ALCALOIDES DE L'ERGOT

ERGOT ALKALOIDS

Abrégé anglais

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.

Revendications

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CLAIMS
1. A process for the preparation of a compound of formula I
<IMG> 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
<IMG> II
wherein R1 and R2 are as defined above, and

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Y is a leaving group,
with a compound of formula III
MXR3 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.

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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.

Description

~5~7;2
100-5863
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~
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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
1 1
Rl-N CH3
wherein Rl and R2 are as defined above, and
Y is a leaving group,
with a ~ompound of formula III
MXR3 III

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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.
, ~

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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
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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 ~ . .~ .
.~ . ,,

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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

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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
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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)

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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.

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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.

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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 /

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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.

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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.