WO1985003299A1 - Side-chain unsaturated 1-hydroxyvitamin d compounds - Google Patents

Side-chain unsaturated 1-hydroxyvitamin d compounds Download PDF

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Publication number
WO1985003299A1
WO1985003299A1 PCT/US1985/000016 US8500016W WO8503299A1 WO 1985003299 A1 WO1985003299 A1 WO 1985003299A1 US 8500016 W US8500016 W US 8500016W WO 8503299 A1 WO8503299 A1 WO 8503299A1
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WO
WIPO (PCT)
Prior art keywords
compounds
compound
hydroxy
vitamin
hydroxyvitamin
Prior art date
Application number
PCT/US1985/000016
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 NL8520003A priority Critical patent/NL8520003A/nl
Priority to DE3590020A priority patent/DE3590020C2/de
Publication of WO1985003299A1 publication Critical patent/WO1985003299A1/en
Priority to DK437585A priority patent/DK437585A/da

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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

  • the invention relates to biologically-active vitamin D compounds. More specifically, this invention relates to 1-hydroxyvitamin D compounds containing a 22,23-cis-double bond in the side chain.
  • Patent 3,697,559 already find use in medical practice. Interest in such compounds is continuing especially new that it has been recognized that in addition to their classical function as regulators of calcium homeostasis, 1 ⁇ ,25-dihyderoxyvitamin D 3 and its analog, 1 ⁇ -hydroxyvitamin D 3 , also affect cellular differentiation processes and are capable of inhibiting the growth and proliferation of certain malignant cells [Suda et al., U.S. Patent 4,391,802; Suda et al., Proc. Natl. Acad. Sci. USA 80, 201 (1983); Reitsma et al., Nature, Vol. 306, p. 492-494 (1983)].
  • vitamin D metabolites and analogs involve binding to an intracellular receptor protein at some stage of the overall process (see DeLuca et al., supra). High affinity for this receptor protein is thus a prerequisite for high potency, and desirable vitamin D analogs are those which compete effectively with the natural hormone, 1,25-(OH) 2 D 3 , for the receptor binding site.
  • Known side chain unsaturated vitamin D compounds include the hydroxy derivatives of vitamin D 2 , namely 25-hydroxy ⁇ vitamin D 2 (U.S. Patent 3,585,221), 1 ⁇ ,25-dihydroxyvitamin D 2
  • novel compounds of the present invention are characterized by the structures A and B shown below: where the hydroxy group (or protected hydroxy group) at carbon 1 may have the ⁇ - or ⁇ -stereochemical orientation, and where X 1 and X 2 represent hydrogen or a hydroxy-protecting group, e.g. acyl, alkylsilyl, methoxymetbyl or tetrahydropyranyl.
  • hydroxy-protecting groups are acyl (alkanoyl) groups of 1 to 6 carbons (e.g. formyl, acetyl, propionyl, butyryl, etc.) or aroyl groups, such as benzoyl, halo- or nitrobenzoyl, or carboxyalkanoyl groups of 2 to 6 carbons, such as oxalyl, malonyl, succinyl, glutaryl or adipyl.
  • acyl (alkanoyl) groups of 1 to 6 carbons e.g. formyl, acetyl, propionyl, butyryl, etc.
  • aroyl groups such as benzoyl, halo- or nitrobenzoyl
  • carboxyalkanoyl groups of 2 to 6 carbons such as oxalyl, malonyl, succinyl, glutaryl or adipyl.
  • the compounds of type A above having a 1 ⁇ -hydroxy group, because these compounds show unexpectedly high affinity for the receptor protein.
  • These compounds as 1-hydroxyvitamin D analogs, are related to the known 1-hydroxylated vitamin D compounds, but because of the presence of a 22Z-double bond, were expected to exhibit low, if any, affinity for the receptor since this 22,23-cis-double bond forces the side-chain into a quite different geometry than that assumed by the fully saturated side-chain as it occurs in 1 ⁇ -hydroxyvitamin D 3 or in the natural hormone, 1,25-(OH) 2 D 3 , both compounds of known high affinity for the receptor protein (DeLuca et al., supra).
  • the starting material for the synthetic process is the diene-protected aldehyde of structure (1) where R is a methoxymethyl group.
  • This starting material is prepared from ergosterol according to the method of Morris et al. (J. Org. Chem. 46, 3422 (1981)). Reaction of compound (1) with aWittig reagent, having the structure shown below,
  • product (2) featuring the desired 22Z-olefinic side chain.
  • product (2) is converted to compound (3) , which is subjected to reduction with a strong hydride reducing agent in an organic solvent to obtain the 5,7-diene sterol, compound
  • This product is then treated with selenium dioxide, and tert.-butylhydroperoxide in an organic solvent, to obtain as the major product the 1 ⁇ -hydroxycyclovitamin D analog of structure (8) , where R is a hydroxy group. It is notable that this allylic hydroxylation at carbon 1 proceeds without complications for a compound like intermediate (7) having the unusual cis-double bond in the side chain with two allylic positions.
  • the intermediate 1-hydroxycycl ⁇ vitamin D product is then solvolyzed in glacial acetic acid to obtain in admixture the 5,6-cis and 5,6-trans vitamin D corrpounds of structures (9) and (10) respectively, having a 3 ⁇ -acetoxy function.
  • These acetate derivatives (9) and (10) are then separated, and individually hydrolyzed in mild base to produce the desired free diol products, characterized by structures 11 and 12 where X 1 represents hydrogen.
  • the 1-hydroxylated cyclovitamin D product described above of which the 1 ⁇ -hydroxy-3,5-cyclo ⁇ vitamin D compound of structure (8) is the major component, also contains a small amount of the corresponding 1 ⁇ -hydroxy-3,5-cyclovitamin D epimer, i.e.
  • Acylated derivatives of the products of this invention are readily prepared by conventional methods.
  • mono-acylates of structures (9), (10) or (14) and (15) result directly from solvolysis; such monoacylates may be further acylated to the corresponding 1,3-diacylates, or desired acylates may be prepared by conventional acylation of the free diols of structures (11), (12) or (16) and (17).
  • the 1-hydrox cyclovitamin D intermediates of structure (8) or (13) can be acylated to the corresponding 1-O-acyl derivatives.
  • Subsequent solvolysis of such acyl derivatives in glacial acetic acid, or in an acidic aqueous medium e.g.
  • a noteworthy property of the novel compounds of this invention is their high potency as expressed by high binding affinity for the protein receptor. It was assumed that thechange in side chain geometry dictated by the presence of a 22,23-cis-double bond (22Z-double bond) would abolish binding affinity, or at least result in a marked decrease in binding affinity, since it is known (e.g. see DeLuca et al., Topics in Curr. Chem., supra) that even subtle changes in stereochemistry (e.g. the change from 24R-hydroxy to 24S-hydroxy) can result in pronounced differences in binding properties, and the compounds were indeed prepared for the purpose of confirming that assumption.
  • the compounds of this invention can be highly useful substitutes for the known metabolites in the therapy or prophylaxis of calcium disorders such as rickets, hypoparathyroidism, osteodystrophy, osteomalacia or osteoporosis in the human, or related calcium deficiency diseases (e.g. milk fever) in animals. likewise these compounds may be used for the treatment of certain malignancies, such as human leukamia. Particularly preferred for the above applications is the analog depicted by structure (11) in Process Scheme I, or the corresponding 5,6-trans compound of structure (12) or their acylated derivatives. Suitable mixtures of the above products may also be used in medical or veterinary applications, e.g. the combination of the products represented by structures (11) and (12).
  • the compounds may be administered by any conventional route of administration and in any form suitable far the method of administration selected.
  • the compounds may be formulated with any acceptable and innocuous pharmaceutical carrier, in the form of pills, tablets, gelatin capsules, or suppositories, or as solutions, amulsions, dispersions or suspensions in innocuous solvents or oils, and such formulation may contain also other therapeutically active and beneficial ingredients as may be appropriate for the specific applications.
  • the compounds are advantageously administered in amounts from about 0.5 to about 10 ⁇ g per day, the specific dosage being adjusted in accordance with the specific compound administered, 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 crude tosylate (6) was treated with NaHCO 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 2ml 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, 0.118mmol) was added.
  • This product is composed chiefly of the 1 ⁇ -hydroxy-cyclovitamin D compound of structure (8), as well as small amount of the corresponding 1 ⁇ -hydroxy-epimer (13). These components may be separated at this stage, if desired, but such separation is not required.
  • the 1-hydroxycyclovitamin product (18mg) as obtained above was heated (55°C/15 min) in glacial acetic acid (0.8 ml), the mixture was neutralized (ice/saturated NaHCO 3 ) and extracted with benzene and ether, to yield after HPLC (1.5% of 2-propanol in hexane as eluent) separation pure 3 ⁇ -acetoxy ⁇ vitamins (9) (6.60 mg, 34%, eluting at 42 ml), (10) (4.20 mg, 22%, eluting at 50 ml), and (14) (1.44 mg, 7%, eluting at 36 ml).
  • the compounds of this invention can be readily obtained by crystallization from suitable solvents such as ethers, hexane, alcohols, 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)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Nutrition Science (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
PCT/US1985/000016 1984-01-30 1985-01-07 Side-chain unsaturated 1-hydroxyvitamin d compounds WO1985003299A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
NL8520003A NL8520003A (nl) 1984-01-30 1985-01-07 1-hydroxyvitamine d verbindingen met onverzadigde zijketen.
DE3590020A DE3590020C2 (de) 1984-01-30 1985-01-07 In der Seitenkette ungesättigte 1-Hydroxyvitamin D-Verbindungen
DK437585A DK437585A (da) 1984-01-30 1985-09-27 Sidekaedeumaettede 1-hydroxyvitamin d forbindelser

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US57511684A 1984-01-30 1984-01-30
US575,116 1984-01-30

Publications (1)

Publication Number Publication Date
WO1985003299A1 true WO1985003299A1 (en) 1985-08-01

Family

ID=24299022

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1985/000016 WO1985003299A1 (en) 1984-01-30 1985-01-07 Side-chain unsaturated 1-hydroxyvitamin d compounds

Country Status (11)

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JP (1) JPS61501146A (enrdf_load_stackoverflow)
AU (1) AU589113B2 (enrdf_load_stackoverflow)
BE (1) BE901602A (enrdf_load_stackoverflow)
CH (1) CH667087A5 (enrdf_load_stackoverflow)
DE (2) DE3590020T1 (enrdf_load_stackoverflow)
DK (1) DK437585A (enrdf_load_stackoverflow)
FR (1) FR2558830B1 (enrdf_load_stackoverflow)
GB (1) GB2153359B (enrdf_load_stackoverflow)
IE (1) IE57947B1 (enrdf_load_stackoverflow)
NL (1) NL8520003A (enrdf_load_stackoverflow)
WO (1) WO1985003299A1 (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001960A1 (en) * 1993-07-09 1995-01-19 Laboratoire Theramex S.A. Novel structural analogues of vitamin d

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6421A (en) * 1987-02-27 1989-01-05 Teijin Ltd Preventive for osteoporosis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3907843A (en) * 1974-06-14 1975-09-23 Wisconsin Alumni Res Found 1{60 -Hydroxyergocalciferol and processes for preparing same
US4225596A (en) * 1978-10-13 1980-09-30 Wisconsin Alumni Research Foundation Method for treating calcium imbalance and improving calcium absorption in mammals

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3697559A (en) * 1971-02-25 1972-10-10 Wisconsin Alumni Res Found 1,25-dihydroxycholecalciferol
US3741996A (en) * 1971-12-02 1973-06-26 Wisconsin Alumni Res Found 1{60 -hydroxycholecalciferol
US4264513A (en) * 1979-05-21 1981-04-28 Wisconsin Alumni Research Foundation 1α-hydroxy-25-keto-27-nor-cholecalciferol and processes for preparing same
NL8320218A (nl) * 1982-07-26 1984-06-01 Wisconsin Alumni Res Found Nieuwe vitamine d analogen.
US4508651A (en) * 1983-03-21 1985-04-02 Hoffmann-La Roche Inc. Synthesis of 1α,25-dihydroxyergocalciferol
NL8520009A (nl) * 1984-01-30 1985-12-02 Wisconsin Alumni Res Found 1alfa.25-dihydroxy-22z-dehydrovitamine d verbinding.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3907843A (en) * 1974-06-14 1975-09-23 Wisconsin Alumni Res Found 1{60 -Hydroxyergocalciferol and processes for preparing same
US4225596A (en) * 1978-10-13 1980-09-30 Wisconsin Alumni Research Foundation Method for treating calcium imbalance and improving calcium absorption in mammals

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001960A1 (en) * 1993-07-09 1995-01-19 Laboratoire Theramex S.A. Novel structural analogues of vitamin d
US6017907A (en) * 1993-07-09 2000-01-25 Laboratoire Theramex S.A. Structural analogues of vitamin D
EP0972762A3 (en) * 1993-07-09 2000-02-23 Laboratoire Theramex Novel structural analogues of vitamin D
CN1103755C (zh) * 1993-07-09 2003-03-26 桑拉米克斯实验公司 维生素ｄ的新型结构类似物

Also Published As

Publication number Publication date
DE3590020C2 (de) 1995-03-09
CH667087A5 (de) 1988-09-15
DK437585D0 (da) 1985-09-27
FR2558830A1 (fr) 1985-08-02
AU589113B2 (en) 1989-10-05
JPH0455424B2 (enrdf_load_stackoverflow) 1992-09-03
IE850212L (en) 1985-07-30
AU3831785A (en) 1985-08-09
BE901602A (fr) 1985-05-17
JPS61501146A (ja) 1986-06-12
NL8520003A (nl) 1985-12-02
FR2558830B1 (fr) 1987-11-20
GB8502163D0 (en) 1985-02-27
DK437585A (da) 1985-09-27
DE3590020T1 (de) 1986-01-23
GB2153359B (en) 1987-08-12
IE57947B1 (en) 1993-05-19
GB2153359A (en) 1985-08-21

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