ERGOLINE DERIVATIVES, THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS THEREOF

DERIVES DE L'ERGOLINE, PRODUCTION ET COMPOSES PHARMACEUTIQUES LES CONTENANT

English Abstract

100-5555
Abstract
A compound of formula I
<IMG> I
in which R1 is H,(C1-4)alkyl or a precursor thereof,
R2 is (C1-4)alkyl,
R3 and R4 independently are H, (C1-4)alkyl or together (C2-5)-
alkylene,
R5 is H or alkyl, and
A and B each are H or both together are a bond
with the proviso that, when R1 and R2 are each CH3,R3
and R4 are each C2H5 and A and B are each H, then R5
is alkyl in free base form or in pharmaceutically
acceptable acid addition salt form.
The compounds are used in the treatment of hypertension and cardiac
insufficiency.
3700/KD/MR

Claims

-19-
Claims:
1. A process for the production of a compound of formula I
<IMG> I
in which R1 is H, (C1-4)alkyl, or a precursor thereof,
R2 is (C1-4)alkyl,
R3 and R4 independently are H, or (C1-4)alkyl or
together (C2-5)alkylene,
R5 is H or alkyl, and
A and B each are H or both together are a bond, with the
proviso that, when R1 and R2 are each CH3,R3
and R4 are each C2H5 and A and B are each H,
then R5 is alkyl,
and pharmaceutically acceptable salts thereof,
which includes the step of
a) oxidizing a compound of formula II
<IMG> II

- 20 -
wherein R1 to R4 and A and B are as defined above, and R6 is
hydrogen or hydroxyl,
or a precursor thereof,
to produce a compound of formula I wherein R5 is hydrogen,
or
b) alkylating a compound of formula I wherein at least one
of R1, R3, R4 and R5 is hydrogen, or a precursor
thereof,
to produce the corresponding compound wherein at least R1
is (C1-4)alkyl, CH2OH or (C1-22)alkanoyloxymethyl and/or at
least R3, R4 and R5 is (C1-4)alkyl, and when required,
converting a resultant formula I compound into another
formula I compound, and when a pharmaceutically acceptable
acid addition salt is required, reacting the free base
obtained with a corresponding acid.
2. Ergoline derivatives of formula I
<IMG> I
in which R1 is H, (C1-4)alkyl, or a precursor thereof,
R2 is (C1-4)alkyl,
R3 and R4 independently are H, or (C1-4)alkyl or
together (C2-5)alkylene,
R5 is H or alkyl, and
A and B each are H or both together are a bond, with the
proviso that, when R1 and R2 are each CH3,R3
and R4 are each C2H5 and A and B are each H,
then R5 is alkyl,

- 21 -
and pharmaceutically acceptable salts thereof, whenever
produced by the process of claim 1 or an obvious chemical
equivalent thereof.
3. A process for producing 1,1-dimethyl-3-(12-hydroxy-
6-methyl-9,10-didehydro-ergolin-8.beta.-ylmethyl)urea or a
pharmaceutically acceptable salt thereof, which comprises
oxidizing 1,1-dimethyl-3-(12-hydroxy-6-methyl-2,3.beta.-dihydro-
9,10-didehydro-ergolin-8.beta.-ylmethyl)urea and when the salt is
required, reacting the free base with a corresponding acid.
4. The compound 1,1-dimethyl-3-(12-hydroxy-6-methyl-9,10-
didehydro-ergolin-8.beta.-ylmethyl)urea or a pharmaceutically
acceptable salt thereof, whenever produced by the process
of claim 3 or an obvious chemical equivalent thereof.
5. A process according to claim 3 wherein the product
obtained is reacted with a methylating agent to produce
1,1-dimethyl-3-(12-methoxy-6-methyl-9,10-didehydro-ergolin-
8.beta.-ylmethyl)urea, and when a pharmaceutically acceptable
salt is required, reacting the free base obtained with a
corresponding acid.
6. The compound 1,1-dimethyl-3-(12-methoxy-6-methyl-9,10-
didehydro-ergolin-8.beta.-ylmethyl)urea, or a pharmaceutically
acceptable salt thereof whenever produced by the process
of claim 5 or an obvious chemical equivalent thereof.

Description

~178~
100-5555
NEh' ERGOLINE DERIVATIVES~ THEIR PRCDUCTION AND PHARMACEU-
TICAL COMPOSITIONS THEREOF
. . .
This invention relates to ergoline derivatives, their pro-
duction and pharmaceutical compos;tions containing them.
German Offenlegungsschrift No 1910~30 discloses a very
broad class of N-acyl-N-(12-hydroxy-1,6-dimethylergol-in-
8-yl-methyl)amino der;vatives, which are stated to be
especially clinically useful in the treatment of migraine,
trigeminal neuralgia, general allergies and inflanllnation
disorders as indicated by antagonism of serotonin. A wide
variety of acyl derivatives are specifically suggested.
One such acyl derivative is the derivative from diethyl
carbamin;c acid. No other carbaminic derivatives are
specifically suggested. There are only 5 characterised
examples, but none of these are carbaminic acid deriva-
tives. We have now found that the ergoline derivatives
encompassed by the following formula I which are nowhere
specifically mentioned or suggested by the above German
Offenlegungsschrift possess especially interesting anti-
hypertensive activity as indicated by e.g. potency in the
tests hereinafter.
The present invention provides compounds of formula I
H R
CH2-N-C-N~
n ~ n ~R
~R5 ~ 4
.. ~'
.

-2- 100-555
in which Rl is H (C.l 4)alkylror A precursor thereof
R2 i5 (C~ -4)al kyl,
P~3 and R4 independently are H or (Cl_4)~1kyl o~ to-
gether are (C2 5)alkylene
R5 is H or alkyl and
A and B each are H or both toge~ller are a bond
with the proviso ~nat .~en "~1 and R~ are
each CH3 R3 and R~l a~e each C~H~ and A and
B are each H~ then R5 is alkyl
hereinafter referred to as compounds of the inYention.
As precursors in position 1 are meant such substituents
15 which under physiologically conditions may be converted into
the other indicated signi-ficances of Rl particularly il.
Such substituents are e.9- CH20H (Cl 22)alkanOyloxymetnyl
or acetyl. R5 if alkyl contains preferably 1~20 especial-
ly 1-4 carbon atoms. Preferred substituents in the com-
20 pounds of formula I are Rl = H (Cl 4)alkylg CH20~ or(Cl 4)alkanoyloxymethyl R3 = H or (Cl 4)alkyl P~4 =(C1_4)
alkyl and/or R5 = H or (C1 4)alkyl.
These preferences are especially combined togetherg A and
B preferably form together a bond.
25 Especially preferred substituents are individually or
combined Rl = H R2 = CH3 R3 = CH3s R4 3 5
or CH3 especially CH3.
A group of compo~lnds com,)rises the compounds of formula Ia

~l d ~ p) r ?~
H / R3a
CH ~N-C -N
0 ~ R4a
Ia
EIN
in which R2 is as defined above, R3a and R4a are independen~ly
(Cl 4~ alkyl and R5a is H or CH3.
Another group of compounds comprises compounds of formula I
wherein when Rl and R2 are each CH3, R3 and R4 are each
(Cl 4)alkyl and A and B are each H, then R5 is alkyl.
The present invention in another aspect provides a process for
the production of a compound of the invention, which includes
the step of
a) oxidizing a compound of formula II
H ~R3
c~2-N-C-N ~R
B~ ~ II
--R2
RlN
wherein Rl to R4 and A and B are as defined above, and
R6 is hydrogen or hydroxyl,
or a precursor thereof,
to produce a compound of formula I wherein R5 is hydrogen, or

li78582
-4- 100-5555
b) alkylating a compound of formula I wherein at least
one of Rl,- R3, ~4 and R5 is hydrogen~or a precursor
to produce the corresponding compound wherein at least
5 Rl is (Cl_4)alkyl, CH20H or (Cl_22)alkanoyloxymethyl and/or
at least R3,~ and R5 is alkyl and if desired converting a
resultant formula ~ compound into another fonmula I~compound . ~
The oxidation according to process a) may be effected in
conventional manner for the introduction of a double bond
into the 2,3 position, and when R6 is hydrogen for the
lOintroduct;on of a hydroxyl ~roup in the 12 position of
the ergoline nucleus. When R6 is hydrogen if desired the
oxidation may be effected simultaneously or in two stages,
one stage being the introduction of the hydroxyl group and
the other stage being the introduction of the double bond.
15The introduction of the 2,3 double bond may be effected in
conventional manner for the conversion of indolines into
the corresponding indoles, e.g. by passing a stream of air
through a solution of the compound. The reaction may be
effected at room temperature..
20The ;ntroduction of the hydro~yl group may be effected wi~h
an appropriate oxidizing agent such as a nitrosodisulphonate,
e.g.in the form of the potassium salt. Generally such reac-
tions also lead to the introduction of the double bond in
the 2,3 position (see Helv.Chim.Acta, 756-769,1964).
25The reactionis preferably effected with the nitrosodisulphonate in
an aqueous~medium at a pH about 3 to about 9,preferably at pH of about 7.
The ergoline may be di~solved in an organic solvent,e.g.chloro-
form, and the system stirred rigorously. The reaction tem-
- perature may be for example from about O~C to abcut 50C.

~.~i7~2,
-5- 100-5555
If there is a group present e.g. CH20H in the 1 position
of the ergoline nucleus, then R6 is preferably hydroxy.
Preferably such groups are introduced after the oxidation
reaction.
The alkylation process b) may be effected in conventional
manner,using appropriate alkylating agents to alkylate
the appropriate group. The term alkylation includes not
only the introduction of unsubstituted alkyl rad;cal but
- also the introduction of CH20H and alkanoyloxymethyl. Where
selective alkylation is required, it may be desirable to
10 block temporarily other reactive groups present.
- Etherification of the hydroxy radical may be effected with
a diazoalkane,e.g. diazomethane. Introduction of the CH20H
radical in position 1 may be effected with formaldehyde.The
CH20H radical may be subsequen~ly acylated with for example
15 an acid halide.
The compounds of formula II wherein R6 is hydrogen are known
or may be prepared in conventional manner.Some compounds of
formula II wherein R6 is hydrogen hereinafter referred to as
compounds of formula III are in general new and may be pre-
20 pared e.g. as described in the following reaction schemeand exemplified for compounds III in which Rl is hydrogen.

5~2
_6 - 1 00-5555
\/ \/
~ T--- ~
I ~ ~ ~
c~ ~ ~ n~ ~ c~
\z/ 2 \~/
Z CC 3
.~, ','-, ~
C
~ ~ C C E
\ / c~ ~ 3 E ~,
N 2

-7- 100-5555
In the reaction scheme R2 to R4 are as defined above.The
several reaction steps are described in extenso in example
1 for the production of a 9,10-didehydro-ergoline compound
of the invention.
The cornpounds of formula I in which R5 is hydrogen may be
converted into other compounds of formula I in conventional
manner,e.g.they may be alkylated or, for the production of
the above mentioned precursor groups,acetylated or formy-
lated in position 1 and the formylated products preferably
10 acylated. The compounds may be optionally alkylated in the
ureamethyl radical and hydrogenated in position 9,10.
The etherification of the 12-hydroxylated product may be
effected in conventional manner for the synthesis of ana-
logous phenol-ethers.
- 15 The alkylation may be effected in conventional manner.The
acetylation and the formylation which may be carried out
conventionally by reaction with ketene, and with formal-
dehyde and an acid respectively.
The acylation of a CH20H radical in position 1 formed by
20 formylation may also be effected by kno~n metllods,e.g.
with an acid halide. Other precursor groups in position 1
may be produced in conventional manner.
The hydrogenation may be carried out in conventional manner,
particularly by catalytic hydrogenation,e.g.with Pd-C as a
25 catalyst.
The compounds of formula I may be recovered in,for example,
free ba~e form or ac;d addition salt form.
The acid addition salt forms of a compound of formula I may
be produced in conventional manner from the free base forms
30 and vîce versa. Suitable acids include fumaric acid and
hydrochloric ac;d.

358~
-8- 100-5555
If compounds of formula I are to be prepared in which one
or more of the subst;tuents are (C1 4)alkyl or A and B
are H, the required alkylation or hydrogenation in posi-
tion 9,10 may occur either before or after the formation
of the 12-hydroxy radical. Precursors of Rl are pre-
ferably introduced after the introduction of the hydroxyl
group.
, ' ' .
;

d ~ 2
-3- 100-5555
x a m p l e 1 `~ dimethyl-3~(12~hydroxy 5-n1ethyl-,10-dt-
yl -methyl )urea
a) l~l~dimeth~1-3~ acetyl-6-methvl-2 3B-dih~dro~9 710-di-
del~dro~er~olin~ eth~ rea
14 ml of triethylamine are added to a suspension of 13 9
(35.8 mM) of 1 l-di1~ethyl-3$(6-Methyl-2 3B-dihydro-9 10-
didehydro~er~olin-8~-ylmethyl)urea-hydrochloride ln
300 ml of absolllte methylene chloride. When the substrate
has dissolved~a solution of 3 6 ml (50.7 mM) of acetyl
chloride in 20 ml of ab,olute methylene chloride is added
in drops at 10 - 15 and the solution is stirred for
1 hour at room temperature. It is subsequently poured
onto water/ice then 20 ml of saturated ~HC03 solution
are added and the solution is extracted twice with me-
thylene chloride which contains S% isopropanol. The
combined organic phases are dried with sodium sulphate
filtered and evaporated on a rotary evaporator. After
drying in a high vacuum the title connpound in free base
form is obtained in the form of a yellow-brown foam.The
hydrogen fumarate of the title compound is obtained and
crystallised from 2-butanone/water/methanol (5:3:2).M.p.:
decomposition froln 135 [a~20 = + 36 [c = 0.355 in
ethanol/water (1:1)].

.10- 100_5555.
b) l,l~dimethx~3-~1-acet~ -6-~eth~ 12-nitro_2,3~-dii!ydro~
9,10-dideh~Jdro-er~olin-8~-~lmethyl~urea
_______ - __ _Y_ ____~ ____ . ___
1~45 ml (35 mM) of nitric acid (100%) are added in drops
at 10 over the course of 3 minutes to a solut1On of 13 9
(35 mM) of the crude iiase obtained under a) in 80 ml of
sulphuric acid (100%), the solution being maintained in an argon
atmosphere. After stirring for 20 minutes at room tempe-
rature, the solution is poured onto ice, set to a pi-l of
8 with 10 N sodium hydroxide at a temperature of 5 - 10,
and extracted with methylene chloride which contains 10~
isopropanol~ The organic phases are combined, dried with
sodium sulphate, Filtered and dried on a rotary evaporator.
After drying in a high vacuum, the title compound is ob-
tained, and this can be reduced further without purifi-
cation.
c) 1 Ll -dimethyl-3-(1-acetyl-12-amino-6-meth~1-2,3i3-dihydro-
9,10-dideh~dro-eroolin-8B-vlmethvl~urea
________-- __ _ ~______ _~___ _ _ _
A solut;on of 13.5 9 (32.7 mM) of 1,1-dimethyl-3-(1-acetyl-
6-methyl-12-nitro-2,3~-dihydro-9,10-didehydroergolin-
8~-ylmethyl)urea in 300 ml of ethyl acetate and 100 ml
of methanol is hydrogenated under normal conditions in
the presence of 1.5 9 of palladium on carbon (10%) until
the calculated amount of hydrogen has been absorbed.
The mi>ture is filtered and evaporated.The resultant crude
product is sub~iected to chromatography on 300 9 of
silicagel with methylene chloride containing 15% methanol
and 0.5% aqueous ammonia,obtaining the title compound.

11- 100-5555
d) l,l-dimeth~1-3-(12-hyc!rox~-6-lneth~l-9~10-didehydro-
_____ _ ___ _ __. _ ., _ _ _ ____
ergolin-8~-ylmeth~llurea
A solution of 4.5 9 (11.7 mM) of the product obtained
under c) in 100 ml o' 1 N HCl is heated with stirring
for 17 hours to 95. l~ith cooling by ice, the solution
is subsequently adjusted to at a pH of 7 ~ith concen-
trated ammonia solution, and is extracted 4 times with
methylene chloride which contairls 10~ isopropanol. The
combined organic phase are dried w-ith sodium sulphate,
filtered and evaporated in a rotary evaporator. The
residue of evaporation, l,l-dimethyl-3-(12-hydroxy-
6-methyl-2,3~-dihydro-9,10-didehydro-ergolin-8~-ylmethyl)
urea, is dissolved in 10 ml of ethanol. After adding 1
ml of concentrated ammonia solutioll, air is blown
through the solution for 1 hour. After evaporation,
the crude product is subjected to chromatoyraphy on
100 9 of silicagel, with methylene chloride containing
10~ methanol and 0.2% ammonia solution. The title com-
pound in free base form is obtained as a beige residue.
In order to produce the hydrochloride, the base ob-
tained is dissolved in methylene chloride/methanol
(1:1), then 2.94 ml (5.9 mM) of 2 N HCl are addecl, and
concentration follows in a rotary evaporator until
crystallisation commences. The hydrochloride of the
title compound is obtained as beige crystals.
M.p.: decomposition from 220C, ~a]20 = + 126.2
[c = 0.435 in ethanol/water (1:1)].

1 00-5555
E)~AMPLE 2~ dimethyl-3-~12-methoxy-6-methyl-9,1a-didehydro
... .. _ _. _ .. . _ _ _ . _
-er~olin-8~-~lmeth~1~urea
200 ml (about 71.5 mM) of an approximately 1.5,c ethereal diazo-
methane solution kept in an argon atmosphere are carefully poured
into a solution wllich i5 cooled to -15~ of 5 ml of 0.08 N methanolic
tetrafluoroboric acid in 150 ml of methanol, and 2.55 9 ~7.5 m,'~)
of the base obtained under ld). Stirring is subsenuently effected for
20 hours at room temperature and in an argoll atmocphere. rhe pro-
cess is finished by concentrating the mixture to ahout 20~ of the
original volume under a water-jet vacuum, arld concentrating further
in a rotary evaporator. After the addition of 50 ml of ethar,ol and
1 ml of concerltrated ammonia solution, concentration is again
effected, and the residue is subjected ~o chrolnatography on 120 9
of silicagel with methvlene chloride, containing 10~ methanol and
0.2% concentrated ammonia solu~ion. The title compound is obtained
as in free base form, wilich crystallises from acetone. '~l.p.:
decomposition from 180; [~]20 - ~- 85~ [c = 0.450 in methanol~.
EXAMPLE 3: 1,1 dimethyl-3-~12-hydroxy-6 methyl-9,10-dideh~dro-
ergol~n-8~-yllne-thyl~urea
A solution of 3.0 y (9.2 mM) of l~l-dinlethyl-3-(~6-lnethyl-2~3~-dihydro-9~lQ
didehydro-eryolin-8~-ylmethyl)urea in 46 ml of isopropanol and 165
ml of chloroform is added at room temperature, while stirring, to a
solution of 10.1 9 (37.7 mM) of potassium nitrosodisulphonate in
water, buffered with phosphate at pH 7Ø
The reaction mixture is stirred further at room temperature for 5
min., the organic phase is separated and the aqueous phase is extrac-
ted with isopropanol chloroform (5:18).
The collected organic phases are dried over sodium sulphate, fil-
traied and evaporated to dryness.

1178582
-13- 100-555~
The residue is chromatographed on silicagel with a mixture of me-
thylene chloride, methanol and ammonia (85:15:o.5), obtaining
the pure title compound.
The following compounds of formula I are produced wherein:-

~it~
-~ 4- 1~0~5555
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cn >' >' >' m m m m m ~ C
O o o o o o o o o o o o
C~ L~ O ~ I~ O O 00 L~
~ = c ~cr) o c ~ ~ ~ ~:
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1~> I I I I I 1: I I ~-
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_~ 5 100-5555
.
i~
, ~ ~ 'o C~ ~ ~
Cll Q' ~ o ON
~, , Cl ~ Cl __ ~i
..
.,
'

~ 3 5~3~
-16- 100-5555
In a 1st group of compounds Rl ;s H
" " 2nd " " " Rl is CH20H
~l 1' 3rd " " Rl is alkanoyloxymethyl
5 " " 5th " '' ' Rl is (Cl 4)alkyl
7th ~ ', ,, R3 is (cl_4)alkyl
9th '' '' '' R4 is (Cl 4)alkyl
" 11th " " " R5 is alkyl
" " 12th " " " A and B are together a bond
" " 13th " " " A and B both are H.

A.~ 1~3 !6
- 17 - lO0-5555
The compounds of the invention exhibit pharmacological activity
and are therefore indi-cated for use as pharmaceuticals.
In particular tney lead to a lowering of the blood pressure as
indicated in tests with the conscious spontaneously hypertensive
rat upon administration of from 0,OOl to 0,l mg/kg s.c.
In addition theJ lo~er blood r)ressure and decrease vascular
resistance in the anaesthetised,normotensive dog upon administration
of a dose of fronl 0,OOl to lO mg~g i.~, especially of frcin
0,OOl to 0,2 mg/i~g i.v,.
The compounds are iherefore indicated f-or use in t:~e t,eatment
lO of hypertension and cardiac insufficiency.
An indicated daily dosage is in the range ~I^Om about 0.2 to
about 300 mg, conveniently administered in divided doses 2
to 4 times a day or in sustained release form~ and dosage forms
suitable for oral administration compose from about O.û5 to about
l5 l50 mg of the compound, admixed witll a solid or liquid pharmaceu-
tic~l carrier or diluent. The compounds of Examples l and 2 are
particularly interesting, especially the compound of Example 2.

- 18 - 100~5555
compound of formula I may be adminlstered in free base or in
phar~aceutically accepta~le acid addition salt form. Such salt
forms exhibit the same order of activi-ty as the free base
forms.
The present inventi~on also provides a pharmaceutical composi~
tion comprising a compound of the invention in association
witll a pharmaceutical carrier or diluent.
Such compositions may be prepared by conventional techniques
to be in con~entional forms for example capsules or tablets.