CA1107720A - Process for preparing ethers of bufadienolide and bufatrienolide - Google Patents
Process for preparing ethers of bufadienolide and bufatrienolideInfo
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- CA1107720A CA1107720A CA304,930A CA304930A CA1107720A CA 1107720 A CA1107720 A CA 1107720A CA 304930 A CA304930 A CA 304930A CA 1107720 A CA1107720 A CA 1107720A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring
- C07J19/005—Glycosides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- 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
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Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides the compounds of the present invention show an increased activity on the heart, in which connection the oral resorption is especially improved.
It should be particularly noted, that the activity firstly increases with increasing chain length of the alkyl ether and then remains constant although the toxicity becomes lower. The compounds also have an especially good tolerance in the stomach and a slightly sedative action, which latter may be a desired side action in case of cardiac diseases. The new compounds can be administered in a form usual for heart glycosides, e.g. in form of tablets, capsules or solutions containing the active substance in pure form or in mixture with xanthine derivatives.
The present invention provides the compounds of the present invention show an increased activity on the heart, in which connection the oral resorption is especially improved.
It should be particularly noted, that the activity firstly increases with increasing chain length of the alkyl ether and then remains constant although the toxicity becomes lower. The compounds also have an especially good tolerance in the stomach and a slightly sedative action, which latter may be a desired side action in case of cardiac diseases. The new compounds can be administered in a form usual for heart glycosides, e.g. in form of tablets, capsules or solutions containing the active substance in pure form or in mixture with xanthine derivatives.
Description
11~77Z~
, The present invention relates to a process for pre-paring ethers of bufadienolide and bufatrienolide.
A process for preparing ethers of bufadienolide and bufatrienolide of the general formula C~
~ , I (I) R' I
\ ~ )H
0/~
HO O ¦
l/~H3 y I - OH
~CH2R
is described and claimed in applicants Austrian patent No. 349,159 from the above formula, X is a double bond between the carbon atoms 4 and 5 or an epoxide group, R' is a methyl, formyl or methylol group, and R is hydrogen, a straight or branched alkyl radical having 1 to 16 carbon atoms, a straight or branched alkenyl radical having 2 to 6 carbon atoms, an ethyinyl radical, a straight or branched alkoxy radical having 2 to 11 carbon atoms, a cycloaliphatic radical, the group CH2 attached on R forming together with R a nucleus having 6 to 12 carhon atoms, an arornatic or aliphatic-aromatic radical, e.g. a phenyl, phenylmethyl, 2-phenylethyl or 3-phenylpropyl radical, a straight or branched dialkylaminoalkyl radical having 1 to 7 carbon atoms, the nitrogen atom of which is tertiary and may carry two alkyl radicals ha~ing 1 to 4 carbon atoms, in which substituents the straight or branched aliphatic chains may be substituted by nitrogen or oxygen-con'ainin~ heterocycles, e.g. pyridine, piperazine, pyrrolidine, furyl, tetrahydrofur~l or morpholino groups or by halogen, e.g.
chlorine or bromine, except for compounds in which X is a double bond, R' is methyl and R is H, R' is methyl, X is a double bond and R is alkyl having 4 or 5 carbon atoms, and R' is formy], X
is a double bond and R is hydrogen or an alkyl group having 1 to 5 carbon atoms.
This process comprises reacting a glycoside of bufadieno-lide or bufatrienolide of the ~eneral formula ~3 ~~ `~"~
~ 1 ~H
O ~ (II) `X
H ~ o OH
OH
in which X and R' are as defined above, with a diazolkane of the general formula R.CH.N2 (II~) in which R is as defined above, in an inert solvent in the presence of a weakly acid catalyst.
Examples of such weakly acid catalysts are iron (III~
chloride in ether, borotrifluoride dietherate, boric acid ester, aluminium chloride, aluminium isoprop~late, p-toluene ~ulfonic acid, polyphosphoric acid in ether, arsenic trioxide titanium-
, The present invention relates to a process for pre-paring ethers of bufadienolide and bufatrienolide.
A process for preparing ethers of bufadienolide and bufatrienolide of the general formula C~
~ , I (I) R' I
\ ~ )H
0/~
HO O ¦
l/~H3 y I - OH
~CH2R
is described and claimed in applicants Austrian patent No. 349,159 from the above formula, X is a double bond between the carbon atoms 4 and 5 or an epoxide group, R' is a methyl, formyl or methylol group, and R is hydrogen, a straight or branched alkyl radical having 1 to 16 carbon atoms, a straight or branched alkenyl radical having 2 to 6 carbon atoms, an ethyinyl radical, a straight or branched alkoxy radical having 2 to 11 carbon atoms, a cycloaliphatic radical, the group CH2 attached on R forming together with R a nucleus having 6 to 12 carhon atoms, an arornatic or aliphatic-aromatic radical, e.g. a phenyl, phenylmethyl, 2-phenylethyl or 3-phenylpropyl radical, a straight or branched dialkylaminoalkyl radical having 1 to 7 carbon atoms, the nitrogen atom of which is tertiary and may carry two alkyl radicals ha~ing 1 to 4 carbon atoms, in which substituents the straight or branched aliphatic chains may be substituted by nitrogen or oxygen-con'ainin~ heterocycles, e.g. pyridine, piperazine, pyrrolidine, furyl, tetrahydrofur~l or morpholino groups or by halogen, e.g.
chlorine or bromine, except for compounds in which X is a double bond, R' is methyl and R is H, R' is methyl, X is a double bond and R is alkyl having 4 or 5 carbon atoms, and R' is formy], X
is a double bond and R is hydrogen or an alkyl group having 1 to 5 carbon atoms.
This process comprises reacting a glycoside of bufadieno-lide or bufatrienolide of the ~eneral formula ~3 ~~ `~"~
~ 1 ~H
O ~ (II) `X
H ~ o OH
OH
in which X and R' are as defined above, with a diazolkane of the general formula R.CH.N2 (II~) in which R is as defined above, in an inert solvent in the presence of a weakly acid catalyst.
Examples of such weakly acid catalysts are iron (III~
chloride in ether, borotrifluoride dietherate, boric acid ester, aluminium chloride, aluminium isoprop~late, p-toluene ~ulfonic acid, polyphosphoric acid in ether, arsenic trioxide titanium-
2~
tetrachloride, molybdenum(VI)~oxychloride, tin dichlorid~, tintetrachloride, tin sulfate, copper(II)-chloride, preferably ~oric acid or m-boric acid.
It has been found, that the yield of the 3'-alkylether can be improved substantially, if a mixture of titaniumtetrachlor-ide and boric acid or of titanic acid ester and titaniumtetrachlor-ide or titanic acid ester alone in absolute dioxane is used as catalyst. As titanic acid esters may be used ethyl titanate, n-propyl-, isopropyl-, n-butyl-, isobutyl-, cresyl-, 2-ethylhexyl-titanate and diisopropoxy-bis-(2,4-pentan-dionato)-titanium(IV) (=titanium acetylacetonate).
These catalysts are advantageous inasmuch as the alkylation in position 3' of the rhamnose occurs more selectively and less non-polar products (dimethylethers) are obtained in comparison with boric acid.
According to the present invention therefore there is provided a process for preparing an ether of bufadienolide and bufatrienolide of the general formula O
oJI~
HO ¦ X
OH
in which formula X is a double bond between the car~on atoms j7~z~
and 5 or an epoxide group, R' is a methyl, formyl or methylol group, and R is hydrogen, a straight or branched alkyl radical having 1 to 16 carbon atoms, a straight or branched alkenyl radical having 2 to 6 carbon atoms, an ethyinyl radical, a straight or branched alkoxy radical having 2 to 11 carbon atoms, a cycloaliphatic radical, the group CH2 attached on R forming together with R a nu_leus h.~ving 6 to 12 carbon atoms, an aromatic or aliphatic-aromatic radical, a straight or branched dialkylamino-alkyl radical havin~ l to 7 carbon atoms, the nitrogen atom of which is tertiary and may carry two alkyl radicals having 1 to 4 carbon atoms, in which substitucnts the straight or branched aliphatic chains may be substituted by nitrogen or oxygen-containing heterocycles, or by halogen, except for compounds in which X is a double bond, R' is methyl and R is H, R is methyl, X is a double bond and R is alkyl having 4 ot 5 carbon atoms, and Rl is formyl, X is a double bond and R is hydrogen or an alkyl group having 1 to 5 carbon atoms, which process comprises reacting a glycoside of bufadienolide or bufatrienolide of the general formula O
l~ ~
CH
R~ ~ 1 OH (II) OH
OH
1~77~ ~
in which X and R~ are as defined above, with a diazoalkane of the general formula R.CH.N2 (III) in which R is as defined above, in an inert solvent and in the presence of a catalyst selected from a mixture of titanium tetra-chloride and boric acid a mixture of a titanic acid ester and titanium tetrachloride and a titanic acid ester alone in absolute dioxane.
The reaction is carried out in an inert absolute solvent, preferably in absolute dioxane. The reaction proceeds more slowly than with boric acid alone, ho~ever it is more selective and more quantitative.
Furthermore, it has been found that the same concen-tration of titanium tetrachloride alone as catalyst or the same concentration of titanic acid ester alone do not provide the same effect as the use of a mixture thereof. Also the mixture of titanium tetrachloride and boric acid has a more selective effect on the alkylation with diazoalkanes than titanium tetra-chloride or boric acid alone. The reaction rate decreases in the following order: titanium tetrachloride, boric acid and titanium tetrachloride and boric acid.
The compounds of the present invention show an increased activity on the hcart, in which connection the oral resorption is especially improved_ .It should be particularly noted, that the acti~ity firstly increased with increasing chain length of the alkyl ether and then remains constant although the toxicity becomes lower. The compounds also have an especially good tolerance in the stomach and a slightly sedative action, which latter may be a desired side action in case of cardiac diseases.
The new compounds can be administered in a form usual for heart glycosides, e.g. in form of ta~lets, capsules or solutions con-taining the active substance in pure form or in mixture with 11~772iD - -xanthine derivatives.
The present invention will be further illustrated by way of the following Examples.
Example 1 2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-4,5-epoxy-~ufa-20,22-dienolide are dissolv~d in 100 ml of ahsolute dioxane and 16 ml of a solution of diazomethane in ether (O.5 mmoles/ml) are added thereto. Finally 4 ml of a solution of 0.1 mmole of boric acid and 0.005 mmoles of titanium tetrachloride/ml ;n absolute dioxane are added ~s catalyst solution. The solution is allowed to stand for 4 to 5 hours at room temperature, the excess of diazomethane is decolored with a few drops of gl~cial acetic acid, evaporated carefully in vacuo and the residue is taken up into chloroform. ~he s~lution is shaken once with a 2~ solution of sodium bicarbonate and twise with water, dried over anhydrous sodium sulfate, r~moved hy filtration and evaporated in vacuo.
The residue is recrystallized several times from methanol-water and 95 to 98~ of pure 3~-O-(~,L-3'-methyl-rhamnosido)-14-hydroXy-4,5-epoxy-bufa-20,22-dienolide is obtained, mp. 220 to 232C.
The solution of the catalyst is prepared as follows:
In a 100 ml graduated flask 0~62 ~ boric acid (J0 mmoles) ~re dissolved in about 50 to 60 ml of absolute dioxane. 10 ml of a solution of titanium tetrachloride in absolute dioxane (0.05 mmoles/ml; i.e. 0.55 ml of titanium tetrachloride/100 ml of absolute dioxane) are added to the above solution and the flask is fillPd up to the marking with absolute dioxane. The solution contalns 0.1 mmole boric acid and 0.005 mmoles titanium tetra-chloride/ml. The initially yellow colored soLution becomes colorless ~fter a period of time. The solution is durable several days at room temperature.
Example 2 .
2 ~ of 3~ ,L-rhamnosido~-14-hydroxy-bufa-4 t 20,22-77~
trien~lide are dissolved in 80 ml of absolute dioxane and 10 ml of a solution of 2-ethyl-diazohexane (0.8 mmoles/ml) in ether are added thereto. Then 4 ml of a catalyst mixture of 0.05 mmoles n-propyltitanate and 0.005 mmoles titanium tetrachloride/
ml in dioxane are added. The reaction mixture is allowed to stand for 16 hours at room temperature. Then the solution is worked up, as descxibed in Ex~mple 1. By recrystallization from methanol-water 90% of pure 3~-O-[~,L-3'-(2"-ethylhexyl)-rhamnosido]-14-hydroxy-bufa-4,20,22-trienolide is obtained, mp. 235 to 241C.
The catalyst solution is prepared by dissolving 0.35 ml of n-propyltitanate in a 25 ml-gradua~ed flask in about the half of the volume of a~solute dioxane and adding 2.5 ml of a solution of titanium tetrachloride in dioxane (0.05 mmoles/ml, see Example 1~ and completing to 25 ml.
Example 3 2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-bufa-4,20,22-trienolide are dissolved in 80 ml of absolute dioxane and 11 ml of a solution of 2-chlorodiazoethane (0.7 mmoles/ml) are added.
Then 4 ml of the mixed c~talyst boric acid/titanium tetrachloride, as described in Example 1, are added and allowed to stand for 4 to 6 hours at room ~mperature. Then it is worked up as descri~ed in Example 1. After recrystallization from acetic acid ethylester
tetrachloride, molybdenum(VI)~oxychloride, tin dichlorid~, tintetrachloride, tin sulfate, copper(II)-chloride, preferably ~oric acid or m-boric acid.
It has been found, that the yield of the 3'-alkylether can be improved substantially, if a mixture of titaniumtetrachlor-ide and boric acid or of titanic acid ester and titaniumtetrachlor-ide or titanic acid ester alone in absolute dioxane is used as catalyst. As titanic acid esters may be used ethyl titanate, n-propyl-, isopropyl-, n-butyl-, isobutyl-, cresyl-, 2-ethylhexyl-titanate and diisopropoxy-bis-(2,4-pentan-dionato)-titanium(IV) (=titanium acetylacetonate).
These catalysts are advantageous inasmuch as the alkylation in position 3' of the rhamnose occurs more selectively and less non-polar products (dimethylethers) are obtained in comparison with boric acid.
According to the present invention therefore there is provided a process for preparing an ether of bufadienolide and bufatrienolide of the general formula O
oJI~
HO ¦ X
OH
in which formula X is a double bond between the car~on atoms j7~z~
and 5 or an epoxide group, R' is a methyl, formyl or methylol group, and R is hydrogen, a straight or branched alkyl radical having 1 to 16 carbon atoms, a straight or branched alkenyl radical having 2 to 6 carbon atoms, an ethyinyl radical, a straight or branched alkoxy radical having 2 to 11 carbon atoms, a cycloaliphatic radical, the group CH2 attached on R forming together with R a nu_leus h.~ving 6 to 12 carbon atoms, an aromatic or aliphatic-aromatic radical, a straight or branched dialkylamino-alkyl radical havin~ l to 7 carbon atoms, the nitrogen atom of which is tertiary and may carry two alkyl radicals having 1 to 4 carbon atoms, in which substitucnts the straight or branched aliphatic chains may be substituted by nitrogen or oxygen-containing heterocycles, or by halogen, except for compounds in which X is a double bond, R' is methyl and R is H, R is methyl, X is a double bond and R is alkyl having 4 ot 5 carbon atoms, and Rl is formyl, X is a double bond and R is hydrogen or an alkyl group having 1 to 5 carbon atoms, which process comprises reacting a glycoside of bufadienolide or bufatrienolide of the general formula O
l~ ~
CH
R~ ~ 1 OH (II) OH
OH
1~77~ ~
in which X and R~ are as defined above, with a diazoalkane of the general formula R.CH.N2 (III) in which R is as defined above, in an inert solvent and in the presence of a catalyst selected from a mixture of titanium tetra-chloride and boric acid a mixture of a titanic acid ester and titanium tetrachloride and a titanic acid ester alone in absolute dioxane.
The reaction is carried out in an inert absolute solvent, preferably in absolute dioxane. The reaction proceeds more slowly than with boric acid alone, ho~ever it is more selective and more quantitative.
Furthermore, it has been found that the same concen-tration of titanium tetrachloride alone as catalyst or the same concentration of titanic acid ester alone do not provide the same effect as the use of a mixture thereof. Also the mixture of titanium tetrachloride and boric acid has a more selective effect on the alkylation with diazoalkanes than titanium tetra-chloride or boric acid alone. The reaction rate decreases in the following order: titanium tetrachloride, boric acid and titanium tetrachloride and boric acid.
The compounds of the present invention show an increased activity on the hcart, in which connection the oral resorption is especially improved_ .It should be particularly noted, that the acti~ity firstly increased with increasing chain length of the alkyl ether and then remains constant although the toxicity becomes lower. The compounds also have an especially good tolerance in the stomach and a slightly sedative action, which latter may be a desired side action in case of cardiac diseases.
The new compounds can be administered in a form usual for heart glycosides, e.g. in form of ta~lets, capsules or solutions con-taining the active substance in pure form or in mixture with 11~772iD - -xanthine derivatives.
The present invention will be further illustrated by way of the following Examples.
Example 1 2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-4,5-epoxy-~ufa-20,22-dienolide are dissolv~d in 100 ml of ahsolute dioxane and 16 ml of a solution of diazomethane in ether (O.5 mmoles/ml) are added thereto. Finally 4 ml of a solution of 0.1 mmole of boric acid and 0.005 mmoles of titanium tetrachloride/ml ;n absolute dioxane are added ~s catalyst solution. The solution is allowed to stand for 4 to 5 hours at room temperature, the excess of diazomethane is decolored with a few drops of gl~cial acetic acid, evaporated carefully in vacuo and the residue is taken up into chloroform. ~he s~lution is shaken once with a 2~ solution of sodium bicarbonate and twise with water, dried over anhydrous sodium sulfate, r~moved hy filtration and evaporated in vacuo.
The residue is recrystallized several times from methanol-water and 95 to 98~ of pure 3~-O-(~,L-3'-methyl-rhamnosido)-14-hydroXy-4,5-epoxy-bufa-20,22-dienolide is obtained, mp. 220 to 232C.
The solution of the catalyst is prepared as follows:
In a 100 ml graduated flask 0~62 ~ boric acid (J0 mmoles) ~re dissolved in about 50 to 60 ml of absolute dioxane. 10 ml of a solution of titanium tetrachloride in absolute dioxane (0.05 mmoles/ml; i.e. 0.55 ml of titanium tetrachloride/100 ml of absolute dioxane) are added to the above solution and the flask is fillPd up to the marking with absolute dioxane. The solution contalns 0.1 mmole boric acid and 0.005 mmoles titanium tetra-chloride/ml. The initially yellow colored soLution becomes colorless ~fter a period of time. The solution is durable several days at room temperature.
Example 2 .
2 ~ of 3~ ,L-rhamnosido~-14-hydroxy-bufa-4 t 20,22-77~
trien~lide are dissolved in 80 ml of absolute dioxane and 10 ml of a solution of 2-ethyl-diazohexane (0.8 mmoles/ml) in ether are added thereto. Then 4 ml of a catalyst mixture of 0.05 mmoles n-propyltitanate and 0.005 mmoles titanium tetrachloride/
ml in dioxane are added. The reaction mixture is allowed to stand for 16 hours at room temperature. Then the solution is worked up, as descxibed in Ex~mple 1. By recrystallization from methanol-water 90% of pure 3~-O-[~,L-3'-(2"-ethylhexyl)-rhamnosido]-14-hydroxy-bufa-4,20,22-trienolide is obtained, mp. 235 to 241C.
The catalyst solution is prepared by dissolving 0.35 ml of n-propyltitanate in a 25 ml-gradua~ed flask in about the half of the volume of a~solute dioxane and adding 2.5 ml of a solution of titanium tetrachloride in dioxane (0.05 mmoles/ml, see Example 1~ and completing to 25 ml.
Example 3 2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-bufa-4,20,22-trienolide are dissolved in 80 ml of absolute dioxane and 11 ml of a solution of 2-chlorodiazoethane (0.7 mmoles/ml) are added.
Then 4 ml of the mixed c~talyst boric acid/titanium tetrachloride, as described in Example 1, are added and allowed to stand for 4 to 6 hours at room ~mperature. Then it is worked up as descri~ed in Example 1. After recrystallization from acetic acid ethylester
3~-O-[a,L-3'-(2"-chloroethyl)-rhamnosido~-14-hydroxy-bufa-4,20, 22-trienolide is obtained in a yield of 95~, mp. 168 to 175C.
Example 4 _ 1 g of 3~-O-I~,L-rhamnosido]-14-h~droxy-4,5-epox~.~-bufa-20,22-dienolide is dissol~ed in 50 ml of absolute dioxane and 20 ml of ethynyldiazome~hane tO.2 mmoles/ml) are added. Then 2 ml of a solution of n-butylti~anate in dioxane (0.05 mmoles/ml; 0.85 ~0 ml of n-butyltitanate in 50 ml of ab~ol~lte dioxane) are added and it is allowed to stand for 4 to 6 hours at room temperature.
Then it is worked up as described in ~xample 1. After recrystal-11~772~ -lization from acetic acid ethyl ester 1 g (93%) of pure 3~-O-(~,L-3'-propargylrhamnosido)-1~-hydroxy-4,5-epoxy-bufa-20,22-dienolide is obtained, mp. 228 to 237C.
Example 5 . _ 1 g of 3~-O-(~,L-rhamno~sido)-14-hydroxy-bufa-4,20,22-trienolide is dissolved in 40 ml of absolute dioxane and 15 ml of a solution of 3-(2-ethyl)-hexyloxydiazopropane-(1) (0.6 mmoles/
ml) in ether are added. Then 2 ml of a solution of n-propyl-titanate (0.05 mmoles/ml) and titan um tetrachloride (0.005 mmoles/
ml) are added, as described in Example 2, and allowed to stand for 16 hours at room temperature. Then the solution is worked up, as described in Example 1. After recrystallization from acetic acid ethylester 1.1 g (85%) of pure 3~-O-[~,L-3'-(3"-(2"-ethyl)-hexyloxypropyl)-rhamnosido]-14-hydroxy-bufa-4,20,22-trienolide are obtained, mp. 225 to 230C.
Example 6 . .
3 g of 3~-O-(a,I,-rhamnosido)-14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 160 ml of absolute diox~ne and ~QLm1 of an etherica~lution of diazoeth~ Q.6 mmoles/ml) are added thereto. 1 ml of a solution of ethyltitanate and titanium tetrachloride in absolute dioxane (0.05 mmoles ethyl-titanate and 0.005 mmoles titanium tetrachloride/ml are added .
thereto and it is allcwed to stand for 4 to 6 hours at room temperature~ After working up as described in Example 1 3.5 g (93%) of pure 3~-O-(a,L-3'-ethylrhamnosido)-14-hydroxy-4,5-epoxy-20,22-kufa-dienolide are obtained after recrystallization from methanol-water, mp. 136 to 143C.
Example 7-2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 50 ml of absolute dioxane and 13 ml of a solution of diazopropane (0.4 mmoles/ml) in ether are added thereto. Then 4 ml of a solution of iso-propyltitanate ~772~
(0.00~ mmoles/ml) and titanium tetrachlcride (0.005 mmoles/ml) in dioxane are added. ~he solution is allGwed to stand for 3 to
Example 4 _ 1 g of 3~-O-I~,L-rhamnosido]-14-h~droxy-4,5-epox~.~-bufa-20,22-dienolide is dissol~ed in 50 ml of absolute dioxane and 20 ml of ethynyldiazome~hane tO.2 mmoles/ml) are added. Then 2 ml of a solution of n-butylti~anate in dioxane (0.05 mmoles/ml; 0.85 ~0 ml of n-butyltitanate in 50 ml of ab~ol~lte dioxane) are added and it is allowed to stand for 4 to 6 hours at room temperature.
Then it is worked up as described in ~xample 1. After recrystal-11~772~ -lization from acetic acid ethyl ester 1 g (93%) of pure 3~-O-(~,L-3'-propargylrhamnosido)-1~-hydroxy-4,5-epoxy-bufa-20,22-dienolide is obtained, mp. 228 to 237C.
Example 5 . _ 1 g of 3~-O-(~,L-rhamno~sido)-14-hydroxy-bufa-4,20,22-trienolide is dissolved in 40 ml of absolute dioxane and 15 ml of a solution of 3-(2-ethyl)-hexyloxydiazopropane-(1) (0.6 mmoles/
ml) in ether are added. Then 2 ml of a solution of n-propyl-titanate (0.05 mmoles/ml) and titan um tetrachloride (0.005 mmoles/
ml) are added, as described in Example 2, and allowed to stand for 16 hours at room temperature. Then the solution is worked up, as described in Example 1. After recrystallization from acetic acid ethylester 1.1 g (85%) of pure 3~-O-[~,L-3'-(3"-(2"-ethyl)-hexyloxypropyl)-rhamnosido]-14-hydroxy-bufa-4,20,22-trienolide are obtained, mp. 225 to 230C.
Example 6 . .
3 g of 3~-O-(a,I,-rhamnosido)-14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 160 ml of absolute diox~ne and ~QLm1 of an etherica~lution of diazoeth~ Q.6 mmoles/ml) are added thereto. 1 ml of a solution of ethyltitanate and titanium tetrachloride in absolute dioxane (0.05 mmoles ethyl-titanate and 0.005 mmoles titanium tetrachloride/ml are added .
thereto and it is allcwed to stand for 4 to 6 hours at room temperature~ After working up as described in Example 1 3.5 g (93%) of pure 3~-O-(a,L-3'-ethylrhamnosido)-14-hydroxy-4,5-epoxy-20,22-kufa-dienolide are obtained after recrystallization from methanol-water, mp. 136 to 143C.
Example 7-2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 50 ml of absolute dioxane and 13 ml of a solution of diazopropane (0.4 mmoles/ml) in ether are added thereto. Then 4 ml of a solution of iso-propyltitanate ~772~
(0.00~ mmoles/ml) and titanium tetrachlcride (0.005 mmoles/ml) in dioxane are added. ~he solution is allGwed to stand for 3 to
4 hours at room temperature. After working up as described in Example 1 2.1 g (96%) of pure 3~-O-(~,L-3'-propylrhamnosido)-14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are obtained after recrystallization from methanol-water, mp. 2~0 to 235~C.
The catalyst solution is prepared by dissolving in a graduated flask 0.35 ml of iso-propyltitanate in absolute dioxane and adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml, see Example 1) in absolute dioxane and filling up to the marking with absolute dioxane.
Example 8 2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 50 ml of absolute dioxane and 63 ml of a solution of 3-methoxydiazopropane in ether (0.8 mmoles/
ml) are added thereto. To the solution 4 ml of a catalyst solution of iso-butyltitanate and titaniu.~ tetrachloride ( n . 05 mmoles iso-butyltitanate and 0.005 mmole.s titanium tetrachloride/ml) in dioxane are a~de~. After standing for 12 hours at room temperature it is worked up as described in Examp~e 1. After recrystalliz~tion from eth~nol-water 2.16 g (95%) of pure 3~-O-(~,L-~'-methoxy-propylrhamnos~do)-14-hydroxy-4,5-epox~-buffa-20,22-dienolide are obtained, mp. 225 to 240C.
The catalyst solution is prepared by dissolving 0.43 ml of iso-butyltitanate in a 25 ml-graduated flask in ab~olute dio-xane and adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml, as de~cribed in Example 1) and fillin~ up to the marking with dioxane.
Example _ 2 g of 3~ ,L-rhamnosido)-14-hydroxy-4,5-epcxy-bufa-20,22-dienolide are dissolved in 50 ml of absolute dioxane and 25 ml of a solution of 2-methoxydiazoethane (O.3 mmoles/ml) in xi 9 7~Y2~
ether are added. 4 ml of a mixture of cresyltitanate and titanium tetrachloride in dioxan~ (0.~% ~resyltitanate and 0.005 ml of titanium tetrachloride/ml) are added to the above solution. The .solution is allowed to stand for 16 hours at room temperature.
After working up as described in Example 1 2.15 g (~5%) of pure 3~-O-t~,L-3'-methoxyethylrhamnosido)-14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are obtained after recrystallization from methanol-water, mp. 21~ to 221C. -- ~
The catalyst solution is prepared by dissolving 0.1 g of cresyltitanate in some absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetrachLoride (0.05 mmoles/ml) in dioxane and filling up to the marking with dioxane.
Example 10 2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-bufa-4,20,22-trienolide are disso~ved in 50 ml of absolute d;oxane ~nd 20 ml - of a solution of 3-dimethylaminodiazopropane (0.4 mmoles/ml) in ether are added thereto. To the solution 4 ml of a solution of 2-ethylhexyltitanate and titanium tetrachloride (0.05 mmoles 2-ethylhexyltitanate and 0.005 mmoles titanium tetrachloride/ml) in absolute dioxane are added. After standing for 17 hours at room temperature the solution is worked up as described in Example 1. After recrystallization from acetic acid ethyl ester 2.1 g (94%~ of pure 3~-0-[~ 3'-(3"-dimethylaminopropyl)-rhamnosido]-14-hydroxy-bufa-4,20t22-trienolide are obtained, mp. 13~ to 146C.
The catalyst solution is prepared by dissolving 0.73 ml of 2-ethylh~xyltitanate in ~bsolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetra-chloride (0.05 mmoles/ml, see Example 1) in dioxane and filling up to the marking with absolutc dicxanc.
Example 11 _ . _ 2 g of 3~-O-~,L-rhamnosido)-l~-hydroxy-bufa-4,20,22-~1~77Z~
trienolide are dissolved in 50 ml of absolu~e dioxane and ~0 ml of a solution of 2-phenyldiazoethane (0.4 mmoles/ml) in ether are added. Then 4 ml of a mixture of e~hyltitanate (0.05 mm~les/
ml) and titanium tetrachloride (0.005 mmoles/ml) in absolute dioxane are added and the solution is allowed to stand 16 hours at room temperature. After working up as described in Example 1 2.2 g (94%! of pure 3~-O-[~,L-3'-(2"-phenylethyl)-rhamnosido]-14-hydroxy-bufa-4,20,22-trienolide are obtained after recrystal-lization from acetic acid ethyl ester, mp. 180 to 195C.
The catalyst solution is prepared b dissolving 0.28 ml of ethyl tit~nate in some absolute dioxane in a 2~ ml-graduated flask, adding 2.5 ml--of a solution of titanium tetrachloride (0.05 mmoles/ml) in dioxane and filljng up to the marking with absolute dioxane.
Ex~mple 12 2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-bufa-4,20,22-trienolide a~e dissolved in 50 ml of absolute dioxane and 25 ml of a solution of diazopropyne (0.3 mmoles) in ether are added.
Then 4 ml of a mixture of titanium acetylacetonate (0.4%) and titanil~m tetrachloride (0.005 mmoles/ml) in dioxane are added.
After standing for 14 hours at room temperature and working up as described in Example 1 2.1 g (93%) of pure 3~-O-[~,L-3'-(propyne-3")-rhamnosido]-14-hydroxy-bufa-4,20,22-trienolide are obtained after ~ecrystallization from acetic acid ethyl ester, mp. 170 to 175~C.
The catalyst so]ution is prepared by dissolving 0.1 ml of titanium acetylacetonate in absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetra-chloride (0.05 mmol~sjml) in absolute dioxane (see Example 1) and filling up to the marking with absolute dioxane.
The catalyst solution is prepared by dissolving in a graduated flask 0.35 ml of iso-propyltitanate in absolute dioxane and adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml, see Example 1) in absolute dioxane and filling up to the marking with absolute dioxane.
Example 8 2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are dissolved in 50 ml of absolute dioxane and 63 ml of a solution of 3-methoxydiazopropane in ether (0.8 mmoles/
ml) are added thereto. To the solution 4 ml of a catalyst solution of iso-butyltitanate and titaniu.~ tetrachloride ( n . 05 mmoles iso-butyltitanate and 0.005 mmole.s titanium tetrachloride/ml) in dioxane are a~de~. After standing for 12 hours at room temperature it is worked up as described in Examp~e 1. After recrystalliz~tion from eth~nol-water 2.16 g (95%) of pure 3~-O-(~,L-~'-methoxy-propylrhamnos~do)-14-hydroxy-4,5-epox~-buffa-20,22-dienolide are obtained, mp. 225 to 240C.
The catalyst solution is prepared by dissolving 0.43 ml of iso-butyltitanate in a 25 ml-graduated flask in ab~olute dio-xane and adding 2.5 ml of a solution of titanium tetrachloride (0.05 mmoles/ml, as de~cribed in Example 1) and fillin~ up to the marking with dioxane.
Example _ 2 g of 3~ ,L-rhamnosido)-14-hydroxy-4,5-epcxy-bufa-20,22-dienolide are dissolved in 50 ml of absolute dioxane and 25 ml of a solution of 2-methoxydiazoethane (O.3 mmoles/ml) in xi 9 7~Y2~
ether are added. 4 ml of a mixture of cresyltitanate and titanium tetrachloride in dioxan~ (0.~% ~resyltitanate and 0.005 ml of titanium tetrachloride/ml) are added to the above solution. The .solution is allowed to stand for 16 hours at room temperature.
After working up as described in Example 1 2.15 g (~5%) of pure 3~-O-t~,L-3'-methoxyethylrhamnosido)-14-hydroxy-4,5-epoxy-bufa-20,22-dienolide are obtained after recrystallization from methanol-water, mp. 21~ to 221C. -- ~
The catalyst solution is prepared by dissolving 0.1 g of cresyltitanate in some absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetrachLoride (0.05 mmoles/ml) in dioxane and filling up to the marking with dioxane.
Example 10 2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-bufa-4,20,22-trienolide are disso~ved in 50 ml of absolute d;oxane ~nd 20 ml - of a solution of 3-dimethylaminodiazopropane (0.4 mmoles/ml) in ether are added thereto. To the solution 4 ml of a solution of 2-ethylhexyltitanate and titanium tetrachloride (0.05 mmoles 2-ethylhexyltitanate and 0.005 mmoles titanium tetrachloride/ml) in absolute dioxane are added. After standing for 17 hours at room temperature the solution is worked up as described in Example 1. After recrystallization from acetic acid ethyl ester 2.1 g (94%~ of pure 3~-0-[~ 3'-(3"-dimethylaminopropyl)-rhamnosido]-14-hydroxy-bufa-4,20t22-trienolide are obtained, mp. 13~ to 146C.
The catalyst solution is prepared by dissolving 0.73 ml of 2-ethylh~xyltitanate in ~bsolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetra-chloride (0.05 mmoles/ml, see Example 1) in dioxane and filling up to the marking with absolutc dicxanc.
Example 11 _ . _ 2 g of 3~-O-~,L-rhamnosido)-l~-hydroxy-bufa-4,20,22-~1~77Z~
trienolide are dissolved in 50 ml of absolu~e dioxane and ~0 ml of a solution of 2-phenyldiazoethane (0.4 mmoles/ml) in ether are added. Then 4 ml of a mixture of e~hyltitanate (0.05 mm~les/
ml) and titanium tetrachloride (0.005 mmoles/ml) in absolute dioxane are added and the solution is allowed to stand 16 hours at room temperature. After working up as described in Example 1 2.2 g (94%! of pure 3~-O-[~,L-3'-(2"-phenylethyl)-rhamnosido]-14-hydroxy-bufa-4,20,22-trienolide are obtained after recrystal-lization from acetic acid ethyl ester, mp. 180 to 195C.
The catalyst solution is prepared b dissolving 0.28 ml of ethyl tit~nate in some absolute dioxane in a 2~ ml-graduated flask, adding 2.5 ml--of a solution of titanium tetrachloride (0.05 mmoles/ml) in dioxane and filljng up to the marking with absolute dioxane.
Ex~mple 12 2 g of 3~-O-(~,L-rhamnosido)-14-hydroxy-bufa-4,20,22-trienolide a~e dissolved in 50 ml of absolute dioxane and 25 ml of a solution of diazopropyne (0.3 mmoles) in ether are added.
Then 4 ml of a mixture of titanium acetylacetonate (0.4%) and titanil~m tetrachloride (0.005 mmoles/ml) in dioxane are added.
After standing for 14 hours at room temperature and working up as described in Example 1 2.1 g (93%) of pure 3~-O-[~,L-3'-(propyne-3")-rhamnosido]-14-hydroxy-bufa-4,20,22-trienolide are obtained after ~ecrystallization from acetic acid ethyl ester, mp. 170 to 175~C.
The catalyst so]ution is prepared by dissolving 0.1 ml of titanium acetylacetonate in absolute dioxane in a 25 ml-graduated flask, adding 2.5 ml of a solution of titanium tetra-chloride (0.05 mmol~sjml) in absolute dioxane (see Example 1) and filling up to the marking with absolute dioxane.
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing an ether of bufadienolide and bufatrienolide of the general formula (I) in which formula X is a double bond between the carbon atoms 4 and 5 or an epoxide group, R' is a methyl formyl or methylol group and R is hydrogen, a straight or branched alkyl radical having 1 to 16 carbon atoms, a straight or branched alkenyl radical having 2 to 6 carbon atoms, an ethyinyl radical a straight or branched alkoxy radical having 2 to 11 carbon atoms, a cycloaliphatic radical, the group CH2 attached on R forming together with R a nucleus having 6 to 12 carbon atoms, an aromatic or aliphatic-aromatic radical, a straight or branched dialkylaminoalkyl radical having 1 to 7 carbon atoms the nitrogen atom of which is tertiary and may carry two alkyl radicals having 1 to 4 carbon atoms, in which substituents the straight or branched aliphatic chains may be substituted by nitrogen or oxygen-containing heterocycles, or by halogen except for compounds in which X is a double bond R' is methyl and R is H, R is methyl, X is a double bond, and R is alkyl having 4 or 5 carbon atoms, and R' is formyl, X is a double bond and R is hydrogen or an alkyl group having 1 to 5 carbon atoms, which process comprises reacting a glycoside of bufadienolide or bufatrienolide of the general formula (II) in which X and R' are as defined above, with a diazoalkane of the general formula R.CH.N2 (III) in which R is as defined above, in an inert solvent and in the presence of a catalyst selected from a mixture of titanium tetra-chloride and boric acid a mixture of an titanic acid ester and titanium tetrachloride and a titanic acid ester alone in absolute dioxane.
2. A process as claimed in claim 1 in which in the compound of formula II is selected from 3.beta.-O-(.alpha.,L-rhamnosido)-14-hydroxy-4,5-epoxy-bufa-20,22-dienolide and 3.beta.-O-(.alpha.,L-rhamnosido)-14-hydroxy-bufa-4,20,22-trienolide and the diazoalkane of formula III is selected from 2 ethyl diazohexane, diazomethane, 2-chloro diazoethane, ethyinyl. diazomethane, 3-(2-ethyl)-hexyloxydiazopropane-(1), diazoethane, diazopropane, 3-methoxy diazopropane, 2-methoxy diazoethane, 3-dimethylamino-diazopropane, 2-phenyl diazoethane and diazopropyne
3. A process as claimed in claim 1 or 2 in which the titanic acid ester is selected from ethyltitanate, n-propyl-, isopropyl-, n-butyl-, isobutyl-, cresyl-, 2-ethyl or -hexyltitan-ate and diisopropoxy-bis-(2,4-pentandionato)-titanium(IV).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0405677A AT368523B (en) | 1977-06-08 | 1977-06-08 | METHOD FOR PRODUCING BUFADIENOLID AND BUFATRIENOLIDAETHERS |
| ATA4056/77 | 1977-06-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1107720A true CA1107720A (en) | 1981-08-25 |
Family
ID=3559053
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA304,930A Expired CA1107720A (en) | 1977-06-08 | 1978-06-07 | Process for preparing ethers of bufadienolide and bufatrienolide |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS5416463A (en) |
| AT (1) | AT368523B (en) |
| BE (1) | BE867944A (en) |
| CA (1) | CA1107720A (en) |
| CH (1) | CH637145A5 (en) |
| DE (1) | DE2824318A1 (en) |
| EG (1) | EG13431A (en) |
| ES (1) | ES470578A2 (en) |
| FI (1) | FI62844C (en) |
| FR (1) | FR2393813A2 (en) |
| GB (1) | GB1601539A (en) |
| IL (1) | IL54850A0 (en) |
| IT (1) | IT1109164B (en) |
| LU (1) | LU79783A1 (en) |
| NL (1) | NL7805797A (en) |
| SE (1) | SE442015B (en) |
| YU (1) | YU40194B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2325467B (en) * | 1997-05-21 | 2000-11-01 | Dainippon Ink & Chemicals | Process for producing material with hydrophilic surface |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1905725A1 (en) * | 1969-02-06 | 1970-08-20 | Boehringer Mannheim Gmbh | Acovenoside A derivatives and processes for making the same |
| DE1910207C3 (en) * | 1969-02-28 | 1978-04-13 | Knoll Ag, 6700 Ludwigshafen | Process for their manufacture |
| DE2404268C2 (en) * | 1974-01-30 | 1982-09-16 | Knoll Ag, 6700 Ludwigshafen | Proscillaridin ethers and process for their preparation |
| AT349159B (en) * | 1974-07-09 | 1979-03-26 | Laevosan Gmbh & Co Kg | PROCESS FOR THE PREPARATION OF NEW BUFADIENOLIDE AND BUFATRIENOLIDE Aethers |
-
1977
- 1977-06-08 AT AT0405677A patent/AT368523B/en not_active IP Right Cessation
-
1978
- 1978-05-23 CH CH557778A patent/CH637145A5/en not_active IP Right Cessation
- 1978-05-26 GB GB22676/78A patent/GB1601539A/en not_active Expired
- 1978-05-29 YU YU1279/78A patent/YU40194B/en unknown
- 1978-05-29 NL NL7805797A patent/NL7805797A/en not_active Application Discontinuation
- 1978-05-31 IT IT24056/78A patent/IT1109164B/en active
- 1978-05-31 SE SE7806364A patent/SE442015B/en not_active IP Right Cessation
- 1978-06-02 DE DE19782824318 patent/DE2824318A1/en active Granted
- 1978-06-02 IL IL7854850A patent/IL54850A0/en unknown
- 1978-06-06 FR FR787816874A patent/FR2393813A2/en active Granted
- 1978-06-06 JP JP6733378A patent/JPS5416463A/en active Granted
- 1978-06-07 ES ES470578A patent/ES470578A2/en not_active Expired
- 1978-06-07 EG EG365/78A patent/EG13431A/en active
- 1978-06-07 FI FI781823A patent/FI62844C/en not_active IP Right Cessation
- 1978-06-07 CA CA304,930A patent/CA1107720A/en not_active Expired
- 1978-06-08 LU LU79783A patent/LU79783A1/en unknown
- 1978-06-08 BE BE188429A patent/BE867944A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6213359B2 (en) | 1987-03-25 |
| SE442015B (en) | 1985-11-25 |
| GB1601539A (en) | 1981-10-28 |
| IL54850A0 (en) | 1978-08-31 |
| FR2393813B2 (en) | 1982-08-27 |
| DE2824318A1 (en) | 1978-12-21 |
| AT368523B (en) | 1982-10-25 |
| CH637145A5 (en) | 1983-07-15 |
| DE2824318C2 (en) | 1987-10-01 |
| ATA405677A (en) | 1982-02-15 |
| FI62844C (en) | 1983-03-10 |
| FI781823A (en) | 1978-12-09 |
| IT1109164B (en) | 1985-12-16 |
| EG13431A (en) | 1982-06-30 |
| BE867944A (en) | 1978-10-02 |
| JPS5416463A (en) | 1979-02-07 |
| FR2393813A2 (en) | 1979-01-05 |
| LU79783A1 (en) | 1978-11-28 |
| YU40194B (en) | 1985-08-31 |
| SE7806364L (en) | 1978-12-09 |
| NL7805797A (en) | 1978-12-12 |
| FI62844B (en) | 1982-11-30 |
| YU127978A (en) | 1982-10-31 |
| IT7824056A0 (en) | 1978-05-31 |
| ES470578A2 (en) | 1979-04-01 |
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