Note: Descriptions are shown in the official language in which they were submitted.
8Z30
Derivatives of 4-aminobutyric acid and drugs, active in partlcular on the
central nervous system, containing same.
. _
The present invention relates to derivatives of lower alkyl
amino aCidshaving pharmacological properties on the central ner-
vous system.
More particularly, the invention relates, as newproducts,
5 to amides of lower ~lkyl amino acids corrresponding to the general
fo rmula:
R-CONH-(CH2)m- ~CH-(CH2)n-CON (I)
X 2
in which:
- R designates a linear or branched alkyl group having from 1 to 7
10 atoms of carbon or a cycloalkyl group;
- m represents an integer of from 0 to 3;
- n represents an integer of from 0 to 2, on condition that m~n
is equal to or greater than l;
- X represents hydrogen, a lower alkyl group (1 to 4 carbon atoms),
15 a phenylalkyl group in which the phenyl group is possibly substituted;
- Rl and R2 considered separately designate hydrogen, a linear or
branclled alkyl group having from I to 18 carbon atoms, an aralkyl
group, a cycloalkyl group or a possibly substituted phenyl group;
or
20 Rl and R2 considered together with the atom of nitrogen to which
they are attached represent a heterocycle with S or 6 groupings
pos6ibly comprising a second heteroatom such as pyrrolidine, mor-
pholine, piperazine or pyridine and its partially or totally hydroge-
nated derivatives.
The compound~ of the invention show interesting activities
on the central nervous system and may be used in particular as
sedatives, tranquilizers, hypnotics and ntinor tranquilizers.
The compounds according to the invention may be obtained
according to the ~ollowing reaction diagram:
H 2 ~~ (CH2 )n~ ~ ICH - ( CH 2 )n ~ COOR ' R - COCl
(R' being H or a lower alkyl radical)
12~3Z3~
-- 2 --
HN ~l
RCONH- (CH2)m-C~H-(CH2) Il-COOR' ~ R2
(2)
RCONH-(CH2)m-1cH~(cH2)n~cON~
X R2
From the known composite aminoacids or aminoesters 1,
the amide acids 2 are obtained by action of the chloride of
R-COCl acid within a suitable solvent, such as wa-ter, eth~r or a
lower aliphatic alcohol and in the presence of an acceptor of
mineral or organic hydracid and, in particular, sodium hydroxide
or triethylamine.
The amide acids or esters 2 are isolated from the
reaction mixture and, most often, are used as such without
purification for the followi~g step.
. ., , ,Rl
Amldlflcatlon (reaction with HN~ ) may be effected
according -to various methods.
When R' represents a lower alkyl radical, the reaction
,Rl
is made of the ester 2 on the amine HN~ in solution in a lower
aliphatic alcohol or using an excess of amine as solvent.
Operation is generally carried out at a temperature of between
about 0 and about 50C and, most often, at ambient temperature.
The duration of the reaction may vary from an hour to several
days. When R' represents hydrogen, the reaction of the acid 2
Rl
on the amine H ~ is made either by passing through the
intermediary of the corresponding ester (conversion of acid into
an ester of lower aliphatic alcohol) or by using a mixed
anhydride formed from the acid 2. This mixed anhydride is
formed by reacting the acid on the chloroformate of ethyl in the
presence of an alkaline agent such as triethylamine. Operation
is carried out in a suitable solvent such as tetrahydrofucan
without it being necessary to isolate the mixed anhydride
obtained. Operation is generally carried out at a temperature
of between 0 and 40C foc a duration which may vary from 3 to 15
hours, about.
~2~ 3~
The following non-limiting examples will enable the
scope of the invention to be more readily understood.
Example 1
~utyl 10 dioxo-4,9 diaza-5,10 tetradecane (GM 40039)
(I) R = CH3-(CH2)2-; m = n = l;X = H; Rl = R2 = -(CH2)3CH3
a) To a solution of 10.3 g of 4-amino butyric acid in
110 ml of a 2N aqueous solution of sodium hydroxide cooled in
ice, are added, drop by drop, with stirringr 11.7 g of butyryl
chloride. After the end of the addition, stirring is continued
for 4 hours.
The aqueous solution is washed with methylene chloride,
then t~e aqueous phase is acidified and saturated with sodium
chloride. It is extracted with methylene chloride, dried over
sodium sulfate and evaporated to dryness in vacuo. The solid
residue is stirred three times with pentane (300 ml) then dried
in vacuo. Weight 9.1 g used as such for the following operation.
b) the acid obtained hereinabove (9.1 g) is dissolved
in 200 ml of dry tetrahydrofuran. 6.06 9 of triethylamine and
6.51g of ethyl chloroformate are added, maintaining the
temperature lower than or equal to 5C. It is left 1 hour with
stirriny, then 7.74 g of dibut~lamine are added drop by drop.
It is left one night with stirring at ambient temperature.
rrhe insoluble substance is filtered and the solvent is
evaporated to dryness. The residue is taken up in ether and the
solution is washed with a dilute solution of sodium hydroxide
andp finally, with a saturated aqueous solution of sodium
chloride. The ethereal solution is dried over sodium sulfate,
t~e solvent is evaporated to dryness and the residue is
distilled in vacuo. 6.2 g of a pale yellow liquid are obtained
b.p./0.01 mm: 170C.
Example 2
Operation is carried out as in Example 1, but varying
the amine used in paragraph b).
The products (I): R = CH3(CH2)2, m = n = 1, X = H
shown in Table I hereinafter are thus obtained.
i ,A ~
.. ` ~
13Z3~1
-- 4
Example 3
Operation is carried out as in Example 1, but varying,
on the one hand, the acid chloride used in the first step and,
possibly, on the other hand, the amine used in the second step.
The products (I) shown in Table II hereinafter are thus
obtained.
_xample 4
ButYl-5 ethYl-l2 methYl-l3 dioxo-6,11 diaza-5,10 pendadecane
_
(CM 40195)
(I) R - CH3CH2-CH -CH- ; m = n = l; X = EI; Rl = R2=-~CH2)3CH3
CH3 C2H5
a) To 9.18 g of the hydrochloride of benzyl ester of
4-amino butyric acid dissolved in 100 ml of tetrahydrofuran, are
added 8.08 g of triethylamine. The mixture is cooled by an ice
bath, then 6.5 g of chloride of ethyl-2 methyl-3 pentanoic acid
are added drop by drop. It is left one night with stirring at
ambient temperature, then the reaction mixture is filtered and
the solvent i 5 evaporated to dryness.
The residue is taken up in ethyl acetate, washed with
water then with a dilute solution of sodium hydroxide, again with
water, then with a dilute solution of hydrochloric acid and,
finally, with a saturated solution of sodium chloride. The
solution is dried over sodium sulfate and the solvent is
evaporated to dryness in vacuo.
11 g of benzyl ester of the ethyl-7 methyl-8 oxo-6
a~a-5 decanoic-l acid are thus obtaned. This ester (llg) is
dissolved in 150 ml of 96 ethanol and hydrogen at atmospheric
pressure in the presence of 1 g of palladium on charcoal with
10% of palladium. At the end of the reaction, the catalyst is
filtered and evaporated to dryness in vacuo. To the residue
taken up in the anhydrous ether (100 ml) are added 6 g of
dicyclohexylamine and the mixture is left one night at 0C. The
salt formed is dewatered and washed with ether. Weight- 7.8 g.
The salt thus obtained is dissolved in 100 ml of
water. The solution is cooled in ice and acidified by
concentrated hydrochloric acid up to pH = 1.5. The solution of
sodium chloride is saturated and extracted with ethyl acetate.
~Z~1~23~
-- 5 --
The organic solution is washed three kimes with a saturated
solution of sodium chloride, dried over sodium sulfate and
evaporated to dryness.
3.9 g of ethyl-7 methyl-8 oxo-6 aza-5 l-decanoic acid
are thus obtained.
b) According to the technique of Example 1 b),
dibutylamine is reacted on this acid. In the same way, CM 40195
is obtained in the form of an oil; b.p./O~Olmm: 200C.
Example 5
Dioxo-4,12 diaza-5,13 heptadecane (CH 40387)
(I) R = CH3CH2CH2-; m = 3; n = 2; X = H; Rl=H; R2=(CH2)3C~3
a) To a solution, cooled in ice, of 5.2 g of 7-amino
heptanoic acid in 80 ml of 4N sodium hydroxide, are slowly added
with stirring, 4.8 g of butyryl chloride. Stirring is continued
for 4 hours, then the mixture is acidified up to pH = 2 by
hydrochloric acid. It is extcacted with ethyl acetate, the
solution is dried over sodium sulEate and the solvent is
evaporated to dryness in vacuo.
An oil (4.2g) is obtained which crystallises. It is
re-chrystallised in hexane; melting point by the Koffler method
(m.p.k) 68C~
b) To the solution of 2.3 y of the acid obtained
previously in 30 ml of dry tetrahydrofuran, are added l.l g of
triethylamine, then 1.2g o~ ethyl chloroformateO It is left 2
hours with stirring, then the solution of 0~85 g of butylamine
in 5 ml of tetrahydrofuran is slowly added. It is left with
stirring for 15 hours at ambient temperature, then water is
added and extracted with ethyl acetate. The organic solu-tion is
washed with a solution of sodium carbonate, dried over sodium
sulfate and the solvent is evaporated to dryness. The residue
is recrystallised in acetonitril ; m.p.k: 132C.
Example 6
By operating as in Example 5 from different aminoacids 1 and by
varying the reagents R-COCl and / NH, the products (I)
R2
shown in Table III hereinafter are obtained.
{~`
12~8;230
- 5a -
Example 7
Dioxo-2, 7 diaza-l, 6 decane (CM 40401)
-
(I) R = CH3(CH2) 2-; m - n = 1; X = H; Rl = R2 = H.
a) To a solution of 17 g o f oxo-6 aza-5 l-nonanoic acid
(obtained according to example la) ) in 500 ml of absolute
ethanol, are added 10 ml of concentrated sulfuric acid and the
mixture is stirred for 4 days at ambient temperature. The
solvent is evaporated at 30C in vacuo and the residue is taken
up in icy water . The miture is neutr alised by addition of
sodium bicarbonate, then extrac-
0 74~X
, .. .
~2~2~
--6-
ted with methylene chloride, It is dried over sodium sulfate and
evaporated to dryness,
16 g of the expected ethyl ester are obtained.
b~ the 16 g of ethyl ester obtained hereinabove are
introduced in 300 ml of a 167~ solution of ammonia in methanol.
Stirring is carried out for 5 days at ambient temperature. The
solvent is ~3vaporated to dryness and the residue is taken up by
ether, The solid i5 dewatered and washed with acetonitril.
Colourless crystals (10 g) are obtained. m.p.k: 135C
(acetonitril ).
Example 8
(dimethoxy-3, 4 ben~yl)-6 dioxo-4~ 9 diaza-5, 10 tetladecane
(CM 40187) ,~<OCH3
(1) R = CH3CH2CH2- m=0; n=2; X= -CH2~OCH3;Rl=H
2 (CH2)3CH3
Operation is carried out as in Example 7, replacing in
the first reaction the 4-chloro benzoyl chloride by an equivalent
quantity of butyryl chloride,
In the same way, the expected compound is obtained in
the form of a colourless solid; m.p,k: 152C,
The products according to the inventlon have been sub-
jected to various tests concerning their pharmacolo~cal activity
and, in particular, their action on the central nervous system.
A) Pharmacolo~ical activitv
1) Sedative and hypnotic effect
a) Study of the actograph
_____.. ________ _ __
The measurement of the actograph is carried out in the
mouse 45 mins, after the product has been administered. Operation
is carried out on batches of 12 animals, each being isolated for 10
30 mins, before rneasurement, The counting of the scores is effected
by cutting of two perpendicular light beams.
Table IV hereinafter shows the re~ults obtained with
various products of the invention administered at the dose of 500 mg/
kg per os. The results are expressed in percentage of variatinn of
35 the ~cores obtained with respect to control animals which have not
been treated.
~2~l~;230
--7--
The products are noted to be distributed in two groups:
- those provoking hypomotility such as 40217, 40039, 40271,
40272, 40319; in the event of the treated animals showing a loss
of the turning-round reflex, which translates the actual effect of
narcosis of the product, PRR has been noted;
- those provoking hypermotility, such as 40142, 40398, 40397,
40404, 40253, 40355, 40209; to specify the results obtained, the
study for two products has been repeated in dose-effect
according to the same pro~ocol.
The results obtained ar~a shown in Table V hereinafter
b) Potentialisation of narcosis by pentobarbital
___ _ ______ _ ___ ______ _ _ ___ ____
The products to be studied were administered per os
in the mouse at a dose of 500 rng/kg, 1 hour before the pento-
barbital injected by the intraperitoneal route at a rate of 20mg~g.
The percentage of the animals having lost the turning-
around reflex is determined. The results are e~Lpressed in percen-
tage or, in some cases, in effective dose 50 (ED 50) or dose pro-
voking narcosis in 50% of the animals treated.
The results are shown in Table VI hereinafter.
c) ~lectroencephalo~raphic study
___ ________ __________
In order better to understand the hypnotic activity of the
products according to the invention9 an electroencephalographic
study has been effected on one of them, namely CM 40039.
The 40039 is studied at the dose of 350 mg/kg p. o.
in three rats. After a period of habituation of 10 days (lightened
perlod from 8 a.m. to 8 p. m. and dark period from 8 p. m. to
8 a,m,~ the animals are recorded for 5 days with the solvent (10%
gum arabic~, then recorded for 4 days during which they receive the
product at 9 o'clock each morning. After this chrnnic administra-
tion, the animals are recorded the following 5 days (c~q~cl~g period).
Results:
~ .
The animals are xecorded 24 hours out of 24, The
statistical study is made on sections of 24 hours. An overall analysis
is made on the three rats by accumulating the 15 control days, the
12 days of treatment, the 15 d~ed~ days In each hourly section of
24 hours, the arouse time (EV), slow sleep (SL), paradoxal sleep (SP),
total sleep (ST), as well as the ratio (in %) paradoxa] sleep/total
-8- ~Z~3~
sleep (SP/ST) are evaluated (cf Table VII herein~er).
Durlng the whole period of study, the recordings have
not shown any morphological changes of the encephalographic
outline
The product provokes a significant reduction in waking
(-8,1%) correlated to a significant increase in the slow sleep
(+6. 6%).
This effect persists during the checking phase.
2 ) anti e}~
The antiepileptic effect was determined vls-à-vis
convulsive crises provoked by electroshock or by bicuculline.
E:lectroshock (12. 5 V for 0. 5 sec) is effected ill the
mouse 60 mins. after administration of the product by the oral
route .
Bicuculline is administered to the mouse by the intra-
venous ~oute at a rate of 1 mg/kg, 60 mins. ater the product to
be studied has been given per os. The protector effect obtained
vis-à-vis the tonic crises is noted.
By operating on various batches of animals with diffe-
20 rent doses of the product to be studied, the median effective dose
( E:D S0) can be determined
The results are shown in Table VIII hereinafter and show
the clear antiepileptic properties of the products studied.
B) Biochemical study
a) Effect on the rate of 4-aminobutyric acid
________________________.. _________
The 40039 was administered 30 mins. before sacrifice
in the mouse, The rate of 4-aminobutyric acld was evaluated on th~
whole brain (batch of 6 animals) (cf. Table IX hereinafter).
The 40039 provokes a rapid Increase in the rate of 4-amino-
30 butyric acid in the whole brain in the mouse.
b) Effect on the central dopaminergy
_______ ________ ____ ___ _
The effect of the products on the central dopaminergicactivity was studied by measurement of the accumulation of homo-
vanillic acid over a period of 24 hours after adminstration of the
35 products in the mouse.
The rate of homovanilllc acid (HVA) is evaluated in the
whole brain, the animal~ receive an injection of probenecidum
,: ~ , ,.
Z3()
9-
(200 mg/kg i p. ) an hour and a half before sacrifice (batch of 10
animals ).
The two products provoke similar ef~ects on the rate of
HVA, in particular, they provoke an increase in the rate 4 hours
after their administration and a considerable reduction 24 hours
after their adminiætration (cf Table X hereinafter).
c) Acute toxicitv
The products to be studied are administered by the oral
route at doses of 500 and 1000 mg/kg to batches of mice. The mice
are observed for 24 hours and the mortality is noted.
The results expressed in percentage of rnortality are
shown in Table XI hereinafter.
They indicate that, at the dose of 500 mg/kg, none o~ the
products studied showed~ny sign of act~te toxicity. At 1000 mg/kg,
a very high dose, a few products show a lOO~o toxicity, but, in
th~ majority of cases, acute toxicity remains low or zero.
I'he tests thus carried out show that the products accor-
ding to the invention present interesting pharmacologlcal properties
and a low toxicity. Coniequently, they may be used in human thera-
peutics, particularly for the treatment of neurological and psychic
disorders.
rn particular, the products according to the invention may
be used for treating disorders in mood or behaviour; nervosism
irritability as well as for treating anxious states and insomnia.
These products may be admlnistered by the oral route or
by injectable route The pharmaceutical compositions may be solid
or liquid and may be in the form, for example, of tablets, capsules,
granules, supposltories or injectable preparation6.
The dosage may vary to wide proportions, in particular
30 depending on the type and seriousness of the disorder to be treated
and a~ cording to the mode of administration. Most often, in the
~ult, by the oral route, it is included between 0.100 and 1 ~ per
day1 possibly spread out in several doses.
By way of examples of pharmaceutical compositions,
35 the following preparations may be cit ed:
-10- ~2~Z3~)
Capsules
CM 40039 at lO0 mg
___~____________
CM 40039 lO0 mg
~`~B Aerosil ~ fl~ 4 /~1oe~k~ o. 5 mg
f 5 Magnesium stearate 1. 5 mg
Starch STA RX 1500
150 mg
Tablet~
CM 40142 at 200 m~
CM 4014? 200 mg
Microcrystalline cellulose 100 mg
'Lactose 197 mg
Magnesium stearate3 m~
S00 mg
LZ~2~(J
.TAELE
CH3 - ( CH2) 2 -C0-NH- ( CH2) 3 C0 N R2
. . . - . ~O
'` Meltlng polnt ~ C)
Code , R (solvent of. cristallisa-
umbe ~ 2 tion) or boiling point
. [ C (pres sure)]
. .
40 142 H -(CH2)3C~3 120,5 (acetonitrile)
40 205 H ¦ ( 2)7 3 118 (acetonitrile)
40 206 ~ 84 ~pqecipitated and
CH_ washed with ether)
~40 207~ H ~ _C --CH3 ~102 t
': 40 208 ~ . 62 ( " )
. 40 209 H a 134 ( " )
. . '.
4 210 H Cl~C~ 122 (isopropanol)
F
40 211 ~ ~ 50C (décompo~i~ion)
. CH3 ICH3
'. 40 216--CH^CH2-CH3 --CH-CH2--CH3 b,p.,: 185-190 (0,01 =~
40 217--(CH2) 2~CH3 --(CH2) 2~CH3 b. p~: 190-194 (0,01 mm)
. 40 218 H C18H37124 (ac~tonitrile)
~ (anhydrou~
40 219 ~ 60 ether) .
40 252 H - CH2CH20H102 ~acetonitrile)
. .
40 316 H ~CH2~ 132 (acetonitrile)
: 40 396 H - CH3 .100 (ac~tonitrile)
40 398 H ~CH2)~CH3130 (acétonitrile)
_ _ . . . ~ .. ~___
-12- 12~B;~30
~_ _~ont,)
I Melting point (C)
Code ~solvent of cristallisa-
numbe Rl R2 ti~n) or boiling point
___ _ [C (Rressure)~
40 463 H -CU2~H 124 (acetonitrile)
40 466 H ~CH3 124 (acetonitrile~
40 521 H -(CH2)4CH3 . 110 (acetonitrile)
40 532 H -CH2~ 124 (PcetOnitrile)
40 947 -(CH2)5-CH3 110 ~ac~tonltrile~
984 -(cH2)4-cH3 -(CH2)4-CH3 Oil (chromatographed)
40 987 H -CH-CH2CH3 97 (acetonitrile~
b,0 988 H CH2 2 C}l 108 (acetonitrile)
40 989 H -C--CH2CH3 72 (acetonitrile)
C 3 CH
40 990 ~ -C~l -C 3C~
-13- ~ E323~
~BLI~ 1I /R
R _CO NH _ (CH2) ~_CO ~ N\
R2
_~ _~ __ __ __
. Code Meltin~ Point
numbe r R R1 R (~c~
2 r C ( p~e s s u re ) ]
CR~ __ ~
40 254 H C ~ _ H (CH2)3 CH3 88 (ether) .
CH3 . .
40 272 H3C - ~ - ~CH2)3CH3 -(CH2)3~CH~ b. p, 165-167
CH3 (o~01 mm)
40 273 CH~-(CH2)6- H -(CH2)j-CH3 118 (acetonitrile~
¦ 40 274 C~l3~(CH2~6 -(CH2)3CH3 -(CH2)3CH3 b.p:~210-215
40 417 \ C~ - CH2- H --(CH2)3-CH3 110 ~ceYta~e ) . .
H3C
I 40 418 / CH - CH2 H -(CH2)2-cH3 122 (ace to~tril e)
: 40 440 ~ H -(CH2)2 CH3 141 (acetonitrile?
40 443 ~ H -(CH2)3-CH3 l45 (ac~tonitr~e)
. 40 462 HH3C ~ CH- ( 2)3 3 ( 2)3 CH3 b.p~, 184(0001mm)
40 467 H33C--CH H -(CH2)3-CH3 98 (acetonitrile) .
40 885 H3 C- CH2CH2 .
__ H3C-CH CH CH- H - (CH2 )3CH3 128 ~acetooitri~e
~14~ 12~82;3 C~
_ _~
~ 3 ~ h
l ~_ ~ O
.~.,.. ~ ` 3~ '~ o ~
.~ ,~ 11 h 1~ ,~ I C or~ O ,14 ,1
~ o ~-~I ou ~
. P., ~ U ~ ~ V V
~ o~ 'a~ o ~ 8
~ . ~ . ~ ,~
_ ~
t~ ~ ~ ~ ~ ~ ~ r~) ~
C~ 'J ~ U t~
r~
P6 ~ X ~ ~
I
_ ~
1~ .
~_~ - _ .,
~q ~ ~,
W ~ ~ _
t-l ~
__ ~
. .
PC ~
_ .,, ~ , ,
~ ~ ~ O O O ~ _ ~ o
_~
.
~ ~ ~ ~ ~ o ~
..
I I C~
'-- ~ S X = 3
t~) 1~ ~ t~ t'') ~ 1
_
~ U~
.D ,-- u~ r~ . ; CO Cl O~ O
O ~1 O O ~ o o O o C O
U ~ I ~r ~ ~ ~ ~ ~ ~ ~r ~
_ ~
;. .
3e~
-15 -
TABLE IV
. ~Ieasurement of actograph
.N products (p. cent score~COntrOlS )
~ .
40 217 - 37 *
________ ________ _.____________________________
40 039 PRR
_________________ ________________ __________~__
40 206 - 8
_________________ ___________________________:__
40 271 - 53 ~
____.____________ __________________________ ___
40 101 - 20
_________________ ___________________________~__
~0 .~9~ + ,~ ~
_________________ ________ _____ _______________
~0 1!~ ______________________________
~0 316 + 16
_____________ ___ ______________________________
40 395 - 35
_________________ _____________________________
~0 397 ~ 91 *~
__~______..____~__ ____________________.._________
40 ~04 ~ 52 *~e
_________________ ____________..~____________O~____
40 272 - ~7 *~
_______________.__ _~____________________________
40 319 - 51 ~
_________________ __________________________..___
. 40 253 + 33 *
_ _ _ _ _ _ _ _ _ _ _ _ _ .. _ _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ _ _ ._ .. _ _ _ _ _ _ _ _ _ _ _ _
40 355 + 62 ~* .
_________________ ________._____________________
~0 209 + 36 ~
_________________ _______________________~______
40 254 - 2
-16_ ~2
TAB~E IV (cont, )
Meas~rement o~ ~ctograph
N Products
(p, cent sCores/ controls)
_,
40 386 - 57 *~
_ _ __ _ _ _ ____ _ _ __ __ _ _ _ _ _ _ __ __ __ _ _ _ __ _ _ _ _ _ _ _ __ ____ _ _ _ .. __ _ _ _ _ _ _
40 417 + 56 $*
_ _ _ __ _ _ __ _ _ _ _ _ __ __ __ _ _ ___ __ __ _ _ _ __ _ _ _ __ _____________..___
40 418 + 93 **
_____ ____ ____ ________ __ ________ _____ ____ _____________0, _____
40 443 + 78 **
_ ______ _~__ _____ ______ ________ ____________ _________ ______
40 463 : + 41 ~
___ __ _____ __ ______ ___ ____________. __________________~__ . ___
40 466 + ~7 *~
_______ ___ ______ ____ __ ______________ ________________ __~ __
40 467 + 115 ~
______ ______ ___ ______ ___ _________--__ ____ ___________________
40 521 + 101 ~
_ __ _ _ _ _ _ _ _ ___ - __ __ __ __ ____ _ _____ ___ _.._ ____ _ __ _____ __ _ __ __
+ 37 ~
p~O,05 ~* p~O,Ol
v
-17 -
_-- ~ _
I o~ i I
. ~o I
I l. .
~ I o I ~ I
l 1"' 1,,1+,
~1
o oI ~ lo o
~ ! ~ ~ I +
b o ~I ~ P~ . l ~
~i ~ ~o I ~ C ~ I lô
p:~ o oo I o I o o I - ~
i~S ~wO ~ ~ I o I ~
~ ,. ~ . . ' I u -~ I P
~o o l~ o ~
t~ P~ P. I ~ I .,
o I ~o I O
u I ~le .~
a~ ~ !~ ! ~
o ~, ~ , ~
a O l u ,, O !
~ I P~ I ~ I P, I
_ _~ _ _~ .
-18 -
823~
TABLE VI
_
Percentage of animals in narcosi3
N Productst 500 mg/kg p. os or dose (p. os
provoking 50 O of induction of
narcosis ( ED 50)
40 217 O
________________ ________________________________
40 039 ED 50 = 200
________________ ______________._______________~_
40 216 100
_ _ _ . _ _ _ _ _ _ _ .. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
40 206 O
________________ ________________________________
40 71 100
________________ ________________________________
40 401 O
________________ __________________ _____________
40 398 ED SO - 350
________________ ________________________________
40 14'' ED aO = '97
_______ ________ ______________________________~_
40 316 70
________________ ______._________________________
40 395 70
_ _ _ _ _ _ _ _ _ _,_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
40 397 100
______________._ ________________________________
~0 L~04 40
____________..___ _________________,______________
40 27~ 7~
________________ _________ ______ _______________
40 319 ED SO - 175
_____________ __ ________________________________..
40 253 SO
________________ ________________________________
40 355 40
________________ ________________________________
40 254 SO
_ _ _ _ _ _ _ _ .
40 318 90
____ ____ _________ _ ____________________.~_______ ____ __
40 443 ~0
____ ______ _______ ______________________ _______________.
40 ~62 30
_________ _________ ____________________ ________ ___ _____
40 466 30
____ ______ _______ _____________ ____________________ _ _.._.
40 984 60
___________________ ____ ___________ ___________ ___ ___ _
. _ ,, . .. ,~
,. , _
1~ 1 1 1 W I tn
~ ~ ,~, lw j~ !~
O ~ r ~
~ ~ ~ I 'n I ~ i ~ I tn
r~l ~ ~ I + r + I ~ I ~
o ~:J ~ i I `D I ~ I 'n
~ c
O ~ n l l ~n
~U . O
U~ O i i ~n I ~ i tn o
~ ~o ~ !rl ~/~
.5 ~ i t~
c~ ~ ~I oo I +I ~ +I
i I tn ~ Im + I ~ + .
~rl E-~ I ~ I oo I o~ I t~
O O ~ I tn I I Lr~I ~ o
~Q - ~ v/
h~ ~ tn
r~ r ~ I r
h ~ + II ~ I I + I
~ a ~ ' ,~
a t~ ~ . , tn, ~,
~ ~ I ~ I I tn I ~ O
a ~ ~
O . i ' ' ' ~ P4
. ~ I rr) I rrJ I rn I P~ ~C
I j i I rr)
¢ __ ___ .
~o~ 3~
TABLE VIII
-
Median effective dose of protection
from tonic crises
N Products .D ~, i-g '1~ I P. J s,
. Bicuculline Elec~roshock
~0 039 300 250
______________ ________________ ___________....___
40 1 4~ 325 1 S0
___ __________ ________________ ________________
~0 253 ~ 500 500
______________ ________________ ________________
40 254 '~500
______________ _________ ______ ________________
40 271 <S00 500
_________________ _________~_________ _____.0__________.___.
40 379 450
_______ _ _______ ___________________ _____~-_______ ______~
40 41~ 300
_________________ ___ ____~__________ _____________~___,___
40 462 150 500
_______ _ __ ____ _________~_ _______ ____________________
40 463 380
_________________ ___________________ ____________________
bO ~67 150 ~ 500
___ _____________ _________ _________ ______________ _____
40 521 250 180
_________________ _~_________________ ______________~___ _
40 947 250 400
_ _ e .
TABI.E . IX
_
__ ~
Treated 40039 p~cent~
. Controls 500 mg/kg p. os /control-s
. ~ _~
Rate of amino ~ _ ~ .
butyric acid2 8 0 - 8 .~ 21 - 1 7 ~ 1 4 o 6
in. ~g/g brain
~_ __
~* p~O,05
_ .
-21- ~ 23(~
_ _ -- o~'' _
~o .~'. o
o - u; ~ o~
~tJ h ~ IC ~`1 ~ ~
et +~ ~o +~ ~CO P~
~: ' ~ ~ O-~ o u~ ~ : .
~1 o ~ r
O ~0 ~0 ~C
~ ,
_____ _ , .
:IL2~l~Z30
TAsLE x~
p. cent of mor~alit y
N Product at 500 mg/kg ,~ U r /-
. p. os p, os
, ____~
40 0~9 . 0 100
________________ _____________ __________________
40 142 0 . o
________________ ______________ __~___ ___________
40 206 0 0
___________~___ _____________ __________________
~0 209 0 20
______ _____ __ _____________ __________________ .
~0 ~16 0 100
_______________ _____________ __________________
~0 217 0 0
_______ _______ _____________ _______________ __
~0 25~ 0 0
_______________ . _________________________.___
L~ 0 254 . 0
________________ _____________ __________________
40 271 0 100 .
_______________ _____________ __________________
~0 272 0 0
________________ ______________ __________~__~___
40 316 0 0
_____________ _ r--------______ __________________
40 319 0 0
_______________ _____________ __________ _______
40 355 0 0
_______________ ______ ______ ______ ___________
. 40 i95 0 20
_______________ __________.__ __________________
40 397 0 20
_______________ _____________ __________________
~0 398 0 0
_______________ _____________ ___~______ _______
40 LtOl 0 0
_ _ _ __ _ __ _ _ _ __ _ _ .. _ . _ __ _ _ _ _ _ __ _ _ _ _ _ __ _ _ _ __ __ _ _ _ _
10 ~ ~ ~__
,. .
12~ 30
-23 -
l`ABLE _~ont. )
. . ~.. . .. . . . . _
p. cent bf morcality
N Product at 500 mg/kg at 1000 mg/kg
e~. osp, 09
40 417 0 20
______________.____ _____-__________ _ ____________________
40 418 0 0
___________________ ____.._,._________ ________________,_____
40 4~3 ~) O
______ ____________ ________________ ..__________~__________
40 462 0 0
___________________ _________________ ________________ _____
40 463 : 0 0
________________..__ _____________.__ ______________________
40 466 0 0
..___________________ _________________ ____________,_________ .
40 467 0 0
___________________ ________________ ___..__________________
40 581 0 0 .
._~_________________ ________________ ____________________~_
. 40 947 0 0
~ __ _ __ _ _ _ _ _ _ _ __ _ ____ _ __ __.~___ _ ..___ __ _ ___ __ _ __ __ ___ ___ _ ____
40 984 0 100 .
___________________ _________________ _____.________________
40 989 . _--~ 80
