GB2167070A - Vitamin d derivatives pharmaceutical compositions containing them and precursors thereof - Google Patents
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- 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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Abstract
New 24-homo-vitamin D compounds, methods for preparing the same and novel intermediate compounds. The compounds are characterized by vitamin D-like activity of the order of 1 alpha ,25-dihydroxyvitamin D3, the recognized circulating hormonal form of vitamin D, or various of its derivatives and are useful in the treatment of disease state characterized by calcium-phosphorous imbalances.
Description
SPECIFICATION
Vitamin D derivatives, pharmaceutical compositions containing them and precursors thereof
This invention relates to novel 24-homovitamin D derivatives.
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 10e,25-dihydroxyvitamin D3 in the kidneys. It is the latter compound which is now recognized as being the circulating hormonal form of vitamin D.
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 treatment of various disease states manifesting calcium and phosphorus imbalance such as hypoparathyroidism, osteodystrophy, osteomalacia and osteoporosis.
These derivatives are 24-homovitamins, particularly 1R,25-dihydroxy-22E(orZ)-dehydro-24-homovitamin D3 and 1a,25-dihydroxy-24-homovitamin D3.
The compounds of the present invention can be represented by the formula:
where RI, R2 and R3 are each independently hydrogen, acyl having from 1 to 4 carbon atoms or benzoyl and R4 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.
In accordance with the process of this invention:
Bisnorcholenic acid acetate (a) was reduced with lithium aluminum hydride and subsequently oxidized with dichloro-dicyanobenzoquinone 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 lar,2a-epoxide (1) in 41% yield. Reduction of (1) with lithium and ammonium chloride in liquid ammonia-tetrahydrofuran at -78 , and subsequent treatment with chloromethyl methyl ether provided the dimethyoxymethyl 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 vinylmagnesium bromide to provide the allylalcohol (5) in 94% yield. This alcohol was heated in refluxed xylene with triethyl orthoacetate and a catalytic amount of propionic acid, to afford the ester (6) in 93% yield. Then, the ester (6) was reacted with methylmagnesium bromide to provide the alcohol (7) in 93% yield. Removal of MOM group, followed by acylation, e.g. acetylation gave (22E)-1a,3ss- diacetoxy-25-hydroxy-24-homo-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, subsequently refluxed for 1 hr, and then hydrolyzed to afford (22E)-1a,25-dihydroxy-22-dehy- dro-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 n-butylammonium fluoride, to provide the 5-ene (12) in 92% yield. This compound was converted to 1cs,25-dihydroxy-24-homovitamin D3 (14) via the 5,7-diene (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 CDC1a with Me4Si as an internal standard, unless otherwise noted. Mass spectra were obtained with a Shimadzu OP-1000 mass spectrometer at 70 eV. UV spectra were obtained in ethanol solution with a Shimadzu UV-200 double beam spectrophoto-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 extract to neutrality, drying over an hydros magnesium sulphate, filtration, and removal of the solvent under reduced pressure. The following abbreviations are used; THP - tetrahydropyranyl; THF - tetrahydrofuran; ether - diethyl ether, MeOH - methanol, MOM - methoxymethyl. Temperatures are in centigrade.
22-Hydroxy-23,24dinorchola- 1,4,6-triene-3-one (b)
To a solution of 3ss-acetoxydinorcholenic acid (a) (7.0 g, 18.04 mmole) in THF (20 mL) lithium aluminum hydride (3.0 g, 78.95 mmole) was added. This mixture was stirred at 60"C for 14 h. To this reaction mix ture 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 the trienone (b) (2.8 g, 47%) mp 156-157 (ether) UVAm"'H nm (e): 299 (13000), 252 (9200), 224 (12000), 'H-NMR (CDC13)3: 0.80 (3H, s, 18-H3), 1.04 (3H, d, J= 6 Hz, 21-H3), 1.21 (3H, s, 19-H3), 3.10-3.80 (3H, m, 22-H3 and OH), 5.90-6.40 (4H, m, 2-H, 4-H,6-H, and 7-H), 7.05 (1H, d, J=10 Hz, 1-H), MS mlz: 326 (M+), 311, 308, 293, 267, 112.
1a,2a-Epoxy-22-tetrahydropyranyloxy-23,24-dinorchola-4,6-dien-3-one (1)
The alcohol (b) (2.7 g, 8.28 mmole) in dichloromethane (50 mL) 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/MeOH (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 g).Elution with benzene-ethyl acetate (100 1) provided the epoxide (1) (1.45 g, 41%): mp 113-115 (hexane) UVA Ett)H nm () 290 (22000), 'H-NMR (CDC13)8: 0.80 (3H, s, 18-H3), 1.07 (3H, d, J=6 Hz, 21-H3), 1.18 (3H, s, 19-H3), 3.38 (1H, dd, J=4 and 1.5 Hz, 1-H), 3.55 (1H, d, J=4 Hz, 2-H), 3.30-4.10 (4H, m, 22-H3 and THP), 4.50 (1H, m, THP), 5.58 (1H, d, J=1.5 Hz, 4-H), 6.02 (2H, s, 6-H and 7-H),
MS m/z: 342 (M -DHP), 324 (M - THPOH), 309, 283, 85.
1α,3ss-Dimethoxymethoxy-23,24-dinorchol-5-en-22-tetra-hydropyranyl ether (2)
Lithium (5.00 g) was added in small portion to liquid ammonia (200 ml) at -78" under argon atmosphere during 30 min. After stirring for 1 hr at -780, 1a-2a-epoxy-22-tetrapyranyl-oxy-23,24-dinorchola-4,6- diene-3-one (1) (2.00 g, 4.69 m mol) in dry THF (150 ml) was added dropwise at -78 during 30 min, and this mixture was stirred for 1 hr at -78 . To this reaction mixture, anhydrous NH4C1 (60 g) 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 ml, 26.34 m mol) and N,N-diethylcyclohexylamine (4.6 ml, 24.93 m mol) in dioxane (20 ml) at 45 for 24 hr. The usual work-up (ethyl acetate) gave a crude product, which was applied to a 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 3 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, -O-CH3), 3.37(3H, s, -O-CH3), 4.63 (2H, ABq, J=7 Hz, nAB=11 Hz, 1a-O-CH2-O-), 4.64 (2H, s, 3p-O-CH3-O-), and 5.50 (1H, m, 6-H).
1α,3ss-Dimethoxymethoxy-23,24-dinorchol-5-en-22-ol (3) The THP ether (2) (922 mg, 1.77 mmol) in THF (8 ml) and MeOH (8 ml) was treated with 2M HCI (1 ml) at room temperature for 2 h. The usual work-up (ethyl acetate) gave a crude product, which was applied to a column of silica gel (40 g). Elution with hexane-ethyl acetate (2 1) gave the alcohol (3) (678 mg, 88%) as an amorphous solid. 'H-NMR 3 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, -O-CH3), 3.38 (3H, s, -O-CH3), 4.65 (2H, ABq, J=7 Hz, LAB = 11 Hz, 1a-O-CH3-O-), 4.66 (2H,s,3ss- O-CH3-O-), 5.53 (1H,m,6-H).
1a,3ss-Dimethoxymethoxy-23t24dinorchol-5-en-22-al (4) To a solution of oxalyl chloride (0.27 ml, 3.09 mmol) in dichloromethane (8 ml) dimethyl sulphoxide (0.44 ml, 6.21 mmol) was added at -78 C under argon. The mixture was stirred at -78 C for 10 min. To the solution the alcohol (3) (660 mg, 1.5 mmol) in dichloromethane (5 ml) was added at -780C. After stirring for 15 min, triethylamine (1.89 ml, 13.6 mmol) was added. The mixture was stirred at -780C 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 crystal. mp 71-72"C (hexane), 1H-NMR 3 0.74 (3H, s, 18-H3), 1.04 (3H, s, 19-H3), 1.12 (3H, d, J=6 Hz, 21-H3), 3.35 (3H, s, -O-CH3), 3.39 (3H, s, -O-CH3), 3.7 (1H, m, 1p-H), 4.65 (2H, ABq, J=7 Hz,
LAB = 11 Hz, 1a-O-CH3-O-), 4.66 (2H, s, 3ss-O-CH-O-), 5.52 (1H, m, 6-H), and 9.61 (1H, d, J=3 Hz, -CHO),
Anal. Calcd for C36H43O5: C, 71:85; H, 9.74. Found: C, 71.71; H, 9.68.
1',3-Dimeth ox ymeth ox ych ola -5, 23-dien-22-ol (5)
To magnesium (70 mg, 2.92 mmol) in THF (3 ml) 50% solution of vinyl bromide in THF (0.42 ml, 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 ml) was added at room temperature.
The mixture was stirred at room temperature for 1 h. 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 allylic alcohol (5) (595 mg, 94%) as an amorphous soiid.'H-NMR 8:: 0.70 (3H, s, 18-H3), 1.02 (3H, s, 19-H3), 3.35 (3H, s, -O-CH3), 3.38 (3H, s, -O-CH3), 3.69 (1H, m, 1p-H), 4.20 (1H, m, 22-H), 4.64 (2H, ABq, J=7 Hz,
LAB = 11 Hz, 1a-O-CH2-O-), 4.65 (2H, s, 3ss-O-CH2-O-), 5.52 (1H, m, 6-H), 4.90-6.0 (3H, m, 23-H and 24-H3). (22EJ- la3p-Dimefh oxymefh oxy-27-n orcholesfa-5,22-dien-26-oic acid ethyl ester (6)
A solution of the allylic alcohol (5) (590 mg, 1.28 mmol), triethyl orthoacetate (1.0 ml, 5.46 mmol), propionic acid (4 drops), and xylene (8 ml) was refluxed under argon for 2 h. 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-H3), 0.97 (3H, d, J=6 Hz, 21-H3), 1.03 (3H, s, 19-H3), 1.24 (3H, t, J=7 Hz, -CO2CH2CH3), 3.35 (3H, s, -O-CH3), 3.39 (3H, s, -O- CH3), 3.70 (1H, m, Ip-H), 4.11 (2H, q, J=7 Hz, -CO3CK3CH3), 4.64 (2H, ABq, J=7 Hz, LAB = 11 Hz, 1a-O- CH3-O-), 4.65 (2H, s, 3ss-O-CH2-O-), 5.29 (2H, m, 22-H and 23-H), 5.52 (1H, 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 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.
{22EJ-1a,3ss-Dimethoxymethoxy-24-homo-cholesta-5,22-diene-25-ol (7) To a solution of the ester (6) (605 mg, 1.14 mmol) in THF (6 ml) 1M solution of methylmagnesium bromide in THF (4.5 ml, 4.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 1 h. 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 oii. 'H- NMR 8: 0.68 (3H, s, 18-H3), 0.97 (3H, d, J=6 Hz, 21 -H3), 1.01 (3H, s, 19-H3), 1.21 (6H, s, 26-H3 and 27-H3), 3.33 (3H, s, -O-CH3), 3.38 (3H, s, -O-CH3), 3.70 (1H, m, 1ss-H), 4.64 (2H, ABq, J=7 Hz, LAB 11 Hz, 1a-O-CH2-O-), 4.65 (2H, s, 3ss-O-CH2-O-), 5.29 (2H, m, 22-H and 23-H), and 5.50 (1H, m, 6-H).
(22EJ-24-Homocholesta-5,22-diene- 1a,325-triol (8)
A solution of the dimethoxymethyl ether (7) (540 mg, 1.04 mmol) in THF (15 ml) was treated with 6M
HC1 (3 ml) at 50"C for 2.5 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 (1:1) gave the triol (8) (428 mg, 95%) as a crystal. mp 164-166"C (hexane-ethyl acetate), 'H-NMR 8: 0.68 (3H, s, 18-H3), 0.95 (3H, s, J=6 Hz, 21
H3), 1.00 (3H, s, 19-H3), 1.20 (6H, s, 26-H3 and 27-H3), 3.80 (1H, m, 1ss-H), 3.92 (1H, m, 3a-H), 5.30 (2H, m, 22-H and 23-H), and 5.53 (1H, m, 6-H).
(22E)- la, 3p-D/acetoxy-25-h ydroxy-24-h om ocholesta-5,22-diene (9)
A solution of the triol (8) (395 mg, 0.919 mmol) in pyridine (2 ml) was treated with acetic anhydride (1 ml) 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. aH-NMR 8: 0.67 (3H, s, 18-H3), 0.97 (3H, d, J=6 Hz, 21-H3), 1.07 (3H, s, 19-H3), 1.21 (6H, ,s, 26-H3 and 27-H3), 2.01 (3H, s, acetyl), 2.04 (3H, s, acetyl), 4.98 (1H, m, 3a-H), 5.05 (1H, m, 1ss-H), 5.31 (2H, m, 22-H and 23-H), and 5.52 (1 H, m, 6-H).
(22E)- 1a,3ss-Diacetoxy-25-hydroxy-24homocholesta-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 carbontetrachloride (3 ml) was refluxed under argon for 20 min. After the mixture had been cooled to 0 C, the resulting precipitate was filtered off. The filtrate was concentrated below 40"C to leave the residue. This in THF (5 ml) 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 ml, 3.5 mmol) at room temperature for 30 min.The usual work-up (ethyl acetate) 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 0.48 was scraped off and eluted with ethyl acetate. Removal of the solvent provided the 5,7-diene (10)12.5 mg, 24%), UVX,,%0,H: 293, 282, and 271.
1a,25-Dihydroxy-22E-dehydro-24-homovitamin D3 (71)
A solution of the 5,7-diene (70) (7.3 mg, 0.0143 mmol) in benzene (90 ml) and ethanol (40 ml) was irradiated with with a medium pressure mercury lamp through a Vycol filter at 0 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 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 umol) in THF (4 ml) was treated with 5% KOH/MeOH (1 ml) 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 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 (17) 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, MeOH-CH2-CI2, 1 : 49; flow rate, 3 milmin; retention time, 11.5 min).The vitamin D3 ana logue (77) had the following spectral data; UVX,H : 265 nm, XEH : 228 nm, MS m/z: 428 (M+), 410, 392 (base peak), 374, 287, 269, 251, 152, 134, 123, 59 'H-NMR (360 MHz) 5:: 0.55 (3H, s, 18-H3), 1.02 (3H, d,
J=6.6 Hz, 21-H3), 1.22 (6H, s, 26-H3 and 27-H3), 2.32 (1H, dd, J=13.2 and 6.7 Hz), 2.60 (1H, dd, J=13.0 and 3.0 Hz), 2.83 (1H, dd, J=12.0 and 3.0 Hz), 4.23 (1H, m, W,2) = 18.4 Hz, 3a-H), 4.43 (1H, m, W,2 = 16.9 Hz, 1ss-H), 5.00 (1H, bs, W,2 = 3.2 Hz, 19-H), 5.30 (1H, dd, J=15.0 and 7.1 Hz, 22-H or 23-H), 5.33 (1H, bs, W,2 = 3.2 Hz, 19-H), 5.37 (1H, dd, J=15.0 and 5.8 Hz, 22-H or 23-H), 6.01 (1h, d, J=11.0 Hz, 7-H), 6.32 (1H, d,
J=11.0 Hz, 6-H).
7a,3-Diacetoxy-24-hom ocholest-5-en-25-ol (12) A mixture of the 5,22-diene (9) (40 mg, 0.0778 mmol) and 10% Pd-C (4 mg) in ethyl acetate (2 ml) was stirred at room temperature under hydrogen for 3 h. The Pd catalyst was filtered off and the filtrate was concentrated to leave the residue, which was applied to a column of silica gel (5 g). Elution with hexaneethyl acetate (4:1) gave the 5-ene (12) (37 mg, 92%) as an oil. 'H-NMR b: 0.66 (3H, s, 18-H 3), 1.08 (3H, s, 19-H3), 1.20 (6H, s, 26-H3 and 27-H3), 2.02 (3H, s, acetyl), 2.05 (3H, s, acetyl), 4.97 (1H, m, 3a-H), 5.07 (1h, m, 1ss-H), 5.53 (1H, m, 6-H).
la,3p-Diacetoxy-24-homocholesta-5, 7-dien-25-ol ( 13) The 5-ene (72) (19 mg, 0.037 mmol) was converted, as described for (10), to the 5,7-diene (13) (5.8 mg, 31%). UV,0,H 293, 282, 271 nm.
7a,25-Dihydroxy-24-homovitamin D3 (14) The 5,7-diene (13) (5.8 mg, 0.0113 mmol) was converted, as described for (77), to the vitamin D3 analogue (14) (890 Fg, 19%). The retention time of (14) under the above-described HPLC condition was 11.0 min. UVhH : 265 nm, hP,H : 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.
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 R1, R3 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 acyl groups such as benzoyl, can be obtained. A partially acylated derivative, e.g. 1,3diacyl 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-acyl 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 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 1a,25-fOH)2-24-homo-D3 compounds.
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 lowcalcium, 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)3D3 or the test compound dissolved in 0.05 ml of 95% ethanol. Rats in the control group were given 0.05 ml 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., Norwalk, Conn.) in presence of 0.1% lanthanum chloride.
Results obtained are shown in the following Table:
TABLE 1
Increase of serum calcium concentration in response to a compound administered
Amount Serum calcium
Compound Administered Concentration
Administered (pmollrat) (mgl 700 mI) Exp.l Ethanol -- 3.6-0,3a)X 1 a,25-(OH)2D3 650 1(x,25-(OH)2-24- 650 4.4+0.2b) homo-D3
Exp.ll Ethanol -- 4.2 + 0.1c) 1a,25-(OH)3D3 325 5.00.5d) 10L,25-(OH)2-22E- 650 5.0+0.5d) dehydro-24-homo
D3 *Standard deviation from the means significantly different
b) from a) p < 0.001 and d) from c)
It can be concluded from the foregoing data that in the vitamin D responsive systems of vitamin Ddeficient animals the compounds of this invention exhibited the same activity as 1a,25-hydroxyvitamin D3, the circulating hormonal form of the vitamin, although, in the case of the 22-dehydro derivative the dosage was significantly higher.
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, for example. Doses of from, say 0.1 Fg to about 2.5 Fg 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 Fg to about 0.5 lag being suitable.
Dosage forms of the compounds can be prepared by combining them with a non-toxic pharmaceutically acceptable carrier as is well known in the art. Such carriers may be either solid or liquids 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 solutions 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 host will 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 other factors known to those skilled in the art in the therapeutic use of such medicinal agents.
Claims (10)
1. A compound having the formula
where R1, R3 and R3 are each independently hydrogen, acyl having from 1 to 4 carbon atoms or benzoyl and R4 and R5 each represent hydrogen or taken together form a carbon to carbon bond.
2. A compound according to claim 1 wherein R1, R3 and R3 are hydrogen and R4 and R5 are hydrogen.
3. A compound according to claim 1 wherein R1, R3 and R3 are hydrogen and R4 and R5 together represent a carbon to carbon bond.
4. The compound of claim 2 or 3 in crystalline form.
5. A compound according to claim 3 wherein the A22 bond is in the E configuration.
6. A compound according to claim 3 wherein the A22 bond is in the Z configuration.
7. A pharmaceutical composition which comprises at least one compound as claimed in any one of the preceding claims and a pharmaceutically acceptable excipient.
8. A compound having the formula
where each R is independently hydrogen, acyl having from 1 to 4 carbon atoms, benzoyl or methoxymethyl.
9. A compound having the formula
where each R is independently acyl having from 1 to 4 carbon atoms or benzoyl and R4 and R5 represent hydrogen atoms or taken together form a carbon to carbon bond.
10. Process for converting a
side chain of a steroid nucleus to a
side chain which comprises reacting the starting material with triethyl orthoacetate to provide the ester side chain
and reacting the ester with a methyl magnesium halide".
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65754984A | 1984-10-04 | 1984-10-04 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8524479D0 GB8524479D0 (en) | 1985-11-06 |
| GB2167070A true GB2167070A (en) | 1986-05-21 |
| GB2167070B GB2167070B (en) | 1988-09-01 |
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| 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 |
| GB08709579A Expired GB2188932B (en) | 1984-10-04 | 1987-04-23 | Steroidal compounds and process for lengthening the side-chain of certain steroids |
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| Application Number | Title | Priority Date | Filing Date |
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| GB08709579A Expired GB2188932B (en) | 1984-10-04 | 1987-04-23 | Steroidal compounds and process for lengthening the side-chain of certain steroids |
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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) | DE3590488T (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) |
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| EP0412110B1 (en) * | 1988-04-21 | 1993-07-07 | Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) | Novel vitamin d analogues |
| US4927815A (en) * | 1988-04-29 | 1990-05-22 | Wisconsin Alumni Research Foundation | Compounds effective in inducing cell differentiation and process for preparing same |
| AU629831B2 (en) * | 1988-04-29 | 1992-10-15 | Wisconsin Alumni Research Foundation | Side chain unsaturated 1 alpha-hydroxyvitamin d homologs for the treatment of leukemia |
| 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 |
| JP2008519808A (en) | 2004-11-12 | 2008-06-12 | ビオエクセル エスピーエー | Combination of vitamin D derivatives and antiproliferative drugs for the treatment of 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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- 1985-08-19 DE DE19853590488 patent/DE3590488T/en active Pending
- 1985-08-19 CH CH2351/86A patent/CH672920A5/de not_active IP Right Cessation
- 1985-08-19 DE DE3590488A patent/DE3590488C2/de not_active Expired - Lifetime
- 1985-08-19 AU AU47761/85A patent/AU582789B2/en not_active Ceased
- 1985-08-19 EP EP85904336A patent/EP0197949A1/en not_active Withdrawn
- 1985-08-19 JP JP60503924A patent/JPS62500301A/en active Granted
- 1985-08-19 NL NL8520265A patent/NL8520265A/en unknown
- 1985-08-19 WO PCT/US1985/001571 patent/WO1986002078A1/en active Application Filing
- 1985-10-04 IE IE244385A patent/IE58104B1/en not_active IP Right Cessation
- 1985-10-04 BE BE0/215682A patent/BE903376A/en not_active IP Right Cessation
- 1985-10-04 FR FR8514758A patent/FR2571369B1/en not_active Expired
- 1985-10-04 IT IT22359/85A patent/IT1190401B/en active
- 1985-10-04 GB GB08524479A patent/GB2167070B/en not_active Expired
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1986
- 1986-06-03 DK DK260086A patent/DK154290C/en active
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1987
- 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
- 1989-04-13 DK DK177489A patent/DK158989C/en active
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1990
- 1990-01-19 DK DK015290A patent/DK158990C/en active
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1992
- 1992-05-19 JP JP4150045A patent/JPH0689022B2/en not_active Expired - Lifetime
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| 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 |