CA1192189A - E-homo-eburnane derivatives and a process for preparing same - Google Patents
E-homo-eburnane derivatives and a process for preparing sameInfo
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- CA1192189A CA1192189A CA000431510A CA431510A CA1192189A CA 1192189 A CA1192189 A CA 1192189A CA 000431510 A CA000431510 A CA 000431510A CA 431510 A CA431510 A CA 431510A CA 1192189 A CA1192189 A CA 1192189A
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- alpha
- process according
- homo
- eburnane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
E-homo-eburnane derivatives process for their preparation, and pharmaceutical compositions containing these compounds A b s t r a c t The invention relates to racemic or optically active E-homo-eburnane derivatives of the formula /I/, /I/
wherein R1 and R2 independently represent an alkyl group having 1 to 6 carbon atoms, and acid addition salts thereof.
The new compounds are pharmaceutically active, for example their certain representatives, in particular from the cis-series, show antidepressive activity, while others, especially the compounds of the trans-series, are potent anthypoxial agents. The compounds of the formula /I/
and pharmaceutically acceptable acid addition salts thereof can therefore be employed as active ingredients of pharmaceutical compositions.
wherein R1 and R2 independently represent an alkyl group having 1 to 6 carbon atoms, and acid addition salts thereof.
The new compounds are pharmaceutically active, for example their certain representatives, in particular from the cis-series, show antidepressive activity, while others, especially the compounds of the trans-series, are potent anthypoxial agents. The compounds of the formula /I/
and pharmaceutically acceptable acid addition salts thereof can therefore be employed as active ingredients of pharmaceutical compositions.
Description
tJ~
E-homo-eburnane derivatl_es, process for th.ir preparatiorl, and_pharmaceutical compositions containin~ these comr,ounds This invention relates to new E-homo eburnane derlvatives, process for their preparation, and pharmaceutical compositions containing them as active ingredient. More particularly, the invention concerns ne~"
racemic or optically active E-homo-eburnane derivatives of the forn~ula /I/, ~ /I/
~\/
E-homo-eburnane derivatl_es, process for th.ir preparatiorl, and_pharmaceutical compositions containin~ these comr,ounds This invention relates to new E-homo eburnane derlvatives, process for their preparation, and pharmaceutical compositions containing them as active ingredient. More particularly, the invention concerns ne~"
racemic or optically active E-homo-eburnane derivatives of the forn~ula /I/, ~ /I/
~\/
2 ) R2 wherein Rl and R2 independently represent an alkyl group having 1 to 6 carbon atoms, and acid addition salts thereof.
According to another aspect of the invention there is provided a process for the preparation of racemic or optically active E-homo-eburnane derivatives of the formula /I/, which process comprises subjecting a racemic A 2915 - 67 PT/Gi or opticall.y active octahydroindolo/~,3-a7quinoline derivative of the formula /II/, P 3 2 C/~ C H 2 wherein A is hydrogen or a -CH2-CH/C02R1/2 or -CH2-c/co2R /2-CH2~cH/co2R /2 in which Rl and R2 are as defined above, R3 is identical with Rl or, il A represents 'nydrosen, R3 may also stand for hydrogen, or an acid addition salt thereof to ring closure, resol.v-ing, if desired, the compounds of the formula /I/ obtained and/or convertin~ the racemic or optically active compounds of the formula /I/ into acid~addition salts thereof.
The compounds of the formula /I/ are pharmaceutical-ly active, for example their certain representatives, in particular those from the cis-series, show antidepressive activity, while others, especially the compounds of the trans-series, are potent antihypoxial agents.
According to a further aspect of the invention there are provided pharmaceutical compositions, which comprise as an active ingredient at l.east one racemic or optically active E-homo-eburnane derivative of the formula /I/ or a pharmaceutically acceptable acid addition salt thereof, in admixture with inert solid or liquid pharmaceutical carriers and/or additives.
The term "alkyl group having 1 to ~ carbon atoms"
as used herei.n means ~traight or branched chained aliphatic hydrocarbon groups having l to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, ter~.--butyl, n-pentyl, isopentyl, n-hexyl or isohexyl groups, etc.
If desired, the compounds of the formula /I/ may be converted into their acid addition sal s. ~uitable acids for this purpose include inorganic acids, such as hydrogen halides, e~G~. hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perhaloic acids e.g.
perchloric acid, etc.; organic carboxylic acids such as formic acid 9 acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicyli.c acid, lactic acid, cinnalmic acid, benzoic acid, phenylacetic acid, ~-amino-benzoic acid, ~-hydroxy-benzoic acid, p-amino-salicylic acid, etc.; alkylsulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, etc ;
cycloaliphatic acids, e.g cyclohexylsulfonic acid; aryl-sulfonic acids, e~g. p-toluene-sulfonic acid, naphthyl-sulfonic acid, sulfanylic acid, etc.; amino acids, such asasparaginic acid, glutaminic acid, ~ acetyl-asparaOinic acid, N-acetyl-glutaric acid, etc.
The starting compounds oE` the for;nula /II/ can be prepared as described in the Belgian patent specification ~lo. 883,576 by electrophilic alkylation of tr.e correspond-ing hexahydroindolo/2,3-a7quinolizinium salts with a methylenemalonic acid dialkylester and subsequent hydrogena-tion and, if desired, a further partial hydrolysis.
The cyclization of the compounds of the form~lla /II/, in which A stands for a hydrogen atom or a CH2-CH/C02~1/2 or -CH2-C/C02Rl/2-CE~2-CEI/C02Rl/2 group, ~3 `~s the same meaning as Rl and Rl and R2 are as defined above, can be carried out with sufficiently strong bases, e.g. alkali metal hydri~es, such as sodium nydride, potassium hydride, etc,, alkali metal alcoholates, suc~ as ootassium or sodium ethylate, preferably potassium ter .-butylate in aprotic or-,anic solvents, such as xy]ene, toluene, preferably benzene. The cyclization is preferably perform-ed at the boiling temperature of the reaction mixture.The reaction is completed in a very short timie, generally in 10 to 40 minutes, preferably 15 to 30 minutes.
The ring closure of the compounds of the formula /II/, in which A and R3 stand for a hydrogen atom, Rl and R2 have the same meaning as defined above, is carried out with a dehydrating agent, preferably phosphorus oxychloride or phosphorus pentoxide, preferably in an organic solvent inert under the reaction conditions, such Df~
as aromatic hydrocarbons, preferably ben~ene, or chlorina~ed hydrocarbons r e.~. chloroform or carbon tetrachloride.
If the compounds of the formula /II/ are used in the form of their acid addition salts, e.g. hydrogen halides, perchlorates, etc., it is preferred to set free the basic compounds from their salts before cyclization.
The liberation of the bases can for example be carried out with a dilute aqueous solution of an inor~anic base, such as an alkali metal carbonate, e.g. sodium carbonate, potassium carbonate, an alkali metal hydroxide, e.~.
sodium hydroxide, potassium hydroxide, etc., in a ~.iater--i;nmiscible inert organic solvent, such as halogenated hydrocarbons, e.g. dichloromethane, chloroform etc.
By the process according to the invention both cis- and trans-compounds of the for.nula /I/ can be prepared from the corresponding cis- and trans-compounds of the formula /II/, respectively.
3y th- process according to the invention racemic and optically active cornpounds of the formula /I/ can equally be prepared. Starting from racemic compouncs, racemic end products of the formula /I/ are obtained which, if desired, can be resolved by conventional techniques. From optically active starting compounds directly optically active end products can be obtained.
The racemic or optically active compounds of the formula /I/ can be converted into their acid addition scllts ;~ith an organic or inorganic acid.
T'ne salls are generally prepared in an inert organic solvent, for examp1e in an aliphatic alcohol havinT 1 to 6 carbon atoms, by dissolvinO the raCeMiC
or optically active compounds of the formula /1/ in said solvent addin~ he correspondin T acid into the solution while the p~ becomes slightly acidic /about pH 6/ ar.d subsequently separatinT the acid addition salt obtained from the re~ction mixture preferably by precipitatinO with a water-immiscible organic solvent, such as diethyl ether.
If desired, the racemic or optically active COmDO-In~S of the formula /I/ or acid addition salts there-of nay be s~lbJected to further purification e.g. re-crystall zation. The solvents used for recrystallization a~e selec'el in accordanc- with the solubility and crystallizability of the comDounds ~o be recrystalli7ed.
Th.e -ntihypoxial activi y of certain compounds ~itnin th-- scope of t'ne invention, par icllarly of
According to another aspect of the invention there is provided a process for the preparation of racemic or optically active E-homo-eburnane derivatives of the formula /I/, which process comprises subjecting a racemic A 2915 - 67 PT/Gi or opticall.y active octahydroindolo/~,3-a7quinoline derivative of the formula /II/, P 3 2 C/~ C H 2 wherein A is hydrogen or a -CH2-CH/C02R1/2 or -CH2-c/co2R /2-CH2~cH/co2R /2 in which Rl and R2 are as defined above, R3 is identical with Rl or, il A represents 'nydrosen, R3 may also stand for hydrogen, or an acid addition salt thereof to ring closure, resol.v-ing, if desired, the compounds of the formula /I/ obtained and/or convertin~ the racemic or optically active compounds of the formula /I/ into acid~addition salts thereof.
The compounds of the formula /I/ are pharmaceutical-ly active, for example their certain representatives, in particular those from the cis-series, show antidepressive activity, while others, especially the compounds of the trans-series, are potent antihypoxial agents.
According to a further aspect of the invention there are provided pharmaceutical compositions, which comprise as an active ingredient at l.east one racemic or optically active E-homo-eburnane derivative of the formula /I/ or a pharmaceutically acceptable acid addition salt thereof, in admixture with inert solid or liquid pharmaceutical carriers and/or additives.
The term "alkyl group having 1 to ~ carbon atoms"
as used herei.n means ~traight or branched chained aliphatic hydrocarbon groups having l to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, ter~.--butyl, n-pentyl, isopentyl, n-hexyl or isohexyl groups, etc.
If desired, the compounds of the formula /I/ may be converted into their acid addition sal s. ~uitable acids for this purpose include inorganic acids, such as hydrogen halides, e~G~. hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perhaloic acids e.g.
perchloric acid, etc.; organic carboxylic acids such as formic acid 9 acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicyli.c acid, lactic acid, cinnalmic acid, benzoic acid, phenylacetic acid, ~-amino-benzoic acid, ~-hydroxy-benzoic acid, p-amino-salicylic acid, etc.; alkylsulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, etc ;
cycloaliphatic acids, e.g cyclohexylsulfonic acid; aryl-sulfonic acids, e~g. p-toluene-sulfonic acid, naphthyl-sulfonic acid, sulfanylic acid, etc.; amino acids, such asasparaginic acid, glutaminic acid, ~ acetyl-asparaOinic acid, N-acetyl-glutaric acid, etc.
The starting compounds oE` the for;nula /II/ can be prepared as described in the Belgian patent specification ~lo. 883,576 by electrophilic alkylation of tr.e correspond-ing hexahydroindolo/2,3-a7quinolizinium salts with a methylenemalonic acid dialkylester and subsequent hydrogena-tion and, if desired, a further partial hydrolysis.
The cyclization of the compounds of the form~lla /II/, in which A stands for a hydrogen atom or a CH2-CH/C02~1/2 or -CH2-C/C02Rl/2-CE~2-CEI/C02Rl/2 group, ~3 `~s the same meaning as Rl and Rl and R2 are as defined above, can be carried out with sufficiently strong bases, e.g. alkali metal hydri~es, such as sodium nydride, potassium hydride, etc,, alkali metal alcoholates, suc~ as ootassium or sodium ethylate, preferably potassium ter .-butylate in aprotic or-,anic solvents, such as xy]ene, toluene, preferably benzene. The cyclization is preferably perform-ed at the boiling temperature of the reaction mixture.The reaction is completed in a very short timie, generally in 10 to 40 minutes, preferably 15 to 30 minutes.
The ring closure of the compounds of the formula /II/, in which A and R3 stand for a hydrogen atom, Rl and R2 have the same meaning as defined above, is carried out with a dehydrating agent, preferably phosphorus oxychloride or phosphorus pentoxide, preferably in an organic solvent inert under the reaction conditions, such Df~
as aromatic hydrocarbons, preferably ben~ene, or chlorina~ed hydrocarbons r e.~. chloroform or carbon tetrachloride.
If the compounds of the formula /II/ are used in the form of their acid addition salts, e.g. hydrogen halides, perchlorates, etc., it is preferred to set free the basic compounds from their salts before cyclization.
The liberation of the bases can for example be carried out with a dilute aqueous solution of an inor~anic base, such as an alkali metal carbonate, e.g. sodium carbonate, potassium carbonate, an alkali metal hydroxide, e.~.
sodium hydroxide, potassium hydroxide, etc., in a ~.iater--i;nmiscible inert organic solvent, such as halogenated hydrocarbons, e.g. dichloromethane, chloroform etc.
By the process according to the invention both cis- and trans-compounds of the for.nula /I/ can be prepared from the corresponding cis- and trans-compounds of the formula /II/, respectively.
3y th- process according to the invention racemic and optically active cornpounds of the formula /I/ can equally be prepared. Starting from racemic compouncs, racemic end products of the formula /I/ are obtained which, if desired, can be resolved by conventional techniques. From optically active starting compounds directly optically active end products can be obtained.
The racemic or optically active compounds of the formula /I/ can be converted into their acid addition scllts ;~ith an organic or inorganic acid.
T'ne salls are generally prepared in an inert organic solvent, for examp1e in an aliphatic alcohol havinT 1 to 6 carbon atoms, by dissolvinO the raCeMiC
or optically active compounds of the formula /1/ in said solvent addin~ he correspondin T acid into the solution while the p~ becomes slightly acidic /about pH 6/ ar.d subsequently separatinT the acid addition salt obtained from the re~ction mixture preferably by precipitatinO with a water-immiscible organic solvent, such as diethyl ether.
If desired, the racemic or optically active COmDO-In~S of the formula /I/ or acid addition salts there-of nay be s~lbJected to further purification e.g. re-crystall zation. The solvents used for recrystallization a~e selec'el in accordanc- with the solubility and crystallizability of the comDounds ~o be recrystalli7ed.
Th.e -ntihypoxial activi y of certain compounds ~itnin th-- scope of t'ne invention, par icllarly of
3~,17cL-Irans-derivatives was ~ested on T;he survival time of mice, in normobaric hypoxia.
The test was carried out as follows:
Five male mice are placed into a 3-litre glass cylinder through which a mixture of 96 3,/ nitrogen and
The test was carried out as follows:
Five male mice are placed into a 3-litre glass cylinder through which a mixture of 96 3,/ nitrogen and
4 % oxygen is passed. The interval between placing the mice into the cylinder and the deat'n of the animals is measured. Animals livinO at least t~lice as long as the average survival time of the untreated animals are cor.sidered protected. The animals are treated in groups of 10, administering an intraperitoneal dose of 50 m3./k,g.
of bodyweight 30 minutes before placing them into the ~lass cylinder.
The results are set forth in the following ~able.
Table -~urvival time Protection Compound Average min.
_ J+/-Trans-14-oxo-15-ethoxycarbonyl-E homo-eburnane 15/3 p,l7c~/ 8.3+1.1 +32 20 Control 6.3+1.45 - 0 Vincamine 7.1+1.30 +13 0 Of the compounds of the formula /I/ especially the 3 ~,17c~-cis compounds are potent antidepressive agents.
The active ingredients of the formula /I/ or pharmaceutically acceptable acid addition salts thereof can be converted into pharmaceutical compositions for parenteral or enteral administration by admixing them with solid and/or liquid carriers and/or further adclitives conventionally used in the preparation of pharmaceutical compositions. As a carrier for example ~ater, gelatine, JL~
lac~ose, starch, pectine, magnesium stearate, stearic acid, talc, vegetable oils, e,g, peanut oil, olive oil, etc, can be employed, The compositions may be finished in the forrn of solid, e.g. tablets, lozen~es, dragées, capsules, such as hard gelatine capsules, suppositories, etc, or liquid, e.g, oily or aqueous solutions, suspensions, emulsions, syrups, soft gelatine capsules, injectable oily or aqueous solutions or suspensions, etc. formulations, The quantity of the solid carrier can be varied within a wide range but preferably is between about 25 mg. and 1 g, The pharrilaceutical compositions optionally contain also conventional pharmaceutical additives, such as preservatives, s'abilizing, wetting, emulsifying agents, salts ca?able of adjusting the osmotic oressure, buffers, flai;ouring agents, aroma aOents, etc. Optionally further phar~aceutical-ly active compoun~s can also be present in the formulations.
lhe pharmaceutical cormpositions are ?ref-rably manufactured in dosage units, suitable for ~he ~esired route of administration, The pharmaceutical com?ositions may be prepared by conventional techni~ues, which comprise i`or example screening, admixing, granulating, pressing or dissolving of the components, The compositions obtained can be subjected to further operations conventionally used in the pharmaceutical industry, for example sterilization;
Further details of the present invention are to be found in the following Examples which are, however, by no means intended to limit the scope of the protection sought, Example 1 /+/-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane /3 ~L,17 ~/
From &00 mg. /1.90 mmoles/ of /+/~lo~-ethy~
/2',2'-diethoxycarbonylethyl/-1,2,3,4,6,7~12bC~-octahydro-indolo/~,3-a7quinolizine hydrochloride prepared according to the Belgian patent specification No. 883,576 the base is liberated in 25 ml. of dichloromethane with 10 ml. of a 10 % aqueous sodium carbonate solution. After separation the extraction is repeated by 5 ml. of dichloromethane.
The organic phases are collected, dried over solid, anhydrous magnesium sulfate, filtered and from the filtrate the solvent is eliminated by distillation in vacuo.
The oily residue is dissolved in 15 ml. of absolute benzene, to the solution ~58 mg. /2.3 mmoles/ of potassium tert.-butylate are added and the reaction mixture is refluxed under nitrogen atmosphere for 20 minutes.
After cooling, under cooling with ice the reaction mixture is neutralized to pH 6 with acetic acid and the solvent is then eliminated by distillation in vacuo. The evaporation residue is dissolved in 20 ml. of dichloro-methane, the solution is shaken with 10 ml. of a 5 %
aqueous sodium carbonate solution to adjust the pH to 9~
After separation the extraction is repeated with a further
of bodyweight 30 minutes before placing them into the ~lass cylinder.
The results are set forth in the following ~able.
Table -~urvival time Protection Compound Average min.
_ J+/-Trans-14-oxo-15-ethoxycarbonyl-E homo-eburnane 15/3 p,l7c~/ 8.3+1.1 +32 20 Control 6.3+1.45 - 0 Vincamine 7.1+1.30 +13 0 Of the compounds of the formula /I/ especially the 3 ~,17c~-cis compounds are potent antidepressive agents.
The active ingredients of the formula /I/ or pharmaceutically acceptable acid addition salts thereof can be converted into pharmaceutical compositions for parenteral or enteral administration by admixing them with solid and/or liquid carriers and/or further adclitives conventionally used in the preparation of pharmaceutical compositions. As a carrier for example ~ater, gelatine, JL~
lac~ose, starch, pectine, magnesium stearate, stearic acid, talc, vegetable oils, e,g, peanut oil, olive oil, etc, can be employed, The compositions may be finished in the forrn of solid, e.g. tablets, lozen~es, dragées, capsules, such as hard gelatine capsules, suppositories, etc, or liquid, e.g, oily or aqueous solutions, suspensions, emulsions, syrups, soft gelatine capsules, injectable oily or aqueous solutions or suspensions, etc. formulations, The quantity of the solid carrier can be varied within a wide range but preferably is between about 25 mg. and 1 g, The pharrilaceutical compositions optionally contain also conventional pharmaceutical additives, such as preservatives, s'abilizing, wetting, emulsifying agents, salts ca?able of adjusting the osmotic oressure, buffers, flai;ouring agents, aroma aOents, etc. Optionally further phar~aceutical-ly active compoun~s can also be present in the formulations.
lhe pharmaceutical cormpositions are ?ref-rably manufactured in dosage units, suitable for ~he ~esired route of administration, The pharmaceutical com?ositions may be prepared by conventional techni~ues, which comprise i`or example screening, admixing, granulating, pressing or dissolving of the components, The compositions obtained can be subjected to further operations conventionally used in the pharmaceutical industry, for example sterilization;
Further details of the present invention are to be found in the following Examples which are, however, by no means intended to limit the scope of the protection sought, Example 1 /+/-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane /3 ~L,17 ~/
From &00 mg. /1.90 mmoles/ of /+/~lo~-ethy~
/2',2'-diethoxycarbonylethyl/-1,2,3,4,6,7~12bC~-octahydro-indolo/~,3-a7quinolizine hydrochloride prepared according to the Belgian patent specification No. 883,576 the base is liberated in 25 ml. of dichloromethane with 10 ml. of a 10 % aqueous sodium carbonate solution. After separation the extraction is repeated by 5 ml. of dichloromethane.
The organic phases are collected, dried over solid, anhydrous magnesium sulfate, filtered and from the filtrate the solvent is eliminated by distillation in vacuo.
The oily residue is dissolved in 15 ml. of absolute benzene, to the solution ~58 mg. /2.3 mmoles/ of potassium tert.-butylate are added and the reaction mixture is refluxed under nitrogen atmosphere for 20 minutes.
After cooling, under cooling with ice the reaction mixture is neutralized to pH 6 with acetic acid and the solvent is then eliminated by distillation in vacuo. The evaporation residue is dissolved in 20 ml. of dichloro-methane, the solution is shaken with 10 ml. of a 5 %
aqueous sodium carbonate solution to adjust the pH to 9~
After separation the extraction is repeated with a further
5-ml. portion of dichloromethane and the organic phase is separated~ The combined organic phases are dried over solid, anhydrous magnesium sulfate, filtered and from the filtrate the solvent is eliminated by distillation in - 10 - .
acuo.
960 mg. of an oily product are obtained, which is then crystallized from 1.5 ml. of methanol.
480 mg. of the aimed compound are obtained.
Yield: 66.5 %.
Melting point: 143 to 144 C /ethanol/.
I~ spectrum /KBr/: 1738 /ester/, 1690 cm 1 /lactame/.
Mass spectrum /m/e, %/: 380 /M+, 100/, 379/35/, 363/20/, 352/17/, 351/26/, 335/12/, 323/9.1/, 307/55/, 252/35/, 237/17/.
lH-NMR sepctrum /CDC13, ~ /: 8.52-7.35 /4H, m,aromatic/, 4.31 /2H, q, J=7, 2Hz, OCH2/, 4.08 /lH, m, 3-H/, 3.75 /lH, d, J=ll Hz, 15-H/, 1.34 /3H, t, J+7.6 Hz, OCH2CH
0.91 /3H, t, J+8.1 Hz, CH2CH3/.
Example 2 /~/-Trans-14-oxo-15-ethoxycarbonyl-E-homo-eburnane /3 d~,17o_/
400 mg. /0.94 mmoles/ of /+/-1~ -ethyl-l~ -/2',2'--diethoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b p -octahydro-indolo/2,3-a7quinolizine obtained as a by-product in Example 1 of the Belgian patent specification ~o. 883,576 are dissolved in 10 ml. of absolute benzene, then 125 mg.
/1.11 mmoles/ of potassium tert.-butylate are added to the solution. The reaction mixture is refluxed under nitrogen atmosphere for 20 minutes.
The pH of the reaction mixture is adjusted to 6 with acetic acid under cooling with ice. Tne solvent is evaporated in vacuo, the residue is dissolved in 10 ml.
of dichloromethane and the solution is shaken with a 5 %
aqueous sodium carbonate solution to adjust the pH to 9.
The extraction is repeated with a further 5-ml portion of dichloromethane, and the combined organic phases are dried over solid anhydrous ma~nesium sulfate, filtered and from the filtrate the solvent is eliminated by distillation in vacuo. 300 mg. of an oily product are obtained which is then crystallized from 2 ml. of ethanol.
260 mg. of the aimed compound are obtained.
Yield: 73.0 %.
Meltin~ point: 173 to 175 C /ethanol/.
IR spectrum /KBr/: 2750-2700 /Bohlmann/, 1735 /ester/, 1680 cm 1 /lactame/.
Mass spectrum /m/e, %/: 380 /M~, 100/, 379/38/, 363/14/, 352/11/, 351/16/, 335/11/, 323/5.5/, 307/34/...
lH-NMR spectrum /CDC13, ~ /: 8.56-7.24 /4H, m, aromatic protones/, 4.32 /2H, q, J=7.6 Hz, OCH2/, 4.08 /lH, dd, Jl= 13-6 Hz J2=2.7 Hz, 15-H/, 3.41 /lH, s~ 3-H/, 1.35 /3H, t, J=7, 6Hz, OCH2CH3/, 0.74 /3H, t, J=6Hz, Example 3 /+/-Cis-14-oxo-15-ethQxycarbonyl-E-homo-eburnane /3dL,17c~/
From 634~5 mg. and 698.0 mg. /1 mmole/ of /+/-1~--ethyl-l ~-/2',2',4',4'-tetraethoxycarbonylbutyl/--1,2,3,4,6,7 t 12,12bO~-octahydroindolo/2,3-a7quinolizine hydrochloride and hydrogen perchlorate, respectively, the corresponding base is liberated with 10 ml. of a 10 %
aqueous sodium carbo~late solutlon in 25 ml. of dichloro-methane. The organic phases are combined, dried over solid, anhydrous magnesium sulfate, flltered and from the filtrate the solvent is distilled off in vacuo.
The residual oil is dissolved in 15 ml. of absolute benzene, then 145 mg. /1.3 mmoles/ of potassium tert.-butylate are added to the solution and the reaction mixture is refluxed under nltrogen atmosphere for half an hour. The reaction mixture is cooled down and its pH is adjusted to 6 with acetic acid. The solvent is distilled off in vacuo, the residue is dissolved in 10 ml. of dichloromethane, the solution is alkalized with 10 ml. of a 5 % aqueous sodium carbonate solution to oH 9 and is then extracted with a further 5-ml. portion of aqueous dichloromethane. The organic phases are collected, dried over solid, anhydrous magnesium sulfate, filtered and from the filtrate the organic solvent is eliminated by distillation in vacuo. Tne residual oily oroduct is crystal]ized from 1 ml. of ethanol.
307 mg. of the aimed compound are obtalned.
Yield: 80.& /0.
~lelting point: 143 to 144 C /ethanol/
Example 4 / /-Cis-14-oxo-15-ethoxycarbonyl-~-homo-eburnane /30_,17d~J
The procedure described in Example 3 is followed starting from 870 mg. /1 mmole/ of /~/-ld_-ethyl~
/2',2',4',4',6',6'-hexaethoxycarbonylhexyl-1,2,3,4,6,7,12,-12b ~octahydroindolo~,3-a7quinolizine hydrogenper-chlorate prepared according to the Belgian patent specification No. 883,576, 264 mg. of the aimed compound are obtained, Yield: 69.5 %.
Melting point: 142 to 143 C /ethanol/.
Example 5 /+/-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane /3 ~,17 ~ hydrochloride 200 mg. of /+/-cis-14-oxo-15-ethoxycarbonyl-E-homo--eburnane/3 ~,170~/ are dissol~ed in a mixture of 3 ml.
of dichloroethane and 2 ml, of ethyl alcohol and the pH of the solution is adjusted to 2 with hydrochloric acid in ethanol. The reaction mixture is evaporated to dryness and the evaporation residue is crystallized from 1.5 ml. o ethanol.
165 mg. of the aimed compound are obtained.
Yield: 75.2 ',~,.
~lelting point: 204 to 207 C /toluene/.
Example 6 /+/-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane /3 dL,17 ~J
300 mg. of /+/-lo~rethyl-l ~-/2'-carboxy-2'-ethoxy-carbonylethyl/-1?2,3,4,6,7,12,12ba~-octahydroindolo-/ 2,3-a7quinolizine prepared according to Example 5 o;r Example 6 of the F3elgian patent specification No. 883,576 are suspended in 2 ml, of absolute benzene and 2 ml. of phosp'norus oxychloride are added to the suspension under _ 14 -cooling with ice, Th- reaction mixture is then refluxed for 8 to 9 hours, with stirring.
The reaction mixture is cooled and is evaporated to dryness in vacuo The residue is triturated with 2 ml.
of ice water, its pH is adjusted to 9 wi~h a lO % aqueous sodium carbonate solution and the organic substance is extracted with three 2-ml. portions of dichloromethane.
The combined organic phases are dried over solid, anhydrous magnesium sulfate, filtered and from the filtrate the solvent is eliminated by distillation in vacuo. 226 mg.
of an oily product are obtained, which is then crys-tallized from 0.5 ml. of ethanol.
156 mg. of /~/-cis-14-oxo-15-ethoxycarbonyl E--homo-eburnane/3 d~,17d~/ are obtained.
Yield: 54,3 %, ~lelting point: 142 to 144 C /ethanol/.
IR spectrum /K3r/: 1725 /ester C0/, 1680 /lactame C0/.
acuo.
960 mg. of an oily product are obtained, which is then crystallized from 1.5 ml. of methanol.
480 mg. of the aimed compound are obtained.
Yield: 66.5 %.
Melting point: 143 to 144 C /ethanol/.
I~ spectrum /KBr/: 1738 /ester/, 1690 cm 1 /lactame/.
Mass spectrum /m/e, %/: 380 /M+, 100/, 379/35/, 363/20/, 352/17/, 351/26/, 335/12/, 323/9.1/, 307/55/, 252/35/, 237/17/.
lH-NMR sepctrum /CDC13, ~ /: 8.52-7.35 /4H, m,aromatic/, 4.31 /2H, q, J=7, 2Hz, OCH2/, 4.08 /lH, m, 3-H/, 3.75 /lH, d, J=ll Hz, 15-H/, 1.34 /3H, t, J+7.6 Hz, OCH2CH
0.91 /3H, t, J+8.1 Hz, CH2CH3/.
Example 2 /~/-Trans-14-oxo-15-ethoxycarbonyl-E-homo-eburnane /3 d~,17o_/
400 mg. /0.94 mmoles/ of /+/-1~ -ethyl-l~ -/2',2'--diethoxycarbonyl-ethyl/-1,2,3,4,6,7,12,12b p -octahydro-indolo/2,3-a7quinolizine obtained as a by-product in Example 1 of the Belgian patent specification ~o. 883,576 are dissolved in 10 ml. of absolute benzene, then 125 mg.
/1.11 mmoles/ of potassium tert.-butylate are added to the solution. The reaction mixture is refluxed under nitrogen atmosphere for 20 minutes.
The pH of the reaction mixture is adjusted to 6 with acetic acid under cooling with ice. Tne solvent is evaporated in vacuo, the residue is dissolved in 10 ml.
of dichloromethane and the solution is shaken with a 5 %
aqueous sodium carbonate solution to adjust the pH to 9.
The extraction is repeated with a further 5-ml portion of dichloromethane, and the combined organic phases are dried over solid anhydrous ma~nesium sulfate, filtered and from the filtrate the solvent is eliminated by distillation in vacuo. 300 mg. of an oily product are obtained which is then crystallized from 2 ml. of ethanol.
260 mg. of the aimed compound are obtained.
Yield: 73.0 %.
Meltin~ point: 173 to 175 C /ethanol/.
IR spectrum /KBr/: 2750-2700 /Bohlmann/, 1735 /ester/, 1680 cm 1 /lactame/.
Mass spectrum /m/e, %/: 380 /M~, 100/, 379/38/, 363/14/, 352/11/, 351/16/, 335/11/, 323/5.5/, 307/34/...
lH-NMR spectrum /CDC13, ~ /: 8.56-7.24 /4H, m, aromatic protones/, 4.32 /2H, q, J=7.6 Hz, OCH2/, 4.08 /lH, dd, Jl= 13-6 Hz J2=2.7 Hz, 15-H/, 3.41 /lH, s~ 3-H/, 1.35 /3H, t, J=7, 6Hz, OCH2CH3/, 0.74 /3H, t, J=6Hz, Example 3 /+/-Cis-14-oxo-15-ethQxycarbonyl-E-homo-eburnane /3dL,17c~/
From 634~5 mg. and 698.0 mg. /1 mmole/ of /+/-1~--ethyl-l ~-/2',2',4',4'-tetraethoxycarbonylbutyl/--1,2,3,4,6,7 t 12,12bO~-octahydroindolo/2,3-a7quinolizine hydrochloride and hydrogen perchlorate, respectively, the corresponding base is liberated with 10 ml. of a 10 %
aqueous sodium carbo~late solutlon in 25 ml. of dichloro-methane. The organic phases are combined, dried over solid, anhydrous magnesium sulfate, flltered and from the filtrate the solvent is distilled off in vacuo.
The residual oil is dissolved in 15 ml. of absolute benzene, then 145 mg. /1.3 mmoles/ of potassium tert.-butylate are added to the solution and the reaction mixture is refluxed under nltrogen atmosphere for half an hour. The reaction mixture is cooled down and its pH is adjusted to 6 with acetic acid. The solvent is distilled off in vacuo, the residue is dissolved in 10 ml. of dichloromethane, the solution is alkalized with 10 ml. of a 5 % aqueous sodium carbonate solution to oH 9 and is then extracted with a further 5-ml. portion of aqueous dichloromethane. The organic phases are collected, dried over solid, anhydrous magnesium sulfate, filtered and from the filtrate the organic solvent is eliminated by distillation in vacuo. Tne residual oily oroduct is crystal]ized from 1 ml. of ethanol.
307 mg. of the aimed compound are obtalned.
Yield: 80.& /0.
~lelting point: 143 to 144 C /ethanol/
Example 4 / /-Cis-14-oxo-15-ethoxycarbonyl-~-homo-eburnane /30_,17d~J
The procedure described in Example 3 is followed starting from 870 mg. /1 mmole/ of /~/-ld_-ethyl~
/2',2',4',4',6',6'-hexaethoxycarbonylhexyl-1,2,3,4,6,7,12,-12b ~octahydroindolo~,3-a7quinolizine hydrogenper-chlorate prepared according to the Belgian patent specification No. 883,576, 264 mg. of the aimed compound are obtained, Yield: 69.5 %.
Melting point: 142 to 143 C /ethanol/.
Example 5 /+/-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane /3 ~,17 ~ hydrochloride 200 mg. of /+/-cis-14-oxo-15-ethoxycarbonyl-E-homo--eburnane/3 ~,170~/ are dissol~ed in a mixture of 3 ml.
of dichloroethane and 2 ml, of ethyl alcohol and the pH of the solution is adjusted to 2 with hydrochloric acid in ethanol. The reaction mixture is evaporated to dryness and the evaporation residue is crystallized from 1.5 ml. o ethanol.
165 mg. of the aimed compound are obtained.
Yield: 75.2 ',~,.
~lelting point: 204 to 207 C /toluene/.
Example 6 /+/-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane /3 dL,17 ~J
300 mg. of /+/-lo~rethyl-l ~-/2'-carboxy-2'-ethoxy-carbonylethyl/-1?2,3,4,6,7,12,12ba~-octahydroindolo-/ 2,3-a7quinolizine prepared according to Example 5 o;r Example 6 of the F3elgian patent specification No. 883,576 are suspended in 2 ml, of absolute benzene and 2 ml. of phosp'norus oxychloride are added to the suspension under _ 14 -cooling with ice, Th- reaction mixture is then refluxed for 8 to 9 hours, with stirring.
The reaction mixture is cooled and is evaporated to dryness in vacuo The residue is triturated with 2 ml.
of ice water, its pH is adjusted to 9 wi~h a lO % aqueous sodium carbonate solution and the organic substance is extracted with three 2-ml. portions of dichloromethane.
The combined organic phases are dried over solid, anhydrous magnesium sulfate, filtered and from the filtrate the solvent is eliminated by distillation in vacuo. 226 mg.
of an oily product are obtained, which is then crys-tallized from 0.5 ml. of ethanol.
156 mg. of /~/-cis-14-oxo-15-ethoxycarbonyl E--homo-eburnane/3 d~,17d~/ are obtained.
Yield: 54,3 %, ~lelting point: 142 to 144 C /ethanol/.
IR spectrum /K3r/: 1725 /ester C0/, 1680 /lactame C0/.
Claims (35)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a racemic mixture or an optically active E-homo-eburnane derivative of the formula (I) or a pharmaceutically acceptable acid addition salt thereof (I) wherein R1 and R2 independently represent an alkyl group having 1 to 6 carbon atoms, which process comprises subjecting a racemic or optically active octahydroindolo[2,3-a]quinoline derivative of the formula (II) (II) wherein A is hydrogen or a -CH2-CH(CO2R1)Z or -CH2-C(CO2R1)2-CH2-CH(CO2R1)2 group, in which R1 and R2 are as defined above, R3 is identical with R1 or, if A stands for hydrogen, R3 may also represent a hydrogen atom, or a suitable acid addition salt thereof to ring closure, and where required resolving the compound of formula (I) so obtained or converting the racemic mixture or optically active compound of formula (I) into a pharmaceutically acceptable acid addition salt thereof.
2. A process according to claim 1, wherein an octahydroindolo [2,3-a]
quinolizine derivative of the formula (II), in which A is hydrogen or a -CH2-CH(CO2R1)2 or -CH2-CH(CO2R1)2-CH2- CH(CO2R1) group, R3 is identical with R1 and R1 and R2 are as defined in claim 1, is subjected to ring closure with a strong base.
quinolizine derivative of the formula (II), in which A is hydrogen or a -CH2-CH(CO2R1)2 or -CH2-CH(CO2R1)2-CH2- CH(CO2R1) group, R3 is identical with R1 and R1 and R2 are as defined in claim 1, is subjected to ring closure with a strong base.
3. A process according to claim 2, wherein an alkali metal hydride or an alkali metal alcoholate is used as the strong base.
4. A process as claimed in claim 1, wherein an octahydroindolo[2,3-a]
quinolizine derivative of the formula (II), in which A and R3 represent hydrogen, and R1 and R2 have the same meaning as defined in claim 1, is subjected to ring closure with phosphorus oxychloride.
quinolizine derivative of the formula (II), in which A and R3 represent hydrogen, and R1 and R2 have the same meaning as defined in claim 1, is subjected to ring closure with phosphorus oxychloride.
5. A process according to claim 1, 2 or 3, wherein the ring closure is carried out in an inert organic, aprotic, apolar solvent.
6. A process as claimed in claim 1, 2 or 3, wherein the ring closure is carried out in an inert organic, aprotic, apolar solvent and an aromatic hydrocarbon is used as the inert organic, aprotic, apolar solvent.
7. A racemic mixture or an optically active E-homo-eburnane derivative of the formula (I) as defined in claim 1 or 2 or a pharmaceutically acceptable acid addition salt thereof whenever prepared by a process according to claim 1 or 2 or by an obvious chemical equivalent thereof.
8. A process according to claim 1 wherein in the starting material R1 and R3 are each ethyl, A is hydrogen and R2 is .alpha.-ethyl.
9. A process for preparing (?)-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane (3.alpha.,17.alpha.) which comprises cyclizing (?)-1.alpha.-ethyl-1.beta.-(2',2'-diethoxycarbonylethyl)-1,2,3,4,6,7,12b.alpha.-octahydro-indolo(2,3-a)quinolizine with a strong base and where required, forming a pharmaceutically acceptable acid addition salt thereof.
10. A process according to claim 9 wherein the strong base is potassium tert.-butylate.
11. A process according to claim 9 or 10 wherein the (?)-1.alpha.-ethyl-1.beta.-(2',2'-diethoxycarbonylethyl)-1,2,3,4,6,7,12b.alpha.-octahydro-indolo(2,3-a)quinolizine is obtained by treating the hydrochloride salt thereof with aqueous sodium carbonate.
12. The compound (?)-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane (3.alpha.,17.alpha.) or a pharmaceutically acceptable acid addition salt thereof whenever prepared by a process according to claim 8, 9 or 10 or by an obvious chemical equivalent thereof.
13. A process for preparing (?)-trans-14-oxo-15-ethoxy-carbonyl-E-homo-eburnane(13.alpha.,17.alpha.) which comprises cyclizing (?)-1.alpha.,-ethyl-1.beta.-(2',2'-diethoxycarbonyl-ethyl)-1,2,3,4,6,7,12,12b .beta.-octahydroindolo(2,3-a)quinolizine with a strong base and where required forming a pharmaceutically acceptable acid addition salt thereof.
14. A process according to claim 13 wherein the strong base is potassium tert.-butylate.
15. The compound (?)-trans-14-oxo-15-ethoxycarbonyl-E-homo-eburnane(3.alpha.,17.alpha.) or a pharmaceutically acceptable acid addition salt thereof whenever prepared by a process according to claim 3, 13 or 14 or by an obvious chemical equivalent thereof.
16. A process according to claim 1 wherein in the starting materials R1 and R3 are each ethyl, A is 2,2-diethoxycarbonylethyl, and R2 is .alpha.-ethyl.
17. A process for preparing (?)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane(3.alpha.,17.alpha.) which comprises cyclizing (?)-l.alpha.-ethyl-1.beta.-(2',2',4',4'-tetraethoxycarbonylbutyl)-1,2,3,4,6,7,12,12b.alpha. -octahydroindolo(2,3-a)quinolizine with a strong base and where required forming a pharmaceutically acceptable acid addition salt thereof.
18. A process according to claim 17 wherein the strong base is potassium tert.-butylate.
19. A process according to claim 17 or 18 wherein the (?)-1.alpha.-ethyl-1.beta.-(2',2',4',4'-tetraethoxycarbonylbutyl)-1,2,3,4,6, 7,12,12b.alpha. -octahydroindolo(2,3-a)quinolizlne is obtained by treating the hydrochloride salt thereof with aqueous sodium carbonate.
20. The compound (?)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane(3.alpha.,17.alpha.) or a pharmaceutically acceptable acid addition salt thereof whenever prepared by a process according to claim 16, 17 or 18 or by an obvious chemical equivalent thereof.
21. A process according to claim 1 wherein in the starting materials R1 and R3 are each ethyl, A is 2,2,4,4-tetraethoxy-carbonylbutyl and R2 is .alpha.-ethyl.
22. A process for preparing (?)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane(3.alpha.,17.alpha.) which comprises cyclizing (?)-1.alpha.-ethyl-1.beta.-(2',2',4',4',6',6'-hexaethoxycarbonylhexyl-1,2,3,4,6,7,12,-12b.alpha.-octahydroindolo(2,3-a)quinolizine with a strong base and where required forming a pharmaceutically acceptable acid addition salt thereof.
23. A process according to claim 22 wherein the strong base is potassium tert.-butylate.
24. A process according to claim 22 or 23 wherein the (?)-1.alpha.-ethyl-1.beta.-(2',2',4',4',6',6'-hexaethoxycarbonylhexyl-1,2,3, 4,6,7,12,-12b.alpha.-octahydroindolo(2,3-a)quinolizine is obtained by treating the hydrogen perchlorate salt thereof with aqueous sodium carbonate.
25. The compound (+)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane(3.alpha.,17.alpha.) or a pharmaceutically acceptable acid addition salt thereof whenever prepared by a process according to claim 21, 22 or 23 or by an obvious chemical equivalent thereof.
26. A process for preparing (+)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane(3.alpha.,17.alpha.)hydrochloride which comprises reacting (?)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane(3.alpha.,17.alpha.) with hydrogen chloride.
27. A process according to claim 10 further comprising the step of reacting the(+)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane(3.alpha.,17.alpha.) so obtained with hydrogen chloride to obtain a hydrochloride salt thereof.
28. A process according to claim 18 further comprising the step of reacting the (+)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane(3.alpha.,17.alpha.) so obtained with hydrogen chloride to obtain a hydrochloride salt thereof.
29. A process according to claim 23 further comprising the step of reacting the (+)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane(3.alpha.,17.alpha.) so obtained with hydrogen chloride to obtain a hydrochloride salt thereof.
30. The compound (+)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane (3.alpha.,17.alpha.)hydrochloride whenever prepared by a process according to claim 26 or 27 or by an obvious chemical equivalent thereof.
31. The compound (?)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane (3.alpha.,17.alpha.)hydrochloride whenever prepared by a process according to claim 28 or 29 or by an obvious chemical equivalent thereof.
32. A process according to claim 1 wherein in the starting materials R1 is ethyl, R2 is .alpha.-ethyl and R3 and A are each hydrogen.
33. A process for preparing (?)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane (3.alpha.,17.alpha.) which comprises cyclizing (?)-1.alpha.-ethyl-1.beta.-(2'-carboxy-2'-ethoxycarbonylethyl)-1,2,3,4,6,7,12,12b.alpha.-octa-hydroindolo-(2,3-a)quinolizine with a dehydrating agent and where required forming a pharmaceutically acceptable salt thereof.
34. A process according to claim 33 wherein the dehydrating agent is phosphorus oxychloride.
35. The compound (?)-cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane(3.alpha.,17.alpha.) or a pharmaceutically acceptable salt thereof whenever prepared by a process according to claim 32, 33 or 34 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU2130/82 | 1982-06-30 | ||
| HU822130A HU190399B (en) | 1982-06-30 | 1982-06-30 | Process for the production of e-homo-eburnane-derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1192189A true CA1192189A (en) | 1985-08-20 |
Family
ID=10957916
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000431510A Expired CA1192189A (en) | 1982-06-30 | 1983-06-29 | E-homo-eburnane derivatives and a process for preparing same |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS5913782A (en) |
| AU (1) | AU553966B2 (en) |
| BE (1) | BE897147A (en) |
| CA (1) | CA1192189A (en) |
| CH (1) | CH660735A5 (en) |
| DE (1) | DE3323584A1 (en) |
| DK (1) | DK300383A (en) |
| ES (1) | ES523696A0 (en) |
| FR (1) | FR2529554B1 (en) |
| GB (1) | GB2122994B (en) |
| GR (1) | GR78602B (en) |
| HU (1) | HU190399B (en) |
| IL (1) | IL69106A (en) |
| NL (1) | NL8302297A (en) |
| NZ (1) | NZ204756A (en) |
| PT (1) | PT76950B (en) |
| SE (1) | SE8303718L (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU181496B (en) * | 1979-08-13 | 1983-07-28 | Richter Gedeon Vegyeszet | Process for preparing 10-bromo-15-hydroxy-e-homo-eburnanes |
-
1982
- 1982-06-30 HU HU822130A patent/HU190399B/en unknown
-
1983
- 1983-06-28 BE BE1/10822A patent/BE897147A/en not_active IP Right Cessation
- 1983-06-29 FR FR8310733A patent/FR2529554B1/en not_active Expired
- 1983-06-29 GB GB08317611A patent/GB2122994B/en not_active Expired
- 1983-06-29 CH CH3566/83A patent/CH660735A5/en not_active IP Right Cessation
- 1983-06-29 SE SE8303718A patent/SE8303718L/en not_active Application Discontinuation
- 1983-06-29 NL NL8302297A patent/NL8302297A/en not_active Application Discontinuation
- 1983-06-29 NZ NZ204756A patent/NZ204756A/en unknown
- 1983-06-29 CA CA000431510A patent/CA1192189A/en not_active Expired
- 1983-06-29 PT PT76950A patent/PT76950B/en unknown
- 1983-06-29 DK DK300383A patent/DK300383A/en not_active Application Discontinuation
- 1983-06-29 IL IL69106A patent/IL69106A/en unknown
- 1983-06-29 AU AU16395/83A patent/AU553966B2/en not_active Ceased
- 1983-06-29 GR GR71805A patent/GR78602B/el unknown
- 1983-06-29 ES ES523696A patent/ES523696A0/en active Granted
- 1983-06-30 JP JP58117176A patent/JPS5913782A/en active Pending
- 1983-06-30 DE DE19833323584 patent/DE3323584A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| IL69106A (en) | 1986-02-28 |
| PT76950A (en) | 1983-07-01 |
| AU553966B2 (en) | 1986-07-31 |
| SE8303718L (en) | 1983-12-31 |
| NZ204756A (en) | 1985-09-13 |
| GB2122994B (en) | 1985-08-29 |
| BE897147A (en) | 1983-12-28 |
| IL69106A0 (en) | 1983-10-31 |
| FR2529554B1 (en) | 1985-08-09 |
| ES8500620A1 (en) | 1984-11-01 |
| GB8317611D0 (en) | 1983-08-03 |
| HU190399B (en) | 1986-08-28 |
| DK300383D0 (en) | 1983-06-29 |
| CH660735A5 (en) | 1987-06-15 |
| JPS5913782A (en) | 1984-01-24 |
| DK300383A (en) | 1983-12-31 |
| FR2529554A1 (en) | 1984-01-06 |
| NL8302297A (en) | 1984-01-16 |
| ES523696A0 (en) | 1984-11-01 |
| DE3323584A1 (en) | 1984-02-09 |
| GR78602B (en) | 1984-09-27 |
| PT76950B (en) | 1986-01-24 |
| AU1639583A (en) | 1984-01-05 |
| GB2122994A (en) | 1984-01-25 |
| SE8303718D0 (en) | 1983-06-29 |
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