Note: Descriptions are shown in the official language in which they were submitted.
0'76107
. ` ~ .,. j
, . .
- The preSent inVention relates to ergoline compounds
having pharmacological propertieS as well aS their preparation
~", and use.
. ;; -~. '
` ~ According to the preSent inVention there are provided ~
. I . .
'~ ergoline compounds having the following general formula:
. ,: -:
':`.',` CH2--RA . :`:
.,, ,J-- ~ .
N-CH3
~ ~ dal
,', R
' ~:;, ' :.: :'
: I . . .
~;i wherein the radicals R~ RA, X yj and Hal have the following
~' meanings: R
' ; a) RA=-C-N \ ~
2 '
in Which Rl and R2 in turn represent hydrogen; Cl ~ C8 alkyls, ~ -~
straight or branched; (C3-C12) alicyclic radicals; phenyl~ benzyl~
. :. ~ . .
phenethyl, substituted in the aromatic ring and/or in the aliphatic
20 ~ c hain with one or more groups selected amongst alkyls, alkoxyls,
a dioxymethylene groUp, hydroxyl~ halogens; Rl and R2 may be
S ~ ~ combined with each other as < R~
. '~.! R2~
to form one or more rings containing (C2~C12) members (e.g. to'
form a piperidino~ hexamethylenimono~ or azabicyclo [3,2,2]
nonane radical) or connected by chains containing also heteroatoms,
such as for example N ~ (CH2)n wherein Z represents
(CH2)n / 1 ~-
an oxygen atom, N-R3 (in which R3 iS H~ alkyl, phenyl aralkyl, etc.
andn = 2 --~ 4)~ to form heterocyclicgroups such ag morpholine~
piperazine;
~ . . .
.' ~ "'' ,`
1(~ 7
,;; `,
:, . ..
~, . .
....................... b) R = H~ Cl-C5 alkyl~ straight or branched;
~ . c) x y can be the radical -CH2-CH (in both the
possible stereoisomeric configurations) or the
radical -CH=C ; and
;. d~ Hal = Cl~ Br~ I.
. It has been found that the compounds having the
~ eneral formula (1) can be prepared starting from . :.
;;~. compounds having the following general formula :
'''1 ` ~ , ' `.
`` ~ x N-CH3
: : wherein R, RA, x'~~y have the above described meaning,
through the halogenation by means of a N-halo-acylamide~ ..
~: I particularly selected amongst N-bromo-acetamide~ ..
;~ N-bromdsuccinimide~ N-chlorosuccinimide~ N-iodosuccinimi.deg
or by means o derivatives of the type chlorobenzotriazole~
`~... in aprotic solvents~ such as dioxane~ tetrahydrofurane~
ethyleneglycol dimethylether~ diethyleneglycol~
dimethylether~ etc. at a temperature of between -10C
. ~. and ~150C.
The resulting halogenated compounds are isolated
and purified according to the commonly known chemi.cal
.............. ......... ....... methods~ for instance by crystallization or by chroma-
~ tography on a column packed with SiO2J A1203~ Fl~oris.i]~ ~ . etc The novel compounds obtained according to the
present invention are generally solid and cry.stalline
I at room temperature and form solid and almost always.
crystalline salts with acids.
The acids used for the preparation of these salts
. ~.. .
~ can be for example inorganic (hydrochloride~ hydrobromic~
.. I ,
3.
'I .
. : :
. ,
.
',, ~ '' `'" ~, .
7~ 7
- -'
- sulphuric acid ) or organic (e.g. maleic~ tartaricJ ;~methansulphonic acid ). ~-
;~ ` In the following exa~ples some general methods ''
'' for the preparation of the novel compounds of the in-
~ vention having general formula (l) are described.
; Furthermore there are listed the novel compounds pre~
' i pared according to the present invention to~ether with
their chemical and physical properties.
` The examples are intended only as illus~rating ''
-10 and not limiting the invention. ~'
,
'~ EXAMPLE
;' `l : . '
;` A solution of D-6-methyl-8beta~N~N-dimethyl-
carbamoyloxymethyl ~-9~ 10 didehydroergoline (1.0 g)
in anhydrous dioxane (60 mls) is supplemented~ under
' ~ ~ stirring and under nitFogen, at room temperature with
a solution of N-br~mosuccinimide ~0.7 g) in anhydrous
dioxane (20 mls.). The reaction mixture is heated to
' -65oC for 15 minutes~ then ~ooled to room temperature
and poured in a 2N water solution of Na2C03(120 mls ). ~ -
-20 ~ The result1ng solution is~extracte'd three times with ~ '
chloroform~ the combined extracte are washed with water
and dry evaporated at temperatures lower than 40-45C.
The residue is chromatographed over a deactivated'si'lica
' gel column (100 g) and the pure product~ as indicated
; - by the~roman number I'~in the~following list'o~ the~
' compounds prepared according to the inrention~ is eluted
with CH2Cl2 + 1% Q 30H and crystallized from ethyl ether.
- ¦ ~ EXAMPLE 2
To a solution of D-6-methyl-8beta-(perhydroazepinyl-
~ , 30 carbonyloxymethyl)-ergoline (2 g) in anhydro~us dioxane 5
'`' tl20 mls) there is added~ under stirring and under~nitrogen~
a solution of N-bromosucoinimide (1.12~g) in anhydrous
dioxane (50 mls). The reaction mixture is heated to '
. . I , .
75C and maintained at this temperature during 3'hours.
."~ . I . , , , ,
~ 4-
. I, - ~ ,.
'' ' I , :
, ,~
t
~ 76~ 7
f . ~ .
, ` .. .
.
It is then poured over a ice-water mixture~ alkalinized
with NH40H and extracted with chloroform. The extracts
are washed with water~ dried over Na2S04 and dry evapo-
rated. The product (II ) is obtained in pure form after
; chromatography on silica gel (150 g ) by elution with
CH2Cl2 + 1% MeOH-
,.. I - .
EXAMPLE 3
To a solution of D-6-methyl-8beta-(perhydroazepinyl-
- carbonyloxymethyl)-ergoline (2 g ) in anhydrous tetra-
hydrofurane (50 mls ) there is added at room tempera-
-~ ' ture a solution of N-chlorobenzotriazole in tetrahydro-
~ furane (20 mls). After 15 minutes the reaction mixture
;~ is poured in water~ alkalinlzed with NH40H and extracted
with ether. The extracts are washed with a saturated
NaCl solution and dry evaporated. The product (III )
is obtained in pure form after chromatography on SiO2
by eluting with CH2Cl + 0.5% MeOH.
According to the same method other compounds have
r been prepared~ which are contemplated in the scope of
i 20 the formula (l), as syntheticaily indicated in the
following Table l, in which :
- In the first column the starting compound is shown~
together with the related meaningsof the radicals
R~ RA and of the group x''~'y.
` - In the second column the reagent is shown~ by the
following abbreviations:
NBS = N-bromosuccinimide
.. ,~..<~
NB~ = N-bromoacetamide
~;~ NIS 5 N-iodosuccinimide
- In the third column the reaction conditions are
reported~ and more particularly :
, a ) the solvent~ by means of the following abbre-
I viations :
GED = ethyleneglycol dimethylether
~'
. ~, 5.
.`' ~ . ' ' .
~ ~ .
-: J
~ ' . ' ,
. .
.. . . .
()76~07
:
DX = dioxane
THF - tetrahydrofurane . :-.
. GDD - Diethylc-neglycol dimethylether ; :-.
; b) the reaction temperature (C)
c ) the reaction time (minutes) ~.
In the fourth column the reaction product is indi~
cated~ it being identified thro~lgh the meanigs of
. R, RA and of the x y group.
...Later on the chemical ~n~. pyisical characteristics
r ~ :,,.
and properties of the thus prepared products are listed~ ~:
10the Roman number correspondln~ to that of the correspond- ~:
;;~` ing Examples. . ~
:.: . . .... .
.. ..
: - . . :. .
; :
'.:'` :
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: ;.
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., ~ .,;
~ 30
.-
~ - 6 ~ ~
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107~107
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o $ ~ ~ ~ ~ ~ ~ ..
o o - U~ o
Fi~ ~ o t~
I U~ ~ ~ , 1~ X
~ ' ¢ l l .__._ ___ . _........ '
'~ C
I ~z; z; Z Z Z ~z; '', '
I _ .
1 X 1 1~ 1~
0 ~ 1 I ~, V ~C V V
`'' I ~\~Z-C~ 11~ > p
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~ 1~76107
.,...... . ~ . ~ .,
., . . -- , . - . .
. ;. S, ~ X ~ ~ ~ X ~X ~ . ~ X
... .
o O
0 ~ O ~ . L~ O O ~ g U~
X' ~ ~ X ~ X
~ Z Z Z ;~ Z Z; ~ Z Z Z I ~
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~ ~. r X ~ ' X' ~3 X ~ C X I ,". ~,. .
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: :. ' ". ' ' :. ~' , ~ ' ' ' ' '' ' -:'
. ; . : ~ : : . . ::
761~
I ) D-2-bromo-6-methyl-8beta-(N~N-dimethylcarbamoyloxy-
methyl)--9? 1~-didehydrohergoline m.p. 187-9C (ethyl
ether); / ~ 7D + 46~3 (c = 0~5~ C5H5N); M~(m/e )403~405.
For ClgH22N302Br (404~3)o calc.%C~ 56~44; Hs 5~48; N~10~39;
found %C~ 56~88; H~5~71; N~ 9~97; u.v. (MeOh ) ~ 302 rm
~ 11700)~ 242 nm ( 23000 ), 228 nm ( 21500)~ I.R.
(KBr ) 1675~ 1603 cm l.
~I ) D-2-bromo-6-methyl-8beta-(perhydroazepinylcarbonyl-
oxymethyl)-ergoline~ m.p. 182-4C (ethyl ether); j ~ 7
-87~oo (c = 0~5~ C5H5N); M~ (m/e ) 459~ 461. ~ ~ D
For C23H30N302B~`(460~4): calc- %C~ 60~0; H~ 6~57; N 9 13;
found %C~ 60~47; H~ 6~65; N~ 9~15; u.v. (MeOH ) 280 nm ( 9220 j~
227 nm ( ~ 32460)~ I.R. (KBr ) 1725~ 1680~ 1603 cm~l.
III ) D-2-chloro-6-methyl-8beta-(perhydroazepinyIcarbomyl-
oxymethyl )-ergoline~ m.p. 179-18~C (ethyl acetate)~
m.p. 215-18C (tartrate), / ~ 7 = 70,5 (c = 0~5 C H N)
(tartrate ); M~ 417~415. D ~ 5 5
For C23H30N302Cl (415~9): calc. %C~ 66~41; H~ 7~27; N~10~10;
found %C~ 66,50; H~ 7~07; N~9,49; u.v. (MeOH ) ~ 273
( 9380)~ 225 ( ~ 33200 )~ I.R. (KBr) 1690 cm~l.
IV) D-2-~romo-6-methyl-8beta-(N~N-dimethylcarba~o~oxymethyl )-
ergoline m.p. 232-234C (EtOAc); ~0~ 7 = -78 (0~5% in MeOH);
M~ 405-407. For C29H24N302Br (406~33): calc. %C~ 56~16;
H~5~95; N~ 10~34; found %C 56~22; H~ 6~13; N~ 9~96; u.v.
(MeOH ) A 282 ( 9700)g 226 ( ~ 34400 )j I~R. (KBr)
16?5~ 1607 cm~~
V) D-2-bromo-6-methyl-8beta-(N~N-diethylcarbamoyloxymethyl-
9~10-didehydroergoline maleate~ m.p. 185-187C; EtOH);
/C~-7D ~ 42 (c = 035 C5H5N ); M~ 433-431-
For C25H30N30~Br (548~49) calc. %C? 54~75; H~5s51; N~ 7~66;
found %C~ 54~77; H~ 5~44; N~ 7~39; u.v.(MeOH )A maX 33
(10.400 )~ 213 (32.000)~ I.R. (KBr) 1685.
~I) D-2-bromo-6-methyl-8beta-(N~N-diethylcarbamoyloxymethyl)-
-ergoline~ m.p. 159-161C (EtOAc); / ~ 7 68 (c = 0~5 MeOH);
435-433 - D,
For C21H28N302Br (434~4) calc. %C~ 58~o6; H~6~50; N~9~67;
,
' .
8.
.. . . .
., '."' ' ., ' ' '''; ~."' ' . .. .
- , ; ,. ; ,
. .
.. . . .
76~L~7
found %C~ 58~01; H~ 6~38; N~ 9~24; u ~. (MeOH )A 277
(9160)~ 227 (30.900)~ I.R. (KBr) 3340~ 1690,
D-2-bromo-6-methyl-8beta-(azetidinylcarbonyloxymethyl)-
ergoline~ m.p. 220-221C (EtOAc); / d 7 - 76~8
(c = 0~5 C5H5N); M 419-417. For C20H24N302Br (418~35 ):
calc. %C~ 57~42; H~ 5~78; N~ 10~05; found %C~ 57~32;
H, 5,65; N~ 9~94; u.v. 5MeOH ) A 276 (9440)~ 225 (32.280)~
I.R. (KBr) 3500~ 1670.
I~ ) D-2-bromo-6-methyl-8beta-(pirrolydyloarbonyloxymethyl)
-9~10 didehydro-ergoline; maleate m.p.218-221C (EtOH); ~c~7
67 (c 0~5 MeOH); M 431-429. For C25H28N306Br (546~4)~
calc. %C~ 54~95; H~ 5~17; N~ i~69; found %C~ 54~77; H~5~35;
N~ 7~39; u.v. (MeOH ) ~ ax 33 (8180)~ 240 (18.100)~
217 (25.780)~ I.R. (KBr) 1690.
X ) D-2-bromo-6-methyl-8beta-(pirrolydy1carbonyloxy-
-methyl )-ergoline maleate~ m.p. 231~233C (EtOH);
-/C~-7D ~ 49 (c = 0~5 MeOH); M 433-431- For C25H30N306Br
(548~8) calc. %C~ 54~75; H~ 5~51; N~ 7~66; found %C~
54S91; H~ 5~74; N~ 7~52; u.v. (MeOH ) A max 258 (10-080 )~
224 (39~600)~ I.R. (KBr) 1690
XI) D-2-bromo-6-methyl-8beta-(piperidinocarbonyloxymethyl)-
9~10-didehydroergoline~maleate m.p. 227-8C (EtOH);
7 + 65~7 (c = 0~5 MeOH); M~ 445-443.
For C26H30N36~r (566~46) calc. %C~ 55~72; H~ 5~40;
N~ 7~50; found %C~ 55~5i; H~ 5~49; N~ 7~20; u.v. (MeOH) A
302 (10.460 )j 214 (33.010)~ I.R. (KBr ) 1685,
XII) D-2-bromo-6-methyl-8beta-(piperidinocarbonyloxymethyl)~
ergoline~ maleate~ m,p, 224-2260C (EtOH ); ~ c~ 7 - 40
(c o 0~5 MeOH); M 447-445. D
26 32N306Br (568~48): calc. %C~ s5,s2; H 5 73; N 7 47
found %C~ 55~66; H~ 5~83; N~ 7~26; u.v. (MeOH )~ 28i
(7330~ 224 (29 630)~ I.R. (KBr) 1685.
XIII D-2-bromo-6 methyl-8beta-(perhydroazepinylcarbonyl-
-oxymethyl)-9~10-didehydroergoline, m.p. 195_1960C tartrate
.~:: ! . . . .
~ I 9
`: ! - ~ . ,
~ ~ .,
. .. "
....
.: . " . . . . ~ ,. . . . . .
. ,, .. - ., ,,, . ... . .. : ... , , . . ~ . :
. . ., '., ., ........ , .. . ; . ~ .. ....
76~)7
(EtOH); /c~ 7 ~ 52~38 ~c = 0~5 C5H5N?; M~ 457-459-
H34N308Br (608,48) calc. %~ 53~3; H 5 63;
Ng 6~91; found %C~ 53~21; H~ 5~92, N~ 6~95; u.v.(MeOH) A
~ ! 302 (~ 11230)~ 242 ( ~ 23750)~ 228 ( ~ 22500 )~ - max
- ; 210 ( ~ 19850 ), I.R. 1760, 1670, 1595 cm~l.
XIV D-2-bromo-1~6-dimethyl-8beta-(perhydroazepinyl-
. ~, . . .. .
carbonyloxyme~hyl )-ergoline, m.p. i81-3C (maleate)
(EtOH 99 ); /c~ 7 = -46~2 ( c = 0~5~ C5H5N ); M~ 47S~473.
For C28H36N306Br ( 490~52 )O calc. %C~ 56~95; H~ 6~14;
10 N~ 7~12; found %C~ 57,49; H~ 6~23; N~ 6~99; u.v.(MeOH) ~ ~x
~ 285 m~ ( ~ 12.160 )~ 227 m~ ( ~ 29.300 )~ IoR~ (KBr)
r~"~ l ~ 1690 cm 1.
XV) D-2-iodo-6-~ethyl-8beta~(perhydroazepinylcarbonyl-
-oxymethyl) ergolineJ m.p. i73-175C (ethyl acetate ),
7D ~77~3 (c = 0~5 C5H5N); ~ 507.
For C23H30N302J (507~43)- calc. %C~ 54~44, H~ 5~96;N~ 8~28;
found %C~ 54~61; H~ 6~04; N~ 8~01; u-v.(MeOH) A max 277
- - ( ~ 10.500); 229 ( ~ 34.400); I~R~ (KBr)-1665 cm~l.
XVI ) D~2-bromo-6-methyl-84eta-(morpholinocarbonyloxy-
-methyl )ergoline~ maleate~ m.p. 213-216C (EtOH);
7 54 (c = 0~5 MeOH); M+ 449-447.
For C25H30N307Br (564~45) calc. %C~ 53~20; H~ 5~36; `~
- N~ 7~45; found %C~ 53~13; H~ 5~65; N~ 7~29; u.v. (MeOH ~ ~ x
282 ~9.300 )~ 278 (9.400 )~ 224 ~35.820)~ I.R. (KBr) 1695.
j XVII ) D~2-bromo-176-dimethyl-8beta-(morpholinocarbonyl-
-oxymethyl )-ergoline~ m.p. 177-179C (EtOAc); / d 7 92
, . (C 5 0~5 C5H5N); M+ 463~461-
For C22H28N303Br (462~4) calc- %C~ 57~15; H~ 6,10; N~ 9~09;
found %C~ 56~84; H~ 6~o3; N~ 8~93; u.v. (MeOH)~ 286
i~ 30 (7.900 )~ 228 (27.400)~ I.R. (CHC13) 1685.
XVIII ) D-2-bromo-6-methyl-8beta-(4-methylpiperazinyl-
-carbonyloxymethyl )-ergoline~ bitartrate m.p. 208-210C
(EtOH); / ~ 7 38~ 1 ( c - 0~5 C5H5N); M~ 462-460-
- l For C30H41N4014Br 761~6) calc- %C~ 47~31; H~ 5~43; N~7~36;
.1
. '
: '~ ' ..
''
, , .. . - . , : .... , ; . . .
7~
~.v. (MeOH) A max 282 (13200)~ 226 (22800)~ I.R. ~KBr )
1695.
XX ) D-2-bromo-6-methyl-8beta-(3-azabicyclo/3~ 2~2 7-
nonanyl-carbonyloxymethyl)-ergoline~ m.p. 226-227C (MeOH);
~_7 - 84~2 (c = 0~ C5H5N); M 487-485.
For C25H32N302Br (486~5); calc. %C~ 61~73; H~ 6~63~N~ 8~64;
found %C~ 61~70; H~ 6~85; N~ ~39; u.v. ~MeOH) A max
280 ( ~ 9680)~ 227 ( ~ 34240)~ I.R. (CHC13) 1670~1605 cm 1!
XXI) D-2-bromo-6-methyl-8beta-(2-phenylisopropyl-carbamoyl-
-oxymethyl)-9~10-didehydroergoline~ m.p. 120-130C tartrate
(EtOH/ethyl ether); M~ 493~495.
For C30H34N308Br (644~5) calc. %~ 55~91; H~ 5~32;
N~ 6~52; found %C~ 57~10; H~ 5~68; N~ 6~52; u.v. (MeOH )~ a
302 ( ~ 11020)~ I.R. (KBr ) 1600~ 1700 cm . ~ -~
The novel compounds can be used as drugs in the
form in which they are obtained or in form of suitable salts
. :~. .
~- with mineral or organic acids of the pharmaceutically~- acceptable types. To this end~ they can be suitably
formulated in appropriate pharmaceutical compositions
in the form o-f tab1ets or dragees or drops or capsule~
or as a solution or suspension in capsules of soft gelatin
for oral use~ ampoules for parenteral use~ suppositories
for enteral use. ~ -
. ; .
It is also possible to prepare delayed release
preparations~ so as to ensure a therapeutical effect which
is prolonged in time.
t
;~ I For all these preparations the fillers and the
- I methods as commonly used in the pharmaceutical practice
can be employed.
It has been found that the novel compounds~ as
obtained according to the present invention show interest-
ing pharmacological properties ab very low dosages on several
regions and organs of several animal species.
, ~ . , . ~
~ , More particularly the novel compounds display
. . . . .
~.. ..i ,
,:`, - ' , ' 11. ' , , ~
~'' 'I .
.. ' I ' ' "
, , :
' , . ., '. . . , ' ' . ' ' .' . ' ~, . ' . :. ~
: ,.. . .... .. .
,: ~ .- , ., , - '
~ f_1076~q)7
A ~
a vaso-dilatory activity on the peripheral circulatory system,
an hypotensive activity and a spasmolytic effect on the gastro-
intestinal smooth muscles or a blocking activity towards the
, . . .
alpha-adrenergic receptors, both in "vitro" and in "vivo".
` 4~f In the following Table 2 some pharmacological data
are reported relating to the above mentioned features, together
' with the corresponding data for two comparison known compounds.
T A B L E_ 2
Ex. Antiadrenalinic AntiBaC12 activity DL e.v.
No. activity (a) (b) (c) 50
vitro vivo vitro ln the mouse
EC50ng/ml e.v. 50 mg/kg
.:,, .
, 4 10 11.2 10 7.1
6 4.7 80.3 3.8 13.7
~ 7 5 50 1.4 8.7
`q 10 2 15.5 4 15 ;
, 12 3.7 20.2 3.5 50
` 2 0.0017 8 3.1 39.4
`~ 17 5.8 41.9 7.5 20.5
18 50 >320 >100 27.3
.. .
375 198 >100 50
i~ . .
~-~ nicer-
goline 7(d) 20(e) 2.1 74.3
dihyd-
roergot-
' oxine 78(e) 5O(e)
, .. . .`-' (a) J. Brugger, Helv. Physiol.Pharmacol.Acta 3, 117
(1945)
(b) F.P. Luduena et al, Arch.Int.Pharmacodyn.122, 111
. .; :
--~ (1959)
(c) Magnus, Pflugers Arch. Ges.Physiol. 1021 123 (1904) ~ -
(d) G. Arcari et al, Brit. J. Pharmacol. 34, 700 P (1968)
`~ (e) " " " , Experientia 28, 819 (1972)
~. ' ,,: ' ' '
~ . .: ""' '
- 12 -
:' :' .
:'' , ,,,, ,,, , .,. ,, ,, . . ... ,.. 1,, ,,~ , .
. ., ., ,: ,-, ,:.-, ,.- ,- . . :, ... ,. ,. , . , . ~ ; :,, , : , ,.:.
- 1076~37
, '
More particularly the compound II, described in the '
Examples, shows some of the above mentioned activities in select~
ive manner, so as to be'particularly useful for the therapeutical
use.' The product is antagonizing the spasmogenic effect of the
adrenaline on the seminal vesicle of guinea pig at concentrations ''
of between 0.1 and 10 pg/ml, as well as the vaso-constricting
effect of the noradrenaline on the isolated and perfused caudal -' '
arteria of rat, at dosages of between 1 and 10 ~g total. Further-
more it antagonizes the contracturing effect of adrenaline and
noradrenaline on the "vas deferens" of guinea pig and rat, at ~' ' '
concentrations of 0.1 to 10 ng/ml.
The substance antagonizes the spasmogenic action of - -
the barium chloride on the isolated ileum of guinea pig at -~
dosages of between 1 to 5 ~g/ml. Such an activity is of the ;
same order as that of nicergoline, but higher than that of the ~ ~
papaverine. On the isolated caudal arteria of rat, the compound ' '
II inhibites the vaso-constricting effect as caused by the per- ; -
fusion with hyperpotassium Ringer's solution. This activity is
displayed at the same doses of the nicergoline and of the papa- ~
verine (10-100 ~g total ), but is longer lasting. ' -
In "vivo" the compound II is capable of protecting rats
(ED508 ~g/kg e.v. and 250 - 400 ~g/kg per os) and miae (ED5051
~g/kg e.v. and 0.61 mg/kg per os) from the lethal effect of the
adrenaline. In this test the product shows in the rat an activ-
ity 2.5 times higher than that of the nicergoline, when the
administration takes place intravenously, whereas its activity ' ;'
is 24 times higher when the administration takes place orally.
In the anaesthetized dog the compound, when administered intra-
venously at dosages of 10 - 50 ~g/kg, does not vary the hearth '' '
rate'and the myocardial contractility, whereas the arterial ~
. . ,
pressure and the f'emoral arterial resistance are reduced, the
femoral arter'ial flow rate being increased by 20 to 100%.
.~' '" ;.
- 13 -
In the anaesthetized cat and rat, the compound
causes the arterial pressure to be reduced, starting from
dosages of 50 and 30 ~g/kg e.v. respectively. In the
"pithed" rat the compound, when intravenously administered,
antagonizes the hypertensive effect of the adrenaline
(ED 46 mg/kg).
The extremely selective action of the compound
is demonstrated by the fact that the anti-acetylcholinic,
anti-histaminic and anti-serotoninic activity, in "vitro",
is displayed at concentrations 4500, 800 and 200 times
respectiveLy higher than those showing the alpha-blocking
effect. Moreover the compound does not antagonize the
beta-adrenergic receptors both in the isolated atrium and ~ -
in the isolated trachea of guinea pig. The LD50 for rats
and mice is respectively 27.7 mg/kg and 39.4 mg/kg by intra- ;~
venous route, and between 0.750 g/kg and 0.45 g/kg per os.
The administration of the substance to Beagle dogs,
for a period of 7 months at the dose of about 8 mg/kg per
`: ~
~` oral route, did not cause modification of the wèight,
hematological and hematochemical parameters, and did not
`~ cause macroscopic or microscopic alterations of the main
organs.
-, The compound belongs to the class of the ergolene
derivatives in which substances are found which cause sti-
.
i, mulating effects on the central nervous system (CNS);
`, several behaviour tests have been carried out on animals,
in order to assess a possible exciting and hallucinogen
action. In the tests carried out (swimming of the rat, ~ ~;
; reserpine induced ptosis, catatonia induced by tetrabenazine,
'
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L076~/[)7
- ,
~ motility and èxploration behaviour of mice and rats
.~ modification of the behaviour in the rabbit and in the
~ dog)~ no evidences were found of any exciting property
- of the compound; on the contrary~ ECG modifications of
~; sedative type were always detected.
: The compound II~ on the basis of pharma-
. cological and toxicological properties and of the high
.~ therapeutical index~ can be used as cerebral and peri~ .
. ! pheral vaso-dilator~ as a anti-hypertensive and for the
~; 10 cerebral arteriosclerosis.
According to the indications given by the
pharmacological tests as above summarily referred to~ the :
foreseen therapeutical use for the compounds of the
. : pre~ent invention would be based on a maximum daily
dosage of 5 to 30 m~ and~ as a consequence~ on the use
. ~ of~pharmaceutical compositions in which the dosage of
:~ ~ the active ingredient is of 1 to 10 mg for the tabloids
. : ~ and 1 to 5 mg for the ampoules (taking of course into
. ~; .
~:~ account the absorption differences above referred to).
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