WO1997016423A1 - 24-homo-26,27-hexafluoro-cholecalciferols - Google Patents

24-homo-26,27-hexafluoro-cholecalciferols Download PDF

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Publication number
WO1997016423A1
WO1997016423A1 PCT/EP1996/004592 EP9604592W WO9716423A1 WO 1997016423 A1 WO1997016423 A1 WO 1997016423A1 EP 9604592 W EP9604592 W EP 9604592W WO 9716423 A1 WO9716423 A1 WO 9716423A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
accordance
treatment
homo
Prior art date
Application number
PCT/EP1996/004592
Other languages
English (en)
Inventor
Jerome Anthony Iacobelli
Milan Radoje Uskokovic
Original Assignee
F.Hoffmann-La Roche Ag
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 F.Hoffmann-La Roche Ag filed Critical F.Hoffmann-La Roche Ag
Priority to JP9517038A priority Critical patent/JPH10512297A/ja
Priority to AU72974/96A priority patent/AU7297496A/en
Priority to EP96934788A priority patent/EP0874813A1/fr
Priority to KR1019980703124A priority patent/KR19990067173A/ko
Publication of WO1997016423A1 publication Critical patent/WO1997016423A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/48—Halogenated derivatives
    • C07C35/52—Alcohols with a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/24—All rings being cycloaliphatic the ring system containing nine carbon atoms, e.g. perhydroindane

Definitions

  • the invention relates to a compound of the formula
  • A is a carbon double bond having the stereochemical configuration E or Z, i.e. of the formula:
  • Compounds of formula I induce differentiation and inhibition of proliferation in certain skin and cancer cell lines. Accordingly, the compounds of formula I are useful as agents for the treatment of hyperproliferative skin diseases such as, psoriasis. Compounds of formula I are also useful as agents for the treatment of neoplastic diseases, such as leukemia.
  • lower alkyl denotes a straight or branched-chain alkyl group containing 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like.
  • ar-lower alkyl are p-tolyl, benzyl, phenylethyl, phenylpropyl, and the like.
  • aryl denotes a group derived from an aromatic hydrocarbon which may be unsubstituted or substituted by one or more lower alkyl groups. Exemplary of "aryl” are phenyl and p-methyl phenyl.
  • halogen denotes the halogens, that is, bromine, chlorine, fluorine, or iodine.
  • the invention relates to a composition
  • a composition comprising a compound of formula I, or a mixture of two or more compounds of formula I.
  • the invention also relates to a method for treating the above ⁇ mentioned disease states by administration of a compound of formula I, or a mixture of two or more compounds of formula I.
  • the invention also relates to a process for preparing compounds of formula I and intermediates of formulas X, XI, XII and V.
  • Rl and A are as described above and R4 and R6 are independently lower alkyl and R-5 is independently lower alkyl, aryl, or ar-lower alkyl.
  • Ph is phenyl
  • Rl , R ⁇ , R5 and R'S are as described above
  • R ⁇ is hydrogen, fluorine or
  • R ⁇ , R-5 and R ⁇ are as described above.
  • the reaction is carried out at -60°C to - 90°C, preferably -78°C, in a polar, aprotic, organic solvent, such as dry ether or more preferably dry tetrahydrofuran, in the presence of a strong base such as an alkyl lithium like butyl lithium.
  • a polar, aprotic, organic solvent such as dry ether or more preferably dry tetrahydrofuran
  • the protecting groups of a compound of formula IVa, IVb or IVc are removed by reaction with a fluorine salt, such as tetrabutyl- ammonium fluoride in a polar, organic solvent such as ether, or more preferably tetrahydrofuran to yield a corresponding compound of formula Ia, Ib or Ic.
  • a fluorine salt such as tetrabutyl- ammonium fluoride
  • a polar, organic solvent such as ether
  • tetrahydrofuran to yield a corresponding compound of formula Ia, Ib or Ic.
  • the compound of formula V is partially hydrogenated to obtain the corresponding compound of formula VI by reaction with a reducing agent such as lithium aluminum hydride, preferably in the presence of an alkali metal alkoxide, like sodium methoxide, in an aprotic organic solvent like dry ether, or more preferably dry tetrahydrofuran, at reflux temperature (about 80°C for tetrahydrofuran) for about 2.5 hours, cooled to about 0°C, and worked up by conventional means.
  • a reducing agent such as lithium aluminum hydride
  • an alkali metal alkoxide like sodium methoxide
  • an aprotic organic solvent like dry ether, or more preferably dry tetrahydrofuran
  • the resulting compound of formula VI is oxidized to the compound of formula VII by treatment with an oxidizing agent such as 2,2'-bipyridinium chlorochromate, or pyridinium dichromate, at room temperature, in an aprotic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride.
  • an oxidizing agent such as 2,2'-bipyridinium chlorochromate, or pyridinium dichromate
  • the compound of formula VII is converted to a compound of formula II, by reaction with, for example, a (trialkylsilyl)imidazole such as (trimethylsilyl)imidazole in an aprotic, organic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride.
  • a (trialkylsilyl)imidazole such as (trimethylsilyl)imidazole in an aprotic, organic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride.
  • the compound of formula II is worked up by conventional means such as extraction followed by chromatography.
  • the compound of formula VIII a known compound (Wovkulich, P.M. et al., Proceedings of the 6th Workshop of Vitamin D, 1985, p. 755-764), is converted to a compound of formula IX by treatment with an oxidizing agent, such as, 2,2'-bipyridinium chlorochromate, or pyridinium chlorochromate, in an aprotic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride under an argon atmosphere.
  • an oxidizing agent such as, 2,2'-bipyridinium chlorochromate, or pyridinium chlorochromate
  • an aprotic solvent such as dry tetrahydrofuran, or more preferably, dry methylene chloride under an argon atmosphere.
  • the compound of formula IX is converted to a compound of formula X by reaction with Wittig reagent, such as, (3-trimethyl-silyl- 2-propynyl)-triphenyl-phosphonium bromide, in an aprotic solvent, such as dry tetrahydrofuran or dry methylene chloride, and a base such as butylithium.
  • Wittig reagent such as, (3-trimethyl-silyl- 2-propynyl)-triphenyl-phosphonium bromide
  • an aprotic solvent such as dry tetrahydrofuran or dry methylene chloride
  • a base such as butylithium
  • the compound of formula X is converted to a compound of formula XI by reaction with silver nitrate in a alcohol solvent, such as ethanol .
  • the compound of formula XI is converted to the compound of formula XII by reaction with a fluorinated acetone, such as hexafluoroacetone.
  • a fluorinated acetone such as hexafluoroacetone.
  • the reaction is carried out at -78° C.
  • the compound of formula XII is converted to the compound of formula V by reaction with a disilylating reagent, such as hydrofluoric acid, in an organic solvent, such as a combination of acetonitrile and te trah ydrofuran .
  • a disilylating reagent such as hydrofluoric acid
  • the compounds of formula I as described above can be administered orally, for the treatment of neoplastic diseases such as leukemia, to warmblooded animals which need such treatment. More specifically, the compounds of formula I as described above can be administered orally to an adult human in dosages that are in the range of about .05 to 50 ⁇ g per day for the treatment of neoplastic diseases such as leukemia.
  • the compounds of formula I as described above can be administered orally, for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratination, and keratosis, to warmblooded animals which need such treatment. More specifically, the compounds of formula I as described above can be administered orally to an adult human in dosages that are in the range of about 0.5 to 50 ⁇ g per day for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis. These compounds can be administered orally for the treatment of acne in humans at a dosage of about .05 to 50 ⁇ g per day; preferably 0.5 to 50 ⁇ g per day.
  • the compounds of formula I as described above can be administered topically, for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis, to warmblooded animals which need such treatment. More specifically, the compounds of formula I as described above can be administered topically in dosages that are in the range of about 0.5 to about 50 ⁇ g per gram of topical formulation per day, for the treatment of hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization, and keratosis.
  • the induction of differentiation of HL-60 cells was assayed by measuring their oxidative burst potential via the reduction of nitrobluetetrazolium (NBT).
  • NBT nitrobluetetrazolium
  • HL-60 cells were maintained in RPMI 1640 medium supplemented with 10% fetal calf serum (FCS), 2mM L-glutamine, ImM sodium pyruvate, 1 % non-essential amino acids, 50 U/ml penicillin, and 50 ⁇ g/ml streptomycin.
  • HL-60 cells (30,000 cells in 90 ⁇ l of supplemented RPMI medium) were seeded into flat-bottomed microliter wells.
  • 10 ⁇ l of test compounds listed below in Table I diluted in supplemented RPMI medium were added to the wells to yield final concentrations of between 10" ! and 10 ⁇ 6 M (starting from stock solutions of 10 * 3 M in ethanol, stored at -20°C and protected from light).
  • compounds of formula I induce differentiation of HL-60 cells and thereby stop these tumor cells from growing. Accordingly, compounds of formula I are useful in the treatment of neoplastic diseases such as leukemia.
  • HaCaT cell line The immortalized human cell line HaCaT was used (originally obtained from N.E. Fusenig, German Cancer Research Center, Heidelberg, Germany). ⁇ H-thymidine incorporation was measured in exponentially growing cultures after 6 days of culture in presence of the test compound.
  • Cell culture - HaCaT cells were cultured in a mixture of Dulbecco's Modified Eagle Medium containing 4.5 g glucose and Nutrient Mixture Ham's F12, 3: 1 (v/v).
  • This mixture was supplemented with 10% FCS, 2mM L-glutamine, 50 Ul/ml, penicillin, 50 ⁇ g/ml streptomycin, 10 ng/ml EGF, 400 ng/ml hydrocortisone, 8.5 ng/ml cholera toxin, and 5 ng/ml insulin.
  • the cells were maintained in a humidified atmosphere containing 5% CO2 and 95% air and passaged every 3-4 days.
  • compounds of formula I inhibit proliferation of keratinocytes. Accordingly, compounds of formula I are useful in the treatment of hyperproliferative skin diseases, such as psoriasis.
  • mice 25-30 g body weight received daily subcutaneous administrations of the compound for 4 consecutive days. Body weight was registered just before and at the end of a 5 day treatment period. The "highest tolerated dose” (HTD) is the dose which results in zero weight gain during this treatment period. The results are set forth in Table III.
  • Oral dosage forms comprising compounds of formula I of the invention may be incorporated in capsules, tablets and the like with pharmaceutically acceptable carrier materials.
  • Illustrative of the pharmaceutically acceptable carrier materials which may be incorporated into capsules, and the like are the following: a binder such as gum tragacanth, acacia, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, algenic acid, and the like; a lubricant such as magnesium stearate, a sweetening agent such as sucrose, lactose, or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry.
  • a binder such as gum tragacanth, acacia, corn starch, or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, algenic acid, and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose, or saccharin
  • a flavoring agent such as pepper
  • Topical dosage forms comprising compounds of formula I of the invention include: ointments and creams encompassing formulations having oleaginous, adsorbable, water-soluble and emulsion-type bases such as petrolatum, lanolin, polyethylene glycols and the like.
  • Lotions are liquid preparations and vary from simple solutions to aqueous or hydroalcoholic preparations containing finely divided substances.
  • Lotions can contain suspending or dispersing agents, for example, cellulose derivatives such as ethyl cellulose, methyl cellulose, and the like; gelatin or gums, which incorporate the active ingredient in a vehicle made up of water, alcohol, glycerin and the like.
  • Gels are semi-solid preparations made by gelling a solution or suspension of the active ingredient in a carrier vehicle.
  • the vehicles which can be hydrous or anhydrous, are gelled using a gelling agent, such as, carboxy polymethylene, and neutralized to a proper gel consistency with the use of alkalies, such as, sodium hydroxide and amines, such as, polyethylenecocoamine.
  • a gelling agent such as, carboxy polymethylene
  • alkalies such as, sodium hydroxide and amines, such as, polyethylenecocoamine.
  • topical denotes the use of the active ingredient, incorporated in a suitable pharmaceutical carrier, and applied at the site of the inflammation for the exertion of local action.
  • the topical composition include those pharmaceutical forms in which the compound is applied externally by direct contact with the skin.
  • the topical dosage forms comprise gels, creams, lotions, ointments, powders, aerosols and other conventional forms for applying medication to the skin obtained by admixing the compounds of formula I with known pharmaceutical topical carrier materials.
  • the topical compositions of this invention can also be employed in the treatment of inflammations of mucous membranes, where such membranes are accessible to topical application of medication.
  • the topical composition can be applied to the mucous lining of the mouth or lower colon.
  • the reaction mixture was filtered through a celite pad and the pad was washed with hexane.
  • the combined filtrates were washed with dilute acid, brine, 2N potassium bicarbonate and water, dried over sodium sulfate and evaporated to dryness.
  • the crude product was recrystallized from hexane.
  • the first crop and mother liquors were separately purified by preparative HPLC with hexane-ethyl acetate 3: 1. Ultimately 220 mg (56% of the title compound was obtained, mm.p.
  • BHT Butylated Hydroxytoluene
  • Polysorbate 60 (Tween 60) 1 .00

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un composé de la formule (I) dans laquelle A représente une liaison carbone double correspondant à la configuration stéréochimique E ou Z, c'est-à-dire respectivement à la formule (a) ou (b), R représente hydroxy et R1 représente hydrogène ou =CH¿2?, ou bien R représente hydrogène ou fluoro et R?1¿ représente =CH¿2?. Des composés répondant à la formule (I) induisent une différenciation ainsi qu'une inhibition de la prolifération dans certaines lignées cellulaires cutanées ou cancéreuses. En conséquence, ces composés sont utiles en tant qu'agents destinés au traitement de maladies de la peau à hyperprolifération, telles que le psoriasis, et ils sont également utiles en tant qu'agents destinés au traitement de maladies néoplasiques telles que la leucémie.
PCT/EP1996/004592 1995-10-31 1996-10-23 24-homo-26,27-hexafluoro-cholecalciferols WO1997016423A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP9517038A JPH10512297A (ja) 1995-10-31 1996-10-23 ２４−ホモ−２６，２７−ヘキサフルオロ−コレカルシフェロール類
AU72974/96A AU7297496A (en) 1995-10-31 1996-10-23 24-homo-26,27-hexafluoro-cholecalciferols
EP96934788A EP0874813A1 (fr) 1995-10-31 1996-10-23 24-homo-26,27-hexafluoro-cholecalciferols
KR1019980703124A KR19990067173A (ko) 1995-10-31 1996-10-23 24-호모-26,27-헥사플루오로-콜레칼시페롤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US712595P 1995-10-31 1995-10-31
US60/007,125 1995-10-31

Publications (1)

Publication Number Publication Date
WO1997016423A1 true WO1997016423A1 (fr) 1997-05-09

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Application Number Title Priority Date Filing Date
PCT/EP1996/004592 WO1997016423A1 (fr) 1995-10-31 1996-10-23 24-homo-26,27-hexafluoro-cholecalciferols

Country Status (9)

Country Link
EP (1) EP0874813A1 (fr)
JP (1) JPH10512297A (fr)
KR (1) KR19990067173A (fr)
CN (1) CN1201452A (fr)
AU (1) AU7297496A (fr)
CA (1) CA2235584A1 (fr)
MX (1) MX9803345A (fr)
WO (1) WO1997016423A1 (fr)
ZA (1) ZA968953B (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114276284A (zh) * 2021-12-30 2022-04-05 正大制药（青岛）有限公司 一种氟骨化醇的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991000855A1 (fr) * 1989-07-10 1991-01-24 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) Nouveaux analogues de la vitamine d
US5206230A (en) * 1991-06-05 1993-04-27 Daikin Industries, Ltd. Fluorine-containing vitamin D3 analogues and pharmaceutical composition containing the same
WO1995001960A1 (fr) * 1993-07-09 1995-01-19 Laboratoire Theramex S.A. Nouveaux analogues structuraux de la vitamine d

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991000855A1 (fr) * 1989-07-10 1991-01-24 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) Nouveaux analogues de la vitamine d
US5206230A (en) * 1991-06-05 1993-04-27 Daikin Industries, Ltd. Fluorine-containing vitamin D3 analogues and pharmaceutical composition containing the same
WO1995001960A1 (fr) * 1993-07-09 1995-01-19 Laboratoire Theramex S.A. Nouveaux analogues structuraux de la vitamine d

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R. MUNKER ET AL: "A New Series of Vitamin D Analogs is Highly Active for Clonal Inhibition, Differentiation, and Induction of WAF1 in Myeloid Leukemia", BLOOD, vol. 88, no. 6, 15 September 1996 (1996-09-15), pages 2201 - 2209, XP002024396 *

Also Published As

Publication number Publication date
EP0874813A1 (fr) 1998-11-04
CN1201452A (zh) 1998-12-09
MX9803345A (es) 1998-09-30
JPH10512297A (ja) 1998-11-24
CA2235584A1 (fr) 1997-05-09
ZA968953B (en) 1997-07-30
KR19990067173A (ko) 1999-08-16
AU7297496A (en) 1997-05-22

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