are delivered to the surface of the eye, one to four times per day, depending on the routine discretion of the right-handed physician. The following examples illustrate formulations and syntheses of compounds of the present invention, but are in no way limiting. Example 1 Component% by weight Angioesthetic Steroid 0.005-5.0 Tyloxapol 0.01-.05 HPMC 0.5 Benzalkonium Chloride 0.01 Sodium Chloride 0.8 Disodium Edetate 0.01 NaOH / HCl c. s. pH 7.4 Purified Water c. s. 100 mL Example 2 Component% by weight 4, 9 (ll) pregnadien-17 «, 21-diol-3, 20 -dione-21 -acetate 1.0 Mannitol 2.40 Carbopol 974P 0.50 Polysorbate 80 0.05 Benzalkonium Chloride 0.01 Sodium Chloride 0.4 Component% by weight Edetato Disodium 0.01 NaOH / HCl is. pH 7.4 Purified Water c. s. 100 mL Example 3 Preparation of 5β-Pregnan-llβ, 17 °, 21-triol-20-one Tetrahydrocortisol-F-21-t-butyldiphenylsilyl ether (PS03842) A solution of 4.75 g (17.3 mmol) of t-butyldiphenylchlorosilane in 5 mL of dry DMF is added dropwise to a stirred solution of tetrahydrocortisol-F (Steraloids No. P9050) and 2.3 g (19 mmol) of 4-dimethylaminopyridine (DMAP) in 30 mL of dry DMF, under N2, at -25 to -30 ° C (which is maintained with C02 - MeCN). After an additional 20 minutes at -30 ° C, the mixture is allowed to warm to 23 ° C overnight. The mixture is partitioned between ether and water, and the organic solution is washed with brine, dried (MgSO 4), filtered and concentrated to give 10.7 g of a white foam. This material is purified by flash column chromatography (400 g of silica, 62.5 to 70% ether / hexane). The 3-siloxy isomer eluted first, followed by mixed fractions, followed by the title compound. Concentrated mixed fractions (4.0 g) were chromatographed on the same column with 35% ethyl acetate / hexane. The total yield of the 3-siloxy isomer was 0.42 g (5%), and of the title compound 5.05 g (53.5%). Continuous elution with 25% MeOH / EtOAc allowed recovery of unreacted tetrahydrocortisol -F. PS03842 NMR (200 MHz H) (CDC13): d 0.63 (s, 3H, Me-18); 1. 11 (s, 9H, t-Bu); 1.12 (s, 3H, Me-19); 2.57 (t, J = 13, 1H, H-8); 2.6 (S, 1H, OH-17); 3.63 (sept, J = 2.5, 1H, H-3); 4.15 (br s, 1H, H-ll); 4.37 and 4.75 (AB, J = 20, 2H, H-21); 7.4 (m, 6H) and 7.7 (m, 4H) (Ph2). NMR (200 MHz ^) (DMSO-d6): d 0.64 (s, 3H, Me-18); 1. 02 (s, 9H, t-Bu); 1.07 (s, 3H, Me-19); 2.50 (t, J = 13, 1H, H-8); 3.37 (m, 1H, H-3); 3.94 (d, J = 2, 1H, OH-11); 4.00 (br s, 1H, H-ll); 4.42 (d, J = 5, 1H, OH-3); 4.38 and 4.83 (AB, J = 20, 2H, H-21); 5.11 (s, 1H, OH-17); 7.45 (m, 6H) and 7.6 (m, 4H) (Ph2). NMR (50.3-MHz 13C) (CDC13): 17.4 (C-18); 19.3 (C-16); 23.7 (C-15); 26.3 (C-7); 26.6 (C-19); 26.8 (Me3C); 27. 2 (C-6); 30.9 (C-2); 31.5 (C-8); 34.1 (Me3C); 34.8 (C-10); 35.2 (C-1); 36.2 (C4); 39.7 (C-13); 43.5 (C-5); 44. 3 (C-9); 47.4 (C-12); 52.1 (C-14); 67.8 (C-ll); 68.9 (C-21); 71.7 (C-3); 89.8 (C-14); 127.8, 129.8, 132.8, 132. 9, 135.7, 135.8 (diastereotopic Ph2); 208.8 (C-20).

Underlined resonances showed investment in the APT experiment. Assignments: E. Breitmaier, W. Voelter "Carbon-13 NMR Spectroscopy" (Carbon-NMR Spectroscopy-13), 3rd edition, VCH, 1987; pp. 345-348. IR (KBr) 3460, 2930, 2860, 1720, 1428, 1136, 1113, 1070, 1039, 703 cm-1. This compound does not show a marked melting point but instead passed to a foam at 80-100 ° C. Numerous recrystallization attempts failed. 5ß-Pregnan-llß, 17 < *, 21-triol-20-one A solution of PS03842 (0.91 g, 1.50 mmol) and thiocarbonyl diimidazole (1.05 g, 5.9 mmol) in 8 mL of anhydrous dioxane is refluxed under N2 for 3.5 hours. The cold solution is divided between ether and water and the organic solution is washed with brine, dried (MgSO 4), filtered and concentrated. The residue was chromatographed (120 g Si02, 35% EtOAc / hexane) to give 0.86 g (80%) of imidazolyl thioester. A solution of 0.75 g (1.05 mmol) of this compound in 100 mL of anhydrous dioxane is added dropwise for 2.2 h to a rapidly stirred solution of 1.6 mL (5.9 mmoles) of Bu3SnH in 100 mL of anhydrous dioxane under N2. After 1 hour more at reflux, the solution is cooled, concentrated and the residue is chromatographed (200 g Si02, 9% EtOAc / hexane) to give 0.43 g (70%) of 3-deoxy-21-silyl ether. This material is dissolved in 20 L of methanol; Bu4NF.3H20 (0.50 g, 1.6 mmol) is added and the mixture is heated to reflux under N2 for 4 hours. The cold solution is diluted with 2 volumes of EtOAc, concentrated to 1/4, partition (EtOAc / H20), and the organic solution is washed with brine, dried (MgSO4), filtered and concentrated. The residue (0.40 g) is chromatographed (30 g Si02, 40% EtOAc / hexane) to give 0.25 g (98%) of an oil. This oil is crystallized (n-BuCl) to give 0.14 g of the title compound as a white solid, m.p. 167-170 ° C. IR (Kbr): 3413 (br), 2934, 1714, 1455, 1389, 1095, 1035 cm "" 1. MS (Cl): 351 (M + 1). NMR (200 Mhz 1H, DMSO-d6): d 0.69 (s, 3H, Me-18); 1.14 (s, 3H, Me-19); 0.8-2.0 (m); 2.5 (t, J = 13, 1H, H-18); 3.96 (d, J = 2, 1H, OH-11); 4.1 (br S, 1H, H-ll); 4.1 and 4.5 (AB, additional division by 5 Hz, 2H, H-21); 4.6 (t, J = 5, 1H, OH-21); 5.14 (s, 1H, OH-17). Anal. Calculated for C21H3404: C, 11.96; H, 9.78. Found: C, 71.69; H, 9.66. Example 4 Preparation of 21-Methyl-5β-Preqnan-3t *, llß, 17 < *, 21-tetrol-20-one 21-methyl ether Sodium hydride (60% dispersion in oil, 0.10 g, 2.5 mmol) is added to a stirred solution of tetrahydrocortisol-F (0.73 g, 2.0 mmol) and CH3I (0.60 g). mL, 9.6 mmol) in 8 mL of anhydrous DMF under N2. Hydrogen is released and the temperature increases to 35 ° C. After 1 hour, the mixture is diluted with EtOAc, extracted with water (until neutral) and brine, dried (MgSO 4), filtered and concentrated. The residue is chromatographed (70 g SiO2, 80% EtOAc / hexane) to give 0.17 g of a white solid, MS (Cl) = 395 (M + 11). This material is recrystallized (EtOAc-n-BuCl) to give 0.12 g (16%) of the title compound as a white, feather-like solid, m.p. 208-213 ° C. IR (KBr): 3530, 3452, 2939, 2868, 1696 (s, CO), 1456, 1366, 1049 cm "1. NMR (200 MHz 1R, DMSO-d6): d 0.74 (s, 3H, Me-18. ), 1.09 (s, 3H, Me-19), 1.14 (d, J = 6.6, 3H, C-21 Me), 0.8-2.0 (m), 2.47 (t, J = 13, 1H, H-8); 3.18 (s, 3H, Ome), 3.35 (m, 1H, H-3), 4.00 (d, J = 2, 1H, OH-11), 4.07 (br S, 1H, H-ll), 4.37 ( q, J = 6.6, 1H, H-21), 4.43 (d, J = 5, 1H, OH-3), 5.16 (s, 1H, OH-17), Anal, calculated for C23H3805: C, 70.; H, 9. 71. Found: C, 70.06; H, 9. 76. Example 5 Preparation of 3β-azido-21-acetoxy-5β-pregnan-llβ, 178, diol-20-one A solution of Triphenylphosphine (2.6 g, 10 mmol) in 10 mL of toluene was carefully added to a stirred solution of PS03842 (see Example 4) (1.75 g, 2.90 mmol), diphenylphosphoryl azide (2.2 mL, 10.2 mmol) and diethyl azodicarboxylate (1.55). mL, 10 mmol) under N2, maintaining the internal temperature below 35 ° C (exothermic) .The solution is stirred for 1.2 hours, then diluted with ether, washed with water and brine, dried (MgSO4) filter and concentrate and the residue (9.5 g, oil) chromatography 175 g Si02, 15% EtOAc / hexane) giving 1.83 g of a viscous oil. A solution of 1.73 g of this material and 1.75 g (5.5 mmoles) of Bu4NF: 3H20 in 20 mL of methanol is refluxed under N2 for 2.5 hours. The crude product (1.94 g) is isolated with ethyl acetate and chromatography (100 g SiO2, 50% EtOAc / hexane) giving 0.60 g (56%) of a white semi-solid. Trituration (4: 1 hexane-ether) gave 0.57 g (53%) of a solid. A stirred solution of 0.40 g of this material in 3 mL of dry pyridine is treated with 0.3 mL of acetic anhydride and stirred overnight at 23 ° C under N2. The mixture is neutralized with 1 mL of methanol, stirred for 15 minutes, diluted with ether, washed with 1M aqueous HCl, water (until neutral), brine, dried (MgSO 4), filtered and concentrated. The residue (0.41 g, oil) is chromatographed (35 g Si02, 33% EtOAc / hexane) to give 0.33 g (76%) of the title compound as a white foam, m.p. 80-90 ° C (dec).

IR (KBr): 3505, 2927, 2866, 2103 (vs), 1721 (sh 1730), 1268, 1235 cm "1. NMR (200 MHz XH, DMSO-d6): d 0.92 (s, 3H, Me-18 ), 1.21 (s, 3H, Me-19), 1.0-2.1 (m), 2.17 (s, 3H, Ac), 2.25 (s 1H, OH-17), 2.74 (m, 1H, H-8); 3.97 (br s, 1H, H-3), 4.31 (br S, 1H, H-ll), 4.94 (AB, J = 17,? V = 60, 2H, H-21) Anal.Calculated for C23H35N305: C, 63.72; H, 8.14; N, 9.69, Found: C, 63.39; H, 8.18; N, 9.45, Example 6 Preparation of 3β-Acetamido-21-acetoxy-5β-preqnan-llβ, 17 ~, diol-20 -one A solution of 3ß-azido-21-acetoxy-5β-pregnan-llβ, 17'-diol-20-one (0.15 g, 0.35 mmol) in 8 mL of absolute ethanol containing 0.03 g of Pd in C to 10 % is stirred under H2 (1 atm) at 23 ° C for 2 hours.The mixture is filtered and concentrated, the residue is dissolved in EtOAc, the basic material is extracted in 1 M aqueous HCl, freed (Na2C03), extracted (EtOAc) and the organic extract is washed with water (until neutrality) and brine, dried (MgSO4), filtered and concentrated to provide 58 mg of a solid. This material is acetylated (1.0 mL of dry pyridine, 0.20 mL of Ac20, 23 ° C, N2, overnight), followed by processing (as described for the steroid of Example 6 [last step]) resulting in a product crude was chromatographed (25 g SiOz, EtOAc). This product is triturated with ether to give 51 mg (33%) of a product as a white solid, m.p. 179-181 ° C. Ms (Cl, isobutane): (M + 1) = 450 (M +), 432, 391, 371, 348.

IR (KBr): 3398 (br), 2932, 2865, 1720 (sh. 1740), 1652, 1538, 1375, 1265, 1236 cm "1. NMR (200 MHz 1H, CDC13): d 0.89, 1.22, 1.99, 2.17 (all ?, s, 3H); 1.0-2.2 (m); 2.7 (t, J = 13, 1H, H-8), 3.03 (s, 1H, OH-17), 4.2 (br s, 1H, H-ll), 4.3 (br s, 1H, H-3); 4. 96 ( , J = 17.5,? V = 42, 2H, H-21); 5.8 (d, J = 10, 1H, NH).

Claims (2)

1. A method for treating glaucoma GLC1A, characterized in that it comprises administering a pharmaceutically effective amount of an angioesthetic agent. 2. The method according to claim 1, characterized in that the angioesthetic agent has the following structure: Structure [A] Structure [B] wherein R is H, ß-CH3 or ß-C2H5; R2 is F, double bond C9-CU / epoxy C9-Cn, H or Cl; R3 is H, OR26, OC (= 0) R27, halogen, double bond C9-C, epoxy C9-C1: L, = 0, -OH, -0-alkyl (-C12), -OC (= 0) alkyl (Ci-C ^), -OC (= 0) ARIL, -0C (= 0) N (R) 2 or -OC (= 0) OR7, where ARILO is furyl, thienyl, pyrrolyl, or pyridyl and each of the portions is optionally substituted with one or two alkyl groups (with 1 to 4 carbon atoms), or ARYL is - (CH2) f-phenyl where f is 0 to 2 and the phenyl ring is optionally substituted with 1 to 3 selected groups of chlorine, fluorine, bromine, alkyl (1 to 3 carbon atoms), alkoxy (1 to 3 carbon atoms), thioalkoxy- (1 to 3 carbon atoms), Cl3C-, F3C-, -NH2 and - NHCOCH3 and R is hydrogen, alkyl (the 4 carbon atoms), or phenyl and each R may be the same or different and R7 is ARIL as defined herein, or alkyl (1 to 12 carbon atoms); R4 is H, CH3, Cl or F; R5 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; R6 is H or CH3; R9 is CH2CH20R26, CH2CH20C (= O) R27, H, OH, CH3, F, = CH2, CH2C (= 0) OR26, OR26, 0 (C = 0) R27 or 0 (C = 0) CH2 (C = 0) ) OR26. R10 is -C = CH, -CH = CH2, halogen, CN, N3, OR26, OC (= 0) R27, H, OH, CH3 or R10 forms a second bond between positions C-16 and C-17; R12 is H or forms a double bond with R? or R14; R13 is halogen, OR26, OC (= 0) R27, NH2, NHR26, NHC (= 0) R27, N (R26) 2, NC (= 0) R27, N (R26) 2, NC (= 0) R27, N3, H, -OH, = 0, 0-P (= 0) (0H) 2, or -0-C (= 0) - (CH2) tC00H wherein t is an integer from 2 to 6; R14 is H or forms a double bond with R12; R15 is H, = 0 or -OH; and R23 with R10 forms a cyclic phosphate; wherein R9 and R15 have the meanings given above; or wherein R23 is -OH, 0-C (= 0) -Ru, -0P (0) - (OH) 2, or -0-C (-0) - (CH2) tC00H wherein t is an integer of 2 to 6; and RX1 is -Y- (CH2) nX- (CH2) m -S03H, -Y1 - (CH2) P-X'- (CH2) q-NR16R17 or -Z (CH2) rQ, wherein Y is a bond or -0-; Y 'is a link, -O-, or -S-; each of X and X1 is a bond, -C0N (R18) -, N (R18) C0-, -0-, -S-, -S (0) -, or -S (02) -; R18 is hydrogen or alkyl (Ci-C.); each of R16 and R17 is a lower alkyl group of 1 to 4 carbon atoms optionally substituted with a hydroxyl or R16 and R17 together with the nitrogen atom to which each is connected, to form 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 from 4 to 9; m is an integer from 1 to 5; p is an integer from 2 to 9; q is an integer from 1 to 5; Z is a bond or -0-; r is an integer from 2 to 9; and Q is one of the following: (1) -R19-CH2COOH wherein R19 is -S-, -S (O) -, -S (0) 2-, -SO2N (R20) -, or N (R20) SO2-; and R20 is hydrogen or lower alkyl- (1 to 4 carbon atoms); 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 (R21) CH (R22) COOH wherein R21 is H and R22 is H, CH3, -CH2COOH, -CH2CH2COOH, -CH20H, -CH2SH, -CH2CH2SCH3, or -CH2Ph-0H wherein Ph-OH is p-hydroxyphenyl; or R21 is CH3 and R22 is H; or R21 and R22 together are -CH2CH2CH2-; or -N (R21) CH (R22) COOH together are -NHCH2CONHCH2COOH; and their pharmaceutically acceptable salts; with the proviso that if R23 is a phosphate, it must form a cyclic phosphate, with R10 when R13 is = 0, except for the compound where R: is β-CH3, R2 and R3 together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, R12 and R14 together form a double bond between positions 4 and 5, R5 is? -F, R9 is ß-CH3, R10 is «-0H, R13 and R15 are = O and R23 is -0P (0) - (OH) 2. R24 = C, double bond Ci-C ,, 0; R25 = C (R15) CH2-R23, OH, 0R26, 0C (= 0) R27, R26, COOH, C (= 0) 0R26, CH0CH20H, CHOHCH2OR26, CHOHCH2OC (= 0) R27, CH2CH2OH, CH2CH2OR26, CH2CH2OC (= 0) R27, CH2CN, CH2N3, CH2NH2, CH2NHR26, CH2N (R26) 2, CH2OH, CH2OR26, CH20 (C = 0) R27, CH20 (P = 0) (0H) 2, CH20 (P = 0) (OR26) 2, CH2SH, CH2S-R26, CH2SC (= 0) R27, CH2NC (= 0) R27, C (= 0) CHR280H, C (= 0) CHR280R26, C (= 0) CHR280C (= 0) R27 or R10 and R25 together they can be = C (R28) 2, this is an optionally substituted alkyl methylene group; wherein R26 = (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl) with 1 to 6 carbon atoms; R27 = R26 + OR26; R28 = H, (alkyl, branched alkyl, cycloalkyl) with 1 to 6 carbon atoms. The method according to claim 2, characterized in that the compound is selected from the group consisting of 21-methyl-5β-pregnan-3 ° 11β, 17", 21-tetrol-20-one 21-methyl ether; 3ß-azido-21-acetoxy-5β-pregnan-llβ, 17 < * -diol-20-one; 3ß-acetamido-21-acetoxy-5β-pregnan-llβ, 17 < * -diol -20 -one; 5β-pregnan-llβ, 17", 21-triol-20-one; 4, 9 (11) -pregnadien-17", 21-diol-3,20-dione-21-acetate and 4, 9 (11) -pregnadien-17", 21-diol-3, 20 -dione. 4. The method according to claim 3, characterized in that the compound is selected from the group consisting of 4, (11) -pregnadien-17", 21-diol-3, 20-dione-21-acetate and 4, 9 (11) -pregnadien-17 < *, 21-diol-3,20-dione. 5. A composition for controlling glaucoma GLC1A, characterized in that it comprises a pharmaceutically effective amount of an angioesthetic agent. 6. A composition according to claim 5, characterized in that the angiostatic steroid has the following structure: Structure [A] Structure [B] wherein Rx is H, ß-CH3 or ß-C2H5; R2 is F, double bond C9-C, epoxy Cg-Cn, H or Cl; R3 is H, OR26, OC (= 0) R27, halogen, C9-C double bond, C9-C epoxy, = 0, -OH, -0-alkyl (Cx-C12), -OC (= 0) alkyl ( Ci-Cxz), -OC (= 0) ARILO, -0C (= 0) N (R) 2 or -0C (= 0) 0R7, where ARILO is furyl, thienyl, pyrrolyl, or pyridyl and each of the portions is optionally substituted with one or two alkyl groups (with 1 to 4 carbon atoms), or ARIL is - (CH2) f-phenyl where f is 0 to 2 and the phenyl ring is optionally substituted with 1 to 3 selected groups of chlorine, fluorine, bromine, alkyl (1 to 3 carbon atoms), alkoxy (1 to 3 carbon atoms), thioalkoxy- (1 to 3 carbon atoms), Cl3C-, F3C-, -NH2 and -NHCOCH3 and R is hydrogen, alkyl (1 to 4 carbon atoms), or phenyl and each R may be the same or different and R7 is ARIL as defined herein, or alkyl (1 to 12 carbon atoms); R4 is H, CH3, Cl or F; R5 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; R6 is H or CH3; R9 is CH2CH20R26, CH2CH20C (= O) R27, H, OH, CH3, F, = CH2, CH2C (= 0) OR26, OR26, 0 (C = 0) R27 or 0 (C = 0) CH2 (C = 0) ) OR26. R10 is -C = CH, -CH = CH2, halogen, CN, N3, OR26, OC (= 0) R27, H, OH, CH3 or R10 forms a second bond between positions C-16 and C-17; R12 is H or forms a double bond with Rx or R14; R13 is halogen, OR26, OC (= 0) R27, NH2, NHR26, NHC (= 0) R27, N (R26) 2, NC (= 0) R27, N (R26) 2, NC (= 0) R27, N3, H, -OH, = 0, 0-P (= 0) (0H) 2, or -0-C (= 0) - (CH2) tC00H wherein t is an integer from 2 to 6; R14 is H or forms a double bond with R12; R15 is H, = 0 or -OH; and R23 with R10 forms a cyclic phosphate; wherein R9 and R15 have the meanings given above; or wherein R23 is -OH, 0-C (= 0) -R11, -0P (0) - (OH) 2, or -0-C (-0) - (CH2) tC00H wherein t is an integer of 2 to 6; and Rn is -Y- (CH2) nX- (CH2) m -S03H, -Y '- (CH2) PX' - (CH2) q-NR16R17 or -Z (CH2) rQ, wherein Y is a bond or - O-; Y 'is a link, -0-, or -S-; each of X and X 'is a bond, -C0N (R18) -, N (R18) C0-, -0-, -S-, -S (0) -, or -S (02) -; Lanes are hydrogen or alkyl (Cx-C4); each of R16 and R17 is a lower alkyl group of 1 to 4 carbon atoms optionally substituted with a hydroxyl or R16 and R17 together with the nitrogen atom to which each is connected, to form 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 from 4 to 9; m is an integer from 1 to 5; p is an integer from 2 to 9; q is an integer from 1 to 5; Z is a bond or -0-; r is an integer from 2 to 9; and Q is one of the following: (1) -R19-CH2COOH wherein R19 is -S-, -S (0) -, -S (0) 2-, -SO2N (R20) -, or N (R20) SO2-; and R20 is hydrogen or lower alkyl- (1 to 4 carbon atoms); 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 (R21) CH (R22) COOH wherein R21 is H and R22 is H, CH3, -CH2COOH, -CH2CH2COOH, -CH20H, -CH2SH, -CH2CH2SCH3, or -CH2Ph-0H wherein Ph-OH is p-hydroxyphenyl; or R21 is CH3 and R22 is H; or R21 and R22 together are -CH2CH2CH2-; or -N (R21) CH (R22) COOH together are -NHCH2CONHCH2COOH; and their pharmaceutically acceptable salts; with the proviso that if R23 is a phosphate, it must form a cyclic phosphate, with R10 when R13 is = 0, except for the compound where Rx is β-CH3, R2 and R3 together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, R12 and R14 together form a double bond between positions 4 and 5, R5 is «- F, R9 is ß-CH3, R10 is« -OH, R13 and R15 are = O and R23 is -OP (O) - (0H) 2. R24 = C, double bond C ^ Cz, O; R25 = C (R15) CH2-R23, OH, OR26, OC (= 0) R27, R26, COOH, C (= 0) OR26, CHOHCH2OH, CHOHCH2OR26, CHOHCH2OC (= 0) R27, CH2CH2OH, CH2CH2OR26, CH2CH2OC (= 0) R27, CH2CN, CH2N3, CH2NH2, CH2NHR26, CH2N (R26) 2, CH2OH, CH2OR26, CH20 (C = 0) R27, CH20 (P = 0) (OH) 2, CH20 (P = 0) (OR26) 2, CH2SH, CH2S-R26, CH2SC (= 0) R27, CH2NC (= 0) R27, C (= 0) CHR28OH, C (= 0) CHR28OR26, C (= 0) CHR28OC (= 0) R27 or R10 and R25 together can be = C (R28) 2, this is a methylene group substituted with optionally alkyl; wherein R26 = (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl) with 1 to 6 carbon atoms; R27 = R26 + OR26; R28 = H, (alkyl, branched alkyl, cycloalkyl) with 1 to 6 carbon atoms. The composition according to claim 6, characterized in that the angioesthetic agent is selected from the group consisting of 21-methyl-5β-pregnan-3", 11β, 17", 21-tetrol-20-one 21 -methyl. ether; 3β-azido-21-acetoxy-5β-pregnan-11β, 17"-diol-20-one; 3β-acetamido-21-acetoxy-5β-pregnan-llβ, 17'-diol-20-one; 5β-pregnan-llβ, 17", 21-triol-20-one; 4, 9 (11) -pregnadien-17", 21-diol-3, 20-dione-21-acetate and 4, 9 (11) -pregnadien- 17", 21-diol-3,20-dione. The composition according to claim 6, characterized in that the compound is present at a concentration between 0.005 and 5.0 weight percent. 9. The composition according to claim 7, characterized in that the compound is 4, 9 (11) -pregnadien-17", 21-diol-3,20-dione-21-acetate or 4, 9 (11) -pregnadien -17 «, 21-diol-3, 20-dione. The composition according to claim 8, characterized in that the compound is present in a concentration between 0.05 and

2.0 weight percent.