CA1208230A - Derivatives of lower alkyl amino acids and drugs, active in particular on the central nervous system, containing same - Google Patents
Derivatives of lower alkyl amino acids and drugs, active in particular on the central nervous system, containing sameInfo
- Publication number
- CA1208230A CA1208230A CA000384370A CA384370A CA1208230A CA 1208230 A CA1208230 A CA 1208230A CA 000384370 A CA000384370 A CA 000384370A CA 384370 A CA384370 A CA 384370A CA 1208230 A CA1208230 A CA 1208230A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- lower alkyl
- group
- acid
- aminobutyric acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
ABSTRACT
"Derivatives of 4-aminobutyric acid and drugs, active in particular on the central nervous system, containing same."
The present invention relates to new derivatives of lower alkyl amino acids of formula (I) in which R is an alkyl, cycloalkyl, possibly substituted phenyl group, m is 0 to 3 and n is 0 to 2, X is H or alkyl or phenyl-alkyl, R1 and R2 are H, alkyl, aralkyl, cycloalkyl or phenyl or form with N a heterocycle with 5 or 6 groupings.
It also relates to a process for preparing said products and the drugs, active in particular on the central nervous system, con-taining said products.
"Derivatives of 4-aminobutyric acid and drugs, active in particular on the central nervous system, containing same."
The present invention relates to new derivatives of lower alkyl amino acids of formula (I) in which R is an alkyl, cycloalkyl, possibly substituted phenyl group, m is 0 to 3 and n is 0 to 2, X is H or alkyl or phenyl-alkyl, R1 and R2 are H, alkyl, aralkyl, cycloalkyl or phenyl or form with N a heterocycle with 5 or 6 groupings.
It also relates to a process for preparing said products and the drugs, active in particular on the central nervous system, con-taining said products.
Description
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) 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~
HN ~l RCONH- (CH2)m-C~H-(CH2) Il-COOR' ~ R2
. _ 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) 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~
HN ~l RCONH- (CH2)m-C~H-(CH2) Il-COOR' ~ R2
(2) RCONH-(CH2)m-1cH~(cH2)n~cON~
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 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 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~
The organic solution is washed three kimes with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated to dryness.
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 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 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~
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) 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~
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 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() (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 ( " ) . . '.
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) 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~
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 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() (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) 40 990 ~ -C~l -C 3C~
-13- ~ E323~
~BLI~ 1I /R
R _CO NH _ (CH2) ~_CO ~ N\
_~ _~ __ __ __ . 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 ) . .
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~
TABLE IV
. ~Ieasurement of actograph .N products (p. cent score~COntrOlS ) ~ .
40 217 - 37 *
________ ________ _.____________________________ _________________ ________________ __________~__ _________________ ___________________________:__ 40 271 - 53 ~
____.____________ __________________________ ___ _________________ ___________________________~__ ~0 .~9~ + ,~ ~
_________________ ________ _____ _______________ ~0 1!~ ______________________________ ~0 316 + 16 _____________ ___ ______________________________ _________________ _____________________________ ~0 397 ~ 91 *~
__~______..____~__ ____________________.._________ 40 ~04 ~ 52 *~e _________________ ____________..~____________O~____ 40 272 - ~7 *~
_______________.__ _~____________________________ 40 319 - 51 ~
_________________ __________________________..___ . 40 253 + 33 *
_ _ _ _ _ _ _ _ _ _ _ _ _ .. _ _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ _ _ ._ .. _ _ _ _ _ _ _ _ _ _ _ _ 40 355 + 62 ~* .
_________________ ________._____________________ ~0 209 + 36 ~
_________________ _______________________~______ -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 _-- ~ _ 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
_ _~ _ _~ .
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) ________________ ________________________________ 40 039 ED 50 = 200 ________________ ______________._______________~_ _ _ _ . _ _ _ _ _ _ _ .. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ________________ ________________________________ ________________ ________________________________ ________________ __________________ _____________ ________________ ________________________________ 40 14'' ED aO = '97 _______ ________ ______________________________~_ ________________ ______._________________________ _ _ _ _ _ _ _ _ _ _,_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ______________._ ________________________________ ~0 L~04 40 ____________..___ _________________,______________ 40 27~ 7~
________________ _________ ______ _______________ _____________ __ ________________________________..
________________ ________________________________ ________________ ________________________________ _ _ _ _ _ _ _ _ .
____ ____ _________ _ ____________________.~_______ ____ __ 40 443 ~0 ____ ______ _______ ______________________ _______________.
40 ~62 30 _________ _________ ____________________ ________ ___ _____ ____ ______ _______ _____________ ____________________ _ _.._.
___________________ ____ ___________ ___________ ___ ___ _ . _ ,, . .. ,~
,. , _ 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 41~ 300 _________________ ___ ____~__________ _____________~___,___ _______ _ __ ____ _________~_ _______ ____________________ _________________ ___________________ ____________________ bO ~67 150 ~ 500 ___ _____________ _________ _________ ______________ _____ _________________ _~_________________ ______________~___ _ _ _ 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 ________________ ______________ __~___ ___________ ___________~___ _____________ __________________ ~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 ________________ ______________ __________~__~___ _____________ _ r--------______ __________________ _______________ _____________ __________ _______ _______________ ______ ______ ______ ___________ . 40 i95 0 20 _______________ __________.__ __________________ _______________ _____________ __________________ ~0 398 0 0 _______________ _____________ ___~______ _______ 40 LtOl 0 0 _ _ _ __ _ __ _ _ _ __ _ _ .. _ . _ __ _ _ _ _ _ __ _ _ _ _ _ __ _ _ _ __ __ _ _ _ _ 10 ~ ~ ~__ ,. .
12~ 30 l`ABLE _~ont. ) . . ~.. . .. . . . . _ p. cent bf morcality N Product at 500 mg/kg at 1000 mg/kg e~. osp, 09 ______________.____ _____-__________ _ ____________________ ___________________ ____.._,._________ ________________,_____ 40 4~3 ~) O
______ ____________ ________________ ..__________~__________ ___________________ _________________ ________________ _____ 40 463 : 0 0 ________________..__ _____________.__ ______________________ ..___________________ _________________ ____________,_________ .
___________________ ________________ ___..__________________ 40 581 0 0 .
._~_________________ ________________ ____________________~_ . 40 947 0 0 ~ __ _ __ _ _ _ _ _ _ _ __ _ ____ _ __ __.~___ _ ..___ __ _ ___ __ _ __ __ ___ ___ _ ____ 40 984 0 100 .
___________________ _________________ _____.________________ 40 989 . _--~ 80
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) 40 990 ~ -C~l -C 3C~
-13- ~ E323~
~BLI~ 1I /R
R _CO NH _ (CH2) ~_CO ~ N\
_~ _~ __ __ __ . 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 ) . .
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~
TABLE IV
. ~Ieasurement of actograph .N products (p. cent score~COntrOlS ) ~ .
40 217 - 37 *
________ ________ _.____________________________ _________________ ________________ __________~__ _________________ ___________________________:__ 40 271 - 53 ~
____.____________ __________________________ ___ _________________ ___________________________~__ ~0 .~9~ + ,~ ~
_________________ ________ _____ _______________ ~0 1!~ ______________________________ ~0 316 + 16 _____________ ___ ______________________________ _________________ _____________________________ ~0 397 ~ 91 *~
__~______..____~__ ____________________.._________ 40 ~04 ~ 52 *~e _________________ ____________..~____________O~____ 40 272 - ~7 *~
_______________.__ _~____________________________ 40 319 - 51 ~
_________________ __________________________..___ . 40 253 + 33 *
_ _ _ _ _ _ _ _ _ _ _ _ _ .. _ _ _ _ _ _ _ _ _ . _ _ _ _ _ _ _ _ _ ._ .. _ _ _ _ _ _ _ _ _ _ _ _ 40 355 + 62 ~* .
_________________ ________._____________________ ~0 209 + 36 ~
_________________ _______________________~______ -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 _-- ~ _ 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
_ _~ _ _~ .
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) ________________ ________________________________ 40 039 ED 50 = 200 ________________ ______________._______________~_ _ _ _ . _ _ _ _ _ _ _ .. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ________________ ________________________________ ________________ ________________________________ ________________ __________________ _____________ ________________ ________________________________ 40 14'' ED aO = '97 _______ ________ ______________________________~_ ________________ ______._________________________ _ _ _ _ _ _ _ _ _ _,_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ______________._ ________________________________ ~0 L~04 40 ____________..___ _________________,______________ 40 27~ 7~
________________ _________ ______ _______________ _____________ __ ________________________________..
________________ ________________________________ ________________ ________________________________ _ _ _ _ _ _ _ _ .
____ ____ _________ _ ____________________.~_______ ____ __ 40 443 ~0 ____ ______ _______ ______________________ _______________.
40 ~62 30 _________ _________ ____________________ ________ ___ _____ ____ ______ _______ _____________ ____________________ _ _.._.
___________________ ____ ___________ ___________ ___ ___ _ . _ ,, . .. ,~
,. , _ 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 41~ 300 _________________ ___ ____~__________ _____________~___,___ _______ _ __ ____ _________~_ _______ ____________________ _________________ ___________________ ____________________ bO ~67 150 ~ 500 ___ _____________ _________ _________ ______________ _____ _________________ _~_________________ ______________~___ _ _ _ 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 ________________ ______________ __~___ ___________ ___________~___ _____________ __________________ ~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 ________________ ______________ __________~__~___ _____________ _ r--------______ __________________ _______________ _____________ __________ _______ _______________ ______ ______ ______ ___________ . 40 i95 0 20 _______________ __________.__ __________________ _______________ _____________ __________________ ~0 398 0 0 _______________ _____________ ___~______ _______ 40 LtOl 0 0 _ _ _ __ _ __ _ _ _ __ _ _ .. _ . _ __ _ _ _ _ _ __ _ _ _ _ _ __ _ _ _ __ __ _ _ _ _ 10 ~ ~ ~__ ,. .
12~ 30 l`ABLE _~ont. ) . . ~.. . .. . . . . _ p. cent bf morcality N Product at 500 mg/kg at 1000 mg/kg e~. osp, 09 ______________.____ _____-__________ _ ____________________ ___________________ ____.._,._________ ________________,_____ 40 4~3 ~) O
______ ____________ ________________ ..__________~__________ ___________________ _________________ ________________ _____ 40 463 : 0 0 ________________..__ _____________.__ ______________________ ..___________________ _________________ ____________,_________ .
___________________ ________________ ___..__________________ 40 581 0 0 .
._~_________________ ________________ ____________________~_ . 40 947 0 0 ~ __ _ __ _ _ _ _ _ _ _ __ _ ____ _ __ __.~___ _ ..___ __ _ ___ __ _ __ __ ___ ___ _ ____ 40 984 0 100 .
___________________ _________________ _____.________________ 40 989 . _--~ 80
Claims (11)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of amides of lower alkyl amino acids corresponding to general formula:
(I) in which:
- R designates a linear or branched alkyl group having from 1 to 7 carbon atoms 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 1;
- X represents hydrogen, a lower alkyl group (1 to 4 carbons), a phenylalkyl group in which the phenyl group is possibly substituted, - R1 and R2 considered separately designate hydrogen, a linear or branched alkyl group having from 1 to 18 carbon atoms, an aralkyl group, a cycloalkyl group or a possibly substituted phenyl group, - or R1 and R2 considered together with the nitrogen atom to which they are attached represent a heterocycle with 5 to 6 groupings possibly comprising a second hetroatom which comprises reacting an aminoacid of formula:
(II) in which m, n and X have the meanings given above and R' is a hydrogen atom or a lower alkyl group (1 to 4 carbon atoms), or ester thereof with an acid chloride of formula R CO Cl so as to convert the amine group thereof into an amide radical, and subjecting the product so formed to amidification with a compound of formula
(I) in which:
- R designates a linear or branched alkyl group having from 1 to 7 carbon atoms 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 1;
- X represents hydrogen, a lower alkyl group (1 to 4 carbons), a phenylalkyl group in which the phenyl group is possibly substituted, - R1 and R2 considered separately designate hydrogen, a linear or branched alkyl group having from 1 to 18 carbon atoms, an aralkyl group, a cycloalkyl group or a possibly substituted phenyl group, - or R1 and R2 considered together with the nitrogen atom to which they are attached represent a heterocycle with 5 to 6 groupings possibly comprising a second hetroatom which comprises reacting an aminoacid of formula:
(II) in which m, n and X have the meanings given above and R' is a hydrogen atom or a lower alkyl group (1 to 4 carbon atoms), or ester thereof with an acid chloride of formula R CO Cl so as to convert the amine group thereof into an amide radical, and subjecting the product so formed to amidification with a compound of formula
2. The process according to claim 1, wherein amidification is effected by reaaction of a product in which R' is lower alkyl with the amine , operating in solution in alcohol or using an excess of amine as solvent, and at a temperature of between about 0 and about 50°C.
3. The process of claim 2, wherein an ester of an acid (R'=H) of formula II with a lower alcohol is amidified with the amine.
4. Amides of lower alkyl amino acids corresponding to the general formula (I) given in claim 1, whenever prepared by a process according to claim l, claim 2 or claim 3, or an obvious chemical equivalent thereof.
5. The process of claim 2, wherein amidification is effected on a mixed anhydride of the acid (R' = H) by action on the acid of an ethyl chloroformate in the presence of an alkaline agent.
6. The process of claim 5 wherein said alkaline agent is triethylamine.
7. Amides of lower alkyl amino acids corresponding to the general formula (I) given in claim 1, whenever prepared by a process according to claim 5 or claim 6, or an obvious chemical equivalent thereof.
8. The process of claim 1 wherein a 4-aminobutyric acid amide of formula is prepared by reaction of 4-aminobutyric acid with butyryl chloride, and reaction of the product so formed with dibutylamine.
9. 4-aminobutyric acid amide of formula whenever prepared by a process according to clam 8 or an obvious chemical equivalent thereof.
10. The process of claim 1 wherein a 4-aminobutyric acid amide of formula is prepared by reaction of 4-aminobutyric acid with butyryl chloride, and reaction of the product so formed with n-butylamine.
11. 4-aminobutyric acid of formula whenever prepared by the process according to claim 10 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8018609 | 1980-08-27 | ||
| FR8018609A FR2489319A1 (en) | 1980-08-27 | 1980-08-27 | DERIVATIVES OF AMINO-4 BUTYRIC ACID AND MEDICAMENTS, PARTICULARLY ACTIVE ON THE CENTRAL NERVOUS SYSTEM, CONTAINING |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1208230A true CA1208230A (en) | 1986-07-22 |
Family
ID=9245433
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000384370A Expired CA1208230A (en) | 1980-08-27 | 1981-08-21 | Derivatives of lower alkyl amino acids and drugs, active in particular on the central nervous system, containing same |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0046707B1 (en) |
| JP (1) | JPS5772949A (en) |
| AT (1) | ATE21099T1 (en) |
| AU (1) | AU547392B2 (en) |
| CA (1) | CA1208230A (en) |
| DE (1) | DE3175030D1 (en) |
| DK (1) | DK378781A (en) |
| ES (1) | ES505004A0 (en) |
| FR (1) | FR2489319A1 (en) |
| GR (1) | GR75299B (en) |
| IE (1) | IE52415B1 (en) |
| NO (1) | NO156608C (en) |
| NZ (1) | NZ198110A (en) |
| PT (1) | PT73558B (en) |
| ZA (1) | ZA815662B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6555585B2 (en) | 2000-07-21 | 2003-04-29 | Teva Pharmaceutical Industries, Ltd. | Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5654301A (en) * | 1985-02-15 | 1997-08-05 | Research Corporation Technologies, Inc. | Amino acid derivative anticonvulsant |
| CA1340902C (en) * | 1985-02-15 | 2000-02-22 | Harold L. Kohn | Amino acid derivative anticonvulsant |
| US5378729A (en) * | 1985-02-15 | 1995-01-03 | Research Corporation Technologies, Inc. | Amino acid derivative anticonvulsant |
| CA1320734C (en) * | 1986-02-04 | 1993-07-27 | Suntory Limited | Pyrrolidineamide derivative of acylamino acid and pharmaceutical composition containing the same |
| US5198458A (en) * | 1986-02-04 | 1993-03-30 | Suntory Limited | Pyrrolidineamide derivatives of acylamino acid and pharmaceutical composition containing the same |
| NZ222045A (en) * | 1986-08-21 | 1989-10-27 | Res Corp Technologies Inc | From diamides up to tetrapeptides for use as anticanvulsants |
| US4992472A (en) * | 1987-06-16 | 1991-02-12 | The United States Of America As Represented By The Department Of Health And Human Services | Chemical differentiating agents |
| US5770625A (en) * | 1988-02-08 | 1998-06-23 | The Trustees Of Columbia University In The City Of New York | Butyryl-tyrosinyl spermine, analogs thereof and methods of preparing and using same |
| DE3915756A1 (en) * | 1989-05-13 | 1990-11-29 | Bayer Ag | CYCLOPROPANOYLAMINOSAEUREAMID DERIVATIVES |
| DE3915755A1 (en) * | 1989-05-13 | 1990-11-29 | Bayer Ag | FUNGICIDAL AGENTS AND SUBSTITUTED AMINO ACID DERIVATIVES AND THE PRODUCTION THEREOF |
| JPH03506045A (en) * | 1989-05-19 | 1991-12-26 | リサーチ・コーポレイション・テクノロジーズ・インコーポレイテッド | Amino acid derivative anticonvulsant |
| DE4102042A1 (en) * | 1991-01-24 | 1992-07-30 | Bayer Ag | SUBSTITUTED AMINO ACID DERIVATIVES THEIR PRODUCTION AND USE AS FUNGICIDES |
| US5585358A (en) * | 1993-07-06 | 1996-12-17 | Yissum Research Development Corporation Of The Hebrew University Of Jerusalem | Derivatives of valproic acid amides and 2-valproenoic acid amides, method of making and use thereof as anticonvulsant agents |
| US6037472A (en) | 1993-11-04 | 2000-03-14 | Syntex (U.S.A.) Inc. | Matrix metalloprotease inhibitors |
| IL114483A0 (en) * | 1994-07-12 | 1995-11-27 | Yissum Res Dev Co | Glycinamide derivatives pharmaceutical compositions containing the same and methods utilizing the same |
| EP1202720A4 (en) * | 1999-08-10 | 2004-02-25 | Uab Research Foundation | Use of gaba agonists for treatment of spastic disorders, convulsions, and epilepsy |
| EP1604656A1 (en) | 2004-06-09 | 2005-12-14 | Schwarz Pharma Ag | Novel use of peptide compounds for treating amyotrophic lateral sclerosis (ALS) |
| TW200829238A (en) * | 2006-11-30 | 2008-07-16 | Cenerx Biopharma Inc | Dialkylamino alkyl esters of pivagabine as medicaments for the treatment of central nervous system disorders |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB732415A (en) * | 1952-07-12 | 1955-06-22 | Ruhrchemie Ag | Process for the production of aroylated aminocarboxylic acids |
| US3022314A (en) * | 1955-06-20 | 1962-02-20 | Upjohn Co | Alpha-phenyl-omega-amino-alkanamides |
| IE33790B1 (en) * | 1968-06-04 | 1974-10-30 | Beecham Group Ltd | Derivatives of n-acylaminoacid amides |
-
1980
- 1980-08-27 FR FR8018609A patent/FR2489319A1/en active Granted
-
1981
- 1981-08-11 GR GR65767A patent/GR75299B/el unknown
- 1981-08-11 IE IE1835/81A patent/IE52415B1/en unknown
- 1981-08-13 EP EP81401299A patent/EP0046707B1/en not_active Expired
- 1981-08-13 AT AT81401299T patent/ATE21099T1/en not_active IP Right Cessation
- 1981-08-13 DE DE8181401299T patent/DE3175030D1/en not_active Expired
- 1981-08-17 ZA ZA815662A patent/ZA815662B/en unknown
- 1981-08-18 AU AU74259/81A patent/AU547392B2/en not_active Ceased
- 1981-08-20 NZ NZ198110A patent/NZ198110A/en unknown
- 1981-08-21 CA CA000384370A patent/CA1208230A/en not_active Expired
- 1981-08-24 PT PT73558A patent/PT73558B/en unknown
- 1981-08-26 NO NO812890A patent/NO156608C/en unknown
- 1981-08-26 ES ES505004A patent/ES505004A0/en active Granted
- 1981-08-26 JP JP56132669A patent/JPS5772949A/en active Pending
- 1981-08-26 DK DK378781A patent/DK378781A/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6555585B2 (en) | 2000-07-21 | 2003-04-29 | Teva Pharmaceutical Industries, Ltd. | Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder |
Also Published As
| Publication number | Publication date |
|---|---|
| NZ198110A (en) | 1984-12-14 |
| PT73558A (en) | 1981-09-01 |
| PT73558B (en) | 1982-11-03 |
| ES8206445A1 (en) | 1982-08-16 |
| NO812890L (en) | 1982-03-01 |
| IE811835L (en) | 1982-02-27 |
| JPS5772949A (en) | 1982-05-07 |
| EP0046707B1 (en) | 1986-07-30 |
| IE52415B1 (en) | 1987-10-28 |
| GR75299B (en) | 1984-07-13 |
| NO156608B (en) | 1987-07-13 |
| DK378781A (en) | 1982-02-28 |
| ES505004A0 (en) | 1982-08-16 |
| FR2489319A1 (en) | 1982-03-05 |
| DE3175030D1 (en) | 1986-09-04 |
| AU7425981A (en) | 1982-03-04 |
| ZA815662B (en) | 1982-08-25 |
| AU547392B2 (en) | 1985-10-17 |
| NO156608C (en) | 1987-10-21 |
| ATE21099T1 (en) | 1986-08-15 |
| FR2489319B1 (en) | 1984-04-06 |
| EP0046707A1 (en) | 1982-03-03 |
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