GB1575852A - Hexahydro-4-indolinol derivatives - Google Patents
Hexahydro-4-indolinol derivatives Download PDFInfo
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- GB1575852A GB1575852A GB17571/77A GB1757177A GB1575852A GB 1575852 A GB1575852 A GB 1575852A GB 17571/77 A GB17571/77 A GB 17571/77A GB 1757177 A GB1757177 A GB 1757177A GB 1575852 A GB1575852 A GB 1575852A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- 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
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- 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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- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
(54) IMPROVEMENTS IN OR RELATING TO HEXAHYDRO-4-INDOLINOL DERIVATIVES
(71) We, SANDOZ LTD., of 35 Lichtstrasse, 4002 Basle, Switzerland, a Swiss Body
Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:
The present invention relates to indoline compounds.
The present invention provides compounds of formula I,
wherein Rl is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 or 6 carbon atoms, alkyl of 1 to 4 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, alkenyl or alkynyl of 3 to 5 carbon atoms and wherein the multiple bond is other than in the a,[:5-position, hydroxyalkyl of 2 to 5 carbon atoms wherein the hydroxy group is attached to other than the carbon atom, or a radical of formula II,
wherein R2 and R3, independently, are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluorine or chlorine, and either (a) n is 1, 2 or 3, and X is a single bond, methylene, vinylene or carbonyl, or (b) n is 2 or 3, and X is oxygen or sulphur, and either (i) R4 and R5, independently, are fluorine, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, and R6 is hydrogen, or (ii) R4 and R5 are attached to adjacent ring carbon atoms, and, together, are -(CH2)m- wherein m is 3 or 4, -CH=CH-CH=CH-, or -CH2-CH=CH-, and R6 is hydrogen, fluorine, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.
In the above formula I, all alkyl and alkoxy moieties, except where otherwise stated, have preferably 2 carbon atoms or especially 1 carbon atom.
R, is preferably alkyl, hydroxyalkyl or a radical of formula II, as defined above. When R1 is alkyl substituted by cycloalkyl, the cycloalkyl moiety preferably has 3, 5 or 6 carbon atoms, and the alkyl moiety preferably one carbon atom. A preferred example is cyclopropylmethyl. The multiple bond of the alkenyl or alkynyl group preferably is in ss,y-position. The alkenyl or alkynyl group preferably has 3 carbon atoms. Hydroxyalkyl preferably has 2 or 3 carbon atoms.
n is preferably 2. X is preferably a single bond. When X is vinylene the hydrogen atoms thereof may be cis or trans to each other.
R2 is preferably hydrogen, fluorine or chlorine. R3 is preferably hydrogen. Preferably R4 and R5 are in the meta and para position relative to the indoline nucleus. R6 is preferably hydrogen, and R4 and R5, independently, are preferably hydrogen or chlorine. When R4 and R5 are together -(CH2)-, -CH=CH-CH=CH- or -CH2-CH=CH-, they are preferably -CH=CH-CH=CH- and/or R6 is preferably hydrogen, chlorine or fluorine, preferably hydrogen.
The present invention also provides a process for the production of a compound of formula I, as defined above, which comprises (a) for the production of a compound of formula Ia,
wherein Rl is Rl as defined above with the proviso that it is other than hydrogen, and
R4, R5 and R6 are as defined above, introducing a group Rl into the 1 position of a compound of formula Ib,
wherein R4, R5 and R6 are as defined above, (b) for the production of a compound of formula Ic,
wherein Rll is hydrogen alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 3 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, or a radical of formula IIa,
wherein nl is 0, 1 or 2, and R2 and R3 are as defined above, and
R4, R5 and R6 are as defined above, reducing the group R7 to a group -CH2-R'i' in a compound of formula II,
wherein R4, R5 and R6 are as defined above, and
R7 is a group capable of being reduced to methyl, or a group CORIll, wherein R:" is as Rill, as defined above, with the proviso that it is other than hydrogen, or (c) for the production of a compound of formula Ib, as defined above, splitting off a group
R8 from a compound of formula III,
wherein R4, R5 and R6 are as defined above, and
R8 is a group capable of being split off.
Process a) may be effected in conventional manner for the alkylation of secondary amines.
For example, as alkylating agent there may be used the appropriate alkyl bromide or iodide. The reaction is conveniently effected in an aprotic solvent such as toluene or dimethylformamide. A basic condensation agent such as sodium carbonate is conveniently present. Suitable reaction temperatures are from 10 to 1600C, preferably boiling temperatures.
Alternatively, for production of compounds wherein X is carbonyl and n is 2 for corresponding compound of formula IV,
wherein R2 and R3 are as defined above, may be used in a Michael addition reaction, e.g. at from 20 to 80".
Alternatively, for compounds of formula I, wherein R1 is hydroxyalkyl, wherein the hydroxy group is attached to the carbon atom, the corresponding a,ss-epoxide may be used as alkylating agent.
A reaction temperature of from 10 to 100"C is suitable.
Process b) may be effected in conventional manner for analogous reduction reactions, e.g. of analogous amides or urethanes to amines.
A suitable reducing agent is a complex metal hydride such as lithium aluminium hydride.
When R7 is a group capable of being reduced to methyl, this may be formyl but is conveniently alkoxycarbonyl or aryloxycarbonyl of up to 11 carbon atoms, especially ethoxycarbonyl. A suitable solvent is tetrahydrofuran. Suitable temperatures are from 10 to 100"C.
Process c) may be effected in conventional manner for the splitting off of amine protecting groups, preferably under solvolytic conditions. R8 is for example alkoxycarbonyl or aryloxycarbonyl of up to 11 carbon atoms, especially ethoxycarbonyl. It is preferred to use alkaline conditions, e.g. sodium hydroxide, in methanol, ethanol or water.
Suitable temperatures are from 10 to 250"C, preferably about 100"C.
Compounds of formula II, wherein R7 is COR}1, alkoxycarbonyl or aryloxycarbonyl, may be produced by condensing a compound of formula Ib with the appropriate halide.
Compounds of formula III, wherein R8 is alkoxycarbonyl or aryloxycarbonyl may be produced by a Grignard reaction between an appropriate Grignard reagent and a corresponding compound of formula V,
wherein R8 is as defined above.
Insofar as the preparation of any of the starting materials has not been particularly described, these compounds are known or may be produced and purified in accordance with known processes or in a manner analogous to processes described herein or known processes.
Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for salt formation include malonic acid and maleic acid.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected.
EXAMPLE 1: (3aRS, 4SR, 7aRS)-4-(3, 4, -dichlorophenyl) hexa-hydro-1- (2-hydroxyethyl)-4-indolinol [process a)]
3.8 g (3aRS ,4SR,7aRS)-4-(3 ,4 ,dichlorophenyl)hexa-hydro-4-indolinol (see Example 3), 1.6 g 2-bromoethanol and 4 g sodium carbonate are heated for 4 hours at 100" is 50 ml dimethylformamide. The resulting mixture is evaporated to dryness, and the residue is partitioned between methylene chloride and 2N tartaric acid. The aqueous phase is made alkaline and repeatedly extracted with methylene chloride. The last-mentioned methylene chloride phase is dried over sodium sulphate, and evaporated to yield as an oily residue, the title compound in crude free base form, which is converted by addition of an equivalent amount of malonic acid, into the hydrogen malonate. M.Pt. 161".
EXAMPLE 2: (3 aR S, 4SR, 7aRS) -4- (3,4, dichlorophenyl) hexa-hydro-1 ro-l -methyl-4-indolinol [process b)]
28.5 g (3aRS,4SR,7aRS)-4-(3,4-dichlorophenyl)hexa-hydro-4-hydroxy-1-indoline carboxylic acid ethyl ester and 6.1 g lithium aluminium hydride in 200 ml tetrahydrofuran are refluxed for 2 1/2 hours. Excess lithium aluminium hydride is decomposed by the addition of water to the cooled reaction mixture. The mixture is partitioned between water and ether. The organic phase is dried over magnesium sulphate and evaporated to yield the title material as an oil which is crystallized from ethanol. M.Pt. 69 -71 .
The title compound may also be produced in analogous manner to that disclosed in
Example 1.
The starting material is obtained as follows:-3,4-dichlorophenylmagnesium bromide (from 4.2 g magnesium and 38.5 g 1-bromo-3,4-dichlorobenzene) is treated with 26.4 g cis-perhydro-4-oxo-1-indoline-carboxylic acid ethyl ester in 300 ml tetrahydrofuran. The mixture is stirred for 4 hours, and then treated with 100 ml 2N hydrochloric acid and 200 ml ether. The organic phase is washed with water, dried over sodium sulphate, and evapoated to yield the starting material as an oil.
EXAMPLE 3: (3aRS, 4SR, 7aRS) -4- (3, 4-d ichlorophenyl) hexa-hydro-4-indolinol [process c)]
24.9 g (3aRS,4SR,7aRS)-4- (3,4-dichlorophenyl)hexa-hydro- 1-indolinecarboxylic acid ethyl ester in 240 ml methanol are treated with 240 ml 10N sodium hydroxide and refluxed for 15 hours. The cooled resulting mixture is repeatedly extracted with methylene chloride.
The organic phase is extracted with 2N tartaric acid. The acidic phase is made alkaline and extracted with methylene chloride. The methylene chloride phases are dried over magnesium sulphate, and evaporated to give the title compound, in crude free base form, as an oil which is converted, by the addition of an equivalent amount of maleic acid, into the hydrogen maleate. M.Pt. 1900 - 191".
In analogous manner the following compounds of formula I may be produced, wherein:
1 produced loop x RiR4flS R4 M. R6 Pt. P t . aaa aoa)ogoos .0. to Rg Example 4 -CIIJ 3-CF 4-1 H 140142; 1 or 2 a -e 3-CF3 4-CI H 141-144 3 3) e I,3-CHC)I-C)I=CH- H 113-315 1 or 2 7 -ClI2-CH2 2.3-CH-CH-CH=CH- H 178' 1)5) 1 or 2 d -Il I.3-CH.CII-CII=CH- H oil 3 1) 9 i 3,4-CH-CH-cH=CH- H 134-135; 1 or 2 2) -CH2-CH2 3,4-CH=CH-of=CH- H 196197 I or 2 4) 3 ~~ ~ 1 4-CU=H-CII=CH- Ii 202-2r4 1) hydrogen malonate 2) hydrogen maleate 3) free base 4) hydrogen fumarate 5) decomposition
The compounds of formula I exhibit pharmacological activity. In particular, the compounds exhibit anti-depressant activity as indicated in the following standard tests:
i) in the tetrabenazine ptosis and catalepsy test according to the principles of G. Stille [Arz. Forsch. 14, 534 (1964)] an antagonism of the ptosis and catalepsy induced in rats by tetrabenazine is observed on administration i.p. of from 2 to 50 mg/kg animal body weight of the compounds;
ii) in the oxo-tremorine test according to the principles of P. Spencer [Brit. J. Pharmacol.
25, 442 (1965)] an antagonism of oxo-tremorine-induced tremors and hypothermia is observed on administration s.c. of 10 to 30 mg/kg animal body weight of the compounds; and
iii) in the 5-hydroxytryptophan potentiation test an inhibition of the uptake of exogenous noradrenaline by rat brain tissue is observed on administration i.p. of 10 to 30 mg/kg animal body weight of the compounds.
The compounds are therefore indicated for use as anti-depressants. An indicated daily dose is from 5 to 150 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 1 to 75 mg of the compound or in sustained release form.
The compounds may be administered in pharmaceutically acceptable acid addition salt form. Such salt forms have the same order of activity as the free base forms. The present invention accordingly provides a pharmaceutical composition comprising a compound of formula I in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent. Such compositions may be formulated so as to be, for example, a solution or tablet.
WHAT WE CLAIM IS:
1. A process for the production of a compound of formula I,
wherein Rl is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 or 6 carbon atoms alkyl of 1 to 4 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, alkenyl or alkynyl of 3 to 5 carbon atoms and wherein the multiple bond is other than in the a,ss-position, hydroxyalkyl of 2 to 5 carbon atoms wherein the hydroxy group is attached to other than the carbon atom, or a radical of formula II,
wherein R2 and R3, independently, are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluorine or chlorine, and either (a) n is 1, 2 or 3, and X is a single bond, methylene, vinylene or carbonyl, or (b) n is 2 or 3, and X is oxygen or sulphur, and either (i) R4 and Rs, independently, are fluorine, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, and
R6 is hydrogen, or (ii) R4 and R5 are attached to adjacent ring carbon atoms, and, together, are -(CH2)m-, wherein m is 3 or 4, -CH--CH-CH=CH-, or -CH2-CH=CH-, and
R6 is hydrogen, fluorine, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, which comprises
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (22)
1) hydrogen malonate 2) hydrogen maleate 3) free base 4) hydrogen fumarate 5) decomposition
The compounds of formula I exhibit pharmacological activity. In particular, the compounds exhibit anti-depressant activity as indicated in the following standard tests:
i) in the tetrabenazine ptosis and catalepsy test according to the principles of G. Stille [Arz. Forsch. 14, 534 (1964)] an antagonism of the ptosis and catalepsy induced in rats by tetrabenazine is observed on administration i.p. of from 2 to 50 mg/kg animal body weight of the compounds;
ii) in the oxo-tremorine test according to the principles of P. Spencer [Brit. J. Pharmacol.
25, 442 (1965)] an antagonism of oxo-tremorine-induced tremors and hypothermia is observed on administration s.c. of 10 to 30 mg/kg animal body weight of the compounds; and
iii) in the 5-hydroxytryptophan potentiation test an inhibition of the uptake of exogenous noradrenaline by rat brain tissue is observed on administration i.p. of 10 to 30 mg/kg animal body weight of the compounds.
The compounds are therefore indicated for use as anti-depressants. An indicated daily dose is from 5 to 150 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 1 to 75 mg of the compound or in sustained release form.
The compounds may be administered in pharmaceutically acceptable acid addition salt form. Such salt forms have the same order of activity as the free base forms. The present invention accordingly provides a pharmaceutical composition comprising a compound of formula I in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent. Such compositions may be formulated so as to be, for example, a solution or tablet.
WHAT WE CLAIM IS:
1. A process for the production of a compound of formula I,
wherein Rl is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 or 6 carbon atoms alkyl of 1 to 4 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, alkenyl or alkynyl of 3 to 5 carbon atoms and wherein the multiple bond is other than in the a,ss-position, hydroxyalkyl of 2 to 5 carbon atoms wherein the hydroxy group is attached to other than the carbon atom, or a radical of formula II,
wherein R2 and R3, independently, are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluorine or chlorine, and either (a) n is 1, 2 or 3, and X is a single bond, methylene, vinylene or carbonyl, or (b) n is 2 or 3, and X is oxygen or sulphur, and either (i) R4 and Rs, independently, are fluorine, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms, and
R6 is hydrogen, or (ii) R4 and R5 are attached to adjacent ring carbon atoms, and, together, are -(CH2)m-, wherein m is 3 or 4, -CH--CH-CH=CH-, or -CH2-CH=CH-, and
R6 is hydrogen, fluorine, chlorine, trifluoromethyl, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, which comprises
a) for the production of a compound of formula Ia,
wherein Rl is Rl as defined above with the proviso that it is other than hydrogen, and
R4, R5 and R6 are as defined above, introducing a group RI into the 1 position of a compound of formula Ib,
wherein R4, R5 and R6 are as defined above, b) for the production of a compound of formula Ic,
wherein Rll is hydrogen, alkyl of 1 to 3 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkyl of 1 to 3 carbon atoms mono-substituted by cycloalkyl of 3 to 7 carbon atoms, or a radical of formula IIa,
-wherein n' is 0, 1 or 2, and R2 and R3 are as defined above, and 11
R4, R5 and R6 are as defined above, reducing the group R7 to a group -CH2-R" in a compound of formula II,
wherein R4, R5 and R6 are as defined above, and
R7 is a group capable of being reduced to methyl, or a group COR',", wherein Rlt is as Rli, as defined above, with the proviso that it is other than hydrogen, or
c) for the production of a compound of formula Ib, as defined above, splitting off a group R8 from a compound of formula III,
wherein R4, R, and R6 are as defined above, and R5 is a group capable of being split off.
2. A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to any one of the Examples.
3. A compound of formula I, whenever produced by a process according to claim 1 or 2.
4. A compound of formula I, as defined in claim 1.
5. A compound of claim 4 which is (3aRS,4SR,7aRS)-4-(3,4, dichlorophenyl)hexahydro-1-(2-hydroxyethyl)-4-indolinol.
6. A compound of claim 4 which is (3aRS,4SR,7aRS)-4-(3,4 dichlorophenyl)hexahydro-1-methyl-4-indolinol.
7. A compound of claim 4 which is (3aRS,4SR,7aRS)-4-(3,4dichlorophenyl)hexahydro-4-indolinol.
8. A compound of claim 4, wherein in formula I R6 is H.
9. A compound of claim 8, wherein Rl, R4 and R5 are respectively -CH3, 3-CF3 and 4-Cl.
10. A compound of claim 8, wherein Rl. R4 and R5 are respectively -H, 3-CF3 and 4-Cl.
11. A compound of claim 8, wherein R4 and R5 together are -CH=CH-CH=CH-.
12. A compound of claim 11. wherein R4 and R5 are attached to the 2 and 3 positions of the phenyl ring respectively.
13. A compound of claim 12, wherein
14. A compound of claim 12. wherein R1
15. A compound of claim 12. wherein
16. A compound of claim 11, wherein R4 and R5 are attached to the 3 and 4 positions of the phenyl ring respectively.
17. A compound of claim 16. wherein Rt is
18. A compound of claim 16, wherein Rl is
19. A compound of claim 16, wherein R, is
20. A compound according to any one of claims 3 to 19 in free base form.
21. A compound according to any one of claims 3 to 19 in acid addition salt form.
22. A pharmaceutical composition comprising a compound of any one of claims 3 to 19 in free base form or pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH575376 | 1976-05-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1575852A true GB1575852A (en) | 1980-10-01 |
Family
ID=4298765
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB17571/77A Expired GB1575852A (en) | 1976-05-07 | 1977-04-27 | Hexahydro-4-indolinol derivatives |
Country Status (15)
Country | Link |
---|---|
JP (1) | JPS52136169A (en) |
AU (1) | AU2498177A (en) |
BE (1) | BE854323A (en) |
DE (1) | DE2718369A1 (en) |
DK (1) | DK186277A (en) |
FI (1) | FI771357A (en) |
FR (1) | FR2364897A1 (en) |
GB (1) | GB1575852A (en) |
IL (1) | IL52017A0 (en) |
NL (1) | NL7704839A (en) |
NZ (1) | NZ184025A (en) |
PT (1) | PT66521B (en) |
SE (1) | SE7704879L (en) |
SU (1) | SU656511A3 (en) |
ZA (1) | ZA772733B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2741009A1 (en) | 1976-09-22 | 1978-03-23 | Sandoz Ag | 4-STYRYL-4-INDOLINOL DERIVATIVES, THEIR USE AND PRODUCTION |
-
1977
- 1977-04-25 DE DE19772718369 patent/DE2718369A1/en active Pending
- 1977-04-27 SU SU772472892A patent/SU656511A3/en active
- 1977-04-27 GB GB17571/77A patent/GB1575852A/en not_active Expired
- 1977-04-28 DK DK186277A patent/DK186277A/en unknown
- 1977-04-28 FI FI771357A patent/FI771357A/fi not_active Application Discontinuation
- 1977-04-28 SE SE7704879A patent/SE7704879L/en unknown
- 1977-05-03 NL NL7704839A patent/NL7704839A/en not_active Application Discontinuation
- 1977-05-05 NZ NZ184025A patent/NZ184025A/en unknown
- 1977-05-05 PT PT66521A patent/PT66521B/en unknown
- 1977-05-05 IL IL52017A patent/IL52017A0/en unknown
- 1977-05-05 BE BE177327A patent/BE854323A/en unknown
- 1977-05-06 ZA ZA00772733A patent/ZA772733B/en unknown
- 1977-05-06 FR FR7713808A patent/FR2364897A1/en not_active Withdrawn
- 1977-05-06 JP JP5131977A patent/JPS52136169A/en active Pending
- 1977-05-06 AU AU24981/77A patent/AU2498177A/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
SU656511A3 (en) | 1979-04-05 |
ZA772733B (en) | 1978-12-27 |
DE2718369A1 (en) | 1977-11-17 |
IL52017A0 (en) | 1977-07-31 |
SE7704879L (en) | 1977-11-08 |
FI771357A (en) | 1977-11-08 |
JPS52136169A (en) | 1977-11-14 |
NZ184025A (en) | 1980-02-21 |
AU2498177A (en) | 1978-11-09 |
BE854323A (en) | 1977-11-07 |
DK186277A (en) | 1977-11-08 |
NL7704839A (en) | 1977-11-09 |
PT66521A (en) | 1977-06-01 |
FR2364897A1 (en) | 1978-04-14 |
PT66521B (en) | 1979-01-22 |
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