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WO1997041867A1 - Utilisation de composes steroides afin d'empecher la croissance tissulaire non cancereuse - Google Patents

Utilisation de composes steroides afin d'empecher la croissance tissulaire non cancereuse Download PDF

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Publication number
WO1997041867A1
WO1997041867A1 PCT/US1997/002809 US9702809W WO9741867A1 WO 1997041867 A1 WO1997041867 A1 WO 1997041867A1 US 9702809 W US9702809 W US 9702809W WO 9741867 A1 WO9741867 A1 WO 9741867A1
Authority
WO
WIPO (PCT)
Prior art keywords
pregnan
alkyl
diol
acetate
triol
Prior art date
Application number
PCT/US1997/002809
Other languages
English (en)
Inventor
Abbot F. Clark
Stephen M. Goode
Original Assignee
Alcon Laboratories, Inc.
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 Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to AU19701/97A priority Critical patent/AU1970197A/en
Publication of WO1997041867A1 publication Critical patent/WO1997041867A1/fr

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Classifications

    • 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
    • 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
    • A61K31/567—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 substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • A61K31/568—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 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone

Definitions

  • This invention relates to compounds and their use in methods and compositions for preventing and treating diseases in mammals, particularly humans, in which non-cancerous tissue growth plays a pathogenic role.
  • Angiogenesis In The Presence of Heparin or Heparin Fragment, Science, 230, pp. 1375- 1378 (December 20, 1985). The authors refer to such steroids as "angiostatic" steroids. Included in the new class of steroids found to be angiostatic are cortisol, cortexolone, and several dihydro and tetrahydro derivatives. In a follow up study directed to testing a hypothesis as to the mechanism by which the steroids inhibit angiogenesis, it was shown that heparin/angiostatic steroid compositions caused dissolution of the basement membrane scaffolding to which anchorage dependent endothelia are attached resulting in capillary involution; see, Ingber, et al. A Possible Mechanism for Inhibition of Angiogenesis by Angiostatic Steroids: Induction of Capillary Basement Membrane Dissolution, Endocrinology 119, pp. 1768-1775 (1986).
  • a group of tetrahydro angiostatic steroids useful in inhibiting angiogenesis is disclosed in International Patent Application WO 87/02672 (Aristoff et al.).
  • the compounds are disclosed for use in treating head trauma, spinal trauma, septic or traumatic shock, stroke, and hemorrhagic shock.
  • the patent discusses the utility of these compounds in embryo implantation and in the treatment of cancer, arthritis, and arteriosclerosis.
  • Some of the steroids disclosed in Aristoff, et al. are disclosed in U.S. Patent No. 4,771,042 in combination with heparin or a heparin fragment for inhibiting angiogenesis in a warm blooded animal.
  • compositions of hydrocortisone, "tetrahydrocortisol-S,” and U-72,745G, each in combination with a beta cyclodextrin have been shown to inhibit corneal neovascularization: Li, et al., Angiostatic Steroids Potentiated by Sulphated Cyclodextrin Inhibit Corneal Neovascularization, Investigative Ophthalmology and Visual Science, Vol. 32, No. 11, pp. 2898-2905 (October, 1-991). The steroids alone reduce neovascularization somewhat but are not effective alone in effecting regression of neovascularization.
  • This invention is directed to compounds useful for treating persons with diseases in which non-cancerous tissue growth, including scar formation, plays a pathogenic role.
  • the compounds are useful for treating pterygium (primary and recurrent), glaucoma filtration bleb failure, hyperkeratosis, cheloid formation, polyp formation and wound healing conditions with excessive scar formation.
  • the invention encompasses methods for controlling these diseases through the systemic or local administration of the compositions of the compounds disclosed herein.
  • the compounds of the present invention have the following formula:
  • R is H, ⁇ -CH 3 or ⁇ -QH,
  • R 2 is F, CcrC,, double bond, C 9 -C n epoxy, H or -Cl;
  • NH 2 and -NHCOCH 3 and R is hydrogen, alkyl (C,-C 4 ), or phenyl and each R can be the same or different, and R 7 is ARYL as herein defined, or aIkyl(C]-C 12 );
  • R is H, CH 3 , Cl or F;
  • Rs is H, OH, F, Cl, Br, CH 3 , phenyl, vinyl or allyl;
  • R* is H or CH 3 ;
  • R, 2 is H or forms a double bond with R, or R, 4 ;
  • R 14 is H or forms a double bond with R 12 ;
  • Y is a bond or -O-; Y is a bond, -0-, or -S-; each of X and X is a bond,- CON(R 18 )-, -N(R 18 )CO-, -0-, -S-, -S(0>, or -S(0 2 )-; R 18 is hydrogen or alkyl (C,-C 4 ); each of R, 6 and R )7 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R 16 and R I7 taken together with the nitrogen atom to which each is attached forms a monocyclic heterocycle selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N(lower)alkyl-piperazino where
  • Z is a bond or -O-; r is an integer of from 2 to 9; and Q is one of the following:
  • R 19 is -S-, -S(O)-, -S(0)r, -SO ⁇ R )-, or N(R 2 ⁇ ) SO ⁇ ; and R 20 is hydrogen or lower alkyl-(C r C 4 ); with the proviso that the total number of carbon atoms in R 20 and (CH 2 ) r is not greater than 10; or
  • the compounds of the present invention are useful in preventing and treating persons with diseases in which non-cancerous tissue growth plays a pathogenic role.
  • the compounds are useful in treating persons suffering from pterygium (primary and recurrent), glaucoma filtration bleb failure, hyperkeratosis, cheloid formation, polyp formation, and post-surgical wound healing conditions with excessive scar formation, such as burns and cuts, including surgical cuts.
  • the compounds of the present invention may be incorporated in various formulations for delivery.
  • the type of formulation topical or systemic
  • topical formulations can be used and can include ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, buffers, sodium chloride, and water to form aqueous sterile ophthalmic solutions and suspensions.
  • a compound is combined with a preservative in an appropriate vehicle, such as mineral oil, liquid lanolin, or white petrolatum.
  • Sterile ophthalmic gel formulations comprising the compounds of the present invention can be prepared by suspending a compound in a hydrophilic base prepared from a combination of, for example, Carbachol-974P (a carboxy vinyl polymer available from the BF Goodrich Company) according to published formulations for analogous ophthalmic preparations. Preservatives and antimicrobial agents may also be incorporated in such gel formulations.
  • Systemic formulations can also be used, for example, orally ingested tablets, suppositories, transdermal patches, and formulations for intraocular injection.
  • Topical aqueous solutions, suspensions, ointments, creams and gels are the preferred dosage forms for the treatment of pterygium, hyperkeratosis, and cheloid and polyp formation.
  • Topical ophthalmic formulations are suitable for preventing glaucoma filtration bleb failure or scar formation associated with ophthalmic surgery.
  • the compound will normally be contained in these formulations in an amount from about 0.01 to about 10.0 weight/percent. Preferable concentrations range from about 0.1 to about 5.0 weight/percent.
  • these formulations are delivered to the disease site one to six times a day, depending on the routine discretion of the skilled clinician.
  • Systemic administration for example, in the form of tablets or suppositories is useful for the treatment of polyp formation. Tablets containing 10-1000 mg of a compound can be taken 2-3 times per day depending on the discretion of the skilled clinician.
  • Example 1 illustrate formulations of the present invention, but are in no way limiting.
  • the formulation is prepared by first placing a portion of the purified water into a beaker and heating to 90°C.
  • the hydroxypropylmethylcellulose (HPMC) is then added to the heated water and mixed by means of vigorous vortex stirring until all of the HPMC is dispersed.
  • the resulting mixture is then allowed to cool while undergoing mixing in order to hydrate the HPMC.
  • the resulting solution is then sterilized by means of autoclaving in a vessel having a liquid inlet and a hydrophobic, sterile air vent filter.
  • the sodium chloride and the edetate disodium are then added to a second portion of the purified water and dissolved.
  • the benzalkonium chloride is then added to the solution, and the pH of the solution is adjusted to 7.4 with 0.1M NaOH/HCl.
  • the solution is then sterilized by means of filtration.
  • the Compound, 4,9(1 l)-Pregnadien-17o ⁇ 21-diol-3,20-dione-21 -acetate is sterilized by either dry heat or ethylene oxide. If ethylene oxide sterilization is selected, aeration for at least 72 hours at 50°C is necessary.
  • the sterilized Compound is weighed aseptically and placed into a pressurized ballmill container.
  • the tyloxapol, in sterilized aqueous solution form, is then added to the ballmill container.
  • Sterilized glass balls are then added to the container and the contents of the container are milled aseptically at 225 rpm for 16 hours, or until all particles are in the range of approximately 5 microns.
  • the micronized drug suspension formed by means of the preceding step is then poured into the HPMC solution with mixing.
  • the ballmill container and balls contained therein are then rinsed with a portion of the solution containing the sodium chloride, the edetate disodium and benzalkonium chloride.
  • the rinse is then added aseptically to the HPMC solution.
  • the final volume of the solution is then adjusted with purified water and, if necessary, the pH of the solution is adjusted to pH 7.4 with NaOH/HCl.
  • the formulation will be given topically, in a therapeutically effective amount.
  • the phrase "therapeutically effective amount” means an amount which is sufficient to substantially prevent or reverse any ocular neovascularization.
  • the dosage regimen used will depend on the nature of the neovascularization, as well as various other factors such as the patient's age, sex, weight, and medical history.
  • Tablet 10-1000 mg of a compound of the present invention with inactive ingredients such as starch, lactose and magnesium stearate can be formulated according to procedures known to those skilled in the art of tablet formulation.
  • each mL contains:
  • Cream 4,9(1 l)-Pregnadien-17 ⁇ ,21-diol-3-20-dione 1 mg/g in cream base of purified water, emulsifying wax, propylene glycol, stearic acid, isopropyl palmitate, synthetic beeswax, polysorbate 60, potassium sorbate, sorbic acid, propyl gallate, citric acid, and sodium hydroxide
  • Ointment 1 mg/g of a compound of the present invention in base of mineral oil and polyethylene

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

Composés conçus pour être utilisés afin d'empêcher la croissance tissulaire non cancéreuse. L'invention concerne aussi des compositions pharmaceutiques à base de ces composés et leurs procédés d'utilisation afin d'empêcher la croissance tissulaire non cancéreuse.
PCT/US1997/002809 1996-05-09 1997-02-21 Utilisation de composes steroides afin d'empecher la croissance tissulaire non cancereuse WO1997041867A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU19701/97A AU1970197A (en) 1996-05-09 1997-02-21 Use of steroid compounds to prevent non-cancerous tissue growth

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1906096P 1996-05-09 1996-05-09
US60/019,060 1996-05-09

Publications (1)

Publication Number Publication Date
WO1997041867A1 true WO1997041867A1 (fr) 1997-11-13

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/002809 WO1997041867A1 (fr) 1996-05-09 1997-02-21 Utilisation de composes steroides afin d'empecher la croissance tissulaire non cancereuse

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AU (1) AU1970197A (fr)
WO (1) WO1997041867A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6262043B1 (en) * 1999-04-13 2001-07-17 Kyowa Hakko Kogyo Co., Ltd. Estra-1,3,5(10),16-tetraene derivatives
US6696433B2 (en) 1996-07-22 2004-02-24 Renovo Limited Use of sex steroids function modulators to treat wounds and fibrotic disorders
US6787530B1 (en) 1996-08-23 2004-09-07 Monash University Use of pregnane-diones as analgesic agents
WO2007076467A3 (fr) * 2005-12-23 2007-08-16 Alcon Inc Utilisation d'acetate d'anecortave comme auxiliaire lors de la chirurgie filtrante
US7288536B2 (en) 2003-07-11 2007-10-30 Glaxo Group Limited Specific glucocorticosteroid compound having anti-inflammatory activity
EP1633339A4 (fr) * 2003-06-13 2009-06-03 Alcon Inc Preparation d'agents anti-inflammatoires non steroidiens pour traiter l'angiogenese oculaire pathologique
US7579335B2 (en) 2005-01-10 2009-08-25 Glaxo Group Limited Androstane 17α-carbonate derivatives for use in the treatment of allergic and inflammatory conditions

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4939135A (en) * 1988-10-03 1990-07-03 Alcon Laboratories, Inc. Pharmaceutical compositions and methods of treatment to prevent and treat corneal scar formation produced by laser irradiation
WO1993010141A2 (fr) * 1991-11-22 1993-05-27 Alcon Laboratories, Inc. Steroïdes angiostatiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4939135A (en) * 1988-10-03 1990-07-03 Alcon Laboratories, Inc. Pharmaceutical compositions and methods of treatment to prevent and treat corneal scar formation produced by laser irradiation
WO1993010141A2 (fr) * 1991-11-22 1993-05-27 Alcon Laboratories, Inc. Steroïdes angiostatiques

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6696433B2 (en) 1996-07-22 2004-02-24 Renovo Limited Use of sex steroids function modulators to treat wounds and fibrotic disorders
US6787530B1 (en) 1996-08-23 2004-09-07 Monash University Use of pregnane-diones as analgesic agents
US6262043B1 (en) * 1999-04-13 2001-07-17 Kyowa Hakko Kogyo Co., Ltd. Estra-1,3,5(10),16-tetraene derivatives
EP1633339A4 (fr) * 2003-06-13 2009-06-03 Alcon Inc Preparation d'agents anti-inflammatoires non steroidiens pour traiter l'angiogenese oculaire pathologique
US7288536B2 (en) 2003-07-11 2007-10-30 Glaxo Group Limited Specific glucocorticosteroid compound having anti-inflammatory activity
US7291609B2 (en) 2003-07-11 2007-11-06 Glaxo Group Limited Specific glucocorticosteroid compound having anti-inflammatory activity
US7524970B2 (en) 2003-07-11 2009-04-28 Glaxo Group Limited Compounds
US7638508B2 (en) 2003-07-11 2009-12-29 Glaxo Group Limited Glucocorticosteroid compound having anti-inflammatory activity
US7579335B2 (en) 2005-01-10 2009-08-25 Glaxo Group Limited Androstane 17α-carbonate derivatives for use in the treatment of allergic and inflammatory conditions
WO2007076467A3 (fr) * 2005-12-23 2007-08-16 Alcon Inc Utilisation d'acetate d'anecortave comme auxiliaire lors de la chirurgie filtrante

Also Published As

Publication number Publication date
AU1970197A (en) 1997-11-26

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