WO1984004527A1 - PROCESS FOR THE PREPARATION OF 1alpha,25-DIHYDROXYLATED VITAMIN D2 AND RELATED COMPOUNDS - Google Patents

PROCESS FOR THE PREPARATION OF 1alpha,25-DIHYDROXYLATED VITAMIN D2 AND RELATED COMPOUNDS Download PDF

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Publication number
WO1984004527A1
WO1984004527A1 PCT/US1984/000714 US8400714W WO8404527A1 WO 1984004527 A1 WO1984004527 A1 WO 1984004527A1 US 8400714 W US8400714 W US 8400714W WO 8404527 A1 WO8404527 A1 WO 8404527A1
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vitamin
dihydroxy
compound
trans
compounds
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PCT/US1984/000714
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English (en)
French (fr)
Inventor
Hector F Deluca
Heinrich K Schnoes
Rafal R Sicinski
Yoko Tanaka
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Wisconsin Alumni Res Found
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Publication of WO1984004527A1 publication Critical patent/WO1984004527A1/en
Priority to DK008685A priority Critical patent/DK171397B1/da
Priority to DK198801845A priority patent/DK172567B1/da

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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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/24—Radicals substituted by singly bound oxygen or sulfur atoms esterified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0036—Nitrogen-containing hetero ring
    • C07J71/0042—Nitrogen only

Definitions

  • This invention relates to the preparation of l ⁇ ,25dihydroylated ccmpounds of the vitamin D 2 series.
  • this invention relates to the preparation of l ⁇ ,25-dihydroxyvitamin D 2 and its (24R)-epimer, the corresponding 5,6-trans-isorrers, and to certain C-25-alkyl or aryl analogs as well as the acyl derivatives of these compounds.
  • Vitamin D 3 is known to be hydroxylated in vivo to 25-hydroxyvitamin D 3 and then to l ⁇ , 25-dihydroxyvitamin D 3 , the latter being generally accepted as the active hormonal form of vitamin D 3 .
  • the very potent vitamin D 2 metabolite, l ⁇ ,25-dihydroxyvitamin D 3 (l ⁇ ,25-(OH) 2 D 2 ) is formed from vitamin D 2 via 25-hydroxyvitamin D 2 (25-OH-D 2 ).
  • Both of these hydroxylated vitamin D 3 compounds have been isolated and identified (DeLuca et al, U.S. Patents 3,585,221; 3,880,894); being derived from vitamin D 2 , these metabolites are characterized by the (S) -stereochemistry at carbon 24. Disclosure of Invention
  • R 1 , R 2 , and R 3 are selected from the group consisting of hydrogen and acyl, and where X is an alkyl or aryl group.
  • the asymmetric center at carbon 24 may have the (R) or (S) configuration.
  • Specific examples of compounds obtainable by the present process include l ⁇ ,25-dihydroxyvitamin D 2 , the corresponding (24R)-epimer,- l ⁇ ,25-dihydroxy-24-epivitamin D 2 , the respective 5,6-trans-isomers, i.e.
  • acyl signifies an aliphatic acyl group (alkanoyl group) of from 1 to 6 carbons, in all possible isomeric forms, e.g. formyl, acetyl, butyryl, isobutyryl, valeryl, etc., or an aromatic acyl group (aroyl group) such as benzoyl, or the methyl, halo, or nitro-substituted benzcyl groups, or an acyl group derived from a dicarboxylic acid having the general formulae ROOC(CH 2 ) n CO- , or ROOCCH 2 -0-CH 2 CO-, where n is an integer having the values of 0 to 4 inclusive, and R is hydrogen or an alkyl radical.
  • dicarboxylic acyl groups are oxalyl, malonyl, succinoyl, glutaryl, adipyl and diglycolyl.
  • alkyl refers to a hydrocarbon group of 1 to 6 carbons in all isomeric forms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.
  • aryl refers to an aromatic radical such as phenyl, benzyl, or the isomeric alkyl-substituted phenyl radicals.
  • a suitable starting material for the process of this invention is the vitamin D-ketal derivative of structure (1) . It is generally convenient (e.g. in the case when both C-24-epimers of 1 ⁇ ,25-dihydroxyvitamin D 2 compounds are desired) to use compound (1) as a mixture of the 24R and S epimers, separation of the individual 24R and S-epimers being acc mplished at a later stage of the process.
  • the pure 24S, or the pure 24R-epimer of (1) are equally suitable starting materials, whereby the former compound upon being processed through the indicated synthetic steps will provide the (24S)-l ⁇ ,25-dihydroxy product, whereas the latter, treated analogously, will yield the corresponding (24R)-1 ⁇ ,25dihydroxylated product.
  • Starting material (1) is converted to the desired l ⁇ hydroxylated form via cyclovitamin D derivatives (DeLuca et al., U.S. patents 4,195,027 and 4,260,549).
  • cyclovitamin D derivatives (DeLuca et al., U.S. patents 4,195,027 and 4,260,549).
  • treatment of compound (1) with toluenesulfonyl chloride in the conventional manner yields the corresponding C-3-tosylate (2) , which is solvolyzed in an alcoholic medium to produce the novel 3,5-cyclovitamin D derivative (3).
  • the formate, propionate, butyrate, benzoate, etc. are prepared by analogous conventional acylation reactions.
  • the 1-0-acyl derivative is then subjected to acid-catalyzed solvolysis.
  • These 5,6-cis and 5,6-transisomers can be separated at this stage, e.g. by high performance liquid chromatography.
  • these 1-0-monoacylates may be further acylated at the C-3-hydroxy groups, using conventional acylation conditions to obtain the corresponding 1,3-di-o-acylates of structure (6) or (7) where R 1 and R 2 , which may be the same or different, represent acyl groups.
  • the next step of the process comprises the removal of the ketal protecting group to produce the corresponding 25-ketone.
  • the 5,6-trans-25-ketal-intermediate of structure (7) subjected to ketal hydrolysis in an analogous manner, provides the 5,6-trans ketone intermediate of structure (10) , which via a Grignard reaction with methyl magnesium bromide or analogous reagent gives the 5,6-trans-1 ⁇ ,25-dihydroxyvitamin D 2 compounds of structure (11), as the 24S or 24R-epimer, or as a mixture of both epimers depending on the nature of the starting material (1) used in the process.
  • the epimers can be separated by chromatography, to obtain 5,6-trans-1 ⁇ ,25-dihydroxyvitamin D 2 (11a) and its 24R-epimer, 5,6-trans-1 ⁇ ,25-dihydroxy-24epivitamin D 2 , of structure (11b).
  • reaction steps utilizing the 5,6-trans-intermediate are conducted in a manner entirely analogous to those applicable to the 5,6-ciscompounds described above.
  • the novel side chain ketones of structures (8) or (10) are most useful and versatile intermediates in that they can be used to prepare a variety of 1 ⁇ ,25-dihydroxyvitamin D 2 -side chain analogs.
  • keto-intermediates can serve for the preparation of 5,6-cis- or 5,6-trans-1 ⁇ -, 25-dihydroxyvitamin D 2 analogs having the general side chain formula shown below, where X is an alkyl or aryl group.
  • ketone (8) with, ethyl magnesium bromide gives the corresponding hydroxyvitamin D 2 analog having the side chain structure shown above wherein X is ethyl group.
  • treatment of (8) with isopropyl magnesium bromide or phenyl magnesium bromide gives the side chain analogs where X is isopropyl or phenyl, respectively.
  • Analogous treatment of the 5,6-trans-25-ketone intermediate of structure (10) with alkyl or aryl-Grignard reagents gives the 5,6-trans-vitamin D 2 analog having the side chain above where X is the alkyl or aryl radical Introduced by the Grignard reagent employed.
  • C-24-epimers in isotopically-labeled form, i.e. as the compounds having the side chain shown above, wherein X is C 3 H 3 , 14 CH 3 , C 2 H 3 , 13 CH 3 , or any other isotopically-labeled alkyl or aryl group selected.
  • hydroxy-protected derivatives are for example the acylated compounds represented by general formulae A and B above, wherein one or more of R 1 , R 2 , and R 3 represents an acyl group.
  • Such acyl derivatives are conveniently prepared from the free hydroxy compounds by conventional acylation procedures i.e. treatment of any of the hydroxyvitamin D 2 products with an acyl halide, or acid anhydride in a suitable solvent such as pyridine, or an alkyl-pyridine.
  • a suitable solvent such as pyridine, or an alkyl-pyridine.
  • the partially or fully acylated derivatives represented by structures A or B above are obtained.
  • treatment of 1 ⁇ ,25-dihydroxyvitamin D 2 (9a) in pyridine solvent with acetic anhydride at room temperature gives the 1,3-diacetate, while the same reaction conducted at elevated temperature yields the corresponding 1,3,25-triacetate.
  • the 1,3-diacetate can be further acylated at C-25 with a different acyl group; e.g. by treatrrent with benzqyl chloride or succinic anhydride there is obtained the 1,3-diacetyl-25-benzoyl-, or 1,3-diacetyl-25-succincylderivative, respectively.
  • a 1,3,25-triacyl derivative can be selectively hydrolyzed in mild base to provide the 1,3-dihydroxy-25-O-acyl compound, the free hydroxy groups of which can be reacylated, if desired, with different acyl groups.
  • a 1,3-diacyl derivative can be subjected to partial acyl hydrolysis to obtain the 1-0-acyl and the 3-0-acyl c ⁇ rpounds, which in turn can be reacylated with different acyl groups.
  • a 1,3-diacyl derivative can be subjected to partial acyl hydrolysis to obtain the 1-0-acyl and the 3-0-acyl c ⁇ rpounds, which in turn can be reacylated with different acyl groups.
  • the otherhydroxyvitamin D 2 products e.g. 9b, lla/b, or their corresponding 25-alkyl or aryl analogs
  • R 1 , R 2 , and R 3 are acyl.
  • the novel compounds of this invention exhibit pronounced vitamin D-like activity, and thus represent desirable substitutes for the kncwn vitamin D 2 or D 3 metabolites in many therapeutic, or veterinary applications.
  • Particularly preferred in this regard are the products of structure 9b and 11a and 11b, or their acylated derivatives.
  • novel compounds may be used for correcting or improving a variety of calcium and phosphate imbalance conditions resulting from a variety of diseases, such as vitamin D-resistant rickets, osteomalacia, hypoparathyroidism, osteodystrophy, pseudohypoparathyroidism, osteoporosis, Paget's disease, and similar bone and irdneral-related disease states known to the medical practice.
  • diseases such as vitamin D-resistant rickets, osteomalacia, hypoparathyroidism, osteodystrophy, pseudohypoparathyroidism, osteoporosis, Paget's disease, and similar bone and irdneral-related disease states known to the medical practice.
  • the c ⁇ rpounds can also be used for the treatment of mineral imbalance conditions in animals, for example, the milk fever condition, poultry leg weakness, or for improving egg shell quality of fcwl. Their use in the treatment of osteoporosis is particul-arly noteworthy.
  • the epi compounds of this invention are eminently suitable for the prevention or treatment of physiological disorders in mammals which are characterized by the loss of bone mass because, although they express some of the recognized vitamin D-like characteristics affecting calcium metabolism, such as, increasing intestinal calcium transport, and effecting bone mineralization, they do not increase serum calcium levels, even at high dosages.
  • Example 1 will serve to illustrate the characteristics of 24-epi-1,25-(OH) 2 D 2 which contribute to its eminent suitability for the prevention or treatment of disease states that evince bone mass loss.
  • Example 1 will serve to illustrate the characteristics of 24-epi-1,25-(OH) 2 D 2 which contribute to its eminent suitability for the prevention or treatment of disease states that evince bone mass loss.
  • Bone ash was determined by removing the femurs fr ⁇ n rats.
  • the femurs were dissected free of adhering connective tissue, extracted for 24 hours in absolute ethanol, and 24 hours in diethyl ether, using a Soxhlet extractor.
  • the bones are ashed at 600°F for 24 hours.
  • the ash weight was determined by weighing to constant weight. Results are shown in Figure 4.
  • 24-epi-1,25-(OH) 2 D 2 offer the rare opportunity to control the various vitamin D-responsive processes (intestinal calcium absorption, bone mineral mobilization, and bone mineralization) in a manner and to a degree heretofore not feasible.
  • 24-epi-1,25-(OH) 2 D 2 alone will, as shown above, stimulate intestinal calcium transport and bone mineralization with no or minimal bone mineral mobilization, but the latter activity can be induced by co-administration of one or more of the known vitamin D derivatives (e.g., 1,25- (OH) 2 D 3 , 1 ⁇ ,25-(OH) 2 D 2 , 1 ⁇ -OH-D 3 , and related analogs) .
  • the known vitamin D derivatives e.g., 1,25- (OH) 2 D 3 , 1 ⁇ ,25-(OH) 2 D 2 , 1 ⁇ -OH-D 3 , and related analogs.
  • Co-administration of the 24-epi compound and other vitamin D compounds with bone mobilizing activity can be particularly advantageous in situation where some degree of bone mobilization is desired. For example, it is believed that in certain circumstances, bone must first be mobilized before new bone can be laid down. In such situations treatment with vitamin D or a vitamin D derivative which will induce bone mobilization, e.g.
  • Suitable and effective mixtures are for example, the combination of l ⁇ -,25-dihydroxyvitamin D 2 and 1 ⁇ ,25-dihydroxy-24-epivitamin D 3 (9a and 9b), or mixtures of the corresponding 5,6-trans-compounds (11a and lib), or any other combination of these four products as the free hydroxy compounds or as their acylated forms.
  • the compounds of this invention or c ⁇ nbinations thereof with other vitamin D derivatives or other therapeutic agents can be readily administered as sterile parenteral solutions by injection or intravenously, or by alimentary canal in the form of oral dosages, or trans-dermally, or by suppository.
  • the compounds are administered in dosage amounts of from 0.1 to 100 micrograms per day. In relation to osteoporosis, doses from about 0.5 to about 25 micrograms per day are generally effective.
  • the compounds can be administered either alone or in combination with other vitamin D derivatives, the proportions of each of the compounds in the c ⁇ rbination being dependent upon the particular disease state being addressed and the degree of bone mineralization and/or bone mobilization desired.
  • the actual amount of the 24-epi-compound used is not critical. In all cases, sufficient of the compound should be used to induce bone mineralization. Amounts in excess of about 25 micrograms per day of the 24-epi-compound or the combination of that compound with bone mobilization-inducing vitemin D derivatives, are generally unnecessary to achieve the desired results and may not be economically sound practice.
  • Dosage forms of the compounds can be prepared by combining them with non-toxic pharmaceutically acceptable carriers as is well known in the art.
  • Such carriers may be either solid or liquid such as, for example, corn starch, lactose, sucrose, peanut oil, olive oil, sesame oil and propylene glycol. If a solid carrier is used the dosage form of the compounds may be tablets, capsules, powders, troches or lozenges. If a liquid carrier is used, soft gelatin ceipsules, or syrup or liquid suspensions, emulsions or solutions may be the dosage form.
  • the dosage forms may also contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, etc. They may also contain other therapeutically valuable substances such as other vitamins, salts, sugars, proteins, hormones or other medicinal compounds.
  • Example 5 gives a mixture of epimers (11a) and (11b) which are separated by high performance liquid chromatography (HPLC) to obtain in pure form 1 ⁇ ,25-dihydroxy- 5,6-trans-vitamin D 2
  • a suitable starting material for the process of this invention is the vitamin D-ketal derivative of structure (1) which can be obtained following Process Schemes II and III as described in British Specification No. 2,127,023 or United States Letters Patent No. 4,448,721. It is generally convenient (e.g. when both C-24-epimers are desired) to use compound (1) as a mixture of 24R and 24S epimers, separation of the individual 24R and 24£3 epimers being accomplished later. However, pure 24S-, or pure 24R-epimer of (1) are equally suitable, the former providing the 24S-1 ⁇ ,25-dihydroxy product and the latter the corresponding 24R-product.

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PCT/US1984/000714 1983-05-09 1984-05-09 PROCESS FOR THE PREPARATION OF 1alpha,25-DIHYDROXYLATED VITAMIN D2 AND RELATED COMPOUNDS WO1984004527A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DK008685A DK171397B1 (da) 1983-05-09 1985-01-08 24-epi-1alfa,25-dihydroxylerede vitamin D2-derivater og præparater til farmaceutisk anvendelse indeholdende disse derivater
DK198801845A DK172567B1 (da) 1983-05-09 1988-04-06 3,5-cyclovitamin D2 derivat-mellemprodukter til brug ved fremstillingen af 1alfa,25-dihydroxylerede vitamin D2-derivater

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US49286383A 1983-05-09 1983-05-09
US60732784A 1984-05-04 1984-05-04

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JP (3) JPH0610188B2 (en, 2012)
AU (1) AU568549B2 (en, 2012)
CH (1) CH665834A5 (en, 2012)
DE (4) DE3490215T (en, 2012)
DK (3) DK171397B1 (en, 2012)
NL (1) NL193245C (en, 2012)
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990001321A3 (en) * 1988-08-02 1990-05-17 Bone Care Int Inc Method for treating and preventing loss of bone mass
EP0386793A1 (en) * 1989-03-09 1990-09-12 Wisconsin Alumni Research Foundation Novel 1 alpha-Hydroxyvitamin D2 epimer and derivatives
EP0390097A1 (en) * 1989-03-31 1990-10-03 Nisshin Flour Milling Co., Ltd. 1 alpha,25-dihydroxyvitamin D4 compounds, ergosta-5,7-diene compounds and processes for the preparation thereof
WO1991000271A1 (en) * 1989-06-29 1991-01-10 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) Novel vitamin d analogues
WO1991012240A1 (en) * 1990-02-14 1991-08-22 Wisconsin Alumni Research Foundation Process for preparing vitamin d2 compounds and the corresponding 1 alpha-hydroxylated derivatives
US5403831A (en) * 1988-08-02 1995-04-04 Bone Care International, Inc. Method of treating and preventing loss of bone mass using 1α-hydroxy-vitamin D2
US5529991A (en) * 1992-06-22 1996-06-25 Lunar Corporation Oral 1α-hydroxyprevitamin D
US5763429A (en) * 1993-09-10 1998-06-09 Bone Care International, Inc. Method of treating prostatic diseases using active vitamin D analogues
US5795882A (en) * 1992-06-22 1998-08-18 Bone Care International, Inc. Method of treating prostatic diseases using delayed and/or sustained release vitamin D formulations
US6503893B2 (en) 1996-12-30 2003-01-07 Bone Care International, Inc. Method of treating hyperproliferative diseases using active vitamin D analogues
US6566353B2 (en) 1996-12-30 2003-05-20 Bone Care International, Inc. Method of treating malignancy associated hypercalcemia using active vitamin D analogues
US6573256B2 (en) 1996-12-30 2003-06-03 Bone Care International, Inc. Method of inhibiting angiogenesis using active vitamin D analogues
US6903083B2 (en) 2000-07-18 2005-06-07 Bone Care International, Inc. Stabilized hydroxyvitamin D
US6929797B2 (en) 1997-02-13 2005-08-16 Bone Care International, Inc. Targeted therapeutic delivery of vitamin D compounds
US7094775B2 (en) 2004-06-30 2006-08-22 Bone Care International, Llc Method of treating breast cancer using a combination of vitamin D analogues and other agents
US7122530B2 (en) 1998-05-29 2006-10-17 Genzyme Corporation 24-hydroxyvitamin D, analogs and uses thereof
US7148211B2 (en) 2002-09-18 2006-12-12 Genzyme Corporation Formulation for lipophilic agents
US11926583B2 (en) 2008-03-12 2024-03-12 Eirgen Pharma Ltd. Stabilized 1, 25-dihydroxyvitamin D2 and method of making same

Families Citing this family (2)

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Publication number Priority date Publication date Assignee Title
DE3590488C2 (en, 2012) * 1984-10-04 1992-10-01 Wisconsin Alumni Research Foundation, Madison, Wis., Us
KR910004337B1 (ko) * 1985-01-17 1991-06-26 위스콘신 알럼니 리서치 화운데이션 비타민 d 유도체 및 이를 함유하는 약제

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US4260549A (en) * 1979-05-21 1981-04-07 Wisconsin Alumni Research Foundation Process for preparing 1α-hydroxylated compounds
US4267117A (en) * 1978-06-19 1981-05-12 The Upjohn Company Compounds and process
US4269777A (en) * 1979-05-21 1981-05-26 Wisconsin Alumni Research Foundation Isotopically labeled vitamin D derivatives and processes for preparing same

Patent Citations (3)

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US4267117A (en) * 1978-06-19 1981-05-12 The Upjohn Company Compounds and process
US4260549A (en) * 1979-05-21 1981-04-07 Wisconsin Alumni Research Foundation Process for preparing 1α-hydroxylated compounds
US4269777A (en) * 1979-05-21 1981-05-26 Wisconsin Alumni Research Foundation Isotopically labeled vitamin D derivatives and processes for preparing same

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2231794B (en) * 1988-08-02 1992-01-15 Bone Care Int Inc Method for treating and preventing loss of bone mass
WO1990001321A3 (en) * 1988-08-02 1990-05-17 Bone Care Int Inc Method for treating and preventing loss of bone mass
GB2231794A (en) * 1988-08-02 1990-11-28 Bone Care Int Inc Method for treating and preventing loss of bone mass
US5403831A (en) * 1988-08-02 1995-04-04 Bone Care International, Inc. Method of treating and preventing loss of bone mass using 1α-hydroxy-vitamin D2
AU634490B2 (en) * 1988-08-02 1993-02-25 Bone Care International, Inc. Method for treating and preventing loss of bone mass
EP0386793A1 (en) * 1989-03-09 1990-09-12 Wisconsin Alumni Research Foundation Novel 1 alpha-Hydroxyvitamin D2 epimer and derivatives
WO1990010619A1 (en) * 1989-03-09 1990-09-20 Wisconsin Alumni Research Foundation NOVEL 1α-HYDROXYVITAMIN D2 EPIMER AND DERIVATIVES
US5157135A (en) * 1989-03-31 1992-10-20 Nisshin Flour Milling Co., Ltd. 1α,25-dihydroxyvitamin D4 compounds, ergosta-5,7-diene compounds and processes for the preparation thereof
EP0390097A1 (en) * 1989-03-31 1990-10-03 Nisshin Flour Milling Co., Ltd. 1 alpha,25-dihydroxyvitamin D4 compounds, ergosta-5,7-diene compounds and processes for the preparation thereof
WO1991000271A1 (en) * 1989-06-29 1991-01-10 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) Novel vitamin d analogues
WO1991012240A1 (en) * 1990-02-14 1991-08-22 Wisconsin Alumni Research Foundation Process for preparing vitamin d2 compounds and the corresponding 1 alpha-hydroxylated derivatives
US6150346A (en) * 1992-06-22 2000-11-21 Bone Care International, Inc. Method and composition for treating or preventing osteoporosis
US5529991A (en) * 1992-06-22 1996-06-25 Lunar Corporation Oral 1α-hydroxyprevitamin D
US5614513A (en) * 1992-06-22 1997-03-25 Bone Care International, Inc. Oral 1α-hydroxyprevitamin D
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Also Published As

Publication number Publication date
AU568549B2 (en) 1988-01-07
NL193245B (nl) 1998-12-01
JPH02288873A (ja) 1990-11-28
DE3490215T (de) 1985-05-15
DK183291D0 (da) 1991-11-07
JPH0339505B2 (en, 2012) 1991-06-14
DK184588D0 (da) 1988-04-06
DK8685A (da) 1985-01-08
DK172733B1 (da) 1999-06-21
DK8685D0 (da) 1985-01-08
JPH0651624B2 (ja) 1994-07-06
JPH0610188B2 (ja) 1994-02-09
DE3490215C2 (en, 2012) 1991-07-25
NL8420137A (nl) 1985-04-01
DE3448360C2 (en, 2012) 1991-10-02
CH665834A5 (de) 1988-06-15
NL193245C (nl) 1999-04-02
AU3011584A (en) 1984-12-04
JPH02288829A (ja) 1990-11-28
JPH02288854A (ja) 1990-11-28
DK183291A (da) 1991-11-07
DE3448412C2 (en, 2012) 1991-12-12
DK184588A (da) 1988-04-06
DK171397B1 (da) 1996-10-14
DK172567B1 (da) 1999-01-18

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