WO1996002501A1 - SYNTHESE DE LA VITAMINE D 1α-HYDROXY - Google Patents

SYNTHESE DE LA VITAMINE D 1α-HYDROXY Download PDF

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Publication number
WO1996002501A1
WO1996002501A1 PCT/US1994/008002 US9408002W WO9602501A1 WO 1996002501 A1 WO1996002501 A1 WO 1996002501A1 US 9408002 W US9408002 W US 9408002W WO 9602501 A1 WO9602501 A1 WO 9602501A1
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WO
WIPO (PCT)
Prior art keywords
vitamin
hydroxy
protected
adduct
diels
Prior art date
Application number
PCT/US1994/008002
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English (en)
Inventor
Robert M. Moriarty
Liang Guo
Raju A. Penmasta
Original Assignee
Lunar Corporation
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 Lunar Corporation filed Critical Lunar Corporation
Priority to AU73640/94A priority Critical patent/AU700668B2/en
Priority to PCT/US1994/008002 priority patent/WO1996002501A1/fr
Priority to US08/776,283 priority patent/US5869472A/en
Priority to JP8504975A priority patent/JPH10506374A/ja
Priority to EP94922581A priority patent/EP0865427A1/fr
Publication of WO1996002501A1 publication Critical patent/WO1996002501A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates generally to vitamin D compounds and their hydroxylated derivatives. More specifically, the invention relates to a novel synthesis of l ⁇ -hydroxy vitamin D.
  • the vitamins D are a group of compounds that are steroid derivatives and are known to be important in the regulation of calcium and phosphate metabolism in animals and man, and in the regulation of bone formation. See , Harrison's Principles of Internal
  • Vitamin D 3 is synthesized endogenously in the skin of animals and man.
  • the biological functions of vitamin D require metabolism to hydroxylated metabolites that are the biologically active agents.
  • vitamin D 3 is activated by being hydroxylated in the C 25 position in the liver, followed by l ⁇ -hydroxylation in the kidney to produce the hormone lo,25-dihydroxy vitamin D 3 . See, U.S. Patent 3,880,894 issued to DeLuca et al.
  • the l ⁇ ,25-dihydroxy vitamin D 3 compound regulates calcium and phosphorus metabolism, bone formation, and subsequent vitamin D 3 activation, by binding to specific cytoplasmic receptor proteins located throughout the body. This binding requires the presence of the l ⁇ -hydroxy group.
  • Hormonally active vitamin D 3 bound to intestinal receptors stimulates calcium and phosphate transport from the intestinal lumen into the systemic circulation.
  • Activated vitamin D 3 bound to receptors in the parathyroid glands, the kidney, the osteoblasts, and other target tissues elicits cellular responses which synergistically stabilize the levels of calcium and phosphorus in the blood, control the formation and removal of bone, and regulate further production of l ⁇ ,25-dihydroxy vitamin D 3 .
  • Vitamin D 3 has also been reported to play a role in cell proliferation and differentiation. See , U.S. Patent 4,800,198 issued to DeLuca et al. It has been suggested that these compounds might be useful in the treatment of diseases characterized by abnormal cell proliferation and/or cell differentiation, such as leukemia, myelofibrosis and psoriasis.
  • Vitamin D 2 is the major naturally occurring form of vitamin D in plants. Vitamin D 2 differs structurally from vitamin D 3 by having a methyl group at C 24 and a double bond between C 22 and C 3 . Various vitamin D analogues, however, elicit strong physiological responses in animals and human beings, and are valuable substitutes for vitamin D 3 compounds.
  • vitamin D is intended to include vitamins D 3 , D 2 , and D 4 .
  • Examples of hydroxylated and dihydroxylated metabolites of vitamins D 3 and D 2 which have been found to occur naturally and/or have been synthesized include 25-hydroxy vitamin D 2 , 24, 25-dihydroxy vitamin D 3 , 25, 26-dihydroxy vitamin D 3 , l ⁇ -hydroxy vitamin D 2 , 23, 25-dihydroxy vitamin D 3 , all of which have been found to exhibit vitamin D-like biological activity in vivo .
  • the present invention responds to a heretofore unmet need by the prior art, and specifically to the inherent inadequacies of prior synthetic processes for preparing l ⁇ -hydroxylated vitamin D compounds.
  • the method of the present invention is distinguished by its simplicity in that it eliminates certain separatory steps characteristic of prior art processes.
  • the present invention provides a method of producing l ⁇ -hydroxy vitamin D which includes the following steps: (a) forming 3-(protected-hydroxy) vitamin D from vitamin D; (b) forming a Diels-Alder adduct at C 6 and C 19 of the 3-(protected-hydroxy) vitamin D; (c) allylically oxidizing and decomposing the Diels-Alder adduct to form trans l ⁇ -hydroxy-3-
  • Steps (a) and (b) are performed without purification of the resulting product of each step.
  • the protecting step (a) preferably uses a trihydrocarbylsilyloxy reagent.
  • the Diels-Alder reactant is preferably N- sulfinyl-p-toluenesulfonamide or selenium di-(p- toluenesulfonamide) while the allylically oxidizing step (c) is preferably accomplished with selenium dioxide and N-methyl morpholine N-oxide.
  • the deprotecting step (e) preferably uses a quaternary ammonium fluoride.
  • the present method is applicable to any vitamin D derivative for which l ⁇ -hydroxylation is desired, and thus, provides a flexibility in terms of starting material chosen and product.
  • the method can be used advantageously for converting any of the known vitamin D metabolites to their l ⁇ -hydroxy forms.
  • the method of the present provides higher yields compared to the known synthesis utilizing a cyclovitamin intermediate and has fewer steps than that process.
  • the method avoids the known maleic anhydride separation of cis and trans l ⁇ -hydroxy vitamin D.
  • Figure 1 illustrates the general schema for the synthesis of l ⁇ -hydroxy-vitamin D starting with vitamin D
  • Figure 2 illustrates the preparative steps for the synthesis of l ⁇ -hydroxy-vitamin D 2 starting with vitamin D 2 .
  • the present invention provides a synthetic route for l ⁇ -hydroxy vitamin D, i.e., the compounds of general formula (I) :
  • R signifies any substituent that may be desired in the final product.
  • steroid side chains that have at least 7 carbon atoms, and can be branched or unbranched, saturated or unsaturated, hetero-substituted or nonhetero- substituted, cyclic or noncyclic and which increase the serum calcium of the vitamin D deficient rat as determined by standard techniques used by biochemists in the vitamin D area.
  • side chains are those where R represents the side chain of cholesterol or ergosterol or modified cholesterol or modified ergosterol side chains.
  • R has the formula:
  • B and C are either hydrogen or a carbon to carbon bond forming a double bond between C 22 and C 23 ;
  • R,, R 3 , R 4 and R 5 are each independently hydrogen, hydroxy, lower alkyl, O-lower alkyl, O-lower acyl, O-aromatic acyl or fluoro; and
  • R 2 is hydrogen or lower alkyl.
  • Most preferred among the compounds of formula (I) are l ⁇ -hydroxy vitamin D 3 , l ⁇ -hydroxy vitamin D 2 , and l ⁇ -hydroxy vitamin D 4 .
  • a wavy line to a substituent indicates that the substituent can exist in stereoisomeric alternate forms.
  • the term "lower” as a modifier of alkyl or acyl is intended to identify a hydrocarbon radical in all isomeric forms, e.g., methyl, ethyl, butyl, formyl.
  • the term "protected-hydroxy” refers to a hydroxyl group in which the hydrogen has been replaced by a hydrocarbon or the like group, i.e., the hydroxyl group is present in derivatized form.
  • a protected-hydroxyl group may include, e.g., O-alkyl, O-acyl, O-benzyloxycarbonyl, and O-alkylsilyl, preferably, trihydrocarbonylsilyloxy groups such as trimethylsilyloxy, n-butyldimethylsilyloxy, and most preferred, tert- butyldimethylsilyloxy.
  • the synthesis of l ⁇ -hydroxy vitamin D is accomplished according to the reaction scheme presented in Figure 1.
  • the synthesis uses a vitamin D compound, i.e., a compound of formula (II) , as the starting material.
  • Vitamin D first undergoes a protection step by applying a protected- hydroxy group to the C 3 position to yield the compound of formula (III) .
  • the protected-hydroxy group is preferably a trihydrocarbylsilyloxy group, most preferably tert-butyldimethylsilyloxy.
  • the 3-(protected-hydroxy) vitamin D (III) is then subjected to a Diels-Alder reaction to form with C 6 and Cj 9 an adduct of formula (IV) .
  • the reagent for the Diels-Alder reaction is preferably an N-sulfinyl or an N-selenium derivative of tosylamide.
  • the Diels-Alder adduct (IV) is then hydroxylated at the C, position to yield the trans l ⁇ -hydroxy-3-(protected-hydroxy) vitamin D compound of formula (V) .
  • This trans compound is then subjected to photoisomerization to yield the cis l ⁇ -hydroxy-3-(protected-hydroxy) compound of formula (VI) .
  • the cis protected-hydroxy compound (VI) is then deprotected to yield the l ⁇ -hydroxy vitamin D of formula (I) .
  • the product of the protection step and the Diels-Alder adduct formation step do not require purification and can be used directly for the next step in the process.
  • the method in accordance with the present invention requires no chromatographic or other separatory technique until the hydroxylation step is completed.
  • Vitamin D 2 is reacted with tert-butyldimethylsilyloxychloride to protect the C 3 position, yielding 3-tert- butyldimethylsilyloxy vitamin D 2 .
  • the unpurified adduct is then hydroxlyated by allylic oxidation at the Cj position, with, e.g.
  • the trans compound is then irradiated to form the cis compound which in turn is deprotected to return the hydroxy group with a quaternary ammonium fluoride such as tetra-n- butyl ammonium fluoride to yield l ⁇ -hydroxy vitamin D 2 .
  • a quaternary ammonium fluoride such as tetra-n- butyl ammonium fluoride to yield l ⁇ -hydroxy vitamin D 2 .
  • the l ⁇ -hydroxylated vitamin D compounds and analogues are medically useful as therapeutic agents for the treatment and prophylaxis of various human and ani al diseases related to calcium imbalance, vitamin D deficiency, and bone loss.
  • Mass spectra were recorded with a Finnigan MAT-90 mass spectrometer at 20eV/CI.
  • Thin layer chromatography (TLC) was performed on silica gel with the solvents as indicated in each example. Melting points (mp) were determined with a Hoover-Thomas (capillary) Uni-Melt or a Fisher-Johns (cover slip-type) Melting Point apparatus.
  • the material of melting point 153-155°C was identical in all respects with a reference sample prepared by a known method. Using this procedure starting with 25 g of vitamin D 2 , 5 g of cis l ⁇ -hydroxy vitamin D 2 was obtained.
  • vitamin D compounds as starting materials, e.g., vitamin D 3 , vitamin D 4 , 25-hydroxy vitamin D 3 , 24, 25-dihydroxy vitamin D 3 , 25, 26-dihydroxy vitamin D 3 , there is obtained their l ⁇ -hydroxylated derivative.
  • the l ⁇ -hydroxylated compounds of the present invention are particularly advantageous for application as effective therapeutic agents in human and veterinary medicine, such as for the treatment of calcium and mineral imbalance conditions, and vitamin D responsive bone diseases, since the presence of a l ⁇ -hydroxy group enhances the activity and efficacy of the vitamin.

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

Abstract

Procédé d'1α-hydroxylation de composés de la vitamine D dans lequel on utilise la vitamine D appropriée en tant que matériau de départ. Ce procédé ne nécessite pas de procédure de séparation avant l'étape d'hydroxylation
PCT/US1994/008002 1994-07-18 1994-07-18 SYNTHESE DE LA VITAMINE D 1α-HYDROXY WO1996002501A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU73640/94A AU700668B2 (en) 1994-07-18 1994-07-18 Synthesis of 1alpha-hydroxy vitamin D
PCT/US1994/008002 WO1996002501A1 (fr) 1994-07-18 1994-07-18 SYNTHESE DE LA VITAMINE D 1α-HYDROXY
US08/776,283 US5869472A (en) 1994-07-18 1994-07-18 Synthesis of 1α-hydroxy vitamin D
JP8504975A JPH10506374A (ja) 1994-07-18 1994-07-18 １α−ヒドロキシビタミンＤの合成
EP94922581A EP0865427A1 (fr) 1994-07-18 1994-07-18 Synthese de la vitamine d 1alpha-hydroxy

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1994/008002 WO1996002501A1 (fr) 1994-07-18 1994-07-18 SYNTHESE DE LA VITAMINE D 1α-HYDROXY

Publications (1)

Publication Number Publication Date
WO1996002501A1 true WO1996002501A1 (fr) 1996-02-01

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EP (1) EP0865427A1 (fr)
JP (1) JPH10506374A (fr)
AU (1) AU700668B2 (fr)
WO (1) WO1996002501A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006218A2 (fr) * 2000-07-18 2002-01-24 Bone Care International, Inc. 1$g(a)hydroxy-vitamine d stabilisée

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987000834A1 (fr) * 1985-08-02 1987-02-12 Leo Pharmaceutical Products Ltd. A/S Nouveaux analogues de la vitamine d
WO1991012240A1 (fr) * 1990-02-14 1991-08-22 Wisconsin Alumni Research Foundation Methode de preparation de composes de vitamine d2 et les derives 1 alpha-hydroxyles correspondants.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987000834A1 (fr) * 1985-08-02 1987-02-12 Leo Pharmaceutical Products Ltd. A/S Nouveaux analogues de la vitamine d
WO1991012240A1 (fr) * 1990-02-14 1991-08-22 Wisconsin Alumni Research Foundation Methode de preparation de composes de vitamine d2 et les derives 1 alpha-hydroxyles correspondants.

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
H. S. GILL ET AL: "Synthesis and biological activity of novel vitamin D analogues: 24,24-difluoro-25-hydroxy-26,27-dimethylvitamin D3 and 24,24-difluoro-1alpha,25-dihydroxy-26,27-dimethylvitamin D3", JOURNAL OF MEDICINAL CHEMISTRY, vol. 33, no. 2, February 1990 (1990-02-01), WASHINGTON US, pages 480 - 490 *
L. CASTEDO ET AL: "Synthesis of potential inhibitors of vitamin D hydroxylases", NATO ASI SERIES, SERIES A: LIFE SCIENCES. BIOORGANIC CHEMISTRY IN HEALTHCARE AND TECHNOLOGY, vol. 207, 1991, NEW YORK, US, pages 251 - 254 *
T. SATO ET AL: "Studies on 1alpha-hydroxyl derivatives of vitamin D3. I. Synthesis of 1alpha-hydroxyvitamin D3 and 1alpha,25-dihydroxyvitamin D3", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 26, no. 10, October 1978 (1978-10-01), TOKYO JP, pages 2933 - 2940 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006218A2 (fr) * 2000-07-18 2002-01-24 Bone Care International, Inc. 1$g(a)hydroxy-vitamine d stabilisée
WO2002006218A3 (fr) * 2000-07-18 2002-07-18 Bone Care Int Inc 1$g(a)hydroxy-vitamine d stabilisée

Also Published As

Publication number Publication date
AU700668B2 (en) 1999-01-14
AU7364094A (en) 1996-02-16
JPH10506374A (ja) 1998-06-23
EP0865427A1 (fr) 1998-09-23

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