CA1071192A - 6-METHYL-8.beta.-(-CH2-S-R)ERGOLENE OR ERGOLINE - Google Patents
6-METHYL-8.beta.-(-CH2-S-R)ERGOLENE OR ERGOLINEInfo
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- CA1071192A CA1071192A CA221,971A CA221971A CA1071192A CA 1071192 A CA1071192 A CA 1071192A CA 221971 A CA221971 A CA 221971A CA 1071192 A CA1071192 A CA 1071192A
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
Case 100-4146 6-METHYL-8 .beta.-(-CH2-S-R) ERGOLENE OR ERGOLINE
Abstract of the Disclosure This invention provides new compounds of formula I, wherein is the group or
Abstract of the Disclosure This invention provides new compounds of formula I, wherein is the group or
Description
iO71192 6-METHYL-8~-(-CH~-S-R)ERGOLENE OR ERGOLINE
The present invention relates to new hetero-cyclic compounds.
In accordance with the invention there are provided new compounds of formula I, x~
J~ - CH 2 wherein x'~~y is the group -CH=C or -CH2-CH , and R is hydrogen, cyano, a 5- or 6-membered unsaturated heterocyclic radical attached through a ring carbon atom and having 1, 2 or 3 hetero ring atoms, the first hetero atom being nitrogen, oxygen or sulphur, and the second and third hetero atoms, if present, being nitrogen, or 2- or 4-pyridyl monosub-stituted by lower alkyl, lower alkoxy or halogen.
When R is a heterocyclic radical, this is preferably fully unsaturated. R has preferably two double bonds when five-membered. R has preferably three double bonds when six-membered.
- 1 - ~ :
---- o7~192
The present invention relates to new hetero-cyclic compounds.
In accordance with the invention there are provided new compounds of formula I, x~
J~ - CH 2 wherein x'~~y is the group -CH=C or -CH2-CH , and R is hydrogen, cyano, a 5- or 6-membered unsaturated heterocyclic radical attached through a ring carbon atom and having 1, 2 or 3 hetero ring atoms, the first hetero atom being nitrogen, oxygen or sulphur, and the second and third hetero atoms, if present, being nitrogen, or 2- or 4-pyridyl monosub-stituted by lower alkyl, lower alkoxy or halogen.
When R is a heterocyclic radical, this is preferably fully unsaturated. R has preferably two double bonds when five-membered. R has preferably three double bonds when six-membered.
- 1 - ~ :
---- o7~192
- 2 - 100-4146 R has preferably one or two hetero atoms.
When R has one hetero atom this is conveniently pyridyl or thienyl. When R has two hetero atoms, this is con-veniently oxazolyl, thiazolyl, imidazolyl or S pyrimidinyl. When R has three hetero atoms, this is conveniently 1,2,4-triazolyl, or 1,3,5-triazinyl.
The ring carbon atom through which R is attached is conveniently ortho or para to a ring hetero atom, e.g. 2-pyridyl or 4-pyridyl,2-thiazoyl, or 1,2,4-triazol-3-yl.
When R is 2- or 4-pyridyl monosubstituted by lower alkyl, the alkyl substituent may, for example, contain 1 to 4, especially 1 or 2 carbon atoms and preferably signifies methyl.
When R is 2- or 4-pyridyl monosubstituted by lower alkoxy, the alkoxy substituent may, for example, contain from 1 to 4, especially 1 or 2 carbon atoms and preferably signifies methoxy.
When R is 2- or 4-pyridyl monosubstituted ` 20 by halogen, the halogen may denote fluorine, bromine and especially chlorine.
The side chain in the 8 position of the ergolene moiety may be in the ~- or ~-configuration.
Any carbon containing radical not particular-ly defined herein preferablv has up to 10 carbon atolls.
When R has one hetero atom this is conveniently pyridyl or thienyl. When R has two hetero atoms, this is con-veniently oxazolyl, thiazolyl, imidazolyl or S pyrimidinyl. When R has three hetero atoms, this is conveniently 1,2,4-triazolyl, or 1,3,5-triazinyl.
The ring carbon atom through which R is attached is conveniently ortho or para to a ring hetero atom, e.g. 2-pyridyl or 4-pyridyl,2-thiazoyl, or 1,2,4-triazol-3-yl.
When R is 2- or 4-pyridyl monosubstituted by lower alkyl, the alkyl substituent may, for example, contain 1 to 4, especially 1 or 2 carbon atoms and preferably signifies methyl.
When R is 2- or 4-pyridyl monosubstituted by lower alkoxy, the alkoxy substituent may, for example, contain from 1 to 4, especially 1 or 2 carbon atoms and preferably signifies methoxy.
When R is 2- or 4-pyridyl monosubstituted ` 20 by halogen, the halogen may denote fluorine, bromine and especially chlorine.
The side chain in the 8 position of the ergolene moiety may be in the ~- or ~-configuration.
Any carbon containing radical not particular-ly defined herein preferablv has up to 10 carbon atolls.
- 3 - 100-4146 Further, in accordance with the invention a compound of formula I may be obtained by a process comprising a) reacting a compound of formula II, {X~
N--C~l II
~1~ .
wherein x y is as defined above, and X is an exchangeable radical capable of being displaced by a thio group with a compound of formula III, MS - R III
wherein R is as defined above, and M is hydrogen or an alkali metal, or b) reducing the-9CN group to an ~SH group. in a compound of formula Ib, ~07~19Z
~ -S-CN
~x ~ N-CH3 Ib HN ~
wherein x y is as defined above, to produce a compound of formula Ia, ,~x ~
y ~N-CH3 Ia HN ~
wherein x y is 2S defined above.
. Process variant a) may be effected in con-ventional manner for nucleophilic substitution by a thio group, bearing in mind the other substituents present.
The radical X may, for example, signify halogen, such as chlorine or bromine, or a radical O-SO2-Rl, wherein Rl is lower alkyl or phenyl or sub-stituted phenyl. It is preferred to use the correspond-ing mesylate or tosylate as compound of formula II.
- 1071~9Z
In general M in the compounds of formula III preferably denotes an alkali metal, especially when R is not basic~ i.e. has no basic nitrogen atom.
The reaction is conveniently effected in a solvent. Specially suitable are inert, aprotic, polar solvents, e.g. amides of organic carboxylic acids, such as dimethyl formamide, or alternatively hexamethylphosphoric acid triamide or acetonitrile, optionally admixed with a small portion of water.
The reaction is preferably effected at an elevated temperature, e.g. between about 50 and 100C.
The reaction is conveniently effected in the absence of oxygen, e.g. in an atmosphere of nitrogen.
It is convenient to use an excess of the compound of formula III, e.g. about 2 to 10 mols of the compound of formula II~, for each mol of the compound of formula II.
The reduction of compounds of formula I_ to compounds of formula Ia may be effected in a manner analogous to known methods for the reduction of similar cyanate compounds to mercapto compounds, bearing in mind the other substituents present. However, it is preferakly effected with lithium aluminium hydride. In this case an ether, such as tetrahydrofuran, is especially used as solvent.
71 ~92 - ~ - 100-4146 The reduction with lithium aluminium hydride may be effected at room temperature.
The working up of the reaction mixture obtained in accordance with the above processes and the purification of the so obtained compounds of formula I may be effected in accordance with known methods.
The compounds of formula I may be present in free form or in the form of acid addition salts thereof. Acid addition salt forms may be produced from the free bases in known manner and vice versa. A
suitable acid for salt formation is tartaric or fumaric acid.
The starting materials of formula II wherein X is chlorine, O-mesyl or O-tosyl, are known.
Compounds of formula II wherein X is bromine, may, for example, be obtained by reaction of a compound of formula IV, ~ H2H
{x~ . ' ~-CH IV
~1~ .
wherein x y is as defined above, with phosphorus oxybro.ride.
--` 10711'~2 Insofar as the production of the starting materials is not described, these are known or may be produced in accordance with known processes, or ; in a manner analogous to the processes described herein or to known processes.
The compounds of formula I exhibit pharma-cological activity. In particular they exhibit central dopaminergic stimulant activity as indicated by, for example, inductlon of turning in rats lesioned with 6-hydroxydopamine in the Substantia nigra [method of U. Ungerstedt, Acta physiol.scand., Suppl. 367, 69-93 (1971)], and additionally by an antagonism of reserp~ne-induced catalepsy in mice, the reserpine being ad-ministered ~p,at 5 mg/kg animal body weight about 17 hours before the test substance and the catalepsy being considered antagonised if the mice can walk off a horizontal twine covered pole in a caordinated manner.
The compounds are therefore indicated for use as anti-Parkinson agents. For this use an indicated daily dose is from about 1 to about 100 mg, con-veniently administered in divided doses 2 to 5 times a dav in unit dosage form con~aining from about 0.2 to about 50 mg, or in sustained release form.
: .
107~192 - ~ - 100-4146 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 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 made in conventional manner to be in the form of, for example, a solution or a tablet.
Additionally the central dopaminergic stimulant activity of a compound of formula Iis synergistically potentiated when administered con-comitantly with an inhibitor of phosphodiesterase activity , as indicated by a superadditive increase in turning movements in the above-indicated test when a compound of formula I is administered after administration of an inhibitor of phospho~
diesterase activity such as caffeine.
Therefore combinations of a compound of formula I and an inhibitor of phosphcdiesterase activity are further especially indicated for use as anti-Parkinson agents. An indicated daily dose of a 07~19Z
compound of formula I is from about 0.5 to about 50 mg and an indicated ratio of formula I compo-lnd to phosphodiesterase inhibitor is from about 10:1 to about 1:5000, preferably 2:1 to 1:1000, e.g. 1:50 to 1:1, e.g.
1:5 to 1:1, 1:25 or 1:10 to 1:50.
Suitable phosphodiesterase inhibitors are especially thoæ which inhibit phosphodiesterase activity in the brain, e.g. methyl xanthlnes such as caffeine or theophylline, but also may be chosen from derivatives of 4-amino-lH-pyrazolo[3,4-b]pyridine-5-carboxyclic acid esters, such as l-ethyl-4-(isopropylidene-hydrazino)-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, l-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester and l-ethyl-4-butylamino-1-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 4-(3,4-dimethoxybenzyl)-2-imidazolidinone and analogues thereof, such as 4-(3-butoxy-4-methoxy-benzyl)-2-imidazolidinone, minor tranquilizers, e.g.
of the 1,4-benzodiazepine series, such as 7-chloro-2-methvlamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide and 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, tricyclic antidepressants, such as
N--C~l II
~1~ .
wherein x y is as defined above, and X is an exchangeable radical capable of being displaced by a thio group with a compound of formula III, MS - R III
wherein R is as defined above, and M is hydrogen or an alkali metal, or b) reducing the-9CN group to an ~SH group. in a compound of formula Ib, ~07~19Z
~ -S-CN
~x ~ N-CH3 Ib HN ~
wherein x y is as defined above, to produce a compound of formula Ia, ,~x ~
y ~N-CH3 Ia HN ~
wherein x y is 2S defined above.
. Process variant a) may be effected in con-ventional manner for nucleophilic substitution by a thio group, bearing in mind the other substituents present.
The radical X may, for example, signify halogen, such as chlorine or bromine, or a radical O-SO2-Rl, wherein Rl is lower alkyl or phenyl or sub-stituted phenyl. It is preferred to use the correspond-ing mesylate or tosylate as compound of formula II.
- 1071~9Z
In general M in the compounds of formula III preferably denotes an alkali metal, especially when R is not basic~ i.e. has no basic nitrogen atom.
The reaction is conveniently effected in a solvent. Specially suitable are inert, aprotic, polar solvents, e.g. amides of organic carboxylic acids, such as dimethyl formamide, or alternatively hexamethylphosphoric acid triamide or acetonitrile, optionally admixed with a small portion of water.
The reaction is preferably effected at an elevated temperature, e.g. between about 50 and 100C.
The reaction is conveniently effected in the absence of oxygen, e.g. in an atmosphere of nitrogen.
It is convenient to use an excess of the compound of formula III, e.g. about 2 to 10 mols of the compound of formula II~, for each mol of the compound of formula II.
The reduction of compounds of formula I_ to compounds of formula Ia may be effected in a manner analogous to known methods for the reduction of similar cyanate compounds to mercapto compounds, bearing in mind the other substituents present. However, it is preferakly effected with lithium aluminium hydride. In this case an ether, such as tetrahydrofuran, is especially used as solvent.
71 ~92 - ~ - 100-4146 The reduction with lithium aluminium hydride may be effected at room temperature.
The working up of the reaction mixture obtained in accordance with the above processes and the purification of the so obtained compounds of formula I may be effected in accordance with known methods.
The compounds of formula I may be present in free form or in the form of acid addition salts thereof. Acid addition salt forms may be produced from the free bases in known manner and vice versa. A
suitable acid for salt formation is tartaric or fumaric acid.
The starting materials of formula II wherein X is chlorine, O-mesyl or O-tosyl, are known.
Compounds of formula II wherein X is bromine, may, for example, be obtained by reaction of a compound of formula IV, ~ H2H
{x~ . ' ~-CH IV
~1~ .
wherein x y is as defined above, with phosphorus oxybro.ride.
--` 10711'~2 Insofar as the production of the starting materials is not described, these are known or may be produced in accordance with known processes, or ; in a manner analogous to the processes described herein or to known processes.
The compounds of formula I exhibit pharma-cological activity. In particular they exhibit central dopaminergic stimulant activity as indicated by, for example, inductlon of turning in rats lesioned with 6-hydroxydopamine in the Substantia nigra [method of U. Ungerstedt, Acta physiol.scand., Suppl. 367, 69-93 (1971)], and additionally by an antagonism of reserp~ne-induced catalepsy in mice, the reserpine being ad-ministered ~p,at 5 mg/kg animal body weight about 17 hours before the test substance and the catalepsy being considered antagonised if the mice can walk off a horizontal twine covered pole in a caordinated manner.
The compounds are therefore indicated for use as anti-Parkinson agents. For this use an indicated daily dose is from about 1 to about 100 mg, con-veniently administered in divided doses 2 to 5 times a dav in unit dosage form con~aining from about 0.2 to about 50 mg, or in sustained release form.
: .
107~192 - ~ - 100-4146 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 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 made in conventional manner to be in the form of, for example, a solution or a tablet.
Additionally the central dopaminergic stimulant activity of a compound of formula Iis synergistically potentiated when administered con-comitantly with an inhibitor of phosphodiesterase activity , as indicated by a superadditive increase in turning movements in the above-indicated test when a compound of formula I is administered after administration of an inhibitor of phospho~
diesterase activity such as caffeine.
Therefore combinations of a compound of formula I and an inhibitor of phosphcdiesterase activity are further especially indicated for use as anti-Parkinson agents. An indicated daily dose of a 07~19Z
compound of formula I is from about 0.5 to about 50 mg and an indicated ratio of formula I compo-lnd to phosphodiesterase inhibitor is from about 10:1 to about 1:5000, preferably 2:1 to 1:1000, e.g. 1:50 to 1:1, e.g.
1:5 to 1:1, 1:25 or 1:10 to 1:50.
Suitable phosphodiesterase inhibitors are especially thoæ which inhibit phosphodiesterase activity in the brain, e.g. methyl xanthlnes such as caffeine or theophylline, but also may be chosen from derivatives of 4-amino-lH-pyrazolo[3,4-b]pyridine-5-carboxyclic acid esters, such as l-ethyl-4-(isopropylidene-hydrazino)-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, l-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester and l-ethyl-4-butylamino-1-ethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester, 4-(3,4-dimethoxybenzyl)-2-imidazolidinone and analogues thereof, such as 4-(3-butoxy-4-methoxy-benzyl)-2-imidazolidinone, minor tranquilizers, e.g.
of the 1,4-benzodiazepine series, such as 7-chloro-2-methvlamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide and 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, tricyclic antidepressants, such as
4-~3-(5H-dibenz[b,f]azepin-5-yl)propyl]-1-piperazine ethanol, phenothiazines such as 4-{3-[2-(trifluoro-metnyl)phenothiazin-lO-yl~propyl}-l-piperazine ethanol 107~192 and 2-chloro-10-(3-dimethylaminopropyl)phenothiazine, 2,6-bis-(diethanolamino)-4,8-diperidino-pyrimidino-~5,4-~ pyrimidine and papaverine.
The present invention also provides a pharmaceutical package containing as active agents a compound of formula I and an inhibitor of phospho-dieterase activity, the active agents being admixed or kept separate until required for concomitant administra-tion.
It is contemplated that all the usual pharmaceutical compositions may be made to encompass the above-indicated two active agents, e.g. tablets, powders, granulates, capsules, sirups and elixirs for oral administration, as well as solutions, dispersions and emulsions for parenteral administration. It is also contemplated that these compositions may be made in conventional manner using conventional pharmaceutical carriers and diluents.
Accordingly the present invention also pro-vides a process for the production of a pharmaceuticalcomposition including the step of bringing a compound of formula I as one active agent into association with an inhibitor of phosphodiesterase activity as another active agent, the active agents being sufficiently pure for pharmaceutical acceptability.
071~92 ~ 100-4146 It will be appreciated that combinations of a compound of formula I and a phosphodiesterase inhibitor may be conveniently administered in unit dosage form 2 to 5 times a day or in sustained release form. Such combinations may contain for example from about 0.1 to about 25 mg of a compound of formula I and the appropriate amount of phosphodiesterase inhibitor to give the indicated ratio range ment~oned above.
The compounds of formula I wherein x y is -CH=\, exhibit especially interesting central dopaminergic stimulating properties. R preferably signifies the 2-pyridyl or cvano group.
In one group of cGmpounds R is hydrogen cyano or a heterocyclic as defined above. In another group of compounds R is cyano, 4-pyridyl or 2-thiazoyl.
In the following non-limitative Examples all temperatures are indicated in d~grees Centigrade.
EX~MPLE 1: 6-methyl-8~-thiocyanomethylerqolene rprocess variant a)]
4.5 g (13.5 millimols) of 6-methyl-8~-methanesulphonyloxymethylergolene are heated together with 4.5 g (approx. 46 millimols) of potassium thiocyanate in a mixture of 45 cc of hexamethyl-phos~horic acid triamide and 3 cc of water to 80 under a stream of nitrogen for 20 hours. Working up is effected by pouring the reaction mixture into 450 cc of a 0.5 normal soda solution and filterirg. The dry re-sidue is dissolved whilst hot in a mixture of methylenechloride/ether and treated with active charcoal. The filtrate is concentrated and the title compound is ob-tained by crystallization from ethanol in the form of pink-tinged prisms having a M.P. of 186-188.
Hydrogen fumarate: from methylene chloride/ethanol, M.P. 182-184; [a]~D= ~ 55 (c = 0.5, dimethyl formamide).
.
:
EX~MPLE 2: 6-methyl-8~-mercaptomethvlerqolene 4.5 g (approx. 60 millimols) of sodium hydrogen sulphide H20 are used in a manner analogous to that described in Examp]e 1. After working up 071~'~Z
rapidly, the crystalline title compound is obtained from methylene chloride/isopropanol; decomposition point approx. 200, [a]D = +86 (c = 0.5, dimethyl formamide).
The following compounds of formula I are : obtained in a manner analogous to that described in Example 1, using the corresponding starting materials of formulae II and III:
EXAMPLE 3~ 6-methyl-8~-(2-pyrid~l-thiomethyl)-erqolene M.P. 200-201 (decomp.) Tartrate: M.P. 195-196; []20= + 26 (c = 1, dimethyl sulphoxide) (using.2-mercaptopyridine as compound Gf formula III).
; EXAMPLE 4: 6-methyl-8~-(2-pvridvl-thiomethvl)-erqoline M.P. 191-195; [a~2D- -113 (c = 1, pyridine).
EXAMPLE 5: 6-methyl-8~-(4-pyridyl-thiomethvl)-erqolene . ~.P. 191-194; [1 D=~52.5 (c = 1, dimethyl sulphoxide).
~()71~2 EXAMPLE 6: 6-methYl-8~-(2-thiazolyl-thiomethYl)-erqolene M.P. i92-L950 (decomp.); [a]20D= + 58.2 (c = 1, dimethyl , sulphoxide).
EXAMPLE 7: 6-methyl-8~-thiocvanomethylerqoline-I
M.P. 189-193; [a] D= -58 (c = 1, dimethyl sulphoxide).
EXAMPLE 8: 6-methyl-8a-thiocyanomethylerqoline-I
M.P. 185-188.
EXA~PLF 9: -methyl-8~-(2-thienYl-thiomethyl)erqolene EXAMPLE 10: 6-methyl-8~-(2-oxazolyl-thiomethyl)erqo]ene EXAMPLE 11: 6-methyl-8~-(2-imidazolyl-thiomethYl)-- erqolene EXAMPLE 12: 6-methvl-8~-(2-pyrimidinyl-thiomethyl)-erqolene EXAMPLE 13: 6-methyl-8~-r3-(1,2,4-triazolYl)thiomethYll-erqolene EXAMPLE 14: 6-methyl-8~-r2-(1,3,5-triazinyl)thiomethYl~-_rqolene ~07~192 .
EXAMPLE 15: 6-methvl-8~-[2-(4-methylpyridyl)thiomethyl~-erqolene EXAMPLE 16: 6-methvl-8~-~2-(4-methoxypyridyl)thiometh erqolene EXAMPLE 17: 6-methyl-8~-[4-(2-chloropyridyl)thiomethyl]-erqolene EXAMPLE 18~ 6-methyl-8~-mercaPtomethvlerqolene [process b)~
11.8 g (40 millimols) of 6-methyl-8~
thiocyanomethyl-9-ergolene are added portionwise at room temperature to a suspension stirred under nitrogen of 15.1 g (0.4 millimols) of lithium aluminium hydride in 800 cc of absolute tetrahydrofuran, and stirring is effected for one hour at this temperature. Working up is effected by carefully decomposing with water while cooling well and stirring into 500 cc of a 5 % aqueous tartaric ' acid solution. The reaction mixture is subsequently rendered alkaline with a potash solution and the aqueous phase is rapidly extracted with methylene chloride containing 10 % of methanol. After drying over sodium sulphate and removing the solvent by distillation, the title compound is obtained.
-`--` 107119Z
- 16 - 100~al46 Decomp. approx. 200, [~20= +86 (c = 0.5, dimethyl formamidP ), EXAMPLE 19: 6-methYl-8a-methanesulphonyloxymethYl-erqoline-I
(starting material for Example 8) A solution of 1.95 cc (25 millimols) of methanesulphonyl chloride in 5 cc of absolute aceto-nitrile is added dropwise at +10 to a stirred suspension of 2.56 g (10 millimols) of 9,10-dihydro-isolysergol I
[Helv. 32, 1947 (1949)3 in 15 cc of absolute pyridine and 25 cc of absolute acetonitrile, and stirring is effected at room temperature for one hour. Working up is effected by cooling to 0, diluting with methanol until a clear solution is obtained, rendering alkaline and distributing between 2N ammonia/methylene chloride. After drying and concentrating the combined organic phases by evapora-tion, 6-methyl-8a-methanesulphonyloxymethyl-ergoline-I
crystallizes from ethanol.
M.P. 139-141, [a~ = -54.6 (c = 1, dimethyl formamide).
:, - :
--` 107119Z
- 17 - 100-4~46 EXAMPLE 20~ Production of a solid pharmaceutical preparation a) 1 mg of a compound of formula I is mixed with lactose and optionally with 25 mg of a phospho-diesterase inhibitor. The mixture is granulated withwater, 0.5 % sodium alginate or 1 % gelatin solution.
The ~ry granulate is pressed into tablets in the presence of some tartaric acid, approx. 5 % of talc, about 5 % of maize starch and approx. 0.1 % of magnesium stearate.
In this manner it is possible to obtain, for example, tablets having th~ following composition:
Compound of formula I1 mg l mg Phosphodiesterase inhibitor - mg 25 mg Lactose 85.9 mg 60.9 mg Tartaric acid 3 mg 3 mg Maize starch 5 mg 5 mg Talc 5 mg 5 mg Magnesium stearate0.1 mg 0.1 mg Tablet of 100.0 mg lO0.0 mg b) Capsules - ~ The capsules may contain the active agent or agents alone. The following capsules may, for example, be obtained in accordance with known methods:
` ~07~92 , Compound of formula I 5 mg 5 mg Phosphodiesterase inhibitor 50 mg - mg Diluent (~.g. k~olin) - 295 mg Capsule content of 55 mg 300 mg EXAMPLE 21: Production of a liquid pharmaceutical preparation A liquid preparation, e.g. a suspension suitable for oral administration, may contain a com-pound of formula I and a phosphodiesterase inhibitor together with an inert, pharmaceutically tolerable liquid solvent or carrier material. It may fur~her contain other additives, e.g. sweetening and colouring agents, flavourings and stabilizing agents.
The following oral suspension ~.ay, for example, be obtained using known methodso Compound of formula I 1.0 mg 1 mg Phos~hodiesterase inhibitor - . 10 Vanilla essence q,5, q,5.
Colouring agent q.s. q-S~
20 Buffer q,5, q.s.
Water q.s. up q.s. up to 5 cc to 5 cc The preferred compounds of formula I for ~ "` 107119Z
_ l9 _ l00-4~6 use in Exam~les 20 and 21 are 6-methyl-8~-thiocyano-methylergolene and 6-methyl-8~-~2-pyrid~l-thiomethyl)-ergolene.
The preferred phosphodiesterase inhibitors for use in Examples 20 and 21 ~re theophylline and caffei.ne.
The present invention also provides a pharmaceutical package containing as active agents a compound of formula I and an inhibitor of phospho-dieterase activity, the active agents being admixed or kept separate until required for concomitant administra-tion.
It is contemplated that all the usual pharmaceutical compositions may be made to encompass the above-indicated two active agents, e.g. tablets, powders, granulates, capsules, sirups and elixirs for oral administration, as well as solutions, dispersions and emulsions for parenteral administration. It is also contemplated that these compositions may be made in conventional manner using conventional pharmaceutical carriers and diluents.
Accordingly the present invention also pro-vides a process for the production of a pharmaceuticalcomposition including the step of bringing a compound of formula I as one active agent into association with an inhibitor of phosphodiesterase activity as another active agent, the active agents being sufficiently pure for pharmaceutical acceptability.
071~92 ~ 100-4146 It will be appreciated that combinations of a compound of formula I and a phosphodiesterase inhibitor may be conveniently administered in unit dosage form 2 to 5 times a day or in sustained release form. Such combinations may contain for example from about 0.1 to about 25 mg of a compound of formula I and the appropriate amount of phosphodiesterase inhibitor to give the indicated ratio range ment~oned above.
The compounds of formula I wherein x y is -CH=\, exhibit especially interesting central dopaminergic stimulating properties. R preferably signifies the 2-pyridyl or cvano group.
In one group of cGmpounds R is hydrogen cyano or a heterocyclic as defined above. In another group of compounds R is cyano, 4-pyridyl or 2-thiazoyl.
In the following non-limitative Examples all temperatures are indicated in d~grees Centigrade.
EX~MPLE 1: 6-methyl-8~-thiocyanomethylerqolene rprocess variant a)]
4.5 g (13.5 millimols) of 6-methyl-8~-methanesulphonyloxymethylergolene are heated together with 4.5 g (approx. 46 millimols) of potassium thiocyanate in a mixture of 45 cc of hexamethyl-phos~horic acid triamide and 3 cc of water to 80 under a stream of nitrogen for 20 hours. Working up is effected by pouring the reaction mixture into 450 cc of a 0.5 normal soda solution and filterirg. The dry re-sidue is dissolved whilst hot in a mixture of methylenechloride/ether and treated with active charcoal. The filtrate is concentrated and the title compound is ob-tained by crystallization from ethanol in the form of pink-tinged prisms having a M.P. of 186-188.
Hydrogen fumarate: from methylene chloride/ethanol, M.P. 182-184; [a]~D= ~ 55 (c = 0.5, dimethyl formamide).
.
:
EX~MPLE 2: 6-methyl-8~-mercaptomethvlerqolene 4.5 g (approx. 60 millimols) of sodium hydrogen sulphide H20 are used in a manner analogous to that described in Examp]e 1. After working up 071~'~Z
rapidly, the crystalline title compound is obtained from methylene chloride/isopropanol; decomposition point approx. 200, [a]D = +86 (c = 0.5, dimethyl formamide).
The following compounds of formula I are : obtained in a manner analogous to that described in Example 1, using the corresponding starting materials of formulae II and III:
EXAMPLE 3~ 6-methyl-8~-(2-pyrid~l-thiomethyl)-erqolene M.P. 200-201 (decomp.) Tartrate: M.P. 195-196; []20= + 26 (c = 1, dimethyl sulphoxide) (using.2-mercaptopyridine as compound Gf formula III).
; EXAMPLE 4: 6-methyl-8~-(2-pvridvl-thiomethvl)-erqoline M.P. 191-195; [a~2D- -113 (c = 1, pyridine).
EXAMPLE 5: 6-methyl-8~-(4-pyridyl-thiomethvl)-erqolene . ~.P. 191-194; [1 D=~52.5 (c = 1, dimethyl sulphoxide).
~()71~2 EXAMPLE 6: 6-methYl-8~-(2-thiazolyl-thiomethYl)-erqolene M.P. i92-L950 (decomp.); [a]20D= + 58.2 (c = 1, dimethyl , sulphoxide).
EXAMPLE 7: 6-methyl-8~-thiocvanomethylerqoline-I
M.P. 189-193; [a] D= -58 (c = 1, dimethyl sulphoxide).
EXAMPLE 8: 6-methyl-8a-thiocyanomethylerqoline-I
M.P. 185-188.
EXA~PLF 9: -methyl-8~-(2-thienYl-thiomethyl)erqolene EXAMPLE 10: 6-methyl-8~-(2-oxazolyl-thiomethyl)erqo]ene EXAMPLE 11: 6-methyl-8~-(2-imidazolyl-thiomethYl)-- erqolene EXAMPLE 12: 6-methvl-8~-(2-pyrimidinyl-thiomethyl)-erqolene EXAMPLE 13: 6-methyl-8~-r3-(1,2,4-triazolYl)thiomethYll-erqolene EXAMPLE 14: 6-methyl-8~-r2-(1,3,5-triazinyl)thiomethYl~-_rqolene ~07~192 .
EXAMPLE 15: 6-methvl-8~-[2-(4-methylpyridyl)thiomethyl~-erqolene EXAMPLE 16: 6-methvl-8~-~2-(4-methoxypyridyl)thiometh erqolene EXAMPLE 17: 6-methyl-8~-[4-(2-chloropyridyl)thiomethyl]-erqolene EXAMPLE 18~ 6-methyl-8~-mercaPtomethvlerqolene [process b)~
11.8 g (40 millimols) of 6-methyl-8~
thiocyanomethyl-9-ergolene are added portionwise at room temperature to a suspension stirred under nitrogen of 15.1 g (0.4 millimols) of lithium aluminium hydride in 800 cc of absolute tetrahydrofuran, and stirring is effected for one hour at this temperature. Working up is effected by carefully decomposing with water while cooling well and stirring into 500 cc of a 5 % aqueous tartaric ' acid solution. The reaction mixture is subsequently rendered alkaline with a potash solution and the aqueous phase is rapidly extracted with methylene chloride containing 10 % of methanol. After drying over sodium sulphate and removing the solvent by distillation, the title compound is obtained.
-`--` 107119Z
- 16 - 100~al46 Decomp. approx. 200, [~20= +86 (c = 0.5, dimethyl formamidP ), EXAMPLE 19: 6-methYl-8a-methanesulphonyloxymethYl-erqoline-I
(starting material for Example 8) A solution of 1.95 cc (25 millimols) of methanesulphonyl chloride in 5 cc of absolute aceto-nitrile is added dropwise at +10 to a stirred suspension of 2.56 g (10 millimols) of 9,10-dihydro-isolysergol I
[Helv. 32, 1947 (1949)3 in 15 cc of absolute pyridine and 25 cc of absolute acetonitrile, and stirring is effected at room temperature for one hour. Working up is effected by cooling to 0, diluting with methanol until a clear solution is obtained, rendering alkaline and distributing between 2N ammonia/methylene chloride. After drying and concentrating the combined organic phases by evapora-tion, 6-methyl-8a-methanesulphonyloxymethyl-ergoline-I
crystallizes from ethanol.
M.P. 139-141, [a~ = -54.6 (c = 1, dimethyl formamide).
:, - :
--` 107119Z
- 17 - 100-4~46 EXAMPLE 20~ Production of a solid pharmaceutical preparation a) 1 mg of a compound of formula I is mixed with lactose and optionally with 25 mg of a phospho-diesterase inhibitor. The mixture is granulated withwater, 0.5 % sodium alginate or 1 % gelatin solution.
The ~ry granulate is pressed into tablets in the presence of some tartaric acid, approx. 5 % of talc, about 5 % of maize starch and approx. 0.1 % of magnesium stearate.
In this manner it is possible to obtain, for example, tablets having th~ following composition:
Compound of formula I1 mg l mg Phosphodiesterase inhibitor - mg 25 mg Lactose 85.9 mg 60.9 mg Tartaric acid 3 mg 3 mg Maize starch 5 mg 5 mg Talc 5 mg 5 mg Magnesium stearate0.1 mg 0.1 mg Tablet of 100.0 mg lO0.0 mg b) Capsules - ~ The capsules may contain the active agent or agents alone. The following capsules may, for example, be obtained in accordance with known methods:
` ~07~92 , Compound of formula I 5 mg 5 mg Phosphodiesterase inhibitor 50 mg - mg Diluent (~.g. k~olin) - 295 mg Capsule content of 55 mg 300 mg EXAMPLE 21: Production of a liquid pharmaceutical preparation A liquid preparation, e.g. a suspension suitable for oral administration, may contain a com-pound of formula I and a phosphodiesterase inhibitor together with an inert, pharmaceutically tolerable liquid solvent or carrier material. It may fur~her contain other additives, e.g. sweetening and colouring agents, flavourings and stabilizing agents.
The following oral suspension ~.ay, for example, be obtained using known methodso Compound of formula I 1.0 mg 1 mg Phos~hodiesterase inhibitor - . 10 Vanilla essence q,5, q,5.
Colouring agent q.s. q-S~
20 Buffer q,5, q.s.
Water q.s. up q.s. up to 5 cc to 5 cc The preferred compounds of formula I for ~ "` 107119Z
_ l9 _ l00-4~6 use in Exam~les 20 and 21 are 6-methyl-8~-thiocyano-methylergolene and 6-methyl-8~-~2-pyrid~l-thiomethyl)-ergolene.
The preferred phosphodiesterase inhibitors for use in Examples 20 and 21 ~re theophylline and caffei.ne.
Claims (5)
- What we claim is:
I. A process for the production of a compound of formula I, I
wherein is the group or , and R is hydrogen, cyano, a 5- or 6-membered unsaturated heterocyclic radical attached through a ring carbon atom and having 1, 2 or 3 hetero ring atoms, the first hetero atom being nitrogen, oxygen or sulphur, and the second ring third hetero atoms, is present, being nitrogen, or 2- or 4-pyridyl monosub-stituted by lower alkyl, lower alkoxy or halogen, or a pharmaceutically acceptable acid addition salt thereof.
which comprises a) reacting a compound of formula II, II
wherein is as defined above, and X is an exchangeable radical capable of being displaced by a thio group with a compound of formula III, MS - R III
wherein R is as defined above, and M is hydrogen or an alkali metal, or b) reducing the-SCN group to an -SH group in a compound of formula Ib, Ib wherein is as defined above, to produce a compound of formula Ia, Ia wherein is as defined above and where required converting the resulting com-pound i-to a pharmaceutically acceptable acid addition salt thereof. - 2. A compound of formula I, whenever produced by a process according to Claim 1.
- 3. A process according to Claim 1 for the production of 6-methyl-8.beta.-(2-pyridyl-thiomethyl)-ergolene or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting 6-methyl-8.beta.-mesyloxyergolene with 2-thiopyridine in an inert solvent, and where necessary converting the resulting compound into a pharmaceutically acceptable acid addition salt thereof.
- 4. 6-methyl-8.beta.-(2-pyridyl-thiomethyl)-ergolene or a pharmaceutically acceptable acid addition salt thereof, whenever produced by a process according to Claim 3 or an obvious chemical equivalent thereof.
- 5. A process according to claim 1 wherein R is a 5- or 6-membered unsaturated heterocyclic radical attached through a ring carbon atoms, having 1, 2 or 3 hetero ring atoms, the first hetero atom being nitrogen, oxygen or sulphur, and the second and third hetero atoms, if present, being nitrogen, or 2- or 4-pyridyl monosub-stituted by lower alkyl, lower alkoxy or halogen.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH356374A CH593972A5 (en) | 1974-03-14 | 1974-03-14 | |
| CH1013874 | 1974-07-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1071192A true CA1071192A (en) | 1980-02-05 |
Family
ID=25693324
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA221,971A Expired CA1071192A (en) | 1974-03-14 | 1975-03-13 | 6-METHYL-8.beta.-(-CH2-S-R)ERGOLENE OR ERGOLINE |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS589111B2 (en) |
| AU (1) | AU500890B2 (en) |
| CA (1) | CA1071192A (en) |
| DD (1) | DD118428A5 (en) |
| DE (1) | DE2509471A1 (en) |
| DK (1) | DK141701B (en) |
| ES (1) | ES435538A1 (en) |
| FI (1) | FI60865C (en) |
| FR (1) | FR2263774B1 (en) |
| GB (1) | GB1497681A (en) |
| HK (1) | HK8481A (en) |
| IE (1) | IE41533B1 (en) |
| IL (1) | IL46809A (en) |
| MY (1) | MY8100331A (en) |
| NL (1) | NL7502807A (en) |
| NO (1) | NO750748L (en) |
| PH (1) | PH12966A (en) |
| SE (1) | SE420094B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4147789A (en) * | 1974-03-14 | 1979-04-03 | Sandoz Ltd. | 6-Methyl-8-thiomethyl-ergolene derivatives |
| JPS5293797A (en) * | 1976-01-30 | 1977-08-06 | Sandoz Ag | Improvement in organic compound |
| GB1555751A (en) * | 1977-02-02 | 1979-11-14 | Farmaceutici Italia | Ergoline deritatives |
| US4166182A (en) * | 1978-02-08 | 1979-08-28 | Eli Lilly And Company | 6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds |
| US4382940A (en) * | 1979-12-06 | 1983-05-10 | Farmitalia Carlo Erba S.P.A. | Ercoline derivatives and therapeutic compositions having CNS affecting activity |
| GB2120242A (en) * | 1982-04-30 | 1983-11-30 | Erba Farmitalia | Ergoline derivatives |
| CH649998A5 (en) * | 1982-08-09 | 1985-06-28 | Sandoz Ag | ERGOL DERIVATIVES, A METHOD FOR THEIR PRODUCTION AND HEALING AGENTS, CONTAINING THESE ERGOL DERIVATIVES AS AN ACTIVE SUBSTANCE. |
| IT1215261B (en) * | 1985-04-05 | 1990-01-31 | Poli Ind Chimica Spa | PHARMACEUTICAL COMPOSITIONS ANTIGALACTOPOIETIC ADAPTITY. |
| US4798834A (en) * | 1987-08-31 | 1989-01-17 | Eli Lilly And Company | Optionally substituted (3β-9,10-didehydro-2,3-dihydro ergoline as serotonergic function enhancement |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL6818658A (en) * | 1968-01-18 | 1969-07-22 |
-
1975
- 1975-02-12 IE IE542/75A patent/IE41533B1/en unknown
- 1975-03-05 DE DE19752509471 patent/DE2509471A1/en not_active Ceased
- 1975-03-05 DK DK89375AA patent/DK141701B/en not_active IP Right Cessation
- 1975-03-05 SE SE7502469A patent/SE420094B/en unknown
- 1975-03-06 NO NO75750748A patent/NO750748L/no unknown
- 1975-03-06 FI FI750644A patent/FI60865C/en not_active IP Right Cessation
- 1975-03-10 NL NL7502807A patent/NL7502807A/en not_active Application Discontinuation
- 1975-03-10 GB GB9807/75A patent/GB1497681A/en not_active Expired
- 1975-03-11 FR FR7507472A patent/FR2263774B1/fr not_active Expired
- 1975-03-12 ES ES435538A patent/ES435538A1/en not_active Expired
- 1975-03-12 DD DD184721A patent/DD118428A5/xx unknown
- 1975-03-12 PH PH16903A patent/PH12966A/en unknown
- 1975-03-12 IL IL46809A patent/IL46809A/en unknown
- 1975-03-13 AU AU79057/75A patent/AU500890B2/en not_active Ceased
- 1975-03-13 CA CA221,971A patent/CA1071192A/en not_active Expired
- 1975-03-13 JP JP50029600A patent/JPS589111B2/en not_active Expired
-
1981
- 1981-03-12 HK HK84/81A patent/HK8481A/en unknown
- 1981-12-30 MY MY331/81A patent/MY8100331A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK89375A (en) | 1975-09-15 |
| DK141701C (en) | 1980-10-20 |
| FR2263774A1 (en) | 1975-10-10 |
| SE420094B (en) | 1981-09-14 |
| DE2509471A1 (en) | 1975-09-18 |
| FI60865B (en) | 1981-12-31 |
| IE41533L (en) | 1975-09-14 |
| JPS589111B2 (en) | 1983-02-18 |
| FR2263774B1 (en) | 1978-08-04 |
| DK141701B (en) | 1980-05-27 |
| MY8100331A (en) | 1981-12-31 |
| SE7502469L (en) | 1975-09-15 |
| IE41533B1 (en) | 1980-01-30 |
| GB1497681A (en) | 1978-01-12 |
| IL46809A (en) | 1978-04-30 |
| ES435538A1 (en) | 1977-03-16 |
| NL7502807A (en) | 1975-09-16 |
| DD118428A5 (en) | 1976-03-05 |
| PH12966A (en) | 1979-10-19 |
| AU500890B2 (en) | 1979-06-07 |
| HK8481A (en) | 1981-03-20 |
| FI60865C (en) | 1982-04-13 |
| FI750644A7 (en) | 1975-09-15 |
| NO750748L (en) | 1975-09-16 |
| JPS50123698A (en) | 1975-09-29 |
| IL46809A0 (en) | 1975-07-28 |
| AU7905775A (en) | 1976-09-16 |
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