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WO2001056982A1 - Derives de vitamine d et leur utilisation dans le cadre du traitement de l'osteoporose et des troubles osseux associes - Google Patents

Derives de vitamine d et leur utilisation dans le cadre du traitement de l'osteoporose et des troubles osseux associes Download PDF

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Publication number
WO2001056982A1
WO2001056982A1 PCT/DK2001/000070 DK0100070W WO0156982A1 WO 2001056982 A1 WO2001056982 A1 WO 2001056982A1 DK 0100070 W DK0100070 W DK 0100070W WO 0156982 A1 WO0156982 A1 WO 0156982A1
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Prior art keywords
compound
methyl
dihydroxy
pregna
seco
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PCT/DK2001/000070
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English (en)
Inventor
Gunnar GRUE-SØRENSEN
Henrik Pedersen
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Leo Pharma A/S
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Publication date
Application filed by Leo Pharma A/S filed Critical Leo Pharma A/S
Priority to AU2001228330A priority Critical patent/AU2001228330A1/en
Publication of WO2001056982A1 publication Critical patent/WO2001056982A1/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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • Vitamin D-derivatives and their use in treating osteoporosis and related bone disorders.
  • the present invention relates to novel pharmacologically active vitamin D analogues as well as pharmaceutical preparations containing these compounds and dosage units of such preparations.
  • a number of thia-analogues of vitamin D 3 are known. 1 ,25-Dihydroxy-23-thiavitamin D 3 is described in European Patent Application, publication number 78704. 23-Thia-aro-vitamin D analogues are described in G. Grue-S ⁇ rensen, E. Binderup and L. Binderup in "Vitamin D. A Pluripotent Steroid Hormone: Structural Studies, Molecular Endocrinology and Clinical
  • Some of these compounds may have advantages over 1 ,25(OH) 2 D 3 , e.g. in having reduced calcium metabolism effects relative to 1 ,25(OH) 2 D 3 . However, there is no report on a possible effect of these compounds in relation to bone anabolism.
  • novel vitamin D analogues represented by the general formula I herein, have shown bone anabolic effects in an in vivo model of osteoporosis and related bone disorders. Moreover, the bone anabolic activity of the analogues of the invention including the novel compounds is accompanied by a strengthening effect on the skeletal muscles.
  • the present invention is directed to novel compounds represented by the general formula I
  • R 1 and R 2 which may be the same or different, represent hydrogen or a residue after removal of 1 hydrogen atom from a straight, branched or cyclic, saturated or unsaturated, CrC 6 - hydrocarbon; or R 1 and R 2 , together with the carbon atom to which they are attached (marked with an asterisk in formula I), can form a C 3 -C 8 carbocyclic ring;
  • Q represents a diradical residue after removal of 2 hydrogen atoms from a straight, branched or cyclic, saturated or unsaturated CrC 8 -hydrocarbon substituted with one or more chlorine or bromine atoms and/or substituted with one or more alkyl or alkoxy groups;
  • R 1 , R 2 and/or Q is optionally substituted with one or more fluorine atoms;
  • m is 0, 1 or 2 and n is 0 or 1.
  • Preferred compounds of formula I are compounds wherein R 1 and R 2 taken together with the carbon atom (starred in formula I) form a C 3 -C 5 alkylene group; and/or compounds of formula I wherein Q represents a C 3 -C 5 alkylene group substituted with one or two chlorine atoms, or Q represents a phenylene group substituted with one bromine atom, one or two chlorine atoms, or one or two methyl or methoxy groups; and compounds of formula I wherein and n is 1.
  • C 3 -C 8 carbocyclic ring includes the saturated cycloalkanes and unsaturated cyclic olefins, such as cycloalkenes having one endocyclic double bond, and having from 3-8 carbon atoms, and includes, for example, cyclopropyl, cyclopentyl, and cyclohexyl groups.
  • Olefinic group refers to a straight or branched acyclic hydrocarbon having one or more carbon- carbon double bonds of either E or Z stereochemistry where applicable, and having the number of carbon atoms specified.
  • the term includes, for example, (C 2 -C-
  • Halogen when used herein means the same or different of fluoro, chloro, bromo, and iodo; fluoro, chloro, and bromo being preferred.
  • the compounds of the invention can comprise several diastereoisomeric forms (e.g. R or S configuration at the starred carbon atom).
  • the invention covers all these diastereoisomers in pure form and also mixtures of diastereoisomers.
  • the compounds of formula I may conveniently be prepared from the vitamin D-derivative Compound (i), cf. Compound 5 in WO 91/15457, for example by the routes outlined in Scheme 1.
  • Photoisomerization of Compound (i) gives Compound (ii).
  • An alternative to this route involves treatment of Compound (i) under basic conditions with a side chain building block HS-R, wherein R is as described above, to give the intermediate II.
  • R in compounds II and III does not necessarily have the same meaning along a particular synthetic sequence.
  • the side chain building block HS-R is prepared by methods analogous to those used to prepare known compounds, such as 4-mercaptobenzoic acid (O. Paquatte, A. Fried and S.-C. Tu, Arch. Biochem. Biophys. 264, 392-399 (1988)) or methyl 4-mercaptobenzoate ( M.S. Newman and H.A. Karnes, J. Org. Chem., 31 , (1966) 3980-3984).
  • 4-mercaptobenzoic acid O. Paquatte, A. Fried and S.-C. Tu, Arch. Biochem. Biophys. 264, 392-399 (1988)
  • methyl 4-mercaptobenzoate M.S. Newman and H.A. Karnes, J. Org. Chem., 31 , (1966) 3980-3984.
  • Dabco 1 ,4- diazabicyclo[2.2.2]octane
  • DMF N,N,-dimethylformamide
  • DMSO dimethylsulphoxide
  • Et ethyl
  • HMPA hexamethylphosphoric triamide
  • Me methyl
  • TBA tetrabutylammonium
  • THF tetrahydrofuran
  • Ts 4-toluenesulphonyl.
  • Optional functional group modification in the R-group e.g. esterification of a carboxyl group with diazomethane or methanol and strong mineral acid, followed by reaction with alkyl lithium, alkylmagnesium bromide or a reducing agent, such as sodium bis(2- methoxyethoxy)aluminium hydride.
  • R-SH may be prepared according to Scheme III, where the thiophenol ring, besides a 2-hydroxy-2-propyl substituent, is substituted with one or more of the following substituents: Cl, Br, methyl and/or methoxy.
  • Y 1 H, Cl, Br, Me or OMe
  • Y 2 Cl, Br, Me or OMe
  • X OMe or Me.
  • the present invention provides a hitherto undisclosed series of vitamin D analogues related to the analogues disclosed in WO 91/15475, and which is characterised by the presence of additional halogen, alkyl or alkoxy groups in the side chain represented by the group Q in formula I herein.
  • the present compounds are intended for use in the preparation of pharmaceutical compositions which are useful in the treatment of specific human and veterinary disorders as described above.
  • the amount required of a compound of formulae I (hereinafter referred to as the active compound or the active ingredient) for therapeutic effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment.
  • the compounds of the invention can be administered by the parenteral, intra-articular, enteral or topical routes. They are well absorbed when given enterally and this is the preferred route of administration in the treatment of systemic disorders. In the treatment of dermatological disorders like psoriasis or eye diseases topical or enteral forms are preferred.
  • novel compounds are intended for use in pharmaceutical compositions which are useful in the local or systemic treatment or prophylaxis of human and veterinary disorders amenable to treatment with vitamin D or vitamin D analogues, such as e.g. psoriasis and other disturbances of keratinization, various cancer forms, such as leukemia, mammary cancer, brain glial tumours, osteosarcoma, myelofibrosis, melanoma, other skin cancers, and of diseases of, or imbalances in, the immune system, such as host versus graft and graft versus host reaction and transplant rejection, and autoimmune diseases, such as discoid and systemic lupus erythema- tosus, diabetes mellitus and chronic dermatoses of autoimmune type, e.g.
  • vitamin D or vitamin D analogues such as e.g. psoriasis and other disturbances of keratinization
  • various cancer forms such as leukemia, mammary cancer,
  • scleroderma and pemphigus vulgaris as well as a number of other disease states including hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal failure, cognitive impairment or senile dementia (Alzheimers disease) and other neurodegenerative diseases, skin atrophy, e.g. steroid induced skin atrophy, skin ageing, including photo-ageing, and to their use for promoting osteogenesis and treating/preventing osteoporosis and osteomalacia.
  • hyperparathyroidism particularly secondary hyperparathyroidism associated with renal failure
  • cognitive impairment or senile dementia Alzheimers disease
  • other neurodegenerative diseases skin atrophy, e.g. steroid induced skin atrophy, skin ageing, including photo-ageing, and to their use for promoting osteogenesis and treating/preventing osteoporosis and osteomalacia.
  • the present compounds may be used in combination with other pharmaceuticals or treatment modalities.
  • the present compounds may be used in combination with other antipsoriatic drugs, e.g steroids, or with other treatments e.g. light- or UV-Iight-treatment or the combined PUVA-treatment.
  • the present compounds may be used in combination with other anti-cancer drugs or anti-cancer treatments, such as radiation treatment.
  • the present compounds may advantageously be used in combination with other immunosuppressive/immunoregulating drugs or treatments, e.g. with cyclosporin A.
  • the active ingredient While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. Conveniently, the active ingredient comprises from 0.1 ppm to 1% by weight of the formulation.
  • the formulations, both for veterinary and for human medical use, of the present invention thus comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredient(s).
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
  • the formulations include e.g. those in a form suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular and topical, nasal or buccal administration.
  • dosage unit a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
  • the formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
  • the active ingredient may also be administered in the form of a bolus, electuary or paste.
  • Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier, or in the form of an enema.
  • Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.
  • Transdermal formulations may be in the form of a plaster.
  • Formulations suitable for intra-articular or ophthalmic administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension.
  • Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra-articular and ophthalmic administration.
  • Formulations suitable for topical or ophthalmic administration include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.
  • compositions may further contain other therapeutically active compounds usually applied in the treatment of the above mentioned pathological conditions.
  • the present invention further concerns a method for treating patients suffering from one of the above pathological conditions, said method consisting of administering to a patient in need of treatment an effective amount of one or more compounds of formula I, alone or in combination with one or more other therapeutically active compounds usually applied in the treatment of said pathological conditions.
  • the treatment with the present compounds and/or with further therapeutically active compounds may be simultaneous or with intervals.
  • Preferred pathological conditions to be treated with the present compounds are osteoporosis and related bone disorders including skeletal muscle weakness.
  • daily doses of from 0.001 -100 ⁇ g per kilogram body weight, preferably from 0.002-15 ⁇ g/kg of mammal body weight, for example 0.003-10 ⁇ g/kg of a compound of formula I are administered, typically corresponding to a daily dose for an adult human of from 0.2 to 750 ⁇ g.
  • topical treatment of dermatological disorders ointments, creams or lotions containing from 0.1 -2500 ⁇ g/g, and preferably from 0.1-500 ⁇ g/g, of a compound of formula I are administered.
  • drops or gels containing from 0.1-2500 ⁇ g/g, and preferably from 0.1 -500 ⁇ g/g, of a compound of formula I are administered.
  • the oral compositions are formulated, preferably as tablets, capsules, or drops, containing from 0.05-250 ⁇ g, preferably from 0.1-125 ⁇ g, of a compound of formula I, per dosage unit.
  • a tablet may be made by compressing or moulding the active ingredient optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier moistened with an inert liquid diluent.
  • the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
  • additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
  • Ether is diethyl ether, and was dried over sodium. THF was dried over sodium-benzophenone. Petroleum ether refers to the pentane fraction. If not specified, % means v/v%. Reactions were run at room temperature unless otherwise noted. The work-up procedure referred to involves dilution with the specified solvent (otherwise the organic reaction solvent), wash with water and then brine, drying over anhydrous MgS0 , and concentration in vacuo to give a residue. Chromatography was performed on silica gel.
  • the compound ii or III (ca. 0.3 mmol) was dissolved in ethyl acetate (0.6 mL) and acetonitrile (8 mL) was added under stirring. A solution of 5% hydrofluoric acid in acetonitrile/water 8:1 (4.0 mL) was added, and the mixture was stirred under argon at room temperature for 90 minutes. Excess 4 M aqueous NaOH was added, and the reaction mixture was worked up with ethyl acetate. The residue was purified by recrystallization from ethyl acetate to give compound (iii) or by chromatography (ethyl acetate as eluant) to give a compound of formula I.
  • Preparation 2 Compound 1 , S-Acetyl-3,3-dichloro-1-mercapto-4-methyl-4- (triethylsilyloxy)pentane. 35 To an ice-cold solution of 3,3-dichloro-2-methyl-5-hexen-2-ol (1.2 g) (cf. WO94/07851) in dichloromethane (10 mL) was added triethylsilyltrifluorosulfonate (1.6 mL) followed by 2,6-lutidine. After 2 h water was added and the mixture was worked up with dichloromethane.
  • Preparation 15 Compound 19 35
  • 13 C NMR: ⁇ 165.4, 148.2, 145.2, 140.0, 135.2, 134.4, 131.6, 128.4, 125.3, 124.6, 122.8, 118.1 , 111.0, 71.8, 67.3, 55.9, 55.5, 52.1 , 45.8, 45.5, 44.6, 40.3, 39.1 , 34.8, 28.6, 26.8, 25.7, 25.6, 23.2, 21.7, 18.8, 18.0, 17.9, 12.4, -4.9, -5.0, -5.3.
  • Example 2 1 (S),3(R)-Dihydroxy-20(R)-(3,3-dichloro-4-hydroxy-4-methyl)-1 -pentylsulphinylmethyl- 9,10-seco-pregna-5(Z),7(E),10(19)-triene, Compound 102 10
  • Method General Procedure 7. Starting material: Compound 101.
  • Example 4 1 (S),3(R)-Dihydroxy-20(R)-(2-chloro-5-((1 -hydroxy-1 -methyl)ethyl))phenylthiomethyl- 9,10-seco-pregna-5(Z),7(E),10(19)-triene, Compound 104 Method: General Procedure 10. 25 Starting material: Compound 18.
  • Example 6 1 (S),3(R)-Dihydroxy-20(R)-(2-chloro-4-((1 -hydroxy-1 -methyl)ethyl)-5- methoxy)phenylthiomethyl-9,10-seco-pregna-5(Z),7(E),10(19)-triene, compound 106 Method: General Procedure 10.
  • Example 7 1 (S),3(R)-Dihydroxy-20(R)-(2-chloro-4-((1 -hydroxy-1 -methyl)ethyl)-6- methyl)phenylthiomethyl-9,10-seco-pregna-5(Z),7(E),10(19)-triene, compound 107 10
  • Method General Procedure 10. Starting material: Compound 24.
  • Example 8 1 (S),3(R)-Dihydroxy-20(R)-(2,6-dichloro-4-((1 -hydroxy-1 - methyl)ethyl))phenylthiomethyl-9, 10-seco-pregna-5(Z),7(E), 10(19)-triene, Compound 108
  • Example 9 1 (S),3(R)-Dihydroxy-20(R)-(3-chloro-4-((1 -hydroxy-1 - methyl)ethyl))phenylsulphinylmethyl-9,10-seco-pregna-5(Z), 7(E), 10(19)-triene, Compound 109
  • Example 10 1 (S),3(R)-Dihydroxy-20(R)-(3-chloro-4-((1 -hydroxy-1 - methyl)ethyl))phenylsulphinylmethyl-9,10-seco-pregna-5(Z),7(E),10(19)-triene, Compound 110 (Stereoisomer with Compound 109) 30 Method: General Procedure 10. Starting material: Compound 29.
  • Example 11 1 (S),3(R)-Dihydroxy-20(R)-(3-chloro-4-((1 -hydroxy-1 - methyl)ethyl))phenylsulphonylmethyl-9,10-seco-pregna-5(Z),7(E),10(19)-triene, Compound 111 35
  • Method General Procedure 10. Starting material: Compound 27.
  • Compound 105 was dissolved in arachis oil to a final concentration of 1 ⁇ g Compound 105/ml oil. 40 10 Parts by weight of gelatine, 5 parts by weight glycerine, 0.08 parts by weight potassium sorbate, and 14 parts by weight distilled water were mixed together with heating and formed into soft gelatine capsules. These were then filled each with 100 ⁇ l of the Compound 105 in oil solution, such that each capsule contained 0.1 ⁇ g Compound 105.
  • 1 ml of solution contains 1 microgram of Compound 105 and 0.04 microgram of Compound 145 per drop.
  • the bottle is closed with a suitable screw cap made of polypropylene.
  • 1 ml of the preparation contains 2 microgram of Compound 105 to be divided into, e.g., 20 drops each corresponding to 0.1 microgram of Compound 105.
  • Example 14 Injection Fluid Containing Compound 105
  • Solutol® HS 15 is dissolved in the water for injection by heating it to a temperature of at the most 5 80°C. A cover of nitrogen is applied. The buffer substances and the sodium chloride are added and then the solution is cooled to at the most 30°C. Then sodium ascorbate is added and, finally, Compound 105 is dissolved in the solution obtained. The solution is subjected to sterile filtration and is autoclaved at an appropriate time-temperature condition.
  • Example 18 1 (S),3(R)-Dihydroxy-20(R)-( 4-((1 -hydroxy-1 -methyl)ethyl)-2- methoxy)phenylthiomethyl-9,10-seco-pregna-5(Z),7(E),10(19)-triene, Compound 115 Method: General Procedure 3. Starting materials: Compound (iii) and Compound 45.
  • Example 20 1 (S),3(R)-Dihydroxy-20(R)-( 4-((1 -hydroxy-1 -methyl)ethyl)-2- methyl)phenylthiomethyl-9,10-seco-pregna-5(Z),7(E),10(19)-triene, Compound 117
  • Example 21 1 (S),3(R)-Dihydroxy-20(R)-(2,6-dichloro-4-((1 -hydroxy-1 - methyl)ethyl))phenylthiomethyl-9,10-seco-pregna-5(Z),7(E),10(19)-triene, Compound 108

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  • Organic Chemistry (AREA)
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  • Orthopedic Medicine & Surgery (AREA)
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Abstract

La présente invention concerne des composés de formule (I) dans laquelle : R1 et R2, qui peuvent être identiques ou différents, représentent hydrogène ou un groupe résultant de l'élimination d'1 atome d'hydrogène à partir d'un hydrocarbure en C¿1?-C6 saturé ou non, linéaire, ramifié ou cyclique ; ou R?1 et R2¿ peuvent former ensemble avec l'atome de carbone auquel ils sont liés (marqué d'un astérisque dans la formule I), un noyau carbocyclique en C¿3?-C8 ; Q représente un groupe diradical résultant de l'élimination de 2 atomes d'hydrogène à partir d'un hydrocarbure en C1-C8 saturé ou non, linéaire, ramifié ou cyclique, substitué avec un ou plusieurs atomes de chlore ou de brome et/ou substitué avec un ou plusieurs groupes alkyle ou alkoxy ; R?1, R2 et/ou Q sont éventuellement substitués avec un ou plusieurs atomes de fluor; m vaut 0, 1 ou 2 et n vaut 0 ou 1.
PCT/DK2001/000070 2000-01-31 2001-01-31 Derives de vitamine d et leur utilisation dans le cadre du traitement de l'osteoporose et des troubles osseux associes WO2001056982A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005027930A1 (fr) * 2003-09-19 2005-03-31 Pfizer Products Inc. Derives de la 2-alkylidene-19-nor-vitamine d pour le traitement de l'osteosarcome
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
EP1769791A3 (fr) * 2001-07-19 2007-07-11 Isis Innovation Limited Strategies therapeutiques pour la prevention et le traitement de la maladie d'alzheimer
CN119185194A (zh) * 2024-09-29 2024-12-27 安徽益普克医药科技发展有限公司 维生素d3注射液药物组合物及其用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0078704A1 (fr) * 1981-11-02 1983-05-11 Research Institute For Medicine And Chemistry Inc. Intermédiaires dans la synthèse de dérivés de vitamine D
WO1991015475A1 (fr) * 1990-03-30 1991-10-17 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) Nouveaux analogues de la vitamine b
EP0567353A1 (fr) * 1992-04-24 1993-10-27 Wisconsin Alumni Research Foundation Utilisation d'1-alpha,25-dihydroxy-22(E)-déhydro-Vitamine 3D pour la fabrication d'un médicament pour le traitement de l'ostéoporose

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0078704A1 (fr) * 1981-11-02 1983-05-11 Research Institute For Medicine And Chemistry Inc. Intermédiaires dans la synthèse de dérivés de vitamine D
WO1991015475A1 (fr) * 1990-03-30 1991-10-17 Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) Nouveaux analogues de la vitamine b
EP0567353A1 (fr) * 1992-04-24 1993-10-27 Wisconsin Alumni Research Foundation Utilisation d'1-alpha,25-dihydroxy-22(E)-déhydro-Vitamine 3D pour la fabrication d'un médicament pour le traitement de l'ostéoporose

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1769791A3 (fr) * 2001-07-19 2007-07-11 Isis Innovation Limited Strategies therapeutiques pour la prevention et le traitement de la maladie d'alzheimer
US8343926B2 (en) 2001-07-19 2013-01-01 Isis Innovation Ltd. Therapeutic strategies for prevention and treatment of alzheimer's disease
US8921321B2 (en) 2001-07-19 2014-12-30 Isis Innovation Ltd. Therapeutic strategies for prevention and treatment of alzheimer's disease
WO2005027930A1 (fr) * 2003-09-19 2005-03-31 Pfizer Products Inc. Derives de la 2-alkylidene-19-nor-vitamine d pour le traitement de l'osteosarcome
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
CN119185194A (zh) * 2024-09-29 2024-12-27 安徽益普克医药科技发展有限公司 维生素d3注射液药物组合物及其用途

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