CA1073452A - 8.alpha.-ERGOLINE I COMPOUNDS - Google Patents
8.alpha.-ERGOLINE I COMPOUNDSInfo
- Publication number
- CA1073452A CA1073452A CA231,773A CA231773A CA1073452A CA 1073452 A CA1073452 A CA 1073452A CA 231773 A CA231773 A CA 231773A CA 1073452 A CA1073452 A CA 1073452A
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- CA
- Canada
- Prior art keywords
- carbon atoms
- methyl
- ergoline
- alpha
- formula
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/02—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hydrocarbon or substituted hydrocarbon radicals, attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
- C07D457/12—Nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
8?-ERGOLINE I COMPOUNDS
Abstract of the Disclosure This invention provides new compounds of formula I, I
wherein X is hydrogen, chlorine or bromine, R1 is methyl or ethyl, and R2 is CH2-CN, or a group NR3R4, wherein R3 is hydrogen or alkyl of 1 to 4 carbon atoms, and R4 is formyl, alkanoyl of 2 to 5 carbon atoms in the aggregate thereof, alkoxycarbonyl of 2 to 5 carbon atoms in the aggregate thereof, mono- to trihalogenalkoxycarbonyl of 3 to 5 carbon atoms in the aggregate thereof, the alkoxy radical of which is substituted by halogen in a position other than .alpha. to the oxygen, or the radical SO2R5, wherein R5 is alkyl of 1 to 4 carbon atoms, mono-to tri-halogenalkyl of 1 to 4 carbon atoms, phenyl, pyridyl, phenyl monosub-stituted by halogen or alkoxy of 1 to 4 carbon atoms, or a group NR6R7, wherein each of R6 and R7 is independently hydrogen or alkyl of 1 to 4 carbon atoms, or R6 and R7 together are one of the groups (CH2)n or (CH2)2-A-(CH2)2, wherein n is a number from 3 to 7, and A is oxygen, sulphur or nitrogen substituted by alkyl of 1 to 4 carbon atoms or phenyl, useful as prolactin secretion agents and anti-parkinson agents.
Abstract of the Disclosure This invention provides new compounds of formula I, I
wherein X is hydrogen, chlorine or bromine, R1 is methyl or ethyl, and R2 is CH2-CN, or a group NR3R4, wherein R3 is hydrogen or alkyl of 1 to 4 carbon atoms, and R4 is formyl, alkanoyl of 2 to 5 carbon atoms in the aggregate thereof, alkoxycarbonyl of 2 to 5 carbon atoms in the aggregate thereof, mono- to trihalogenalkoxycarbonyl of 3 to 5 carbon atoms in the aggregate thereof, the alkoxy radical of which is substituted by halogen in a position other than .alpha. to the oxygen, or the radical SO2R5, wherein R5 is alkyl of 1 to 4 carbon atoms, mono-to tri-halogenalkyl of 1 to 4 carbon atoms, phenyl, pyridyl, phenyl monosub-stituted by halogen or alkoxy of 1 to 4 carbon atoms, or a group NR6R7, wherein each of R6 and R7 is independently hydrogen or alkyl of 1 to 4 carbon atoms, or R6 and R7 together are one of the groups (CH2)n or (CH2)2-A-(CH2)2, wherein n is a number from 3 to 7, and A is oxygen, sulphur or nitrogen substituted by alkyl of 1 to 4 carbon atoms or phenyl, useful as prolactin secretion agents and anti-parkinson agents.
Description
- 10'7345Z Case_100-4208 80<-ERGOLINE I COMPOUNDS
The pre~ent invention relates to new organlc compounds.
- In accordance with the invention there are prov$ded new compounds of formula I, - -^
wherein X i8 hydsogen, chlor$ne or bromine, Rl ~s methyl or ethyl, and R2 i-~ C~2-CN, or a group NR3R~, wherein R3 ls hydrogen or aLkyl of 1 to 4 carbon atoms, and R4 is formyl, aIkanoyl of 2 to 5 carbon atoms in ~he aggregate thereof, aLkoxycarbonyl of 2 to 5 - carbon atcms in the aggregate thereof, mono- to ~rihalogenaIkoxycarbonyl of 3 to 5 carbon atoms in the aggregate thereof, the alkoxy radical of which is substituted by haloge~ in a position other than a to the oxygen, or the radical S0 Rc, wherein R~ is alkyl of 1 to 4 carbon atoms, mono-to tri-halogenalkyl of 1 to 4 carbon atoms, phenyl, pyridyl, phenyl monosub-~, ~; .
The pre~ent invention relates to new organlc compounds.
- In accordance with the invention there are prov$ded new compounds of formula I, - -^
wherein X i8 hydsogen, chlor$ne or bromine, Rl ~s methyl or ethyl, and R2 i-~ C~2-CN, or a group NR3R~, wherein R3 ls hydrogen or aLkyl of 1 to 4 carbon atoms, and R4 is formyl, aIkanoyl of 2 to 5 carbon atoms in ~he aggregate thereof, aLkoxycarbonyl of 2 to 5 - carbon atcms in the aggregate thereof, mono- to ~rihalogenaIkoxycarbonyl of 3 to 5 carbon atoms in the aggregate thereof, the alkoxy radical of which is substituted by haloge~ in a position other than a to the oxygen, or the radical S0 Rc, wherein R~ is alkyl of 1 to 4 carbon atoms, mono-to tri-halogenalkyl of 1 to 4 carbon atoms, phenyl, pyridyl, phenyl monosub-~, ~; .
- 2 - 100-4208 stituted by halogen or alkoxy of 1 to 4 carbon atoms, or a group NR6R7, wherein each of R6 and R7 is independently hydrogen or ~
- 15 alkyl of 1 to 4 carbon atoms, or R6 and R7 together are one of the groups (CH2)n or (CH2)2 A (CH2)2' wherein - n is a number from 3`to 7, and ~0 ~ A is oxygen, sulphur or nitrogen - substituted by alkyl of 1 to 4 carbon atoms or phenyl D
- - -- `` ~
- _ _ _ . . _ _ - ~ X preferably signifies chlorine, especially - ` hydrogen.
-- ` 15 Rl especially denotes methyl.
.
- R3 especially signifies hydrogen, methyl or - - ethyl, preferably hydrogen.
When the radical R4 or R5 has a halogen sub-stituent, this signifies fluorine, chlorine or bromine.
2~ When the radical R4 or R5 is d~- or trihalogenated, the halogen substituents of these radicals are prefera~ly ' `` ` identical.
The preferred radicals R4 are methoxycarbonyl, ethoxycarbonyl, (2,2,2-tri-halogenalkoxy)carbonyl or the group 502R5-preferably`wherein R5 i5 alkyl or phenyl.
.
. - ' ' ' - .
) 10734S2 -' _ 3 _ 100-4208 ' ' ' ' " ' Any halogen substituents ln the radical R4 espec$ally signlfy fluor$ne or chlorine.
- When R5 is alkyl of l to 4 carbon atoms or no- to tri-halogenaLkyl of 1 to 4 carbon atoms, these S radicals preferably contain 1 or 2 carbon atoms.
When R5 is phenyl monosubstituted by alkoxy -- of 1 to 4 carbon atoms, the alkoxy subs~ituent especlally , . . .
- contains 1 o~ 2, carbon atoms, and preferably 1 carbon atom.
. _ .
~ R~ preferabiy signifies methyl, phenyl, pyr~dyl or a group NR6R7 -- When-both of R6 and ~ are alkyl of 1 to 4 - - carbon atoms, each of these groups preferably contains l or 2 carbon atoms.
n is preferably 5.
- - A especially sign~ fies. oxygen, or n~trogen lS substituted by methyl or phenyl.
-- NR6~ preferably signifies amino, dimethylamino, dl-thylamino or the 4-methyl-l-plperaziny1 group. -~ ~
- Further, in accordance with the in~ent~on - ~ -~ _~ a compou~d of formula I may be obtained by a process -~
comprislng - a) producing a compound of formula Ta, .
- ~ "~C~2 C~ , - ~ ~l Ia . ' ' '' , ' , " ' '~ - , . .
., . ~.\X
_ _ , 10~345Z
_ 4 _ 100-4208 - whereln X and Rl are as defined above, by exchanging the radical Z for a cyano group ln a compound of formula II, ~ ~' ` ` ' ` ' ` ` ' ~ ' `
~ NRl II
.`"' `-`' -" '` ' ~' -, , ` ~ - X, . ,, :
: ` wherein Z is a radical capable of being exchanged : S in a nucleophiiic substitution reaction, and - X and Rl are as defined above, or b) producing ~a compound of formula Ib,
- 15 alkyl of 1 to 4 carbon atoms, or R6 and R7 together are one of the groups (CH2)n or (CH2)2 A (CH2)2' wherein - n is a number from 3`to 7, and ~0 ~ A is oxygen, sulphur or nitrogen - substituted by alkyl of 1 to 4 carbon atoms or phenyl D
- - -- `` ~
- _ _ _ . . _ _ - ~ X preferably signifies chlorine, especially - ` hydrogen.
-- ` 15 Rl especially denotes methyl.
.
- R3 especially signifies hydrogen, methyl or - - ethyl, preferably hydrogen.
When the radical R4 or R5 has a halogen sub-stituent, this signifies fluorine, chlorine or bromine.
2~ When the radical R4 or R5 is d~- or trihalogenated, the halogen substituents of these radicals are prefera~ly ' `` ` identical.
The preferred radicals R4 are methoxycarbonyl, ethoxycarbonyl, (2,2,2-tri-halogenalkoxy)carbonyl or the group 502R5-preferably`wherein R5 i5 alkyl or phenyl.
.
. - ' ' ' - .
) 10734S2 -' _ 3 _ 100-4208 ' ' ' ' " ' Any halogen substituents ln the radical R4 espec$ally signlfy fluor$ne or chlorine.
- When R5 is alkyl of l to 4 carbon atoms or no- to tri-halogenaLkyl of 1 to 4 carbon atoms, these S radicals preferably contain 1 or 2 carbon atoms.
When R5 is phenyl monosubstituted by alkoxy -- of 1 to 4 carbon atoms, the alkoxy subs~ituent especlally , . . .
- contains 1 o~ 2, carbon atoms, and preferably 1 carbon atom.
. _ .
~ R~ preferabiy signifies methyl, phenyl, pyr~dyl or a group NR6R7 -- When-both of R6 and ~ are alkyl of 1 to 4 - - carbon atoms, each of these groups preferably contains l or 2 carbon atoms.
n is preferably 5.
- - A especially sign~ fies. oxygen, or n~trogen lS substituted by methyl or phenyl.
-- NR6~ preferably signifies amino, dimethylamino, dl-thylamino or the 4-methyl-l-plperaziny1 group. -~ ~
- Further, in accordance with the in~ent~on - ~ -~ _~ a compou~d of formula I may be obtained by a process -~
comprislng - a) producing a compound of formula Ta, .
- ~ "~C~2 C~ , - ~ ~l Ia . ' ' '' , ' , " ' '~ - , . .
., . ~.\X
_ _ , 10~345Z
_ 4 _ 100-4208 - whereln X and Rl are as defined above, by exchanging the radical Z for a cyano group ln a compound of formula II, ~ ~' ` ` ' ` ' ` ` ' ~ ' `
~ NRl II
.`"' `-`' -" '` ' ~' -, , ` ~ - X, . ,, :
: ` wherein Z is a radical capable of being exchanged : S in a nucleophiiic substitution reaction, and - X and Rl are as defined above, or b) producing ~a compound of formula Ib,
3~4 H
~ 1 Ib : ~ - HN
` ` wherein X, Rl, R3 and R4 are as defined above, by acyl-ttng a compound of formula I~I, `' " ` ~ , ' ` ' `- - `
- .
- .: : - :,: , . - .
0~452 _ 5 _ 100-4208 H NHR r " 3 Rl III
HN
X
-wherein X, Rl and R3 are as defined above, with a reactive functional derivative of an acid R40H, wherein R4 is as defined above.
The reaction of a compound of formula II for 5` the obtention of a compound of formula Ia ~process a)]
- = and the reaction of a compound of formula III to obtain a compound of formula Ib [process b)] may be effected in accordance with known methods.
. . .
.
. .
. . -~he radical Z in the compounds of formula II
: 10 may, for example, signify halogen-such as chlorine or bromine, or an aliphatic or aromatic sulphonyloxy radical, preferably the mesyloxy or the ~-tosyloxy - - radical. The reaction may, for example, ~e effected by reacting a compound of formula II with a cyano group - 1~ donor, e.g. an alkali metal cyanide such as sodium or - . potassium cyanide.
.
'~ .
-~ . . - . ..
0~4~2 The reaction ls preferably effected ln solution. It ls conven~ent to use aprotlc solvents such as dlmethyl formamlde, hexamethylphosphorlc acid .
triamlde or acetonitrile, if necessary in admixture with a small portion of water.
The reaction is preferably effected with heating, e.g. to 50-100C.
Process b) is an N-acylation process. The following reactive functional derivatives of R40H may, for example, be used for the introduction of the radical R4 in a compound of formula III: for the introduction of the formyl radical the mixed anhydride of formic acid wlth acetlc acid, for the introduction of the remaining - radicals R4 a halide corresponding to the acid, e.g.
1~ the acid chloride or acid bromide, and for the intro-~ duction of an alkanoyl radical the corresponding - anhydrides ttalkanoyl)20~. ~
- Process b) is conveniently effected in solutlon. Suitable solvents are, for example, methylene - ~ ~ 20 chloride and dioxane. When an anhydride is used as acylating agent it is also possible to use an excess - of anhydride as solvent.
.
The reaction is generally conveniently effected at a reaction temperature between -10C and about room temperature. However, the N-formylation with ` the mixed anhydride of acetic acid and formic acid is .
" ~ ,", ~ " ", ` ~,"~ " "- ~ ; ~
7 - ` 100-4 208 conveniently effected at a slightly elevated temperature, e.g. about 40-60C.
Process b) is conveniently effected in the presence of a tertiary base such as triethylamine, or preferably in the presence of pyridine or a homologue thereof.
- The compounds obtained in accordance with processes a) and b~ may be obtained in the form of - a base or in the form of acid addition salts thereof.
Acid addition salt forms may be produced fro~m the - free bases in known manner and vice versa.
The starting materials are known or may be produced in accordance with known methods, e.g. as described in the Examples.
In the following non-limitative Examples all ~- temperatures are indicated in degrees Centigrade. The compounds of formula I are herein named 8a-ergoline I
compounds. The 8-cyanomethylergoline I compounds of ~ormula Ia may also be named (5R,8R,lOS)-8-cyanomethvl-ergoline I compounds, and the 8a-aminoergoline I com-- pounds of formula Ib may be named ~5R,8S,lOS)-8-aminoergoline I compounds.
.
.
lOq3452 _ 8 - 100-4208 EXAMPLE l: 6-methYl-8a-cvano-methYl erqoline I
3.35 g (lO millimols) of 6-methyl-8-mesyloxymethyl ergoline I are dissolved in 20 cc of dimethyl formamide, and a solution of 3.25 g of potassium cyanide (50 millimols) in 4 cc of water i9 added. After standing at 80 for 48 hours, the reaction solution is poured into an excess of a 2 normal soda solution, the precipitate is filtered off, dried in the air and sub-sequently chromatographed on 150 g of aluminium oxi~de . activity II-III. The title compound is eluted with 0.2 % of methanol in methylene chloride and crystallizes from methanol (M.P. 160 to 162, [] D- -96 (c = 0.3, dimethyl formamide).
The 6~methyl-8-mesyloxymethyl ergoline I, required as starting material, is obtained as follows:
(a) lO0 g of ~ '8-lysergic acid methyl ester are dissolved in 900 cc of dimethyl formamide while heating, dilution is effected with l.5 litres of gla~ial acetic acid, and after the addition of lO g of platinum ~- 20 oxide, hydrogenation is effected at ~40-50 and normal - pressure until the take up of hydrogen stops. The catalyst is filtered off and the filtrate is further ~ ogen-ted under the abo~e conditions after the .
.
_ 9 _ 100-4208 .
addition of 5 g of platinum oxide. Working up i8 effected by filtering and evaporating the filtrate to dryness. The resulting resin is dissolved in 1.5 litres of methylene chloride containing 5 % of methyi alcohol, the solution is stirred well with 20 g of active charcoal, filtration is effected, after cooling well, it is slowly covered with a layer of one litre a 2 N sodium carbonate solution and carefully shaken.
The aqueous phase is again extracted twice with 500 cc of methylene chloride. After drying the organic phase -over sodium sul~hate and concentrating to about 1/5 of the original volume, dilution with about 500 cc of ether and scratching are effected. After standing at 0 for 2 hours, 9,10-dihydro-isolysergic acid methyl . - . ..
ester I crystallizes. Working up of the e~aporation ~ residue in accordance with known methods yields an - ~ - additional amount of 9,10-dihydro-isolysergic acid - methyl ester I. After recrystallization from methylene chloride/ethyl acetate or ethanol, the ester has a M.P. of 178 to 180, [a] D- -82 (c = 1, pyridine~.
.
- - ~b) 38 g of lithium aluminium hydride are suspended in 2.5 litres of absol~te tetrahydrofuran under nitrogen, cooling is effected to 0, and a solu-tion of 200 g of 9,10-dihydro-isolysergic acid m thyl '` '' " `-' . ' ' .
' 10'~345Z
.
ester I in 2.5 litres of absolute tetrahydrofuran i8 added dropwise within 15 minutes while stirrins vigorously. The reaction product is subsequently diluted with 2.5 litres of absolute tetrahydrofuran and stirred for a further 30 minutes. Working up is effected by the careful successive dropwise addition of 100 cc of ethyl acetate, 100 cc of methanol and 50 cc of water. Dilution is subsequently effected with 2 litres of 30 % methanol in methylene chloride and filtration is effected. The residue is again boiled out
~ 1 Ib : ~ - HN
` ` wherein X, Rl, R3 and R4 are as defined above, by acyl-ttng a compound of formula I~I, `' " ` ~ , ' ` ' `- - `
- .
- .: : - :,: , . - .
0~452 _ 5 _ 100-4208 H NHR r " 3 Rl III
HN
X
-wherein X, Rl and R3 are as defined above, with a reactive functional derivative of an acid R40H, wherein R4 is as defined above.
The reaction of a compound of formula II for 5` the obtention of a compound of formula Ia ~process a)]
- = and the reaction of a compound of formula III to obtain a compound of formula Ib [process b)] may be effected in accordance with known methods.
. . .
.
. .
. . -~he radical Z in the compounds of formula II
: 10 may, for example, signify halogen-such as chlorine or bromine, or an aliphatic or aromatic sulphonyloxy radical, preferably the mesyloxy or the ~-tosyloxy - - radical. The reaction may, for example, ~e effected by reacting a compound of formula II with a cyano group - 1~ donor, e.g. an alkali metal cyanide such as sodium or - . potassium cyanide.
.
'~ .
-~ . . - . ..
0~4~2 The reaction ls preferably effected ln solution. It ls conven~ent to use aprotlc solvents such as dlmethyl formamlde, hexamethylphosphorlc acid .
triamlde or acetonitrile, if necessary in admixture with a small portion of water.
The reaction is preferably effected with heating, e.g. to 50-100C.
Process b) is an N-acylation process. The following reactive functional derivatives of R40H may, for example, be used for the introduction of the radical R4 in a compound of formula III: for the introduction of the formyl radical the mixed anhydride of formic acid wlth acetlc acid, for the introduction of the remaining - radicals R4 a halide corresponding to the acid, e.g.
1~ the acid chloride or acid bromide, and for the intro-~ duction of an alkanoyl radical the corresponding - anhydrides ttalkanoyl)20~. ~
- Process b) is conveniently effected in solutlon. Suitable solvents are, for example, methylene - ~ ~ 20 chloride and dioxane. When an anhydride is used as acylating agent it is also possible to use an excess - of anhydride as solvent.
.
The reaction is generally conveniently effected at a reaction temperature between -10C and about room temperature. However, the N-formylation with ` the mixed anhydride of acetic acid and formic acid is .
" ~ ,", ~ " ", ` ~,"~ " "- ~ ; ~
7 - ` 100-4 208 conveniently effected at a slightly elevated temperature, e.g. about 40-60C.
Process b) is conveniently effected in the presence of a tertiary base such as triethylamine, or preferably in the presence of pyridine or a homologue thereof.
- The compounds obtained in accordance with processes a) and b~ may be obtained in the form of - a base or in the form of acid addition salts thereof.
Acid addition salt forms may be produced fro~m the - free bases in known manner and vice versa.
The starting materials are known or may be produced in accordance with known methods, e.g. as described in the Examples.
In the following non-limitative Examples all ~- temperatures are indicated in degrees Centigrade. The compounds of formula I are herein named 8a-ergoline I
compounds. The 8-cyanomethylergoline I compounds of ~ormula Ia may also be named (5R,8R,lOS)-8-cyanomethvl-ergoline I compounds, and the 8a-aminoergoline I com-- pounds of formula Ib may be named ~5R,8S,lOS)-8-aminoergoline I compounds.
.
.
lOq3452 _ 8 - 100-4208 EXAMPLE l: 6-methYl-8a-cvano-methYl erqoline I
3.35 g (lO millimols) of 6-methyl-8-mesyloxymethyl ergoline I are dissolved in 20 cc of dimethyl formamide, and a solution of 3.25 g of potassium cyanide (50 millimols) in 4 cc of water i9 added. After standing at 80 for 48 hours, the reaction solution is poured into an excess of a 2 normal soda solution, the precipitate is filtered off, dried in the air and sub-sequently chromatographed on 150 g of aluminium oxi~de . activity II-III. The title compound is eluted with 0.2 % of methanol in methylene chloride and crystallizes from methanol (M.P. 160 to 162, [] D- -96 (c = 0.3, dimethyl formamide).
The 6~methyl-8-mesyloxymethyl ergoline I, required as starting material, is obtained as follows:
(a) lO0 g of ~ '8-lysergic acid methyl ester are dissolved in 900 cc of dimethyl formamide while heating, dilution is effected with l.5 litres of gla~ial acetic acid, and after the addition of lO g of platinum ~- 20 oxide, hydrogenation is effected at ~40-50 and normal - pressure until the take up of hydrogen stops. The catalyst is filtered off and the filtrate is further ~ ogen-ted under the abo~e conditions after the .
.
_ 9 _ 100-4208 .
addition of 5 g of platinum oxide. Working up i8 effected by filtering and evaporating the filtrate to dryness. The resulting resin is dissolved in 1.5 litres of methylene chloride containing 5 % of methyi alcohol, the solution is stirred well with 20 g of active charcoal, filtration is effected, after cooling well, it is slowly covered with a layer of one litre a 2 N sodium carbonate solution and carefully shaken.
The aqueous phase is again extracted twice with 500 cc of methylene chloride. After drying the organic phase -over sodium sul~hate and concentrating to about 1/5 of the original volume, dilution with about 500 cc of ether and scratching are effected. After standing at 0 for 2 hours, 9,10-dihydro-isolysergic acid methyl . - . ..
ester I crystallizes. Working up of the e~aporation ~ residue in accordance with known methods yields an - ~ - additional amount of 9,10-dihydro-isolysergic acid - methyl ester I. After recrystallization from methylene chloride/ethyl acetate or ethanol, the ester has a M.P. of 178 to 180, [a] D- -82 (c = 1, pyridine~.
.
- - ~b) 38 g of lithium aluminium hydride are suspended in 2.5 litres of absol~te tetrahydrofuran under nitrogen, cooling is effected to 0, and a solu-tion of 200 g of 9,10-dihydro-isolysergic acid m thyl '` '' " `-' . ' ' .
' 10'~345Z
.
ester I in 2.5 litres of absolute tetrahydrofuran i8 added dropwise within 15 minutes while stirrins vigorously. The reaction product is subsequently diluted with 2.5 litres of absolute tetrahydrofuran and stirred for a further 30 minutes. Working up is effected by the careful successive dropwise addition of 100 cc of ethyl acetate, 100 cc of methanol and 50 cc of water. Dilution is subsequently effected with 2 litres of 30 % methanol in methylene chloride and filtration is effected. The residue is again boiled out
4 times with 1 litre amounts of 30 % methanol in ` methylene chloride. After con~entration and crystalli-zation from methanol, the combined filtrates yield 9,10-dihydro-isolysergol I having a M.P. of 189 to 193.
lS A further amount of g,10-dihydro-isolysergol I may be isolated fFom the mother liquor by chromatography.
(c~ 100 g of 9,10-dihydro-lysergol I are sus-pended in ~00 cc of absolute pyridine and 1.1 litres of àbsolute acetonitrile, and a solution of 80 cc of methane-sulphochloride in 200 cc of absolute aceto-nitrile is added dropwise at 0 while stirring. After - - removing the cooling bath, the reaction mixture is stirred for a further hour at room temperature, whereby a yellowish precipitate results. Working up is effected lOq3g5Z' ~ 100-4208 by again cooling to 0 and adding a 2 N ammonia sOlution until an alkaline reaction is obtained. After scratching, 6-methyl-8a-methane-sulphonyloxymethyl ergoline I crystallizes (M.P. 139-141; [a] D- -54.6 . (c = 1, dimethyl formamide).
. The following compounds of formula la are obtained in a manner analogous to that described - in process (a) above, ~y using the corresponding com-. pounds of formula II (Z = mesyloxy):
.... .. .
.
Ex. Nr. X Rl ~.P. .
~ 2 Cl CH3 267-268 : . : 3 ... C2~5 182 ~base) -- 10 EXAMPLE 4: 6-methYl-8-N,N-dimethYl-sulphamylamino ergoline I
.` . 2.41 g (10 millimols) of 6-methyl-8a-amino ergoline I are dissolved in a mixture of 200 cc of methylene chloride and 25 cc of absolute pyridine, and - 15 a solution of 3~58 g (25 millimols) of dimethyl-~ulphamyl chloride in 25 cc of methylene chloride is added dropwise with stirring :
.
lOq345Z
_ 12 _ 100-4208 at room temperature. After stirring for 12 hours, working up is effected as described in Example 1. The orange red crude base is chromatographed on a 50-fold quantity of silica gel, whereby the title compound is
lS A further amount of g,10-dihydro-isolysergol I may be isolated fFom the mother liquor by chromatography.
(c~ 100 g of 9,10-dihydro-lysergol I are sus-pended in ~00 cc of absolute pyridine and 1.1 litres of àbsolute acetonitrile, and a solution of 80 cc of methane-sulphochloride in 200 cc of absolute aceto-nitrile is added dropwise at 0 while stirring. After - - removing the cooling bath, the reaction mixture is stirred for a further hour at room temperature, whereby a yellowish precipitate results. Working up is effected lOq3g5Z' ~ 100-4208 by again cooling to 0 and adding a 2 N ammonia sOlution until an alkaline reaction is obtained. After scratching, 6-methyl-8a-methane-sulphonyloxymethyl ergoline I crystallizes (M.P. 139-141; [a] D- -54.6 . (c = 1, dimethyl formamide).
. The following compounds of formula la are obtained in a manner analogous to that described - in process (a) above, ~y using the corresponding com-. pounds of formula II (Z = mesyloxy):
.... .. .
.
Ex. Nr. X Rl ~.P. .
~ 2 Cl CH3 267-268 : . : 3 ... C2~5 182 ~base) -- 10 EXAMPLE 4: 6-methYl-8-N,N-dimethYl-sulphamylamino ergoline I
.` . 2.41 g (10 millimols) of 6-methyl-8a-amino ergoline I are dissolved in a mixture of 200 cc of methylene chloride and 25 cc of absolute pyridine, and - 15 a solution of 3~58 g (25 millimols) of dimethyl-~ulphamyl chloride in 25 cc of methylene chloride is added dropwise with stirring :
.
lOq345Z
_ 12 _ 100-4208 at room temperature. After stirring for 12 hours, working up is effected as described in Example 1. The orange red crude base is chromatographed on a 50-fold quantity of silica gel, whereby the title compound is
- 5 eluted with 2 % of methanol in methylene chloride.
M.P. 223-226 from ethanol; yellowish needles.
1] D- -51.6 (c = 0.5 in pyridine).
.
The following compounds of formula Ib ` - are obtained in a manner analogous to that described in - - 10 Example 4, by acylating the corresponding compounds of - formula III with the acid chloride:
' ,.. ';.. :...... . - - - ' -. Nr X Rl ~ R~ M.P.
- 5 CH3 H C2C2~5 ~c - 0,;5, dimethyl formamide)
M.P. 223-226 from ethanol; yellowish needles.
1] D- -51.6 (c = 0.5 in pyridine).
.
The following compounds of formula Ib ` - are obtained in a manner analogous to that described in - - 10 Example 4, by acylating the corresponding compounds of - formula III with the acid chloride:
' ,.. ';.. :...... . - - - ' -. Nr X Rl ~ R~ M.P.
- 5 CH3 H C2C2~5 ~c - 0,;5, dimethyl formamide)
6 H c~3 P, C2CH3 of the hydrochloride:
ie ~h b~
. , .~ "
, ..
- - . .... . ~
- lOq3~152 - _13 _ 100-4208 Ex. X 1 R3 R4 M.P.
Nr. . . ... . . ........ .... ~ .......... .~
. __ . _ ` ; 9 H C~3 H 2 2 H CH3 H S02NH-C(CH3)3 11 H c~3 H S02-N~ .
. ` 12 d C33 N ...... . ........... .. . .
EXAMPLE 13: 6-methyl-8-formylamino erqoline I
.
. 2.41 g (10 millimols) of 6-methyl-8a-- amino ergoline I are dissolved in 5 cc of formic acid, and 5 cc of acetic anhydriae are added dropwise at 50-60 while stirring. After stirring for one hour, gas evolution stops; cooling is subsequently effected to 0, and the reaction mixture is carefully neutralized with 4 N potash solution, and extraction is effected ~ with chloroform containing methanol. After drying and concentrating the organic phases by evaporation, the title compound crystallizes from ethanol, and is ob-- tained in pure form after recrystallization from _ thylene chloride/ethanol. Non-characteristic M.P.
.
10~34~Z
' - 14 ~ 100-4208 (from 250 decomp.) lal2D- ~23 (c = 0.3, pyridine).
EXAMæLE 14: 6-methvl-8~-PivaloYlamino erqoline I
The process is effected in a manner analogous to that described in Example 7 , ex~ept that pivalic acid anhydride is used in place of pivalic acid chloride as acylating agent, whereby the title compound, having a M.P. of 199 to 200, is obtained.
- . . ' ':.: ~ ' .' :.
- . ' '' ' -, . ' . . . .
' ' . ' 10~4~ -The compounds of formula I exhlbit pharma-cological activity. In particular, the ccmpounds exhibit central dopaminergic stimulant activity, as ~ndicated in standard tests, for example according to the principles of U. Ungerstedt Acta Physiol.
Scand.Suppl. (1971) 367, 69-93, by an induction of contralateral turning in rats lesioned unilaterally in the substantia nigra by 6-hydroxydop2mine and by an induction of dose dependent stereotyped sniffing, licking and biting behaviour in the rat according to the following test:
Rats, 180-222 g, are placed in Perspex"* cylinders of 30 cm diameter on a wire grid floor. After 30 mlnutes to allow acclimatisation to the cage, the rats -~
are injected with the compound under investigation. -The behaviour of the rats is observed for 2 minutes at 30 mlnute intervals for 2 hours and then at 60 mlnute intervals for a total of up to 7 hours.The~
degree of stereotyped behaviour obs~r~ed is assessed us~ng a scoring system based on that described by Costall, Naylor and Olley ~Euro J. Pharmac. 18, 83-94 `-(1972)}.
The scores and criteria are as follows:
1. Intermlttent sni fing 2. Persistent sniffing, occasional licking 3. Lickins, occasional biting 4. Intense and persistent biting .. . , . . . . . _ . . . ............ . . .
*Trademark for poly(methyl methacrylate) resins in sheet form. It is a hard, rigid,highly transparent material having a very high refractive index.
~0~45Z
The compounds are, therefore, indicated for use as centraldopaminergic stimulant agents, for example, for treating Morbus Parkinson. For this use an indicated dose in from about 0.5 to 100 mg, especially 1 - 50 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.1 to about 50 mg, or in sustained release form.
The Example 1 compound shows interesting activity.
The compounds additionally exhibit prolactin secretion inhibition activity as indicated in standard tests, for example, in rats by an inhibition of ovum implantion as follows:
The compound under investigation is administered to female rats 5 days after coitus and shown to be sperm positive according to the vaginal smear test.
The rats are sacrificed on day 12 and their uteri are examined by means of the Salewski reaction for proof that the nidations process has been interrupted LArch.exp.Path. Pharm. 247, 367 ~1967)~.
The compounds are, therefore, indicated for use as prolactin secretion inhibitor agents. For this use an indicated daily dose in form about 0.05 to about 10 mg, con~eniently administerea in divided doses 2 to 4 times a day in unit dosage form containing from about 0.01 to abou L 5 mg, or in sustained release form.
10';~5Z
The Example 4 compound shows interesting activity.
The compounds of formula I may be ad-ministered 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 prepared in conventional manner. The present invention also 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 in conventional manner, so as to be, for example, a solution or a tablet.
In one group of compounds R2 is CH2.CN.
In another group of compounds R2 is -NHR, wherein R is formyl, alkanoyl, alkoxycarbonyl or ~ 3 2 \
~herein R3 and R4 are alkyl or together are -[CH2]n,-, wherein n is from 3 to 5.
.
ie ~h b~
. , .~ "
, ..
- - . .... . ~
- lOq3~152 - _13 _ 100-4208 Ex. X 1 R3 R4 M.P.
Nr. . . ... . . ........ .... ~ .......... .~
. __ . _ ` ; 9 H C~3 H 2 2 H CH3 H S02NH-C(CH3)3 11 H c~3 H S02-N~ .
. ` 12 d C33 N ...... . ........... .. . .
EXAMPLE 13: 6-methyl-8-formylamino erqoline I
.
. 2.41 g (10 millimols) of 6-methyl-8a-- amino ergoline I are dissolved in 5 cc of formic acid, and 5 cc of acetic anhydriae are added dropwise at 50-60 while stirring. After stirring for one hour, gas evolution stops; cooling is subsequently effected to 0, and the reaction mixture is carefully neutralized with 4 N potash solution, and extraction is effected ~ with chloroform containing methanol. After drying and concentrating the organic phases by evaporation, the title compound crystallizes from ethanol, and is ob-- tained in pure form after recrystallization from _ thylene chloride/ethanol. Non-characteristic M.P.
.
10~34~Z
' - 14 ~ 100-4208 (from 250 decomp.) lal2D- ~23 (c = 0.3, pyridine).
EXAMæLE 14: 6-methvl-8~-PivaloYlamino erqoline I
The process is effected in a manner analogous to that described in Example 7 , ex~ept that pivalic acid anhydride is used in place of pivalic acid chloride as acylating agent, whereby the title compound, having a M.P. of 199 to 200, is obtained.
- . . ' ':.: ~ ' .' :.
- . ' '' ' -, . ' . . . .
' ' . ' 10~4~ -The compounds of formula I exhlbit pharma-cological activity. In particular, the ccmpounds exhibit central dopaminergic stimulant activity, as ~ndicated in standard tests, for example according to the principles of U. Ungerstedt Acta Physiol.
Scand.Suppl. (1971) 367, 69-93, by an induction of contralateral turning in rats lesioned unilaterally in the substantia nigra by 6-hydroxydop2mine and by an induction of dose dependent stereotyped sniffing, licking and biting behaviour in the rat according to the following test:
Rats, 180-222 g, are placed in Perspex"* cylinders of 30 cm diameter on a wire grid floor. After 30 mlnutes to allow acclimatisation to the cage, the rats -~
are injected with the compound under investigation. -The behaviour of the rats is observed for 2 minutes at 30 mlnute intervals for 2 hours and then at 60 mlnute intervals for a total of up to 7 hours.The~
degree of stereotyped behaviour obs~r~ed is assessed us~ng a scoring system based on that described by Costall, Naylor and Olley ~Euro J. Pharmac. 18, 83-94 `-(1972)}.
The scores and criteria are as follows:
1. Intermlttent sni fing 2. Persistent sniffing, occasional licking 3. Lickins, occasional biting 4. Intense and persistent biting .. . , . . . . . _ . . . ............ . . .
*Trademark for poly(methyl methacrylate) resins in sheet form. It is a hard, rigid,highly transparent material having a very high refractive index.
~0~45Z
The compounds are, therefore, indicated for use as centraldopaminergic stimulant agents, for example, for treating Morbus Parkinson. For this use an indicated dose in from about 0.5 to 100 mg, especially 1 - 50 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.1 to about 50 mg, or in sustained release form.
The Example 1 compound shows interesting activity.
The compounds additionally exhibit prolactin secretion inhibition activity as indicated in standard tests, for example, in rats by an inhibition of ovum implantion as follows:
The compound under investigation is administered to female rats 5 days after coitus and shown to be sperm positive according to the vaginal smear test.
The rats are sacrificed on day 12 and their uteri are examined by means of the Salewski reaction for proof that the nidations process has been interrupted LArch.exp.Path. Pharm. 247, 367 ~1967)~.
The compounds are, therefore, indicated for use as prolactin secretion inhibitor agents. For this use an indicated daily dose in form about 0.05 to about 10 mg, con~eniently administerea in divided doses 2 to 4 times a day in unit dosage form containing from about 0.01 to abou L 5 mg, or in sustained release form.
10';~5Z
The Example 4 compound shows interesting activity.
The compounds of formula I may be ad-ministered 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 prepared in conventional manner. The present invention also 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 in conventional manner, so as to be, for example, a solution or a tablet.
In one group of compounds R2 is CH2.CN.
In another group of compounds R2 is -NHR, wherein R is formyl, alkanoyl, alkoxycarbonyl or ~ 3 2 \
~herein R3 and R4 are alkyl or together are -[CH2]n,-, wherein n is from 3 to 5.
.
Claims (8)
1. A process for the production of a compound of formula I, I
wherein X is hydrogen, chlorine or bromine, R1 is methyl or ethyl, and R2 is CH2-CN, or a group NR3R4, wherein R3 is hydrogen or alkyl of 1 to 4 carbon atoms, and R4 is formyl, alkanoyl of 2 to 5 carbon atoms in the aggregate thereof, alkoxycarbonyl of 2 to 5 carbon atoms in the aggregate thereof, mono- to trihalogenalkoxycarbonyl of 3 to 5 carbon atoms in the aggregate thereof, the alkoxy radical of which is substituted by halogen in a position other than .alpha. to the oxygen, or the radical SO2R5, wherein R5 is alkyl of 1 to 4 carbon atoms, mono-to tri-halogenalkyl of 1 to 4 carbon atoms, phenyl, pyridyl, phenyl monosub-stituted by halogen or alkoxy of 1 to 4 carbon atoms, or a group NR6R7, wherein each of R6 and R7 is independently hydrogen or alkyl of 1 to 4 carbon atoms, or R6 and R7 together are one of the groups (CH2)n or (CH2)2-A-(CH2)2, wherein n is a number from 3 to 7, and A is oxygen, sulphur or nitrogen substituted by alkyl of 1 to carbon atoms or phenyl, which comprises a) producing a compound of formula Ia, Ia wherein X and R1 are as defined above, by exchanging the radical Z for a cyano group in a compound of formula II, II
wherein Z is a radical capable of being exchanged in a nucleophilic substitution reaction, and X and R1 are as defined above, or b) producing a compound of formula Ib, Ib wherein X, R1, R3 and R4 are as defined above, by acylating a compound of formula III, III
wherein X, R1 and R3 are as defined above, with a reactive functional derivative of an acid R4OH, wherein R4 is as defined above.
wherein X is hydrogen, chlorine or bromine, R1 is methyl or ethyl, and R2 is CH2-CN, or a group NR3R4, wherein R3 is hydrogen or alkyl of 1 to 4 carbon atoms, and R4 is formyl, alkanoyl of 2 to 5 carbon atoms in the aggregate thereof, alkoxycarbonyl of 2 to 5 carbon atoms in the aggregate thereof, mono- to trihalogenalkoxycarbonyl of 3 to 5 carbon atoms in the aggregate thereof, the alkoxy radical of which is substituted by halogen in a position other than .alpha. to the oxygen, or the radical SO2R5, wherein R5 is alkyl of 1 to 4 carbon atoms, mono-to tri-halogenalkyl of 1 to 4 carbon atoms, phenyl, pyridyl, phenyl monosub-stituted by halogen or alkoxy of 1 to 4 carbon atoms, or a group NR6R7, wherein each of R6 and R7 is independently hydrogen or alkyl of 1 to 4 carbon atoms, or R6 and R7 together are one of the groups (CH2)n or (CH2)2-A-(CH2)2, wherein n is a number from 3 to 7, and A is oxygen, sulphur or nitrogen substituted by alkyl of 1 to carbon atoms or phenyl, which comprises a) producing a compound of formula Ia, Ia wherein X and R1 are as defined above, by exchanging the radical Z for a cyano group in a compound of formula II, II
wherein Z is a radical capable of being exchanged in a nucleophilic substitution reaction, and X and R1 are as defined above, or b) producing a compound of formula Ib, Ib wherein X, R1, R3 and R4 are as defined above, by acylating a compound of formula III, III
wherein X, R1 and R3 are as defined above, with a reactive functional derivative of an acid R4OH, wherein R4 is as defined above.
2. A compound of formula I, as defined in claim 1, when produced by a process according to claim 1 or by an obvious chemical equivalent thereof.
3. A process for the production of 6-methyl-8 .alpha.-cyano-methyl ergoline I, comprising reacting 6-methyl-8 .alpha. -mesyloxymethyl ergoline I with potassium cyanide.
4. 6-Methyl-8 .alpha.-cyano-methyl ergoline I, whenever produced by the process claimed in claim 3 or by an obvious chemical equivalent thereof.
5. A process for the production of 6-methyl-8 .alpha. -N,N-dimethyl-sulphamylamino ergoline I, comprising reacting 6-methyl-8 .alpha. -amino ergoline I with dimethyl-sulphamyl chloride.
6. 6-Methyl-8 .alpha. -N,N-dimethyl-sulphamylamino ergoline I, whenever prepared by the process claimed in claim 5 or by an obvious chemical equivalent thereof.
7. A process for the production of 6-methyl-8 .alpha. -formylamino ergoline I, comprising reacting 6-methyl-8 .alpha. -amino ergoline I with formic acid.
8. 6-Methyl-8 .alpha. -formylamino ergoline I, whenever produced by the process as claimed in claim 7 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH998374A CH605936A5 (en) | 1974-07-19 | 1974-07-19 | 8-Alpha-(Amino-or cyanomethyl)-ergoline derivs |
| CH1103174A CH605938A5 (en) | 1974-08-13 | 1974-08-13 | 8-Alpha-(Amino-or cyanomethyl)-ergoline derivs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1073452A true CA1073452A (en) | 1980-03-11 |
Family
ID=25705648
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA231,773A Expired CA1073452A (en) | 1974-07-19 | 1975-07-18 | 8.alpha.-ERGOLINE I COMPOUNDS |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS5134199A (en) |
| AU (1) | AU505314B2 (en) |
| CA (1) | CA1073452A (en) |
| DD (1) | DD118635A5 (en) |
| DE (1) | DE2530577A1 (en) |
| DK (2) | DK143902C (en) |
| ES (1) | ES439548A1 (en) |
| FI (1) | FI61188C (en) |
| FR (1) | FR2282889A1 (en) |
| GB (3) | GB1517971A (en) |
| HK (2) | HK56980A (en) |
| IE (1) | IE41426B1 (en) |
| IL (1) | IL47735A (en) |
| MY (2) | MY8100215A (en) |
| NL (1) | NL7508416A (en) |
| NO (1) | NO752493L (en) |
| PH (1) | PH16594A (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1573621A (en) * | 1976-01-02 | 1980-08-28 | Sandoz Ltd | Acylated 6-methyl-8a-amino-ergoline i compounds |
| DE2656344A1 (en) * | 1975-12-23 | 1977-07-07 | Sandoz Ag | ERGOLIN DERIVATIVES, THEIR USE AND MANUFACTURING |
| IT1064473B (en) * | 1976-11-24 | 1985-02-18 | Simes | 8-BETA-AMINOMETHYLERGOLINE DERIVATIVES ON SULFAMOIL |
| BE889713A (en) * | 1980-07-25 | 1982-01-25 | Sandoz Sa | NEW ERGOLIN DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS |
| DE3127845A1 (en) * | 1980-07-25 | 1982-04-22 | Sandoz-Patent-GmbH, 7850 Lörrach | ERGOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE IN THE THERAPEUTIC TREATMENT |
| CH644606A5 (en) * | 1980-09-23 | 1984-08-15 | Sandoz Ag | METHOD FOR ISOMERIZING 9,10-DIHYDROLYSE ENERGY DERIVATIVES. |
| DE3101535A1 (en) * | 1981-01-14 | 1982-08-12 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW (2-HALOGEN-ERGOLINYL) -N'.N'-DIETHYL-UREA DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
| JPS58174081A (en) * | 1982-04-05 | 1983-10-13 | Mitsubishi Heavy Ind Ltd | Ventilator for engine room of ship |
| CH664568A5 (en) * | 1984-01-12 | 1988-03-15 | Sandoz Ag | 8-ALPHA ACYLAMINE OERGOLINE. |
| CH666035A5 (en) * | 1984-12-24 | 1988-06-30 | Sandoz Ag | 8-ALPHA ACYLAMINOERGOLENE. |
| NL8700046A (en) * | 1986-01-24 | 1987-08-17 | Sandoz Ag | 8 ALFA-ACYLAMINOERGOLINES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. |
| AT392945B (en) * | 1988-06-27 | 1991-07-10 | Gerhard Mader Ges M B H Ing | STORAGE AND TRANSPORTATION CONTAINERS FOR Bulk goods and loose materials |
| DE4033496A1 (en) * | 1990-10-20 | 1992-04-23 | Sandoz Ag | NEW ERGOL DERIVATIVES, THEIR PRODUCTION AND USE |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3218323A (en) * | 1965-11-16 | Esters of i,g-dimethyl-b-ergolenyl carbamic acid | ||
| FR1360618A (en) * | 1963-06-17 | 1964-05-08 | Sandoz Sa | New urethanes of the lysergic series and their preparation |
| BE712054A (en) * | 1967-03-16 | 1968-07-15 | ||
| NL6818658A (en) * | 1968-01-18 | 1969-07-22 | ||
| AR206772A1 (en) * | 1972-07-21 | 1976-08-23 | Lilly Co Eli | PROCEDURE TO PREPARE A NEW D-2-HALO-6-METHYL-8-CYANE (CARBOXAMIDE) METHYL ERGOLINE |
-
1975
- 1975-07-04 GB GB28238/75A patent/GB1517971A/en not_active Expired
- 1975-07-04 GB GB4648/78A patent/GB1517972A/en not_active Expired
- 1975-07-04 GB GB4649/78A patent/GB1517973A/en not_active Expired
- 1975-07-09 DE DE19752530577 patent/DE2530577A1/en active Granted
- 1975-07-10 FI FI752011A patent/FI61188C/en not_active IP Right Cessation
- 1975-07-11 NO NO752493A patent/NO752493L/no unknown
- 1975-07-12 DK DK313175A patent/DK143902C/en not_active IP Right Cessation
- 1975-07-15 NL NL7508416A patent/NL7508416A/en not_active Application Discontinuation
- 1975-07-16 DD DD187329A patent/DD118635A5/xx unknown
- 1975-07-17 AU AU83162/75A patent/AU505314B2/en not_active Expired
- 1975-07-17 ES ES439548A patent/ES439548A1/en not_active Expired
- 1975-07-17 IE IE1596/75A patent/IE41426B1/en unknown
- 1975-07-17 PH PH17392A patent/PH16594A/en unknown
- 1975-07-18 FR FR7522484A patent/FR2282889A1/en active Granted
- 1975-07-18 IL IL47735A patent/IL47735A/en unknown
- 1975-07-18 CA CA231,773A patent/CA1073452A/en not_active Expired
- 1975-07-18 JP JP50087425A patent/JPS5134199A/ja active Pending
-
1980
- 1980-07-10 DK DK298980A patent/DK145542C/en not_active IP Right Cessation
- 1980-10-09 HK HK569/80A patent/HK56980A/en unknown
- 1980-10-09 HK HK568/80A patent/HK56880A/en unknown
-
1981
- 1981-12-30 MY MY215/81A patent/MY8100215A/en unknown
- 1981-12-30 MY MY217/81A patent/MY8100217A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI61188B (en) | 1982-02-26 |
| ES439548A1 (en) | 1977-06-16 |
| GB1517972A (en) | 1978-07-19 |
| IE41426B1 (en) | 1980-01-02 |
| MY8100215A (en) | 1981-12-31 |
| NO752493L (en) | 1976-01-20 |
| IE41426L (en) | 1976-01-19 |
| FR2282889A1 (en) | 1976-03-26 |
| HK56880A (en) | 1980-10-16 |
| DK298980A (en) | 1980-07-10 |
| DE2530577C2 (en) | 1990-11-08 |
| DE2530577A1 (en) | 1976-01-29 |
| PH16594A (en) | 1983-11-22 |
| GB1517973A (en) | 1978-07-19 |
| DK143902B (en) | 1981-10-26 |
| AU505314B2 (en) | 1979-11-15 |
| DK313175A (en) | 1976-01-20 |
| DK145542B (en) | 1982-12-06 |
| JPS5134199A (en) | 1976-03-23 |
| AU8316275A (en) | 1977-01-20 |
| NL7508416A (en) | 1976-01-21 |
| IL47735A0 (en) | 1975-10-15 |
| FR2282889B1 (en) | 1979-08-10 |
| FI752011A (en) | 1976-01-20 |
| GB1517971A (en) | 1978-07-19 |
| MY8100217A (en) | 1981-12-31 |
| FI61188C (en) | 1982-06-10 |
| DK143902C (en) | 1982-04-13 |
| HK56980A (en) | 1980-10-16 |
| DK145542C (en) | 1983-05-02 |
| IL47735A (en) | 1979-11-30 |
| DD118635A5 (en) | 1976-03-12 |
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