Note: Descriptions are shown in the official language in which they were submitted.
The invention is related to l-substituted N-~8~-
ergolinyl7-N',N'-diethylureas of the general formula (I):
~ ,~NHCON[C2H~72
2 ~ _ Rl (I~
R
5 wherein Rl represents a lower alkyl group having 1 to 4
carbon atoms and
R represents a lower alkyl group having 1 to 4
carbon atoms, a benzyl group, an allyl group or a
group of general formula - CcH2-7ncooR3~ where R3
stands for a hydrogen atom or an alkylgroup having
1 to 2 carbon atoms and n is an integer of from 1 to 4,
and to a process for their preparation.
It is known that 1-unsubstituted 8a-ergolinyl-
N',N'-diethylureas of the general formula II presented
below, for example N-~-6-methyl-8a-ergolinyl7-N',N'-
diethylurea (Czechoslovak Author's Certificate no. 152 153)
and 6-propyl analogue thereof, exhibit on animals strong
inhibiting effect on secretion of prolactine and growth
hormone and stimulative effect on secretion of gonadotro-
pins. Authors of this invention have now found that also
l-substituted derivatives of these ureas of the general
formula I are strong inhibitors of prolactine secretion on
experimental animals.
-~r
.. -- 1 --
lZ03~,
8~-Ergolinylureas of the general formula I contain
in the molecule, three asymmetric carbons in positions 5,8
and 10, spatial arrangement of which is the same as for the
D-9,10-dihydroisolysergic acid - I: hydrogen at C/5~ has a
~-position (configuration at this carbon is 5R), urea
residue at C/8/ is in ~-position (configuration at this
carbon is 8S) and hydrogen at C/lo/ is in ~-position (con-
figuration at this carbon is lOR).
According to the invention the l-substituted 8~-
ergolinylureas of the general formula I can be produced inthe way that in position 1 unsubstituted 8~-ergolinyl-N',N'-
diethylurea of the general formula (II):
H ,NHCON[C2H ~ 2
~ ~H ~II)
H
wherein Rl has the above meaning, is reacted with alkylating
agent of the general formula (III):
R2 _ X (III)
wherein R2 has the meaning presented in general formula I
and X represents a halogen atom or a residue of ester-bound
aliphatic or aromatic sulfonic acid or a residue of ester-
bound sulfuric acid.
Starting compounds of the general formula II can
be prepared by known processes and according to the above
mentioned references.-
Alkylation of compounds of the general formula II
is performed according to the present invention by the
-- 2 --
1~3S31
action o 1 to 5 molequivalents of alkylating agent of the
general formula II with a solution of compound of the
-general formula II in an inert solvent in the presence of
a base for binding liberated acid at a temperature ranging
from -40 to +50C.
As an alkylating agent of the general formula III,
alkylhalogenides can be used, preferably iodides or alkyl
bromides, allyl bromide, benzyl bromide or ~-bromoalkanoic
acids and esters thereof of alkyl esters of sulfuric acid
such as dimethylsulphate or diethyl sulfate, or esters of
aliphatic or aromatic sulfonic acids, for example alkyl-
methane sulfonates or alkyl-p-toluene sulfonates.
As an inert solvent polar aprotic solvents can be
used such as dimethylformamide, dimethylsulfoxide, hexa-
methyltriamide of phosphoric acid or acetone, or liquid
ammonia.
As a base for binding released acid, strong bases
can be used, for example sodium or potassium amide, lithium
diisopropylamide, sodium methylate or sodium or potassium
hydroxide. Especially advantageous process for preparation
-of compounds of the general formula (I) consists in alkylat-
ing of compounds of the general formula (II) with alkyl
halogenides in a medium of liquid ammonia in the presence
of sodium amide or potassium amide prepared in situ in the
existing medium. The originated compounds of the general
formula (I) can be isolated from the reaction mixture using
common separating and isolating methods, for example by
evaporating the solvent and by chromatography and/or by
crystallization of the crude products thus obtained.
l-substituted N-L8~-ergoliny~7-N',N'-diethylureas
of the general formula (I) are colourless crystalline com-
pounds of basic character which yield addition salts with
strong inorganic and organic acids. For therapeutic
purposes water-soluble salts with pharmaceutically accept-
3 --
1203531
able nontoxic acids are suitable, such acids as hydrochloric,
sulfuric, methane sulfonic, ethane sulfonic, maleic, malic,
tartaric, citric and similar acids. The salts named can be
prepared by the reaction of at least 1 molequivalent of the
acid with 1 molequivalent of the compound of the general
formula (I) in a suitable inert solvent, preferably in
methanol, ethanol, acetone, water of in mixtures thereof.
The compounds of the general formula (I) are
significant inhibitors of secretion of prolactine and growth
hormone and stimulators of secretion of gonadotropins on
animals, affect the physiological and pathological processes
controlled by the named hormones and exert dopaminergic
action on the physiological and pathological dopamine-
receptor controlled functions. They can be therefore used
in human and veterinary therapy for suppression of the
levels of prolactin and growth hormone, for example in
medical treatment of hyperpropactinemies, acromegaly and
parkinsonism or they can be used for enhancement the levels
of gonadotropins, for example at inducing estrus to mammals
and for inducing laying of eggs to birds.
The process for producing l-substituted 8a-
ergolinylureas of the general formula (I) is further eluci-
dated by the following examples of embodiment which never-
theless do not limit the scope of the invention. Melting
temperatures of the compounds were determined using the
Kofler stage and they are presented, as well as other tem-
perature data, in C. The values of specific rotation are
related to compounds free of crystal solvent.
- Example 1
N-L~-1,6-Dimethyl-8a-ergolinyl~-N',N'-diethylurea
0.225 g (4 mmoles) of powdered potassium hydroxide
- is added to a solution of 0.34 g (1 mmole) of N-~D-6-methyl-
8a-ergolinyl7-N',N'-diethylurea in 20 ml of anhydrous
acetone, the mixture is stirred 10 minutes at 23 to 26C
-12~1
and 0.284 g (2 mmoles) of methyl iodide is then added drop-
wise at the same temperature. Reaction mixture is stirred
2 hours at room temperature, further 0.284 g (2 mmoles) of
methyl iodide are then added and the mixture is stirred
three more hours. Inorganic fraction is filtered off,
solvent is distilled out from the filtrate under reduced
pressure, evaporation residue is taken off into a mixture
of chloroform and water, organic fraction is dried with
anhydrous sodium sulfate and the solvent is distilled off
under reduced pressure. Crude product (0.4 g) is purified
using column chromatography at silica gel using a mixture
of chloroform and ethanol (95:5) for elution of the com-
pounds and united homogeneous fractions are recrystallized
from acetone after evaporation of the solvents. The so
desired compound is obtained (I, Rl=R2=methyl) in the form
of colourless crystals having m. p. 136 to 138C, specific
rotation ~]D = +24.4 [c = 0.2, pyridine~.
Example 2
N-L~ Methyl-6-n-propyl-8~-ergolinyl7-N',N'-diethylurea
Approximately 10 mg of iron III nitrate is added under
mixing to a solution of 62.4 mg (2.715 mmoles) of sodium in
approximately 100 ml of liquid ammonia and after decolour-
izing the solution 500 mg (1.357 mmoles) of N-CD-6-propyl-
8~-ergoliny~7-N',N'-diethylurea is added to the originated
suspension of sodium amide. After dissolution of the urea,
approximately after 30 minutes, 385 mg (2.715 mmoles) of
methyl iodide is added dropwise and the reaction mixture is
stirred for 1 hour at the boiling point of ammonia. Ammonia
is then evaporated, evaporation residue is taken off into a
mixture of chloroform and water, chloroform fraction is
washed with water, dried with anhydrous sodium sulfate and
the solvent is distilled off under reduced pressure. Crude
product (0.55 g) yields after recrystallization from acetone
the so desired compound; (I, R2 = methyl, Rl = propyl) in
lZO~l`' "
the form of colourless crystals havin~ m. p. 117 to 119C;
~]D = +26.3 rc = O.2, pyridine~7.
Example 3
N-L~D-l-Methyl-6-ethyl-8~-ergolinyl7-N',N'-diethylurea,
m. p. 103 to 105C, C~]20 = +26.3 L~ = 0.2, pyridine~7, and
N-rD-l-methyl-6-butyl-8~-ergolinyl~-N',N'-diethylurea,
m. p. 75 to 77C, ~DO = +32.9 [c = 0.2, pyridine7, are
prepared by the same process as in the Example 2 with the
difference that equimolar amounts of N-[D-6-ethyl-8~-
ergolinyl~7- or N-L~-6-butyl-8a-ergoliny y N',N'-diethyl-
ureas are used instead of N-L~D-6-propyl-8~-ergolinyl~-
N',N'-diethylurea.
Example 4
N-L~-l-Ethyl-6-propyl-8a-ergolinyl7-N',N'-
diethylurea, m. p. 85 to 85C, C~20 = +30 4O ~c = 0.2,
pyridine~, and N-L~-1,6-dipropyl-8~-ergolinyl~-N' ,N'-
diethylurea are prepared by the same process as in the
Example 2 with the difference that equimolar amounts of
ethyl iodide or propyl bromide are used instead of methyl
iodide.
Example 5
Following compounds:
N-L~-l-ethyl-6-methyl-8~-ergolinyl7-N',N'-diethylurea,
m. p. 124 to 126C, C~]DO = +20.5 L~c = 0.2, pyridine~;
N-cD-l-propyl-6-methyl-8~-ergolinylJ-N~,N~-diethylurea,
m. p. 63 to 66C, ~DO = +21.9 Cc = 0.2, pyridinç7;
N-[D-l-butyl-6-methyl-8~-ergolinylJ-N~,N~-diethylurea;
N- @-l-allyl-6-methyl-8~-ergolinyl~7-N',N'-diethylurea,
m. p. 82 to 84C; ~D0 = +18,0 [c = 0.2, pyridin~7;
N- CD-l-benzyl-6-methyl-8~-ergoliny y -N',N'-diethylurea,
m. p. 167 to 169C, ~]DO = +15.0 L~c = 0.2, pyridine~7; and
N-Lp-l-ethoxycarbonylmethyl-6-methyl-8~-ergolinyl~-N',N'-
diethylurea, m. p. 57 to 59C, [~ D0 = +17,0 E = 0,2,
pyridin~7 are prepared by the same process as in the
-- 6 --
:~53~.
Example 2 with the difference that equimolar amounts of
N-L~-6-methyl-8~-ergolinyl~ -N',N'-diethylurea is used
instead of N-~p-6-propyl-8~-ergoliny Y -N',N'-diethylurea
and that equimolar amounts of alkyl bromides, allyl bromide,
benzyl bromide or ethyl bromoacetate are used.
-- 7 --
