JPH04506066A - Suramin-type compounds and anti-angiogenic steroids to inhibit angiogenesis - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Suramin-type compounds and antiangiogenic steroids to inhibit angiogenesis Ids The present invention relates to sumarin or sumarin-type compounds and vasostatic steroids. (angiostatic 5teroid) and feeding that requires it A method of treating angiogenesis in an animal. Diseases for which this combination can be used are angiogenic diseases such as cancer, diabetes and arthritis.

2. Description of related technology Angiogenesis is typically the development of blood vessels leading to a vascular bed that can sustain viable tissue. It is. Vasculogenesis is a process necessary for the establishment of embryonic tissue and the development of a viable embryo. Ru. Similarly, angiogenesis plays a role in the establishment and development of tumor tissues and certain inflammatory diseases. This is a necessary process. Inhibition of angiogenesis is associated with embryogenesis, inflammatory diseases, and tumor progression, among others. and may be useful in controlling a number of other diseases.

European Patent Application No. 83870132.4 published August 1, 1984 (Publication number 01 14589) in combination with heparin in inhibiting angiogenesis. 11α-hydrocortisone, hydrocortisone, and 11α-hydrocortisone. Ru.

The antiangiogenic effect of heparin and heparin fragments in combination with cortisone is Science 221. □Listed in 719 (19133) There is. The use of heparin and heparin fragments in combination with hydrocortisone AA It is described in the newsletter of CR 26, 384 (1985).

Heparin is currently used as an inhibitor of angiogenesis, especially to treat diseases involving angiogenesis. used in conjunction with vasostatic steroids. Biochemical Pharmacology - (Biochem, P'harmaco1.) 34.905 (1985) and Annals or Surgery 2 See 06.374 (1987). The heparin may be used in combination with other drugs, such as L-azetidide. Enhances the angiogenesis inhibitory activity of collagen biosynthesis inhibitors such as carboxylic acids.

The problem with using heparin is that the effectiveness of each manufacture/batch of heparin is Anti-angiogenic therapy, including steroids, is different due to the chemical mixture of phosphorus molecules. It is known that it can be used as a substitute for heparin in medical treatment. Science ( See) 243.1490 (1989).

Suramin has been shown to bind to its receptors in the fibroblast acid, Nagashio, during in vitro experiments. suppress the occurrence of Fibroblast growth factor is one of many known vascular growth factors. be. Journal on Cellular Physiology (J, Ce1l Ph ysiol, ), 132.143 (1987).

Suramine and 4,4″-bis[[4-(o-hydroxyanilino)-f3-( m-sulfoanilino)-, s-triazin-2-ylcoamino]-2.2° Tilbendisulfonic acid is reported to have antitumor activity. Cancer (Ga nn) 6.1.569 (1970) and Journal on Clinic See Colo, G. (J, Cl1n, 0nco1.) 7.499 (1989). .

U.S. Pat. No. 4,599,331 is useful as an anti-angiogenic agent and is Discloses 20-substituted Δ1.4-16-methylsteroids having no heavy bonds. .

U.S. Pat. No. 4,771,042 discloses steroids with heparin or heparin fragments. 21-hydroxysteroids useful in inhibiting angiogenesis, including co-administration with is disclosed.

International Application Publication No. WO 37102672 discloses various CIt- Functionalized steroids are disclosed.

The Journal on the Pear Cancer Institute (T he Journal of the National Cancer In 5 titute) 8L 1346 (1989) states that ``Suramin also has anti-angiogenic activity. "It appears to have a sexual nature."

The combination of suramin-type compounds and vasostatic steroids is effective in warm-blooded mammals. was found to treat angiogenesis.

Dervent abstract 89- No. 300681/41 discloses that suramin has anti-cancer utility.

Summary of the invention Specialized in administering a combination of suramin-type compounds and vasostatic steroids. Treating angiogenesis in warm-blooded mammals in need of treatment for symptomatic angiogenesis Disclose the method.

Also, formula (■): [In the formula, (A-1) RIO is α-R8o-1:β-R10-1, where R1G-1 is - CH,, R,, and R2 together represent -CH, -CH, -CH, -CH= , where R3 is α-R8-1:β-Rt-t, where Rt-1 and R1- One of 3 is -H, and the other of R8-1 and R1-2 is -H, -CH ,, -CQ or -F1 where R is =O or a-R, -0: 13-R s-*, Coconi% One of Rs-r and R3-t is -H and Rs- The other of + and Rs-* is "-ORs -z, where R1-8 is -H, - PO(OH)! or -SO,H.

(A-n)R,. is α-R1゜-3: β-R6゜-4, where R8゜=4 is - CH,, R2゜1 and R5 together form -CH-CH-Co-CH=; (A-f[[)R,O is α-R+a-s:β-RIG-@ and R5 is α-R s-s: β-R, -1, where R8°-6 is -CH,, R7-5 and R61 , one of which is -H and the other of R1-1 and L-* is equal to R+o-s. Together -CHI-CRI-CR, -CH, -1 where R8 and R3 are Same as above definition; R1 is α-Rs-t:β-R1-8, where one of R1-1 and R1-2 One is -H, and the other of Ro-1 and R1-2 is -H and -F.

CQs -Br or -CHs; R1 is α-R,-, :β-R,,8, Hey, R? -1 and Rt- one of which is -H and R7-1 and R, -1 The other is -H or -CH3; R1, is Tomi CH4 or α-R8o-1: β-RI@-1, where R+s-+ or and RI@-1, one is -H, and the other of Rre-+ and RIO-* -H, -CH,, -OH or -F; R1? is C, -C,. Alkyl, 1~ C, -C,, fluoroalkyl, (C, -C,)a containing 23 -F atoms lucylamino(C,-Cs)alkyl, (C,-C,)cycloalkyl(C,- C,) alkyl, optionally 1 to 3 =CH,, -F, -CQ, -OH, - Phenyl (C, +C6) alkyl, C, -C, cycloalkyl, c, -c to alkenyl, (Cs C0) cycloalkyl (cm-ct.) alkenyl: X is partially - or -S-: Rtt is C, -C, optionally substituted with 1 to 10 -F, -CQ or -Br. a Lucil, C, -C,, alkyl substituted with 1 to 10 =CH, R□-3 is C, -C, , alkyl, C, -C, cycloalkyl, C, -C, cycloalkenyl, optionally may be substituted with 10H, -F, -C& or -B (, 1 to 4 di C, -C, containing a heavy bond. alkenyl-CH,-COOR,,,n l is 0 or 1 and phenyl is optionally 1 to 3 F, CQ, Br, OH ,OCH3,-0C,H,,C,-C.

Alkyl, -NH,, N (CH3)t, -N (C, H,), or -NO -(CHI)nl-phenyl optionally substituted with 2; R□1 and Rff1 l-3 is the same or different, -H, C, -C,, alkyl, C, -C, cycloa Rukiru, -φ, -CH, -φ, or R1+-1 and R1+-3 together with the bonded nitrogen atom to form 1-pyrrolidine, 1-piperidine, 1-piperazi 1CH,- forming a heterocycle selected from the group consisting of Co-NR□-fRlll] Δ9(1)-ethianic acid ester Disclose the tell.

Detailed description of the invention The present invention describes the vasoformation of suramin-type compounds in combination with vasostatic steroids. For warm-blooded mammals in need of angiogenic treatment characterized by the administration of growth-inhibiting doses. including methods of treating angiogenesis in a patient.

Preferably, the mammal is a human.

Suramin-type compounds mimic the antiangiogenic effects of suramin and are vasostatic drugs. It is a compound that increases the activity of terrorism. Suramin and suramin-type compounds The materials are known to those skilled in the art. The suramin type compound is suramin, 3-hydroxy-2,7-naphthalenesulfonic acid, 4,5-dihydroxy-2, 7-Naphthalenedisulfonic acid, 2.2°-[(1,S-dihydroxy-3,6- Disulfo-2゜7-naphthylene)bis(azo)dibenzene arsonic acid, 4.4' -bis[[4-(o-hydroxyanilino)-6-(m-sulfoanili/)-s -) riazin-2-yl]amino]-2.2'stilbenedisulfonic acid, 4.5-dihydroxy-3-[(p-nitrophenyl)azo]-2,7-naphtha rangesulfonic acid, 4.5-dihydroxy-3,6-bis[(4-sulfo-1-naphthyl)azo]- 2.7-naphthalenedisulfonic acid, 3-[(5-chloro-2-hydroxyphenylphenyl) azo]-4,5-dihydroxy-2,7-naphthalenedisulfonic acid, 4.5 ゛-dihydroxy-3,6'　[(3,3'-dimethoxy-4゜4゛-bipheny rylene)bis(azo)-di-1-naphthalenesulfonic acid, 3.6-[(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazoline -4-yl)azo]-4,'5-dihydroxy-2゜7-naphthalene disul fonic acid, 5.5'-[ureylenebis[2-sulfo-p-)dinidine] -amino-4-hydroxy-2-naphthalenesulfonic acid, 4-[(o-arsonophenyl)azoyo3-hydroxy-2°7-naphthalene disulfonic acid, 4.5-dihydroxy-3-(phenylazo)-2,7-naphthalenedisulfone acid, 4-acetamido-5-hydroxy-6-(phenyl7zo)-1゜7-naphthalene disulfonic acid, 2-[p-[(1-hydroxy-4-sulfo-2-naphthyl)azo]phenyl] -6-methyl-7-benzothiazolesulfonic acid, 4-[(2,4-dimethylphthalate) phenyl)azoyo3-hydroxy-2,7-naphthalenedisulfonic acid, 3-[(4-sulfophenyl)azo]-4,5-dihydroxy-2,7-naphtha rangesulfonic acid, 3-[(4-nitrophenyl)azocor-4-ami/-5-hydroxy-2,7- Naphthalene disulfonic acid, 1-nitro-4,6,8-naphthalenetrisulfonic acid , 1-amino-4,6,8-naphthalenedisulfonic acid and their pharmaceutically acceptable salt; The compound is suramin or 4,4′-bis[[4-(o-hydroxyanilino)- 6-(rr+-sulfoanilino)-s-)riazin-2-yl]ami/]-2 , 2° stilbenedisulfonic acid is more preferred.

Angiostatic steroids are those that interfere with the process of vasculogenesis/angiogenesis or Steroids that cause degeneration of new vasculature that results from plastic stimulation means. The vasostatic steroids are 21-hydro of the known formula (n) Xysteroid [see US Pat. No. 4,711,042], CI of the known formula (DI) 1-Functionalized steroids [see International Application Publication WO 8710267216], as follows: 6α-fluoro-17α, 21-dihydroxy-16α, which is a known steroid -Methylpregna-4,9(11)-diene-3,20-dione/21-acetate 6α-fluoro-17α,21-dihydroxy-16β-methylpregna -4,9(11)-diene-3,20-dione, 21-phosphonooxin and pharmaceutically acceptable salts thereof, hydrocortisone, tetrahydrocortisol, 17α-hydroxy-progesterone, 11α-shrimp hydrocortisone, fluti xolone, flutixolone, desoxycortyphsterone, dexamethacin, Lutisone 21-acetate, hydrocortisone 21-phosphate, 17α -Hydroxy-6α-methylbredan-4-ene-3,20-dione 17-a Cetate, 6α-fluoro-17α, 21-7hydroxy-16α-methylpre guna-4,9(11)-diene-3,20-dione and the novel Δ9 flll+ - Refers to and includes ethyanate ester (IV).

The Δ9(■)-ethyanate ester (IV) can be prepared from starting materials known to those skilled in the art. prepared by methods known to those skilled in the art. The Δ9(b)-ethianic acid ester (IV ) is the starting material for the preparation of the corresponding 17α,21-dihydrohemacysteroid (V). be. These compounds are oxidized by known methods to remove C11 and C3° to , substituted with -H'', where X is -0- or -S- rather than -CH, -OH Produces steroids that are The oxidation reaction is carried out using an aqueous solution of an oxidizing agent such as peroxide. Do it with It is preferred to use an excess amount of oxidizing agent (approximately 2 equivalents). 1 of the mixture After refluxing for ~10 hours, the carboxylic acid product (VI) was isolated, which is well known to those skilled in the art. As you know, it can be purified by recrystallization. of the desired corresponding 17-ester (■) Esterification of the carboxylic acid (VI) at CI 7 by reaction with anhydride do. The anhydride has the formula R, 7-Co-0-Co-R, , as known to those skilled in the art. Ru. See U.S. Pat. No. 4,599,331. Then, esters well known to those skilled in the art The desired 17-ester (■) can be obtained by chemical reaction techniques (e.g. diazoalkyl reagents) Δ8(■)-ethyanic acid ester (IV).

Regarding the Δ9(■)-ethianic acid ester (IV), R1 is +0. is preferred, and more preferably the steroid A-ring is Δ4-3-keto. R 8 is α-R where Rs-t is -H and R, -4 is -H, -F or CH, -, :β-R61 is preferable, and R8 is more preferably -F. R 7 is preferably -H knee H. R1, is R11-1 and Rllll-1 One of them is -H, and the other of RI@-I and R14-* is -CH, A certain α-R111-1:β-Rts-1 is preferred. R1? is C, -C , alkyl or n is 0 to 3 - (CFs)nt-CF3 is preferred R1? is -CH,, -C,H,, -C,H,, -CF, or -CF, -C F, is more preferable. Preferably R11 is C, -C, alkyl ; R11 is more preferably -CH,, C-Hs or -C-(CH,); stomach. It is preferable that a portion of X be negative.

Vascular depressant steroids have the formula (■): [In the formula, R7° is α-R+o-+: β-R,,-, where Rto-1 is -CH ,,R□. -7 and R5 together are -CH, -CR, -CR, -CH=, Here, R11t-H: -H and Atte R-It = O.

R6 is α-Re-+: β-R@-ts where R, -3 is -H, and R8-1 is -H, -F or -CHs, R? -H: -H.

R1, is α-Rl@-1:β-Rre-*, where R+1-1 and R,,- , one of which is -H and the other of Rl@-1 and Rl@-1 is -CH, , R1? is C, -C, alkyl or n is O~3 - (CF,)nt- CFs, Rll is C, -C, alkyl, X means partially-] Δ9...)-ethianic acid ester represented by formula (I): [In the formula, R4 is -H1 R and R are the same or different and are -H, -F, -CQ.

R11 is selected from the group consisting of hydroxy and keto, Rto is methoxy and and thiomethyl, and R87 is selected from the group consisting of A group selected from the group consisting of alkyl groups. 20-substituted steroids; 6α-fluoro-17α, 21-dihydroxy-16α ~ methylpregna-4, 9(11)-diene-3,20-dione 21-acetate, 6α-fluoro-17α, 21-dihydroxy-16β-methylpregna-4, 9(11)-di-3,20-dione, 6α-fluoro-17α, 21-dihy Droxy-16β-methylpregna-4,9(11)-diene-3,2o-dio 21-phosphonooxy, Hydrocortisone, tetrahydrocortisol, 17α-hydroxyprogeste Ron, 11α-ebihydrocortisone, flutixolone, flutixolone, des Oxycorticosterone, dexamethacin, 21-acetate in cortisone, human Drocortisone 21-phosphate, 1 17α-human axy-6α-methylbregn-4-ene-3°20-dione ・17-acetate, 6α-fluoro-17α, 21-dihydroxy-16α-methylpregna-4, 9(11)-diene-3,20-dione is preferred.

tMW tract inhibiting steroids are 6α-fluoro-17α, 21-dihydroxy-16 α-Methylpregna-4,9(11)-diene-3゜20-dione・21-acetic acid Tate, 6α-fluoro-17α, 21-dihydroxy-16β-methylpregna-4, 9(11)-diene-3,20-dione, 6α-fluoro-17α,21-dihyde Dorotei Sea 16β-methylpregna-4,9(11)-diene-3,20~geo 21-hydrocortisone, tetrahydrocortisol, 17α-hydroxy Cyprogesterone, 11α-shrimp hydrocortisone, cortixolone, coltiki Solon, desoxycorticosterone, dexamethacin, cortisone 21-a Cetate, hydrocortisone 21-acetate, 17α-hydroxy-6α- Methylpredan-4-ene-3,20-dione I7-acetate, 6α-fur Oro- is more preferred.

The angiogenic treatment method is preferably for treating angiogenic diseases. solid tumors, diabetes, arthritis, Atherosclerosis, ocular neovascularization, parasitic diseases, psoriasis, abnormal wound healing processes hypertrophy following surgery, burns, injuries, hair growth, ovulation and luteinization, transplantation and Preferably, the embryo is selected from the group consisting of embryonic development in the uterus. Angiogenic diseases are hard Preferably, the patient has a body tumor, diabetes, arthritis or psoriasis.

Slamane-type compounds and vasostatic steroids are administered in the same pharmaceutical dosage form. There is no need to give it. Slamane-type compounds usually cause intravenous stimulation due to their stimulation. whereas vasostatic steroids are administered orally or parenterally (intramuscularly, subcutaneously, intravenously). ) Can be administered.

The dose of Slamane type compound is about 1 to about 1000 mg/m 27 days, preferably 5 to about 500 mg/m''7 days. blood concentration of about 50 to about 300 μg/mQs, preferably about 250 to about 3 Administer until reaching 00 μs/m (l).

As is known to those skilled in the art, at that point the administration of Sulaman type compounds is Stop. The dosage of vasostatic steroids is about 0.1 to about 1oOmg/kg/day, preferably Preferably, it is about 0.1 to about 50 mg/kg/day.

For inhibition of angiogenesis, vasostatic steroids are combined with sulfated glycosaminoglycans. and sulfated polysaccharides, or effective fragments of these molecules. Can be combined with other agents.

Preferred gelcosaminoglulins include heparin and heparin sulfate. Ru. When heparin and heparin sulfate contain a minimum of 6 sugar residues, Fragments of heparin or heparin sulfate may also be used; Heparin sulfate fragments are heparin isolated from natural sources or heparin sulfate fragments. can be prepared from acid esters or they can be prepared by chemical synthesis. It can also be manufactured. Vascular steroids include bentosan polysulfate and cyclodextrin. It can also be combined with Strine or other sulfated polysaccharides isolated from natural sources. Ru. Preferred polysaccharides include β-cyclodextrin tetradeca sulfate. β-Cyclodextrin, Bentosan polysulfate, or Arthrobac 9- Polysaccharide-peptidoglycan sulfate isolated from (Arthrobacter) It is in the form of a stell. Journal on Biochemistry f　Biochemistry) 92゜1775 (1982). These polysaccharides are It can be isolated from natural sources or prepared by chemical synthesis.

Additionally, vasostatic steroids are compounds that contain compounds that interfere with collagen biosynthesis. It can also be used in combination therapy. Preferred compounds in this group are L-aze Includes tidine-2-carboxylic acid, thioproline, and related proline analogs do. Also, 8,9-dihydroxy-7-methyl-benzo(b) chimeridinium Other inhibitors of basement membrane collagen synthesis such as bromides are also included.

As known to those skilled in the art, suramin-type compounds and vasostatic steroids The exact route of administration, dose, and frequency of administration will depend on the individual treatment of pre-scheduled angiogenesis. , the severity of the disease, the general physical condition and weight of the individual patient to be treated, and depends on other clinical abnormalities.

Definitions and promises The following definitions and explanations are set forth in the entirety of this application, including both the specification and claims. This is about the terms used throughout.

1. Promises regarding formulas and definitions of variables Various provisions in the specification and claims A chemical formula representing a compound or molecular fragment is based on clearly defined structural features. Additionally, variable substituents may be contained. These variable substituents can be followed by a letter or numeric subscript. identity by a digit character, e.g. rZ, J or "R1" where "i" is an integer is confirmed. These variable substituents are monovalent or divalent. That is, these are 1 represents a group attached to the formula by one or two chemical bonds. For example, the group ZI has the formula When bonded to CH, -C(=Z,)H, it represents a bivalent variable. The groups R and RJ are , the formula CH, -CH! - Univalent variable substitution when binding to C(R=)(RJ)Hl represents a group. When a chemical formula is drawn in a straight line as shown above, the variable substituents placed in parentheses are Bonds to the atom immediately to the left of the substituent included in the parentheses. 2 or more in a row When placing variable substituents in parentheses, each variable substituent must be placed immediately to the left of the parentheses. Bonded to the preceding atom. Thus, in the above formula, R4 and R are both is bonded to the preceding carbon atom.

In addition, any part of the carbon atom number 1 < ring such as steroids has been established. For children, these carbon atoms are also denoted as CI, where "4" is the carbon atom number. is an integer corresponding to . For example, C1l is described by those skilled in the art of steroid chemistry. Represents the 6th position or carbon atomic number in the steroid nucleus as shown systematically. same Similarly, the term "R6" represents a variable substituent (-valent or divalent) at the 6-position.

A chemical formula or part thereof drawn in a straight line represents a linear group of atoms.

The symbol "-" generally represents a bond between two atoms in a chain. Thus, CH, −0− CH, -CH(R,)-CH, represents a 2-substituted-1-methoxypropane compound . Similarly, the symbol [=yo represents a double bond, e.g., CH,=C(R,)-0-CH3 , symbol rl! ! represents a triple bond, e.g. HC30-CH(R,)-CH,-CH, vinegar. The carbonyl group can be formed in one of two ways: -CO- or -C(=C)- The former is preferred due to its simplicity.

Cyclic (ring) compounds or molecular fragments can be represented as straight lines. Hidden In the compound 4-chloro-2-methylpyridine, the atoms marked with an asterisk (*) are mutually exclusive. N=C(CH3)-CH=CCQ-C under the promise that it bonds to form a ring. H=(, kH. Similarly, the cyclic molecular fragment, 4- (Ethyl)-1-piperazinyl is -N*-(CH,), -N (C,H,)-C It can be represented by H, -C*+t.

If a variable substituent is divalent, the valences can be - together or may exist separately or together. For example, a carbon atom as in -C(=Ri)- The variable R, bound to is divalent and defined as oxo or keto (thus, (forming carbonyl (-CO-)) or two separately linked monovalent variable substitutions The groups α-Rt-4 and β-Rr-* are defined. A two-valued variable R□ is a two-valued variable When defined as consisting of several substituents, the convention used to define the bivalent variable is "α-RL-J: β-R, -, J format or some modification thereof. Ru. In such a case, α-Rt-a and β-R1, have a bond to a carbon atom. to give -C(α-R, -JXβ-R, -k). For example, bivalent variables R, -C If (=R,) is defined as consisting of two monovalent variable substituents, then two monovalent variables Substituents are α-Ra-, : β-R6-, ... α-Re-i: β-R, -1 ° etc., and -C<a　-R,-,)(β-R,-,)-1-...-C(α-R ee) (β-R-IO), etc. Similarly, the bivalent variable R11, -C(-R, For υ-, the two univalent variable substituents are α-R++-+:β-R114 . Separate α and β coordinations exist (e.g. due to the presence of carbon double bonds in the ring). For non-existent ring substituents, for substituents attached to carbon atoms that are not part of the ring, In this case, the convention is still used, but the representation of α and β is omitted.

Just as a bivalent variable can be defined as just two separate monovalent variable substituents, two separate The monovalent substituents of may be defined as taken together to form a divalent variable. For example, the expression − 〇, (R,)H-C, (RJ)H-(C.

and Ct are arbitrarily defined as the first and second carbon atoms, respectively). , R4 and R4 together create a second bond between (1) C, and C1. (2) is defined as forming a divalent group such as oxa (-0-), and the chain formula is This describes epoxides.

R1 and R4 together form a more complex group such as -X-Y- In this case, the coordination of the atomic group is such that C1 in the above formula is bonded to X, and C1 is bonded to Y. It seems like they match. Thus, according to the convention, the representations r-1, -R, and R1 together form -CH, -C)I, -0-CO-...'' is, It means a lactone in which carbonyl is bonded to C7. However, the display “... ...RJ and R4 together partially form H, -CH, -0-CO- , the promise refers to a lactone in which the carbonyl is attached to C3.

The carbon content of variable substituents is indicated in one of two ways. The first method is rC , -C, J, etc., where "1" and and "4" are both 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, C, -C, alkyl is 1 represents alkyl of from to 4 carbon atoms (unless otherwise specified, its isomeric forms) (also includes). If this single prefix is given, it is the variable being defined. shows the total carbon content of or (C, -C, alkoxycarbonyl, n is 0 , 1 or 2, the group CH3-(CH,) n-0-CO- is described. second According to the method, the carbon atom content of only each part of the definition is collectively expressed as "C1-CJ". by placing it in an arc and placing it immediately before (without spaces) the part of the definition being defined. is shown. By this arbitrary convention, (C,-C,)alkoxycarbonyl is , C, -C, has the same meaning as alkoxycarbonyl. Because rc, This is because CsJ refers only to the carbon atom content of the alkoxy group. Similarly, Ct- C, alkoxycarbonyl and (C, -C,)alkoxy(C, -C,)al Kyl both define alkoxycarbonyl containing 2 to 6 carbon atoms However, the two definitions are different. This is because the former definition is alkoxy or alkoxy. one which allows that the alkyl moiety alone contains 4 or 5 carbon atoms. On the other hand, the latter definition limits any of these groups to 3 carbon atoms. .

■, Definition All temperatures are in degrees Celsius.

TLC refers to thin layer chromatography.

THF refers to tetrahydrofuran.

φ refers to phenyl (CsHg).

MS refers to mass spectrometry expressed as m/e or mass/charge units. [ M+Hdo refers to a parent atom and a cation of a hydrogen atom.

CI refers to chemical ionization. FAB refers to fast atom bombardment.

Ether refers to diethyl ether.

Pharmaceutically acceptable means that it is tolerated by patients from a pharmacological/toxicological standpoint. physical/ Refers to properties and/or substances that are acceptable to the manufacturing medicinal chemist from a chemical point of view. .

Treatment refers to suppression and/or prevention.

Vasostatic steroids are vasostatic steroids that interfere with the process of vasculogenesis/angiogenesis or Steroids that cause degeneration of new blood vessel structures due to stimulation.

When using a mass/industrial solvent pair, the ratio of the solvent to be used is determined by a person skilled in the art. It may be possible to carry out the invention to its fullest extent using what has been described without further elaboration. I believe it can be done. The following detailed examples describe the preparation of various compounds and/or the present invention. It describes how to carry out various methods of the invention and is merely exemplary. Therefore, it should not be construed as limiting the invention in any way. A person skilled in the art would be able to Appropriate modifications can be made immediately by both methods regarding the reactant and reaction conditions and techniques. will recognize it.

Mi flJ1 6α-fluoro-17α, 21-dihydroxy-16α-methy Lupregna-4,9(11)-diene-3,20-m12 in methanol with 6α -Fluoro-17α,21-dihydroxy-16α-methylpregna-4,9( 11)-Diene-3,20-dione 21-acetate (U.S. Pat. No. 32918 No. 15) Add to 1.0 g. Neutralize the reaction mixture with acetic acid and concentrate to dryness under reduced pressure. Ru.

Partition the concentrate between water and chloroform. Separate the organic layer and wash twice with water. , dried over anhydrous sodium sulfate. The crude solid was dissolved in ethyl acetate/hexane (3 The title compound was chromatographed on silica gel eluting with 5/65) get. Melting point 206-207° Preparation example 26α-fluoro-17α, 21-dihydro Roxy-16α-methylpregna-1,4,9(11)-triene-3,20 -Dione (V) Following the general procedure of Preparation Example 1, 6α-fluoro-17α,21-dihydroxy- 16α-methyl pregna-4,9(11)-diene-3,20-dione 21- With non-significant changes other than starting with acetate (U.S. Pat. No. 4,704,358) to obtain the title compound.

Example 16α-fluoro-17α-hydroxy-16α-methylandrosta- 4,9(11)-dien-3-one 17β-carboxylic acid (VI) 26m+2 of THF and 0.677g of percholic acid in 10mQ of water were mixed with 6α-fluor Oro-17,21-dihydroxy-16α-methylpregna-4,9(1,1) -Diene-3,20-dione (■) (Preparation Example 1) 611 mg (1,62 mmol ). The resulting solution was heated to reflux for 2 hours, then cooled to 25a and reduced pressure Concentrate to a volume of 5 ml. 15ml of water was added to the residue and the resulting mixture The compound is extracted with dityl acetate 2×25 mσ. Combine the ethyl acetate extracts and add sulfuric anhydride Dry over sodium, filter and concentrate to dryness. Crude material in acetone/hexane The title compound is obtained by crystallization from . Melting point 213.8-214°, MS calculated value 363.1971, actual value 363.1962 Example 26α-fluoro-17α- Hydroxy-16α-methylandroster-4,9(11)-dien-3-one ・17β-carboxylic acid methyl ester ・17-acetate-acetic anhydride 0.5rru2 and 0.3 mQ of triethylamine to 6α-fluoro-17α-hydroxy-1 6α-methylandrosta-4°9(11)-dien-3-one 17β-cal Add to bonic acid (■, Example 1.300 mg). Dissolution of the resulting mixture takes place. Stir at 20-25° until solid, then stir for an additional 40 minutes. Reduce the pressure of the reaction solution Concentrate to dryness under water, dissolve the residue in methanol and stir at 25° for 30 minutes. Mail Crude 6α-fluoro-1 was obtained by evaporation of tanol and final drying under high vacuum. 7α-hydroxy-16α-methylandrosta-4,9(11)-diene-3 -one 17β-carboxylic acid 17-acetate (■) is obtained in quantitative yield. T LCRf=0.05 (ethyl acetate/hexane, 35/65) part 2 The crude 17-acetate (■) was dissolved in 8 ml of THF, and then all the output Freshly prepared dia in ether until the starting material has reacted according to TLC. Treat with zomethane. Elute the crude product with ethyl acetate/hexane (25/75) Purify by chromatography on silica gel. Pool appropriate fractions and concentrated to give the title compound; TLCRf=o, 6 (ethyl acetate/hexane ( 35/65); MS calculated value: 419.2234, actual value 419.2212 Androster 4.9(11)-dien-3-one 17β-carboxylate methyl Ester 1-foot trifluoroacetate (IV) Following the general procedure of Example 2 (parts r and ■), trifluoroacetic anhydride was With minor modifications other than those used, the labeled product is obtained. MS calculated value 473.1 951, actual value 473.1944 Example 46 α-fluoro-17α-hydroxy -16α-methylandrosta-4,9(11)-dien-3-one 17β- Carboxylic acid methyl ester/17β-propionate (■) Following the general procedure of Example 2 (Part I), but using propionic anhydride. 6α-fluoro-17α-hydroxy-16α-methylamine with minor changes. Ndrosta-4,9(11)-dien-3-one 17β-carboxylic acid 17- Propionate (■) was obtained at 6°TLCRf=0.05 (ethyl acetate/hexane, 35/65): MS calculated value 419.2234. Actual value 419.2212 actual Following the general procedure of Example 2 (part n), 6α-fluoro-17α-hydroxy -16α-methylandrosta-4,9(11)-dien-3-one 17β- No significant changes were made except for starting with carboxylic acid 17-propionate (■). The title compound is obtained.

TLCRf=0.5 (dityl acetate/hexane, 35/65); MS calculated value 4 33.2390. Actual value 433.2377 Example 56α-fluoro-17α-hyper Droxy-16α-methylandrosta-4,9(11)-dien-3-one. 17β-carboxylic acid methyl ester/17-pentafluoropropionate (I V) Example 2 (Part I and ■) except using pentafluoropropionic anhydride ) to obtain the title compound. TLCRf=0.05 (ethyl acetate /Hex 7.35/65); MS calculated value 523.1919. Actual value 523.1 952 Example 66α-fluoro-17α-hydroxy-16α-methylandro Star-4,9(11)-dien-3-one 17β-carboxylic acid methyl ester ・17-butyrate (IV) Follow the general procedure of Example 2 (Part ■), except for using butyric anhydride. 6α-fluoro-17α-hydroxy-16α-methylandrosta -4,9(11)-dien-3-one 17β-carboxylic acid 17-butyrate Obtain (■). TLCRf=0.05 (ethyl acetate/hexane, 35/65) ; MS Calculated value 423.2390, Actual value 433.2377 Example 7 6α- Fluoro-17α-hydroxy-16β-methylandrosta-4,9(11) -Dien-3-one 17β-carboxylic acid (VI) Following the general procedure of Example 1, 6α-fluoro-17,21-dihydroxy-1 6β-methylpregna-4,9(11)-diene-3,20-dione (V, U.S. Patent No. 4099537, Preparation Example 3) 3, no significant changes other than starting with OOg After further modification, the title compound is obtained. Melting point 215-216° with decomposition, MS calculated value 363°197L actual value 383.1952 Example 8 6α-fluoro-17α-hydroxy-16β-methylandrosta -4,9(11)-dien-3-one 17β-carboxylic acid methyl ester 6α-fluoro-17α-hydroxy-16β-methylandrosta-4,9( 11)-dien-3-one 17β-carboxylic acid (Vl.

Example 7) Following the general procedure of Example 2 (Part II) but starting with 181 mg The title compound is thus obtained. TLCRf=0.8 (dityl acetate/chloroform, 25/75), melting point 181-182°; MS calculated value 377.212B, actual measurement Value 377.2146 Examples 96α-fluoro-17α-hydroxy-16β-methane Tyrandrosta-4,9(11)-dien-3-one 17β-carboxylic acid Tyl ester 17-propionate (IV) 6α-fluoro-17α-hydroxy-16β-methylanda star 4.9 ( 11)-dien-3-one 17β-carboxylic acid (V[.

Example 7) Following the general procedure of Example 4 but starting with 250 mg, fluoro-17α-hydroxy-16β-methylandrosta-4,9(11)- Dien-3-one, 17β-carboxylic acid, 17-propionate (■) [without bubbles] Melting point 191° while emitting; Ms calculated value 419.2234, actual value 419.250 ] and 6α-fluoro-17α-hydroxy-16β-methylandrosta- 4゜9(11)-dien-3-one 17β-carboxylic acid methyl ester 17 -BcyPit* -T (■) [TLCRf=0.8 (Ethyl acetate/hegyo+n, 25/75); Melting point 185-166°: Ms calculated value 433.2390, actual measurement We get the value 433.2398.

Example 106 α-Fluoro-17α-hydroxy-16β-methylandrosta -4,9,(11)-dien-3-one 17β-carboxylic acid methyl ester 17-butyrate (IV) 6α-fluoro0-17α-hydroxy-16β-methylandrosta-4,9( 11)-dien-3-one 17β-carboxylic acid (IV.

Using the general procedure of Example 6 but starting with Example 7), 6α-fluoro0-1 7α-hydroxy-16β-methylandrosta-4゜9　(11)-diene- 3-one 7β-carboxylic acid 17-butyrate (■) [melting point 150-152' , MS calculated value 433.2390, measured value 433.241B] and 6α-ful oro-17β-hydroxy-16β-methylandrosta-4,9(1’l)- Dien-3-one 17β-carboxylic acid methyl ester 17-butyrate (I V) [TLCRf=0.8 (ethyl acetate/hexane, 25/75).

Melting point 166-167° Two MS calculated value 447.2547, actual value 447.25 64] is obtained.

Practical example 11 6α-fluoro-17α-hydroxy-16α-methylandros Ta~1. 4. 9 (11) -1-dien-3-one 17β-carboxylic acid (Vl) 6α-fluoro-17α,21-dihydride according to the general procedure of Example 1 Roxy-16α-methylpregna-1,4,9(11)-triene-3,20- Dione (V, Preparation Example 2) Expressed with minor changes except starting with 0.25 g Obtain the compound. Melting point 204.8-205.3°, MS calculated value (Ct, Ht sF O4) 360.1737, actual value 3so, 1'yt5 Example + 26α-fluoro-17α-hydroxy-16α-methylandrosta -1,4,9(11)-) dien-3-one 17β-carboxylic acid methyl s Tel-17-propionate (■) Following the general procedure of Example 2 (Bert and II), 6α-fluoro-17α -Hydroxy-16α-methylandrosta-1,4°9(11)-1-diene Starting with 250 mg of -3-one 17β-carboxylic acid (■, Example 11), With minor modifications other than the use of pionic anhydride, the title compound is obtained. Melting point 1 72-172.5°; TLCRf=0.6 (ethyl acetate/hexane, 35/6 5), MS calculated value (as CxsH3IFOs) 430.2155, actual value 43 0° real mN136α-fluoro-17α-hydroxy-16α-methylandro Methyl star-1,4,9(11)-trien-3-one-17β-carboxylate Ester 17-butyrate (IV) Following the general procedure of Example 2 (bars 1-I and ■), 6α-fluoro-17α -Hydroxy-16α-methylandros9<,4゜9　(11)-4riene- Starting with 250 rr+g of 3-one 17β-carboxylic acid (Vl, Example 11), With minor modifications other than the use of butyric anhydride, the title compound is obtained. TLCRf =0.6 (ethyl acetate/hexane 35/65); melting point 141-141.5° :MS (as C,.Hs aF O4) Calculated value 444.2312, Actual value 444, 2309 Chart A (III) Submission of translation of written amendment (Article 184-8 of the Patent Act) 1. Display of patent application PCT/US 90102673 2. Name of the invention Suramin-type compounds and antiangiogenic steroids to inhibit angiogenesis Ids 3. Patent applicant Name: The Abduction Company 4. Agent Address: 2-1-61-5, Chuo Ward, Osaka City, Osaka Prefecture, Date of submission of amendment June 5, 1991 The scope of the claims 1. Characterized by consisting of a suramin type compound and a vein inhibiting steroid. combinations for simultaneous, combined or sequential use in angiogenic therapy in warm-blooded mammals A product.

2. The composition according to claim 1, wherein the mammal is a human.

3. The suramin type compound is suramin, 3-human axy-2,7-naphthalenesulfonic acid, 4,5-dihydroxy-2, 7-naphthalenedisulfonic acid, 2.2'-[(1,8-dihydroxy-3,6 -disulfo-2゜7-naphthylene)bis(azo]dibenzene arsonic acid, 4.4 '-Bis[[4-(o-hydroxyanilino)-6-(m-sulfoanilino)- S-) riazin-2-yl]amino]-2.2'stilbendisulfonic acid, 4.5-dihydroxy-3-[(p-nitrophenyl)azogo 2,7-naph taledisulfonic acid, 4.5-disodroxy3,6-bis[(4-sulfo-1-naphthyl)azo]- 2.7-naphthalenedisulfonic acid, 3-[(5-chloro-2-hydroxyphenylphenyl) azo]-4,5-dihydroxy-2,7-naphthalenedisulfonic acid, 4.5 °-dihydroxy-3,6” [(3,3’-dimethoxy-4,4°-biphenate) nyrylene)bis(azo)-di-1-naphthalenesulfonic acid, 3, 6-[(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazoli (-4-yl)ab]-4,5-dihydroxy-2゜7-naphthalenedisulfone acid, 5.5"-〇ureylenebis[2-sulfo-p-phenylene)azo]bis[6 -amino-4-hydroxy-2-naphthalenesulfonic acid, 4-[(o-arsonophenyl)azoco-3-hydroxy-2°7-naphthalene disulfonic acid, 4.5-dihydroxy-3-(phenylazo)-2,7-naphthalenedisulfone acid, 4-acetamido-5-hydroxy-6-(phenylazo)-1゜7-naphthalene disulfonic acid, 2-[p-[(1-hydroxy-4-sulfo-2-naphthyl)azo]phenyl] -6-methyl-7-benzothiazolesulfonic acid, 4-[(2,4-dimethylphthalate) phenyl) azoco-3-hydroxy-2,7-naphthalenedisulfonic acid, 3-[(4-sulfophenyl)azo]-4; 5-dihydroxy-2,7-naph taledisulfonic acid, 3-[(4-nitrophenyl)azo-4-amino-5-hydroxy~2.7- Naphthalenedisulfonic acid, 1-nitro4. 6. 8- Naphthalene trisulfo acid, 1-amino-4,6,8-naphthalenetrisulfonic acid and these drugs Above acceptable salt; The composite acid according to claim 1 or 2, which is selected from the group consisting of:

4. The suramin type compound is suramin or 4,4°-bis[[4-( o-hydroxyanilino)-6-(m-sulfoanili/)-S-)riazine-2 -ylcoami7]-2,2' stilbenedisulfonic acid, Claim 3 Compositions as described.

5. The composition according to claim 4, wherein the suramin type compound is suramin. thing.

6. The vasostatic steroid has the formula (I): [wherein R4, R6 and Ro are the same or or differently, -H, -F or -Ce; Ro is hydroxy or keto; R7° is hydroxy, methoxy or thiomethyl, and thiomethyl; and R5, means an alkyl group having less than 6 carbon atoms] 20- Replacement sroid: [In the formula, the dotted line between the C- and C-2 positions indicates the presence or absence of a double bond. Taste; ~ bond at C-6 position indicates α or β: R1, is CH, or -〇 ,H,; R1, is CHs or some tHs; R1 is H, RII is at the α-position, -0H1-〇-alkyl (C +-Ct*), QC(=O) full+ru(C,-C,,),-QC(-〇)a Reel, -QC(=O)N (R), or -QC(=O)OR,,, Coconi , aryl is optionally substituted with l) one or two (C,-C,)-alkyl groups. furyl, chenyl, pyrrolyl or pyridyl, which may be substituted with The nyl ring may optionally be chlorine, nitrogen, bromine, alkyl (C, -C,), alkyl (C, -C,), or alkoxy (C, -C,), thioalkoxy (C, -C,), C (2sC-1 One selected from the group consisting of F, C-1-N Hm and -NHCOCH, Optionally substituted with 3 groups, and where R is hydrogen, alkyl (C, -C, ), or phenyl, and each R may be the same or different: and Ro-1 is aryl or alkyl (C, -C,,) as defined above; or Ro is α-C12 and R3l is β-CQ: or Ro and Ro together oxygen (-0-) bridging the C-9 and C-11 positions; or R1 and Ro together form a double bond between the C-91 and C-11 positions; R, is H, CHs, CQ or F; R1 is H, OH%F, CQ%Br, CH,,7x Nyl, vinyl or allyl ; R7 is H or CHs; ate is -OH or α-R, -, : β-R,, -, where RI@-1 and Rto-t, one of which is -H, and of R,,-, and R,,-, The other is H, OH%CHs or F: and R1? is H, OH, CH, or R1, and R1? together create a second bond between C-16 and C-17 positions 21-hydroxysteroid represented by the formula (■): Cchi-1゜ [wherein R, is β-CHs or β-CHtHs:'-koL, RrhaH, and Rsf*=O, OH, -0-furkyl (C, -C, t), -QC (=○) -a Lucil (C, -C,,), -OC (=O) 71J -ru, QC (=O) N (R) t, Mataha-QC(=O)OR,, here, aryl is frill, check nyl, pyrrolyl or birifle, where each of said hetero groups is optionally one or may be substituted with two (C,-C4) alkyl groups, or aryl , f is 0 to 2 and the phenyl ring is optionally chlorine, bromine, alkyl ( C, -C,), alkoxy (C, -C,), thioalkoxy (C, -C,) , CQ3C-1F3C-1-NH, and -NHCOCH, -(CHJr-phenyl or phenyl, which may be substituted with 1 to 3 groups) and each R may be the same or different; and wherein R7 is as defined above. Aryl or alkyl (C, -C, or where R2 is α-CQ) and R8 is β-Ca; or here, R1 and R8 together are C Oxygen (-0-) bridging the -9 and C-11 positions; where R1 and R3 are together form a second bond between the C-9 and C-11 positions; alternatively, R2 α-F and R8 is β-〇H; Here, R4 is H, CH,, CQ or F; Here, R5 is α-Rs-, :β- R1-1 Particularly, one of R2-1 and Rs-t is -H, and R3-1 and Rs-t, the other is H, OH, FSC12, B r, CHs, 7 Any -ru, vinyl or allyl; Here, Ro is H or CH; Ro is =CH, or α-R,-, :β-Rs-t, where Rs-+ and R , -, one is -H and the other is H, OH, CH3, F or =CH, .

Here, R8o is H1α-OH, α-CHs, or Rt. is C-16 and forming a second bond between the C-17 position; where R11 is α-H1β-H or forming a second bond with R14: Here, R゛・1. is +0 or α-R+a-+:β-R12-1, where R One of +3-1 and R+3-1 is -H, and R+3-4 and Rt3- The other of 1 is -0H1-0-P'(0)'(OH), or -0-C-(= 'O)-(CH,) tCOOH, where t is an integer from 2 to 6; Here, Re4 is H or forms a second bond with R1.

Here, Rlfi is +0 or α-R+s-+: β-RI5-1, here, Rm 5-1 and R+s-t, one is -H and the other is -○H; here, R 13 and R1° form a cyclic phosphate of formula (3); where R, and R1, has the meaning as defined above; or Kokoni, R,, +t-OH,O-,C, ( =,)-R,,,-C)-P(0)(OH)t, also +! −0−C(=O)=− (CH,), C, C) OH, this is an integer from 1 to 6; and R11 is - Y,−,(CH,). -X-, (CH,), -soO, Hl-Z (CH hat Q s where Y is a bond, or -〇-, Y' is a bond, -〇-1 or -S-: Each X and Xo are bonds 1. C0N(R,,)-17N (R,,)CO-1- o-1-s-1,7S, (,,0)-1 or -3(Os)-; Re5i st hydrogen or lt full (c, c4); Rts and R1? each of the desired lower of 1 to 4 carbon atoms optionally substituted with 1 hydroxyl is an alkyl group, or R18 and R17 are each a nitrogen atom to which they are bonded. Together with the child, pyrrolidino, piperidino, morpholino, thiomorpholino, pipette Radino or N (lower) alkylpi 9 in which the alkyl has 1 to 4 carbon atoms Integer; m is an integer of 1 to 5; p is an integer of 2 to 9; q is an integer of 1 to 5; 2 is a bond or or a part -; r is an integer from 2 to 9: and Q is (1) -R,, -CH,C0OH , where R10 is -S-1-S(○)-1-6(0) ff1-1-5OtN (Rto-Alt-N(R,,)SO,-.

and R2゜ is hydrogen or lower alkyl (C, -C,); however, R2゜ and ( The total number of carbon atoms in CH exceeds 10; (2) -Co-COOH; tala! (3)-CON　(R,,)CH(R1riC0OH*taitso(7)Physician a pharmaceutically acceptable salt, where Rtl is H and R1ff1+±H%CH,,- CH, C0OH.

=CH, CH, COOH, -CH,OH, -CHtSH.

-CH, CH, SCH, or -CH, Ph-OH, where Ph-OH is p- hydroxyphenyl; or RlI is CH2 and Ro is H; or Rl l and R*t+! -Together CHtc HICH*-;A6L’i*N( RlI)CH(R1riC0OH together -N HCHICON HCHt c means OOH; provided that (a) when n is 2, R+s is other than hydrogen; (b) the sum of m and n is 10 or less; (c) the sum of p and q is 10 (d) When X is a bond, the sum of m and n is 5 to 10; (e ) If X' is a bond, the sum of p and q is 4 to 9; (f) R, is CQ or F, the C-1 position is saturated; and (g) When Re is =CH, RIO is the position between C-16 and C-17. Other than the conclusion of 2] C11-functionalized steroid represented by or its mono- or bis salt: formula (■) : [In the formula, (A-1) R111 is α-R1゜-1:β-Lo-*, where Rto-* is = CH,, R1゜-1 and R, taken together =CH1-CHl-CH, -CH =, where R is α-R1-1:β-R*,! , where R3-1 and R2 One of -3 is -H, and the other of R1-3 and Rx-t is -H, -C H,, -c2 or -F1 where R1 is =0 or α-Rs-t:β-R3- 2. Here, one of R5-1 and R5-2 is -H, and R3-1 and R5, , the other C is -ORs-s, where R5-1 is -H, -PO(OH ), or -3o, H; (A-II) Rto is α-R3゜-3: β-R1゜-4, where R4゜-4 number=CH,, R1゜-5 and R1 together =CH=CH-Co-CH =.

(A-III) R, O are α-R16-5:β-RIG-@ and Rsgtα -Rs-s: β-R5-6, where RIO-1 is =CH,, where R5-6 and RS-@, one is -H and the other of Rs-s and R5-6 is ζ yo Rto-s together with =CH, -CR, -CR, -CH, -1 here, R 3 and R3 are the same as defined above; R1 is α-Re-1:β-R8-2, where R6-8 and R1,! one of them One is -H, and the other of R1-9 and R6-1 is -H, -F.

-CQ, -Br or -CHs; R9 is α-Rt-t: β-R9-3, where R? -1 and R? -1 out of 2 one is -H and R7, and the other of R7-3 is -H or =CH.

R1, =CH1* or α-Rts-+: β-RII-1, where R, , -.

and one of Rl@-1 is -H and among R, , -, and Rl@-1 The other is -H, -CH,, -OH;/:+t-F;R+? is C-Ct. alkyl , C containing 1 to 23 -F atoms, -C,, fluoroalkyl, c, -c, Alkoxy, (C1Cs)alkylamino(C,-C,)alkyl, (Cs-C ? )cycloalkyl(c,-c.)alkyl, optionally 1 to 3 =CH. , -F, -C12, -OH, -OCH. , -0C. H. *Replacement with it-NHt Phenyl (C, -C,) alkyl, C, -C, cycloalkyl, C, -C,. alkenyl, (C3c-)cycloalkyl(C,-C,,)alke Nil: X is a part- or -S-- Ro is C, -C, optionally substituted with 1 to 10 -F, -CQ or -Br. a Lukiru, C, -C, substituted with 1 to 10 moieties. Alkyl, R11-1 is C, -C ,. Alkyl, C, -C, cycloalkyl, C8-08 cycloalkenyl, as desired may be substituted with -OH, -F, -cff or -Br, 1 to 4 C, -C,, alkenyl containing a double bond of -CH, -COOR,, □ ; n is O or 1, and phenyl is optionally 1 to 3 F, CQ, Br , OH, OCH3, -0C,H,, C, -C4 alkyl, N Ht, N ( CH3) r, N ('CtHs) may be substituted with t or -No, i-(c H’2) n 1-phenyl; R21-1 and Rfl-3 are the same or or different, -H, C, -C, 0furkyl, C, -C, cycloalkyl, -φ, -CH, -φ, or R□-1 and R211 are the same as the bonded nitrogen atom. Together, 1-pyrrolidine, l-piperidine, 1-piperazine and l-morpho Forming a heterocycle selected from the group consisting of phosphorus, Δ8 (eyes)-ethia phosphoric acid ester, 6α-fluoro-17α, 21-dihydroxy-16α-methyl Pregna-4,9(11)-diene-3,20-dione, 6α-fluoro-17 α,21-dihydroxy-16α-methylpregna-4,’9(11)-die -3,20-dione 21-acetate, 6α-fluoro-17α, 21-dihydroxy-16β-methylpregna-4, 9(11)-diene-3,20-dione, 6α-fluoro-17α, 21-dihyde Droxy-16β-methylpregna-4,9(11)-diene-3,20-dio 21-phosphonooxy, hydroxycortisone, tetrahydrofrutisol, 17α-hydroxyprogesterone, 11α-shrimp hydrocortisone, cortixolone, cortixolone, desoxycorticosterone, dexamethacin, cortisone 21-acetate, Hydrocortisone/21-phosphate, 17α-hydroxy-6α-methylbutylene Redan-4-ene-3,20-dione 17-acetate A composition according to any one of the preceding claims ζ selected from the group consisting of.

7. The vasostatic steroid is Formula (■): [In the formula, RIG is α-R+o-+:β-R,. -,, here RIQ-2 is -CH 3, R1゜-1 and R5 together represent -C,,,H, -CR, -CR, -C H=, where R, is −H knee I (and R8 is =0°R, is α−Rs−+:β -R64, where R8-3 is -H and R, -3 is -H, -F or partially H, , R7 is -H: -H.

R4 is α-R,,,-,: β-R+, *-t, where R88□ and Rl@-1 One of them is -H, which is Rl@-1 and Ro. 1, the other is -CHs, R 1? is C, -C, alkyl or n is 0 to 3 -(CF,)nt-CF, , R□ is C, -C, alkyl, X means partially-] Δll+Il+-ethianic acid ester represented by formula (I): [In the formula, R4 is -H1 R8 and R, are the same or different and are -H1-F, -C(.

Ro is selected from the group consisting of hydroxy and keto, Rto is metquin and selected from the group consisting of thiomethyl, R17 is an alkyl group having less than 6 carbon atoms; [selected from the group consisting of kill group] 20-substituted steroids, 6α-fluoro-17α, 21-dihydroxy-16α-methylpregna-4, 9(11)-diene-3,20-dione 21-acetate, 6α-fluoro-17α,21-dihydroxy-16β-methylpregna-4, 9(11)-diene-3,20-dione, 6α-fluoro-17α, 21-dihyde Droxy-16β-methylpregna-4,9(11)-diene-3,20-dio 21-phospho/oxy, hydrocortisone, tetrahydrocortisol, 17α ~ hydroxyprogesterone, 11α-shrimp hydrocortisone, flutixolone, fluticosterone, desoxycorticosterone, Dexamethacin Cortisone 21-acetate, Hydrocortisone-21-phosphate, 17α-hydroxy-6α-methylpropylene Regn-4-ene-3゜20-dione 17-acetate, 6α-fluoro-17α, 21-dihydroxy-16α-methylpregna-4, Claim No. 9(11)-diene-3,20-dione selected from the group consisting of Composition according to item 6.

8. The vasostatic steroid is 6α-fluoro-17α, 21-dihydroxy-16α-methylpregna-4, 9(11)-diene-3,20-dione 21-acetate, 6α-fluoro-17α, 21-dihydroxy-16β-methylpregna-4, 9(11)-diene-3,20-dione 6α-fluoro-17α,21-dihydro Roxy-16β-methylpregna-4,9(11)-diene-3,20-dione ・21-phospho/oxy, hydrocortisone, tetrahydrocortisol, 17α-hydroxyprogesterone, 11α-shrimp hydrocortisone, cortixolone, fluticosterone, desoxycorticosterone, Hydrocortisone/21-phosphate, 17α-hydroxy-6α-methylpropylene Redan-4-ene-3゜20-dione 17-acetate, 6α-Fluof-1Fα, 21-dihydroxy-16α-methylpregna-4, Claim No. 9(11)-diene-3,20-dione selected from the group consisting of Composition according to item 6.

9. The suramin type compound and the vasostatic steroid in one dosage unit. A composition according to any one of the preceding claims, which is not administered.

10. The suramin type compound is adapted for IV administration and the vasostatic steroid 10. A composition according to claim 9, which is adapted for oral or parenteral administration.

11. The composition according to any one of the preceding claims for use in treating angiogenic diseases. thing.

12. The angiogenic disease is solid tumor, diabetes, arthritis, atherosclerosis, eye neovascularization, parasitic diseases, xerosis, abnormal wound healing processes, hypertrophy following surgery, burns, injuries, hair growth, ovulation and luteinization, implantation and embryonic development in the uterus. 12. The composition according to claim 11, wherein the composition is selected from the group consisting of:

13. Claim No. 1, wherein the angiogenic disease is solid abscess, diabetes, arthritis or psoriasis. Composition according to item 11.

14. of suramin-type compounds and vasostatic steroids in warm-blooded mammals. Use in the manufacture of medicinal products used to treat angiogenesis.

15. The suramin type compound is defined in any one of claims 3 to 5. The use according to claim 14 as defined.

16. The vasostatic steroid is defined in any one of claims 6 to 8. 16. The use according to claim 14 or 15.

17. Claims 14 to 16 that the pharmaceutical product is suitable for oral or parenteral administration. Use as described in any one of the paragraphs.

18. The angiogenesis is defined in any one of claims 11 to 13. The use according to any one of claims 14 to 17.

international search report 1---＾----Pσlυg　90702673lllmm1～-m--11 PCTlυS 901026F3 International Search Report

Claims (1)

[Claims] 1. in a warm-blooded mammal in need of treatment for angiogenesis characterized by administering an angiogenic dose of a combination of a suramin-type compound and a vasostatic steroid. Angioplasty treatment method. 2. 2. The method of claim 1, wherein said mammal is a human. 3. The suramin type compounds include suramin, 3-hydroxy-2,7-naphthalenesulfonic acid, 4,5-dihydroxy-2,7-naphthalenedisulfonic acid, 2,2'-[(1,8-dihydroxy-3 , 6-disulfo-2,7-naphthylene)bis(azo]dibenzene arsonic acid, 4,4'-bis[[4-(o-hydroxyanilino)-6-(m-sulfoanilino)-s-triazine- 2-yl]amino]-2,2'stilbendisulfonic acid, 4,5-dihydroxy-3-[(p-nitrophenyl)azo]-2,7-naphtha Disulfonic acid, 4,5-dihydroxy-3,6-bis[(4-sulfo-1-naphthyl)azo]-2,7-naphthalenedisulfonic acid, 3-[(5-chloro-2-hydroxyphenylphenyl) azo]-4,5-dihydroxy-2,7-naphthalenedisulfonic acid, 4,5'-dihydroxy-3,6'[(3,3'-dimethoxy-4,4'-biphenylyl) ren)bis(azo)-di-1-naphthalenesulfonic acid, 3,6-[(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)azo]-4,5- Dihydroxy-2,7-naphthalene disulfonic acid, 5,5'-[claylenebis[2-sulfo-p-phenylene)azo]bis[6-amino-4-hydroxy-2-naphthalenesulfonic acid, 4-[(o- azo]-3-hydroxy-2,7-naphthalene disulfonic acid, 4,5-dihydroxy-3-(phenylazo)-2,7-naphthalenedisulfonic acid, 4-acetamido-5-hydroxy-6-( (phenylazo)-1,7-naphthalene 2-[p-[(1-hydroxy-4-sulfo-2-naphthyl)azo]phenyl]-6-methyl-7-benzothiazolesulfonic acid, 4-[(2,4-dimethylphenyl) phenyl)azo]-3-hydroxy-2,7-naphthalenedisulfonic acid, 3-[(4-sulfophenyl)azo]-4,5-dihydroxy-2,7-naphtha Disulfonic acid, 3-[(4-nitrophenyl)azo]-4-amino-5-hydroxy-2,7-naphthalenedisulfonic acid, 1-nitro-4,6,8-naphthalene trisulfonic acid, 1-amino -4,6,8-naphthalene trisulfonic acid and their pharmaceutical approval 2. The method of angiogenesis treatment according to claim 1, wherein the method is selected from the group consisting of; 4. The suramin type compound is suramin or 4,4'-bis[[4-(o-hydroxyanilino)-6-(m-sulfoanilino)-s-triazin-2-yl]amino]-2,2' The angiogenesis treatment method according to claim 1, which is stilbenedisulfonic acid. 5. 2. An angiogenesis treatment method according to claim 1, wherein said suramin type compound is suramin. 6. The vasostatic steroid has the formula (I): ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [wherein R4, R6 and R9 are the same or different, -H, -F, -Cl; R11 is 20- selected from the group consisting of hydroxy and keto; R20 is selected from the group consisting of hydroxy, methoxy and thiomethyl; and R17 is selected from the group consisting of alkyl groups having less than 6 carbon atoms. Substituted Suroid; Formula (II); ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, the dotted line between the C-1 and C-2 positions means the presence or absence of a double bond. ; ~bond at C-6 position indicates α or β; R10 is CH3 or -C2H5; R19 is CH3 or -C2H5; R9 is H, R11 is in the α-position, -OH, -O -Alkyl-(C1 -C12), -OC(=O)alkyl(C1-C12), -OC(=O)ary -OC(=O)N(R)2, or -OC(=O)OR8-1, where Ryl is optionally substituted with one or two (C1-C4)-alkyl groups. optionally furyl, thienyl, pyrrolyl or biridyl, or aryl is -(CH2)r-phenyl, where f is 0-2, and where the phenyl ring is optionally chlorine, fluorine, bromine, alkyl (C1-C3 ), alkoxy (C1-C3), thioalkoxy (C1-C3), Cl3C-, F3C-, -NH2 and -NHCOCH3. and where R is hydrogen, alkyl (C1-C4), or phenyl, and each R may be the same or different; and R8-1 is aryl or alkyl (C1-C12) as defined above; or R8 is α-Cl and R11 is β-Cl; or R9 and R11 together are oxygen (-O-) bridging the C-9 and C-11 positions; or R9 and R11 are together C- A double bond is formed between the 9 and C-11 positions; R2 is H, CH3, Cl or F; R6 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; R7 is H or CH3 ; R10 is =CH2 or α-R16-1:β-R16-2, where one of R16-1 and R16-2 is -H, and R16-1 and R16-2 are and the other is H, OH, CH3 or F; and R17 is H, OH, CH3 or R16 and R17 together form a second bond between the C-16 and C-17 positions]; Formula (III): ▲Mathematical formulas, chemical formulas, tables, etc. are available▼ (III) [wherein R1 is β-CH3 or β-CH2H5; where R2 is H, and R3 is =O, OH, -O-alkyl (C1-C12), -OC(=〇)-alkyl (C1-C12), -OC(=O)aryl, -OC(=O)N(R)2, or -OC(=O)OR7, where aryl is furyl, thienyl, pyrrolyl or pyridyl, where Each of said hetero groups may be optionally substituted with one or two (C1-C4) alkyl groups, or aryl may be substituted with f from 0 to 2 and said phenyl ring is optionally substituted with one or two (C1-C4) alkyl groups; chlorine, bromine, alkyl (C1-C3), alkoxy (C1-C3), thioal -(CH2) r-phenyl or phenyl, optionally substituted with 1 to 3 groups selected from the group consisting of Koxy (C1-C3), Cl3C-, F3C-, -NH2 and -NHCOCH3, and each R may be the same or different; and where R7 is aryl or alkyl (C1-C12) as defined above; or where R2 is α-Cl and R3 is β-Cl; or where R2 and and R3 together form an oxygen (-O-) bridging the C-9 and C-11 positions; where R2 and R3 together form a second bond between the C-9 and C-11 positions. the shape or R2 is α-F and R3 is β-OH; where R4 is H, CH3, Cl or F; where R5 is α-R5-1:β-R5-2, here where one of R5-1 and R5-2 is -H, and the other of R5-1 and R5-2 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; , R5 is H or CH3; R9 is =CH2 or α-R8-1; β-R8-2, where one of R8-1 and R8-2 is -H and the other is H, OH , CH3, F or =CH2; where R10 is H, α-OH, α-CH3, or R10 forms a second bond between the C-16 and C-17 positions; where R12 is α-H, β-H, or forms a second bond with R14; where R13 is =O or α-R13-1:β-R13-2, where R13-1 and One of R13-2 is -H, and the other of R13-1 and R13-2 is -OH, -O-P(O)(OH)2, or -O-C-(=O)-( CH2) tCOOH, where t is an integer from 2 to 6; where R14 is H or forms a second bond with R12; where R15 is =O or α-R15-1: β-R15-2, where one of R15-1 and R15-2 is -H and the other is -OHH; where R23 forms a cyclic phosphate of formula IV with R10; , R9 and R1 5 have the meaning as defined above; or here R23 is -OH, O-C(=) -R11, -O-P(O)(OH)2, or -O- C(=O)-(CH2)t COOH, where t is an integer from 2 to 6; and RH is -Y-(CH2)n-X-(CH2)m-SO3H, -Y'-(CH2)p -X'-(CH2)q-NR16 R17 or -Z(CH2)rQ, where Y is a bond or -O-; Y' is a bond, -O-, or -S-: each X and X' is a bond, -CON(R18)-, -N(R18)CO-, -O-, -S-, -S(O)-, or -S(O2)-; R18 is hydrogen or alkyl (C1- C4); each of R16 and R17 is a lower alkyl group of 1 to 4 carbon atoms optionally substituted with one hydroxyl, or R16 and R17 are each bonded nitrogen pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N (lower) alkylpi in which the alkyl together with the elementary atoms has 1 to 4 carbon atoms; n is an integer of 4 to 9; m is an integer of 1 to 5; p is an integer of 2 to 9; q is an integer of 1 to 5; Z is an integer of 1 to 5; Bond or -O-: r is an integer from 2 to 9; and Q is (1) -R19-CH2COOH, where R18 is -S-, -S(O)-, -S(O)2-, -SO2N- (R20- also is -N(R20)SO2-; and R20 is hydrogen or lower alkyl (C1-C4); provided that the total number of carbon atoms in R20 and (CH2)r exceeds 10; (2) -CO-COOH; or (3) -CON(R21)CH(R22)COOH or a pharmaceutically acceptable salt thereof, where R21 is H and R22 is H, CH3, -CH2COOH, -CH2CH2COOH, -CH2OH, -CH2SH, - CH2CH2SCH 3, or -CH2Ph-OH, where Ph-OH is p-hydroxyphenyl; or R21 is CH3 and R22 is H; or R21 and R22 are mono together -CH2CH2CH2-; or -N(R21)CH(R22)C OOH together mean -NHCH2CONHCH2COOH; provided that (a) if n is 2, R16 is other than hydrogen; (b) The sum of m and n is 10 or less; (c) The sum of p and q is 10 or less; (d) When X is a bond, the sum of m and n is 5 to 10; ( e) When X' is a bond, the sum of p and q is 4 to 9; (f) When R4 is Cl or F, the C-1 position is saturated. and (g) when R9 is =CH2, R10 is other than the second bond between the C-16 and C-17 positions] or its mono- or Bis salt, formula (IV); ▲Mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula, (A-I) R10 is α-R10-1: β-R10-2, where R10-2 is - CH3, R10-1 and R5 taken together -CH2-CH2-CH2-CH =, where R2 is α-R2-1:β-R2-2, where R2-1 and R2- One of 2 is -H and the other of R2-1 and R2-2 is -H, -C H3, -Cl or -F, where R3 is =O or α-R3-1:β- R3-2, where one of R3-1 and R3-2 is -H and the other of R3-1 and R3-2 is -OR3-2, where R3-3 is -H, - PO(OH) 2 or -SO3H; (A-II) R10 is α-R10-2:β-R10-4, where R10-4 is -CH3, R10-3 and R5 together are -CH =CH-CO-CH=; (A-III) R10 is α-R10-5; β-R10-6, and R5 is α-R 5-5:β-R5-6, where R10-6 is -CH3, where R5-5 and One of R5-5 and R5-6 is -H, and the other of R5-5 and R5-6 together with R10-5 is -CH2-CR2-CR3-CH2-, where R2 and and R3 are the same as defined above; R6 is α-R6-1:β-R6-2, where one of R6-1 and R6-2 one is -H and the other of R6-1 and R6-2 is -H, -F, -Cl, -Br or -CH3; R7 is α-R7-1:β-R7-2, where, One of R7-1 and R7-2 one is -H and the other of R7-1 and R7-2 is -H or -CH3; R16 is =CH2 or α-R16-1:β-R16-2, where R16-1 and R16- One of 2 is -H and the other of R16-1 and R16-2 is -H, -CH3, -OH or -F; R17 is C1-C20 alkyl, containing 1 to 23 -F atoms C1-C10 fluoroalkyl, C1-C6 alkyl Coxy, (C1-C6)alkylamino(C1-C6)alkyl, (C5-C7)cycloalkyl(C1-C6)alkyl, optionally 1 to 3 -CH3, -F, -Cl, -OH, - Phenyl (C1-C6) alkyl, C3-C6 cycloalkyl, C2-C10 alkenyl, (C3-C6) cycloalkyl (C2-C10) alkenyl, which may be substituted with OCH3, -OC2H5 or -NH2; X is - O- or -S-; R21 is C1-C10 atom optionally substituted with 1 to 10 -F, -Cl or -Br C2-C10 alkyl substituted with 1 to 10 -OH, R21-1 is C2-C10 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, optionally -OH, -F, -Cl or -CH2-COOR21-1 which may be substituted with -Br and is a C2-C10 alkenyl containing 1 to 4 double bonds; n1 is 0 or 1 and phenyl is optionally 1 to 3 -F, -Cl, -Br, -OH, -OCH3, -OC2H5, C1-C4 alkyl, -NH2, -N(CH3)2, -N(C2H5)2 or -NO2 good-(CH2)n1-phenyl; R21-2 and R21-3 are the same or different, -H, C1-C10 alkyl, C3-C8 cycloalkyl, -φ, -CH2-φ; or, -CH2-CO-NR21- in which R21-1 and R21-3 together with the bonded nitrogen atom form a heterocycle selected from the group consisting of 1-pyrrolidine, 1-piperidine, 1-piperazine and 1-morpholine; Δ9(11)-ethianic acid ester, 6α-fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(11)-di ene-3,20-dione, 6α-fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(11)-diene-3,20-dione/21-acetate tate, 6α-fluoro-17α,21-dihydroxy-16β-methylpregna-4,9(11)-diene-3,20-dione, 6α-fluoro-17α,21-dihydroxy Droxy-16β-methylpregna-4,9(11)-diene-3,20-dio 21-phosphonooxy, hydroxycortisone, tetrahydrocortisol, 17α-hydroxyprogesterone, 11α-epihydrocortisone, cortexolone, corticosterone, desoxycorticosterone, dexamethasone, cortisone 21-acetate, hydrocortisone 21-phosphate, 17α- Hydroxy-6α-methylp The angiogenesis treatment method according to claim 1, wherein the angiogenesis treatment method is selected from the group consisting of regn-4-ene-3,20-dione 17-acetate. 7. The vasostatic steroid has the formula (IV): where R10 is α-R10-1:β-R10-2, where R10-2 is -CH3, R10-1 and R5 taken together -CH2-CR2-CR3-CH=, where R2 is -H:-H and R3 is =O, R6 is α-R6-1:β-R6-2, where R6-2 is -H R6-1 is -H, -F or -CH3, R7 is -H:-H, R16 is α-R16-1:β-R16-2, where one of R16-1 and R16-2 is -H, the other of R16-1 and R16-2 is -CH3, R17 is C1-C4 alkyl or n2 is 0 to 3 -(CF2)n2-CF3, R21 is C1-C4 alkyl, X means -O-] Δ6(11)-ethianic acid ester represented by the formula (I): [wherein R4 is -H, R8 and R9 are the same or different and -H, -F, -Cl , R11 is selected from the group consisting of hydroxy and keto, and R20 is selected from the group consisting of methoxy and thiomethyl. 6α-fluoro-17α,21-dihydroxy-16α-methylpregna-4, 9(11)-Diene-3,20-dione 21-acetate, 6α-fluoro-17α,21-dihydroxy-16β-methyl pregna-4, 9(11)-diene-3,20-dione, 6α-fluoro- 17α,21-dihi Droxy-16β-methylpregna-4,9(11)-diene-3,20-dio 21-phosphonooxy, hydrocortisone, tetrahydrocortisol, 17α-hydroxyprogesterone, 11α-epihydrocortisone, cortexolone, corticosterone, desoxycorticosterone, dexamethasone Cortisone 21-acetate, hydrocortisone 21-phosphate, 17α-hydroxy- 6α-methylp selected from the group consisting of regn-4-ene-3,20-dione 17-acetate, 6α-fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(11)-diene-3,20-dione; The angiogenesis treatment method according to claim 1. 8. The vasostatic steroid is 6α-fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(11)-diene-3,20-dione 21-acetate, 6α-fluoro-17α,21-dihydroxy- 16β-Methylpregna-4,9(11)-diene-3,20-dione 6α-fluoro-17α,21-dihyde Roxy-16β-methylpregna-4,9(11)-diene-3,20-dione ・21-phosphonooxy, hydrocortisone, tetrahydrocortisol, 17α-hydroxyprogesterone, 11α-epihydrocortisone, cortexolone, corticosterone, desoxycorticosterone dexamethasone, cortisone 21-acetate, hydrocortisone 21-phosphate, 17α-hydroxy-6α-methylpropylene selected from the group consisting of regn-4-ene-3,20-dione 17-acetate, 6α-fluoro-17α,21-dihydroxy-16α-methylpregna-4,9(11)-diene-3,20-dione; The angiogenesis treatment method according to claim 1. 9. The route of administration of suramin-type compounds is intravenous and vasostatic steroids. 2. The method for angiogenesis treatment according to claim 1, wherein the route of administration of the id is oral or parenteral. 10. 2. A method of treating angiogenesis according to claim 1, wherein the suramin-type compound and the vasostatic steroid are not administered in one dosage unit. 11. Doses of suramin-type compounds are from about 1 to about 1000 mg/m2/day. 2. The method of treating angiogenesis according to claim 1, wherein the dose of the vasostatic steroid is from about 0.1 to about 100 mg/kg/day. 12. The vasculature according to claim 1, wherein the angiogenic treatment is treatment of angiogenic disease. Treatment method. 13. The angiogenic diseases include solid tumors, diabetes, arthritis, atherosclerosis, neovascularization of the eye, parasitic diseases, psoriasis, abnormal wound healing processes, hypertrophy following surgery, burns, injuries, hair growth, ovulation and the corpus luteum. formation, implantation and embryonic development in the uterus. 13. The angiogenesis treatment method according to claim 12, wherein the angiogenesis treatment method is selected from the group consisting of: 14. 13. The method for treating angiogenesis according to claim 12, wherein the angiogenic disease is solid tumor, diabetes, arthritis, or psoriasis. 15. Formula (IV); ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula, (A-I) R10 is α-R10-1:β-R10-2, where R10-2 is -CH3 , R10-1 and R5 together are -CH2-CH2-CH2-CH =, where R2 is α-R2-1:β-R2-2, where R2-1 and R2-2 are One is -H and the other of R2-1 and R2-2 is -H, -C H3, -Cl or -F, where R3 is =O or α-R3-1:β-R3-2 , where one of R3-1 and R3-2 is -H and the other of R3-1 and R3-2 is -OR3-3, where R3-3 is -H, -PO(OH ) 2 or -SO3H; (A-II) R10 is α-R10-3:β-R10-4, where R10-4 is -CH3, R10-3 and R5 together are -CH=CH- CO-CH=; (A-III) R10 is α-R10-5:β-R10-6 and R5 is α-R5-5:β-R5-6, where R10-6 is -CH3 , here, R5-5 and One of R5-68 and R5-68 is -H, and the other of R5-5 and R5-6 together with R10-5 is -CH2-CR2-CR3-CH2-, where R2 and and R3 are the same as defined above; R6 is α-R6-1:β-R6-2, where one of R6-1 and R6-2 is -H and R6-1 and R6-2 The other is -H, -F, -Cl, -Br or -CH3; R7 is α-R7-l:β-R7-2, where one of R7-1 and R7-2 one is -H and the other of R7-1 and R7-2 is -H or -CH3; R16 is =CH2 or α-R16-1; β-R16-2, where R16-1 and R16- One of 2 is -H and the other of R16-1 and R16-2 is -H, -CH3, -OH or -F; R17 is C1-C20 alkyl, containing 1 to 23 -F atoms C1-C10 fluoroalkyl, C1-C6 alkyl Coxy, (C1-C6)alkylamino(C1-C6)alkyl, (C5-C7)cycloalkyl(C1-C8)alkyl, optionally 1 to 3 -CH3, -F, -Cl, -OH, - Phenyl (C1-C6) alkyl, C3-C6 cycloalkyl, C2-C10 alkenyl, (C3-C8) cycloalkyl (C2-C10) alkenyl optionally substituted with OCH3, -OC2H5 or -NH2; X is - O- or -S-; R21 is C1-C10 atom optionally substituted with 1 to 10 -F, -Cl or -Br C2-C10 alkyl substituted with 1 to 10 -○H, R21-1 is C1-C10 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, optionally -OH, -F, - -CH2-COOR21-1 which is a C2-C10 alkenyl optionally substituted with Cl or -Br and containing 1 to 4 double bonds; n1 is 0 or 1 and phenyl is optionally 1 to Substituted with 3 -F, -Cl, -Br, -OH, -OCH3, -OC2H5, C1-C4 alkyl, -NH2, -N(CH3)2, -N(C2H5)2 or -NO2 -(CH2)n1-phenyl: R21-2 and R21-3 are the same or different and are -H, C1-C10 alkyl, C3-C8 cycloalkyl, -φ, -CH2-φ, or , R21-1 and R21-3 together with the bonding nitrogen atom form a heterocycle selected from the group consisting of 1-pyrrolidine, 1-piperidine, 1-piperazine and 1-morpholine -CH2-CO-NR21 -2R21-3] Δ9(11)-ethianic acid ester. 16. R10 is α-R10-1:β-R10-2, where R10-2 is -CH3, R10-1 and R5 together are -CH2-CR2-CR3-C H=, where Δ9(11)-ethyanate ester of formula (IV) according to claim 15, wherein R2 is -H:-H and R3 is =O. 17. The formula according to claim 15, wherein R6 is α-R6-1:β-R6-2, where R6-2 is -H and R6-1 is -H, -F or -CH3. Δ9(11)-ethianic acid ester of (IV). 18. R16 is α-R16-1:β-R16-2, where R16-1 and Δ9(11)-ethia of formula (IV) according to claim 15, wherein one of R16-1 and R16-2 is -H and the other of R16-1 and R16-2 is -CH3. acid ester. 19. The Δ9(11)-ethianic acid ester of formula (IV) according to claim 15, wherein R17 is C1-C4 alkyl. 20. R17 is -(CF2)n2-CF3, where n2 is 0 to 3. Δ9(11)-ethianic acid ester of formula (IV) according to item 15. 21. The Δ9(11)-ethianic acid ester of formula (IV) according to claim 15, wherein R21 is C1-C4 alkyl. 22. Δ9(11)-ethianate ester of formula (IV) according to claim 15, wherein X is -O-. 23.6α-fluoro-17α-hydroxy-16α-methylandrosta-4,9(11)-dien-3-one 17β-carboxylic acid methyl ester 17-acetate, 6α-fluoro-17α-hydroxy-16α -Methylandros ter-4,9(11)-dien-3-one 17β-carboxylic acid methyl ester 17-trifluoroacetate, 6α-fluoro-17α-hydroxy-16α-methylandrosta-4,9(11)-diene -3-one 17β-carboxylic acid methyl ester 17-propionate, 6α-fluoro-17α-hydroxy C-16α-methylandrosta-4,9(11)-dien-3-one, 17β-carboxylic acid methyl ester, 17-pentafluoropropionate, 6α-ph Fluoro-17α-hydroxy-16a-methylandrosta-4,9(11)-dien-3-one 17β-carboxylic acid methyl ester 17-butyrate, 6α-fluoro-17α-hydroxy-16β-methylandrosta- 4,9(11)-dien-3-one/17β-carboxylic acid methyl ester/17-propylene onate, 6α-fluoro-17α-hydroxy-16β-methylandrosta-4,9(11)-dien-3-one 17β-carboxylic acid methyl ester 1 7-butyrate, 6α-fluoro-17α-hydroxy-16α -Methylandrosta-1,4,9(11)-trien-3-one 17β-carboxylic acid methyl ester 17-propionate, 6α-fluoro-17α-hydroxy-16α-methylandroster Δ9(11 )-ethyanate ester. 24.6α-fluoro-17α,21-dihydroxy-16α-methylpregna -4,9(11)-diene-3,20-dione.