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Molecule
(16/ 26)
[6][_]
apovincaminic acid
(6)
[7][_]
VINCAMINE
(3)
[8][_]
phthalIDyl NAPHThYRIDIN-12-CARBOXYLate
(2)
[9][_]
DES
(2)
[10][_]
H-
(2)
[11][_]
C-H
(1)
[12][_]
protec
(1)
[13][_]
contrac
(1)
[14][_]
serotonin
(1)
[15][_]
tritium
(1)
[16][_]
naphthyridin
(1)
[17][_]
bromophthalide
(1)
[18][_]
Br
(1)
[19][_]
Me
(1)
[20][_]
potassium
(1)
[21][_]
dimethylformamide
(1)
[22][_]
Physical
(8/ 11)
[23][_]
de 5 mg
(3)
[24][_]
50 mg
(2)
[25][_]
2 m
(1)
[26][_]
de 7,3 minutes
(1)
[27][_]
de 72 minutes
(1)
[28][_]
15 mg
(1)
[29][_]
de 1 %
(1)
[30][_]
5 %
(1)
[31][_]
Substituent
(7/ 7)
[32][_]
phthalIDyl
(1)
[33][_]
13a-ethyl-2,3,5,6,13a,13b-hexahydro
(1)
[34][_]
13A-ETHYL
(1)
[35][_]
13B-HEXAHYDRO
(1)
[36][_]
?-ethyl-2,3,5,6,13a,13b-hexahydro
(1)
[37][_]
ethyl
(1)
[38][_]
2,3,5,6,13a,13b-hexahydro
(1)
[39][_]
Generic
(4/ 6)
[40][_]
carboxylate
(2)
[41][_]
salt
(2)
[42][_]
alkali metal
(1)
[43][_]
alkali
(1)
[44][_]
Gene Or Protein
(3/ 4)
[45][_]
Etre
(2)
[46][_]
Soa
(1)
[47][_]
Ciz
(1)
[48][_]
Organism
(1/ 3)
[49][_]
rat
(3)
[50][_]
Disease
(2/ 3)
[51][_]
Ischemic
(2)
[52][_]
Cerebrovascular
(1)
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Publication
_________________________________________________________________
Number FR2510114A1
Family ID 4586825
Probable Assignee Ausonia Farma Srl
Publication Year 1983
Title
_________________________________________________________________
FR Title phthalIDyl, SON PROCEDE DE PREPARATION ET SON APPLICATION EN
THERAPEUTIQUE
Abstract
_________________________________________________________________
13a-ethyl-2,3,5,6,13a,13b-hexahydro-1H-indolo (3,2,1-de)pyrido
(3,2,1-ij) (1,5) naphthiridin-12-phthalidile carboxylate, having the
formula given below, and a procedure for its preparation, are
described. The compound lends itself to the prevention and treatment
of cerebrovascular affections and organic and functional syndromes
caused by a deterioration of cerebral circulation.
<P>NOUVEAU DERIVE DE LA VINCAMINE.</P><P>CE DERIVE EST LE
13A-ETHYL-2,3,5,6,13A, 13B-HEXAHYDRO-1H-INDOLO(3,2,1-DE) PYRIDO
(3,2,1-IJ) (1,5) phthalIDyl
NAPHThYRIDIN-12-CARBOXYLate.</P><P>MEDICAMENT POUR LE TRAITEMENT DES
AFFECTIONS CEREBROVASCULAIRES ET DES SYNDROMES ORGANIQUES ET
FONCTIONNELS PROVOQUES PAR UNE DETERIORATION DE LA CIRCULATION
CEREBRALE.</P>
Description
_________________________________________________________________
La presente invention concerne un nouveau derive de la vincami-
ne, et plus precisement le 13 ?-ethyl-2,3,5,6,13a,13b-hexahydro-l
Hindolo ( 3, 2,1-de) pyrido ( 3,2,1-ij) ( 1,5) phthalidyl
naphthyridin-12-carboxylate, de formule (I): i C-H 3000 i.p 684 (
638-720)
2 510114
que AP 698 est capable de supprimer ou d'attenuer un certain nombre de
mo-
difications de l'EEG consecutives a l'ischemie experimentale et
observees
au cours de la phase post ischemic.
En particulier, contrairement a ce qu'il se produit chez les temoins,
chez les animaux traites avec AP 698 on constate que:
la frequence du rythme theta n'est pas acceleree, l'amplitude n'est
pas re-
duite entre les 10 mes et 20 mes minutes et les temps relatifs de
representa-
tion ne sont pas disperses.
Le rythme beta est moins reduit par rapport a celui des temoins.
Les valeurs des rapports theta + beta, entre les 14 es et 25 emes
minutes, delta + alpha
diminuent moins que chez les temoins.
2.2 Modifications de la mortalite provoquee par hypoxie hypobar.
Les experiences ont ete conduites sur des souris confinees dans des
cages dans lesquelles la pression est progressivement reduite jusqu'a
un niveau ( 190 mmlg) qui provoque la mort des animaux.
Apres avoir determine le temps de survie des temoins, on a
etudie les effets de divers niveaux de dosage de AP 698.
Les resultats obtenus sont rassembles dans le tableau III; ceux-
ci font clairement ressortir comment le produit a l'etude est capable
de
prolonger de maniere significative le temps de survie avec un effet
protec-
teur substantiel sur l'hypoxie hypobar induite chez la souris.
2.3 Effet sur la musculature lisse En utilisant l'ileum isole du lapin
comme modele experimental,
AP 698 a prouve qu'il possede une considerable activite myorelaxante,
net-
tement superieure a celle mise en evidence par la vincamine dans les
memes
conditions experimentales.
Cet effet superieur sur le tonus et sur l'amplitude des contrac-
tions se manifeste soit sur la musculature dans des conditions de base
soit
sur la musculature rendue hypertonique avec du serum ou de la
serotonin.
TABLEAU II
Effet de AP 698 sur l'evolution post ischemic de l'activite electrique
cerebrale chez le lapin eveille o-. Temps necessaire pour la
reapparition de: Dose Produit mg/kg il.v EEG Amplitude Reponse Depart
de Reactivite Trace Cortex Cortex normale produite la
reactivitinormale normal l { anterieur posterieur t L Temoiis 1 '25 "
1 '14 " 25 '51 " 25 '19 " 8 '48 " &#x003E; 60 ' &#x003E; 60 '
AP 698 0,25 140 ' 19 '20 21 '20 " 18 '27 " 19 &#x003E; 60 '
i 0,50 39 " 29 " 18 '53 " 13 ' 4 25 ' 23 '30 "
1,00 1 '8 " 46 " 10 '13 " 16 '30 " 6 '34 " 12 '53 " 13 '25 "
t __ __ __ Ln CD (W)UOT:4 uz&#x003E;Tg Tu 2 TS % Soa;-Zas ue sauuauom
sana Tv A) xnvm Tu-ep 2 j/2 m) ap e 12 aa uol:lu Tlt A a Ttans ap
sdmal e;Lqm ON asoa -i -r v- qr, CD Tl, Ln m ( 2 uva 1) uaul Tlqm-uuvw
ap isai al uoles (* 4) To'o lo 6 o S'N
96 LIT+
176 oq+ 6,9- o T 96 cz 9 T z'Icc z ciul
'lz -
"U;
6 " L T
U, 9 T-1
i Lq ciz/ s-ranos VI zatloit-qodtq e Txod iq a Vd OIT Ivla O m VI -Ins
269 c W a P an'a:iaa:4 oid:4 ajgs III liv 9 ligvi
3 PHARMACOCINETIQUE
On a etudie la pharmacocinetique de l'hydrolyse enzymatique tant in
vitro qu'in vivo chez le rat apres administration par voie orale de AP
698
marque avec le tritium.
Les comparaisons effectuees ont mis en evidence les aspects ci-
netiques particuliers suivants, par rapport a ceux deja connus de la
vinca-
mine: a) l'hydrolyse enzymatique in vitro determinee en incubant AP
698 avec du
plasma de rat et en mesurant l'apovincaminic acid forme par chromato-
graphie en phase gazeuse a donnee une demi vie de 7,3 minutes.
b) Les tests in vivo chez le rat ont permis de retrouver dans le
plasma soit
AP 698 inchange soit l'apovincaminic acid; la demi-vie de AP 698 in-
change est de 72 minutes, tandis que la demi-vie de l'
apovincaminic acid
qui se forme in vivo a partir de AP 698 est de 7,5 heures.
Ainsi la presence de niveaux persistants d'apovincaminic acid apres
l'administration de AP 698 peut etre interpretee comme un facteur
d'une
meilleure activite et latence, et d'une moindre toxicite de AP 698 par
rap-
port a la vincamine.
Le compose selon la presente invention peut etre administre par
voie orale ou parenterale.
Des exemples de formulations pharmaceutiques sont les suivants:
capsules de 5 mg a 50 mg -comprimes de 5 mg a 50 mg ampoules i m / i v
de 5 mg a 15 mg
gouttes de 1 % a 5 %.
? 510114
Claims
_________________________________________________________________
REVENDICATIONS
1 A titre de produit nouveau, le 13 a-ethyl-
2,3,5,6,13a,13b-hexahydro-l H- indolo (
3,2,1-de) pyrido ( 3,2,1-i J% 1,5) naphthyridin-12 carboxylate de
phtcarboxylate- lidyle, repondant a la formule: -H O -o O C 2 H 5 (i)
2 Procede de preparation du compose selon la revendication 1,
caracterise en ce qu'on fait reagir le bromophthalide de formule (II)
avec un salt metalli- que de l'apovincaminic acid repondant a la
formule (III) selon le schema de reaction: i CH Br + l/ il o(I) (II)-
A&#x003E; I O ie C C 2 H 5 \ G C 2 H 5 ) (I) (III) o Me represente un
alkali metal ou l'equivalent d'un alkalioterreux. 3 Procede selon la
revendication 2, caracterise en ce que l'on utilise le potassiumsalt
de l'apovincaminic acid.
4 Procede selon l'une quelconque des revendications 2 et 3,
caracterise en ce que l'on utilise des solvants polaires aprotiques.
5 Procede selon la revendication 4, caracterise en ce que l'on utilise
le dimethylformamide.
6 A titre de medicament, le compose selon la revendication 1.
7 Compositions pharmaceutiques possedant une activite en metabolique
cerebrale caracterisees en ce qu'elles contiennent le medicament selon
la revendication 6.
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