CA1070300A - Diazep inoisoquinoline derivatives - Google Patents
Diazep inoisoquinoline derivativesInfo
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- CA1070300A CA1070300A CA242,064A CA242064A CA1070300A CA 1070300 A CA1070300 A CA 1070300A CA 242064 A CA242064 A CA 242064A CA 1070300 A CA1070300 A CA 1070300A
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- carbon atoms
- hydrogen
- diazepino
- alkoxy
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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
- C07D471/02—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 system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
DIAZEPINOISOQUINOLINE DERIVATIVES
Abstract of the Disclosure This invention provides new compounds of formula I, I
wherein R1 is hydrogen or alkyl of 1 to 5 carbon atoms, R2 is a group
Abstract of the Disclosure This invention provides new compounds of formula I, I
wherein R1 is hydrogen or alkyl of 1 to 5 carbon atoms, R2 is a group
Description
` 1070;~oo D ~
The lnvention reIates to octahydro-1,4~dlazeplno-~1,7-b]l~oquinolines~
The pre~ent lnvention provldes compounds of formula I, H
whers$n Rl i8 hydrogen or alkyl of 1 to 5 carbon atom-q, a group -~CH2) n ~7 I 10 whereln n ls a whole number from 0 to 3, ~ R5 and R6, lndependently, are hydrogen, i alkyl of 1 to 4 carbon atoms, alkoxy of ! 1 to 4 carbon atom~, halogen of atomlc number from 9 to 35, or together are 3,4-methylenedloxy, R7 ls hydrogen, or when ~oth R5 ,~nd R6 are . ~ .
.
~ . .
.. . . .. . , - . -. . . :
~ ' ' ' ' ' ' ' ' ' ' ' ; ! ' , 10703~0 alkoxy of 1 to 4 carbon atoms also may be alkoxy of 1 to 4 carbon atoms, R3 is hydrogen, alkyl of 1 to 4 carbon atoms, alko~y of 1 to 4 carbon atoms, or halogen or atomic number from 9 to 35, and R4 is hydrogen or alkoxy of 1 to 4 carbon - a~oms; and pharmaceutically acceptable acid addition salts thereof.
The configuration of the hydrogen atoms in the 10 7 and 12a positions of the 1,2,3,4,5,7,12,12a-octahydro- i -1,4-diazpeinotl,7-b~isoquinoline residue may be cis ~7RS,12aRS) or trans (7RS, 12aSR~.
Preferably Rl is alkyl. Preferably R5 and R6 are hydrogen, halogen or alkoxy. Especially R6 is hydrogen and R5 is in the ~-position.
~ R3 and ~4 are in the 9 or lO~position of the ¦ tricyclic molety and preferably are both hydrogen, or I alkoxy, especially hydrogen.
i Halogen is preferably chlorine. The alkyl and
The lnvention reIates to octahydro-1,4~dlazeplno-~1,7-b]l~oquinolines~
The pre~ent lnvention provldes compounds of formula I, H
whers$n Rl i8 hydrogen or alkyl of 1 to 5 carbon atom-q, a group -~CH2) n ~7 I 10 whereln n ls a whole number from 0 to 3, ~ R5 and R6, lndependently, are hydrogen, i alkyl of 1 to 4 carbon atoms, alkoxy of ! 1 to 4 carbon atom~, halogen of atomlc number from 9 to 35, or together are 3,4-methylenedloxy, R7 ls hydrogen, or when ~oth R5 ,~nd R6 are . ~ .
.
~ . .
.. . . .. . , - . -. . . :
~ ' ' ' ' ' ' ' ' ' ' ' ; ! ' , 10703~0 alkoxy of 1 to 4 carbon atoms also may be alkoxy of 1 to 4 carbon atoms, R3 is hydrogen, alkyl of 1 to 4 carbon atoms, alko~y of 1 to 4 carbon atoms, or halogen or atomic number from 9 to 35, and R4 is hydrogen or alkoxy of 1 to 4 carbon - a~oms; and pharmaceutically acceptable acid addition salts thereof.
The configuration of the hydrogen atoms in the 10 7 and 12a positions of the 1,2,3,4,5,7,12,12a-octahydro- i -1,4-diazpeinotl,7-b~isoquinoline residue may be cis ~7RS,12aRS) or trans (7RS, 12aSR~.
Preferably Rl is alkyl. Preferably R5 and R6 are hydrogen, halogen or alkoxy. Especially R6 is hydrogen and R5 is in the ~-position.
~ R3 and ~4 are in the 9 or lO~position of the ¦ tricyclic molety and preferably are both hydrogen, or I alkoxy, especially hydrogen.
i Halogen is preferably chlorine. The alkyl and
2~ alkoxy moieties preferably have 1 or 2 carbon atoms.
I n is preferably 0 or 1.
The inYention also provides a process for the production of a compound of formula I, as defined above, which comprises reducing a compound of formula II, '3 ' ;
10~0300 R ~ ~ ._z II , whèrein R2, R3 and R4 are as defined above, and either X - is carbonyl, Y is carbonyl or methylene, and Z is the same as Rl, as deflned above, or X and Y are methylene and Z is alkanoyl of 1 to 5 carbon atoms, or alkoxycarbonyl of 2 to 5 carbon atoms; -and where necessary, converting the resulting product into a pharmaceutically acceptable acid addition salt thereof. .
Y is preferably methylene. When Rl is methyl, Z
is preferably alkoxycarbonyl, especially ethoxycarbonyl, or methyl. ~en Rl has more than 1 carbon atom, X is preferably carbonyl.
The process may be carried out in conventional manner for such reductions, e.g. under known conditions for the reduction of an N-substituted amide to the j correspondlng secondary or tertiary amine.
'l 20 As reducing agents may be used metal hydrides, such as aluminium hydride, dialkylaluminium hydride , .
.
I n is preferably 0 or 1.
The inYention also provides a process for the production of a compound of formula I, as defined above, which comprises reducing a compound of formula II, '3 ' ;
10~0300 R ~ ~ ._z II , whèrein R2, R3 and R4 are as defined above, and either X - is carbonyl, Y is carbonyl or methylene, and Z is the same as Rl, as deflned above, or X and Y are methylene and Z is alkanoyl of 1 to 5 carbon atoms, or alkoxycarbonyl of 2 to 5 carbon atoms; -and where necessary, converting the resulting product into a pharmaceutically acceptable acid addition salt thereof. .
Y is preferably methylene. When Rl is methyl, Z
is preferably alkoxycarbonyl, especially ethoxycarbonyl, or methyl. ~en Rl has more than 1 carbon atom, X is preferably carbonyl.
The process may be carried out in conventional manner for such reductions, e.g. under known conditions for the reduction of an N-substituted amide to the j correspondlng secondary or tertiary amine.
'l 20 As reducing agents may be used metal hydrides, such as aluminium hydride, dialkylaluminium hydride , .
.
- 3 -.
.. . . . , ... , . . . .. .. .. .. . . ~
or complex hydrides, especially complex aluminium hydrides such as lithium alumlnium hydride, lithium aluminium hydride~aluminlum chlorlde or disodium (2-methoxyethoxy) aluminium hydride in an inert solvent.
When complex aluminium hydrides are used chlorine or bromtne substituents may be replaced by hydrogen.
Disod~um (2-methoxyethoxy) aluminium hydride is especially preferred for the reductlon of an allkoxy-carbonyl group.
Generally it is convenient ~o use 1 to 4 moles j of reducing agent per mole of compound of formula II.
The xeaction temperature can vary between room temperature and 100C, bearing in mind the type of substituents present. For the reduction of an alkoxy-carbonyl group the reflux temperature is convenientlyused.
The compounds of formula II are new, and may be produced according to known methods for the productio~n ! of N-substituted amides and urethanes, e.g. from the corresponding ~-phenylacetoacetic acid ethyl ester.
Insofar as the production of any starting j material is not particularly described these compounds are known, or may be produced and purified in accordance with known processes, or in a manner analogous to ,~
:` ~
l~Y7Q;~OO
processes. described he.rein, e.g. in the Examples, or to kno~n processes. ;
Free base forms of compounds of foxmula I ~ -. may be converted into acid addition salt forms ln ; 5 conventional manner and vice v sa. Suitable acids for salt formatlon include hydrochIoric acid, maleic -acid, fumaric acid In the following Examples all temperatures are in degrees Centigrade and are uncorrected. :*
`.' . ,.
_ 5- :
' .
' , . , , , ~
1070300 100-4~73 .
.... ....
EX~IPLE l: ~7RS~12a~S)-7-~-methoxy~henyl-3-methyl-~
li2L3L4,1,5 L7,~12L12~--otahydro--114--diazeE~ino-- , ~
[lL7-b]iso~ulnoline 1.41 g of lithium aluminium hydride was added 5 in portions to a solution of 12.5 g of ~7RS,12aRS~-1,4, .
5,7,12,12a-hexahydro-7-E-methoxyphenyl-3-methyl-1,4-, diazepino[l,7-b~isoquinoline-2~3H~-one in 210 ml of tetrahydrofuran. The temperature rose to about 50C.
The reaction mixture was refluxed for 30 minutes, ' 10 stirred for another 2 hours and then to this mixture was added carefully dropwise 10 ml of methanol and 15 ml of a '-saturated solution of sodlum sulphate. The resultant precipitat~ was filtered off. The filtrate was concentra- ' ted~to dryness to afford the title compound (M.P. of ' ' ¦ 15 the maleate from methanol/ether -163 - lC4).
The starting material was obtained as follows~
a) ~ -Phenylacetoacetic acid ethyl ester was converted into 3-amino-4-phenylbutyric acid ethyl ester (M.P.of 1 ~ hydrogen oxalate 151-153). Further reaction with ` ,~
'I 20 ~-anisolyl chloride gavè 3-~-methoxybenzamido-4-phenylbutyric acid ethyl ester tM.P. 102-104)',.' ;~
A BischIer-Napieralski reaction (boillng wlth phosphorus oxychloride~ ~ave-3,4-dihydro-1-~-methoxy-phenyl-3-iso~uinolinylace~ic acid ethyl ester.
25 Hydrogenat~on using a palladium~charcoal ~10% W/w~
10~0300 100-~273 .......... gave. cis~ -methoxyphenyl-1,2,3,4-tetrahydro-3-lsoquinolinylacetic acid ethyl ester. :
b~ Reaction of this ester with paraformaldehyde and potassi~m cyanide gave cis-2 cyanomethyl~ methoxy-phenyl-1,2,3,4-tetrahydro-3-lsoguinolinyl acetic - acid ethyl ester, whlch was hydrogenated in crude form in the presence of Raney nlckel to give cis-2-(2-aminoethyl)-1-~-methoxyphenyl-1,2,3,4- . ..
tetrahydro-3-isoquinol1nylacetic acid ethyl ester.
Cyclization gave ~7RS~12aRS)-1,4,5,7,12,12a-hexa-hydro-7-~-methoxyphenyl-1, 4-ai azepino[l,-7-b]isoqulnolin-: 2 (3H)-one (M.P. 196-198).
. c) This aminoketone was alkylated with methyl iodide ,f to glve (7RS,12aRS)-1,4,5,7,12,12a-hexahydro-7-fp-i 15 methoxyphenyl-3-methyl-1,4-diazepino~1,7-b]isoquinolin-(3H)-one (M.P. 170-172).
, EXAMPLE ~: ~_RS1l2aRSl-_-methyl-lL2L3l4l5l7,l_ll_a_ octahydro-7-~henyl-1,4-diazepinofrlL_b~_ ;
!~lu~ -n-oll -ne In analogous manner to Example 1. ~7RS,12aRS)-3-mefthyl-7-phenyl-1,7,12,12a-tetrahydro-1,4-diazepino-~1,7-b]lsoquinolin-2,5~3H~4H~-dione was reacted to yleld the title compound ~M.P. of maleate from methanollether 184-186).
: .
- . . : .
10703~0 The startlng material was obtained as follows:-Cis-l-phenyl-1,2,3,4-tetrahydro-3-isoquinolinyl-ace~ic acid ethyl ester ~M.P. o hydrochloride 219-222) was obtained in analogous manner to Example 1 a) using benzoyl chlorlde instead of ~-anlsolyl chloride.
Reaction of this ester with bromoacetyl chloride at -10 in the presence of trie~hylamine gave cis-2-bromo-acetyl-l-phenyl-1,2,3,4-tetrahydro-3-isoquinolinylacetic acid ethyl ester (M.P. 107-109). Reaction with methyl-amine in tetrahydrofuran in an autoclave at 50 gave~7RS,12aRS)-1,7,12,12a-3-methyl-7-phenyl-1,7,12,12a-tetrahydro-1,4-diazepino[1,7-b]isoquinolin-2~5~3H,4H)-dione (M.P. 208-211).
EXAMPLE 3. ~7aRS1l2aRS)_3-ethV~3,2,3L4,5,7Ll2,12a-octahydro-7-~henyl-1,4-diaze~ino ~1L7-b]-iso~uinoline ___ ________ A solution of 6.0 g of (7RS,12aRS)-3-acetyl-1l 1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino-j l1,7-b~isoquinoline in 100 ml of dioxane was added dropwlse into a boiling suspension of 3.14 g of lithium aluminium hydride in 75 ml of dioxane. ~he reaction ~ mixture was boiled for 1 hour, cooled to 0, and to ; th~ mlxture was added carefully dropwise 50 ml of methanol and 50 ml of a saturated solution of sodium sulphate. The resultant precipitate was filtered off. The filtrate was - ~ . . . . . --. - - . . . ... - . . -` 1070300 evaporated to dryness to a~ford the title compound (M P.
of maleate from~methanol~ether 15~-158~.
~he starting material was obtalned as follows:-, a~ (7 RS,12aRS)~ ,5,7,12,12a-hexahydro-7-phenyl-1,4-diazepino[l,7-b~isoquinolin-2(3H~-one ~M.P. 232-2343 was produced in analogous manner to Examples 1 a) and b) using benzoyl chloride instead of ~-anisolyl -~
., .
chIoride. Reduction analogous to Example 1 gave S,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline tM.P. of maleate . ~ .
204-205).
'' b) 3.08 g of acetyl chloride diluted wlth 10 ml of methylene chloride was added dropwise to a solution of 9.9 g ~7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinollne in 100 ml of methylene chloride. The reaction mixture was stirred for 1 hour, then washed tw~ce with water, then dried with magnesium sulphate and concentrated to dryness to give t7Rsll2aRs)-3-acety~ 2l3l4l5l7 12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]iso-qulnoline tM.P. 145-147).
1 ~ 0 30 0 100-4273 ... ....
EXAMPLE 4 (7RSla2aRS)-3-methyl-1L2L3,415l7ll2~a2a_ octahydro_7-E~henyl_aL4_diaZe lBo[lL7_b]_ iso~uinoline ___ ________ A solutlon of 6.8 g of ~7RS,12aRS~-1/2,3,4,5,7,12,12a- r~
octahydro-7-pheny~ 4-diazepino[l~7-b~isoquinollne ll - 3-carboxylic acid ethyl ester ln toluene was added i dropwise slowly into a stirred and boiling mixture of 200 ml of toluene and 21.6 ml of 70~ disodium ~2-methoxyethoxy)aluminium hydride in benzene. The i 10 reaction mixture was refluxed ~or a further 30 minutes, and cooled to 0. The complex and remaining reducing agent was decomposed by the slow dropwise addition of ~
60 ml of a 20~ sodium hydroxide solutlon. The organic --phase was separated off, washed with 100 ml of a ~0%~
! 15 sodium hydroxide solution, then washed three times with water, then dried with magnesium sulphate, and finally concentrated to dryness to give th~ title compound ~M.P. o~ maleate from methanol/ether 184-186).
~he starting material was obtained as ~ollows:-5,4 g of (7RS,12aRS~-1,2,3,4,5,7,12,12a-octa-hydro-7-phenyl-1,4-diazepino[1,7-b3isoquinoline was dissolYed in 75 cc of chloroform and 30 cc of water are added. 4.3 g of chloroformic acid ethyl ester and subsequently a solution of 1.58 g of sodium hydroxlde in 30 cc of water were added dropwlse at a temperature 07 0 30 0 100-~273 of 0-5. The reaction mlxture was stirred for another . :.
hour wlthout coollng. The l.ayers were then separated and the organic phase was washed twice wlth water.
After drying wlth magnesium sulphate and concentration by evaporation of the filtered chloroform solution, .
the (7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-pheny~-1~4-diazepin~O[1~7-b}isoquinoline-3-carboxylic acid ethyl ester was obtained ln crude form.
Further compounds o formula I obtained are tebuleted below~
~ ,-'1 ' ' ' , ' ' , ~ .. . . . ~ . , , 1070300 loo-4273 .......................... .......... .
. I , l Example¦ Rl R2 l R3 R4 ura- I M.P.
. ......... ................. ....... .... ,. lon l~ -,, . _ _. _ . Ahalogous to Exampl~e~ l~ ~J', ~' 4~l:
5Me phenyl lO~OMe HcisO m 159-161 6~e phenyl 9~0Me Hcis ~) m 173-175 -7Me p-Cl-phenyl H Hcis ) m 186-188 8Me P-Cl-phenyl H Htrans~ ~h 198-201 9Me m-Cl'-phenyl H H cis ~) m 172-174 .l . 10Me o-Cl-phenyl H Hcls ~) f 192-195 11Me phenyl 10-Cl Hcis ~) m 192-193 12Me phenyl H ~trans ~ 210-212 13Me phenyl 9-Me Hcis ~) m 191-192 14Me phenyl 10-Me Hcis O m 171-173 15Me phenyl 9-MeO 10-OMe cis ~) m 1i8-179 16Me benzyl H, Hcis ~) m 1~9-150 17Me phenyl 9-'~Cl Hcis ~) m 200-201 18- Me phenyl 9-Cl Htrans ,~. 182-184 19 Me p-Cl-benzyl H Hcis ~) b 85-87 20Me m-MeO-phènyi H Hcis ~) m 161-162 21Me m,p-Di-MeO- H Hcis O m 174-175 phenyl 22~e p-MeO-benzyl H Hcis ~ m 120--121 23Me o-MeO-phenyl H Hcis ~) m 134-137 ` 107~)3~)0 .
.. .... . . .... . . . . .. . . . . . . . ...
I EXamP1e IR1 ~ R2 1 3 1; 4~ COnf1gUr-I M.P
`` ~ ``` ~ation :. .`.`.. ``
. , . , _ ____ . Analo~ous to Exam~le ~ ~', 3~' and 4 - :
. ~
24 ¦Me ¦ P-MeO-PhenY1¦ H ¦H CiS Z) m 163-1640 Analo~ous to ExamPlë 1`` and 2 3): .
H phenyl H H ~is O m 204-205 26 H phenyl 10-OMe H ¦cis O b Oil 27 H phenyl 9-OMe ~ ~cis ~) m 188-19G
28 H m-Me~-phenyl H H (cis ~) b Oil 29 H p-Cl-phenyl H ~ ~ci~ ~ m 201-202 H phenyl 10-Cl H ~is ~) m 196-197 31 H phenyl H H trans ~ f 176-178 32 H p-MeO-phenyl H H cls O m 186-188 33 ~ phenyl 10-Me H cis O m 209-210 34 H phenyl 9-~e H cis ~) m 188-189 . 35 H phenyl H H cis ~) m 158-1600 . Analogous to ~ample 1 ) ,a~d 3~,:
36 ~e ¦ phenyl ~ ~ cia Z) m 134-186 I~ the Table:
Configuratlon - Configuration of the hydrogen atoms in the 7 and 12a positions.
b = base; dh = dlhydrochloride; f = fumarate; m = maleate;
Et ~ ethyl; Me - methyl.
`-` 1070;~00 ~
~) from the corresponding. compound of formula II, whereln X = -C0-; Y = -CH2- and Z = Rl :
from the corresponding compound of formula II, whereln ~ -- Y = -C0- and Z = R
- 5 ~ from the corresponding compound of formula II, wherein .
i X = Y = -CH2- and Z = -CH0 . ~) from the corresponding compound o formula II, wherein - ` X = Y = -CH2 - and Z is ethoxycar~onyl For the preparation of the starting material the subs~ituted cis or trans 1,2,3,4,-tetrahydro-3-iso-quinolinyl-acetic acid ethyl ester was produced according to Example 1 a); however, in the last step the reduction of the corresponding substituted 3,~-dihydro-3-isoquinolinylacetic acid ethyl ester ~,Jas carried out using sodium borohydride in methanol instead of hydrogen gas. The product was a cis/trans ' mixture .~hich was separated by chromatography on a . 50 fold amount of aluminium oxlde (aciti~ity . basicity II) with methylene chloride as eluent.
0 The condltlons of a caA A180 be ~ed.
'l .
:', ~ X4 -0~ 0 30 100-4273 The compounds of formula I exhibit pharmacologlcal activity. In parti-cular the' compounds exhlbit sleep-inducing and sleep-prolonging activity as indicated in Jj standard tests in anlmals.
In one standard test chronically implanted, unrestrained Charles River rats are used. The rats were' implanted according to the method of Sayers A.C. and Stille G. ~Elec~roenceph. clin. Neurophysiol. 27, 87-89 (1969)]. For the EEG monopolar connections were made 10 in a Cortex occipitalls, and a right Hippc~ampus ,~
, , dorsalis. The E.M.G. of the neck muscles was also ,, recorded. The rats were used at least 14 days after the I operation.
',1 The test substance was administered to the ani~al in dissolved or suspendad form per os. using a stomach tube. The EEG was then observed over the next 3 hours. The animals were kept in a box in which they also lived outside the observation period. During thls time the animals were under constant ligh~ing con-~,, 20 ditions and insulated against noise and electrlcal disturbances. Food and water wexe available ad libitum.
The increase'in the sleep phase-and decrease in the wake phase was observed by ~,ear.s o~ the E.E.G.
' Additionally the''compounds exhibit locomotor-depressant activity in the well kno~m light box test.
` - 15 -: . .
., .`
.
1070~00 100-4273 The compounds are therefore further indicated for use as sleep-inducing and sleep-promoting agents.
For thls use an indicated daily dose is from about l to about 200 mg, conveniently administered in one dose shortly before retiring to sleep.
The compounds of Examples l and 2 are the most interesting compounds.
Furthermore the compounds exhibit anti-aggressive activity as indicated in standard tests. In one standard lO test the compouncls inhibit isolation-induced aggressive ;-behaviour according to the method of H.C.Y. Yen et al [J. Pharmacol. exp. Ther.122, 85A (1958)~.
The compounds are therefore further indicated for use as anti-aggressive agents. For this use an 15 indicated daily dose is from about 30 to about 300 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 7 to about 150 mg, or in sustained release form.
The compounds of Examples 1,2 and 19 are the most interesting compounds.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily . .
- . .;. . - - - ;, ~
~07(~3(~0 prepared in conventional manner. The present lnvention also provides a pharmaceutical composition comprising a compound of formula I, ln free base form or in pharmaceutically acceptable acid addltion salt form, ln association with a pharmaceutical carriex or diluent.
Such compositions may be in the form of, for example, a solution or a tablet.
Preferably Rl is ethyl or especially methyl.
Preferably R2 ls phenyl or benzyl, conveniently preferably para-substituted by halogen, e.g. chlorine, or methoxy.
Preferably the 7 and 12a bydrogen atoms are cis.
, ,~, , 1~ .
.. ... . . . .. .. : . - .: ~: . .... ..
.. . . . , ... , . . . .. .. .. .. . . ~
or complex hydrides, especially complex aluminium hydrides such as lithium alumlnium hydride, lithium aluminium hydride~aluminlum chlorlde or disodium (2-methoxyethoxy) aluminium hydride in an inert solvent.
When complex aluminium hydrides are used chlorine or bromtne substituents may be replaced by hydrogen.
Disod~um (2-methoxyethoxy) aluminium hydride is especially preferred for the reductlon of an allkoxy-carbonyl group.
Generally it is convenient ~o use 1 to 4 moles j of reducing agent per mole of compound of formula II.
The xeaction temperature can vary between room temperature and 100C, bearing in mind the type of substituents present. For the reduction of an alkoxy-carbonyl group the reflux temperature is convenientlyused.
The compounds of formula II are new, and may be produced according to known methods for the productio~n ! of N-substituted amides and urethanes, e.g. from the corresponding ~-phenylacetoacetic acid ethyl ester.
Insofar as the production of any starting j material is not particularly described these compounds are known, or may be produced and purified in accordance with known processes, or in a manner analogous to ,~
:` ~
l~Y7Q;~OO
processes. described he.rein, e.g. in the Examples, or to kno~n processes. ;
Free base forms of compounds of foxmula I ~ -. may be converted into acid addition salt forms ln ; 5 conventional manner and vice v sa. Suitable acids for salt formatlon include hydrochIoric acid, maleic -acid, fumaric acid In the following Examples all temperatures are in degrees Centigrade and are uncorrected. :*
`.' . ,.
_ 5- :
' .
' , . , , , ~
1070300 100-4~73 .
.... ....
EX~IPLE l: ~7RS~12a~S)-7-~-methoxy~henyl-3-methyl-~
li2L3L4,1,5 L7,~12L12~--otahydro--114--diazeE~ino-- , ~
[lL7-b]iso~ulnoline 1.41 g of lithium aluminium hydride was added 5 in portions to a solution of 12.5 g of ~7RS,12aRS~-1,4, .
5,7,12,12a-hexahydro-7-E-methoxyphenyl-3-methyl-1,4-, diazepino[l,7-b~isoquinoline-2~3H~-one in 210 ml of tetrahydrofuran. The temperature rose to about 50C.
The reaction mixture was refluxed for 30 minutes, ' 10 stirred for another 2 hours and then to this mixture was added carefully dropwise 10 ml of methanol and 15 ml of a '-saturated solution of sodlum sulphate. The resultant precipitat~ was filtered off. The filtrate was concentra- ' ted~to dryness to afford the title compound (M.P. of ' ' ¦ 15 the maleate from methanol/ether -163 - lC4).
The starting material was obtained as follows~
a) ~ -Phenylacetoacetic acid ethyl ester was converted into 3-amino-4-phenylbutyric acid ethyl ester (M.P.of 1 ~ hydrogen oxalate 151-153). Further reaction with ` ,~
'I 20 ~-anisolyl chloride gavè 3-~-methoxybenzamido-4-phenylbutyric acid ethyl ester tM.P. 102-104)',.' ;~
A BischIer-Napieralski reaction (boillng wlth phosphorus oxychloride~ ~ave-3,4-dihydro-1-~-methoxy-phenyl-3-iso~uinolinylace~ic acid ethyl ester.
25 Hydrogenat~on using a palladium~charcoal ~10% W/w~
10~0300 100-~273 .......... gave. cis~ -methoxyphenyl-1,2,3,4-tetrahydro-3-lsoquinolinylacetic acid ethyl ester. :
b~ Reaction of this ester with paraformaldehyde and potassi~m cyanide gave cis-2 cyanomethyl~ methoxy-phenyl-1,2,3,4-tetrahydro-3-lsoguinolinyl acetic - acid ethyl ester, whlch was hydrogenated in crude form in the presence of Raney nlckel to give cis-2-(2-aminoethyl)-1-~-methoxyphenyl-1,2,3,4- . ..
tetrahydro-3-isoquinol1nylacetic acid ethyl ester.
Cyclization gave ~7RS~12aRS)-1,4,5,7,12,12a-hexa-hydro-7-~-methoxyphenyl-1, 4-ai azepino[l,-7-b]isoqulnolin-: 2 (3H)-one (M.P. 196-198).
. c) This aminoketone was alkylated with methyl iodide ,f to glve (7RS,12aRS)-1,4,5,7,12,12a-hexahydro-7-fp-i 15 methoxyphenyl-3-methyl-1,4-diazepino~1,7-b]isoquinolin-(3H)-one (M.P. 170-172).
, EXAMPLE ~: ~_RS1l2aRSl-_-methyl-lL2L3l4l5l7,l_ll_a_ octahydro-7-~henyl-1,4-diazepinofrlL_b~_ ;
!~lu~ -n-oll -ne In analogous manner to Example 1. ~7RS,12aRS)-3-mefthyl-7-phenyl-1,7,12,12a-tetrahydro-1,4-diazepino-~1,7-b]lsoquinolin-2,5~3H~4H~-dione was reacted to yleld the title compound ~M.P. of maleate from methanollether 184-186).
: .
- . . : .
10703~0 The startlng material was obtained as follows:-Cis-l-phenyl-1,2,3,4-tetrahydro-3-isoquinolinyl-ace~ic acid ethyl ester ~M.P. o hydrochloride 219-222) was obtained in analogous manner to Example 1 a) using benzoyl chlorlde instead of ~-anlsolyl chloride.
Reaction of this ester with bromoacetyl chloride at -10 in the presence of trie~hylamine gave cis-2-bromo-acetyl-l-phenyl-1,2,3,4-tetrahydro-3-isoquinolinylacetic acid ethyl ester (M.P. 107-109). Reaction with methyl-amine in tetrahydrofuran in an autoclave at 50 gave~7RS,12aRS)-1,7,12,12a-3-methyl-7-phenyl-1,7,12,12a-tetrahydro-1,4-diazepino[1,7-b]isoquinolin-2~5~3H,4H)-dione (M.P. 208-211).
EXAMPLE 3. ~7aRS1l2aRS)_3-ethV~3,2,3L4,5,7Ll2,12a-octahydro-7-~henyl-1,4-diaze~ino ~1L7-b]-iso~uinoline ___ ________ A solution of 6.0 g of (7RS,12aRS)-3-acetyl-1l 1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino-j l1,7-b~isoquinoline in 100 ml of dioxane was added dropwlse into a boiling suspension of 3.14 g of lithium aluminium hydride in 75 ml of dioxane. ~he reaction ~ mixture was boiled for 1 hour, cooled to 0, and to ; th~ mlxture was added carefully dropwise 50 ml of methanol and 50 ml of a saturated solution of sodium sulphate. The resultant precipitate was filtered off. The filtrate was - ~ . . . . . --. - - . . . ... - . . -` 1070300 evaporated to dryness to a~ford the title compound (M P.
of maleate from~methanol~ether 15~-158~.
~he starting material was obtalned as follows:-, a~ (7 RS,12aRS)~ ,5,7,12,12a-hexahydro-7-phenyl-1,4-diazepino[l,7-b~isoquinolin-2(3H~-one ~M.P. 232-2343 was produced in analogous manner to Examples 1 a) and b) using benzoyl chloride instead of ~-anisolyl -~
., .
chIoride. Reduction analogous to Example 1 gave S,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline tM.P. of maleate . ~ .
204-205).
'' b) 3.08 g of acetyl chloride diluted wlth 10 ml of methylene chloride was added dropwise to a solution of 9.9 g ~7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinollne in 100 ml of methylene chloride. The reaction mixture was stirred for 1 hour, then washed tw~ce with water, then dried with magnesium sulphate and concentrated to dryness to give t7Rsll2aRs)-3-acety~ 2l3l4l5l7 12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]iso-qulnoline tM.P. 145-147).
1 ~ 0 30 0 100-4273 ... ....
EXAMPLE 4 (7RSla2aRS)-3-methyl-1L2L3,415l7ll2~a2a_ octahydro_7-E~henyl_aL4_diaZe lBo[lL7_b]_ iso~uinoline ___ ________ A solutlon of 6.8 g of ~7RS,12aRS~-1/2,3,4,5,7,12,12a- r~
octahydro-7-pheny~ 4-diazepino[l~7-b~isoquinollne ll - 3-carboxylic acid ethyl ester ln toluene was added i dropwise slowly into a stirred and boiling mixture of 200 ml of toluene and 21.6 ml of 70~ disodium ~2-methoxyethoxy)aluminium hydride in benzene. The i 10 reaction mixture was refluxed ~or a further 30 minutes, and cooled to 0. The complex and remaining reducing agent was decomposed by the slow dropwise addition of ~
60 ml of a 20~ sodium hydroxide solutlon. The organic --phase was separated off, washed with 100 ml of a ~0%~
! 15 sodium hydroxide solution, then washed three times with water, then dried with magnesium sulphate, and finally concentrated to dryness to give th~ title compound ~M.P. o~ maleate from methanol/ether 184-186).
~he starting material was obtained as ~ollows:-5,4 g of (7RS,12aRS~-1,2,3,4,5,7,12,12a-octa-hydro-7-phenyl-1,4-diazepino[1,7-b3isoquinoline was dissolYed in 75 cc of chloroform and 30 cc of water are added. 4.3 g of chloroformic acid ethyl ester and subsequently a solution of 1.58 g of sodium hydroxlde in 30 cc of water were added dropwlse at a temperature 07 0 30 0 100-~273 of 0-5. The reaction mlxture was stirred for another . :.
hour wlthout coollng. The l.ayers were then separated and the organic phase was washed twice wlth water.
After drying wlth magnesium sulphate and concentration by evaporation of the filtered chloroform solution, .
the (7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-pheny~-1~4-diazepin~O[1~7-b}isoquinoline-3-carboxylic acid ethyl ester was obtained ln crude form.
Further compounds o formula I obtained are tebuleted below~
~ ,-'1 ' ' ' , ' ' , ~ .. . . . ~ . , , 1070300 loo-4273 .......................... .......... .
. I , l Example¦ Rl R2 l R3 R4 ura- I M.P.
. ......... ................. ....... .... ,. lon l~ -,, . _ _. _ . Ahalogous to Exampl~e~ l~ ~J', ~' 4~l:
5Me phenyl lO~OMe HcisO m 159-161 6~e phenyl 9~0Me Hcis ~) m 173-175 -7Me p-Cl-phenyl H Hcis ) m 186-188 8Me P-Cl-phenyl H Htrans~ ~h 198-201 9Me m-Cl'-phenyl H H cis ~) m 172-174 .l . 10Me o-Cl-phenyl H Hcls ~) f 192-195 11Me phenyl 10-Cl Hcis ~) m 192-193 12Me phenyl H ~trans ~ 210-212 13Me phenyl 9-Me Hcis ~) m 191-192 14Me phenyl 10-Me Hcis O m 171-173 15Me phenyl 9-MeO 10-OMe cis ~) m 1i8-179 16Me benzyl H, Hcis ~) m 1~9-150 17Me phenyl 9-'~Cl Hcis ~) m 200-201 18- Me phenyl 9-Cl Htrans ,~. 182-184 19 Me p-Cl-benzyl H Hcis ~) b 85-87 20Me m-MeO-phènyi H Hcis ~) m 161-162 21Me m,p-Di-MeO- H Hcis O m 174-175 phenyl 22~e p-MeO-benzyl H Hcis ~ m 120--121 23Me o-MeO-phenyl H Hcis ~) m 134-137 ` 107~)3~)0 .
.. .... . . .... . . . . .. . . . . . . . ...
I EXamP1e IR1 ~ R2 1 3 1; 4~ COnf1gUr-I M.P
`` ~ ``` ~ation :. .`.`.. ``
. , . , _ ____ . Analo~ous to Exam~le ~ ~', 3~' and 4 - :
. ~
24 ¦Me ¦ P-MeO-PhenY1¦ H ¦H CiS Z) m 163-1640 Analo~ous to ExamPlë 1`` and 2 3): .
H phenyl H H ~is O m 204-205 26 H phenyl 10-OMe H ¦cis O b Oil 27 H phenyl 9-OMe ~ ~cis ~) m 188-19G
28 H m-Me~-phenyl H H (cis ~) b Oil 29 H p-Cl-phenyl H ~ ~ci~ ~ m 201-202 H phenyl 10-Cl H ~is ~) m 196-197 31 H phenyl H H trans ~ f 176-178 32 H p-MeO-phenyl H H cls O m 186-188 33 ~ phenyl 10-Me H cis O m 209-210 34 H phenyl 9-~e H cis ~) m 188-189 . 35 H phenyl H H cis ~) m 158-1600 . Analogous to ~ample 1 ) ,a~d 3~,:
36 ~e ¦ phenyl ~ ~ cia Z) m 134-186 I~ the Table:
Configuratlon - Configuration of the hydrogen atoms in the 7 and 12a positions.
b = base; dh = dlhydrochloride; f = fumarate; m = maleate;
Et ~ ethyl; Me - methyl.
`-` 1070;~00 ~
~) from the corresponding. compound of formula II, whereln X = -C0-; Y = -CH2- and Z = Rl :
from the corresponding compound of formula II, whereln ~ -- Y = -C0- and Z = R
- 5 ~ from the corresponding compound of formula II, wherein .
i X = Y = -CH2- and Z = -CH0 . ~) from the corresponding compound o formula II, wherein - ` X = Y = -CH2 - and Z is ethoxycar~onyl For the preparation of the starting material the subs~ituted cis or trans 1,2,3,4,-tetrahydro-3-iso-quinolinyl-acetic acid ethyl ester was produced according to Example 1 a); however, in the last step the reduction of the corresponding substituted 3,~-dihydro-3-isoquinolinylacetic acid ethyl ester ~,Jas carried out using sodium borohydride in methanol instead of hydrogen gas. The product was a cis/trans ' mixture .~hich was separated by chromatography on a . 50 fold amount of aluminium oxlde (aciti~ity . basicity II) with methylene chloride as eluent.
0 The condltlons of a caA A180 be ~ed.
'l .
:', ~ X4 -0~ 0 30 100-4273 The compounds of formula I exhibit pharmacologlcal activity. In parti-cular the' compounds exhlbit sleep-inducing and sleep-prolonging activity as indicated in Jj standard tests in anlmals.
In one standard test chronically implanted, unrestrained Charles River rats are used. The rats were' implanted according to the method of Sayers A.C. and Stille G. ~Elec~roenceph. clin. Neurophysiol. 27, 87-89 (1969)]. For the EEG monopolar connections were made 10 in a Cortex occipitalls, and a right Hippc~ampus ,~
, , dorsalis. The E.M.G. of the neck muscles was also ,, recorded. The rats were used at least 14 days after the I operation.
',1 The test substance was administered to the ani~al in dissolved or suspendad form per os. using a stomach tube. The EEG was then observed over the next 3 hours. The animals were kept in a box in which they also lived outside the observation period. During thls time the animals were under constant ligh~ing con-~,, 20 ditions and insulated against noise and electrlcal disturbances. Food and water wexe available ad libitum.
The increase'in the sleep phase-and decrease in the wake phase was observed by ~,ear.s o~ the E.E.G.
' Additionally the''compounds exhibit locomotor-depressant activity in the well kno~m light box test.
` - 15 -: . .
., .`
.
1070~00 100-4273 The compounds are therefore further indicated for use as sleep-inducing and sleep-promoting agents.
For thls use an indicated daily dose is from about l to about 200 mg, conveniently administered in one dose shortly before retiring to sleep.
The compounds of Examples l and 2 are the most interesting compounds.
Furthermore the compounds exhibit anti-aggressive activity as indicated in standard tests. In one standard lO test the compouncls inhibit isolation-induced aggressive ;-behaviour according to the method of H.C.Y. Yen et al [J. Pharmacol. exp. Ther.122, 85A (1958)~.
The compounds are therefore further indicated for use as anti-aggressive agents. For this use an 15 indicated daily dose is from about 30 to about 300 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 7 to about 150 mg, or in sustained release form.
The compounds of Examples 1,2 and 19 are the most interesting compounds.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the same order of activity as the free base forms and are readily . .
- . .;. . - - - ;, ~
~07(~3(~0 prepared in conventional manner. The present lnvention also provides a pharmaceutical composition comprising a compound of formula I, ln free base form or in pharmaceutically acceptable acid addltion salt form, ln association with a pharmaceutical carriex or diluent.
Such compositions may be in the form of, for example, a solution or a tablet.
Preferably Rl is ethyl or especially methyl.
Preferably R2 ls phenyl or benzyl, conveniently preferably para-substituted by halogen, e.g. chlorine, or methoxy.
Preferably the 7 and 12a bydrogen atoms are cis.
, ,~, , 1~ .
.. ... . . . .. .. : . - .: ~: . .... ..
Claims (5)
1. A process for the production of a compound of formula I, I
wherein R1 is hydrogen or alkyl of 1 to 5 carbon atoms, R2 is a group wherein n is a whole number from 0 to 3, R5 and R6, independently, are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen of atomic number from 9 to 35, or together are 3,4-methylenedioxy, R7 is hydrogen, or when both R5 and R6 are alkoxy of 1 to 4 carbon atoms also may be alkoxy of 1 to 4 carbon atoms, R3 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen of atomic number from 9 to 35, and R4 is hydrogen or alkoxy of 1 to 4 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof, which comprises reducing a compound of formula II, II
wherein R2/ R3 and R4 are as defined above, and either X is carbonyl, Y is carbonyl or methylene, and Z is the same as R1, as defined above, or X and Y are methylene and Z is alkanoyl of 1 to 5 carbon atoms, and where necessary converting the resulting product into a pharma-ceutically acceptable acid addition salt thereof.
wherein R1 is hydrogen or alkyl of 1 to 5 carbon atoms, R2 is a group wherein n is a whole number from 0 to 3, R5 and R6, independently, are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen of atomic number from 9 to 35, or together are 3,4-methylenedioxy, R7 is hydrogen, or when both R5 and R6 are alkoxy of 1 to 4 carbon atoms also may be alkoxy of 1 to 4 carbon atoms, R3 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen of atomic number from 9 to 35, and R4 is hydrogen or alkoxy of 1 to 4 carbon atoms, or a pharmaceutically acceptable acid addition salt thereof, which comprises reducing a compound of formula II, II
wherein R2/ R3 and R4 are as defined above, and either X is carbonyl, Y is carbonyl or methylene, and Z is the same as R1, as defined above, or X and Y are methylene and Z is alkanoyl of 1 to 5 carbon atoms, and where necessary converting the resulting product into a pharma-ceutically acceptable acid addition salt thereof.
2. A compound of formula I, as stated in claim 1, or a pharmaceutically acceptable acid addition salt thereof, whenever produced by a process according to claim 1 or an obvious chemical equivalent thereof
3. A process according to claim 1 for the produc-tion of. (7RS,12aRS)-7-p-methoxyphenyl-3-methyl-1,2,3,4, 5,7,12,12a-octahydro-1,4-diazepino-[1,7-b]isoquinoline or a pharmaceutically acceptable acid addition salt thereof, which comprises reducing a compound of formula II, as defined in clalm 1, wherein R2 is 7-p-methoxyphenyl, R3 and R4 are hydrogen, the configuration of the hydrogen atoms in the 7 and 12a.positions of the 1,2,3,4,5,7,12, 12a-octahydro-1,4-diazepino[1,7-b]isoquinoline residue is cis and either X is carbonyl, Y is carbonyl or methylene, and Z is methyl, or X and Y are methylene and Z is formyl or alkoxycarbonyl of 2 to 5 carbon atoms, and where necessary converting the resulting product into a pharma-ceutically acceptable acid addition salt thereof.
4. A process according to claim 3 which comprises reducing (7RS,12aRS)-1,4,5,7,12,12a-hexahydro-7-p-methoxy-phenyl-3-methyl-1,4-diazepino[1,7-b]isoquinoline-2(3H)-one, (7RS,12aRS-1,7,12,12a-tetrahydro-7-p-methoxyphenyl-3-methyl-1,4-diazepino[1,7-b]isoquinoline-2,5(3H,4H)-di-one, (7RS,12aRS)-3-formyl-1,2,3,4,5,7,12,12a-octahydro-7-p-methoxyphenyl-1,4-diazepino[1,7-b]isoquinoline or (7RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-p-methoxy-phenyl-1,4-diazepino[1,7-b)isoquinoline-3-carboxylic acid lower alkyl ester with a complex aluminium hydride, and where necessary converting the resulting product into a pharmaceutically acceptable acid addition salt thereof.
5. (7RS,12aRS)-7-p-methoxyphenyl-3-methyl-1,2,3,4,5, 7,12,12a-octahydro-1,4-diazepino-[1,7-b]isoquinoline or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1702074A CH599210A5 (en) | 1974-12-20 | 1974-12-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1070300A true CA1070300A (en) | 1980-01-22 |
Family
ID=4422153
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA242,064A Expired CA1070300A (en) | 1974-12-20 | 1975-12-18 | Diazep inoisoquinoline derivatives |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS5186496A (en) |
| AT (1) | ATA966475A (en) |
| AU (1) | AU502638B2 (en) |
| BE (1) | BE836823A (en) |
| CA (1) | CA1070300A (en) |
| CH (1) | CH599210A5 (en) |
| DE (1) | DE2555532A1 (en) |
| DK (1) | DK139680B (en) |
| FI (1) | FI753495A (en) |
| FR (1) | FR2294709A1 (en) |
| GB (1) | GB1528370A (en) |
| IL (1) | IL48688A (en) |
| NL (1) | NL7514629A (en) |
| NO (1) | NO754239L (en) |
| SE (1) | SE7514100L (en) |
| YU (1) | YU323075A (en) |
| ZA (1) | ZA757882B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4120965A (en) * | 1974-12-20 | 1978-10-17 | Sandoz Ltd. | Octahydro-1,4-diazepino[1,7-b]isoquinolines |
-
1974
- 1974-12-20 CH CH1702074A patent/CH599210A5/xx not_active IP Right Cessation
-
1975
- 1975-12-10 DE DE19752555532 patent/DE2555532A1/en active Pending
- 1975-12-11 FI FI753495A patent/FI753495A/fi not_active Application Discontinuation
- 1975-12-11 DK DK564375AA patent/DK139680B/en unknown
- 1975-12-12 NO NO754239A patent/NO754239L/no unknown
- 1975-12-12 SE SE7514100A patent/SE7514100L/en unknown
- 1975-12-16 NL NL7514629A patent/NL7514629A/en not_active Application Discontinuation
- 1975-12-17 GB GB51576/75A patent/GB1528370A/en not_active Expired
- 1975-12-18 CA CA242,064A patent/CA1070300A/en not_active Expired
- 1975-12-18 BE BE162897A patent/BE836823A/en unknown
- 1975-12-18 YU YU03230/75A patent/YU323075A/en unknown
- 1975-12-18 IL IL48688A patent/IL48688A/en unknown
- 1975-12-18 AU AU87685/75A patent/AU502638B2/en not_active Expired
- 1975-12-19 AT AT966475A patent/ATA966475A/en not_active Application Discontinuation
- 1975-12-19 JP JP50150696A patent/JPS5186496A/ja active Pending
- 1975-12-19 ZA ZA757882A patent/ZA757882B/en unknown
- 1975-12-19 FR FR7539160A patent/FR2294709A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| CH599210A5 (en) | 1978-05-12 |
| ATA966475A (en) | 1980-03-15 |
| DK139680C (en) | 1979-09-10 |
| BE836823A (en) | 1976-06-18 |
| DK564375A (en) | 1976-06-21 |
| FR2294709B1 (en) | 1979-09-21 |
| DK139680B (en) | 1979-03-26 |
| FR2294709A1 (en) | 1976-07-16 |
| NL7514629A (en) | 1976-06-22 |
| IL48688A (en) | 1978-01-31 |
| ZA757882B (en) | 1977-07-27 |
| GB1528370A (en) | 1978-10-11 |
| YU323075A (en) | 1982-02-28 |
| IL48688A0 (en) | 1976-02-29 |
| SE7514100L (en) | 1976-06-21 |
| DE2555532A1 (en) | 1976-07-01 |
| JPS5186496A (en) | 1976-07-29 |
| AU8768575A (en) | 1977-06-23 |
| FI753495A (en) | 1976-06-21 |
| AU502638B2 (en) | 1979-08-02 |
| NO754239L (en) | 1976-06-22 |
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