CA1215972A - Ergot alkaloids - Google Patents
Ergot alkaloidsInfo
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- CA1215972A CA1215972A CA000434064A CA434064A CA1215972A CA 1215972 A CA1215972 A CA 1215972A CA 000434064 A CA000434064 A CA 000434064A CA 434064 A CA434064 A CA 434064A CA 1215972 A CA1215972 A CA 1215972A
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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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- Animal Behavior & Ethology (AREA)
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- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
ERGOT ALKALOIDS
Abstract of the Disclosure 2-methyl-lysergyl ethers and thioethers are useful neuroleptics, anti-migraine agents, cerebral insufficiency agents, agents for senile dementia and anti-depressants.
Abstract of the Disclosure 2-methyl-lysergyl ethers and thioethers are useful neuroleptics, anti-migraine agents, cerebral insufficiency agents, agents for senile dementia and anti-depressants.
Description
~5~7;2 ERGOT ALKALOIDS
.
This inventlon relates to ergot alkaloids.
The invention provides compounds of formula I
C~-X-R3 ~-R2 Rl-N - CH
~1 ~2~59~
.
This inventlon relates to ergot alkaloids.
The invention provides compounds of formula I
C~-X-R3 ~-R2 Rl-N - CH
~1 ~2~59~
- 2 - 100-5863 wherein X is -0- or -S-, R1 is hydrogen, (C1_4)alkyl or phenyl, R2 is (C1 3)alkyl and R3 is phenyl or pyridyl, unsubstituted or monosubstituted or independently di- or tri-substituted by halogen of atomic number from 9 to 35 (Cl 4)alkyl or (Cl 4~alkoxy or (Cl ~3alkyl.
and acid addition salts thereof, hereinafter referred to as compounds of the invention.
A compound of formula I or an acid addition salt may be produced by a process which includes the step of reacting a compound of formula II
CH~-Y
Rl-N CH3 wherein Rl and R2 are as defined above, and Y is a leaving group, with a ~ompound of formula III
12~5~72
and acid addition salts thereof, hereinafter referred to as compounds of the invention.
A compound of formula I or an acid addition salt may be produced by a process which includes the step of reacting a compound of formula II
CH~-Y
Rl-N CH3 wherein Rl and R2 are as defined above, and Y is a leaving group, with a ~ompound of formula III
12~5~72
- 3 - l00-5863 wherein R3 and X are as defined above and M is hydrogen or an alkali metal, and recovering the compound of formula I as such or as an acid addition salt thereof.
The above process may be effected in conventional manner.
Y may be for example halogen, e.g. chlorine or bromine, or a group of formula -O-S02-R wherein R is lower alkyl or optionally substituted phenyl, containing e.g. up to lO carbon atoms.
Preferably Y is mesyloxy or tosyloxy.
Conveniently an excess of a compound o~ formula III is used. For example from 2 ~o lO Mol compound of formula III per mole of compound of formula II may be used. Preferably M is an alkali metal.
Conveniently the reaction is effected in a solvent, e~g. an lS inert apro~ic pol ar solvent such as an organic carboxylic acid amide such as dimethyl formar,ide or hexamethylphosphoric tri-amide or ace~onitile. If desired water, p.eferably in small quantities, may be present.
Suitable reaction temperatures may be elevated temperatures, e.g. from about 50 to about 100C.
.~ ... ,, i -- ~2~5~
_ 4 _ 100-5863 Conveniently the reaction is effected in an inert gas atmosphere, e.g. under nitrogen.
The side chain in the 8 position in the compound of formula I may have the a or B configuration. Any alkyl or alkoxy radical has preferably 2 carbon atoms and especially 1 carbon atom.
Halogen is preferably chlorine or bromine. X is preferably S.
Rl is preferably hydrogen. R3 is conveniently unsubstituted pyridyl, preferably 2-pyridyl.
In one group of compounds X is -S-, R1 is hydrogen and R3 is 2-pyridyl.
The compounds of the invention may be isolated and purified in conventional manner.
The compounds of the invention may be converted into acid addition salts in conventional manner and vice versa. A suitable acid for salt formation includes hydrochloric acid.
, ~
lS~7~
- 5 - lOO-5863 The starting materials may be produced in conventional manner. For example compounds of formula II may be produced by reducing a compound of formula IV
QH2-y ~U
R~ -N-~S~
5Compounds of formula N may be produced by reaction of a compound of formula V
~H2_Y
~ R2 V, Rl-N
with 1,3-dithiane as described in the examples.
~2~L591'72 Compounds of formula II may alternatively be produced from the known lysergic acid or 6-homologue thereof, reducing it to the alcohol and then replacing ~he hydroxyl group by the radical Y.
Insofar the prepration of any particular starting material is not particularly described this is known or may be produced in conventional manner.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected. Optical rotations are at 20 and at the D line wi~h the substance in ethanol/water 1:1 unless otherwise stated.
Abbreviations:
1 = optical rotation in pyridine 2 = Decompos;tion 3 = Hydrochloride Nomenclature: lysergyl - 9,10-didehydro-6-methylergolin-8B-yl-methyl.
,j ~ . .~ .
.~ . ,, ~z~5g~
EXAMPLE_1 9,10-didehydro-2,6-dimethyl-8~-(2-pyridylthio-methyl)ergoline a~ ~
2.9 ml sulfuryl chloride in 15 ml chloroform are added S dropwise to a solution of 4.2 9 1,3-dithiane in 100 ml chloroform at -30- ~ithin 30 minutes. After the temperature has risen to 20-, the mixture is stirred ~or 30 minutes at 20. 7.5 9 lysergyl mesylate in 100 ml chloro~orm are added at -10-. After the temperature has risen to 20, the mixture is stirred for a 10 further 30 minutes at 20. To work up the mixture is treated with ice/water~ neutralised with 2N sodium carbonate and extracted with methylene chloride containing 10X isopropanol. The extracts are dried with sodiuM sulphate, filtered and concentrated. Tile resultant product is chromato~raphed on silicagel using mPthyene 15 chloride conta,ning 2% mathanol as eluant to gi~e the heading compoulld .
. .
b) 2-methyl-lyser~yl mesylate 100 ml of a suspension of Raney-Nickel in water is washed four times each with 100 ml dimethylformamide/acetone 1:4. The 20 washed Raney-Nickel is treated under argon with 115 ml dimethylformamide/acetone (1:4)~ and the stirred suspension is treated at room temperature with a solution o~ 4.~ 9 2-(1,3 di-thian-2-yl)lysergyl mesylate in 80 ml dimethylformamide/acetone (1:4). The mixture is stirred for 2 112 hours at room 25 temperature, filtered and the filter residue washed twice ~5~
each time with 115 ml dime~hylforma~ide/ace~one (1:2). The filtrate is concentrated and dried up in a high vacuum to give the crude product which is chromatographed on 90 9 silicagel with methylene chloride containing 2% methanol as eluant to give the heading compound as a beige foam.
c) ergoline A solution of 1.3 9 2-methyl-lysergyl mesylate and 2-mercap-topyridine in 20 ml dimetllylfor,~amide ~s treated with 4.5 inl 2N
10 sodium hydroxide and stirred at room temperature. The mixture is stirred with water and extracted with methylene chloride containing 10% isopropanol. The extracts are dried wi~h sodium sulphate, filtered, concentrated and dried in a high v~cuum. lhe crude product is chromatographed on 120 g silicagel with 15 chloroform containins 2~ methanol and 0.1X concentrated ammonia to give the heading compound. M.pt. decomp. from 253,[a] =
+ 58 (c = 0.37).
~Z~L5972 -9- 100-5~63 The following compounds of formula I having an 8B side ~h~in are produced in analogous manner:-Example R1 R2 R3 X M.pt. ta]
(c) 2 H C2Hs 2-pyridyl S 2102 + 45 (0.435) 3 CH3C2Hs 2-pyridyl S 1852 3 + 28 (0.33)
The above process may be effected in conventional manner.
Y may be for example halogen, e.g. chlorine or bromine, or a group of formula -O-S02-R wherein R is lower alkyl or optionally substituted phenyl, containing e.g. up to lO carbon atoms.
Preferably Y is mesyloxy or tosyloxy.
Conveniently an excess of a compound o~ formula III is used. For example from 2 ~o lO Mol compound of formula III per mole of compound of formula II may be used. Preferably M is an alkali metal.
Conveniently the reaction is effected in a solvent, e~g. an lS inert apro~ic pol ar solvent such as an organic carboxylic acid amide such as dimethyl formar,ide or hexamethylphosphoric tri-amide or ace~onitile. If desired water, p.eferably in small quantities, may be present.
Suitable reaction temperatures may be elevated temperatures, e.g. from about 50 to about 100C.
.~ ... ,, i -- ~2~5~
_ 4 _ 100-5863 Conveniently the reaction is effected in an inert gas atmosphere, e.g. under nitrogen.
The side chain in the 8 position in the compound of formula I may have the a or B configuration. Any alkyl or alkoxy radical has preferably 2 carbon atoms and especially 1 carbon atom.
Halogen is preferably chlorine or bromine. X is preferably S.
Rl is preferably hydrogen. R3 is conveniently unsubstituted pyridyl, preferably 2-pyridyl.
In one group of compounds X is -S-, R1 is hydrogen and R3 is 2-pyridyl.
The compounds of the invention may be isolated and purified in conventional manner.
The compounds of the invention may be converted into acid addition salts in conventional manner and vice versa. A suitable acid for salt formation includes hydrochloric acid.
, ~
lS~7~
- 5 - lOO-5863 The starting materials may be produced in conventional manner. For example compounds of formula II may be produced by reducing a compound of formula IV
QH2-y ~U
R~ -N-~S~
5Compounds of formula N may be produced by reaction of a compound of formula V
~H2_Y
~ R2 V, Rl-N
with 1,3-dithiane as described in the examples.
~2~L591'72 Compounds of formula II may alternatively be produced from the known lysergic acid or 6-homologue thereof, reducing it to the alcohol and then replacing ~he hydroxyl group by the radical Y.
Insofar the prepration of any particular starting material is not particularly described this is known or may be produced in conventional manner.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected. Optical rotations are at 20 and at the D line wi~h the substance in ethanol/water 1:1 unless otherwise stated.
Abbreviations:
1 = optical rotation in pyridine 2 = Decompos;tion 3 = Hydrochloride Nomenclature: lysergyl - 9,10-didehydro-6-methylergolin-8B-yl-methyl.
,j ~ . .~ .
.~ . ,, ~z~5g~
EXAMPLE_1 9,10-didehydro-2,6-dimethyl-8~-(2-pyridylthio-methyl)ergoline a~ ~
2.9 ml sulfuryl chloride in 15 ml chloroform are added S dropwise to a solution of 4.2 9 1,3-dithiane in 100 ml chloroform at -30- ~ithin 30 minutes. After the temperature has risen to 20-, the mixture is stirred ~or 30 minutes at 20. 7.5 9 lysergyl mesylate in 100 ml chloro~orm are added at -10-. After the temperature has risen to 20, the mixture is stirred for a 10 further 30 minutes at 20. To work up the mixture is treated with ice/water~ neutralised with 2N sodium carbonate and extracted with methylene chloride containing 10X isopropanol. The extracts are dried with sodiuM sulphate, filtered and concentrated. Tile resultant product is chromato~raphed on silicagel using mPthyene 15 chloride conta,ning 2% mathanol as eluant to gi~e the heading compoulld .
. .
b) 2-methyl-lyser~yl mesylate 100 ml of a suspension of Raney-Nickel in water is washed four times each with 100 ml dimethylformamide/acetone 1:4. The 20 washed Raney-Nickel is treated under argon with 115 ml dimethylformamide/acetone (1:4)~ and the stirred suspension is treated at room temperature with a solution o~ 4.~ 9 2-(1,3 di-thian-2-yl)lysergyl mesylate in 80 ml dimethylformamide/acetone (1:4). The mixture is stirred for 2 112 hours at room 25 temperature, filtered and the filter residue washed twice ~5~
each time with 115 ml dime~hylforma~ide/ace~one (1:2). The filtrate is concentrated and dried up in a high vacuum to give the crude product which is chromatographed on 90 9 silicagel with methylene chloride containing 2% methanol as eluant to give the heading compound as a beige foam.
c) ergoline A solution of 1.3 9 2-methyl-lysergyl mesylate and 2-mercap-topyridine in 20 ml dimetllylfor,~amide ~s treated with 4.5 inl 2N
10 sodium hydroxide and stirred at room temperature. The mixture is stirred with water and extracted with methylene chloride containing 10% isopropanol. The extracts are dried wi~h sodium sulphate, filtered, concentrated and dried in a high v~cuum. lhe crude product is chromatographed on 120 g silicagel with 15 chloroform containins 2~ methanol and 0.1X concentrated ammonia to give the heading compound. M.pt. decomp. from 253,[a] =
+ 58 (c = 0.37).
~Z~L5972 -9- 100-5~63 The following compounds of formula I having an 8B side ~h~in are produced in analogous manner:-Example R1 R2 R3 X M.pt. ta]
(c) 2 H C2Hs 2-pyridyl S 2102 + 45 (0.435) 3 CH3C2Hs 2-pyridyl S 1852 3 + 28 (0.33)
4 Phenyl CH3 2-pyridyl S 191-22 3 ~ 294 (0.85) H CH3 p-methyl- S 206-82 + 22 (0.54)1 phenyl 6 H CH3 phenyl S 178-802 + 33- (0,76)1 10 7 H CH3 p-methyl- 0 173-52 ~ 39 (0.65) phenyl 8 H CH3 CH3 S 288-93 ~ 92 (0.5) 9 H nC3H7 CH3 S 252-32 3 CH3 CH3 2-pyridyl S 188 92 3 + 49O (0.59) ~5~33'72 -lO- 100-5B63 /UK
The compounds of the invention are pharmacologically active and are therefore indicated for ùse as pharmaceuticals.
The compounds of the invention exhibit antagonistic effects sn dopamine receptors as indicated in standard animal tests, e.g. using the rat brain. Thus~ the compounds lead on administration p.o. of about 10 mg/kg to an increase of concentration of the dopamine metabolites, 3,4 dihydroxyphenyl-acetic acid (DOPAC) and homovallinic acid (HVA~ in the striatum.
The biochemica1 parameters may be measured accord;ng to the lO principles of F. Karoum et al., Europ. J. Pharmacol. 44~ 311-318, (1977) and H.R. Burki et al., Psychopharmacology 57, 227-237 ~1978).
At ~he same doses the activity of tyrosine hydroxylase in vivo is increased according to the method of A.Carlson et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 275, 163-1~8.
The compounds furthermore antagonise in vitro at about 1 mg/ml the apomorphine effect on electrically-stimulated acetyl-choline release in striatum slices of the rat in accordance with the method of R.Markstein, J. Neural. Transmission 51~ 39-59 (1981).
The co~pounds are thereforeindicated for use as neuroleptics, especially for the treatment of schizophrenia.
The compounds of the invention also exhibit sero~onin agonist activity as indicated in standard animal tests.
For example~ the compounds also increase at from about 0.1 to 0.5 mg/ml the electrically induced acetyl choline release in the Hippocampus in the rat.
This is confirmed in the observation test over 6 hours on administration i.p. at from about 30 to about 50 mg/kg in rats or p.o. at from about 3 to about 10 mg/kg body weight in mice wherein the compounds induce a prolongation of the wake phase and 10 an increased reaction to exterllal stimuli, in accordance with the principles described in J.M. Vigouret et al., Pharmacology, 16, (Suppl. 1), 1, 156-173 (1978).
The cGmpounds are therefore indicated for use in dementia, especially senile dementia.
The compounds of the invention also exhibit anti-depressant activity as indicated in standard animal tests. For example in the 48 hour chronically implanted rat test effected according to H.Kleinlogel et al., Wakiny and Sleeping,1980, 4~ 77-85~ the compounds in p.o. administration of from about 3 to about 30 20 mg/kg9 lead to a reduction of the paradoxical sleep phase without a significant rebound.
~59D7~
The compounds are therefore additionally ~ndicated for use as anti-depressants, esoecially for aeriatrics.
The compounds also have a vasoconstricting activity as indicated by a noradrenaline potentiation in tne method of S E.Muller-Schweinitzer, Naunyn-Schmiedeberg's Arch, Phar~acol~, - 292, 113-118 (1976) in vitro on isolated st.rips of canine Arteria carotis externa at doses of from about 10-1 to 10-~ M / litre.
The compounds are therefore of use as anti-migraine agents and for the treatment of tension headache.
Moreover, the compoun~s increase the 10CQ1 cerebral ~lucose utilisation in the sensomotor cortex, e.g. lateral Nucleus habenula, as indicated by the carbon-14-2-deoxyglucose autoradio-gra~hic technique with the rat brain on administration i.v. of from about 0.01 to about 0.1 mg/kg or p.o. 10 mg/kg of the 15 compounds ~for method see e.g. L.Solokoff, Journal of Cerebral B100d Flow and Metabolism~ 1981, (l), 7-36; H.E. Savaki et al., Brain Research 1982, 233, 347-358, and J. McCulloch et al., Journal of Cerebral Blood Flow and Metabolism 1981, 1. 133-136.
~ 'r' ~ 17`'i /
~2~LS~7;~
The compounds of the invention are thus additionally indicated for use in the treatment of cere~ral insuffic;ency.
For all the above indications an indicated daily dose is from about 1 to about 100 mg conveniently administered in didived doses 2 to 4 times a day in unit dosage form containing about 0.3 to about 50 mg, or in sustained release form.
The present invention provides also a compound of the invention in pharmaceutically acceptable form for use as an anti-depressant, neuroleptic, for the treatment of dementia, cerebral lO insufficiency or migraine.
The preferred indication is senile dementia. The preferred compound is the compound of Example 1.
The compounds of the invention may be administered as such or as the pharmaceutically acceptable acid addi~ion salt 15 thereof. Such acid addition salts exhibit the same order of activity as the free bases. The present invention provides accordingly a pharrnaceutical composition which comprises a compound of the invention in a pharmaceutically acceptable form in association with a pharmaceutical carrier or diluent. Such 20 compositions may be formulated in conventional manner so as to be for example tablets or solutions.
The compounds of the invention are pharmacologically active and are therefore indicated for ùse as pharmaceuticals.
The compounds of the invention exhibit antagonistic effects sn dopamine receptors as indicated in standard animal tests, e.g. using the rat brain. Thus~ the compounds lead on administration p.o. of about 10 mg/kg to an increase of concentration of the dopamine metabolites, 3,4 dihydroxyphenyl-acetic acid (DOPAC) and homovallinic acid (HVA~ in the striatum.
The biochemica1 parameters may be measured accord;ng to the lO principles of F. Karoum et al., Europ. J. Pharmacol. 44~ 311-318, (1977) and H.R. Burki et al., Psychopharmacology 57, 227-237 ~1978).
At ~he same doses the activity of tyrosine hydroxylase in vivo is increased according to the method of A.Carlson et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 275, 163-1~8.
The compounds furthermore antagonise in vitro at about 1 mg/ml the apomorphine effect on electrically-stimulated acetyl-choline release in striatum slices of the rat in accordance with the method of R.Markstein, J. Neural. Transmission 51~ 39-59 (1981).
The co~pounds are thereforeindicated for use as neuroleptics, especially for the treatment of schizophrenia.
The compounds of the invention also exhibit sero~onin agonist activity as indicated in standard animal tests.
For example~ the compounds also increase at from about 0.1 to 0.5 mg/ml the electrically induced acetyl choline release in the Hippocampus in the rat.
This is confirmed in the observation test over 6 hours on administration i.p. at from about 30 to about 50 mg/kg in rats or p.o. at from about 3 to about 10 mg/kg body weight in mice wherein the compounds induce a prolongation of the wake phase and 10 an increased reaction to exterllal stimuli, in accordance with the principles described in J.M. Vigouret et al., Pharmacology, 16, (Suppl. 1), 1, 156-173 (1978).
The cGmpounds are therefore indicated for use in dementia, especially senile dementia.
The compounds of the invention also exhibit anti-depressant activity as indicated in standard animal tests. For example in the 48 hour chronically implanted rat test effected according to H.Kleinlogel et al., Wakiny and Sleeping,1980, 4~ 77-85~ the compounds in p.o. administration of from about 3 to about 30 20 mg/kg9 lead to a reduction of the paradoxical sleep phase without a significant rebound.
~59D7~
The compounds are therefore additionally ~ndicated for use as anti-depressants, esoecially for aeriatrics.
The compounds also have a vasoconstricting activity as indicated by a noradrenaline potentiation in tne method of S E.Muller-Schweinitzer, Naunyn-Schmiedeberg's Arch, Phar~acol~, - 292, 113-118 (1976) in vitro on isolated st.rips of canine Arteria carotis externa at doses of from about 10-1 to 10-~ M / litre.
The compounds are therefore of use as anti-migraine agents and for the treatment of tension headache.
Moreover, the compoun~s increase the 10CQ1 cerebral ~lucose utilisation in the sensomotor cortex, e.g. lateral Nucleus habenula, as indicated by the carbon-14-2-deoxyglucose autoradio-gra~hic technique with the rat brain on administration i.v. of from about 0.01 to about 0.1 mg/kg or p.o. 10 mg/kg of the 15 compounds ~for method see e.g. L.Solokoff, Journal of Cerebral B100d Flow and Metabolism~ 1981, (l), 7-36; H.E. Savaki et al., Brain Research 1982, 233, 347-358, and J. McCulloch et al., Journal of Cerebral Blood Flow and Metabolism 1981, 1. 133-136.
~ 'r' ~ 17`'i /
~2~LS~7;~
The compounds of the invention are thus additionally indicated for use in the treatment of cere~ral insuffic;ency.
For all the above indications an indicated daily dose is from about 1 to about 100 mg conveniently administered in didived doses 2 to 4 times a day in unit dosage form containing about 0.3 to about 50 mg, or in sustained release form.
The present invention provides also a compound of the invention in pharmaceutically acceptable form for use as an anti-depressant, neuroleptic, for the treatment of dementia, cerebral lO insufficiency or migraine.
The preferred indication is senile dementia. The preferred compound is the compound of Example 1.
The compounds of the invention may be administered as such or as the pharmaceutically acceptable acid addi~ion salt 15 thereof. Such acid addition salts exhibit the same order of activity as the free bases. The present invention provides accordingly a pharrnaceutical composition which comprises a compound of the invention in a pharmaceutically acceptable form in association with a pharmaceutical carrier or diluent. Such 20 compositions may be formulated in conventional manner so as to be for example tablets or solutions.
Claims (8)
1. A process for the preparation of a compound of formula I
I
wherein X is -O- or -S-R1 is hydrogen, (C1-4)alkyl or phenyl R2 is (C1-3)alkyl and R3 is phenyl or pyridyl, unsubstituted mono-substituted or independently di- or tri-substituted by halogen of atomic number from 9 to 35, (C1-4)alkyl or (C1-4)alkoxy, or (C1-4)alkyl or an acid addition salt thereof, which includes the step of reacting a compound of formula II
II
wherein R1 and R2 are as defined above, and Y is a leaving group, with a compound of formula III
wherein R3 and X are as defined above and M is hydrogen or an alkali metal, and recovering the compound of formula I as such or as an acid addition salt thereof.
I
wherein X is -O- or -S-R1 is hydrogen, (C1-4)alkyl or phenyl R2 is (C1-3)alkyl and R3 is phenyl or pyridyl, unsubstituted mono-substituted or independently di- or tri-substituted by halogen of atomic number from 9 to 35, (C1-4)alkyl or (C1-4)alkoxy, or (C1-4)alkyl or an acid addition salt thereof, which includes the step of reacting a compound of formula II
II
wherein R1 and R2 are as defined above, and Y is a leaving group, with a compound of formula III
wherein R3 and X are as defined above and M is hydrogen or an alkali metal, and recovering the compound of formula I as such or as an acid addition salt thereof.
2. A compound of formula I as defined in claim 1 or an acid addition salt thereof, whenever produced by the process according to claim 1 or an obvious chemical equivalent.
3. A process according to claim 1 wherein X is sulphur.
4. A compound of claim 2 wherein X is sulphur or an acid addition salt thereof, whenever produced by the process according to claim 3 or an obvious chemical equivalent.
5. A process according to claim 1 wherein X is sulphur, R1 is hydrogen and R3 is 2-pyridyl.
6. A compound of claim 2 wherein X is sulphur, R1 is hydrogen, and R3 is 2-pyridyl or an acid addition salt thereof, whenever produced by the process according to claim or an obvious chemical equivalent.
7. A process according to claim 1 wherein R3 is phenyl, unsubstituted or substituted by (C1-4)alkyl, pyridyl or (C1-4)alkyl and the 8 side chain has the beta configuration.
8. A compound of claim 2 wherein R3 is phenyl, unsubstituted or substituted by (C1-4)alkyl, pyridyl or (C1-4)alkyl and the 8 side chain has the beta configuration or an acid addition salt thereof, whenever produced by the process according to claim 7 or an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH4772/82A CH649998A5 (en) | 1982-08-09 | 1982-08-09 | ERGOL DERIVATIVES, A METHOD FOR THEIR PRODUCTION AND HEALING AGENTS, CONTAINING THESE ERGOL DERIVATIVES AS AN ACTIVE SUBSTANCE. |
| CH4772/82 | 1982-08-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1215972A true CA1215972A (en) | 1986-12-30 |
Family
ID=4282273
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000434064A Expired CA1215972A (en) | 1982-08-09 | 1983-08-08 | Ergot alkaloids |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPS5948480A (en) |
| AT (1) | AT383125B (en) |
| AU (1) | AU563736B2 (en) |
| BE (1) | BE897473A (en) |
| CA (1) | CA1215972A (en) |
| CH (1) | CH649998A5 (en) |
| DE (1) | DE3327705A1 (en) |
| DK (1) | DK361983A (en) |
| ES (1) | ES8502992A1 (en) |
| FI (1) | FI73679C (en) |
| FR (1) | FR2531433B1 (en) |
| GB (1) | GB2125041B (en) |
| GR (1) | GR78923B (en) |
| HU (1) | HU187600B (en) |
| IL (1) | IL69450A (en) |
| IT (1) | IT1168961B (en) |
| MY (1) | MY8700166A (en) |
| NL (1) | NL8302776A (en) |
| NZ (1) | NZ205181A (en) |
| PH (1) | PH20385A (en) |
| PT (1) | PT77168B (en) |
| SE (1) | SE8304315L (en) |
| ZA (1) | ZA835850B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4675322A (en) * | 1984-12-10 | 1987-06-23 | Eli Lilly And Company | 1-Substituted-6-n-propyl-8β-methylthio-methylergolines |
| HU193782B (en) * | 1985-06-21 | 1987-11-30 | Richter Gedeon Vegyeszet | Process for producing 2-halogeno-nicergoline derivatives and acid additional salts thereof |
| FR2589734B1 (en) * | 1985-11-13 | 1988-09-02 | Roussel Uclaf | USE OF ERGOLIN DERIVATIVES FOR OBTAINING A GERIATRIC MEDICINE |
| 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 |
| DE3913756A1 (en) * | 1989-04-21 | 1990-10-25 | Schering Ag | 8 (BETA) SUBSTITUTED ERGOLINE, METHOD FOR THE PRODUCTION AND USE THEREOF |
| DE10212564B4 (en) * | 2002-03-12 | 2007-04-19 | Neurobiotec Gmbh | 1-Allyl ergot alkaloid derivatives and their use for the prophylaxis and treatment of migraine |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE41533B1 (en) * | 1974-03-14 | 1980-01-30 | Sandoz Ltd | Thiomethyl ergolene derivatives |
| US3901894A (en) * | 1974-06-06 | 1975-08-26 | Lilly Co Eli | 8-thiomethylergolines |
| US3959288A (en) * | 1974-12-13 | 1976-05-25 | Eli Lilly And Company | 8-Oxymethylergolines and process therefor |
| 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 |
-
1982
- 1982-08-09 CH CH4772/82A patent/CH649998A5/en not_active IP Right Cessation
-
1983
- 1983-08-01 DE DE19833327705 patent/DE3327705A1/en not_active Withdrawn
- 1983-08-02 FI FI832789A patent/FI73679C/en not_active IP Right Cessation
- 1983-08-04 FR FR8313018A patent/FR2531433B1/en not_active Expired
- 1983-08-05 BE BE1/10847A patent/BE897473A/en not_active IP Right Cessation
- 1983-08-05 GB GB08321222A patent/GB2125041B/en not_active Expired
- 1983-08-05 NL NL8302776A patent/NL8302776A/en not_active Application Discontinuation
- 1983-08-08 AT AT0286383A patent/AT383125B/en not_active IP Right Cessation
- 1983-08-08 SE SE8304315A patent/SE8304315L/en not_active Application Discontinuation
- 1983-08-08 GR GR72165A patent/GR78923B/el unknown
- 1983-08-08 IL IL69450A patent/IL69450A/en unknown
- 1983-08-08 ES ES524815A patent/ES8502992A1/en not_active Expired
- 1983-08-08 PT PT77168A patent/PT77168B/en unknown
- 1983-08-08 HU HU832798A patent/HU187600B/en unknown
- 1983-08-08 AU AU17672/83A patent/AU563736B2/en not_active Expired - Fee Related
- 1983-08-08 CA CA000434064A patent/CA1215972A/en not_active Expired
- 1983-08-08 DK DK361983A patent/DK361983A/en unknown
- 1983-08-08 NZ NZ205181A patent/NZ205181A/en unknown
- 1983-08-08 JP JP58144843A patent/JPS5948480A/en active Pending
- 1983-08-09 PH PH29378A patent/PH20385A/en unknown
- 1983-08-09 ZA ZA835850A patent/ZA835850B/en unknown
- 1983-08-09 IT IT22490/83A patent/IT1168961B/en active
-
1987
- 1987-12-30 MY MY166/87A patent/MY8700166A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2531433B1 (en) | 1985-10-18 |
| SE8304315D0 (en) | 1983-08-08 |
| GB2125041B (en) | 1986-04-23 |
| DE3327705A1 (en) | 1984-02-09 |
| ATA286383A (en) | 1986-10-15 |
| FI832789A0 (en) | 1983-08-02 |
| ES524815A0 (en) | 1985-02-01 |
| IT1168961B (en) | 1987-05-20 |
| FI73679B (en) | 1987-07-31 |
| PH20385A (en) | 1986-12-08 |
| HU187600B (en) | 1986-01-28 |
| MY8700166A (en) | 1987-12-31 |
| ZA835850B (en) | 1985-03-27 |
| AT383125B (en) | 1987-05-25 |
| IL69450A0 (en) | 1983-11-30 |
| CH649998A5 (en) | 1985-06-28 |
| FR2531433A1 (en) | 1984-02-10 |
| IL69450A (en) | 1986-10-31 |
| DK361983D0 (en) | 1983-08-08 |
| ES8502992A1 (en) | 1985-02-01 |
| SE8304315L (en) | 1984-02-10 |
| NZ205181A (en) | 1986-07-11 |
| IT8322490A0 (en) | 1983-08-09 |
| PT77168A (en) | 1983-09-01 |
| JPS5948480A (en) | 1984-03-19 |
| GB2125041A (en) | 1984-02-29 |
| GR78923B (en) | 1984-10-02 |
| AU563736B2 (en) | 1987-07-23 |
| NL8302776A (en) | 1984-03-01 |
| PT77168B (en) | 1986-03-27 |
| DK361983A (en) | 1984-02-10 |
| FI73679C (en) | 1987-11-09 |
| AU1767283A (en) | 1984-02-16 |
| FI832789A (en) | 1984-02-10 |
| BE897473A (en) | 1984-02-06 |
| GB8321222D0 (en) | 1983-09-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |