WO1989010352A1 - HOMOLOGUES DE 1alpha-HYDROXYVITAMINE D INSATURES A CHAINE LATERALE - Google Patents

HOMOLOGUES DE 1alpha-HYDROXYVITAMINE D INSATURES A CHAINE LATERALE Download PDF

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Publication number
WO1989010352A1
WO1989010352A1 PCT/US1989/001632 US8901632W WO8910352A1 WO 1989010352 A1 WO1989010352 A1 WO 1989010352A1 US 8901632 W US8901632 W US 8901632W WO 8910352 A1 WO8910352 A1 WO 8910352A1
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WO
WIPO (PCT)
Prior art keywords
compound
solution
hexane
compounds
activity
Prior art date
Application number
PCT/US1989/001632
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English (en)
Inventor
Hector F. Deluca
Heinrich K. Schnoes
Kato L. Perlman
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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
Application filed by Wisconsin Alumni Research Foundation filed Critical Wisconsin Alumni Research Foundation
Priority to KR1019890702480A priority Critical patent/KR940003360B1/ko
Priority to SU894742994A priority patent/RU2057117C1/ru
Priority to JP1505246A priority patent/JPH0699454B2/ja
Publication of WO1989010352A1 publication Critical patent/WO1989010352A1/fr
Priority to DK665989A priority patent/DK665989A/da

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom

Definitions

  • This invention relates to novel vitamin D compounds which are specifically active in inducing the differentiation of malignant cells to normal cells. More specifically, this invention relates to side chain unsaturated and side chain extended analogs of 1 ⁇ ,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ), which show selectivity of action as antineoplastic agents by virtue of increased activity in differentiating malignant cells and much reduced activity on calcium metabolism.
  • D vitamins vitamins D 3 or D 2
  • D 3 the dihydroxylated metabolite normally formed from vitamin D 3 in the animal or human
  • 1 ⁇ ,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3
  • the dihydroxylated metabolite normally formed from vitamin D 3 in the animal or human is the active species responsible for stimulating calcium transport in the intestine, and calcium resorption from bone (bone mobilization), thereby regulating the overall blood calcium level of the organism.
  • 1,25-(OH) 2 D 3 Certain structural analogs of 1,25-(OH) 2 D 3 , such as for example, 1 ⁇ -hydroxyvitamin D 3 , 1 ⁇ -hydroxyvitamin D 2 , 1 ⁇ ,25-dihydroxyvitamin D 2 , or fluoro-substituted derivatives of 1,25-(OH) 2 D 3 , are also known as highly active calcemic agents, and as a result 1,25-(OH) 2 D 3 and its active analogs have been used, or proposed, as pharmaceuticals in the propylaxis or treatment of various calcium metabolism and bone disorders, such as renal osteodystrophy, vitamin D-resistant rickets, or osteoporosis and related diseases.
  • 1,25-(OH) 2 D 3 in addition to its well-known 'calcemic action' discussed above, also expresses other biological functions.
  • 1,25-(OH) 2 D 3 and closely related analogs (1 ⁇ -OH-D 3 , 1,25-(OH) 2 D 2 , fluoro-substituted analogs, etc.) are capable of inducing cellular differentiation [Abe et al., Proc. Natl. Acad. Sci. USA 78, 4990 (1981); Honma et al., Proc. Natl. Acad. Sci USA 80, 201 (1983)].
  • 1,25-(OH) 2 D 3 and its analogs has been shown to inhibit the proliferation of malignant cells grown in culture (e.g. human leukemia cells) and induce their differentiation to normal macrophage-type cells. (These types of activities will henceforth be referred to collectively as the "differentiation activity" of vitamin D compounds.) Because of their remarkable potency as differentiation-inducing agents, these vitamin D derivatives are potentially useful for anticancer agents, and their use for the treatment of human leukemias has indeed been proposed (Suda et al., U.S. Patent No. 4,391,802).
  • 1,25-(OH) 2 D 3 or its fluorinated derivatives are exceedingly potent cell differentiation agents, but they also are the most potent compounds with respect to calcemic activity, and at the levels required in vivo for effective use as anticancer (e.g. antileukemic) agents, these same compounds can produce dangerously elevated blood calcium levels by virtue of their inherent calcemic activity.
  • Other known vitamin D derivatives show a similar correspondence between differentiation activity and calcemic activity, and their practical use as potential anticancer agents, therefore, is subject to the same limitations and hazard.
  • Vitamin D-related compounds have now been found which exhibit a desired and very advantageous activity pattern in terms of their differentiation vs. calcemic responses. These new vitamin analogs exhibit very pronounced activity in inhibiting the proliferation of malignant cells and inducing their differentiation to normal monocyte-type cells (similar to or greater than that of 1,25-(OH) 2 D 3 ), but they are much less active than 1,25-(OH) 2 D 3 , as far as their calcemic action is concerned.
  • these new compounds exhibit a dramatically improved differentiation/calcemic activity ratio, and by virtue of this characteristic, the compounds represent preferred agents for the treatment of neoplastic diseases.
  • these compounds can be administered without inducing excessively elevated blood calcium levels, thereby overcoming a major practical problem associated with high calcemic activity.
  • novel compounds are characterized structurally as side chain unsaturated homologs of 1,25-(OH) 2 D in which the side chain is elongated by insertion of two or three methylene units into the carbon chain. They may be represented, therefore, by the following general structure:
  • X, Y and X which may be the same or different, are selected from the group consisting of hydrogen and a hydroxy- protecting group and where n has the values 3 or 4.
  • 24-dihomo-1,25-dihydroxy-22-dehydrovitamin D 3 i.e. the compound shown above, where X, Y and Z are hydrogen and n equals 3
  • 24-trihomo-1,25-dihydroxy-22-dehydrovitamin D 3 i.e. the compound having the structure shown above, where X, Y and Z are hydrogen and n equals 4.
  • 3 ⁇ -Acetoxy-22,23,-bisnor-5-cholenic acid (1) was purchased from Steraloids (Wilton, NH) . All other chemicals were of the best quality from commercially available sources. Solvents were purified by standard methods.
  • TLC Thin-layer chromatography
  • High-performance liquid chromatography was performed using a Waters Associates liquid chromatograph equipped with a Model 6000A solvent delivery system, a Model 6 UK Universal injector and a Model 450 variable wavelength detector.
  • Zorbax-Sil (Phenomenex) columns (6.2 mm ⁇ 25 cm and 10 mm ⁇ 25 cm) were used.
  • Solvent systems A: 3% 2-propanol in hexane; B: 2% 2-propanol in hexane; C: 6% 2-propanol in hexane; D: 10% 2-propanol in hexane; E: 20% 2-propanol in hexane.
  • Silica gel Sep-Pak (Waters Associates) cartridges were used for the prefiltration of HPLC samples.
  • UV absorption spectra were recorded with a Hitachi Model 60-100 UV-Vis spectrophotometer.
  • Vitamin ester (5) (298 mg, 36%) was eluted using a mixture of
  • isomers (11) and (12) can also be effectively and advantageously separated by the maleic anhydride procedure described in U.S. Patent 4,554,106.
  • Diisobutylaluminumhydride (15 ⁇ L, 1.5 M solution toluene) was added with stirring to a solution of compound (11) (2 mg) in 0.5 mL of anhydrous toluene at -70oC under nitrogen. The mixture was stirred at -70oC for 10 min and 0.2 mL of methanol was slowly added to decompose the organometallic complex. The mixture was warmed up to room temperature and extracted with ethyl ether. The organic phase was washed with water and driedover anhydrous magnesium sulfate. Preparative HPLC, using a solvent system E afforded compound (13) and compound (14).
  • Lithium aluminum hydride (25 mg, 0.65 mmol) was added to a stirred solution of compound (16) (136.2 mg, 0.23 mmol) in anhydrous THF (5 mL) under argon at 0oC. The suspension was stirred for 15 min at 0oC and the excess of lithium aluminum hydride was decomposed by the dropwise addition of 10% water in THF. The suspension was diluted with 10 mL of THF and the stirring was continued for an additional 15 min at room temperature. The product was isolated by the standard extraction with ethyl acetate. Compound (17) was obtained as a colorless oil (118.4 mg) in 91% yield. IR (film) 3450, 2952,
  • the mixture was decomposed by the addition of 1 mL of saturated NH 4 Cl solution, warmed to 0oC, and extracted with ethyl acetate. The ethyl acetate was washed with water and brine, dried over anhydrous MgSO 4 , filtered and evaporated.
  • chloro-alcohol 28 was distilled in vacuo to give chloro-alcohol 28 as a colorless liquid (2.1 g, 70%).
  • Chloro-alcohol 28 (1.5 g, 10 mmol) in anhydrous dimethylformamide (5 mL) was then added to a stirred solution of thiophenol (1.32 g, 12 mmol) and potassium t-butoxide (1.32 g, 11.3 mmol) in anhydrous dimethylformamide (25 mL) .
  • the reaction mixture was stirred at room temperature overnight and the solution was partitioned between dichloromethane and water.
  • the organic layer was washed with aqueous sodium carbonate, water and dried over anhydrous magnesium, sulfate.
  • sulfone 30 (1.1 g, 97%) as a colorless liquid.
  • sulfone 30 (1.3 g, 5.1 mmol) and imidazole (1.5 g, 22.7 mmol) in dry dimethylformamide (50 mL)
  • triethylsilyl chloride (1.15 g, 7.7 mmol) was added.
  • the reaction mixture was kept at room temperature for 2 h and then diluted with dichloromethane. The mixture was washed with aqueous ammonium chloride solution and water.
  • Hexaethyldisiloxane was first eluted with hexane; 3% ethyl acetate in hexane eluted the sulfinate ester with some of the sulfone, and 10% ethyl acetate in hexane eluted the protected pure sulfone (35) (3,4 g, 60%). Anal, calcd.
  • mice Male weanling rats were obtained from the Harlan-Sprague Dawley Company of Madison, Wisconsin, and fed the low calcium, rachitogenic diet (0.02% Ca, 0.3% P) described by Suda et al. (J. Nutr. 100, 1049-1052, 1970). They were fed on this diet for a total of 4 weeks ad libitum. At the end of the third week the animals were divided into groups of 6 rats each. One group received a daily injection of vehicle (.1 mL of 95% propylene glycol, 5% ethanol) interperitoneally for 7 days.
  • vehicle 1.1 mL of 95% propylene glycol, 5% ethanol
  • the remaining groups received the same amount of vehicle over the same period of time but containing one of the following doses: 12.5 ng or 25 ng of 1,25-(OH) 2 D 3 or 125 ng of 24-dihomo-1 ⁇ ,25-dihydroxy-22-dehydrovitamin D 3 (compound 25).
  • the animals were killed 24 h after the last dose, the intestines removed, and the duodenal segments were used to measure intestinal calcium transport as described by Ealloran and DeLuca (Arch. Biochem. Biophys. 208, 477-486, 1981). Results are given in Table 2 below.
  • mice Male weanling rats were obtained from the Harlan Sprague Dawley Company and fed the low calcium (0.02% Ca, 0.3% P) vitamin D-deficient diet described by Suda et al. (J. Nutr. 100, 1049-1052, 1970) for a period of 4 weeks. At the end of the third week the animals were divided into groups of 6 animals each and received the indicated doses (see Table 3) dissolved in 0.1 mL 95% propylene glycol and 5% ethanol. The control group received the solvent vehicle only. The other groups received the indicated dosage of 1,25-(OH) 2 D 3 or the dihomo compound (25) each day for 7 days. Serum calcium was measured at the end of 7 days of dosing by atomic absorption. Results of two such experiments are given in Table 3 below. Table 3
  • the intestinal calcium transport assay represented by Table 2, for example, shows the known active metabolite, 1,25-(OH) 2 D 3 to elicit, as expected, very pronounced responses (compared to control) when administered at doses of 12.5 or 25 ng/day for 7 days.
  • the new dihomo analog is at least 10 times less active than 1,25-(OH) 2 D 3 .
  • the same type of activity pattern is observed for the trihomo compound 26 of this invention.
  • This substance also exhibits a highly favorable and dramatically enhanced differentiation/calcemic activity ratio, by virtue of showing pronounced activity in inducing HL-60 cell differentiation, while eliciting no significant response (compared to control) on serum calcium levels in rats.
  • This type of activity pattern is, of course, exactly what is uesired for a compound designed for use as a differentiation agent in the treatment of neoplastic diseases.
  • the desired activity the cellular differentiation of malignant cells, is highly pronounced, while the undesired activity, the calcemic action, is dramatically reduced, thus giving a very greatly enhanced differentiation/calcemic activity ratio.
  • Known 1 ⁇ -hydroxyvitamin D compounds have been shown to be effective therapeutic agents for the treatment of leukemic diseases (Suda et al., U.S. Patent 4,391,802).
  • the new side chain homo compounds of this invention when administered at the same dosage level as the prior art compounds, would exhibit none or less than one-tenth of the undesired calcemic activity of the prior art compounds, thereby largely eliminating the problem of producing excessively elevated blood calcium levels in the treated subjects. Furthermore, based on the results presented in Table 1, one can expect the new homo compounds to exhibit a very high differentiation activity against malignant cells, especially leukemic cells, thus further enhancing their therapeutic benefit. Hence, the new compounds of this invention represent an effective practical embodiment of the concept of differentiation therapy of malignant diseases, and their activity patterns clearly suggest that they would be preferred therapeutic agents for such treatment.
  • these compounds can be formulated as solutions in innocuous solvents, or as emulsions, suspensions or dispersions in suitable and innocuous solvents or carriers, or as pills, tablets or capsules by conventional methods known in the art.
  • Such formulations may also contain other pharmaceutically-acceptable and non-toxic excipients, such as stabilizers, anti-oxidants, binders, coloring agents or emulsifying or taste-modifying agents.
  • the compounds are advantageously administered by injection, or by intravenous infusion of suitable sterile solutions, or in the form of oral doses via the alimentary canal.
  • the homovitamin D compounds of this invention are administered to subjects in dosages sufficient to induce the differentiation of leukemic cells to macrophages.
  • Suitable dosage amounts are from 0.5 ⁇ g to 50 ⁇ g per day, it being understood that dosages can be adjusted (i.e. still further increased) according to the severity of the disease or the response or the condition of subject as well-understood in the art.

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

Abstract

Cette invention concerne de nouveaux composés apparentés à la vitamine D et caractérisés par des structures à chaîne latérale étendues insaturées. De tels composés présentent une activité plus intense pour arrêter la prolifération et promouvoir la différentiation de cellules malignes avec seulement une activité calcémique minime et constitue donc de nouveaux agents thérapeutiques applicables et utiles dans une thérapie de différentiation pour des maladies malignes. Les caractéristiques de l'activité de ces composés constitue la base d'un procédé de traitement de maladies néoplastiques, en particulier des maladies leucémoïdes.
PCT/US1989/001632 1988-04-29 1989-04-18 HOMOLOGUES DE 1alpha-HYDROXYVITAMINE D INSATURES A CHAINE LATERALE WO1989010352A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR1019890702480A KR940003360B1 (ko) 1988-04-29 1989-04-18 불포화 측쇄를 갖는 1α-히드록시비타민 D동족체
SU894742994A RU2057117C1 (ru) 1988-04-29 1989-04-18 ГОМОЛОГИ 1α - ГИДРОКСИВИТАМИНА D3 С НЕНАСЫЩЕННОЙ БОКОВОЙ ЦЕПЬЮ, КОМПОЗИЦИЯ, СПОСОБСТВУЮЩАЯ СТИМУЛЯЦИИ И УСИЛЕНИЮ ДИФФЕРЕНЦИАЦИИ ЗЛОКАЧЕСТВЕННЫХ КЛЕТОК ЛЕЙКЕМИИ ЧЕЛОВЕКА, СПОСОБ СТИМУЛЯЦИИ И УСИЛЕНИЯ ДИФФЕРЕНЦИАЦИИ ЗЛОКАЧЕСТВЕННЫХ КЛЕТОК ЛЕЙКЕМИИ ЧЕЛОВЕКА
JP1505246A JPH0699454B2 (ja) 1988-04-29 1989-04-18 １α―ヒドロキシビタミンＤ同族体
DK665989A DK665989A (da) 1988-04-29 1989-12-22 D-vitamin homologer

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US18767588A 1988-04-29 1988-04-29
US187,675 1988-04-29

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EP (1) EP0374219A1 (fr)
JP (1) JPH0699454B2 (fr)
KR (1) KR940003360B1 (fr)
AU (1) AU629831B2 (fr)
FR (1) FR2630739A1 (fr)
GB (1) GB2217716A (fr)
HU (1) HU206316B (fr)
IE (1) IE67953B1 (fr)
IL (1) IL90065A (fr)
IN (1) IN169818B (fr)
NL (1) NL8920392A (fr)
RU (1) RU2057117C1 (fr)
WO (1) WO1989010352A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991012239A1 (fr) * 1990-02-14 1991-08-22 Wisconsin Alumni Research Foundation DES COMPOSES DE VITAMINE D2 HOMOLOGUES ET LES DERIVES DE 1α-HYDROXYLES CORRESPONDANTS
WO1994000429A1 (fr) * 1992-06-30 1994-01-06 Schering Aktiengesellschaft Derives 22-en-25-oxa de la serie de la vitamine d, leur procede de production, preparations pharmaceutiques contenant ces derives et leur utilisation comme medicaments
US5414098A (en) * 1990-02-14 1995-05-09 Wisconsin Alumni Research Foundation Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives
WO1995012575A1 (fr) * 1993-11-03 1995-05-11 Wisconsin Alumni Research Foundation Composes de (e)-20(22)-deshydrovitamine d
EP0717034A1 (fr) * 1994-12-14 1996-06-19 Duphar International Research B.V Dérivés de vitamine D et procédé pour la préparation de ces composés
WO2009067578A2 (fr) * 2007-11-20 2009-05-28 Abbott Laboratories Nouveaux activateurs du récepteur de la vitamine d et procédés de fabrication

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5225579A (en) * 1988-03-16 1993-07-06 Hoxan Corporation Method of manufacturing vitamin D2, Vitamin D3, activated type vitamin D2, activated type vitamin D3, and their derivatives
US4927815A (en) * 1988-04-29 1990-05-22 Wisconsin Alumni Research Foundation Compounds effective in inducing cell differentiation and process for preparing same
JPH0325053A (ja) * 1989-06-23 1991-02-01 Takata Kk プリテンショナー装置
GB8914963D0 (en) * 1989-06-29 1989-08-23 Leo Pharm Prod Ltd Chemical compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986002078A1 (fr) * 1984-10-04 1986-04-10 Wisconsin Alumni Research Foundation Derives de vitamine d et leurs procedes de preparation
WO1986004333A1 (fr) * 1985-01-17 1986-07-31 Wisconsin Alumni Research Foundation Derives de vitamine d et leurs procedes de preparation

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0412110B1 (fr) * 1988-04-21 1993-07-07 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) Nouveaux analogues de vitamine d

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986002078A1 (fr) * 1984-10-04 1986-04-10 Wisconsin Alumni Research Foundation Derives de vitamine d et leurs procedes de preparation
WO1986004333A1 (fr) * 1985-01-17 1986-07-31 Wisconsin Alumni Research Foundation Derives de vitamine d et leurs procedes de preparation

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5532391A (en) * 1990-02-14 1996-07-02 Wisconsin Alumni Research Foundation Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives
US5414098A (en) * 1990-02-14 1995-05-09 Wisconsin Alumni Research Foundation Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives
US5750746A (en) * 1990-02-14 1998-05-12 Wisconsin Alumni Research Foundation Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives
WO1991012239A1 (fr) * 1990-02-14 1991-08-22 Wisconsin Alumni Research Foundation DES COMPOSES DE VITAMINE D2 HOMOLOGUES ET LES DERIVES DE 1α-HYDROXYLES CORRESPONDANTS
WO1994000429A1 (fr) * 1992-06-30 1994-01-06 Schering Aktiengesellschaft Derives 22-en-25-oxa de la serie de la vitamine d, leur procede de production, preparations pharmaceutiques contenant ces derives et leur utilisation comme medicaments
US5484782A (en) * 1993-11-03 1996-01-16 Wisconsin Alumni Research Foundation (E)-20(22)-dehydrovitamin D compounds
US5488044A (en) * 1993-11-03 1996-01-30 Wisconsin Alumni Research Foundation Method of treating metabolic bone disease with (E)-20(22)-dehydrovitamin D compounds
US5484781A (en) * 1993-11-03 1996-01-16 Wisconsin Alumni Research Foundation (E)-20(22)-dehydrovitamin D compounds
US5536828A (en) * 1993-11-03 1996-07-16 Wisconsin Alumni Research Foundation (E)-20 (22)-dehydrodiels-alder compounds
US5565589A (en) * 1993-11-03 1996-10-15 Wisconsin Alumni Research Foundation 17-formyl-5,6-trans-vitamin D compounds
WO1995012575A1 (fr) * 1993-11-03 1995-05-11 Wisconsin Alumni Research Foundation Composes de (e)-20(22)-deshydrovitamine d
EP0717034A1 (fr) * 1994-12-14 1996-06-19 Duphar International Research B.V Dérivés de vitamine D et procédé pour la préparation de ces composés
WO2009067578A2 (fr) * 2007-11-20 2009-05-28 Abbott Laboratories Nouveaux activateurs du récepteur de la vitamine d et procédés de fabrication
WO2009067578A3 (fr) * 2007-11-20 2009-11-26 Abbott Laboratories Nouveaux activateurs du récepteur de la vitamine d et procédés de fabrication
US8377913B2 (en) 2007-11-20 2013-02-19 Abbvie Inc. Vitamin D receptor activators and methods of making
RU2535448C2 (ru) * 2007-11-20 2014-12-10 Эббви Инк. Новые активаторы рецепторов витамина d и способы их получения
CN104211626A (zh) * 2007-11-20 2014-12-17 Abbvie公司 新型维生素d受体活化剂及制造方法
CN101918358B (zh) * 2007-11-20 2015-10-14 Abbvie公司 新型维生素d受体活化剂及制造方法

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Publication number Publication date
NL8920392A (nl) 1990-04-02
EP0374219A1 (fr) 1990-06-27
HU894747D0 (en) 1990-06-28
JPH02504149A (ja) 1990-11-29
IL90065A0 (en) 1989-12-15
GB2217716A (en) 1989-11-01
KR900700448A (ko) 1990-08-13
GB8909573D0 (en) 1989-06-14
IE67953B1 (en) 1996-05-15
IN169818B (fr) 1991-12-28
HUT52476A (en) 1990-07-28
JPH0699454B2 (ja) 1994-12-07
AU629831B2 (en) 1992-10-15
HU206316B (en) 1992-10-28
AU3553389A (en) 1989-11-24
KR940003360B1 (ko) 1994-04-21
FR2630739A1 (fr) 1989-11-03
IE891407L (en) 1989-10-29
RU2057117C1 (ru) 1996-03-27
IL90065A (en) 1996-05-14

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