SURAMIN TYPE COMPOUNDS AND ANGIOSTATIC STEROIDS TO INHIBIT ANGIOGENESIS

Abstract: The invention is a method of treating angiogenesis in a warm blooded mammal who is in need of such treatment which comprises administration of an angiogenic inhibiting amount of a combination of a suramin-type compound and an angiostatic steroid. Angiostatic steroids include the known 20-substituted steroids of formula (I), 21-hydroxy steroids of formula (II), C11-functionalized steroids of formula (III) as well as the novel DELTA <9(11)>-etianic esters of formula (IV), as well as various individual known steroids.

Description: SURAMIN TYPE COMPOUNDS AND ANGIOSTATIC STEROIDS TO INHIBIT ANGIOGENESIS BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is a method of treating angiogenesis in mammals who have a need for the same which utilizes suramin or suramin-type compounds and an angiostatic steroid. Conditions in which this combination may be used are diseases of neovascularization such as cancer, diabetes and arthritis. 2. Description of the Related Art Angiogenesis is the development of blood vessels which typically would lead to a vascular bed capable of sustaining viable tissue. Angiogenesis is a necessary process in the establishment of embryonic tissue and development of a viable embryo. Similarly, angiogenesis is a necessary step in the establishment and development of tumor tissue as well as certain inflammatory conditions. The inhibition of angiogenesis would be useful in the control of embryogenesis, inflam¬ matory conditions, and tumor growth, as well as numerous other condi¬ tions. European patent application No 83870132.4 (Publication No 0 114 589) published August 1, 1984 describes the use of cortisone, hydro- cortisone and llα-hydrocortisone in combination with heparin in the inhibition of angiogenesis. The angiogensis inhibitory effects of heparin and heparin frag- ments in combination with cortisone is described in Science 221, 719 (1983) . The use of heparin and heparin fragments in combination with hydrocortisone is set forth in the Proceedings of AACR 26, 384 (1985). Heparin is presently used with inhibitors of angiogenesis, especially angiostatic steroids to treat diseases involving neovas¬ cularization, see Biochem. Pharmacol. 34, 905 (1985) and Annals of Surgery 206, 374 (1987). The heparin potentiates the angiogenesis- inhibiting activity of other drugs, for example of collagen bio¬ synthesis inhibitors such as L-azetidine carboxylic acid. The problem with using heparin is that the efficacy of each prepara¬ tion/batch of heparin differs due to the chemical heterogeneity of the heparin molecules. ^-Cyclodextrin tetradecasulfate is known to be a substitute for heparin in anti-angiogenesis treatments containing angiostatic steroids, see Science 243, 1490 (1989). Sura in inhibits the binding of fibroblast growth factor to its receptor during in vitro experiments. Fibroblast growth factor is one of a number of known angiogenic growth factors. See, J. Cell Physiol. 132, 143 (1987). Suramin and 4,4'-bis[ [4-(o-hydroxyanilino)-6-(m-sulfoanilino)-s- triazin-2-yl]amino]-2,2'stllbenedisulfonic acid have been reported to possess antitumor activity. See, Gann 61, 569 (1970) and J. Clin. Oncol., 7, 499 (1989). US Patent 4,599,331 discloses 20-substituted Δ 1 ' 4 -16-methyl steroids which did not have a Δ ' ' double bond which are useful as antiangiogenics. US Patent 4,771,042 discloses 21-hydroxy steroids which are useful in the inhibition of angiogenesis involving the co-adminis¬ tration of steroids with heparin or heparin fragments. International Patent Publication W087/02672 discloses various C^^-functionalized steroids useful in the inhibition of angiogenesis. The Journal of the National Cancer Institute 81, 1346 (1989) discloses that "Suramin also appears to have antiangiogenesis activity ...". The combination of suramin-type compounds and angiostatic steroids have been found to treat angiogenesis in a warm blooded mammal. Derwent abstract 89-300681/41 discloses that suramin has anticancer utility. SUMMARY OF INVENTION Disclosed is a method of treating angiogenesis in a warm blooded mammal who is in need of such treatment which comprises administra¬ tion of an angiogenic inhibiting amount of a combination of a suramin-type compound and an angiostatic steroid. Also disclosed is a Δ '^'-etianic ester of formula (IV) where (A-l) R 10 is α-R 10 -l : - R 10-2 where χo-2 is _CH 3. R-lθ-1 and R 5 taken together are -CH2-CR2-C 3-CH- where R2 is °."R.2-l : ."Il2-2 where one of R2-I and R2-2 ^ s "H an< the other of R2-I and R2-2 is " H > " CH 3> -Cl or -F, where R3 is -0 or a-R^-l '-β-^-Z-l where one 3.1 and R3.2 s *** and the other of R3.1 and R3.2 s -OR3.3 where R3.3 is -H, -P0(0H)2 or -SO3H; (A-II) R o is α-R 10 . 3 :/3-Rιo-4 where R 10-4 is - CH 3> R 10-3 and R 5 taken together are -CH-CH-C0-CH-; (A-III) where R 10-6 s " c ^3> one °f R 5-5 and 5-6 - s "^ and t ^ ιe ot her of R5-5 and R 5 .g taken with Rio-5 is -CH2-CR2-CR3-CH2- where R2 and R3 are as defined above; Rg is a-R- _ι : β-R( ) _2 where one of Rg-i and Rg-2 is " H and tΛϊe other of Rg_ι and R _2 is -H, -F, -Cl, -Br and -CH 3 ; R7 is a-R-j _ι : β-H-7 _2 where one of R7.1 and 7-2 is " H and the other of R7-1 and R7.2 is -H or -CH3; R^ is -CH2 or α-Rιg.ι:/3-Rιg.2 w n er e one of Rχ .ι and Rig-2 -H and the other of Rι _ι and Rχg_2 i s -H, -CH3, -OH or -F; fluoroalkyl containing from 1-23 -F atoms, C^-Cg alkoxy, (C -Cg)alkylamino(Cι-Cg)alkyl, (C5-C7)cyclo- alkyl(Cι-Cg)alkyl, phenyl(Cι-Cg)alkyl optionally substituted with 1-3 -CH 3 , -F, -Cl, -OH, -OCH3, -OC 2 H 5 and - H 2 , C3-C0. cycloalkyl, C 2 -C 10 alkenyl, (C3-Cg)cyclo lkyl(C2-C o) alkenyl; X is -0- or -S-; R21 is alkyl optionally substituted with 1 to 10 -F, -Cl or -Br, c 2" c 10 alk yi substituted with 1 to 10 -OH, -CH2-COOR21.I where R21-I is CI-CIQ alkyl, C3-Cg cyclo- alkyl, C3-C3 cycloalkenyl, C2-C10 alkenyl containing 1 thru 4 double bonds optionally substituted with -OH, -F, -Cl or -Br, -(CH2) n ι-phen l where n^ is 0 or 1 and phenyl is optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH, -OCH3, -OC2H5, C1-C alkyl, -NH 2 , -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or -N0 2 , -CH2-CO-NR21.2R2I-3 where R21-2 and 21-3 are tne same or different and are -H, alkyl, C3-C3 cycloalkyl, -φ , -CE2 - and where R21-2 an R 21-3 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidine, 1-piperidine, 1-piperazine and 1-morpholine. DETAILED DESCRIPTION OF THE INVENTION The present invention involves a method of treating angiogenesis in a warm blooded mammal who is In need of such treatment which co prises administration of an angiogenic inhibiting amount of a combination of a suramin-type compound and an angiostatic steroid. It is preferred that the mammal be a human. Suramin-type compounds are compounds which mimic the anti- angiogenic action of suramin and which augment the activity of angio¬ static steroids. Suramin and the suramin-type compounds are known to those skilled in the art. It is preferred that the suramin-type compound be selected from the group consisting of suramin, 3-hydroxy-2,7-naphthalenesulfonic acid, 4,5-dihydroxy-2,7-naphthalenedisulfonic acid, 2,2' - [ (l,8-dihydroxy-3,6-disulfo-2,7-nap hylene)bis(azo]di- benzenearsonic acid, 4,4' -bis [ [4- (o-hydroxyanilino)-6-(m-sulfoanilino)-s-triazin-2- yl]amino] -2,2'stilbenedisulfonic acid, 4,5-dihydroxy-3- [ (p-nitrophenyl)azo]-2,7-naphthalenedisulfonic acid, 4,5-dihydroxy-3,6-bis[(4-sulfo-l-naphthyl)azo]-2,7-naphthalene¬ disulfonic acid, 3-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydroxy-2,7-naphthalene¬ disulfonic acid, 4,5'-dihydroxy-3,6' [(3,3'-dimethoxy-4,4'-biphenylylene)bis(azo)- di-1-naphthalenesulfonic acid, 3,6- [ (2, 3-dimethyl-5-oxo-l-phenyl-3-pyrazolin-4-yl)azo] -4,5- dihydroxy-2,7-naphthalenedisulfonic acid, 5,5'-[ureylenebis[2-sulfo-p-phenylene)azo]bis[6-amino-4-hydroxy- 2-naphthalenesulfonic acid, 4-[(o-arsonophenyl)azo]3-hydroxy-2,7-naphthalenedisulfonic acid, 4,5-dihydroxy-3-(phenylazo)-2,7-naphthalenedisulfonic acid, 4-acetamido-5-hydroxy-6- (phenylazo)-1,7-naphthalenedisulfonic acid, 2- [p- t (l-hydroxy-4-sulfo-2-naphthyl)azo]phenyl] -6-methyl-7- benzothiazolesulfonic acid, 4- [ (2,4-dimethylphenyl)azo]-3-hydroxy-2,7-napthalenedisulfonic acid, 3- [ (4-Sulfophenyl)azo] -4,5-dihydroxy-2,7-naphthalenedisulfonic acid, 3- [ (4-ni rophenyl)'azo] -4-amino-5-hydroxy-2,7-naphthalene¬ disulfonic acid, l-nitro-4,6,8-naphthalenetrisulfonic acid, l-amino-4,6,8-naphthalenetrisulfonic acid and pharmaceutically acceptable salts thereof. It is more preferred that the suramin-type compound be suramin and 4,4' -bis[[4-(o-hydroxyanilino)-6-(m- sulfoanilino)-s-triazin-2-yl]amino] -2,2'stilbenedisulfonic acid. It is even more preferred that the suramin-type compound be suramin. Angiostatic steroids refer to those steroids which prevent the process of angiogenesis/neovascularization, or cause the regression of new vasculature which results from angiogenic stimuli. Angio¬ static steroids refer to, and include, the known 20-substituted steroids of formula (I) see US Patent 4,599,331,the known 21-hydroxy steroids of formula (II) see US Patent 4,771,042, the known C^i- functionalized steroids of formula (III) see International Patent Publication WO87/02672, the following known steroids 6α-fluoro- 17α,21-dihydroxy-16α-methylpregna-4,9(ll)-diene-3,20-dione 21- acetate, 6α-fluoro-17α,21-dihydroxy-16?-methylpregna-4,9(11)-diene- 3,20-dione, 6α-fluoro-17α,21-dihydroxy-16?-methylpregna-4,9(ll)- diene-3,20-dione 21-phosphonooxy and pharmaceutically acceptable salts thereof, hydrocortisone, tetrahydrocortisol, 17α-hydroxy- progesterone, llα-epihydrocortisone, cortexolone, corticosterone, desoxycorticosterone, dexamethasone, cortisone 21-acetate, hydro¬ cortisone 21-phosphate, 17α-hydroxy-6 -methylpregn-4-ene-3,20-dione 17-acetate, 6α-fluoro-17α,21-dihydroxy-16α-meth lpregna-4,9(11)- diene-3,20-dione and the novel Δ"(")-etianic esters (IV). The Δ'( i )-etianic esters (IV) are prepared by methods known to those skilled in the art from steroid starting material known to those skilled in the art, see CHART B. The starting materials for preparation of the Δ 9 ^ 11 ^-etianic esters (IV) are the corresponding 17α,21-dihydroxy steroids (V). These compounds are oxidized by known procedures to remove C21 and produce a steroid where C20 i sub¬ stituted with -X-H where X is -0- or -S-, rather than -CH2-OH. The oxidation reaction is performed with an aqueous solution of an oxidizing agent such as periodate. It is preferred to use an excess of the oxidizing agent (about 2 equivalents) . After refluxing the mixture for 1-10 hr the carboxylic acid product (VI) is isolated and can be purified by recrystallization as is known to those skilled in the art. The carboxylic acids (VI) are esterified at C by reaction with the an anhydride of the desired corresponding 17-esters (VII). The anhydride is of the formula R17-CO-O-CO-R17 as is known to those skilled in the art, see US Patent 4,599,331. The 17-esters (VII) are then transformed to the desired Δ^'ϋ)-etianic esters (IV) by esterification procedures (for example with diazoalkyl reagents) well known to those skilled in the art. With the Δ 9 ^ 11 )-etianic esters (IV) it is preferred that R3 is " 0 and it is further preferred that the steroid A-ring be Δ -3-keto. It Is preferred that Rg is α.-Rg_ι: 3-Rg_2 where Rg_2 s -H and Rg_ι is -H, -F and -CH3, it is more preferred that Rg is -F. It is preferred that R7 is -H:-H. It is preferred that Ri is α-Ri6-i. J _.-Ri6-2 where one of Ri6_ι and Ri6_2 "H and the other of Rι _ι and i .2 i s "CH3. It is preferred that R17 is C^-C^. alkyl or -(CF2) n 2 _ CF3 where n2 is 0-3; it is more preferred that R 7 is -CH3, -C2H5, -C3H7, -CF3 or -CF2-CF3. It is preferred that R 2 is C -C alkyl; it is more preferred that R21 is -CH3, -C2H5 or -C- CH3 3. It is preferred that X is -0-. It is preferred that the angiostatic steroid be Δ^d-1)-etianic esters of formula (IV) where RlO is wnere Rl0-2 i s "CH3, R 10-l and 5 taken together are -CH2-CR2-CR3-CH- where R2 is -H:-H and R3 is -0, Rg is α-Rg_ι:;S-Rg_2 where Rg_2 is -H and Rg_ι is -H, -F and -CH 3 , R 7 is -H:-H, R is c--Rιg_ι:5-Rι ..2 where one °f Rl6-1 and R 16-2 "** and the other of Rig-i and R _2 is -CH3, R is C1-C4 alkyl or -(CF2) n 2"CF3 where n2 is 0-3, R 2 ι is C1-C4 alkyl, X is -0-; 20-substituted steroids of formula (I), where R 4 is -H, Rg and R9 are be the same or different and are -H, -F, -Cl, R^i Is chosen from the group consisting of hydroxy and keto, R20 is chosen from the group consisting of methoxy and thiomethyl, and Rl is chosen from the group consisting of alkyl groups having less than 6 carbon atoms; 6α-fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(ll)-diene-3,20- dione 21-acetate, 6α-fluoro-17α,21-dihydroxy-16,S-methylpregna-4,9(ll)-diene-3,20- dione, 6β-fluoro-17α,21-dihydroxy-16^-meth lpregna-4,9(ll)-diene-3,20- dione 21-phosphonoox , hydrocortisone, tetrahydrocortisol, 17α- hydroxyprogesterone, llα-epihydrocortisone, cortexolone, corticos- terone, desoxycorticosterone, dexamethasone, cortisone 21-acetate, hydrocortisone 21-phosphate, 17α-hydroxy-6 -methylpregn-4-ene-3,20- dione 17-acetate, 6α-fluoro-17α,21-dihydroxy-16α-methylpregna- 4,9(ll)-diene-3,20-dione. It is more preferred that the angiostatic steroid be 6α-fluoro- 17α,21-dihydroxy-16α-methylpregna-4,9(ll)-diene-3,20-dione 21- acetate, 6α-fluoro-17α,21-dihydroxy-168-methylpregna-4,9(ll)-diene-3,20- dione, 6α-fluoro-17 ,21-dihydroxy-160-methylpregna-4,9(11)-diene-3,20- dione 21-phosphonoox , hydrocortisone, tetrahydrocortisol, 17 - hydroxyprogesterone, llα-epihydrocortisone, cortexolone, corticos- terone, desoxycorticosterone, dexamethasone, cortisone 21-acetate, hydrocortisone 21-phosphate, 17o-hydroxy-6α-methylpregn-4-ene-3,20- dione 17-acetate, 6α-fluoro-17α,21-dihydroxy-16α-methylpregna- 4,9(ll)-diene-3,20-dione. It is preferred that the method of treating angiogenesis is the treating of diseases of neovascularization. It is preferred that neovascular diseases are selected from the group consisting of solid tumors, diabetes, arthritis, atherosclerosis, neovascularization of the eye, parasitic diseases, psoriasis, abnormal wound healing processes, hypertrophy following surgery, burns, injury, hair growth, ovulation and corpus luteum formation, implantation and embryo development in the uterus. It is more preferred that the neovascular disease is solid tumors, diabetes, arthritis or psoriasis. The suramin-type compounds and angiostatic steroids do not have to be administered in the same pharmaceutical dosage form. The suramin-type compounds are usually administered IV because of their irritation whereas the angiostatic steroids can be administered either orally or parenterally (IM, SQ, IV) . The dose of the suramin-type compounds is from about 1 to about 1,000 mg/mVday, preferably from about 5 to about 500 mg/m 2 /day. The suramin-type compound Is given until the appropriate blood level is reached which is about 50 to about 300 μg/ml, preferably about 250 to about 300 μg/ml. At that point the administration of the suramin- type compound is stopped as is known to those skilled in the art. The dose of the angiostatic steroids is from about 0.1 to about 100 mg/kg/day, preferably from about 0.1 to about 50 mg/kg/day. For the inhibition of angiogenesis, angiostatic steroids may be combined with agents other than suramin including sulfated glycos- aminoglycans and sulfated polysaccharides, or effective fragments of these molecules. The preferred glycosaminoglycans include heparin and heparan sulfate. Fragments of heparin or heparan sulfate may also be used if they contain a minimum of six saccharide residues; fragments of heparin or heparan sulfate may be prepared from heparin or heparan sulfate isolated from natural sources, or they may be prepared by chemical synthesis. Angiostatic steroids may also be combined with polysaccharides including pentosan polysulphate, cyclodextrins, or other sulfated polysaccharides isolated from natural sources. The preferred polysaccharides are sulfated forms of / S-cyclodextrin Including 3-cyclodextrin tetradecasulfate, pentosan polysulphate, or the polysaccharide-peptidoglycan isolated from Arthrobacter, Journal of Biochemistry 92, 1775 (1982). These polysaccharides may be isolated from natural sources, or prepared by chemical synthesis. Angiostatic steroids may also be used in combination treatments containing compounds which interfere with collagen biosynthesis. Preferred compounds in this group include L-azetidine-2-carboxylic acid, thioproline, and related proline analogs. Also included are other inhibitors of basement membrane collagen synthesis such as 8,9- dihydroxy-7-methyl-benzo(b)quinolizinium bromide. The exact route of administration, dose, frequency of ad¬ ministration of both the suramin-type compound and angiostatic steroids depends on the particular treatment of angiogenesis per- for ed, the severity of the disease, the age, general physical condition, weight, or other clinical abnormaliites, etc., of the par¬ ticular patient to be treated as is known to those skilled in the art. DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims. I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES The chemical formulas representing various compounds or molecu¬ lar fragments in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical or letter subscript, for example, "Z " or "R j _" where "i" is an integer. These variable substituents are either onovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Zi would represent a bivalent variable if attached to the formula CH3- C(-Zι)H. Groups R^ and Rj would represent monovalent variable sub- stituents if attached to the formula C^-C^-C^)(R * )H2- When chem¬ ical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in par¬ entheses. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substitu¬ ents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both R^ and Rj are bonded to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as ster- oids, these carbon atoms are designated as C j _, where "i" is the inte¬ ger corresponding to the carbon atom number. For example, Cg repre¬ sents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chem¬ istry. Likewise the term "Rg" represents a variable substituent (either monovalent or bivalent) at the Cg position. Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol "-" In general repre- sents a bond between two atoms in the chain. Thus CH3-0-CH2"CH R^)- CH3 represents a 2-substituted-l-methoxypropane compound. In a similar fashion, the symbol "—" represents a double bond, e.g., CH2~C(R£)-0-CH3, and the symbol " ~ - n represents a triple bond, e.g., HC * C-CH Rι)-CH2-CH3. Carbonyl groups are represented in either one of two ways: -CO- or -C(-O)-, with the former being preferred for simplicity. Chemical formulas of cyclic (ring) compounds or molecular frag¬ ments can be represented in a linear fashion. Thus, the compound 4- chloro-2-meth lρyridine can be represented in linear fashion by N*-C(CH 3 )-CH-CC1-CH-C*H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring. Likewise, the cyclic molecular fragment, 4- (ethyl)-1-piperazinyl can be represented by -N -(CH2)2"N(C2H5)-CH2- C*H 2 . When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the vari¬ able. For example, a variable R^ attached to a carbon atom as -C(=R^)- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monovalent variable substituents α-R j * and yS-Ri-k* Wh en a bivalent variable, R^, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form "α-R^ * ^-R^-ic" or some variant thereof. In such a case both o-R^_j and J-Ri-fc are attached to the carbon atom to give -C(α- R i-i)( _ i-k)~ • ^ or example, when the bivalent variable Rg, -C(-Rg)- is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are α-Rg_ι_?-Rg_2 α " R 6- g.yS-Rg.i Q , etc., giving -C(α-Rg.ι)(0-Rg_ 2 )- -C(α-Rg_ 9 )(0-Rg_ IQ)-, etc. Likewise, for the bivalent variable R^, -C(= ^)-, two monovalent variable substituents are a ring substituent for which separate and β orientations do not exist (e.g., due to the presence of a carbon carbon double bond in the ring) , and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, but the α and β designations are omitted. Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula -Cι(R i )H-C 2 (Rj)H- (Ci and C2 define arbitrarily a first and second carbon atom, respectively) R^ and R - may be defined to be taken together to form (1) a second bond between C and C2 or (2) a bivalent group such as oxa (-0-) and the formula thereby describes an epoxide. When R^ and R are taken together to form a more complex entity, such as the group -X-Y- , then the orientation of the entity is such that Ci in the above formula is bonded to X and C2 is bonded to Y. Thus, by convention the designa¬ tion "... Ri and Rj are taken together to form -CH2-CH2-O-CO- ..." means a lactone in which the carbonyl is bonded to C2. However, when designated "... R- and R^ are taken together to form -CO-O-CH2-CH2- the convention means a lactone in which the carbonyl is bonded to Ci. The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as "C -C ", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "C1-C4 alkyl" represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given) . Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C2-C alkoxycarbonyl describes a group CH3-(CH2) n -0- CO- where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is Indicated separately by enclosing the "C^-Cj" designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C1-C3)- alkoxycarbonyl has the same meaning as C2-C alkoxycarbonyl because the "C1-C3" refers only to the carbon atom content of the alkoxy group. Similarly, while both C2"Cg alkoxyalkyl and (Ci-C3)alkox (Ci- C3)alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms. When the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substit¬ uent will be a notation in (parentheses) which will correspond to the same name/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent. II. DEFINITIONS All temperatures are in degrees Centigrade. TLC refers to thin-layer chroma ograph . THF refers to tetrahydrofuran. φ refers to phenyl (CgH 5 ). MS refers to mass spectrometry expressed as m/e or mass/charge unit. [M + H] + refers to the positive ion of a parent plus a hydro¬ gen atom. El refers to electron impact. CI refers to chemical ion- Ization. FAB refers to fast atom bombardment. Ether refers to diethyl ether. Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacologi- cal/toxicological point of view and to the manufacturing pharmaceut¬ ical chemist from a physical/chemical point of view regarding compo- sition, formulation, stability, patient acceptance and bioavailabil- ity. Treating refers to inhibiting and/or preventing. Angiostatic steroids refer to those steroids which prevent the process of angiogenesis/neovascularization, or cause the regression of new vasculature which results from angiogenic stimuli. When solvent pairs are used, the ratios of solvents used are volume/volume (v/v) . EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the ■ various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. PREPARATION 1 6α-Fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(ll)- diene-3,20-dione (V) Methanol (20 ml) and sodium methoxide (25%, 0.2 ml) is added to 6α-fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(ll)-diene-3,20-dione 21-acetate (US Patent 3,291,815, 1.0 g) in methanol. The reaction mixture is neutralized with acetic acid and concentrated to dryness under reduced pressure. The concentrate is distributed between water and chloroform. The organic layer is separated and washed twice with water and dried over anhydrous sodium sulfate. The crude solid is chromatographed over silica gel eluting with ethyl acetate/hexane (35/65). The appropriate fractions are pooled and concentrated to give the title compound, mp 206-207°. PREPARATION 2 6α-Fluoro-17α,21-dihydroxy-16α-methylpregna-l,4,9(ll)- triene-3,20-dione (V) Following the general procedure of PREPARATION 1 and making non- critical variations but starting with 6α-fluoro-17α,21-dihydroxy-16α- methylpregna-4,9(ll)-diene-3,20-dione 21-acetate (US Patent 4,704,358), the title compound is obtained. EXAMPLE 1 6α-Fluoro-17α-hydroxy-16α-methylandrosta-4,9(ll)- dien-3-one 17^-carboxylic acid (VI) THF (26 ml) and periodic acid (0.677 g) in water (10 ml) is added to 611 mg (1.62 mmol) of 6α-fluoro-17,21-dihydroxy-16α-methyl- pregna-4,9(ll)-diene-3,20-dione (V, PREPARATION 1, 611 mg) . The resulting solution is heated at reflux for 2 hours, then cooled to 25° and concentrated under reduced pressure to a volume of 5 ml. Water (15 ml) is added to the residue and the resulting mixture is extracted with ethyl acetate (2 x 25 ml) . The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate, filtered, and con¬ centrated to dryness. The crude material is crystallized from acetone/hexane to give the title compound, mp 213.8-214°, MS calculated 363.1971, found 363.1962. EXAMPLE 2 6α-Fluoro-17α-hydroxy-16α-methylandrosta-4,9(ll)- dien-3-one 17.-carboxylic acid methyl ester 17- acetate (IV) Part I Acetic anhydride (0.5 ml) and triethylamine (0.3 ml) are added to 6α-fluoro-17α-hydroxy-16α-methylandrosta-4,9(ll)-dien-3-one 17J- carboxylic acid (VI, EXAMPLE 1, 300 mg) . The resulting mixture is stirred at 20-25° until dissolution occurrs, and then stirred for an additional 40 min. The reaction solution is concentrated to dryness under reduced pressure, and the residue is dissolved in methanol and allowed to sit at 25° for 30 min. Evaporation of the methanol and final drying under high vacuum gives crude 6α-fluoro-17α-hydroxy-16α- methylandrosta-4,9(ll)-dien-3-one 17jS-carboxylic acid 17-acetate (VII) in quantitative yield, TLC Rf - 0.05 (ethyl acetate/hexane, 35/65). Part 2 The crude 17-acetate (VII) is dissolved in THF (8 ml) and then treated with freshly prepared diazomethane in ether until all of the starting material appeared to have reacted by TLC. The crude product is purified by chromatography over silica gel eluting with ethyl acetate/hexane (25/75) . The appropriate fractions are pooled and concentrated to give the title compound, TLC Rf - 0.6 (ethyl acetate/ hexane (35/65); MS calculated 419.2234, found 419.2212. EXAMPLE 3 6α-Fluoro-17α-hydroxy-16α-methylandrosta-4,9(ll)- dien-3-one 17 -carboxylic acid methyl ester 17-tri- fluoroacetate (IV) Following the general procedure of EXAMPLE 2 (Parts I and II) and making non-critical variations but using trifluoroacetic an¬ hydride, the title compound is obtained, MS calculated 473.1951, found 473.1944. EXAMPLE 4 6α-Fluoro-17α-hydroxy-16α-methylandrosta-4,9(ll)- dien-3-one 17^-carboxylic acid methyl ester 17- propionate (IV) Following the general procedure of EXAMPLE 2 (Part I) and making non-critical variations but using propionic anhydride, 6α-fluoro-17α- hydroxy-16c_-methylandrosta-4,9(ll)-dien-3-one 173-carboxylic acid 17- propionate (VII), is obtained, TLC Rf - 0.05 (ethyl acetate/hexane, 35/65); MS calculated 419.2234, found 419.2212. Following the general procedure of EXAMPLE 2 (Part II) and making non-critical variations but starting with 6α-fluoro-17α- hydroxy-16α-methylandrosta-4,9(ll)-dien-3-one 17^-carboxylic acid 17- propionate (VII), the title compound is obtained, TLC Rf ~~ 0.5 (ethyl acetate/hexane, 35/65); MS calculated 433.2390, found 433.2377. EXAMPLE 5 6α- Fluoro- 17α-hydroxy-16α-methylandrosta-4 , 9 (ll) - dien-3-one 17£-carboxylic acid methyl ester 17- pentafluoropropionate (IV) Following the general procedure of EXAMPLE 2 (Parts I and II) but using pentafluoropripionic anhydride, the title compound is obtained, TLC R f - 0.05 (ethyl acetate/hexane, 35/65); MS calculated 523.1919, found 523.1952. EXAMPLE 6 6α-Fluoro-17α-hydroxy-16α-methylandrosta-4,9(ll)- dien-3-one 17/3-carboxylic acid methyl ester 17- butyrate (IV) Following the general procedure of EXAMPLE 2 (Part I) and making non-critical variations but using butyric anhydride, 6α-fluoro-17α- hydroxy-16α-methylandrosta-4,9(ll)-dien-3-one 173-carboxylie acid 17- butyrate (VII), is obtained, TLC Rf - 0.05 (ethyl acetate/hexane, 35/65); MS calculated 433.2390, found 433.2377. Following the general procedure of EXAMPLE 2 (Part II) and making non-critical variations but starting with 6 -fluoro-17α- hydroxy-16α-methylandrosta-4,9(ll)-dien-3-one 173-carboxylic acid 17- butyrate (VII), the title compound is obtained, TLC Rf - 0.5 (ethyl acetate/hexane, 35/65); MS calculated 447.2547, found 447.2533. EXAMPLE 7 6α-Fluoro-17α-hydroxy-16/3-methylandrosta-4,9(11)- dien-3-one 17/3-carboxylic acid (VI) Following the general procedure of EXAMPLE 1 and making non- critical variations but starting with 6α-fluoro-17,21-dihydroxy-16J- meth lpregna-4,9(11)-diene-3,20-dione (V, US Patent 4,088,537, Preparation 3, 3.00 g) , the title compound is obtained, mp 215-216° with decomposition; MS calculated 363.1971, found 363.1952. EXAMPLE 8 6α-Fluoro-17α-hydroxy-160-methylandrosta-4,9(ll)- dien-3-one 17/3-carboxylic acid methyl ester Following the general procedure of EXAMPLE 2 (Part II) but starting with 6α-fluoro-17α-hydroxy-16/3-methylandrosta-4,9(ll)-dien- 3-one 173-carboxylic acid (VI, EXAMPLE 7, 181 mg) , the title compound is obtained, TLC R f - 0.8 (ethyl acetate/chloroform, 25/75), mp 181- 182°; MS calculated 377.2128, found 377.2146. EXAMPLE 9 6α-Fluoro-17α-hydroxy-16^-methylandrosta-4,9(11)- dien-3-one 17.-carboxylic acid methyl ester 17- propionate (IV) Following the general procedure of EXAMPLE 4 but starting with 6α-fluoro-17α-hydroxy-160-methylandrosta-4,9(ll)-dien-3-one 170- carboxylic acid (VI, EXAMPLE 7, 250 mg) , 6α-fluoro-17α-hydroxy-160- methylandrosta-4,9(ll)-dien-3-one 170-carboxylic acid 17-propionate (VII), mp 191° with bubbling; MS calculated 419.2234, found 419.2250 and 6α-fluoro-17α-hydroxy-160-methylandrosta-4,9(ll)-dien-3-one 170- carboxylic acid methyl ester 17-propionate (IV) are obtained, TLC Rf - 0.8 (ethyl acetate/hexane, 25/75); mp 165-166 ; MS calculated 433.2390, found 433.2398. EXAMPLE 10 6α-Fluoro-17α-hydroxy-160-methylandrosta-4,9(ll)- dien-3-one 170-carboxylic acid methyl ester 17- butyrate (IV) Following the general procedure of EXAMPLE 6 but starting with 6α-fluoro-17α-hydroxy-160-methylandrosta-4,9(ll)-dien-3-one 170- carboxylic acid (VI, EXAMPLE 7), 6α-fluoro-17α-hydroxy-160-methyl- androsta-4,9(ll)-dien-3-one 170-carboxylic acid 17-butyrate (VII), mp 150-152°; MS calculated 433.2390, found 433.2418 and 6α-fluoro-17α- hydroxy-160-methylandrosta-4,9(ll)-dien-3-one 170carboxylic acid methyl ester 17-butyrate (IV) are obtained, TLC Rf - 0.8 (ethyl acetate/hexane, 25/75), mp 166-167°; MS calculated 447.2547, found 447.2564. EXAMPLE 11 6α-Fluoro-17α-h y droxy-16α-methylandrosta-l,4.9(11)- trien-3-one 170-carboxylic acid (VI) Following the general procedure of EXAMPLE 1 and making non- critical variations but starting with 6 -fluoro-17a,21-dihydroxy-16α- meth lpregna-l,4,9(ll)-triene-3,20-dione (V, PREPARATION 2, 0.25 g) , the title compound is obtained, mp 204.8-205.3°; MS calculated (for C21H25FO4) 360.1737, found 360.1715. EXAMPLE 12 6α-Fluoro-17α-hydroxy-16α-methylandrosta-l,4,9(ll)- trien-3-one 170-carboxylic acid methyl ester 17- propionate (IV) Following the general procedure of EXAMPLE 2 (Parts I and II) and making non-critical variations but starting with 6α-fluoro-17 - hydroxy-16α-methylandrosta-l,4,9(ll)-trien-3-one 170-carboxylic acid (VI, EXAMPLE 11, 250 mg) and using propionic anhydride, the title compound is obtained, mp 172-172.5°; TLC Rf - 0.6 (ethyl acetate/- hexane, 35/65), MS calculated (for C25H31FO5) 430.2155, found 430.2156. EXAMPLE 13 6α-Fluoro-17α-hydroxy-16α-methylandrosta-l,4,9(ll)- trien-3-one 170-carboxylic acid methyl ester 17- butyrate (IV) Following the general procedure of EXAMPLE 2 (Parts I and II) and making non-critical variations but starting with 6 -fluoro-17 - hydroxy-16α-methylandrosta-l,4,9(ll)-trien-3-one 17 -carboxylic acid (VI, EXAMPLE 11, 250 mg) and using butyric anhydride, the title compound is obtained, TLC Rf - 0.6 (ethyl acetate/hexane, 35/65); mp 141-141.5°; MS calculated (for C 2 H33F0 5 ) 444.2312, found 444.2309. CHART A 15 (III) CHART A - Continued 10 X-R 21 (IV) 7 CHART B CH 2 -0H of C 20 carboxyl

Claims: CLAIMS 1. A method of treating angiogenesis in a warm blooded mammal who is in need of such treatment which comprises administration of an angio¬ genic inhibiting amount of a combination of a suramin-type compound and an angiostatic steroid. 2. A method of treating angiogenesis according to claim 1 where the mammal is a human. 3. A method of treating angiogenesis according to claim 1 where the suramin-type compound is selected from the group consisting of suramin, 3-hydroxy-2,7-naphthalenesulfonic acid, 4,5-dihydroxy-2,7-naphthalenedisulfonic acid, 2,2' - [ (1,8-dihydroxy-3 , 6-disulfo-2 ,7-napthylene)bis(azo]di- benzenearsonic acid, 4,4' -bis[ [4- (o-hydroxyanilino)-6-(m-sulfoanilino)-s-triazin-2- yl]amino] -2,2'stilbenedisulfonic acid, 4,5-dihydroxy-3- [ (p-nitrophenyl)azo] -2,7-naphthalenedisulfonic acid, 4, 5-dihydroxy-3,6-bis[ (4-sulfo-l-naphthyl)azo] -2,7-naphthalene¬ disulfonic acid, 3- [(5-chloro-2-hydroxyphenyl)azo] -4,5-dihydroxy-2,7-naphthalene¬ disulfonic acid, 4,5'-dihydroxy-3,6' [ (3,3' -dimethoxy-4,4'-biphenylylene)bis(azo)- di-1-naphthalenesulfonic acid, 3, 6- [ (2, 3-dimethyl-5-oxo-l-phenyl-3-pyrazolin-4-yl)azo] -4,5- dihydroxy-2,7-naphthalenedisulfonic acid, 5,5' - [ureylenebis[2-sulfo-p-phenylene)azo]bis[6-amino-4-hydroxy- 2-naphthalenesulfonic acid, 4- [ (o-arsonophenyl)azo]3-hydroxy-2,7-naphthalenedisulfonic acid, 4,5-dihydroxy-3-(phenylazo)-2,7-naphthalenedisulfonic acid, 4-acetamido-5-hydroxy-6- (phenylazo)-1,7-naphthalenedisulfonic acid, 2- [p- [ (l-hydroxy-4-sulfo-2-naphthyl)azo]phenyl] -6-me hyl-7- benzothiazolesulfonic acid, 4- [ (2 ,4-dimethylphenyl)azo] -3-hydroxy-2,7-napthalenedisulfonic acid, 3 - [ (4- Sulfophenyl) azo] -4 , 5 -dihydroxy -2 , 7 -nap thalenedisulfonic acid, 3 - [ ( 4 - nitrophenyl) azo ] -4-amino- 5 -hydroxy- 2 , 7 -naphthalene - disulfonic acid, l-nitro-4,6,8-naphthalenetrisulfonic acid, l-amino-4,6,8-naphthalenetrisulfonic acid and pharmaceutically acceptable salts thereof. 4. A method of treating angiogenesis according to claim 1 where the suramin-type compound is suramin and 4,4'-bis[[4-(o-hydrox anilino)- 6-(m-sulfoanilino)-s-triazin-2-yl]amino]-2,2'stilbenedisulfonic acid. 5. A method of treating angiogenesis according to claim 1 where the suramin-type compound is suramin. 6. A method of treating angiogenesis according to claim 1 where the angiostatic steroid is selected from the group consisting of 20-substituted steroids of formula (I) where R4, Rg and Rg are be the same or different and are -H, -F, -Cl; Rll is chosen from the group consisting of hydroxy and keto; R20 chosen from the group consisting of hydroxy, methoxy and thiomethyl; and Rl7 is chosen from the group consisting of alkyl groups having less than 6 carbon atoms; 21-hydroxy steroids of formula (II) where the dotted line between positions C-l and C-2 means the presence or absence of a double bond; the - bond at C-6 denotes α or 0; R g is CH 3 or -C2H5; Rig is CH3 or -C2H5; R9 is H, and R-^i is in the α-position and is -OH, -0-alkyl- (Ci-C^), -0C(-0)alkyl(Cι-Cι 2 ). -0C(-0)aryl, -0C(-0)N(R) 2 , or where aryl is furyl, thienyl, pyrrolyl, or pyridyl optionally substituted with one or two (C -C )-alkyl groups or aryl is - CH2)f-phenyl wherein f is 0 to 2 and wherein the phenyl ring is optionally substituted with one to three groups selected from chlor¬ ine, fluorine, bromine, alkyl(Cι-C3) , alkoxy(Ci-C3) , thioalkoxy- (C1-C3), CI3C-. F3C-, -NH 2 and -NHCOCH3 and wherein R is hydrogen, alk l(C -C ) , or phenyl and each R can be the same or different; and Rg_l is aryl as herein defined or alkyl(Ci-C12) ; or Rg is α-Cl and R^ is 0-C1; or Rg and R^ taken together are oxygen (-0-) bridging positions C-9 and C-ll; or Rg and Rn taken together form a double bond between positions C-9 and C-ll; R 2 is H, CH 3 , Cl or F; Rg is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; R 7 is H or CH3; R is -CH2 or α-Ri6-l : .S-Ri6-2 where one of Ri -i and Ri .2 is -H and the other of Rig.i and R g.2 is H, OH, CH3 or F; and R 7 is H, OH, CH3 or Rig and R 7 are taken together to form a second bond between positions C-16 and C-17; C i-functionalized steroids of formula (III) where Rl is 0-CH 3 or 0-CH 2 H 5 ; wherein R2 is H, and R3 is -=0, OH, -0-alkyl(C -Ci2) , -OC(-O) -alkyl- (Cι-C 12 ) > -OC(=0)aryl, -0C(-=0)N(R) 2 , or -0C(=0)0R 7 , wherein aryl is furyl, thienyl, pyrrolyl, or pyridyl wherein each of said hetero moiety is optionally substituted with one or two (Cι-C )alkyl groups or aryl is -(CH2)f-phenyl wherein f is 0 to 2 and wherein the phenyl ring is optionally substituted with one to 3 groups selected from chlorine, bromine, alk l(Cι-C ) , alkoxy(C -C3) , thioalkox (Cι-C3 , CI3C-, F3C-, -NH 2 and -NHCOCH3 and wherein R is hydrogen, alkyl(Cι- C4) , or phenyl and each R can be the same or different; and wherein R7 is aryl as hereindefined or alkyl(Ci-C12) ; or wherein R2 isα-Cl and R3 is 0-C1; or wherein R and R3 taken together are oxygen (-0-) bridging positions C-9 and C-ll; wherein R2 and R3 taken together form a second bond between positions C-9 and C-ll; or R2 is α-F and R 3 is 0-OH; wherein R4 is H, CH3, Cl or F; wherein R5 is α-R5_ι: -R5.2 where one of R5.1 and R5.2 i " H and the other of R5.1 and R5.2 s H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; wherein Rg is H or CH3; wherein Rg is « =CH2 or α-Rg_ι_0-Rg_2 where one of Rg_ι and R9.2 is -H and the other is H, OH, CH3, F or - " CH2; wherein RIQ is H, α-OH, α-CH3 or R Q forms a second bond between positions C-16 and C-17; wherein R 2 is α-H, 0-H or forms a second bond with R14; wherein R13 is -0 or α-Ri3_ι:0-Ri3.2 where one of R13. and R13.2 -H and the other of R13.1 and R13.2 is -OH, -0-P(0)(0H) , or -0-C- (-0)-(CH2) t COOH where t is an integer from 2 to 6; wherein R is H or forms a second bond with R12. wherein R15 is -0 or <*- i5-.ι:/9*Rl5-2 where one of R15-I and R15.2 is -H and the other is -OH; wherein R23 with R Q forms a cyclic phosphate of the formula IV wherein Rg and R15 have the meaning defined above; or wherein R23 is -OH, 0-C(-)-Rn, -0-P(0)(0H) 2 , or -O-C(-O)-(CH 2 ) t C00H wherein t is an integer from 2 to 6; and Rn is -Y-(CH 2 ) n -X-(CH 2 ) m -Sθ3H, -Y'-(CH 2 ) p - X'-(CH 2 ) q -NR gRi7 or -Z(CH 2 ) r Q, wherein Y is a bond or -0-; Y' is a bond, -0-, or -S-; each of X and X' is a bond, -CON(Rιg)-, -N(Rιg)C0- , -0-, -S-, -S(0)-, or -S(θ2)-; Ri β is hydrogen or alkyl(Cι-C4) ; each of Ri and R is a lower alkyl group of from one to 4 carbon atoms optionally substituted with one hydroxyl or Ri and R17 taken together with the nitrogen atom to which each is attached forms a monocyclic heterocyclic selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N(lower)alkylpiperazino wherein alkyl has from one to 4 carbon atoms; n is an integer of from 4 to 9; m is an integer of from one to 5; p is an integer of from 2 to 9; q is an integer of from one to 5; Z is a bond or -0-; r is an integer of from 2 to 9; and Q is (1) -Rιg-CH 2 C00H wherein R i9 is -S-, -S(0)-, -S(0) 2 -, -S0 2 N- ( 20_"> or - N ( R 20) Su 2"! an 20 s hydrogen or lower alkyl(Cι-C ) ; with the proviso that the total number of carbon atoms in R20 aι * d (CH2) r is not greater than 10; (2) -C0-C00H; or (3) -CON(R 2 ι)CH(R 2 2)COOH wherein R 2 ι is H and R 2 2 is H, CH3, -CH 2 C0OH, -CH 2 CH 2 COOH, -CH 2 0H, -CH 2 SH, -CH2CH2SCH3, or -CH 2 Ph-0H wherein Ph-OH is p-hydroxyphenyl; or R21 is CH3 and R22 is H; or R21 and R 2 2 taken together are -CH2CH2CH2-; or -N(R2i)CH(R22)COOH taken together is -NHCH2CONHCH2COOH; and pharmaceutically acceptable salts thereof; with the further provisos that: (a) when n is 2, Ri is other than hydrogen; (b) the sum of m and n is not greater than 10; (c) the sum of p and q is not greater than 10; (d) when X is a bond the sura of m and n is from 5 to 10; (e) when X' is a bond the sum of p and q is from 4 to 9; (f) when R4 is Cl or F, the C-l position is saturated; and (g) when Rg is -CH2, R o is other than a second bond between positions C-16 and C-17; and mono and bis salts thereof; Δ"(II -etianic esters of formula (IV) where (A-I) Rio is o_-Rιo_ι:0-Rιo-2 where Ri0-2 is -CH3, R 10-l and R 5 taken together are -CH2-CR2-CR3-CH- where R2 is α ' R 2-l : /3" R 2-2 where one of R2-I and R2.2 is * H and the other of R2.1 and R2-2 i -H, -CH3, -Cl or -F, where R3 is -0 or α-R3.ι:0-R3_2 where one R3.1 and R3_2 is -H and the other of R3.1 and R3.2 is -OR3.3 where R3.3 is -H, -P0(0H) 2 or -SO3H; (A-II) Rio is α-Rιo_3:0-Rιo-4 where RIQ.4 is -CH3, Rιo-3 and R5 taken together are -CH=CH-C0-CH«; (A-III) Rio is O; -RIO-5 : - R 10-6 and R 5 is where R 10-6 is _CH 3> one of R 5-5 and R 5 .g is -H and the other of R5.5 and R 5 .g taken with io-5 i -CH2-CR2-CR3-CH2- where R2 and R3 are as defined above; Rg is α-Rg_ι:0-Rg_2 where one of Rg_ι and Rg_2 i -H and the other of Rg_ι and g_2 i -H, -F, -Cl, -Br and -CH3; R7 is α-R7_ :0-R7_2 where one of R7.1 and R7.2 is -H and the other of 7.1 and R7.2 is -H or -CH3; Ri is =CH 2 or α- R i6-i:0- R l6-2 where one of Rιg_ι and Rig.2 -H and the other of Rι _ and Ri .2 is -H, -CH3, -OH or -F; R 7 is C1-C20 alkyl, CI-CIQ fluoroalkyl containing from 1-23 -F atoms, Ci-C alkoxy, (C -Cg)alkylamino(Cι-Cg)alkyl, (C5-C 7 )c clo- alkyl Ci-C )alkyl, phenyl(Ci-Cg alkyl optionally substituted with 1-3 -CH 3 , -F, -Cl, -OH, -0CH 3 , -0C 2 H 5 and -NH 2 , C 3 -C 8 cycloalkyl, C 2 -C 10 alkenyl, (C3-C )cycloalkyl(C2-C10) alkenyl; X is -0- or -S-; R 2 ι is C -C10 alkyl optionally substituted with 1 to 10 -F, -Cl or -Br, c 2* c 10 alk Yl substituted with 1 to 10 -OH, -CH2-COOR21. where R21-I is CI-CIQ alkyl, C3-C cyclo¬ alkyl, C3-Cg cycloalkenyl, C2-C10 alkenyl containing 1 thru 4 double bonds optionally substituted with -OH, -F, -Cl or -Br, -(CH2) n ι-phenyl where i is 0 or 1 and phenyl is optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH, -OCH3, -OC2H5. C1-C alkyl, -NH 2 , -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or -N0 2 , -CH2-CO-NR21.2R2I-3 where R21-2 and R 21-3 are t ^ ιe same or different and are -H, CI-CIQ alkyl, C3-C cycloalkyl, -φ , -CH2-^ and where R2I-2 and 21-3 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidine, 1-piperidine, 1-piperazine and 1-morpholine, 6α-fluoro-17α,21-dihydrox -16α-methylpregna-4,9(11)-diene-3,20- dione, 6α-fluoro-17α,21-dihydroxy-16 -meth lpregna-4,9(11)-diene-3,20- dione 21-acetate, 6α-fluoro-17α,21-dihydroxy-160-meth lpregna-4,9(11)-diene-3,20- dione, 6α-fluoro-17α,21-dihydroxy-160-methylpregna-4,9(ll)-diene-3,20- dione 21-phosphonooxy, hydrocortisone, tetrahydrocortisol, 17α-hydroxyprogesterone, llα-epihydrocortisone, cortexolone, corticosterone, desoxycorticosterone, dexamethasone, cortisone 21-acetate, hydrocortisone 21-phosphate, 17α-hydroxy-6α-methylpregn-4-ene-3,20-dione 17-acetate. 7. A method of treating angiogenesis according to claim 1 where the angiogstatic steroid is selected from the group consisting of Δ' ii '-etianic esters of formula (IV) where Rχo is α-Rιo_ι:0-Rιo.2 where Rιo_2 is -CH 3 , ιo-1 and R 5 taken together are -CH2-CR2-CR3-CH- where R 2 is -H:-H and R3 is -0, Rg is α-Rg_ι:0-Rg_2 where Rg_2 is -H and Rg.i is -H, -F and -CH3, R 7 is -H:-H, Ri is ee- ι -i:0-Ri6-2 where one of Ri - and Rig.2 "H and the other of Rιg_ and R .2 is -CH3, Rl is C1-C alkyl or -(CF2) n 2-CF3 where n2 is 0-3, R2 is C1-C4 alkyl, X is -0-; 20-substituted steroids of formula (I), where R4 is -H, Rg and Rg are be the same or different and are -H, -F, -Cl, Rll is chosen from the group consisting of hydroxy and keto, R20 is chosen from the group consisting of methoxy and thiomethyl, and l7 is chosen from the group consisting of alkyl groups having less than 6 carbon atoms; 6α-fluoro-17α,21-dihydroxy-16α-meth lpregna-4,9(11)-diene-3,20- dione 21-acetate, 6α-fluoro-17α,21-dihydroxy-160-methylpregna-4,9(ll)-diene-3,20- dione, 6α-fluoro-17α,21-dihydroxy-160-methylpregna-4,9(11)-diene-3,20- dione 21-phosρhonooxy, hydrocortisone, tetrahydrocortisol, 17α-hydroxyprogesterone, llα-epihydrocortisone, cortexolone, corticosterone, desoxycorticosterone, dexamethasone, cortisone 21-acetate, hydrocortisone 21-phosphate, 17α-hydroxy-6α-methylpregn-4-ene-3,20-dione 17-acetate, 6α-fluoro-17α,21-dihydroxy-16α-meth lpregna-4,9(11)-diene-3,20- dione. 8. A method of treating angiogenesis according to claim 1 where the angiogstatic steroid is selected from the group consisting of 6α-fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(11)-diene-3,20- dione 21-acetate, 6α-fluoro-17α,21-dihydroxy-160-methylpregna-4,9(11)-diene-3,20- dione, 6α-fluoro-17α,21-dihydroxy-160-meth lpregna-4,9(11)-diene-3,20- dione 21-phosphonooxy, hydrocortisone, tetrahydrocortisol, 17α-hydroxyprogesterone, llα-epihydrocortisone, cortexolone, corticosterone, desoxycorticosterone, dexamethasone, cortisone 21-acetate, hydrocortisone 21-phosphate, 17α-hydroxy-6α-methylpregn-4-ene-3,20-dione 17-acetate, 6α-fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(11)-diene-3,20- dione. 9. A method of treating angiogenesis according to claim 1 where the the route of administration of the suramin-type compounds is IV and the route of administration of the angiostatic steroids is oral or parenteral. 10. A method of treating angiogenesis according to claim 1 where the the suramin-type compound and angiostatic steroid are not adminis¬ tered in one dosage unit. -so¬ il. A method of treating angiogenesis according to claim 1 where the dose of the suramin-type compound is from about 1 to about 1000 mg/ m da and the dose of angiostatic steroid is from about 0.1 to about 100 mg/kg/day. 12. A method of treating angiogenesis according to claim 1 where the treating angiogenesis is treating diseases of neovascularization. 13. A method of treating angiogenesis according to claim 12 where neovascular diseases are selected from the group consisting of solid tumors, diabetes, arthritis, atherosclerosis, neovascularization of the eye, parasitic diseases, psoriasis, abnormal wound healing proc¬ esses, hypertrophy following surgery, burns, injury, hair growth, ovulation and corpus luteum formation, implantation and embryo development in the uterus. 14. A method of treating angiogenesis according to claim 12 where the neovascular disease is solid tumors, diabetes, arthritis or psoriasis. 15. A Δ 9 L1)-etianic ester of formula (IV) X-R 21 where: (A-I) IQ is a-Rio-i:/3-RlO-2 where Rιo-2 is -CH 3 , R-10-1 and R5 taken together are -CH2-C 2-CR3-CH- where R2 is o_" R 2-l : .~ R 2-2 where one of 2-I and 2-2 i "-- an t * ιe other of R2-I and R -2 i " H . -CH3, -Cl or -F, where R3 is -0 or α-R3_ι: -R 3 _2 where one 3. and R3.2 i -H and the other of R3.1 and R3.2 i -OR3.3 where R3.3 is -H, -P0(0H) 2 or -SO3H; (A-II) R i0 is α-R 0 .3: -R 10 . where Rιo- i -CH 3 , Ri0-3 and R 5 taken together are -CH-CH-C0-CH-; (A-III) Rio is αr-RiQ_ 5 :0-Rιo_g a ™* R5 is α-R 5 _5:0-R 5 .g, where Riθ-6 is " H 3> one °f R 5-5 and R 5-6 is " H and lve otlιer of R 5-5 and R 5 .g taken with R 0-5 is -CH2-CR 2 -CR3-CH2- where R 2 and R3 are as defined above; Rg is α-Rg_ι:0-Rg.2 where one of Rg.i and Rg_2 is -H and the other of Rg.i and Rg.2 is -H, -F, -Cl, -Br and -CH3; R7 is α-R7.ι: -R7_2 where one of R7.1 and R7.2 is -H and the other of R7.1 and R7.2 is -H or -CH3; Rig is -CH2 or <*-Rι -i: -Rι _2 where one of R g_ι and Ri .2 -H and the other of Ri .i and Rig.2 is -H, -CH3, -OH or -F; R 17 is C1-C20 alkyl, Cι-C 10 fluoroalkyl containing from 1-23 -F atoms, Ci-Cg alkoxy, (C -Cg)alkylamino(Cι-Cg) lkyl, (C5-C7)cyclo¬ alkyl(Ci-Cg)alkyl, phenyl(Cι-Cg)alkyl optionally substituted with 1-3 -CH 3 , -F, -Cl, -OH, -OCH3, -° C 2 H 5 and _NH 2 > c 3" c 8 cycloalkyl, C 2 -Cι 0 alkenyl, (C3-C )cycloalkyl(C2-C Q ) alkenyl; X is -0- or -S-; R 2 ι is CI-CIQ alkyl optionally substituted with 1 to 10 -F, -Cl or -Br, c 2" c 10 aik yl substituted with 1 to 10 -OH, -CH2-COOR21. where R21-I is CI-C Q alkyl, C3-Cg cyclo¬ alkyl, C3-Cg cycloalkenyl, C2-C 0 alkenyl containing 1 thru 4 double bonds optionally substituted with -OH, -F, -Cl or -Br, -(CH2 n ι-phenyl where ni is 0 or 1 and phenyl is optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH, -OCH3, -OC2H5, C1-C alkyl, -NH 2 , -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or -N0 2 , -CH2-CO- R21.2R2I-3 where R21.2 and 21-3 are tιe ame or different and are -H, CI-CIQ alkyl, C3~C cycloalkyl, -φ , -C^-^ and where R21-2 and R 21-3 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidine, 1-piperidine, 1-piperazine and 1-morpholine. 16. A Δ' (ii -etianic ester of formula (IV) according to claim 15 where RIQ is α-RiQ_ι:0-Rιo-2 where Rιo_2 i -CH3, Rio-l and R5 taken together are -CH2-CR 2 -CR3-CH= where R2 is -H:-H and R3 is =0. 17. A Δ 0 ^-*- -etianic ester of formula (IV) according to claim 15 where Rg is α-Rg_ι:0-Rg_2 where Rg.2 i -H and Rg_ι is -H, -F and -CH 3 . 18. A Δ 9 ^^- -etianic ester of formula (IV) according to claim 15 where Ri is <*-R g_ι:0-Rιg_2 where one of Rig.i and Ri .2 -H and the other of Rιg_ι and Rι _2 is -CH3. 19. A Δ°(H)-etianic ester of formula (IV) according to claim 15 where R 7 is C1-C alkyl. 20. A Δ' L I)-etianic ester of formula (IV) according to claim 15 where R1 is -(CF2 n 2"CF3 where n2 is 0-3. 21. A Δ 9( ϋ ) -etianic ester of formula (IV) according to claim 15 where R21 is C -C alkyl. 22. A Δ'(ii)-etianic ester of formula (IV) according to claim 15 where X is -0-. 23. A Δ'^i i )-etianic ester of formula (IV) according to claim 15 where where the Δ 9 (ϋ)-etianic ester is selected from the group consisting of 6α-fluoro-17α-hydroxy-16α-methylandrosta-4,9(ll)-dien-3-one 170- carboxylic acid methyl ester 17-acetate, 6α-fluoro-17α-hydroxy-16α-methylandrosta-4,9(ll)-dien-3-one 170- carboxylic acid methyl ester 17-trifluoroacetate, 6α-fluoro-17α-hydroxy-16α-methylandrosta-4,9(ll)-dien-3-one 170- carboxylic acid methyl ester 17-propionate, 6α-fluoro-17α-hydroxy-16α-methylandrosta-4,9(ll)-dien-3-one 170- carboxylic acid methyl ester 17-pentafluoropropionate, 6α-fluoro-17α-hydroxy-16α-methylandrosta-4,9(ll)-dien-3-one 170- carboxylic acid methyl ester 17-butyrate, 6α-fluoro-17α-hydroxy-160-methylandrosta-4,9(ll)-dien-3-one 170- carboxylic acid methyl ester 17-ρropionate, 6α-fluoro-17α-hydroxy-160-methylandrosta-4,9(ll)-dien-3-one 170- carboxylic acid methyl ester 17-butyrate, 6α-fluoro-17α-hydroxy-16α-methylandrosta-l,4,9(ll)-trien-3-one 170-carboxylic acid methyl ester 17-propionate, 6α-fluoro-17α-hydroxy-16α-me hylandrosta-l,4,9(ll)-trien-3-one 17 -carboxylic acid methyl ester 17-butyrate. 24. 6α-Fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(11)-diene-3,20- dione.

Inventors: ARISTOFF PAUL A, MITCHELL MARK A, WILKS JOHN W, ARISTOFF, PAUL, A., MITCHELL, MARK, A., WILKS, JOHN, W.
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1990
Main classification: A61K31
IPC codes: A61K31, A61P3, A61P9, A61P13, A61P15, A61P17, A61P27, A61P33, A61P35, C07J3, C07J31, C07J43