[go: up one dir, main page]

EP0477195A1 - Verbindungen des suramin-typs und angiostatische steroide zur verhütung der angiogenesis - Google Patents

Verbindungen des suramin-typs und angiostatische steroide zur verhütung der angiogenesis

Info

Publication number
EP0477195A1
EP0477195A1 EP90907622A EP90907622A EP0477195A1 EP 0477195 A1 EP0477195 A1 EP 0477195A1 EP 90907622 A EP90907622 A EP 90907622A EP 90907622 A EP90907622 A EP 90907622A EP 0477195 A1 EP0477195 A1 EP 0477195A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydroxy
fluoro
dihydroxy
dione
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP90907622A
Other languages
English (en)
French (fr)
Inventor
Paul A. Aristoff
Mark A. Mitchell
John W. Wilks
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of EP0477195A1 publication Critical patent/EP0477195A1/de
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • 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.
  • 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, inflammatory conditions, and tumor growth, as well as numerous other conditions.
  • Heparin is presently used with inhibitors of angiogenesis, especially angiostatic steroids to treat diseases involving neovascularization, see Biochem. Pharmacol. 34, 905 (1985) and Annals of Surgery 206, 374 (1987).
  • the heparin potentiates the angiogenesisinhibiting activity of other drugs, for example of collagen biosynthesis inhibitors such as L-azetidine carboxylic acid.
  • the problem with using heparin is that the efficacy of each preparation/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).
  • Fibroblast growth factor is one of a number of known angiogenic growth factors. See, J. Cell Physiol. 132, 143 (1987).
  • US Patent 4,599,331 discloses 20-substituted ⁇ 1,4 -16-methyl steroids which did not have a ⁇ 9 (11) 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-administration of steroids with heparin or heparin fragments.
  • R 10 is ⁇ -R 10-5 : ⁇ -R 10-6 and R 5 is ⁇ -R 5-5 : ⁇ -R 5-6 , where R 10-6 is -CH 3 , one of R 5-5 and R 5-6 is -H and the other of R 5-5 and R 5-6 taken with R 10-5 is -CH 2 -CR 2 -CR 3 -CH 2 - where R 2 and R 3 are as defined above;
  • R 6 is ⁇ -R 6 - 1 : ⁇ -R 6 - 2 where one of R 6-1 and R 6-2 is -H and the other of R 6-1 and R 6-2 is -H, -F, -Cl, -Br and -CH 3 ;
  • R 7 is ⁇ -R 7 - 1 : ⁇ -R 7 - 2 where one of R 7-1 and R 7-2 is -H and the other of R 7-1 and R 7-2 is -H or -CH 3 ;
  • R 17 is C 1 -C 20 alkyl, C 1 -C 10 fluoroalkyl containing from 1-23 -F atoms, C 1 -C 6 alkoxy, (C 1 -C 8 )alkylamino(C ⁇ -Cg)alkyl, (C 5 -C 7 )cycloalkyl(C 1 -C 6 )alkyl, phenyl(C 1 -C 6 )alkyl optionally substituted with 1-3 -CH 3 , -F, -Cl, -OH, -OCH 3 , -OC 2 H 5 and -NH 2 , C 3 -C 8 cycloalkyl, C 2 -C 10 alkenyl, (C 3 -C 8 )cycloalkyl(C 2 -C 10 ) alkenyl;
  • X is -O- or -S-;
  • R 21 is C 1 -C 10 alkyl optionally substituted with 1 to 10 -F, -Cl or -Br,
  • R 21-1 is C 1 -C1 0 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, C 2 -C 10 alkenyl containing 1 thru 4 double bonds optionally substituted with -OH, -F, -Cl or -Br,
  • n 1 is 0 or 1 and phenyl is optionally substituted with 1 thru 3 -F, -Cl, -Br, -OH, -OCH 3 , -OC 2 H 5 , C 1 -C 4 alkyl, -NH 2 , -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or -NO 2 ,
  • R 21-2 and R 21-3 are tne same or different and are -H, C 1 -C 10 alkyl, C 3 -C 8 cycloalkyl, - ⁇ , -CE 2 - ⁇ and where R 21-2 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.
  • the present invention involves 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.
  • the mammal be a human.
  • Suramin-type compounds are compounds which mimic the anti-angiogenic action of suramin and which augment the activity of angiostatic 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
  • 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.
  • Angiostatic 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 11 -functionalized steroids of formula (III) see International Patent Publication WO87/02672, the following known steroids 6 ⁇ -fluoro17 ⁇ ,21-dihydroxy-16 ⁇ -methylpregna-4,9(11)-diene-3,20-dione 21- acetate, 6 ⁇ -fluoro-17 ⁇ ,21-dihydroxy-16 ⁇ -methylpregna-4,9(11)-diene-3,20-dione, 6 ⁇ -fluoro-17 ⁇ ,21-dihydroxy-16 ⁇ -methylpregna-4,9(11)-diene-3,20-dione 21-phosphonooxy and pharmaceutically
  • the ⁇ 9(11) -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 ⁇ 9(11) -etianic esters (IV) are the corresponding 17 ⁇ ,21-dihydroxy steroids (V).
  • These compounds are oxidized by known procedures to remove C21 and produce a steroid where C 20 is substituted with -X-H where X is -O- or -S-, rather than -CH 2 -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).
  • the carboxylic acid product (VI) is isolated and ean be purified by recrystallization as is known to those skilled in the art.
  • the carboxylic acids (VI) are esterified at C 17 by reaction with the an anhydride of the desired corresponding 17-esters (VII).
  • the anhydride is of the formula R 17 -CO-O-CO-R 17 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 ⁇ 9(11) -etianic esters (IV) by esterification procedures (for example with diazoalkyl reagents) well known to those skilled in the art.
  • R 6 is ⁇ -R 6-1 : ⁇ -R 6-2 where R 6-2 is -H and R 6-1 is -H, -F and -CH 3 , it is more preferred that R 6 is -F.
  • R 7 is -H: -H.
  • R 16 is ⁇ -R 16-1 : ⁇ -R 16-2 where one of R 16-1 and R 16-1 -H and the other of R 16-1 and R 16-2 is -CH 3 .
  • R 17 is C 1 -C 4 .
  • angiostatic steroid be ⁇ 9(11) -etianic esters of formula (IV) where
  • R 6 is ⁇ -R 6-1 : ⁇ -R 6-2 where R 6-2 is -H and R 6-1 is -H, -F and -CH 3,
  • R 7 is -H:-H
  • R 16 is c--R 16-1 : ⁇ -R 16-2 where one of R 16-1 and R 16-2 -H and the other of R 16-1 and R 16-2 is -CH 3 ,
  • R 17 is C 1 -C 4 alkyl or -(CF 2 ) n2 -CF 3 where n2 is 0-3,
  • R 21 is C 1 -C 4 alkyl
  • X is -O-
  • R 4 is -H
  • R 6 and R 9 are be the same or different and are -H, -F, -Cl, R 11 Is chosen from the group consisting of hydroxy and keto,
  • R 20 is chosen from the group consisting of methoxy and thiomethyl
  • R 17 is chosen from the group consisting of alkyl groups having less than 6 carbon atoms
  • angiostatic steroid be 6 ⁇ -fluoro-17 ⁇ ,21-dihydroxy-16 ⁇ -methylpregna-4,9(11)-diene-3,20-dione 21-acetate,
  • the method of treating angiogenesis is the treating of diseases of neovascularization.
  • 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 ⁇ g/ml, preferably about 250 to about 300 ⁇ g/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.
  • angiostatic steroids may be combined with agents other than suramin including sulfated glycosaminoglycans 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.
  • 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 administration of both the suramin-type compound and angiostatic steroids depends on the particular treatment of angiogenesis per formed, the severity of the disease, the age, general physical condition, weight, or other clinical abnormaliites, etc., of the particular patient to be treated as is known to those skilled in the art.
  • R i and R j would represent monovalent variable sub- stituents if attached to the formula CH 3 -CH 2 -C(R i ) (R j )H 2 .
  • variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parentheses.
  • each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses.
  • both R i and R j are bonded to the preceding carbon atom.
  • C i represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry.
  • R 6 represents a variable substituent (either monovalent or bivalent) at the Cg position.
  • Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion.
  • the cyclic molecular fragment, 4- (ethyl)-1-piperazinyl can be represented by -N -(CH 2 ) 2 -N(C 2 H 5 )-CH 2 -C*H 2 .
  • variable substituent when a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable.
  • R i is defined to consist of two monovalent variable substituents
  • the convention used to define the bivalent variable is of the form " ⁇ -R i-j : ⁇ -R i-k " or some variant thereof.
  • both ⁇ -R i-j and ⁇ -R i-k are attached to the carbon atom to give -C( ⁇ - Ri-j) ( ⁇ -R i-k )-.
  • 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.
  • R i and R j may be defined to be taken together to form (1) a second bond between C 1 and C 2 or (2) a bivalent group such as oxa (-0-) and the formula thereby describes an epoxide.
  • 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 1 -C 4 ", 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.
  • C 1 -C 4 alkyl represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given).
  • the prefix indicates the entire carbon atom content of the variable being defined.
  • C 2 -C 4 alkoxycarbonyl describes a group CH 3 - (CH 2 ) n -o- CO- where n is zero, one or two.
  • the carbon atom content of only each portion of the definition is Indicated separately by enclosing the "C i -C j " designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined.
  • this optional convention (C 1 -C 3 )- alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxycarbonyl because the "C 1 -C 3 " refers only to the carbon atom content of the alkoxy group.
  • C 2 -C 6 alkoxyalkyl and (C 1 -C 3 )alkoxy(C 1 -C 3 )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.
  • the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substituent 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.
  • TLC refers to thin-layer chromatography
  • THF refers to tetrahydrofuran
  • ⁇ refers to phenyl (C 6 H 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 hydrogen 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 pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • 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.
  • the ratios of solvents used are volume/volume (v/v).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Nutrition Science (AREA)
  • Reproductive Health (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP90907622A 1989-06-16 1990-05-17 Verbindungen des suramin-typs und angiostatische steroide zur verhütung der angiogenesis Ceased EP0477195A1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US36693589A 1989-06-16 1989-06-16
US366935 1989-06-16
US48304490A 1990-02-16 1990-02-16
US483044 1990-02-16

Publications (1)

Publication Number Publication Date
EP0477195A1 true EP0477195A1 (de) 1992-04-01

Family

ID=27003588

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90907622A Ceased EP0477195A1 (de) 1989-06-16 1990-05-17 Verbindungen des suramin-typs und angiostatische steroide zur verhütung der angiogenesis

Country Status (4)

Country Link
EP (1) EP0477195A1 (de)
JP (1) JPH04506066A (de)
AU (1) AU5640390A (de)
WO (1) WO1990015816A1 (de)

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2143978T3 (es) * 1990-06-11 2000-06-01 Alcon Lab Inc Utilizacion de esteroides para la inhibicion de la angiogenesis.
US5972922A (en) * 1990-06-11 1999-10-26 Alcon Laboratories, Inc. Steroids which inhibit angiogenesis
CA2425849C (en) * 1991-11-22 2007-02-27 Alcon Laboratories, Inc. Angiostatic steroids
US5474765A (en) * 1992-03-23 1995-12-12 Ut Sw Medical Ctr At Dallas Preparation and use of steroid-polyanionic polymer-based conjugates targeted to vascular endothelial cells
GB9225475D0 (en) * 1992-12-05 1993-01-27 Imp Cancer Res Tech Compounds to combat angiogenesis
US5795860A (en) * 1993-03-01 1998-08-18 Repligen Corporation Analogs for specific oligosaccharide-protein interactions and uses therefor
US6908910B2 (en) 1993-08-06 2005-06-21 The Children's Medical Center Corporation Estrogenic compounds as anti-mitotic agents
US5504074A (en) 1993-08-06 1996-04-02 Children's Medical Center Corporation Estrogenic compounds as anti-angiogenic agents
FR2736914B1 (fr) * 1995-07-21 1997-08-22 Adir Nouveaux derives d'acide aminophenylphosphonique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
IT1276031B1 (it) * 1995-10-31 1997-10-24 Angelini Ricerche Spa Composizione farmaceutica per il trattamento delle malattie autoimmuni
AU2438297A (en) * 1996-05-09 1997-11-26 Alcon Laboratories, Inc. Combinations of angiostatic compounds
CA2208916A1 (en) * 1997-07-03 1999-01-03 Hyal Pharmaceutical Corporation Promotion of wound healing utilizing steroids having reduced deterioroussystemic side effects typical of glucocorticoids, mineralocorticoids andsex steroids
US6596703B1 (en) 1997-07-11 2003-07-22 Jagotec Ag Promotion of wound healing utilizing steroids having reduced deteriorous systemic side effects typical of glucocorticoids, mineralocorticoids and sex steroids
CA2339835C (en) 1998-08-11 2008-12-16 Entremed, Inc. Use of estrogenic compounds as anti-fungal agents
AUPP609198A0 (en) * 1998-09-22 1998-10-15 Curtin University Of Technology Use of non-peptidyl compounds for the treatment of insulin related ailments
US6933272B1 (en) 1998-09-22 2005-08-23 Erik Helmerhorst Use of non-peptidyl compounds for the treatment of insulin related ailments
US7087592B1 (en) 1999-08-23 2006-08-08 Entre Med, Inc. Compositions comprising purified 2-methoxyestradiol and methods of producing same
PT2348032E (pt) 2000-08-05 2015-10-14 Glaxo Group Ltd Éster s-fluorometílico do ácido 6.alfa.,9.alfa.-difluoro- 17.alfa.-'(2-furanilcarboxil)oxi]-11.beta.-hidroxi-16.alfa.- metil-3-oxo-androsta-1,4-dieno-17-carbotióico como um agente anti-inflamatório
US6777399B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6759398B2 (en) 2000-08-05 2004-07-06 Smithkline Beecham Corporation Anti-inflammatory androstane derivative
US6858596B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivative
GB0019172D0 (en) 2000-08-05 2000-09-27 Glaxo Group Ltd Novel compounds
US7135581B2 (en) 2000-08-18 2006-11-14 Entremed, Inc. Antiangiogenic agents
US6995278B2 (en) 2000-08-18 2006-02-07 Entre Med, Inc. Antiangiogenic agents
GB2389530B (en) 2002-06-14 2007-01-10 Cipla Ltd Pharmaceutical compositions
EP1603543A4 (de) * 2003-02-28 2009-03-04 Florey Howard Inst Therapeutische zusammensetzungen
AU2004275693A1 (en) 2003-05-28 2005-04-07 Entremed, Inc. Antiangiogenic agents
WO2005089256A2 (en) 2004-03-12 2005-09-29 Entremed, Inc. Antiangiogenic agents
IL169622A0 (en) * 2005-07-11 2007-07-04 Yeda Res & Dev Methods of screening modulators of interleukin-32 (il-32)modulators of il-32 identified by said methods and their use
US8399440B2 (en) 2006-03-20 2013-03-19 Entremed, Inc. Disease modifying anti-arthritic activity of 2-methoxyestradiol
US8207151B2 (en) 2008-05-28 2012-06-26 Validus Biopharma Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
EP2556083A4 (de) 2010-04-05 2013-12-04 Validus Biopharma Inc Nichthormonale steroide modulatoren von nf-kappa-b zur krankheitsbehandlung
ES3048113T3 (en) 2013-03-29 2025-12-09 Biomed Valley Discoveries Inc C. novyi for the treatment of solid tumors in humans
US11033621B2 (en) 2014-06-09 2021-06-15 Biomed Valley Discoveries, Inc. Combination therapies targeting tumor-associated stroma or tumor cells
US9676746B2 (en) 2015-01-30 2017-06-13 Biomed Valley Discoveries, Inc. Crystalline forms of C21H22Cl2N4O2
US9670177B2 (en) 2015-01-30 2017-06-06 Biomed Valley Discoveries, Inc. Crystalline C21H22Cl2N4O2 malonate
WO2017004205A1 (en) 2015-06-29 2017-01-05 Reveragen Biopharma, Inc. NON-HORMONAL STEROID MODULATORS OF NF-κB FOR TREATMENT OF DISEASE
US11382922B2 (en) 2019-03-07 2022-07-12 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3291815A (en) * 1958-12-05 1966-12-13 Pfizer & Co C 6-fluoro-16alpha-methyl corticosteroids
CH628355A5 (de) * 1976-02-24 1982-02-26 Ciba Geigy Ag Verfahren zur herstellung neuer androstadien-17beta-carbonsaeuren und ihrer ester und salze.
CH634081A5 (en) * 1977-04-13 1983-01-14 Ciba Geigy Ag Process for the preparation of novel androstadiene-17beta-carboxylic acid esters
IT7967677A0 (it) * 1978-04-05 1979-03-30 Syntex Inc Erivati dell acido 4 alogeno etiani co ad azione antinfiammatoria e procedimento per la loro preparazione
US4607028A (en) * 1983-08-18 1986-08-19 Ciba-Geigy Corporation Novel carboxylic acid esters

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9015816A1 *

Also Published As

Publication number Publication date
JPH04506066A (ja) 1992-10-22
AU5640390A (en) 1991-01-08
WO1990015816A1 (en) 1990-12-27

Similar Documents

Publication Publication Date Title
EP0477195A1 (de) Verbindungen des suramin-typs und angiostatische steroide zur verhütung der angiogenesis
AU657690B2 (en) Steroids which inhibit angiogenesis
US4771042A (en) Inhibition of angiogenesis involving the coadministration of steroids with heparin or heparin fragments
JP3328938B2 (ja) アンドロステン誘導体
US5972922A (en) Steroids which inhibit angiogenesis
JP3333210B2 (ja) 新規プレドニソロン誘導体および該化合物を含有する薬剤
RU2415864C2 (ru) Нитрооксипроизводные стероидов
JPS60123496A (ja) 新規なアンドロスタン―１７β―カルボン酸エステルおよびその製法
HU190746B (en) Process for producing 6-alpha-methyl-corticoides and pharmaceutical compositions containing them
FI57114B (fi) Foerfarande foer framstaellning av nya vid cancerterapi anvaendbara terapeutiskt vaerdefulla enolestrar av steroider
PH26685A (en) Novel steroid derivatives pharmaceutical compositions containing them and method of use thereof
US3481957A (en) Novel androstane and 19-norandrostane steroidal esters and their preparation
DE3400188A1 (de) Neue 6(alpha),16(alpha)-dimethylkortikoide
JPS6129960B2 (de)
EP0546875B1 (de) Neues Verfahren zur Herstellung von 20-Oxo, 17-Alpha, 21-Dihydroxy Derivaten von Pregnan und neue Zwischenprodukte dafür
SU902668A3 (ru) Способ получени производных 9-хлорпреднизолона
US3483235A (en) New oestratrienes and process for their manufacture
US3467677A (en) 17alpha-oxa-d-homo-pregnanes and methods for their manufacture
US20040034003A1 (en) 7-Hydroxy-16alpha-fluoro-5-androsten-17-ones and 7-hydroxy-16alpha-fluoro-5-androstan-17-ones and derivatives thereof
KR820002025B1 (ko) 하이드로 코르티죤 유도체의 제조방법
CS244663B2 (cs) Způsob výroby nových derivátů 9-chlorprednisolonu
CN120289552A (zh) 一种甾体磷酸酯化合物及其应用
JPS5857440B2 (ja) プレグナン酸誘導体の製法
HK1013078B (en) Use of steroids for the inhibiton of angiogenesis
CS244662B2 (cs) Způsob výroby nových derivátů 9-chlorprednisolonu

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19920109

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB IT LI LU NL SE

17Q First examination report despatched

Effective date: 19921123

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 19940311