WO1996001811A1 - Derives de 1,25-dihydroxyvitamine d3 substituee en 2 - Google Patents

Derives de 1,25-dihydroxyvitamine d3 substituee en 2 Download PDF

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Publication number
WO1996001811A1
WO1996001811A1 PCT/US1995/007595 US9507595W WO9601811A1 WO 1996001811 A1 WO1996001811 A1 WO 1996001811A1 US 9507595 W US9507595 W US 9507595W WO 9601811 A1 WO9601811 A1 WO 9601811A1
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WIPO (PCT)
Prior art keywords
analogue
alcohol
mmol
vitamin
substituent
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PCT/US1995/007595
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English (en)
Inventor
Gary H. Posner
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The Johns-Hopkins University
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.)
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Application filed by The Johns-Hopkins University filed Critical The Johns-Hopkins University
Publication of WO1996001811A1 publication Critical patent/WO1996001811A1/fr

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    • 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 present invention relates to novel biologically active vitamin D 3 analogues which include an alcohol or fluoride substituent in the 2-position and methods for their preparation.
  • Vitamin D 3 analogues have been recognized as having important biological activities. It is known, for example, that vitamin D 3 analogues can be used to control calcium and phosphate
  • vitamin D 3 produces 1 ⁇ ,25-dihydroxyvitamin D 3 (calcitriol) during normal metabolism.
  • Calcitriol is a potent regulator of cell differentiation
  • Calcitriol is also known to affect the immune system and this compound, as well as a variety of synthetic vitamin D 3 derivatives have been used in practical, clinical chemotherapy of such diverse human illnesses as osteoporosis, cancer, immunodeficiency syndromes and skin disorders such as dermatitis and psoriasis.
  • Calcitriol may be structurally represented as follows:
  • the upper and lower ring portions of calcitriol may be called, for ease of reference, the C/D-ring and A-ring, respectively. DESCRIPTION OF THE RELATED ART
  • osteoporosis is a very serious illness that causes physical deformity and high susceptibility to bone (e.g., hip) fractures.
  • bone e.g., hip
  • osteoporosis ranks third to heart disease and cancer in terms of prevalence. It is estimated that 30% of women at 75 years and 40% of women at 85 years have abnormal bone loss. Calcitriol is being used, especially in Japan where dietary intake of calcium is low, for treatment of osteoporosis .
  • the Chugai The Chugai
  • ED-71 (1) as a synthetic derivative of calcitriol, having a batter therapeutic index than calcitriol 4 .
  • 2ß-(3'-hydroxypropyloxy)-calcitriol has a two-fold stronger binding affinity to the rat plasma vitamin D-binding protein (DBP) than does
  • the present invention is for a vitamin D 3 analogue which includes a 2-substituted alcohol or fluoride.
  • the preferred alcohol substituent is exemplified by the structural formula -(CH 2 ) 4 OH and the preferred fluoride substituents by the
  • the present invention is also for the related method of preparation of a vitamin D 3 analogue which includes a 2-substituted alcohol or fluoride starting with 2+4-cycloaddition of commercially available methyl 2-pyrone-3-carboxylate.
  • Diastereomeric 2-substituted calcitriol analogues were prepared in only eleven chemical operations, starting with 2+4-cycloaddition of commercially available methyl 2-pyrone-3-carboxylate.
  • dienophile 4E led exclusively to trans-4,5- oriented products 5a and 5b
  • dienophile 4Z led exclusively to cis-4, 5-oriented products 6a and 6b. Therefore, these polarized 2+4- cycloadditions must occur in a concerted rather than in a step-wise fashion.
  • the assignments of the 4,5-positional relationships were based on extensive precedent 5, and the assignments of the 4,5-stereochemical relationships were based on the match of the 400 MHz 1 H NMR J 4,5 coupling constants with those calculated using the Karplus eguation for energy-minimized structures generated using
  • Bicyclic lactone 6a the very major cycloadduct, differed in a characteristic way from bicyclic lactone 6b in terms of the chemical shift of the bridgehead hydrogen atom ( ⁇ 4.98 vs. 5.04) and the chemical shift of the C 4 hydrogen atom ( ⁇ 4.55 vs. 3.83). Also,
  • silylated vinylic ether 7Z prepared according to literature precedent as illustrated in Scheme II 9 , and commercially available methyl 2-pyrone-3-carboxylate were subjected to high pressure cycloaddition (eq. 1).
  • Bicycloadduct 8 was the major product, isolated on gram scale in 60% yield, with the oxygen substituted at position-4, as expected based on the polar nature of the Diels-Alder cycloaddition and also on literature precedent, with a cis-4,5-stereochemical relationship. This stereochemical outcome was expected based on the results in Scheme I with the 3-sulfonyl-2-pyrone and was confirmed by the observed large 1 H NMR J 4.5 coupling constant (8.6 Hz) and by the
  • the l ⁇ -substituted diastereomer characteristically showed a lower field absorption for the C 18 -methyl group and for one proton of the C 19 -methylene group (Table II).
  • Diastereomer 3 had significantly higher affinity than ED-71 (1) for the vitamin D binding protein, but it had extremely low affinity for the vitamin D receptor; whether this separation of binding affinities has important mechanistic and/or medicinal value remains to be established.
  • Diastereomer 3' had lower affinity than ED-71 (1) for the vitamin D binding protein, but it had higher affinity than ED-71 (1) for the vitamin D receptor. Determining the impact of these differences on possible use of these new analogues for chemotherapy of
  • osteoporosis requires further biological testing.
  • Tetrahydrofuran and diethyl ether were distilled from benzophenone ketyl prior to use.
  • Methylene chloride and triethylamine were
  • a 12 cm piece of 3/8" heat shrinkable teflon tubing (Ace Glass cat. #12685-40) was sealed on one end with a glass dowel plug by using a heat gun.
  • a heat gun To this 500.0 mg (3.24 mmol) of methyl 2- pyrone-3-carboxylate (Aldrich), 2g (4.26 mmol) of silylated vinylic ether 7Z, 10 mg of barium carbonate, and 2 mL of dry CH 2 Cl 2 was added.
  • the open end of tubing was then sealed in a similar fashion with a second glass dowel plug. This 'sealed tube' was the pressurized at 10-11 Kbar at room temperature for 4 days.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

La présente invention concerne des analogues de la vitamine D3 incluant un alcool ou un fluorure substitué en position 2. Le substituant préféré de l'alcool est représenté par la formule structurelle -(CH2)4OH, et les substituants préférés du fluorure sont représentés par les formules structurelles -(CH2)3F et -(CH2)4F. L'invention concerne également la préparation d'un analogue de vitamine D3 incluant un alcool ou un fluorure substitué en position 2 à partir d'une cycloaddition en 2+4 du 2-pyrone-3-carboxylate de méthyle du commerce.
PCT/US1995/007595 1994-07-11 1995-06-22 Derives de 1,25-dihydroxyvitamine d3 substituee en 2 WO1996001811A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US27266594A 1994-07-11 1994-07-11
US08/272,665 1994-07-11

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WO1996001811A1 true WO1996001811A1 (fr) 1996-01-25

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998041500A1 (fr) * 1997-03-17 1998-09-24 Wisconsin Alumni Research Foundation Derives 2-alkyle-19-nor- de la vitamine d
WO1998041501A1 (fr) * 1997-03-17 1998-09-24 Wisconsin Alumni Research Foundation Derives 2-alkylidene-19-nor- de la vitamine d
US6114317A (en) * 1998-05-21 2000-09-05 Wisconsin Alumni Research Foundation Method of locking 1α-OH of vitamin D compounds in axial orientation
EP1072582A1 (fr) * 1998-02-27 2001-01-31 Chugai Seiyaku Kabushiki Kaisha Composes intermediaires entrant dans la synthese de la fraction cyclique de derives 2-substitues de la vitamine d
WO2001016099A1 (fr) * 1999-08-27 2001-03-08 Chugai Seiyaku Kabushiki Kaisha DÉRIVÉS DE VITAMINE D AYANT DES SUBSTITUANTS À LA POSITION 2$g(a)
US6306844B1 (en) 1997-03-17 2001-10-23 Wisconsin Alumni Research Foundation Use of 2α-methyl-19-nor-20(S)-1α, 25-dihydroxyvitamin D3 to increase bone strength
US6316642B1 (en) 1997-03-17 2001-11-13 Wisconsin Alumni Research Foundation 26,27-Homologated-20-EPI-2alkyl-19-nor-vitamin D compounds
US6537981B2 (en) 1997-03-17 2003-03-25 Wisconsin Alumni Research Foundation 26,27-Homologated-20-EPI-2-alklidene-19-nor-vitamin D compounds
US6566352B1 (en) 2002-02-18 2003-05-20 Wisconsin Alumni Research Foudation 1 α-hydroxy-2-methylene-19-nor-pregnacalciferol and its uses
US6627622B2 (en) 2002-02-18 2003-09-30 Wisconsin Alumni Research Foundation (20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol and its uses
US6806262B2 (en) 2000-05-31 2004-10-19 Wisconsin Alumni Research Foundation 2-ethyl and 2-ethylidene-19-nor-vitamin D compounds
US6894037B2 (en) 2003-07-03 2005-05-17 Wisconsin Alumni Research Foundation 2-methylene-19-nor-20(S)-25-methyl-1α-hydroxycalciferol and its uses
JP2006523239A (ja) * 2003-04-10 2006-10-12 ウィスコンシン・アルムニ・リサーチ・ファウンデーション ２−プロピリデン−１９−ノル−ビタミンｄ化合物
US7713951B2 (en) 2004-04-09 2010-05-11 Wisconsin Alumni Research Foundation 2-alkylidene-18,19-dinor-vitamin D compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0641059A (ja) * 1991-11-01 1994-02-15 Chugai Pharmaceut Co Ltd ２β位に置換基を有するビタミンＤ誘導体
US5389622A (en) * 1992-03-12 1995-02-14 The John Hopkins University Vitamin D3 analogues

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0641059A (ja) * 1991-11-01 1994-02-15 Chugai Pharmaceut Co Ltd ２β位に置換基を有するビタミンＤ誘導体
US5389622A (en) * 1992-03-12 1995-02-14 The John Hopkins University Vitamin D3 analogues

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF ORGANIC CHEMISTRY, Volume 59, Number 25, issued 16 December 1994, POSNER et al., "Stereocontrolled Total Synthesis of Calcitriol Derivatives: 1,25-Dihydroxy-2-(4'-Hydroxybutyl) Vitamin D Analogs of an Osteoporosis Drug", pages 7855-7861. *

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6306844B1 (en) 1997-03-17 2001-10-23 Wisconsin Alumni Research Foundation Use of 2α-methyl-19-nor-20(S)-1α, 25-dihydroxyvitamin D3 to increase bone strength
US7094774B2 (en) 1997-03-17 2006-08-22 Wisconsin Alumni Research Foundation 26,27-homologated-20-epi-2-alkylidene-19-nor-vitamin D compounds
US5936133A (en) * 1997-03-17 1999-08-10 Wisconsin Alumni Research Foundation 2-alkylidene-19-nor-vitamin D compounds
US5945410A (en) * 1997-03-17 1999-08-31 Wisconsin Alumni Research Foundation 2-alkyl-19-nor-vitamin D compounds
US6667298B2 (en) 1997-03-17 2003-12-23 Wisconsin Alumni Research Foundation 26,27-Homologated-20-EPI-2-alkyl-19-NOR-vitamin D compounds
US6544969B2 (en) 1997-03-17 2003-04-08 Wisconsin Alumni Research Foundation 26,27-homologated-20-epi-2-alkyl-19-nor-vitamin D compounds
WO1998041501A1 (fr) * 1997-03-17 1998-09-24 Wisconsin Alumni Research Foundation Derives 2-alkylidene-19-nor- de la vitamine d
US6277837B1 (en) 1997-03-17 2001-08-21 Wisconsin Alumni Research Foundation 2-alkyl-19-nor-vitamin D compounds
US7112579B2 (en) 1997-03-17 2006-09-26 Wisconsin Alumni Research Foundation 26,27-Homologated-20-EPI-2-alkyl-19-nor-vitamin D compounds
US6316642B1 (en) 1997-03-17 2001-11-13 Wisconsin Alumni Research Foundation 26,27-Homologated-20-EPI-2alkyl-19-nor-vitamin D compounds
WO1998041500A1 (fr) * 1997-03-17 1998-09-24 Wisconsin Alumni Research Foundation Derives 2-alkyle-19-nor- de la vitamine d
US6939868B2 (en) 1997-03-17 2005-09-06 Wisconsin Alumni Research Foundation Use of 2α-methly-19-nor-20(S)-1α,25-dihydroxyvitamin D3 to increase bone strength
US6537981B2 (en) 1997-03-17 2003-03-25 Wisconsin Alumni Research Foundation 26,27-Homologated-20-EPI-2-alklidene-19-nor-vitamin D compounds
US6696431B2 (en) 1997-03-17 2004-02-24 Wisconsin Alumni Research Foundation 26,27-homologated-20-EPI-2-alkylidene-19-nor-vitamin D compounds
EP1072582A4 (fr) * 1998-02-27 2005-02-02 Chugai Pharmaceutical Co Ltd Composes intermediaires entrant dans la synthese de la fraction cyclique de derives 2-substitues de la vitamine d
EP1072582A1 (fr) * 1998-02-27 2001-01-31 Chugai Seiyaku Kabushiki Kaisha Composes intermediaires entrant dans la synthese de la fraction cyclique de derives 2-substitues de la vitamine d
US6369099B1 (en) 1998-05-21 2002-04-09 Wisconsin Alumni Research Foundation Method of locking 1 α-OH of vitamin D compounds in axial orientation
US7094776B2 (en) 1998-05-21 2006-08-22 Wisconsin Alumni Research Foundation Method of locking 1α-OH of vitamin D compounds in axial orientation
US6114317A (en) * 1998-05-21 2000-09-05 Wisconsin Alumni Research Foundation Method of locking 1α-OH of vitamin D compounds in axial orientation
US6506912B2 (en) 1998-05-21 2003-01-14 Wisconsin Alumni Research Foundation Method of locking 1α-OH of vitamin D compounds in axial orientation
US7071179B2 (en) 1998-05-21 2006-07-04 Wisconsin Alumni Research Foundation Method of locking 1α-OH of vitamin D compounds in axial orientation
US6482812B2 (en) 1998-05-21 2002-11-19 Wisconsin Alumni Research Foundation Method of locking 1α-OH of vitamin D compounds in axial orientation
US7056904B2 (en) 1998-05-21 2006-06-06 Wisconsin Alumni Research Foundation Method of locking 1α-OH of vitamin D compounds in axial orientation
US6890914B2 (en) 1998-05-21 2005-05-10 Wisconsin Alumni Research Foundation Method of locking 1α-OH of vitamin D compounds in axial orientation
US6458827B2 (en) 1998-05-21 2002-10-01 Wisconsin Alumni Research Foundation Method of locking 1α-OH of vitamin D compounds in axial orientation
WO2001016099A1 (fr) * 1999-08-27 2001-03-08 Chugai Seiyaku Kabushiki Kaisha DÉRIVÉS DE VITAMINE D AYANT DES SUBSTITUANTS À LA POSITION 2$g(a)
US7141558B2 (en) 2000-05-31 2006-11-28 Wiscousin Alumni Research Foundation 2-ethyl and 2-ethylidene-19-nor-vitamin D compounds
US6992074B2 (en) 2000-05-31 2006-01-31 Wisconsin Alumni Research Foundation 2-Ethyl and 2-ethylidene-19-nor-vitamin D compounds
US7468361B2 (en) 2000-05-31 2008-12-23 Wisconsin Alumni Research Foundation 2-ethyl and 2-ethylidene-19-nor-vitamin D compounds
US6806262B2 (en) 2000-05-31 2004-10-19 Wisconsin Alumni Research Foundation 2-ethyl and 2-ethylidene-19-nor-vitamin D compounds
US7300925B2 (en) 2000-05-31 2007-11-27 Wisconsin Alumni Research Foundation 2-ethyl and 2-ethylidene-19-nor-vitamin D compounds
US7534778B2 (en) 2001-12-13 2009-05-19 Wisconsin Alumni Research Foundation (20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol and its uses
USRE41491E1 (en) 2001-12-13 2010-08-10 Wisconsin Alumni Research Foundation (20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol and its uses
US6566352B1 (en) 2002-02-18 2003-05-20 Wisconsin Alumni Research Foudation 1 α-hydroxy-2-methylene-19-nor-pregnacalciferol and its uses
US6627622B2 (en) 2002-02-18 2003-09-30 Wisconsin Alumni Research Foundation (20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol and its uses
US6887860B2 (en) 2002-02-18 2005-05-03 Wisconsin Alumni Research Foundation (20S)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol and its uses
USRE41474E1 (en) 2002-02-18 2010-08-03 Wisconsin Alumni Research Foundation (20S)-1α-Hydroxy-2-Methylene-19-Nor-Bishomopregnacalciferol and its uses
JP2006523239A (ja) * 2003-04-10 2006-10-12 ウィスコンシン・アルムニ・リサーチ・ファウンデーション ２−プロピリデン−１９−ノル−ビタミンｄ化合物
US7531527B2 (en) 2003-04-10 2009-05-12 Wisconsin Alumni Research Foundation 2-Propylidene-19-nor-vitamin D compounds
US6894037B2 (en) 2003-07-03 2005-05-17 Wisconsin Alumni Research Foundation 2-methylene-19-nor-20(S)-25-methyl-1α-hydroxycalciferol and its uses
US7713951B2 (en) 2004-04-09 2010-05-11 Wisconsin Alumni Research Foundation 2-alkylidene-18,19-dinor-vitamin D compounds

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