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WO2000042008A1 - Nouveaux analogues de la vitamine d - Google Patents

Nouveaux analogues de la vitamine d Download PDF

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Publication number
WO2000042008A1
WO2000042008A1 PCT/EP2000/000288 EP0000288W WO0042008A1 WO 2000042008 A1 WO2000042008 A1 WO 2000042008A1 EP 0000288 W EP0000288 W EP 0000288W WO 0042008 A1 WO0042008 A1 WO 0042008A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
nmr
compound
mhz
vitamin
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
PCT/EP2000/000288
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English (en)
Inventor
Antonio MOURIÑO MOSQUERA
Ana Isabel Gacio Fernandez
Christian Vitale
Jan-Paul Van De Velde
Jan Zorgdrager
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.)
Abbott Healthcare Products BV
Original Assignee
Solvay Pharmaceuticals BV
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 Solvay Pharmaceuticals BV filed Critical Solvay Pharmaceuticals BV
Priority to AU22916/00A priority Critical patent/AU2291600A/en
Publication of WO2000042008A1 publication Critical patent/WO2000042008A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

Definitions

  • the invention relates to new vitamin D compounds, to methods of preparing these compounds and to their use in pharmacotherapy and cosmetics.
  • vitamin-D compounds or vitamin-D related compounds are known, that vitamin-D compounds or vitamin-D related compounds
  • vitamin-D analogs have a strong biological activity and may be used in all those cases in which problems with the calcium metabolism play a part.
  • various active vitamin-D compounds also have other pharmacotherapeutic activities and may be used successfully, for example, for the treatment of certain skin and bone diseases, for cosmetic applications and for treating diseases which are related to cell differentiation, cell proliferation or imbalance in the immune system, including diabetes mellitus, hypertension and inflammatory diseases such as rheumatoid arthritis and asthma.
  • these compounds may be used in various veterinary applications, and for diagnostic purposes.
  • Vitamin D compounds which are of interest for the above applications are hydroxylated vitamin D compounds, in particular vitamin D compounds hydroxylated in the 1a-, 24- and/or 25-positions. Further developments in the field of active vitamin D compounds are 19-nor-vitamin D compounds (EP-A-0387077) and C 18 - modified vitamin D compounds (EP-A-0521550), preferably also hydroxylated in the 1a-position and optionally in the C 17 -side chain. Other modifications of the C 17 -side chain have been proposed, likewise to improve the intended activity and to suppress detrimental side-effects. Examples of modifications of the C 17 -side chain are 22-oxa modifications (e.g. WO 90/09991), fluor substitutions, epoxy groups (e.g. WO 90/09991)), fluor substitutions, epoxy groups (e.g. WO 90/09991)), fluor substitutions, epoxy groups (e.g. WO 90/09991)), fluor substitutions, epoxy groups (e.g. WO 90/09
  • R. is a hydrogen atom or a hydroxy group
  • a and B represent hydrogen or methyl, or together form the methylene group
  • R 2 is a group of the formula (II)
  • R 3 is a group -(CH 2 ) n -C(R 4 ) 2 OH, wherein n has the value 0, 1 or 2, and R 4 is a straight, branched or cylcic alkyl group having 1-3 C-atoms, or the vinyl group, p is 1 (when the dotted line is a double bond) or 2, have interesting biological properties.
  • p is 1 (when the dotted line is a double bond) or 2
  • both the E and Z isomers belong to the invention.
  • the above defined new 21 -nor vitamin D analogs are valuable compounds, which are promising as biologically active substances and may be used in the above mentioned pharmacotherapeutic indications, for example for the treatment of osteoporosis, renal osteodystrophy, osteomalacia, skin disorders such as psoriasis and other hyperproliferative skin diseases, eczema, dermatitis, myopathy, leukemia, breast and colon cancer, osteosarcomas, squamous cell carcinomas, melanoma, certain immunological disorders, and transplant rejections.
  • skin disorders such as psoriasis and other hyperproliferative skin diseases, eczema, dermatitis, myopathy, leukemia, breast and colon cancer, osteosarcomas, squamous cell carcinomas, melanoma, certain immunological disorders, and transplant rejections.
  • the new vitamin D analogs of the invention can be obtained according methods known for this type of compounds, for example as indicated in scheme 1 :
  • Reaction step 2 gives an E/Z mixture of 4.4:1. If it is desired to prepare the Z- compound the mixture obtained after step 3 can be treated with 9-fluorenone in THF under the influence of light, giving a mixture wherein E/Z ratio is 1 :4.2.
  • step 3 for the E-isomer
  • step 3 for the E-isomer
  • product obtained after this additional fluorenone treatment for the Z-isomer
  • step 3 To prepare corresponding compounds wherein C 17 and C 20 are linked by a single bond the product obtained after step 3 can be hydrogenated in a manner known oer se:
  • the so-obtained C 17 -C 20 -staturated compound can be reacted as indicated in the above steps 4 to 8.
  • step 2 (scheme 1 )
  • step 2 (scheme 1 )
  • the so-obtained compound B can be further reacted as indicated in steps 4 to 8.
  • reaction steps 1 to 8 According to reaction steps 1 to 8, and the optional steps for changing the E/Z-ratio and/or hydrogenating the C 17 -C 20 double bond and/or introducing a group R 3 as indicated above, the compounds having formula (I) as defined above can be obtained.
  • the bromide (1.85 g, 4.24 mmol) was dissolved in dry DMSO (70 ml) and dry MeOH (25 ml) in a 250 ml round-bottomed flask, equipped with a magnetic rod and condenser with an argon supply. Dry Et 3 N (543 ⁇ l, 4.24 mmol), dppp (385 mg, 0.93 mmol) and Pd(OAc) 2 (191 mg, 0.85 mmol) were then added. The suspension was purged with CO and stirred at 80°C in an atmosphere of CO for 16 h. The reaction was stopped by addition of H 2 0 (40 ml). The aqueous phase was extracted with EtOAc (3 x 20 ml).
  • the alcohol (163 mg, 0.54 mmol) was dissolved in dry CH 2 CI 2 (25 ml) in a 50 ml round-bottomed flask, equipped with a magnetic rod.
  • PPTS (catalytic) and PDC (307 mg, 0.82 mmol) were successively added to the solution with stirring.
  • the reaction mixture was stirred under argon with light excluded for 14 h.
  • the mixture was filtered through a No. 4 filter plate, equipped with a layer of Celite, washing the solids with CH 2 CI 2 .
  • the ester (59 mg, 0.089 mmol) was dissolved in dry THF (10 ml) in a 25 ml round- bottomed flask, equipped with a magnetic rod and a septum. A solution of MeLi in Et 2 0 (0.59 ml, 0.89 mmol, 1.5 M) was added rapidly to the solution cooled to - 78°C while stirring. The reaction mixture was stirred for 20 min. The reaction was stopped at -78°C by addition of H 2 0 (3 ml). The aqueous phase was extracted with EtOAc (2 x 10 ml).
  • the E/Z -ratio of the compound obtained in Example 1c) has an E/Z ratio of 4.4:1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un groupe de nouveaux analogues de la vitamine D de formule (I), dans laquelle R1 désigne un atome d'hydrogène ou un groupe hydroxy, A et B désignent un hydrogène ou méthyle, ou forment, pris ensemble, le groupe méthylène, R2 désigne un groupe de formule (II), dans laquelle R3 désigne un groupe -(CH2)n-C(R4)2OH, où n a la valeur 0, 1 ou 2 et R4 désigne un groupe alkyle cyclique, droit ou ramifié à 1-3 C-atomes ou le groupe vinyle, p désigne 1 (lorsque la ligne en pointillé est une double liaison) ou 2. Ces nouveaux arocalciférols sont dotés de propriétés biologiques appréciables.
PCT/EP2000/000288 1999-01-14 2000-01-12 Nouveaux analogues de la vitamine d Ceased WO2000042008A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22916/00A AU2291600A (en) 1999-01-14 2000-01-12 New vitamin d analogs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP99200095 1999-01-14
EP99200095.0 1999-01-14

Publications (1)

Publication Number Publication Date
WO2000042008A1 true WO2000042008A1 (fr) 2000-07-20

Family

ID=8239802

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/000288 Ceased WO2000042008A1 (fr) 1999-01-14 2000-01-12 Nouveaux analogues de la vitamine d

Country Status (2)

Country Link
AU (1) AU2291600A (fr)
WO (1) WO2000042008A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047866A2 (fr) * 1997-04-21 1998-10-29 F. Hoffmann-La Roche Ag Derives d'arylsecocholadiene

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047866A2 (fr) * 1997-04-21 1998-10-29 F. Hoffmann-La Roche Ag Derives d'arylsecocholadiene

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FIGADERE, BRUNO ET AL: "Studies of vitamin D (calciferol) and its analogs. 39. Arocalciferols: synthesis and biological evaluation of aromatic side-chain analogs of 1.alpha.,25-dihydroxyvitamin D3", J. MED. CHEM. (1991), 34(8), 2452-63 CODEN: JMCMAR;ISSN: 0022-2623, XP002101748 *
NORMAN, ANTHONY W. ET AL: "Selective biological response by target organs (intestine, kidney, and bone) to 1,25-dihydroxy D3 and two analogs", CANCER RES. (1993), 53(17), 3935-42 CODEN: CNREA8;ISSN: 0008-5472, XP002101747 *

Also Published As

Publication number Publication date
AU2291600A (en) 2000-08-01

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