GB2188932A - Steroid precursors for 24-homo-vitamin d compounds - Google Patents
Steroid precursors for 24-homo-vitamin d compounds Download PDFInfo
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- 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
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- 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
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Description
GB 2 188 932 A 1
SPECIFICATION
Vitamin D derivatives, pharmaceutical compositions containing them and precursors thereof This invention relates to novel 24-homovitamin D derivatives. 5 Vitamin D is known to regulate calcium and phosphorus 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. Thus vitamin D3 is hydroxylated in vivo to 25-hydroxyvitamin D3 in the liver which in turn is converted into 1 (x,25-dihydroxyvitamin D3 in the kidneys. It is the latter compound which is now recognized as being the circulating hormonal form of vitamin D. 10 Because of their biological activity in promoting calcium and phosphorus 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.
New Derivatives of vitamin D3 have now been found which express excellent vitamin D-like activity and which, therefore, could readily serve as a substitute for vitamin D3 in known applications, such as the 15 treatment of various disease states manifesting calcium and phosphorus imbalance such as hypo pa rathyroid ism, osteodystrophy, osteomalacia and osteoporosis.
These derivatives are 24-homovitamins, particularly 'I o-,25-dihydroxy22E(orZ)-dehydro-24-homovitamin D3 and la,25-dinydroxy-24-homovitamin D3.
The compoundsof the present invention can be represented bytheformula: 20 k OR 3 25 30 30 oR R,0 where R,, R2 and R3 are each independently hydrogen, acyl having from 1 to 4 carbon atoms or benzoyl and R4 35 and R5 each represent hydrogen atoms or taken together form a carbon to carbon bond.
The compounds of this invention can be prepared in accordance with the following schematic and detailed description where like numbers identify like compounds.
2 GB 2 188 932 A 2 5 cwo 10 Z R=THP 20 R 25 R=.mom R= A.c 30 014 ACD 35 40 0H 45 50 55 3 GB 2 188 932 A 3 In accordance with the process of this invention:
Bisnorcholenic acid acetate (a) was reduced with lithium aluminum hydride and subsequently oxidized with clichloroclicyanobenzoqui none 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 la,2eL-epoxide (1) in 41 % yield. Reduction of (1) with lithium and ammonium chloride in liquid ammonia-tetrahydrofu ran at -780C, and subsequent treatment with 5 chloromethyl methyl ether provided the climethyoxymethyl ether (MOMO) (2) in 38% yield. Removal of the THP group, followed by Swern oxidation gave the aldehyde (4) in 81 % yield. This was reacted with vinyimagnesium bromide to provide the allylalcohol (5) in 94% yield. This alcohol was heated in refluxed xylene with triethyi orthoacetate and a catalytic amount of propionic acid, to afford the ester (6) in 93% yield.
Then, the ester (6) was reacted with methyimagnesium bromide to provide the alcohol (7) in 93% yield. 10 Removal of MOM group, followed by acylation. e.g. acetylation gave (221E)- 1 oL,3p-diacetoxy-25-hydroxy-24homo-cholesta-5,22-diene (9) in 73% yield.
Allylic bromination of (9) with N-bromosuccinimide. followed by treatment with tetra-n-butylammonium bromide and then with tetra-n-butylammonium fluoride gave the 5,7,22-triene (10) as a main product in 24% yield. The 5,7-diene (10) was irradiated with a medium pressure mercury lamp in benzene-ethanol for 5 min.15 subsequently refluxed for 1 hr, and then hydrolyzed to afford (22E)-1 eL, 25-dihydroxy-22-dehydro-24 homovitamin D3 (11) in 22% yield by analogous methods well known in the art other acylates or benzoates can be prepared which would be equally useful in the succeeding process steps.
The 5,22-diene (9) was selectively hydrogenated, e.g. using tetra nbutylammonium fluoride, to provide the 5-ene (12) in 92% yield. This compound was converted to la,25-dihydroxy- 24-homovitamin D3 (14) via the 20 5,7-cliene (13) as described above in 12% overall yield.
In the following detailed description melting points were determined with a hot-stage microscope and were uncorrected. 'H-NMR spectra were taken with a Hitachi R-24A (60 MHZ) in CDC13 with Me4Si as an internal standard, unless otherwise noted. Mass spectra were obtained with a Shimadzu QP-1000 mass spectrometer at 70 eV. UV spectra were obtained in ethanol solution with a Shimadzu UV- 200 double beam spectrophoto- 25 meter. Column Chromatography was effected using silica gel (E. Merck, Kieselgel 60 70-230 mesh).
Preparative thin layer chromatography was carried out on precoated plates of silica gel (E. Merck, Kieselgel 60 F254,0.25 mm thickness). The "usual work-up- refers to dilution with water. extraction with an organic solvent indicated in parenthesis, washing the extractto neutrality, drying over anhydrous magnesium sulphate, filtration, and removal of the solvent under reduced pressure. The following abbreviations are used; THP- 30 tetra hyd ropyra ny]; TI-IF-tetrahydrofuran; ether- diethyl ether, MeOH - methanol, MOM - methoxymethy].
Temperatures are in ' centigrade.
22-Hydroxy-23,24-dinorchola-1,4,6-triene-3-one (b) To a solution of 3p-acetoxydinorcholenic acid (a) (7.0 g, 18.04 mmole) in THF (20 mIL) lithium aluminum 35 hydride (3.0 gr 78.95 mmole) was added. This mixture was stirred at WC for 14 h. To this reacion mixture water and ethyl acetate were carefully added. Filtration and removal of the solvent gave the residue (5.2 g).
This in dioxane (140 mL) was treated with dichlorodicyanobenzoquinone (11. 7 g, 51.54 mmole) under reflux for 14 h. After cooling to room temperature the reaction mixture was filtered and the filtrate was evaporated to leave the residue, which was applied to a column of alumina (200 g). Elution with dichloromethane provided 40 ) UVXt1H the trienone (b) (2.8 g, 47%) mp 156-157' (ether nax n m (E): 299 (13000), 252 (9200), 224 (12000)rl WN M R (C13CIA: 0.80 (3H, s, 18-1-130.04 (3H, cl, J=6 Hz, 21-H3),1.21 (3H, s, 191-13), 3.10-3.80 (3H, m, 22-H2 and OH), 5.90-6.40 (4H, m, 2-H, 4-H,6-H, and 7-H), 7.05 (1 H, cl J=10 Hz, 1-H), MS mIz: 326 (M'), 311,308,293,267,112.
la,2a-Epoxy-22-tetrahydropyranyloxy-23,24-dinorchola-4,6-dien-3-one (1) 45 The alcohol (b) (2.7 g, 8.28 mmole) in dichloromethane (50 mO was treated with dihydropyrane (1.5 mL, 16.42 mmole) and p-toluenesulfonic acid (50 mg) at room temperature for 1 h. The usual work-up (ethyl acetate for extraction) gave a crude product. To a solution of this product in MeOH (70 mL), 30% H202 (4.8 mL) and 10% NaOH/Me01-1 (0.74 mL) were added and this mixture was stirred at room temperature for 14 h. The usual work-up (ethyl acetate for extraction) gave a crude product, which was applied to a column of silica gel 50 (50 g). Elution with benzene-ethyl acetate (100: 1) provided the epoxide (1) (1.45 g, 41 %): mp 113-115'(hexane UVktcH -NIVIR (C1DC13)3: 0.80 (3H, s, 18-H30.07 (3H, cl, J=6 Hz, 21-1-13), , ax rim (E): 290 (22000), 'H 1. 18 (3H, s, 19-H,), 3.38 (1 H, dd, J=4 and 1.5 Hz, 1-H), 3.55 (1 Hr cl, J= Hz, 2H), 3. 30-4.10 (4H, m, 22-1-12 and THP), 4.50 (1H, m, THP), 5.58 (1 H, cl, J=1.5 Hz, 4-H), 6.02 (2H, s, 6-H and 7-H), MS mIz: 342 (M'-DHP), 324 (M'-THPOH), 309, 283,85. 55 la,3f3-Dimethoxymethoxy-23,24-dinorchol-5-en-22-tetrahydropyrany1 ether (2) Lithium (5.00 g) was added in small portion to liquid ammonia (200 m]) at -780 under argon atmosphere during 30 min. After stirring for 1 hr at -780, lu-,2(x-epoxy-22- tetrapyranyloxy-23,24-dinorchola-4,6-diene-3- one (1) (2.00 g 4.69 m mol) in dryTHF (150 m]) was added dropwise at 78'during 30 min, and this mixture 60 was stirred for 1 hr at -78'. To this reaction mixture, anhydrous NH4C1 (60 9) was added in small portion at -78' during 1 hr. After 1.5 hr the cooling bath was removed and most of the ammonia was removed by bubbling argon. The usual work-up (ether was used as a solvent) gave a crude product. This was treated with chloro-methyl methyl ether (2.0 m], 26.34 m mol) and N.Ndiethylcyclohexylarnine (4.6 mi, 24.93 m mol) in dioxane (20 mi) at45'for 24 hr. The usual work-up (ethyl acetate) gave a crude product, which was applied to a 65 4 GB 2 188 932 A 4 column of silica gel (40 g). Elution with hexane-ethyl acetate (5: 1) provided the dimethoxymethyl ether (2) (922 mg, 38%) as an oil. 'H-NMR 8 0.70 (3H, s, 18-H30.02 (311, s, 19-1-130.04 (3H, d, J=6 Hz, 21 -H3), 3.34 (3H, s, 5.50 (1 H, m, 6-H).
5 la,30-Dimethoxymetho)cy-23,24-dinorchol-5-en-22-of (3) The THP ether (2) (922 mg, 1.77 mmol) in THF (8 mi) and MeOH (8 m]) was treated with 2M HCI (1 mi) at room temperature for 2 hr. The usual work-up (ethyl acetate) gave a crude product, which was applied to a column of silica gel (40 g). Eution with hexane-ethyl acetate (2: 1) gave the alcohol (3) (678 mg, 88%) as an amorphous solid. 'WNMR 8 0.70 (3H, s, 18-H3),1.02(3H,s,19-H3),1.04 (3H, d, J=6 Hz, 21-H3),3.34 (3H, s, 10 -O-CHA3.38 (3H, s, -0-CH3),4.65 (2H, ABq, J=7 Hz, AA13=1 1 Hz, let-O-CH2- 0-),4.66 (2H,s,3p-O-CH2-0-),5.53 (1 H^6-H), la,3p-Dimethoxymethoxy-23,24-dinochol-5-en-22-al (4) To a solution of oxalyl chloride (0.27 mi, 3.09 mmol) in dichloromethane (8 mi) dimethyl sulphoxide (0.44 15 m], 6.21 mmol) was added at -780C under argon. The mixture was stirred at -78'for 10 min. To the solution the alcohol (3) (660 mg, 1.51 mmol) in dichloromethane (5 mi) was added at -78'C. After stirring for 15 min, triethylamine (1.89 mi, 13.6 mmol) was added. The mixture was stirred at - 78'C under argon for 5 min, and warmed up to room temperature. The usual work-up (ether) gave a crude product, which was applied to a column of silica gel (30 g). Elution with hexane-ethyl acetate (4: 1) gave the aldehyde (4) (607 mg, 92%) as a 20 crystal. mp 71-72'C (hexane), 'H-NMR 8 0.74 (3H, s, 18-1-130.04 (3H, s, 19-1-130.12 (3H, d' J=6 Hz, 21-H3),3.35 (3H,s,-0-CH3),3.39(3H,s,-0-CH3),3.7(1H,m,lp-H),4.65(2H,ABq,J=7Hz,AAB=11 Hz,1OL-O-CH2-0-),4.66 (2H, s, 3p-O-CH-O-), 5.52 (1 H, m, 6-H), and 9.61 (1 H, d, J=-3 Hz, -CHO), Anal. Calcd for C26H4205: C, 71:85; H, 9.74. Found: C, 71.71; H, 9.68.
25 la,3j3-Dimethoxymethoxychola5,23-dien-22-ol (5) To magnesium (70 mg, 2.92 mmol) in THF (3 m]) 50% solution of vinyl bromide in THF (0.42 mi, 2.98 mmol) was added. The mixture was stirred at room temperature under argon for 30 min. To the resulting Grignard reagent the aldehyde (4) (595 mg, 1.37 mmol) in THF (6 mi) was added at room temperature. The mixture was stirred at room temperature for 1 hr. The usual work-up (ether) gave a crude product, which was applied to a 30 column of silica gel (30 g). Elution with hexane-ethyl acetate Q: 1) gave the allylic alcohol (5) (595 mg, 94%) as an amorphous solid. 'H-NMR 8: 0.70 (3H, s, 18-H3),1.02 (3H, s, 19-H3),3. 35 (3H, s, -0-CHA3.38 (3H, s, -0-CH3), 3.69 (1 H, m, 1PM), 4.20 (1H, m, 22-H), 4.64 (2H, ABq, J=7 Hz, AA13=1 1 Hz 1(X-O-CH2-0-),4.65 (2H, s, 3p-O-CH,-0-), 5.52 (1 H, m, 6-H), 4.90-6.0 (3H, m, 23-H and 24-1-12).
35 (22E)-1a,3,8-Dimethoxymethoxy-27-norcholesta-5,22-dien-26-oic acid ethyl ester (6) A solution of the ailylic alcohol (5) (590 mg, 1.28 mmol), triethyl orthoacetate (1.0 mi, 5.46 mmol), propionic acid (4 drops), and xylene (8 mi) was refluxed under argon for 2 hr. Removal of the solvent under reduced pressure gave the residue, which was applied to a column of silica gel (30 g). Elution with hexane-ethyl acetate (4:1) gave the ester (6) (630 mg, 93%) as an oil. 'H-NMR 8: 0.68 (3H, s, 18-HA0.97 (3H, d, J=6 Hz, 21-1-130.03 40 (3H, s, 19-1-130.24 (3H, t, J=7 Hz, -C02CH2CH3),3.35 (3H, s, -0-CHA3.39 (3H, s, -0-CH3L3.70 (1 H, m, 1 P-H), 4.11 (2H, q, J=7 Hz, -C02CH2CH3),4.64 (2H, ABq, J=7 Hz, AA13=1 1 Hz, la-0- CH2-0-),4.65 (2H, s, 3p-O-CH2-0-), 5.29 (2H, m, 22-H and 23-H), 5.52 (1 H, m, 6-H).
If desired the 22E stereo isomer, compound (6), can be readily converted to the 22Z stereo isomer by treatment with iodine. Thus, treatment of compound (6) in ether with a catalytic amount of iodine (2%) of the 45 amount of (6) while under diffuse daylight for 1 hr. results in a transto cis isomerization which, after HPLC purification, (Zorbax-Sil column, 4.6x25 em, 6% 2-propanollhexane) yielded the 22Z stereo isomer.
(22E)1a,3p-Dimethoxymethoxy-24-homo-cholesta-5,22-diene-25-of (7) To a solution of the ester (6) (605 mg, 1.14 mmol) in THF (6 mi) 1 M solution of methyimagnesium bromide in 50 THF (4.5 m], 4.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 hr.
The usual work-up (ether) gave a crude product, which was applied to a column of silica gel (30 g). Elution with hexane-ethyl acetate (3:1) gave the alcohol (7) (548 mg, 93%) as an oil. 'H-NMR 8: 0.68 (3H, s, 18-H3),0.97 (3H, d, J =6 Hz, 21 -1-130.01 (3H, s, 19-1-130.21 (6H, s, 26-1-13 and 27-1-13), 3.33 (3H, s, -0-CH3), 3.38 (3H, s, -0-CH3), 3.70 (1 H, m, 1 P-H), 4.64 (2H, ABq, J =7 Hz, AA13= 11 Hz, 1 (x-0-CH2-0-), 4. 65 (2H, s, 3p-O-CH2-0-), 5.29 (2H, m, 22-H 55 and 23-H), and 5.50 (1 H, m, 6-H).
(22E)-24-Homocholesta-5,22-diene- la,313,25-triol (8) A solution of the dimethoxymethyl ether (7) (540 mg, 1.04 mmol) in THF (15 m]) was treated with 6M HCl (3 mi) at 5M for 2.5 h. The usual work-up (ethyl acetate) gave a crude product, which was applied to a column of 60 silica gel (20 g). Elution with hexane-ethyl acetate (1: 1) gave the trio[ (8) (428 mg, 95%) as a crystal. mp 164-16M (hexane-ethyl acetate), 1 H-NMR 8: 0.68 (3H, s, 18-1-13), 0.95 (3H, s, J=6 Hz, 21 -1-130.00 (3H, s, 19-H3), 1.20 (6H, s, 26-1-13 and 27-H3),3.80 (1 H, m, 1 P-H), 3.92 (1 H, m, 3u-- H), 5.30 (2H, m, 22-H and 23-H), and 5.53 (1 H, m, 6-H).
GB 2 188 932 A 5 (22E)-1a,3p-Diacetoxy-25-hydroxy-24-homocholesta-5,22-diene (9) A solution of the triol (8) (395 mg, 0.919 mmol) in pyridine (2 mi) was treated with acetic anhydride (1 m]) at room temperature for 16 h. The usual work-up (ethyl acetate) gave a crude product, which was applied to a column of silica gel (20 g). Elution with hexane-ethyl acetate (2: 1) gave the diacetate (9) (361 mg, 77%) as an oil. 1 H-NMR 8: 0.67 (3H, s, 18-H3),0.97 (3H, cl, J=6 Hz, 21-1-130.07 (3H, s, 19-1-130.21 (6H, s, 26-H3 and 27-1-13), 5 2.01 (3H, s, acetyl), 2.04 (3H, s, acetyl), 4.98 (1 H, m, 3ot-H), 5.05 (1 H, m, 1 P-H), 5.31 (2H, m, 22-H and 23-H), and 5.52 (1 H, m, 6-H).
(22E)-1a,3p-Diacetoxy-25-hydroxy-24-homocholesta-5,7,22-triene (10) A solution of the 5-ene (9) (51 mg, 0.0992 mmol) and N-bromo-succinimide (21 mg, 0.118 mmol) in 10 ca rbontetrach 1 o ride (3 mi) was refluxed under argon for 20 min. After the mixture had been cooled to O'C, the resulting precipitate was filtered off. The filtrate was concentrated below 4WC to leave the residue. This in THF (5 mi) was treated with a catalytic amount of tetra- n-butylammonium bromide at room temperature for 50 min. Then, the mixture was treated with a solution of tetra-n-butylammonium fluoride in THF (3.5 m], 3.5 mmol) at room temperature for 30 min. The usual work-up (ethyl acetate) gave a crude product, which was 15 submitted to preparative thin layer chromatography (hexane-ethyl acetate, 4: 1, developed five times). The band of Rf value 0.48 was scraped off and eluted with ethyl acetate. Removal of the solvent provided the 5,7- cliene (10) 12.5 mg, 24%), UW%0a.H: 293,282, and 271.
la,25-Dihydroxy-22E-dehydro-24-homovitamin D3 (11) 20 A solution of the 5,7-cliene (10) (7.3 mg, 0.0143 mmol) in benzene (90 mi) and ethanol (40 mi) was irradiated with with a medium pressure mercury lamp through a Vycol filter to O'C under argon for 5 min. The reaction mixture was refluxed under argon for 1 h. Removal of the solvent under reduced pressure gave a crude product, which was submitted to preparative thin layer chromatography (hexane-ethyl acetate, 4: 1, developed five times). The band of Rf value 0.38 was scraped off and eluted with ethyl acetate. Removal of the solvent 25 gave the vitamin D3 diacetate (1.8 mg, 25%). The band of Rf value 0.43 was scraped off and eluted with ethyl acetate. Removal of the solvent recovered the 5,7-diene (10) (2.1 mg, 29%).
The vitamin D3 diacetate (1.8 mg, 2.15 limol) in THF (4 m]) was treated with 5% KOH/MeOH (1 m]) at room temperature for 20 min. The usual work-up (ethyl acetate) gave a crude product, which was submitted to preparative thin layer chromatography (hexane-ethyl acetate, 1:2, developed three times). The band of Rf 30 value 0.43 was scraped off and eluted with ethyl acetate. Removal of the solvent gave the vitamin D3 analogue (11) (1.4 mg, 90%). The purity of the product (11) was determined as 100% by high performance liquid chromatography (a Shimadzu LC-3A; column, Zorbax ZIL normal phase, 4.6 mm i,d,x 15 cm; solvent, Me01-1-CH2C12,1:49; flow rate, 3 milmin; retention time, 11.5 min). The vitamin D3 analogue (11) had the following spectral data UV4W,,H: 265 nm, ktn9,nH: 228 nm, Ms mlz: 428 W), 410,392 (base peak), 374,287, 269, 35 251,152,134,123,59, 'H-NMR (360 MHz) 5: 0.55 (3H, s, 18-1-130.02 (3H, d, J=6.6 Hz, 21-H3),1.22 (6H, s, 26-1-13 and 27-H3),2.32 (1 H, dd, J=13.2 and 6.7 Hz), 2.60 (1 H, dd, J=13.0 and 3. 0 Hz), 2.83 (1 H, dd, J=12.0 and 3.0 Hz), 4.23 (1 H, M, W1/2)=18.4 Hz, 3et-H), 4.43 (1 H, rn, W112=16.9 Hz, lp-H), 5.00 (1 H, bs, W112=3.2 Hz, 19-H), 5.30 (1 H, dd, J=15.0 and 7.1 Hz, 22-H or 23-H), 5.33 (1 H, bs, W112=3.2 Hz, 19-H), 5.37 (1H, dd, J=15.0 and 5.8 Hz, 22-H or 23-H), 6.01 (1 H, cl, J=1 1.0 Hz, 7-H), 6.32 (1 H, d, J=1 1.0 Hz, 6-H). 40 la,3p-Diacetoxy-24-homocholest-5-en-25-o1 (12) A mixture of the 5,22-dienne (9) (40 mg, 0.0778 mmol) and 10% Pd-C (4 mg) in ethyl acetate (2 m]) was stirred at room temperature under hydrogen for 3 h. The Pcl catalyst was filtered off and the filtrate was concentrated to leave the residue, which was applied to a column of silica gel (5 g). Eution with hexane-ethyl 45 acetate (4: 1) gave the 5- ene (12) (37 mg, 92%) as an oil. 'H-NMR 8: 0.66 (3H, s, 18-1-130.08 (3H, s, 19-1-130.20 (6H, s, 26-1-13 and 27-1-13), 2.02 (3H, s, acetyl), 2.05 (3H, s, acetyl), 4.97 (1 H, m, 3u--H), 5.07 (1 H, m, 1 P-H), 5.53 (1 H, m, 6-H).
4 50 la,3p-Diacetoxy-24-homocholesta-5,7-dien-25-of (13) 50 The 5-ene (12) (19 mg, 0.037 mmol) was converted, as described for (10), to the 5,7-diene (13) (5.8 mg, 31 %).
UV4'0,H: 293,282,271 NM la,25-Dihydroxy24-homovitamin D3 (14) The 5,7-cliene (13) (5.8 mg, 0.0113 mmol) was converted, as described for (11), to the vitamin D3 analogue 55 (14) (890 [Lg, 19M. The retention time of (14) under the above -described HPLC condition was 11.0 min.
UV4'0;,H: 265 nm, C9inH: 228 nm. MS m/z 430 (M'), 412,394 (base peak, 376, 287,269,251,152,134,59.
If desired, 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. 60 Also if desired the compounds may be acylated according to the standard methods to yield the corresponding partially or completely hydroxy-protected products where each of R,, R2 and R3 is hydrogen or acyl. For example, treatment of the trihydroxy product with acetic anhydride at room temperature in pyridine yields the 1,3-diacetyl compound whereas at elevated temperatures (75'- 100'C) the 1,3,25-triacetyl compound is obtained. By analogous methods fully or partially hydroxy-protected derivatives, i.e. derivatives with other 65 6 GB2188932A 6 acyl groups such as benzoyl, can be obtained. A partially acylated derivative, e.g. 1,3-diacyl may also be further acylated, e.g. at C-25, by a different acyl group to obtain derivatives carrying mixed hydroxy-protecting functions. Selected removal of protecting groups can also readily be accomplished by selective hydrolysis (e.g. 10% KOH/MeOH at room temperature) of a 1,3,25-tri-0-acyi derivatives, to yield 1,3-dihydroxy-25-0-acyl compound. Different protecting groups can then be introduced at the free hydroxy-positions and it is thus 5 obvious that a combination of selective protection/deprotection steps will yield derivatives with any desired combination of hydroxy-protecting groups in the product.
Bone calcium mobilization activities of a la,25-(OH)2-24-homo-D3 compounds.
Bone calcium mobilization activity was assayed by measuring the rise in serum calcium levels in response 10 to the compound administered. Male, weanling rats (Holtzman Co., Madison, W1) were fed a low calcium, vitamin D deficient diet (Suda et al, J. Nutr. 100 1049-1050,1970) 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)2D3 or the test compound dissolved in 0.05 mi of 95% ethanol. Rats in the control group were given 0.05 mi ethanol vehicle in the same manner. Eighteen hours after the dose, the rats were killed and their blood was collected 15 and centrifuged to obtain serum. Serum calcium concentrations were determined with an atomic absorption spectrometer Model 403 (Perkin-Elmer Co., Norwalk, Conn.) in presence of 0.1 % lanthanum chloride.
Results obtained are shown in the following Table:
TABLE 1 20
Increase of serum calcium concentration in response to a compound administered Amount Serum calcium Compound Administered Concentration 25 Administered (Pmollrat) (Mglloo m/) Exp.1 Ethanol - 3.6 0.3a).
leL,25-(OH)2D,3 650 4.9 0.2 b) 1 ot,25-(OH)2-24- 30 homo-D3 650 4.4 0.2 b) Exp 11 Ethanol - 4.2 + 0.1 c) 1(Y,25-(0)2D3 325 5.0+0.5 d) lot,25-(OH)2-22E- 35 dehydro-24-homo-D3 650 5.0 0.5 d) Standard deviation from the means significantly different b) from a) P<0. 001 and d) from c) 40 It can be concluded from the foregoing data that in the vitamin D responsive systems of vitamin D-deficient animals the compounds of this invention exhibited the same activity as 1 a-,25-hydroxyvitamin D3, the circulating hormonal form of the vitamin, although, in the case of the 22dehydro derivative the dosage was significantly higher.
The compounds of this invention may be readily administered in sterile parenteral solutions by injection or 45 intravenously or by alimentary canal in the form of oral dosages, or by suppository or even transcutaneously, for example. Doses of from, say. 0.1 jig to about 2.5 jig per day are generally effective in obtaining the physiological calcium balance responses characteristic of Vitamin D-like activity with maintenance dosage of from, say, 0.1 ig to about 0.5 Kg being suitable.
Dosage forms of the compounds can be prepared by combining them with a non-toxic pharmaceutical ly 50 acceptable carrier as is well known in the art. Such carriers may be either solid or liquid such lactose, sucrose, peanut oil, olive oil, sesame oil and water. If a solid carrier is used the dosage forms of the compounds of the invention may be e.g. tablets, capsules, powders, troches or lozenges. If a liquid carrier is used, soft gelatin capsules or syrup or liquid suspensions, emulsions or solutions are typically the dosage form. The dosage forms may also contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents or solution 55 promoters. They may also contain other therapeutically valuable substances.
It should be understood that although dosage ranges are given the particular dose to be administered to a hostwill depend upon the specific disease state being treated, the end results being sought in a particular case, the physical size of the host, as well as otherfactors known to those skilled in the art in the therapeutic use of such medicinal agents. 60
Claims (14)
1. A compound having the formula 7 GB 2 188 932 A 7 R 1 0 5 wherein each R is independently hydrogen, acyl having from 1 to 4 carbon atoms, benzoyl or methoxymethyl.
2. A compound according to claim 1 wherein each R is methoxymethyi. 10
3. A compound according to claim 1 wherein each R is hydrogen.
4. A compound according to claim 1 wherein each R is acetyl.
5. A compound having the formula 15 20 1 wherein R.i, R2 and R3 are each independently acyl having from 1 to 4 carbon atoms or benzoyl and R4 and R5 25 represent hydrogen atoms or taken together form a carbon to carbon bond.
6. A compound according to claim 5 wherein R, and R2 are both acetyl and R3 is hydrogen.
7. A compound according to claim 5 or 6 wherein R4 and R5 together form a carbon to carbon bond.
8. A compound according to claim 7 wherein the A22 bond is in the E configuration.
9. A compound according to claim 7 wherein the A22 bond is in the Z configuration. 30
10. A compound according to claim 5 or 6 wherein R4 and R5 represent hydrogen atoms.
11. Process for converting a OH 35 side chain of a steroid nucleus to a OH 40 side chain which comprises reacting the starting material with triethyl orthoacetate to provide the ester side 45 chain C02Et 50 and reacting the ester with a methyl magnesium halide.
12. Process according to claim 11 wherein the ha 1 ide is methyl magnesium bromide.
13. Process according to claim 11 or 12 wherein the reaction with triethyl orthoacetate is carried out in the presence of propionic acid, as catalyst. 55
14. Process according to claim 11 substantially as hereinbefore described.
Printed for Her Majesty's Stationery Office by Croydon Printing Company (UK) Ltd, 8187, D8991685.
Published by The Patent Office, 25 Southampton Buildings, London WC2A lAY, from which copies may be obtained.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65754984A | 1984-10-04 | 1984-10-04 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8709579D0 GB8709579D0 (en) | 1987-05-28 |
| GB2188932A true GB2188932A (en) | 1987-10-14 |
| GB2188932B GB2188932B (en) | 1988-09-01 |
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08524479A Expired GB2167070B (en) | 1984-10-04 | 1985-10-04 | Vitamin d derivatives pharmaceutical compositions containing them and precursors thereof |
| GB08709579A Expired GB2188932B (en) | 1984-10-04 | 1987-04-23 | Steroidal compounds and process for lengthening the side-chain of certain steroids |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
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| GB08524479A Expired GB2167070B (en) | 1984-10-04 | 1985-10-04 | Vitamin d derivatives pharmaceutical compositions containing them and precursors thereof |
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| Country | Link |
|---|---|
| EP (1) | EP0197949A1 (en) |
| JP (3) | JPS62500301A (en) |
| AU (2) | AU582789B2 (en) |
| BE (1) | BE903376A (en) |
| CH (1) | CH672920A5 (en) |
| DE (2) | DE3590488C2 (en) |
| DK (5) | DK154290C (en) |
| FR (1) | FR2571369B1 (en) |
| GB (2) | GB2167070B (en) |
| IE (1) | IE58104B1 (en) |
| IT (1) | IT1190401B (en) |
| NL (1) | NL8520265A (en) |
| WO (1) | WO1986002078A1 (en) |
Families Citing this family (9)
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| KR0144358B1 (en) * | 1988-04-21 | 1998-07-15 | 피. 라이달 크리스텐슨 | Novel vitamin d analogues |
| 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 (en) * | 1989-10-02 | 1991-04-11 | Schering Ag | 24-HOMO-VITAMIN-D DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1286761A (en) * | 1969-03-17 | 1972-08-23 | Upjohn Co | Compounds related to 25-hydroxycholecalciferol |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (en) * | 1983-05-09 | 1988-06-15 | Wisconsin Alumni Res Found | METHOD FOR PRODUCING 1ALPHA, 25-DIHYDROXYLATED VITAMIN D (2) AND RELATED COMPOUNDS. |
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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/en active Pending
- 1985-08-19 JP JP60503924A patent/JPS62500301A/en 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/en unknown
- 1985-10-04 FR FR8514758A patent/FR2571369B1/en not_active Expired
- 1985-10-04 GB GB08524479A patent/GB2167070B/en not_active Expired
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- 1985-10-04 IT IT22359/85A patent/IT1190401B/en active
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- 1986-06-03 DK DK260086A patent/DK154290C/en active
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- 1987-04-23 GB GB08709579A patent/GB2188932B/en not_active Expired
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1988
- 1988-03-02 DK DK111188A patent/DK159389C/en active
- 1988-12-29 AU AU27614/88A patent/AU605007B2/en not_active Ceased
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- 1989-04-13 DK DK177489A patent/DK158989C/en active
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1286761A (en) * | 1969-03-17 | 1972-08-23 | Upjohn Co | Compounds related to 25-hydroxycholecalciferol |
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| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19981004 |