WO1985003300A1 - 1alpha,25-DIHYDROXY-22Z-DEHYDROVITAMIN D COMPOUND - Google Patents

1alpha,25-DIHYDROXY-22Z-DEHYDROVITAMIN D COMPOUND Download PDF

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Publication number
WO1985003300A1
WO1985003300A1 PCT/US1985/000017 US8500017W WO8503300A1 WO 1985003300 A1 WO1985003300 A1 WO 1985003300A1 US 8500017 W US8500017 W US 8500017W WO 8503300 A1 WO8503300 A1 WO 8503300A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
vitamin
product
dehydrovitamin
mixture
Prior art date
Application number
PCT/US1985/000017
Other languages
English (en)
French (fr)
Inventor
Hector F. Deluca
Heinrich K. Schnoes
Rafal R. Sicinski
Yoko Tanaka
Original Assignee
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 NL8520009A priority Critical patent/NL8520009A/nl
Priority to DE19853590021 priority patent/DE3590021C2/de
Publication of WO1985003300A1 publication Critical patent/WO1985003300A1/en
Priority to DK437685A priority patent/DK437685A/da

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • 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 a biologically active vitamin D compound.
  • the invention relates to a novel 1 ⁇ ,25-dihydroxylated vitamin D compound with a 22,23-cis-double bond in the side chain, and to a method for its preparation.
  • Patents 3,741,996; 3,907,843; 3,880,894; 4,226,788; 4,358,406) Most of the known active analogs are characterized by the type of sterol side chain as it occurs in vitamin D 3 (i.e. saturated side chain).
  • Known analogs with 22,23-unsaturated side chain are represented by compounds of the vitamin D 2 series (i.e. 22,23-trans-unsaturated with a C-24-methyl substituent), and include, in addition to the compounds named above, 25-hydroxyvitamin D 2 (U.S. Patent 3,585,221) and the 24- and 24,25-dihydroxy derivatives (Jones et al. Acch. Biochem. Biophys.
  • This novel compound is characterized by a 22,23-double bond in the side chain having the cis (or Z) geometry. Because of the presence of this 22Z-double bond, which results in a quite different side chain geometry from that pertaining to compounds having the normal saturated side chain (e.g. as in 1 ⁇ ,25-dihydroxyvitamin D 3 ) or a 22,23-trans (22E)-unsaturated side chain (e.g. as in 1 ⁇ ,25-dihydraxyvitamin D 2 ) , it was assumed that this cis-unsaturated product would exhibit lew biological activity, if any. Surprisingly, this material, in spite of its altered side chain structure, shows high activity, being as active as 1 ⁇ ,25-dihydroxyvitamin D 3 in its ability to raise serum calcium levels in test animals.
  • novel product of this invention was prepared from a 22Z-dehydrovitamin D precursor having the structure II shown below, by in vitro enzymatic hydroxylation at carbon 25 using a liver homogenate preparation from vitamin D-deficient rats.
  • Incubation was carried out in 10 ml incubation medium in a 125 ml Erle ⁇ mayer flask containing an aliquot of liver homogenate representing 1 g of tissue, 0.125 M sucrose, 50 mM phosphate buffer (pH 7.4) , 22.4 mM glucose-6-phosphate, 20 m ATP, 160 mM nicotinamide, 25 mM succinate, 0.4 mM NADP, 5 mM MgCl 2 , 0.1 M KCl and 0.5 units glucose-6-phosphatedehydrogenase.
  • the reaction was initiated by addition of 400 ⁇ g of the substrate, compound II above, dissolved in 100 ⁇ l 95% ethanol.
  • the incubation mixture was incubated at 37°C with shaking at 80 oscillations/min for 3 h.
  • the reaction was stopped by addition of 20 ml methanol and 10 ml dichloromethane.
  • the organic phase was collected while the aqueous phase was re-extracted with 10 ml dichloromethane.
  • the organic phases from total of three extractions were combined and evaporated with a rotary evaporator.
  • the residue containing the desired product was dissolved in 1 ml of CHCl 3 :hexane (65:35) mixture and applied to a Sephadex LH-20 column (0.7 cm x 14 cm) packed, equilibrated and eluted with the same solvent.
  • the mass spectrum of the substance contains a molecular ion at m/e 414 as required for a 25-hydroxylated product. Elimination of one and two molecules of H 2 O gives fragment ions at m/e 396 and 378. Loss of the entire steroid side chain (cleavage of C 17 /C 20 bond) results in the fragment of m/e 287, which by elimination of one and two molecules of H 2 O, gives rise to the peaks at m/e 269 and 251. The spectrum shews prominent peaks at m/e 152 and 134 (152-H 2 O) which represent ring A fragments and are diagnostic for 1 ⁇ ,3 ⁇ -dihydroxyvitamin D compounds.
  • Serum obtained by centrifugation of the blood was diluted with
  • the compound of this invention will find application as a therapeutic agent in the therapy or prophylaxis of disorders such as the various types of rickets, hypoparathyroidism, osteodystrophy, osteomalacia or osteoporosis in the human, or for the treatment of related calcium deficiency diseases (e.g. milk fever, leg weakness, egg shell thinness) in animals.
  • disorders such as the various types of rickets, hypoparathyroidism, osteodystrophy, osteomalacia or osteoporosis in the human
  • related calcium deficiency diseases e.g. milk fever, leg weakness, egg shell thinness
  • the compound may be used for the treatment of certain malignancies, such as human leukemia.
  • the compound may be administered by any conventional route of administration and in any form suitable for the method of administration selected.
  • the compound may be formulated with any acceptable and innocuous pharmaceutical carrier, in the form of pills, tablets, gelatin capsules, or suppositories, or as solutions, emulsions, dispersions or suspensions in innocuous solvents or oils, and such formulations may contain also other therapeutically active and beneficial ingredients as may be appropriate for the specific applications.
  • the compound is advantageously administered in amounts from 0.25 to 10 ⁇ g per day, the specific dosage being adjusted in accordance with the disease to be treated and the medical history, condition and response of the subject, as is well understood by those skilled in the art.
  • the 22Z-dehydro precursor substrate, compound II above, required for the preparation of the novel product of this invention is itself prepared by the process depicted in Process Scheme I, appended, and described below.
  • compound designation by Arabic numerals e.g. (1) r (2) , (3) , etc.
  • the desired substrate (compound II) for the above described 25-hydroxylation reaction is identified by Arabic numeral (11) in Process Scheme I and in the following description.
  • Vitamin analog (5) is a known compound (Bogoslovskii et al. , supra) . 1-Hydroxylation of compound (5) . Freshly recrystallized p-toluenesulfonyl chloride (50 mg, 0.26 mmol) was added to a solution of vitamin (5) (50 mg, 0.13 mmol) in dry pyridine (300 ⁇ l) . After 30 h at 4°C, the reaction mixture was poured into ice/saturated NaHCO 3 with stirring.
  • the mixture was stirred for 15 min and extracted with benzene.
  • the organic extract was washed with saturated NaHCO 3 , saturated copper sulfate and water, dried (Na 2 SO 4 ) and concentrated in vacuo to obtain the oily tosylate (6) .
  • the crude tosylate (6) was treated with NaECO 3 (150 mg) in anhydrous methanol (10 ml) and the mixture was stirred for 8.5 h at 55°C. After cooling and concentration to 2 ml the mixture was diluted with benzene (80 ml) , washed with water, dried (Na 2 SO 4 ) and evaporated under reduced pressure.
  • the oily 3,5-cyclovitamin D compound (7) thus obtained was sufficiently pure to be used for the following oxidation step without any purification.
  • tert-butylhydroperoxide (16.5 ⁇ l, 0.118 mmol) was added.
  • dry pyridine 50 ⁇ l was added and the mixture was stirred for additional 25 min at room temperature, diluted with CH 2 Cl 2 (3 ml) and cooled to 0°C.
  • the crude 3,5-cyclovitamin product (7) in CH 2 Cl 2 (4.5 ml) was then added.
  • the reaction proceeded at 0°C for 15 min and then it was allowed to warm slowly (30 min) to room tarperature.
  • the mixture was transferred to a separatory funnel and shaken with 30 ml of 10% NaOH.
  • Ether 150 ml was added and the separate organic phase was washed with 10% NaOH, water and dried over Na 2 SO 4 .
  • HPLC high pressure liquid chromatography
  • a Waters Associates Model ALC/GPC 204 using a Zorbax-Sil (DuPont) (6.2mm x 25 cm column, flow rate 4 ml/min, 1500 psi).
  • Column chromatography was performed on Silica Gel 60, 70-230 mesh ASTM (Merck) .
  • Preparative thin-layer chromatography (TLC) was carried out on Silica 60 PF-254 (20 x 20 cm plates, 1 mm silica gel). Irradiations were carried out using a Hanovia 608A36 mercury arc lamp fitted with a Vycor filter. All reactions are preferably performed under an inert atmosphere (e.g. argon).
  • the compound of this invention can, if desired, be readily obtainedin crystalline form by crystallization from suitable solvents such as hexane, ethers and alcohols (absolute or aqueous) , and mixtures thereof as will be evident and well known to those skilled in the art.
  • suitable solvents such as hexane, ethers and alcohols (absolute or aqueous) , and mixtures thereof as will be evident and well known to those skilled in the art.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Nutrition Science (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
PCT/US1985/000017 1984-01-30 1985-01-07 1alpha,25-DIHYDROXY-22Z-DEHYDROVITAMIN D COMPOUND WO1985003300A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
NL8520009A NL8520009A (nl) 1984-01-30 1985-01-07 1alfa.25-dihydroxy-22z-dehydrovitamine d verbinding.
DE19853590021 DE3590021C2 (de) 1984-01-30 1985-01-07 1alpha-Hydroxyvitamin D-Derivat und dieses enthaltendes Arzneimittel
DK437685A DK437685A (da) 1984-01-30 1985-09-27 1alfa,25-dihydroxy-22z-dehydrovitamin d forbindelser

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US57511484A 1984-01-30 1984-01-30
US575,114 1984-01-30

Publications (1)

Publication Number Publication Date
WO1985003300A1 true WO1985003300A1 (en) 1985-08-01

Family

ID=24299012

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1985/000017 WO1985003300A1 (en) 1984-01-30 1985-01-07 1alpha,25-DIHYDROXY-22Z-DEHYDROVITAMIN D COMPOUND

Country Status (11)

Country Link
JP (1) JPS61501147A (enrdf_load_stackoverflow)
AU (1) AU587174B2 (enrdf_load_stackoverflow)
BE (1) BE901601A (enrdf_load_stackoverflow)
CH (1) CH665835A5 (enrdf_load_stackoverflow)
DE (2) DE3590021T (enrdf_load_stackoverflow)
DK (1) DK437685A (enrdf_load_stackoverflow)
FR (1) FR2558828B1 (enrdf_load_stackoverflow)
GB (1) GB2153358B (enrdf_load_stackoverflow)
IE (1) IE57936B1 (enrdf_load_stackoverflow)
NL (1) NL8520009A (enrdf_load_stackoverflow)
WO (1) WO1985003300A1 (enrdf_load_stackoverflow)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0387077A1 (en) * 1989-03-09 1990-09-12 Wisconsin Alumni Research Foundation 19-Nor vitamin D compounds
WO1990010620A1 (en) * 1989-03-09 1990-09-20 Wisconsin Alumni Research Foundation 19-nor-vitamin d compounds
US5342975A (en) * 1989-03-09 1994-08-30 Wisconsin Alumni Research Foundation 19-nor-vitamin D compounds

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3590020C2 (de) * 1984-01-30 1995-03-09 Wisconsin Alumni Res Found In der Seitenkette ungesättigte 1-Hydroxyvitamin D-Verbindungen
NL8520021A (nl) * 1984-03-05 1986-02-03 Wisconsin Alumni Res Found 1alpha-hydroxyvitamine d2 analoga en werkwijze voor het bereiden daarvan.
DE3687377T2 (de) * 1985-01-17 1993-04-29 Wisconsin Alumni Res Found Vitamin-d-abkoemmlinge und deren herstellungsverfahren.

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4260549A (en) * 1979-05-21 1981-04-07 Wisconsin Alumni Research Foundation Process for preparing 1α-hydroxylated compounds
US4284577A (en) * 1979-02-16 1981-08-18 Sachiko Yamada Novel vitamin D3 derivative and process for preparing the same
US4292249A (en) * 1979-02-15 1981-09-29 Teijin Limited 25-Hydroxy-24-oxocholestane derivatives and preparation thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4292249A (en) * 1979-02-15 1981-09-29 Teijin Limited 25-Hydroxy-24-oxocholestane derivatives and preparation thereof
US4284577A (en) * 1979-02-16 1981-08-18 Sachiko Yamada Novel vitamin D3 derivative and process for preparing the same
US4260549A (en) * 1979-05-21 1981-04-07 Wisconsin Alumni Research Foundation Process for preparing 1α-hydroxylated compounds

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0387077A1 (en) * 1989-03-09 1990-09-12 Wisconsin Alumni Research Foundation 19-Nor vitamin D compounds
WO1990010620A1 (en) * 1989-03-09 1990-09-20 Wisconsin Alumni Research Foundation 19-nor-vitamin d compounds
US5342975A (en) * 1989-03-09 1994-08-30 Wisconsin Alumni Research Foundation 19-nor-vitamin D compounds
US5561123A (en) * 1989-03-09 1996-10-01 Wisconsin Alumni Research Foundation Method of treating proliferative skin disorders with 19-nor-vitamin D compounds
US5587497A (en) * 1989-03-09 1996-12-24 Wisconsin Alumni Research Foundation 19-nor-vitamin D compounds
US5618805A (en) * 1989-03-09 1997-04-08 Wisconsin Alumni Research Foundation 19-nor-vitamin D compounds
US5633241A (en) * 1989-03-09 1997-05-27 Wisconsin Alumni Research Foundation 19-nor-vitamin D compounds
US5710294A (en) * 1989-03-09 1998-01-20 Wisconsin Alumni Research Foundation 19-nor vitamin D compounds

Also Published As

Publication number Publication date
DK437685D0 (da) 1985-09-27
CH665835A5 (de) 1988-06-15
IE850213L (en) 1985-07-30
FR2558828A1 (fr) 1985-08-02
DE3590021C2 (de) 1992-09-10
AU3837285A (en) 1985-08-09
NL8520009A (nl) 1985-12-02
JPS61501147A (ja) 1986-06-12
FR2558828B1 (fr) 1987-11-20
IE57936B1 (en) 1993-05-19
GB2153358B (en) 1987-07-22
GB8502161D0 (en) 1985-02-27
JPH0455425B2 (enrdf_load_stackoverflow) 1992-09-03
GB2153358A (en) 1985-08-21
DE3590021T (de) 1986-01-23
DK437685A (da) 1985-09-27
BE901601A (fr) 1985-05-17
AU587174B2 (en) 1989-08-10

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