NZ204756A - E-homo-eburnane derivatives and pharmaceutical compositions - Google Patents
E-homo-eburnane derivatives and pharmaceutical compositionsInfo
- Publication number
- NZ204756A NZ204756A NZ204756A NZ20475683A NZ204756A NZ 204756 A NZ204756 A NZ 204756A NZ 204756 A NZ204756 A NZ 204756A NZ 20475683 A NZ20475683 A NZ 20475683A NZ 204756 A NZ204756 A NZ 204756A
- Authority
- NZ
- New Zealand
- Prior art keywords
- formula
- racemic
- optically active
- acid addition
- acid
- Prior art date
Links
Classifications
-
- 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
-
- 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
Description
New Zealand Paient Spedficaiion for Paient Number £04756
2 04756
Priority <' »•- - '5): .. . . . . .
Complete Specification Filed: -r.•
Class: 6£>7?JP.h.7.{i
Publication Date: .,§^P.1§fP.. P.O. Journal, No: G?.?.
"0 BRAWIKSS
'f %
[*29 JUHiooJ^
Patents Form No. 5
NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION
"E-HOMO-EBURNANE DERIVATIVES AND A PROCESS FOR PREPARING SAME"
-t,WE RICHTER GEDEON VEGYESZETI GYAR RT., of Budapest X. lilt Gyomr°i ut%l. Hungary, a Hungarian company,
#*
hereby declare the invention, for which 5/we pray that a patent may be granted to Trre/us, and the method by which it is to be performed, to be particularly described in and by the following statement
(followed by pape I A >
2 047 5
\a.
E-homo-eburnane derivatives, process for their preparation, and pharmaceutical compositions containing these compounds
This invention relates to new E-homo-eburnane derivatives, process for their preparation, and pharmaceutical compositions containing them as active ingredient. More particularly,- the invention concerns new racemic or optically active E-homo-eburnane derivatives 10 of the formula /I/,
wherein
1 2
R and R independently represent an alkyl group having
1 to 6 carbon atoms,
and acid addition salts thereof.
According to another aspect of the invention there 25 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
204756
or optically active octahydroindolo/2,3-a7quinoline derivative of the formula /II/,
R1
/II/
wherein
R"
is hydrogen or a -Cf^-CH/CO^R /^ or -CH2-C/"C02R1/"2-CH2-CH/C02R1/2 group ,
in which
1 2
R and R are as defined above,
is identical with R1" or, if A represents hydrogen, ,3
R may also stand for hydrogen,
or an acid addition salt thereof to ring closure, resolving, if desired, the compounds of the formula /I/ obtained and/or converting 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.
2 0475 6
According to a further aspect of the invention there are provided pharmaceutical compositions, which comprise as an active ingredient at least one racemic or optically active E-homo-eburnane derivative of the 5 formula /I/ or a pharmaceutical^ acceptable acid addition salt thereof, in admixture with inert solid or liquid pharmaceutical carriers and/or additives.
The term "alkyl group having 1 to 6 carbon atoms" as used herein means straight or branched chained aliphatic 10 hydrocarbon groups having 1 to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.--butyl, n-pentyl, isopentyl, n-hexyl or isohexyl groups,
etc.
If desired, the compounds of the formula /I/ may be 15 converted into their acid addition salts. Suitable 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 20 formic acid, acetic acid, propionic acid, glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, citric acid, malic acid, salicylic acid, lactic acid, cinnamic acid, benzoic acid, phenylacetic acid, £-amino-benzoic acid, jD-hydroxy-benzoic 25 acid, £-amino-salicylie acid, etc.; alkylsulfonic acids,
such as methanesulfonic acid, ethanesulfonic acid, etc.; cycloaliphatic acids, e.g. cyclohexylsulfonic acid; aryl-sulfonic acids, e.g. £-toluene-sulfonic acid, naphthyl-
204756
sulfonic acid, sulfanylic acid, etc.; amino acids, such as asparaginic acid, glutaminic acid, N-acetyl-asparaginic acid, M-acetyl-glutaric acid, etc.
The starting compounds of the formula /II/ can be 5 prepared as described in the New Zealand Patent Specification Mo. 193795 by electrophilic alkylation of the corresponding hexahydroindolo/2,3-a7quinolizinium salts with a ir.ethylenemalonic acid dialkylester and subsequent hydrogena-tion and, if desired, a further partial hydrolysis. 10 The cyclization of the compounds of the formula /II/,
in which A stands for a hydrogen atom or a CF^-CH/CO^R^/^
or -CH^-C/CO^R^/^-C^-CH/CO^R^/^ group, R"^ has che same
112 meaning as R and R and R are as defined above, can be carried out with sufficiently strong bases, e.g. alkali
metal hydrides, such as sodium hydride, potassium hydride,
etc., alkali metal alcoholates, such as potassium or sodium ethylate, preferably potassium tert.-outylate in aprotic organic solvents, such as xylene, 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 time, generally in 10 to 40 minutes, preferably 15 to 30 minutes.
The ring closure of the compounds of the
3
formula /II/, in which A and R stand for a hydrogen atom, 1 2
R and R have the same meaning as defined above, is carried out with a dehydrating agent, preferably phosphorus oxychloriae or phosphorus pentoxide, preferably in an organic solvent inert under the reaction conditions-^-'^-ue.ti^
iu4/5 6
as aromatic hydrocarbons, preferably benzene, or chlorinated hydrocarbons, e.g. 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 inorganic base, such as an alkali metal carbonate, e.g. sodium carbonate, potassium carbonate, an alkali metal hydroxide, e.g.
sodium hydroxide, potassium hydroxide, etc., in a water--immiscible 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 formula /I/ can be prepared from the corresponding cis- and trans-compounds of the formula /II/, respectively.
By the process according to the invention racemic and optically active compounds of the formula /I/ can equally be prepared. Starting from racemic compounds, 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
salts with an organic or inorganic acid.
The salts are generally prepared in an inert organic solvent, for example in an aliphatic alcohol having 1 to 6 carbon atoms, by dissolving the racemic or optically active compounds of the formula /I/ in said solvent, adding the corresponding acid into the solution while the pH becomes slightly acidic /about pH 6/ and subsequently separating the acid addition salt obtained from the reaction mixture preferably by precipitating with a water-immiscible organic solvent, such as diethyl ether.
If desired, the racemic or optically active compounds of the formula /I/ or acid addition salts thereof may be subjected to further purification, e.g. re-crystallization. The solvents used for recrystallization are selected in accordance with the solubility and crystallizability of the compounds to be recrystallized.
The antihypoxial activity of certain compounds within the scope of the invention, particularly of 3£,17CL -trans-derivatives was tested on the 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 % nitrogen and 4 % oxygen is passed. The interval between placing the mice into the cylinder and the death of the animals is measured. Animals living at least twice as long as the average survival time of the untreated animals are considered protected. The animals are treated in groups
•• 2 047 5 6
of 10, administering an intraperitoneal dose of 50 rag./kg. of bodyweight 30 minutes before placing them into the glass cylinder.
The results are set forth in the following Table.
Table
Survival time Protection Compound
Average
min. %
/ + /-Trans-14-oxo-
-ethoxycarbonyl-
E-homo-eburnane
/3f»,17dL/
8.3+1.1
+32
Control
6.3+1.45
-
0
Vincamine
7.1+1.30
+ 13
0
Of the compounds of the formula /I/ especially the 3(2, ,17cC-cis compounds are potent antidepressive agents.
The active ingredients of the formula /I/ or pharmaceutical^ acceptable acid addition salts thereof can be converted into pharmaceutical compositions for 25 parenteral or enteral administration by admixing them with solid and/or liquid carriers and/or further additives conventionally used in the preparation of pharmaceutical compositions. As a carrier for example water, gelatine,
2 04756
lactose, 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 form of 5 solid, e.g. tablets, lozenges, dragees, 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 10 of the solid carrier can be varied within a wide range but preferably is between about 25 mg. and 1 g. The pharmaceutical compositions optionally contain also conventional pharmaceutical additives, such as preservatives, stabilizing, wetting, emulsifying agents, salts capable 15 of adjusting the osmotic pressure, buffers, flavouring agents, aroma agents, etc. Optionally further pharmaceutical-ly active compounds can also be present in the formulations.
The pharmaceutical compositions are preferably manufactured in dosage units, suitable for the desired 20 route of administration. The pharmaceutical compositions may be prepared by conventional techniques, which comprise for example screening, admixing, granulating, pressing or dissolving of the components. The compositions obtained can be subjected to further operations conventionally used 25 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.
204756
Example 1
/+/-Cis-14-oxo-15-ethoxycarbonyl-E-homo-eburnane /3 oL,17 oL /
From 800 mg. /1.90 mmoles/ of /+/-1 cC-ethy 1-113-
/2' ,2'-diethoxycarbonylethyl/-l,2,3,4,6,7,12b O/—octahydro-
indolo/2,3-a7quinolizine hydrochloride prepared according Zealand !
to the New / patent specification No. 193795 the base is liberated in 25 ml. of dichloromethane with 10 mi. of a 10 % aqueous sodium carbonate solution. After separation 10 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 15 benzene, to the solution 258 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 20 solvent is then eliminated by distillation in vacuo. The evaporation residue is dissolved in 20 ml. of dichloromethane, 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 25 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
'"A
^ A?
204756
vacuo.
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/.
IR 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/, 10 252/35/, 237/17/.
^H-NMR sepctrum /CDCl^, cT/: 8.52-7.35 /4H, n^aromatic/, 4.31 /2H, q, J = 7, 2Hz, 0CH2/, 4.08 /1H, m, 3-H/, 3.75 /1H, d, J=ll Hz, 15-H/, 1.34 /3H, t, J+7.6 Hz, 0CH2CH^ 0.91 /3H, t, J+8.1 Hz, CH2CH3/.
Example 2
/+/-Trans-14-oxo-15-ethoxycarbony1-E-homo-eburnane
13/3, 17 a/
400 mg. /0.94 mmoles/ of /+/-!£*.-ethyl-l(3-/2', 2' -
-diethoxycarbony1-ethy1/-1,2,3,4,6,7,12,12b P-octahydro-
indolo/2,3-a7quinolizine obtained as a by-product in
Zealand
Example 1 of the New / patent specification No. 193795 . are dissolved in 10 ml. of absolute benzene, then 125 mg. /l.ll mmoles/ of potassium tert.-butylate are added to the solution. The reaction mixture is refluxed under nitrogen 25 atmosphere for 20 minutes.
The pH of the reaction mixture is adjusted to 6 with acetic acid under cooling with ice. The solvent is evaporated in vacuo, the residue is dissolved in lO jnl .
/:
IX
,\
fA
■V
o\.
°r? '
204756
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-ral. portion of dichloromethane, and the combined organic phases are 5 dried over solid anhydrous magnesium 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. 10 Yield: 73.0 %.
Melting 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/, 15 352/11/, 351/16/, 335/11/, 323/5.5/, 307/34/...
^H-NMR spectrum /CDCl^, /'■ 8.56-7.24 /4H, m, aromatic protones/, 4.32 /2H, q, J=7.6 Hz, OCK /, 4.08 /1H, dd, J1= 13.6 Hz J2=2.7 Hz, 15-H/, 3.41 /1H, s, 3-H/, 1.35 /3H, t, Jr7, 6Hz, 0CH2CH3/, 0.74 /3H, t, J=6Hz, 20 CH2CH3/.
Example 3
/+/-Cis-l4-oxo-15-ethoxycarbonyl-E-homo-eburnane /3 oL,17oC/
From 634.5 mg. and 698.0 mg. /I mmole/ of /+/-loC-25 -e thy 1-1^-/2',2',4', 4' - tetraethoxy car bony 1 butyl /-
-1,2,3,4,6,7,12,12b 0L-octahydroindolo/_2 ,3-a7quinolizine hydrochloride and hydrogen perchlorate, respectively, the corresponding base is liberated with 10 ml. of a 10 %
204-7 56
aqueous sodium carbonate solution in 25 ml. of dichloromethane. The organic phases are combined, dried over solid, anhydrous magnesium sulfate, filtered 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 nitrogen atmosphere for half an hour. The reaction mixture is cooled down and its pH is 10 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 pH 9 and is then extracted with a further 5-ml. portion of aqueous 15 dichloromethane. The organic phases are collected, dried over solid, anhydr.ous magnesium sulfate, filtered and from the filtrate the organic solvent is eliminated by distillation in vacuo. The residual oily product is crystallized from 1 ml. of ethanol.
307 mg. of the aimed compound are obtained.
Yield: 80.8 %.
Melting point: 143 to 144 °C /ethanol/
Example 4
/+/-Cis-l4-oxo-15-ethoxycarbonyl-E-homo-eburnane 25 /3 0L,17 cU
The procedure described in Example 3 is followed starting from 870 mg. /I mmole/ of /+/-1 oC-ethyl-1 £> -/2 ' , 2 ' , 4 ',4' ,6', 6 ' -hexaethoxycarbonylhexyl-1,2,3,4,6,7,12,-
204756
12b oC-octahydroindolo/2 , 3-a7quinolizine hydrogenper-chlorate prepared according to the New Zealand Patent specification Mo. 193795. .
264 mg. of the aimed compound are obtained.
Yield: 69.5 %.
Melting point: 142 to 143 °C /ethanol/.
Example 5
/+/-Cis-14-oxo-15-ethoxycarbony1-E-homo-eburnane /3 oL,17 cU hydrochloride
200 mg. of /+/-cis-14-oxo-15-ethoxycarbonyl-E-homo-
-eburnane/3 , 17(3(_/ are dissolved 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 15 the evaporation residue is crystallized from 1.5 ml. of ethanol.
carbonylethyl/-l,2,3,4,6,7>12,12bo£_-octahydroindolo-
_/~2,3-a7quinolizine prepared according to Example 5 or
Zealand
Example 6 of the New / patent specification No. 193795
are suspended in 2 ml, of absolute benzene and 2 ml. of
" A > , \-
phosphorus oxychloride are added to the suspension und'ejs-
165 mg. of the aimed compound are obtained. Yield: 75.2 %.
Melting point: 204 to 207 °C /toluene/.
Example 6
/+/-Cis-14-oxo-15-ethoxycarbony1-E-homo-eburnane /3 cL,17oC/
300 mg. of /+/-loO-ethyl-l (3-/2'-carboxy-2'-ethoxy-
Claims (13)
1. Racemic or optically active E-horao-eburnane derivatives of the formula /!/, 5 1 to 6 carbon atoms, and acid addition salts thereof.
2. Pharmaceutical compositions, which comprise as an active ingredient at least one racemic or optically 20 active compound of the formula /I/ /as defined in claim 1/ or a pharmaceutical^ acceptable acid addition salt thereof, in admixture with inert solid or liquid pharmaceutical carriers and/or additives.
3. Pharmaceutical compositions as claimed in claim 2 25 in forms suitable for parenteral or enteral administration. k. Pharmaceutical compositions as claimed in claim 2 or 3 in dosage unit form. 10
/I/ wherein 1 2 15 R ana R independently represent an alkyl group having 2 047 5 6 - 16 -
5. A process for the preparation of racemic. or optically active E-hono-eburnane derivatives of the formula /I/, 10 /I/ wherein 1 2 R and R independently represent an alkyl group having 15 1 to 6 carbon atoms, and acid addition salts thereof, which process comprises subjecting a racemic or optically active octahydroindolo-/2,3-a7quinoline derivative of the formula /II/, 20 25 /II/ - 17 - 204756 wherein A is hydrogen or a -CH2-CH<^CQ2R^2 -CH2-C^C02RLJ2-CH2»CH^C02R1;2 group, in which 1 2 R and R are as defined above, R"^ is identical with R1 or, if A stands for 3 hydrogen, R may also represent a hydrogen atom, or an acid addition salt thereof to ring closure, resolving, if desired, the compounds of the formula /I/ obtained and/or converting the racemic or optically active compounds of the formula /I/ into acid addition salts thereof.
6. A process as claimed in claim 5, wherein octa-hyaroindolo/2,3-a7quinolizine derivatives of the formula /II/, in which A is hydrogen or a -CHg-CH^CO^R1^ or -CH2-C:^t02R"1'^2-CH2-CH^P02R''"_32 group, R^ is identical 112 with R and R and R are as defined in claim 5, are subjected to ring closure with a strong base.
7. A process as claimed 'in claim o, wherein an alkali metal hydride or an alkali metal alcoholate is used as a strong base.
8. A process as claimed in claim 5, wherein an octahydroindolo/2 ,3-a7quinoli'z'ine derivative of the 3 formula /II/, in which A and R represent hydrogen, and 1 2 R and R have the same meaning as defined in claim 5, is subjected to ring closure with pto?>horus oxychloride.
9. A process as claimed in any one of claims 5 to 8, wherein the ring closure is carried out in an inert - 18 - 204756 organic, aprotic, apolar solvent.
10. A process as claimed in claim 9, wherein an aromatic hydrocarbon is used as an inert organic, aprotic, apolar solvent.
11. A process for the preparation of pharmaceutical compositions, which process comprises admixing at least one racemic or optically active compound of the formula /I/ / as defined in claim 5/ or a pharmaceutically acceptable acid addition salt thereof with inert solid or liquid pharmaceutical carriers and/or additives.
12. A process for the preparation of racemic or optically active E-homo-eburnane derivatives of formula I specifically as described herein in any one of the Examples.
13. Products of the process of claim 12. teys ,CAREY VEGYESZETI GYAR RT.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU822130A HU190399B (en) | 1982-06-30 | 1982-06-30 | Process for the production of e-homo-eburnane-derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ204756A true NZ204756A (en) | 1985-09-13 |
Family
ID=10957916
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ204756A NZ204756A (en) | 1982-06-30 | 1983-06-29 | E-homo-eburnane derivatives and pharmaceutical compositions |
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) | ES8500620A1 (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 IL IL69106A patent/IL69106A/en unknown
- 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 DK DK300383A patent/DK300383A/en not_active Application Discontinuation
- 1983-06-29 NZ NZ204756A patent/NZ204756A/en unknown
- 1983-06-29 NL NL8302297A patent/NL8302297A/en not_active Application Discontinuation
- 1983-06-29 PT PT76950A patent/PT76950B/en unknown
- 1983-06-29 CH CH3566/83A patent/CH660735A5/en not_active IP Right Cessation
- 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/ES8500620A1/en not_active Expired
- 1983-06-29 SE SE8303718A patent/SE8303718L/en not_active Application Discontinuation
- 1983-06-29 CA CA000431510A patent/CA1192189A/en not_active Expired
- 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 |
|---|---|
| CA1192189A (en) | 1985-08-20 |
| FR2529554A1 (en) | 1984-01-06 |
| CH660735A5 (en) | 1987-06-15 |
| PT76950B (en) | 1986-01-24 |
| GB2122994B (en) | 1985-08-29 |
| DE3323584A1 (en) | 1984-02-09 |
| SE8303718L (en) | 1983-12-31 |
| DK300383A (en) | 1983-12-31 |
| AU553966B2 (en) | 1986-07-31 |
| GB8317611D0 (en) | 1983-08-03 |
| BE897147A (en) | 1983-12-28 |
| ES523696A0 (en) | 1984-11-01 |
| NL8302297A (en) | 1984-01-16 |
| IL69106A0 (en) | 1983-10-31 |
| DK300383D0 (en) | 1983-06-29 |
| ES8500620A1 (en) | 1984-11-01 |
| GR78602B (en) | 1984-09-27 |
| IL69106A (en) | 1986-02-28 |
| FR2529554B1 (en) | 1985-08-09 |
| GB2122994A (en) | 1984-01-25 |
| PT76950A (en) | 1983-07-01 |
| HU190399B (en) | 1986-08-28 |
| SE8303718D0 (en) | 1983-06-29 |
| JPS5913782A (en) | 1984-01-24 |
| AU1639583A (en) | 1984-01-05 |
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