EP0000546A1 - D-Homo-Oxasteroide, Verfahren zu ihrer Herstellung und ihre Anwendung zur Herstellung von pharmazeutischen Zusammensetzungen mit antiinflammatorischer Aktivität, sowie diese enthaltene pharmazeutische Zusammensetzungen - Google Patents

D-Homo-Oxasteroide, Verfahren zu ihrer Herstellung und ihre Anwendung zur Herstellung von pharmazeutischen Zusammensetzungen mit antiinflammatorischer Aktivität, sowie diese enthaltene pharmazeutische Zusammensetzungen Download PDF

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Publication number
EP0000546A1
EP0000546A1 EP78100445A EP78100445A EP0000546A1 EP 0000546 A1 EP0000546 A1 EP 0000546A1 EP 78100445 A EP78100445 A EP 78100445A EP 78100445 A EP78100445 A EP 78100445A EP 0000546 A1 EP0000546 A1 EP 0000546A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydrogen
homo
hydroxy
formula
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.)
Withdrawn
Application number
EP78100445A
Other languages
English (en)
French (fr)
Inventor
Christopher M. Cimarusti
Paul Grabowich
Ravi K. Varma
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.)
ER Squibb and Sons LLC
Original Assignee
ER Squibb and Sons LLC
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 ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
Publication of EP0000546A1 publication Critical patent/EP0000546A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to novel D-homo oxasteroids, processes for their preparation and their use in the treatment of inflammatory conditions.
  • German Offenlegungsschrift 2, 526,788 published December 23, 1976 discloses that the oxidation of certain 17-alkanoyloxy-A l6 -steroids with osmium tetroxide opens the D-ring of the steroids yielding a 16, 17-seco-steroid of the type wherein "St” symbolizes A, B and C rings of the steroid and R symbolizes methyl or ethyl. Ring closure of the 16,17-seco-steroid pictured above yields a D-homo- oxasteroid of the type
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • a preferred sub-genus of the steroids of the above formula or the 1,2-dehydro derivatives thereof has the formula
  • the D-homo oxasteroids of this invention wherein R 1 is hydrogen, acyloxy or halogen (this subgrouping of substituents is hereinafter referred to as "R' 1 ") and R 2 is hydrogen, can be prepared by reacting the corresponding A 16- pregnene having the formula II with ozone, and an alkanol having the formula III and then treating the reaction mixture with a reducing agent, e.g., a dialkylsulfide such as dimethylsulfide, in an organic solvent, e.g., a halogenated hydrocarbon such as dichloromethane.
  • a reducing agent e.g., a dialkylsulfide such as dimethylsulfide
  • organic solvent e.g., a halogenated hydrocarbon such as dichloromethane.
  • the steroid product has the formula I-a
  • an acid catalyst e.g., p-toluenesulfonic acid
  • Saponification of a steroid of formula I-b, wherein R' 1 is acyloxy yields the corresponding 21-hydroxy steroid having the formula I-c
  • the saponification reaction is run in the presence of a base, e.g., an alkali metal carbonate, and can be carried out in an organic solvent, e.g., an alkanol.
  • the steroids of formula I having a halogen substituent in the 21-position can be prepared from the corresponding 21-hydroxy steroids via the 21 - mesylate.
  • Another example involves the trans-etherification of a steroid of formula I-a.
  • a steroid of formula I-a especially one with a large, sterically hindered R 3 group (e.g., isopropyl or t-butyl) can be prepared by reacting a steroid of formula I-a with the appropriate alkanol, in the presence of an acid catalyst at room temperature.
  • the preparation of the steroids of formula I will yield a solvate of the steroid, rather than the steroid per se. These solvates are also contemplated as a part of this invention.
  • the steroids of formula I can be used in lieu of known glucocorticoids in the treatment of inflammatory conditions, e.g. rheumatoid arthritis. They can be administered in the same manner as hydrocortisone, the dosage being adjusted for the relative potency of the particular steroid. Additionally, the steroids of this invention can be used topically in lieu of known glucocorticoids in the treatment of skin conditions, such as dermatitis, psoriasis, sunburn, neurodermatitis, eczema or anogenital pruritus.
  • the steroids of this invention may be used in a dosage range of 0.1 to 200 milligrams, preferably 0.3 to 100 milligrams, for a 70 kg. mammal. If administered topically, the steroids of this invention may be used in the range of 0.01 to 5.0% by weight, preferably 0.05 to 2.0% by weight, in a conventional cream, ointment, lotion or the like.
  • a solution of 1.9 g of 21-chloro-9-fluoro-11 ⁇ -hydroxypregna-1,4,16-triene-3,20-dione in 100 ml of dichloromethane and 50 ml of ethanol is cooled to -78°C and a 10% excess of ozone in oxygen passed through.
  • the solution is treated with 5 ml of dimethylsulfide and allowed to warm to ambient temperature and stand for about 16 hours.
  • the solvents are evaporated and a chloroform solution of the residue is washed with water, dried, and evaporated.
  • the residue is dissolved in chloroform and chromatographed on a 40 g-silica gel column. Elution with chloroform and then chloroform-ethyl acetate (5:1) gives TLC pure material that cyrstallizes from methanol-dichloromethane to give 563 mg, melting point 171-173°C.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
EP78100445A 1977-07-20 1978-07-19 D-Homo-Oxasteroide, Verfahren zu ihrer Herstellung und ihre Anwendung zur Herstellung von pharmazeutischen Zusammensetzungen mit antiinflammatorischer Aktivität, sowie diese enthaltene pharmazeutische Zusammensetzungen Withdrawn EP0000546A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US817315 1977-07-20
US05/817,315 US4116978A (en) 1977-07-20 1977-07-20 D-homo oxasteroids

Publications (1)

Publication Number Publication Date
EP0000546A1 true EP0000546A1 (de) 1979-02-07

Family

ID=25222799

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100445A Withdrawn EP0000546A1 (de) 1977-07-20 1978-07-19 D-Homo-Oxasteroide, Verfahren zu ihrer Herstellung und ihre Anwendung zur Herstellung von pharmazeutischen Zusammensetzungen mit antiinflammatorischer Aktivität, sowie diese enthaltene pharmazeutische Zusammensetzungen

Country Status (6)

Country Link
US (2) US4116978A (de)
EP (1) EP0000546A1 (de)
JP (1) JPS5422356A (de)
AU (1) AU517482B2 (de)
CA (1) CA1113925A (de)
IT (1) IT1097826B (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0061416A1 (de) * 1981-03-09 1982-09-29 Schering Aktiengesellschaft Verfahren zur Herstellung von Delta-9(11)- und delta-16-21-chlor-20-keto-Steroide der Pregnan- und D-Homopregnanreihen und ihre Anwendung als Zwischenprodukte für die Synthese von hochwirksamen Kortikoiden

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU665455B2 (en) * 1992-09-30 1996-01-04 Teikoku Hormone Mfg. Co., Ltd. Novel 7-substituted oxa- or azasteroid compound
CN113173969B (zh) * 2021-03-01 2022-06-17 广州中医药大学(广州中医药研究院) 海洋真菌来源的杂萜化合物及其在制备抗肝纤维化药物中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1490967A (fr) * 1965-08-30 1967-08-04 Squibb & Sons Inc Procédé de préparation de 7-oxa-d-homo-pregnènes et-alpha-nor-pregnènes

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2832772A (en) * 1953-06-15 1958-04-29 Monsanto Chemicals 21-diazo-compounds for synthesizing steroids
US3257412A (en) * 1964-04-27 1966-06-21 Searle & Co D-ring lactams of 3-oxygenated estra-1, 3, 5(10)-trienes and derivatives thereof
US3294819A (en) * 1964-12-17 1966-12-27 Squibb & Sons Inc Synthesis of steroids
US3467677A (en) * 1967-04-21 1969-09-16 Schering Corp 17alpha-oxa-d-homo-pregnanes and methods for their manufacture
DE2526788A1 (de) * 1975-06-13 1976-12-23 Schering Ag Verfahren zur herstellung von d-homo- steroiden

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1490967A (fr) * 1965-08-30 1967-08-04 Squibb & Sons Inc Procédé de préparation de 7-oxa-d-homo-pregnènes et-alpha-nor-pregnènes

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0061416A1 (de) * 1981-03-09 1982-09-29 Schering Aktiengesellschaft Verfahren zur Herstellung von Delta-9(11)- und delta-16-21-chlor-20-keto-Steroide der Pregnan- und D-Homopregnanreihen und ihre Anwendung als Zwischenprodukte für die Synthese von hochwirksamen Kortikoiden

Also Published As

Publication number Publication date
US4116978A (en) 1978-09-26
IT1097826B (it) 1985-08-31
AU517482B2 (en) 1981-08-06
JPS5422356A (en) 1979-02-20
AU3777478A (en) 1980-01-10
IT7825879A0 (it) 1978-07-19
CA1113925A (en) 1981-12-08
US4155917A (en) 1979-05-22

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Effective date: 19820408

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Inventor name: VARMA, RAVI K.

Inventor name: GRABOWICH, PAUL

Inventor name: CIMARUSTI, CHRISTOPHER M.