EP0197949A1 - Vitamin d derivatives and methods for preparing same - Google Patents
Vitamin d derivatives and methods for preparing sameInfo
- Publication number
- EP0197949A1 EP0197949A1 EP85904336A EP85904336A EP0197949A1 EP 0197949 A1 EP0197949 A1 EP 0197949A1 EP 85904336 A EP85904336 A EP 85904336A EP 85904336 A EP85904336 A EP 85904336A EP 0197949 A1 EP0197949 A1 EP 0197949A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- vitamin
- gave
- ethyl acetate
- mmol
- derivatives
- 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.)
- Withdrawn
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
- C07J9/005—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 containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
-
- 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
-
- 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
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
-
- 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
Definitions
- This invention relates to novel vitamin D derivatives.
- this invention relates to 24-homovitamins.
- this invention relates to hydroxylated 24-hom ovitamins.
- Vitamin D is known to regulate calcium and phosphorous metabolism in animals and humans and it has now been firmly established that the biological efficacy of vitamin D depends upon its metabolic conversion, in vivo, to hydroxylated derivatives.
- vitamin D 3 is hydroxylated in vivo to 25-hydroxyvitamin D 3 in the liver which in turn is converted into 1 ⁇ ,25-dihydroxyvitamin D 3 in the kidneys. It is the latter compound which is now recognized as being the circulating hormonal form of vitamin D.
- vitamin D Because of their biological activity in promoting calcium and phosphorous transport in the intestine and the mobilization and mineralization of bone these forms of vitamin D are important pharmaceutical products which are eminently suitable for use in the treatment of various bone disorders.
- Vitamin D derivatives and their preparation and application are discussed in many references in the patent and other literature.
- U.S. Patent No. 3,565,924 is directed to 25-dihydroxycholecalciferol
- U.S. Patent No. 3,697,559 is directed to 1,25-dihydroxycholecalciferol
- U.S. Patent No. 3,741,996 is directed to 1 ⁇ -hydroxycholecalciferol
- U.S. Patent No. 3,786,062 is directed to 22-dehydro-25-hydroxycholecalciferol
- U.S. Patent No. 3,880,894 is directed to 1,25-dihydroxyergocalciferol
- New derivatives of vitamin D 3 have now been found which express excellent vitamin D-like activity and which, for that reason, could readily serve as a substitute for vitamin D 3 , as well as various of its derivatives, in known applications, such as, for example the treatment of various disease states manifesting calcium and phosphorous imbalance as hyp ⁇ parathyroidism, osteodystrcphy, osteomalacia and osteoporosis.
- These derivatives are 24-homovitamins and particularly 1 ⁇ ,25-dihydroxy-22E(orZ)-dehydro-24-homovitamin D 3 and 1 ⁇ ,25dihydroxy-24-homooitamin D 3 .
- R 1 , R 2 and R 3 are each selected from the group consisting of hydrogen, an acyl group having from 1 to about 4 carbon atcms, and benzoyl and R 4 and R 5 each represent hydrogen atoms or taken together form a carbon to carbon double bond.
- Bisnorcholenic acid acetate (a) was reduced with lithium aluminum hydride and subsequently oxidized with dichlorodicyanobenzoquinone to afford the 1,4,6-triene-3-one (b) in 47% yield.
- the 22-THP-ether of b was treated with alkaline hydrogen peroxide to give the 1 ⁇ ,2 ⁇ -epoxide (1) in 41% yield.
- Reduction of (1) with lithium and ammonium chloride in liquid a mm o nia-tetrahydrofuran at -78°, and subsequent treatment with chloromethyl methyl ether provided the dimethyoxyirethyl ether (2) in 38% yield.
- the 5,22-diene (9) was selectively hydrogenated to provide the 5-ene (10) in 92% yield.
- This compound was converted to 1 ⁇ ,25-dihydroxy-24-harovitamin D 3 (14) via the 5,7-diene (13) as described above in 12% overall yield.
- Lithium (5.00g) was added in small portion to liquid airmonia (200 ml) at -78° under argon atmosphere during 30 min. After stirring for 1 hr at -78°, 1 ⁇ ,2 ⁇ -epoxy-22-tetrapyranyloxy-23,24-dinorchola-4,6-diene-3-one (1) (2.00g, 4.69 mmol) in dry THF (150ml) was added dropwise at -78° during 30 min, and this mixture was stirred for 1 hr at -78°. To this reaction mixture, anhydrous NH 4 Cl (60 g) was added in small portion at -78° during 1 hr.
- the 22E stereo isomer, ccxrpound (6) can be readily converted to the 22Z stereo isomer by treatment with iodine.
- treatment of compound (6) in ether with a catalytic amount of iodine (2%) of the amount of (6) while under diffuse daylight for 1 hr. results in a trans to cis isomerization which, after HPLC purification, (Zorbax-Sil column, 4.6 x 25 cm, 6% 2-propanol/hexane) yielded the 22Z stereo isomer.
- the vitamin D 3 analogue (11) was determined as 100% by high performance liquid chromatography (a Shimadzu IC-3A; column, Zorbax ZIL normal phase, 4.6 mm i.d. x 15cm; solvent, MeOH-CH 2 Cl 2 , 1 : 49; flow rate, 3ml/min; retention time, 11.5 min).
- the vitamin D 3 analogue (11) had the following spectral data; U : 265 nm, : 228 nm, MS m/z: 428 (M + ), 410, 392 (base peak),
- the 5,7-diene (13) (5.8 mg, 0.0113 mmol) was converted, as described for (11), to the vitamin D 3 analogue (14) (890 ⁇ g, 19%).
- the retention time of (14) under the above-described HPLC condition was 11.0 min. : 265 nm, : 228 nm.
- the compounds of this invention can be readily obtained in crystalline form by crystallization from suitable solvents, e.g. hexane, ethers, alcohols, or mixtures thereof as will be apparent to those skilled in the art.
- suitable solvents e.g. hexane, ethers, alcohols, or mixtures thereof as will be apparent to those skilled in the art.
- Bone calcium mobilization activity was assayed by measuring the rise in serum calcium levels in response to the compound administered.
- Male, weanling rats (Holtzman Co., Madison, WI) were fed a lew-calcium, vitamin D deficient diet (Suda et al, J. Nutr. 1001049-1050, 1970) and water ad libitum for 3 weeks.
- the rats were then divided into three groups of 5-6 rats each and were given intrajugularly either 1,25-(OH) 2 D 3 or the test compound dissolved in 0.05ml of 95% ethanol. Rats in the control group were given 0.05ml ethanol vehicle in the same manner. Eighteen hours after the dose, the rats were killed and their blood was collected and centrifuged to obtain serum. Serum calcium concentrations were determined with an atomic absorption spectrometer Model 403 (Perkin-Elmer Co., Nbrwalk, Conn.) in presence of 0.1% lanthanum chloride.
- the compounds of this invention may be readily administered in sterile parenteral solutions by injection or intravenously or by alimentary canal in the form of oral dosages, or by suppository or even transcutaneously.
- Doses of from about 0.1 ⁇ g to about 2.5 ⁇ g per day are effective in obtaining the physiological calcium balance responses characteristic of vitamin D-like activity with maintenance dosage of from about 0.1 ⁇ g to about 0.5 ⁇ g being suitable.
- Dosage forms of the compounds can be prepared by combn ing them with a non-toxic pharmaceutically acceptable carrier as is well known in the art.
- Such carriers may be either solid or liquid such as, for example, corn starch, lactose, sucrose, peanut oil, olive oil, sesame oil and water.
- the dosage forms of the compounds of the invention 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 forms may also contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, etc. They may also contain other therapeutically valuable substances.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US65754984A | 1984-10-04 | 1984-10-04 | |
US657549 | 1984-10-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0197949A1 true EP0197949A1 (en) | 1986-10-22 |
Family
ID=24637652
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP85904336A Withdrawn EP0197949A1 (en) | 1984-10-04 | 1985-08-19 | Vitamin d derivatives and methods for preparing same |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0197949A1 (it) |
JP (3) | JPS62500301A (it) |
AU (2) | AU582789B2 (it) |
BE (1) | BE903376A (it) |
CH (1) | CH672920A5 (it) |
DE (2) | DE3590488C2 (it) |
DK (5) | DK154290C (it) |
FR (1) | FR2571369B1 (it) |
GB (2) | GB2167070B (it) |
IE (1) | IE58104B1 (it) |
IT (1) | IT1190401B (it) |
NL (1) | NL8520265A (it) |
WO (1) | WO1986002078A1 (it) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR0144358B1 (ko) * | 1988-04-21 | 1998-07-15 | 피. 라이달 크리스텐슨 | 비타민 d 동족체 |
EP0374219A1 (en) * | 1988-04-29 | 1990-06-27 | Wisconsin Alumni Research Foundation | SIDE CHAIN UNSATURATED 1$g(a)-HYDROXYVITAMIN D HOMOLOGS |
US4927815A (en) * | 1988-04-29 | 1990-05-22 | Wisconsin Alumni Research Foundation | Compounds effective in inducing cell differentiation and process for preparing same |
GB2229921B (en) * | 1989-04-05 | 1992-12-16 | Chugai Pharmaceutical Co Ltd | Treatment for hyperparathyroidism with use of vitamin d derivatives |
DE3933034A1 (de) * | 1989-10-02 | 1991-04-11 | Schering Ag | 24-homo-vitamin-d-derivate, verfahren zu ihrer herstellung |
US5030772A (en) * | 1990-02-14 | 1991-07-09 | Deluca Hector F | Process for preparing vitamin D2 compounds and the corresponding 1 α-hydroxylated derivatives |
US5260290A (en) * | 1990-02-14 | 1993-11-09 | Wisconsin Alumni Research Foundation | Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives |
US5891865A (en) * | 1996-10-04 | 1999-04-06 | Wisconsin Alumni Research Foundation | Treatment of arthritic disease induced by infectious agents |
WO2006051106A1 (en) | 2004-11-12 | 2006-05-18 | Bioxell Spa | Combined use of vitamin d derivatives and anti-proliferative agents for treating bladder cancer |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3833622A (en) * | 1969-03-17 | 1974-09-03 | Upjohn Co | Crystalline 25-hydroxycholecalciferol hydrate and structurally related compounds |
US3880894A (en) * | 1974-05-24 | 1975-04-29 | Wisconsin Alumni Res Found | 1,25-Dihydroxyergocalciferol |
AU527805B2 (en) * | 1978-07-27 | 1983-03-24 | Research Institute For Medicine And Chemistry Inc. | 1alpha, 1beta dihydroxy steroid-5-enes |
US4225596A (en) * | 1978-10-13 | 1980-09-30 | Wisconsin Alumni Research Foundation | Method for treating calcium imbalance and improving calcium absorption in mammals |
US4448721A (en) * | 1982-09-20 | 1984-05-15 | Wisconsin Alumni Research Foundation | Hydroxyvitamin D2 compounds and process for preparing same |
US4508651A (en) * | 1983-03-21 | 1985-04-02 | Hoffmann-La Roche Inc. | Synthesis of 1α,25-dihydroxyergocalciferol |
CH665834A5 (de) * | 1983-05-09 | 1988-06-15 | Wisconsin Alumni Res Found | Verfahren zur herstellung von 1alpha,25-dihydroxyliertem vitamin d(2) und verwandten verbindungen. |
-
1985
- 1985-08-19 WO PCT/US1985/001571 patent/WO1986002078A1/en active Application Filing
- 1985-08-19 DE DE3590488A patent/DE3590488C2/de not_active Expired - Lifetime
- 1985-08-19 EP EP85904336A patent/EP0197949A1/en not_active Withdrawn
- 1985-08-19 DE DE19853590488 patent/DE3590488T/de active Pending
- 1985-08-19 JP JP60503924A patent/JPS62500301A/ja active Granted
- 1985-08-19 AU AU47761/85A patent/AU582789B2/en not_active Ceased
- 1985-08-19 CH CH2351/86A patent/CH672920A5/de not_active IP Right Cessation
- 1985-08-19 NL NL8520265A patent/NL8520265A/nl unknown
- 1985-10-04 FR FR8514758A patent/FR2571369B1/fr not_active Expired
- 1985-10-04 GB GB08524479A patent/GB2167070B/en not_active Expired
- 1985-10-04 IE IE244385A patent/IE58104B1/en not_active IP Right Cessation
- 1985-10-04 BE BE0/215682A patent/BE903376A/fr not_active IP Right Cessation
- 1985-10-04 IT IT22359/85A patent/IT1190401B/it active
-
1986
- 1986-06-03 DK DK260086A patent/DK154290C/da active
-
1987
- 1987-04-23 GB GB08709579A patent/GB2188932B/en not_active Expired
-
1988
- 1988-03-02 DK DK111188A patent/DK159389C/da active
- 1988-12-29 AU AU27614/88A patent/AU605007B2/en not_active Ceased
-
1989
- 1989-04-13 DK DK177489A patent/DK158989C/da active
-
1990
- 1990-01-19 DK DK015390A patent/DK158991C/da active
- 1990-01-19 DK DK015290A patent/DK158990C/da active
-
1992
- 1992-05-19 JP JP4150044A patent/JPH0635475B2/ja not_active Expired - Lifetime
- 1992-05-19 JP JP4150045A patent/JPH0689022B2/ja not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
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See references of WO8602078A1 * |
Also Published As
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
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STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
Effective date: 19860905 |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: TANAKA, YOKO Inventor name: DELUCA, HECTOR, F. Inventor name: IKEKAWA, NOBUO |