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WO1997011053A1 - Derives de calcitriol et leurs utilisations - Google Patents

Derives de calcitriol et leurs utilisations Download PDF

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Publication number
WO1997011053A1
WO1997011053A1 PCT/US1996/015184 US9615184W WO9711053A1 WO 1997011053 A1 WO1997011053 A1 WO 1997011053A1 US 9615184 W US9615184 W US 9615184W WO 9711053 A1 WO9711053 A1 WO 9711053A1
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WO
WIPO (PCT)
Prior art keywords
group
vitamin
compound
acyl group
hydrogen
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/US1996/015184
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English (en)
Inventor
Hector F. Deluca
Heinrich K. Schnoes
Zu Yun Cai
Mary E. Phelps
Connie M. Smith
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Wisconsin Alumni Research Foundation
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Wisconsin Alumni Research Foundation
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
Priority claimed from US08/531,403 external-priority patent/US5952317A/en
Priority to JP51294597A priority Critical patent/JP3372259B2/ja
Priority to NZ319819A priority patent/NZ319819A/en
Priority to KR1019980702077A priority patent/KR100327922B1/ko
Priority to US09/043,509 priority patent/US5976784A/en
Priority to AU72426/96A priority patent/AU717238B2/en
Application filed by Wisconsin Alumni Research Foundation filed Critical Wisconsin Alumni Research Foundation
Priority to CA002229316A priority patent/CA2229316C/fr
Priority to EP96933853A priority patent/EP1021401A1/fr
Publication of WO1997011053A1 publication Critical patent/WO1997011053A1/fr
Priority to NO981282A priority patent/NO981282L/no
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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • This invention relates to biologically active vitamin D compounds, and more particularly to vitamin D compounds with hydrolyzable groups at one or more of the 1 , 3 and 25 carbon positions, such as esters of 1 ⁇ ,25-dihydroxyvitamin D 3 or esters of 1 ,25-dihydroxyvitamin D 3 analogs, and their use to regulate over time the function of 1 ,25(OH) 2 D 3 (or of 1 ,25(OH) 2 D 3 analogs) during the treatment of a variety of diseases such as osteoporosis, renal osteodystrophy, hypoparathyroidism or proliferative skin disorders.
  • diseases such as osteoporosis, renal osteodystrophy, hypoparathyroidism or proliferative skin disorders.
  • the 1 ⁇ -hydroxylated metabolites of vitamin D - - most importantly 1 ⁇ ,25-dihydroxyvitamin D 3 and 1 ⁇ ,25-dihydroxyvitamin D 2 -- are known as highly potent regulators of calcium homeostasis in animals and humans.
  • 1 ⁇ ,25-dihydroxyvitamin D 3 as the active form of the vitamin has come an intense investigation of analogs of this hormonal form of vitamin D with the intent of finding analogs that have selective biological activity.
  • many structural analogs of these metabolites such as compounds with different side chain structures, different hydroxylation patterns, or different stereo chemistry, have been prepared and tested.
  • osteoporosis Various forms of osteoporosis are known, e.g. ,
  • This disease is generally known as postmenopausal osteoporosis and presents a major medical problem, both in the United States and most other countries where the life-span of females reaches ages of at least 60 and 70 years.
  • the disease which is often accompanied by bone pain and decreased physical activity, is diagnosed by one or two vertebral crush fractures with evidence of diminished bone mass. It is known that this disease is accompanied by diminished ability to absorb calcium, decreased levels of sex hormones, especially estrogen and androgen, and a negative calcium balance.
  • a conventional treatment is to administer a calcium supplement to the patient.
  • calcium supplementation by itself has not been successful in preventing or curing the disease.
  • Another conventional treatment is the injection of sex hormones, especially estrogen, which has been reported to be effective in preventing the rapid loss of bone mass experienced in
  • U.S. Patent No. 4,255,596 suggests the use of various metabolites of vitamin D 3 for increasing calcium absorption and retention within the body of mammals displaying evidence of or having a physiological tendency toward loss of bone mass.
  • the metabolites specifically named in that patent i.e. , 1 ⁇ -hydroxyvitamin D 3 , 1 ⁇ -hydroxyvitamin D 2 , 1 ⁇ ,25-dihydroxyvitamin D 3 (calcitriol), 1 ⁇ ,25-dihydroxyvitamin D 2 and 1 ,24,25-trihydroxyvitamin D 3 , although capable of the activity described and claimed in that patent, can, however, also cause hypercalcemia, especially if used with the conventional calcium supplement.
  • Calcitriol treatment has also been found to be effective in reducing bone loss in women with postmenopausal osteoporosis by increasing intestinal calcium absorption and reducing bone resorption. Aloria et al, "Calcitriol In The
  • in vivo calcitriol is produced slowly and continuously by the kidney and thus is available throughout the day and night. When given by mouth or by injection, large amounts are available to the tissues initially but little is left after 2-4 hours due to metabolism and
  • the present invention provides a method for modulating and regulating the in vivo activity of biologically active vitamin D compounds, such as calcitriol or analogs of calcitriol. More specifically, this invention provides modified vitamin D
  • these compounds represent novel therapeutic agents for the treatment of all diseases where vitamin D compounds have been shown effective, such as metabolic bone diseases or proliferative skin disorders (e.g.
  • the modified vitamin D compounds having these desirable biological attributes are derivatives of 1 ⁇ ,25-dihydroxyvitamin D 3 , or derivatives of 1 ⁇ ,25-dihydroxyvitamin D 3 analogs, in which a hydrolyzable group is attached to the hydroxy group at carbon 25 and, optionally, to any other of the hydroxy groups present in the molecule.
  • a hydrolyzable group is attached to the hydroxy group at carbon 25 and, optionally, to any other of the hydroxy groups present in the molecule.
  • these derivatives are thought to hydrolyze to 1 ⁇ ,25-dihydroxyvitamin D 3 , or to a 1 ⁇ ,25-dihydroxyvitamin D 3 analog, at different rates in vivo, thus providing for the "slow release" of the biologically active vitamin D compound (i.e. 1 ,25-dihydroxyvitamin D 3 , or an analog thereof) in the body.
  • the “slow release" in vivo activity profiles of such compounds can, of course, be further modulated by the use of mixtures of derivatives (e.g. mixtures of different derivatives of 1 ,25-dihydroxyvitamin D 3 , or different derivatives of 1 ,25-dihydroxyvitamin D 3 analogs) or the use of mixtures consisting of one or more vitamin D derivative together with underivatized vitamin D compounds.
  • mixtures of derivatives e.g. mixtures of different derivatives of 1 ,25-dihydroxyvitamin D 3 , or different derivatives of 1 ,25-dihydroxyvitamin D 3 analogs
  • mixtures consisting of one or more vitamin D derivative together with underivatized vitamin D compounds e.g. mixtures of different derivatives of 1 ,25-dihydroxyvitamin D 3 , or different derivatives of 1 ,25-dihydroxyvitamin D 3 analogs
  • the critical structural feature of the vitamin derivatives identified above is the presence of a hydrolyzable group attached to the hydroxy group at carbon 25 of the molecule.
  • a hydrolyzable group at that position imparts on the resulting derivatives the desirable "slow-release" biological activity profile mentioned above.
  • Other hydroxy functions occurring in the molecule e.g. hydroxy functions at carbons 1 or 3 may be present as free hydroxy groups, or one or more of them may also be derivatived with a hydrolyzable group.
  • the fact that the introduction of a hydrolyzable group at carbon 25 of the vitamin D molecule markedly modulates the in vivo biological activity pattern of the resulting derivative was not appreciated previously. The realization of the importance of this specific modification, and the demonstration of its marked and highly beneficial biological effects form the basis of this invention.
  • the "hydrolyzable group" present in the above-mentioned derivatives is preferably an acyl group, i.e. a group of the type Q 1 CO-, where Q 1 represents hydrogen or a hydrocarbon radical of from 1 to 18 carbons that may be straight chain, cyclic, branched, saturated or unsaturated.
  • the hydrocarbon radical may be a straight chain or branched alkyl group, or a straight chain or branched alkenyl group with one or more double bonds, or it may be an optionally substituted cycloalkyl or cycloalkenyl group, or an aromatic group, such as substituted or unsubstituted phenyl, benzyl or naphthyl.
  • acyl groups are alkanoyl or alkenoyl groups, of which some typical examples are formyl, acetyl, propanoyl, hexanoyl, isobutyryl, 2-butenoyl, palmitovi or oleoyl.
  • Another suitable type of hydrolyzable group is the hydrocarbyloxycarbonyl group, i.e. a group of the type Q 2 -O-CO-, where Q 2 is a C 1 to C 18 hydrocarbon radical as defined above.
  • hydrocarbon radicals are methyl, ethyl, propyl, and higher straight chain or branched alkyl and alkenyl radicals, as well as aromatic hydrocarbon radicals such as phenyl or benzoyi.
  • an especially important and preferred class are certain acyl ester derivatives of calcitriol, i.e. the calcitriol derivatives characterized by the following general structure:
  • X 1 and X 2 independently represent hydrogen or an acyl group
  • X 3 represents an acyl group as previously defined.
  • Two other very important groups of modified vitamin D compounds are the corresponding acyl esters of the calcitriol side chain homologs, and the acyl derivatives of the 19-nor- 1,25-dihydroxyvitamin D analogs.
  • the present invention therefore, provides a series of modified vitamin D compounds that are useful for the treatment of metabolic bone disease (such as the various forms of
  • osteoporosis osteomalacia, osteodystrophy, etc.
  • osteodystrophy etc.
  • a method of treating such diseases comprises the administration of an effective amount of the above-indicated acyl ester derivatives of 1 ⁇ ,25-dihydroxyvitamin D 3 or of the
  • the above compounds may be administered alone or in combination with other pharmaceutically acceptable agents.
  • the above method involving the administration of the indicated dosages of these compounds is effective in restoring or maintaining bone mass, and thus provides a novel method for the treatment or prevention of various forms of osteoporosis such as postmenopausal osteoporosis, senile osteoporosis and steroid-induced osteoporosis. It will be evident that the method will find ready application for the prevention or treatment of disease states other than those named, in which the loss of bone mass is an indication. Also, it will be further evident that the method will find ready application for the prevention or treatment of hypercalcemia and hypocalcemia as the rate of conversion of these analogs, i.e. the in vivo hydroxylation process, can be controlled and regulated in the manner described above.
  • Fig. 1 is a graph illustrating the activity of di- and tri-acetates of 1 ⁇ ,25-dihydroxyvitamin D 3 on serum calcium, and particularly illustrates the milligrams percent calcium found in blood over time;
  • Fig. 2 is a graph similar to Fig. 1 except illustrating the activity of a 25-mono-acetate of 1 ⁇ ,25-dihydroxyvitamin D 3 on serum calcium. Disclosure of the Invention
  • the present invention provides novel modified vitamin D compounds which are useful in the treatment of metabolic bone diseases, such as osteoporosis, as well as other disease states.
  • modified vitamin D compounds are hydrolyzable in vivo to calcitriol, or analogs of calcitriol, over a period of time following administration, and as a consequence regulate the in vivo availability of active calcitriol, or analogs of calcitriol, thereby also modulating their activity profile in vivo.
  • the term "activity profile” refers to the biological response over time of vitamin D compounds such as calcitriol or analogs of calcitriol. Individual modified compounds, or mixtures of such compounds, can be administered to "fine tune" a desired time course of response.
  • vitamin D compound As used herein the term "vitamin D compound"
  • vitamin D compounds encompassed herein include those having a "vitamin D nucleus” comprising substituted or unsubstituted A-, C-, and D-rings interconnected by a 5, 7 diene double bond system typical of vitamin D together with a side chain attached to the D-ring.
  • modified vitamin D compound encompasses any vitamin D compound in which one or more of the hydroxy functions present in such a compound are modified by derivatization with a hydrolyzable group.
  • hydrolyzable group is a hydroxy-modifying group that can be hydrolyzed in vivo, so as to regenerate the free hydroxy functions.
  • hydrolyzable group preferably includes acyl and hydrocarbyloxycarbonyl groups, i.e. groups of the type Q 1 CO- and Q 2 -O-CO, respectively, where Q 1 and Q 2 have the meaning defined earlier.
  • R 5 and R 6 each represent hydrogen, or taken together R 5 and R 6 represent a methylene group.
  • the side chain group R in the above-shown structure represents a steroid side chain of the structure below:
  • stereochemical center corresponding to C-20 in steroid numbering
  • the stereochemical center may have the R or S configuration, (i.e.
  • n and n independently, represent the integers from 0 to
  • R 1 is selected from hydrogen, OX 4 , fluoro,
  • R 2 is selected from hydrogen, fluoro, trifluoromethyl and C 1 -5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy substituent
  • R 3 and R 4 independently represent trifluoromethyl or C 1 -5 alkyl, which may be straight chain or branched and, optionally, bear a hydroxy substituent
  • hydrocarbyloxycarbonyl group and X 3 represents an acyl group or a hydrocarbyloxycarbonyl group, as previously defined herein.
  • modified vitamin D compounds include calcitriol derivatives such as: 1 ⁇ ,25(OH) 2 -D 3 - 1 ,3,25-Triacetate where
  • UV absorption spectra were obtained on the following instruments: Ultraviolet (UV) absorption spectra were taken with Perkin-Elmer Lambda
  • This example illustrates the serum calcium response of rats over time to three compounds, namely, 1 ⁇ ,25(OH) 2 D 3 -
  • vitamin D-deficient diet for a period of 8 weeks to deplete them of vitamin D. They were then provided a single oral dose of 1 ,000 pmol or 1 nanomole of each of the
  • Figure 1 is a graph illustrating the data of Table 1. Because calcium is present in the diet and hence their intestine, the rise in serum calcium largely represents intestinal calcium absorption. The results show clearly that the 1 ,3-diacetate and un-esterified calcitriol produce essentially the same time course of response,
  • This example illustrates the serum calcium response of rats over time to two compounds, namely, 1 ⁇ ,25(OH) 2 D 3
  • modified vitamin D compound or combinations thereof 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.
  • Doses of from about 0.5 micrograms to about 10 micrograms per day or modified vitamin D compound per se, or in combination with other modified vitamin D compounds, the proportions of each of the compounds in the combination being dependent upon the particular disease state being addressed and the degree of bone mineralization and/or bone mobilization desired, are generally effective to practice the present invention. In all cases sufficient amounts of the compound should be used to restore bone mass.
  • Amounts in excess of about 10 micrograms per day of modified vitamin D compound, or the combination of that compound with other modified vitamin D compounds, are generally unnecessary to achieve the desired results, may result in hypercalcemia, and may not be an economically sound practice. In practice the higher doses are used where
  • Dosage forms of the various compounds can be prepared by combining them with non-toxic pharmaceutically acceptable carriers to make either immediate release or slow release formulations, as is well known in the art.
  • suitable carriers may be either solid or liquid such as, for example, com 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 capsules, or syrup or liquid
  • suspensions, emulsions or solutions may be the dosage form.
  • the dosage form may also contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, etc. They may also contain other therapeutically valuable substances.
  • the modified vitamin D compounds may also include any of the following compounds in which one or more hydroxy
  • - P stands for hydrogen, alkyl or acyl
  • - X represents part of the side-chain of vitamin D or of one of its established analogues
  • V which may be the same or different, stand for hydrogen or alkyl or, when taken together, represent an alky ⁇ dene group, or form a carbocyclic ring;
  • W which may be the same or different, stand for hydrogen or alkyl or, when taken together, represent an alkylidene group, or form a carbocyclic ring;
  • one of the carbon atoms of the central part corresponding to positions 14, 13, 17 or 20, together with the R and R' substituents connected to it, may be replaced by an oxygen (O), a sulfur (S) or a nitrogen bearing an R substituent (NR).
  • O oxygen
  • S sulfur
  • NR nitrogen bearing an R substituent
  • R and R' i.e., R, R 1 , R 2 , R' 2 , R 3 , R' 3 , R 4 , R' 4 , R 5 , R' 5 ) :
  • R 1 and R 3 or R' 3 , R 2 or R' 2 and R 4 or R' 4 , R 3 or R' 3 and R 5 or R' 5 taken together with three adjacent atoms of the central chain, which correspond to positions 8, 14, 13 or 14, 13, 17 or 13, 17, 20, respectively, can form a saturated or unsaturated carbocyclic or heterocyclic 3-, 4-, 5% 6- or 7-membered ring
  • R 1 and R'3 form a 6-membered carbocyclic ring of the following nature (1 ) unsubstituted and saturated (2) mo ⁇ osubstituted at C-11 or (3) having a double bond between C-9 and C-11 , R 2 and R 4 do not form a five-membered carbocyclic ring when R3 is methyl, etnyl or ethenyl o when located in a relative 1 ,2-position (i.e., vicinal) along the central chain, such as R 1 and R 2 or R' 2 , R 2 or R' 2 and R 3 or R 3 , R 3 or R' 3 and R 4 or R' 4 , R 4 or R' 4 and R 5 or R' 5 , and when not being part of a ring as described above, taken together with two adjacent atoms of the central chain, which correspond to positions 8,14 or 14,
  • R 2 and R' 2 , or R 3 and R' 3 , or R 4 and R' 4 or R 5 and R' 5 when not being part of a ring as described above, taken together with the carbon bearing the R and R' substituents can form either a saturated or unsaturated carbocyclic or heterocyclic 3-, 4-, 5-, or 6-membered ring.
  • lower alkyl group indicates a straight or branched saturated or unsaturated carbon chain containing from 1 to 7 carbon atoms
  • lower alkylidene group indicates a straight or branched saturated or unsaturated carbon chain containing from 1 to 7 carbon atoms, which is connected to one of the main chain atoms 14, 13, 17 and/or 20 through a double bond.
  • part of the side-chain of vitamin D or of one of its established analogues stands for a 2 to 15 carbon atom substituted alkyl chain especially as present in vitamin D 2 (C-22 to C-28) or D3 (C-22 to C-27) or partially modified as shown below with the vitamin D numbering, especially :
  • the ring can be saturated, unsaturated or aromatic and may optionally be substituted at any possible position(s) with the substituent mentioned above and/or - cyclized between the carbon atoms 26 and 27 by 1 to 4 atoms to form a heterocyclic ring, including aromatic, which may optionally be substituted at any possible position with the substituent mentioned above and/or
  • these unsaturated chains may be substituted at any possible position by the substituents mentioned above and/or
  • - epoxide function can be present between carbon atoms 22,23 or 23,24 or
  • the invention relates to a series of analogues with widely varying structures .
  • the compounds of the invention are represented by one of the formulas
  • - Z represents a saturated or unsaturated hydrocarbon chain consisting of zero (hence Z represents a bond between two 1 ,3-related carbon atoms of the central chain), one, two, three or four atoms, which may all be substituted and/or replaced by a heteroatom such as oxygen, sulfur and nitrogen.
  • o which may be the same or different, stand for hydrogen or lower alkyl, such as methyl, ethyl or n-propyl.
  • - n is an integer equal to 2 or 3;
  • - X represents one of the following vitamin D side-chain parts : (4-hydroxy- 4-methyl)pentyl, (R)- or (S)-(3-hydroxy-4-methyl)pentyl, (3'-hydroxy-3'- methyl)butyloxy, (4-hydroxy-4-ethyl)hexyl, (4-hydroxy-4-methyl)-2-pentynyI, (4'-hydroxy-4'-ethyl)hexyloxy; 4,5-epoxy, 4-methyl-2-pentynyl; 4-hydroxy-4- ethyI-2-hexynyl; (3-methyl-2,3-epoxy)-butyloxy; (3-hydroxy-3-ethyl)- pentyloxy; (4-hydroxy-4-ethyI)-hexyloxy
  • R 1 , R 2, R' 2, R 3, R' 3, R 4, R' 4, R 5 and R' 5, which may be the same or different, stand for hydrogen or methyl.

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Abstract

L'invention se rapporte à un procédé de traitement des maladies osseuses métaboliques telles que l'ostéoporose, ainsi que d'autres états pathologiques pouvant être traités avec des composés de la vitamine D, ce procédé consistant à administrer une quantité efficace d'un ou plusieurs composés modifiés de la vitamine D. Le composé modifié contient un noyau type de vitamine D, mais présentant des groupes hydrolysables in vivo à une ou plusieurs des positions de carbone 1, 3 et 25. Il est possible de réguler le temps de conversion à sa forme active du composé modifié, tel que le calcitriol, en vue d'obtenir une libération régulée du composé in vivo sur plusieurs heures, en changeant ou modifiant les groupes hydrolysables.
PCT/US1996/015184 1995-09-21 1996-09-20 Derives de calcitriol et leurs utilisations Ceased WO1997011053A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP96933853A EP1021401A1 (fr) 1995-09-21 1996-09-20 Derives de calcitriol et leurs utilisations
NZ319819A NZ319819A (en) 1995-09-21 1996-09-20 Calcitriol derivatives and their uses
KR1019980702077A KR100327922B1 (ko) 1995-09-21 1996-09-20 칼시트리올유도체및그의용도
US09/043,509 US5976784A (en) 1996-09-20 1996-09-20 Calcitriol derivatives and their uses
AU72426/96A AU717238B2 (en) 1995-09-21 1996-09-20 Calcitriol derivatives and their uses
JP51294597A JP3372259B2 (ja) 1995-09-21 1996-09-20 カルシトリオール誘導体およびそれらの用途
CA002229316A CA2229316C (fr) 1995-09-21 1996-09-20 Derives de calcitriol et leurs utilisations
NO981282A NO981282L (no) 1995-09-21 1998-03-20 Calcitriolderivater og deres anvendelser

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US53186795A 1995-09-21 1995-09-21
US08/531,403 US5952317A (en) 1995-09-21 1995-09-21 Calcitriol derivatives and their uses
US08/531,403 1995-09-21
US08/531,867 1995-09-21

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WO1997011053A1 true WO1997011053A1 (fr) 1997-03-27

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EP (1) EP1021401A1 (fr)
JP (1) JP3372259B2 (fr)
KR (1) KR100327922B1 (fr)
AU (1) AU717238B2 (fr)
CA (1) CA2229316C (fr)
HU (1) HUP9802303A3 (fr)
NO (1) NO981282L (fr)
NZ (2) NZ501318A (fr)
WO (1) WO1997011053A1 (fr)

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WO2001011986A1 (fr) * 1999-08-17 2001-02-22 Wisconsin Alumni Research Foundation Aliments pour animaux contenant des derives de calcitriol hydrolysables
WO2001040177A2 (fr) 1999-12-02 2001-06-07 Women And Infants Hospital Esters de vitamine d3 et utilisation de ces ceux-ci
WO2003082300A1 (fr) * 2002-03-25 2003-10-09 Wisconsin Alumni Research Foundation Utilisation d'analogues de vitamine d modifiee sur le carbone 2 afin d'induire la formation d'os nouveau
WO2005082375A2 (fr) 2004-03-01 2005-09-09 Bioxell Spa Methodes permettant de traiter la cystite interstitielle et composes et compositions connexes
WO2006051106A1 (fr) 2004-11-12 2006-05-18 Bioxell Spa Emploi combiné de dérivés de vitamine d et d'agents antiproliférants pour le traitement de cancers de la vessie
US7199151B2 (en) 1996-05-22 2007-04-03 Luitpold Pharmaceuticals, Inc. DHA-pharmaceutical agent conjugates of taxanes
US8207149B2 (en) 2007-04-25 2012-06-26 Cytochroma, Inc. Method for treating secondary hyperparathyroidism in CKD
US8329677B2 (en) 2006-06-21 2012-12-11 Cytochroma, Inc. Method of treating and preventing secondary hyperparathyroidism
US8426391B2 (en) 2006-02-03 2013-04-23 Proventiv Therapeutics, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US8592401B2 (en) 2007-04-25 2013-11-26 Proventiv Therapeutics, Llc Methods and compounds for vitamin D therapy
US9861644B2 (en) 2013-03-15 2018-01-09 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US10220047B2 (en) 2014-08-07 2019-03-05 Opko Ireland Global Holdings, Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US10302660B2 (en) 2008-04-02 2019-05-28 Opko Renal, Llc Methods useful for vitamin D deficiency and related disorders
US11173168B2 (en) 2016-03-28 2021-11-16 Eirgen Pharma Ltd. Methods of treating vitamin D insufficiency in chronic kidney disease
CN114656413A (zh) * 2022-03-30 2022-06-24 南通华山药业有限公司 一种阿法骨化醇杂环酯类衍生物及其制备方法
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WO2001040177A2 (fr) 1999-12-02 2001-06-07 Women And Infants Hospital Esters de vitamine d3 et utilisation de ces ceux-ci
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WO2003082300A1 (fr) * 2002-03-25 2003-10-09 Wisconsin Alumni Research Foundation Utilisation d'analogues de vitamine d modifiee sur le carbone 2 afin d'induire la formation d'os nouveau
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