NZ198110A - Amides of amino alkanoic acids:pharmaceutical compositions - Google Patents
Amides of amino alkanoic acids:pharmaceutical compositionsInfo
- Publication number
- NZ198110A NZ198110A NZ198110A NZ19811081A NZ198110A NZ 198110 A NZ198110 A NZ 198110A NZ 198110 A NZ198110 A NZ 198110A NZ 19811081 A NZ19811081 A NZ 19811081A NZ 198110 A NZ198110 A NZ 198110A
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Amides of 4-aminobutyric acid corresponding to general formula : see diagramm : EP0046707,P19,F3 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 possibility 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 or 6 groupings possibly comprising a second heteroatom such as pyrrolidine, morpholine, piperazine or pyridine and its partially or totally hydrogenated derivatives. 1. Claims for the Contracting State : AT Process for preparing amides of 4-aminobutyric acid corresponding to general formula (I) : see diagramm : EP0046707,P20,F3 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 from 0 to 2, 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 theterocycle with 5 or 6 groupings possibly comprising a second heteroatom such as pyrrolidine, morpholine, piperazine or pyridine and its partially or totally hydrogenated derivatives, characterized in that the starting product is constituted by an aminoacid of formula : see diagramm : EP0046707,P20,F4 in which m, n and X are such as defined above and R' is a hydrogen atom or a lower alkyl group (1 to 4 carbon atoms), said product is reacted on an acid chloride of formula R-COCI so as to convert the amine of the starting product into an amide radical and the product obtained is subjected to an amidification with a product of formula see diagramm : EP0046707,P21,F1
Description
New Zealand Paient Spedficaiion for Paient Number 1 98110
1 ? 3 ! 1
Priority Date(s):
v^crr.picto S;3ccif,'c2-iion Filsd* • $1 , flblKaijlU
PBbfaUsn CteSB Jii'SMi"'
'■ .0-. oci/rna), No.
C07C1V7fztfZit fro c*fbzir/ttf
Patents Form No. 5
o
NEW ZEALAND
PATENTS ACT 1953
COMPLETE SPECIFICATION
"Derivatives of aminoalkanoic acids and drugs, active in particular on the central nervous system, containing "same"
-3/WESANOFI, a French company, of 40 Avenue George V, 75008 Paris, France,
hereby declare the invention, for which 1/we pray that a patent may Ipe granted to -roe/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- ^
24 MAY 1934
(followed by page 1 A.)
198110
- 1A -
The present invention relates to derivatives of aminoalkanoic acids having pharmacological properties on the central nervous system.
More particularly, the invention relates, as new products, to amides of aminoalkanoic acids corresponding to the general formula: n
/K
i (l)
v
^ ■ m | v.' n x R2
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), or a phenylalkyl group in which the phenyl group is optionally substituted, and
- R-^ and R2 considered separately designate hydrogen, a linear or branched alkyl group having from 1 to 18 carbon atoms, an araalkyl group, a cycloalkyl group or an optionally substituted phenyl group,
- or R, and R~ considered together with the nitrogen atom to
1 z a which they are attached represent/saturated or unsaturated heterocyclic ring with 5 or 6 ring atoms optionally with a second heteroatom.
The compounds of the invention show interesting activities on the central nervous system and may be used in particular as sedatives, tranquilizers, hypnotics and minor tranquilizers.
The compounds according to the invention may be obtained according to the following reaction diagram:
H0N-(CH„) -CH—(CH~) -COOR" R-COCL
2 2 m | 2 n 7
X I
(R' being H or a lower alkyl radical) - "'JAT^TOrnCB
193110
' Ri
RCONH-(CHj -CH-(CHj -COOR' HN \R0 2 m j 2 n P 2
X
(2)
/R1
RCONH-(CH-) -CH-(CH-) -CON v 2'm | 2'n
X 2
From the known composite aminoacids or aminoesters JL, the amide acids 2^ are obtained by action of the chloride of 5 R-COC1 acid within a suitable solvent, such as water, ether 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 10 reaction rrixture. and, most often, are used as such without purification for the following step. D
/I
Amidification (reaction with HN ) may be effected according to various methods. c ,, . . , ,
& (1 to 4 carbon atoms)
When R1 represents a lower alkyl radical the reaction is
made of.the ester 2 on the amine in solution in a lower ali-
having 1 to 4 carbon atoms NR2 p haticAlcohol or using an excess of amine as solvent. Operation is generally carried out at a temperature of between about 0 and about
50°C and, most often, at ambient temperature. The duration of the reaction may vary from an hour to several days. When R1 represents
hydrogen, the reaction of the acid 2 on the amine HN^ * is made
2
either by passing through the intermediary of the corresponding ester navmg I to 1 carbon atcrr (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 25 in the presence of an alkaline agent such as triethylamine. Operation is carried out in a suitable solvent such as tetrahydrofuran without it being necessary to isolate the mixed anhydride obtained. Operation is generally carried out at a temperature of between 0 and 40°C for a duration which may vary from 3 to 15 hours, about.
The following non-limiting examples will enable the scope of the invention to be more readily understood.
Example 1
Butyl-10 dioxo-4, 9 djaza-5,10 tetradecane (CM 40039)
2 4 HAY 1984
nCSWED
(I) R = CH3-(CH2)2-; m.P n = 1; X,= H; Rj = 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 stirring, 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 the aqueous phase is acidified and saturated with sodium chloride. It is extracted with methylene chloride, dried over 10 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 g of triethylamine and 6. 51g
of ethyl chloroformate are added,. maintaining the temperature lower than or equal to 5°C. It is left 1 hour with stirring, then 7. 74 g of dibutylamine are added drop by drop. It is left one night with stirring at ambient temperature.
The insoluble substance is filtered and the solvent is 20 evaporated to dryness. The residue is taken up in ether and the solution is washed with a dilute solution of hydrochloric acid, then with a dilute solution of sodium hydroxide and , finally, with a saturated aqueous solution of sodium chloride. The ethereal solution is dried over sodium sulfate, the solvent is evaporated to 25 dryness and the residue is distilled in vacuo. 6. 2 g of a pale yellow liquid are obtained.b.p/0. 01 mm: 170°C.
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 = l, X = H
shown in Table I hereinafter are thus obtained.
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, possi-35 bly, on the other hand, the amine used in the second step.
The products (I) shown in Table II hereinafter are thus ob-
t
tained.
Example 4
Butyl-5 ethyl-12 methyl-13 dioxo-6.11 diaza-5,10 pendadecane (CM 40195)
(I) R = CH3CH2-CH—CH- ; m = n = 1; X = H; Rj =
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 10 are added drop by drop. It is left one night with stirring at ambient temperature, then the reaction mixture is filtered and the solvent is evaporated to dryness.
The residue is taken up in ethyl acetate, washed with water then with a dilute solution of sodium hydroxide, again with 15 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 aza-5 20 decanoic-1 acid are thus obtained. 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 25 (100 ml) are added 6 g of dicyclohexylamlne and the mixture is left one night at 0°C. 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 hydro-30 chloric acid up to pH = 1. 5. The solution of sodium chloride is saturated' and extracted with ethyl acetate. The organic solution is washed three times 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 1-decanoic acid 35 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. /0. 01mm: 200°C.
Example 5
Dioxo-4,12 diaza-5,13 heptadecane (CM 40387)
(I) R = CH3CH2CH2-; m = 3; n = 2; X = H; R^H; R2=(CH2)3CH3
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 cont inued for
4 hours, then the mixture is acidified up to pH = 2 by hydrochloric acid. It is extracted with ethyl acetate, the solution is dried over sodium sulfate and the solvent is evaporated to dryness in vacuo.
An oil (4. 2g) is obtained which crystallises. It is re-crystallised in hexane; melting point by the Koffler method (m. p. k)
68°C.
b) To the solution of 2. 3 g of the acid obtained previously in 30 ml of dry tetrahydrofuran, are added 1.1 g of triethylamine,
then 1, 2g of ethyl chloroformate. It is left 2 hours with stirring, then the solution of 0. 85 g of butylamine in 5 ml of tetrahydrofuran is slow-
ly added. It is left with stirring for 15 hours at ambient temperature, then water is added and extracted with ethyl acetate. The organic solution 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: 132<>C.
Example 6
By operating as in Example 5 from different aminoacids 1_ and by
Ri w varying the reagents R-COC1 and the products (I) shown k2 —**
in Table III hereinafter are obtained.
Example 7
Dioxo-2, 7 djaza-1, 6 decane (CM 40401)
(i) r = ch3(ch^_. m _ n _ i; x = h; r = r£ = h.
a) To a solution of 17 g of oxo-6 aza-5 1-nonanoic acid (obtained according to example 1 a)) 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 30°C in vacuo and the residue is taken up in icy water. The mixture is neutralised by addition of sodium bicarbonate, thai extrac-
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 5 introduced in 300 ml of a 16% solution of ammonia in methanol. Stirring is carried out for 5 days at ambient temperature. The solvent is evaporated to dryness and the residue is taken up by ether. The sold is dewatered and washed with acetonitril.
Colourless crystals (10 g) are obtained, m.p.k: 135°C 10 (acetonitril ).
Example 8
(dimethoxy-3. 4 benzyl)-6 dioxo-4. 9 diaza-5,10 tetradecane
(CM 40187) jj- ^OCH3
(I) R = CH3CH2CH2- m=0; n=2; X= -CH2~^ XWOCH^R^H
R2 = -(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 20 the form of a colourless solid; m.p.k: 152°C.
The products according to the invention have been subjected to various tests concerning their pharmacological activity and, in particular, their action on the central nervous system. A) Pharmacological activity 25 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 measurement. The counting of the scores is effected by cutting of two perpendicular light beams.
Table IV hereinafter shows the results obtained with various products of the invention administered at the dose of 500 mg/ kg per os. The results are expressed in percentage of variation of 35 the scores obtained with respect to control animals which have not been treated.
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, 403 55, 40209; to specify the results obtained, the study for two products has been repeated in dose-effect according to the same protocol.
The results obtained are shown in T&ble 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 mg/kg, 1 hour before the pentobarbital injected by the intraperitoneal route at a rate of 20 mg/kg.
The percentage of the animals having lost the turning-
around reflex is determined. The results are expressed in percentage or, in some cases, in effective dose 50 (ED 50) or dose provoking narcosis in 50% of the animals treated.
The results are shown in Table VI hereinafter.
c) Electroencephalographic study
In order better to understand the hypnotic activity of the products according to the invention, 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 period 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 chronic administra-
tion, the animals are recorded the following 5 days (checling period). Results :
The animals are recorded 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 checking 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 %) paradoxal sleep/total
sleep (SP/ST) are evaluated (cf. Table VII hereinafter).
During 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) antiepileptic effect 10 The antiepileptic effect was determined vis-k-vis convulsive crises provoked by e-lectroshock or by bicuculline.
Electroshock (12. 5 V for 0. 5 sec) is effected in the mouse 60 mins. after administration of the product by the oral route.
Bicuculline is administered to the mouse by the intra venous route at a rate of 1 mg/kg, 60 mins. after the product to be studied has been given per os. The protector effect obtained vis-k-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 (ED 50) can be determined.
The results are shown in Table VIII hereinafter and show the clear antiepileptic properties of the products studied. B) Biochemical study 25 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 acid was evaluated on the 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 dopaminer^y
The effect of the products on the central dopaminergic activity 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 homovanillic acid (HVA) is evaluated in the whole brain, the animals receive an injection of probenecidum
(200 mg/kg i. p.) an hour and a half before sacrifice (batch of 10 animals).
The two products provoke similar effects on the rate of HVA, in particular, they provoke an increase in the rate 4 hours 5 after their administration and a considerable reduction 24 hours after their administration (cf. Table X hereinafter).
c) Acute toxicity
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 10 are observed for 24 hours and the mortality is noted.
The results expressed in percentage of mortality are shown in Table XI hereinafter.
They indicate that, at the dose of 500 mg/kg, none of the products studied showed any sign of acute toxicity. At 1000 mg/kg, 15 a very high dose, a few products show a 100% toxicity, but, in the majority of cases, acute toxicity remains low or zero.
The tests thus carried out show that the products according to the invention present interesting pharmacological properties and a low toxicity. Consequently, they may be used in human thera-20 peutics, particularly for the treatment of neurological and psychic disorders.
In 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. 25 These products may be administered 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, suppositories or injectable preparations.
The dosage may vary to wide proportions, in particular 30 depending on the type and seriousness of the disorder to be treated and according to the mode of administration. Most often, in the adult, by the oral route, it is included between 0.100 and 1 g per day, possibly spread out in several doses.
By way of examples of pharmaceutical compositions, 35 the following preparations may be cited:
Capsules
CM 4 003 9_ at 100 mj
CM 40039 100 mg
Aerosil 0. 5 mg
Magnesium stearate 1. 5 mg
Starch STA RX 1500 48 mg
150 mg
Tablets
CM 40142 at 200 m|
CM 4014?. 200 mg
Microcrystalline cellulose 100 mg
'Lactose 197 mg
Magnesium stearate 3 mg
500 mg
.table i
^ R1
CH3-(CH2)2-CO-NH-(CH2)3-CO-N^Ri
Code , numbei
*1
~ Melting point (°C) (solvent of. cristallisa-tion) or boiling point [°C (pressure)]
40 142 40 205
40 206 40 207
40 208 40 209
40 210
h h
(ch2)3CH3
-<ch2)7-ch3
h h
h
40 211
40 216
40 217 40 218
40 219
40 252
40 316 40 396 40 398
CH3
ch-ch--ch-2 j
— (ch2)2-ch3
120,5 (acetonitrile) 118 (acetonitrile)
84 precipitated and' washed with ether)
h
O
■ch - ch2-ch3
-(ch2)2-ch3
C18H37
102 (
62 (
134 (
1 22 (isopropanol)
iv 50°C (decomposition)
b,p„ : 185-190 (0,01 mm)
b. p. : 190-194 (0#01 mm)
124 (acfetonitrile) 60
(anhydrous ether)
h h h h
—ch2ch2oh
— ch
.-O
ch,
—(ch.,),ch
102 (acetonitrile)
132 (acetonitrile)
100 (acfetonitrile)
130 (acetonitrile)
TABLE I (cont. )
Code lumbei
R1
R2
Melting point (°c) (solvent of cristallisa-tion) or boiling point * [°c (pressare)J
40 463
h
-ch2ch3
124 (acetonitrile)
40 466
h
^ch3
-ch
^ch3
124 (acetonitrile)
40 521
h
-(ch2)4gh3
110 (acetonitrile)
40 532
h
-CH2<
124 (acetonitrile)
40 947
h
-(ch2)5-ch3 -(CH2>4-CH3
110 (acetonitrile)
40 984
-Cch2)4-ch3
Oil (dhromatographed)
40 987
h
-ch-ch-ch
97 (acetonitrile)
40 988 40 989
h h
1
ch3 ch3
-ch ch2-6h cho ch3
-c—ch2ch3
108 (acetonitrile) 72 (acetonitrile)
40 990
h
™3
ch3 -ch2-c-ch3 ch3
70 (acetonitrile)
-13
table. ii
/ '
r co nh— (ch.,), co — n
2
Co de
R
Melting^ jj>oint "
Boiling point ; (*0C(pressure) ]
numbe
R1
R2
ch3
40 254
H3C~V~
ch.
ch,
1 0
h
(ch2)3-ch3
88 (ether)
40 272
h,c — c — J 1
ch3
-(ch2),ch3
-(ch2)3-ch.
b.p; 165-167
(0#01 mm)
40 273
ch,-(ch2)6-
h
-(ch2)3-ch3
118 (acetonitrile)
40 274
ch3-(ch2)6
-Cch2)3ch3
-(ch2)3ch3
b. p:, 210-215
(0o01 moi)
40 417
h3c
^ch— CH?
h
-(ch2)3-ch3
(pthyl 1 1 0 acetate)
40 418
h,c 5 \
^ch — ch-/ ^
h,c
J
h
-Cch2)2-ch3
122 (acetonitrile)
40 440
>-
h
-Cch2)2-ch3
141 (acetonitrile)
40 443
O-
h
-(ch2)3-ch3
145 (acetonitrile)
40 462
^c>CH-
-(o^a-ota
-(cVs-ay b. pi 184 (0,01 mm)
40 467
h3c^ch-
h
-(012)3-013
98 (acetonitrile)
40 885
H3c-ch2chf^ch_
SC-C^CH^
h
-(ch2)3ch3
128 (ac6tonitrije)
TABLE III
I Code number
R
m n
X
R1
"2
Melting point ^ boiling point l.V (pressure) A„.
40 21 5
ch3-
2
2
h
—(c.ii2)3-ch3
— (ch2)3ch^
69 (ether-hexane]
40 253
ch3— (cii2)2 —
1
0
ii
11
— (ch2)3ch3
17Q (ether)
40 271
ch3— (c1i2)2 —
1
0
ii
— (c"2) 3c,i3
-(cm2)3ch3
b. p.: 165-7
(0#01 mm)
40 31 8
fh3
h3c-f-ch3
1
0
H
II
-(ch2)3ch3
74 (precipitated)
4 0 319
ch, 1 3
.l3c-c_ ch3
1
0
h
—cch2)3ch3
-(ch2)3ch3
b. p.- 136-140
(0^01 mm)
40 386
ch7
1 3
h c— c
3 1 ch3
3
2
ii
11
-(ch2)3ch3
82 /iso-pylic benzene ether
40 395
chj — (ch2)2
0
1
- ch3
11
— (ch2)3ch3
154 (acetonitrile)
40 397
ch3— (ch2)2
0
2
" CH3
ii
-Cch2)3ch3
110 (acetonitrile )
o
^T
o c"3 2
2
0
- cii3
ii
(CH2)3CI13
100 (aceco-ni tril e)
TABLE IV
N° Products
Vieasurement of actograph /p. cent scores^ > V /controls J
40 21 7
- 37 *
40 059
PRR
40 206
- 8
40 271
- 5 3 s*
40 401
- 20
40 398
+ 54 **
40 142
+ 5 0**
40 316
+ 16
40 395
- 35
40 397
+ 91 **
40 404
+ 52 **
40 272
- 47 **
40 31 9
- 51 **
40 253
+ 33 *
40 355
+ 62 **
40 209
+ 36 s
40 254
- 2
TABLE IV (cont. )
N° Products
Measurement of actograph
(p. cent scores/ controls)
AO 386
- 57 **
40 417
+ 56 **
40 418
+ 93 **
40 443
+ 78 **
40 463
+ 41 **
40 466
+ 97 i*
40 467
+ 115 **
40 521
+ 101 **
\
40 947
+ 37 *
* p^0,05 ** p^0,01
TABLE. V
Dose effect of 40 039 and of 40 142 on actograph.
CM 40 039
Dose (mg/kg p. os)
40
80
160
p. cent scores/
/controls
- 30 X
- 38 XX
- 37 XX
. - 28
X p N< 0,05
XX
p ^ 0,01
CM 40 142
Dose (mg/kg p. os)
100
200
300
400
p. cent scores/
ycontrols
+ 1
+ 31
+ 38 XX
+ 50 XX
p ^ 0,01
TABLE VI
N° Products
Percentage of animals in narcosis at 500 mg/kg p. os or dose (p. os) provoking 50 1 of induction of narcosis (ED 50)
40 21 7
0
40 039
ED 50 = 200
40 216
100
40 206
0
40 271
1 00
40 401
0
40 398
ED 50 = 350
40 142
ED 50 = 297
40 316
70
40 395
70
40 397
100
40 404
40
40 272
72
40 319
ED 50 = 175
40 253
50
40 355
40
40 254
50
40 318
90
40 4 43
40
40 46 2
40 466
40 98 4
60
40 9 8 9
50
TABLE. VII
Analysis of the encephalographic outline per hourly section of 24 hours
Controls
Treated 40039 (325 mg/kg)
Check
EV
44,2 - 3,3
40.6 - 3 XXX - 8,1
4 0.3 - 3,6 XXX - 8,8
SL
48,3 - 2,5
51,5- 2 XXX + 6,6
51 - 3 XX + 5.6
SP
7,6 - 1.4
8,1 - 1,4 n.s. + 6,6
8,6 - 1,7 X + 15.2
ST
55,9 - 3
9.5 - 2.6 XXX + 6.4
59,6 - 3.9 XXX + 6,6
SP/ST
12,8 - 2,1'
13.2 - 1.9 n.s. + 3,1
13,5 - 1,8 n.s. + 5,5
x p ^ 0,1 xx p ^ 0,05 ; xxx p ^ o.oi
• • • • • •••
TABLE. VIII
N° Products"
Median effective dose of protection from tonic crises
(.ED 50) (mg/kg p. osj
Bicuculline
Electroshock
40 039
300
250
40 142
325
150
40 253
< 500
500
40 254
<500
-
40 271
<500
500
40 379
450
-
40 418
300
-
40 462
150
500
40 463
380
-
40 467
150
< 500
40 521
250
180
40 947
250
400
TABLE. . IX
Controls
Treated 4 0039 500 mg/kg p. os p. cent/-
/controls
Rate of amino butyric acid in. }Jg/g brain
280 - 8
321 - 12 *
14,6
* P ^ 0,05
TABLE . X
Rate of HVA in ng/g
0
2 hr i. 4 hn
6 hrs,
24 hrs.
40 039
500 mg/kg p.os
658-40
798-34 + 21 U
894-37 + 3 6 ?o XX
659-29 0%
441-19 - 3 31XX
40 142
500 mg/kg p.os
521-29 »
379-11 - 27°oXX
793-52 + 5 2 o XX
571-23 + 9
290-16 - 44 XX
X p ^ 0,05 XX p ^ 0,01
TABLE XI
N° Product p. cent of mortality at 500 mg/kg p. OS
at 1000 mg/kg p. OS
40 039
0
100
40 142
0
0
40 206
0
0
40 209
0
40 216
0
100
40 21 7
0
0
40 253.
0
0
40 254
0
40 271
0
100
40 272
0
0
40 31 6
0
0
40 31 9
0
0
40 355
0
0
40 395
0
40 397
0
40 398
0
0
40 401
0
0
40 404
0
0
TABLE XI (cont. )
N Product p. cent of mortality at 500 mg/kg p. OS
at 1000 mg/kg p. OS
40 417
0
40 418
0
0
-40 443
0
0
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
0
80
iqt/IO
Claims (12)
1. Amides of aminoalkanoic acids corresponding to general formula: R-CONH - (CH-) - CH - (CH-) - CON (I) 2 m i 2 n \ X R2 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), or a phenylalkyl group in which the phenyl group is optionally substituted, and R^ 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 an optionally substituted phenyl group, or R-^ and R2 considered together with the nitrogen atom to which they are attached represent a saturated or unsaturated heterocyclic ring with 5 or 6 ring atoms .optionally with a second heteroatom.
2. A process for preparing the amides according to Claim 1, wherein the starting product is constituted by a compound of formula: x H-N - (CH_) - CH - (CH„) - COOR1 2 2. m 2 n in which m, n and X have the Iheaning given in Claim 1 and R' is a lower alkyl group (1 to 4 carbon atoms), said product is reacted with an acid chloride of formula R CO CI so as to convert the amine of the starting product into a amide radical and^ product obtained is subjected to an amidification with a product of formula HNr~"Rl. Aj'v,
3. A process for preparing the amides according to Claim 1,^-y, wherein the starting product is constituted by a compound of 198110 - 25 - formula: X H0N - (CH0) - CH - (CH~) ~ COOR' 2 2 m Z n in which m, n and X have the meanings given in Claim 1 and R" is a hydrogen atom, said product is reacted with an acid chloride of formula R CO Cl so as to convert the amine of the starting product into an amide radical and the product obtained is subjected to an amidification with a product of R1 formula HN^ R2
4. The process according to Claim 2, wherein said amidif ication is effected by reaction of a product in which R' is lcwer alkyl (1 to 4 carbon a tans) with the amine , operating in solution in lower alcohol (1 to 4 carbon atoms) or using an excess of said amine as solvent, and at a temperature of between 0 and 50°C.
5. The process of Claim 3, wherein a starting product in which R' is hydrogen is first converted to a starting product in which R' is lower alkyl (1 to 4 carbon a tans) and the latter is reacted with the acid chloride and then subjected to the amidif ication.
6. The process of Claim 3, wherein amidification is effected on a mixed anhydride of the product obtained (R' = H) by action on the product obtained of ethyl chloroformate in the presence of an alkaline agent.
7. A composition useful for the treatment of neurological and psychic disorders, wherein it comprises, as active ingredient, at least^one product according to Claim 1.
8. The composition of claim 7, wherein it is prepared in a form suitable for daily administration to man at a dose of 0.1 to lg of the active ingredient in one or more doses.
9. The composition of claim 8, wherein it is prepared in a form suitable for oral administration.
10. The composition of claim 8, wherein it is prepared in a form suitable for administration by injection.
11. Amides of aminoalkanoic acids substantially as>^p^^rfically f/' described herein in any one of the Examples. '/ ^ g - 26 -
12. A process for preparing amides of aminoalkanoic acids substantially as specifically described herein in any one of the Examples. by their attorneys BALDWIN SON & CAREY 24M AYtW
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
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 |
---|---|
NZ198110A true NZ198110A (en) | 1984-12-14 |
Family
ID=9245433
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ198110A NZ198110A (en) | 1980-08-27 | 1981-08-20 | Amides of amino alkanoic acids:pharmaceutical compositions |
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) | ES8206445A1 (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) |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE62222T1 (en) * | 1985-02-15 | 1991-04-15 | Res Corp Technologies Inc | AMINO ACID DERIVATIVES AND THEIR APPLICATION FOR THE PREPARATION OF AN ANTI-SEMPK AGENT. |
US5654301A (en) * | 1985-02-15 | 1997-08-05 | Research Corporation Technologies, Inc. | 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 |
CA2378955A1 (en) * | 1999-08-10 | 2001-02-15 | Uab Research Foundation | Use of gaba agonists for treatment of spastic disorders, convulsions, and epilepsy |
KR100843703B1 (en) | 2000-07-21 | 2008-07-04 | 이섬 리서치 디벨러프먼트 컴파니 오브 더 히브루 유니버시티 오브 예루살렘 | Use of derivatives of valproic acid and 2-valproenic acid amides for the treatment of mania in bipolar disorder |
EP1604656A1 (en) | 2004-06-09 | 2005-12-14 | Schwarz Pharma Ag | Novel use of peptide compounds for treating amyotrophic lateral sclerosis (ALS) |
CL2007003426A1 (en) * | 2006-11-30 | 2008-04-25 | Cenerx Biopharma Inc | COMPOUNDS DERIVED FROM DIALQUILAMINOALQUILO DE PIGAVABINA; PREPARATION PROCEDURE; PHARMACEUTICAL COMPOSITION; AND ITS USE TO TREAT AFFECTIVE, DEPRESSIVE, ANXIETY DISORDERS. |
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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 IE IE1835/81A patent/IE52415B1/en unknown
- 1981-08-11 GR GR65767A patent/GR75299B/el unknown
- 1981-08-13 AT AT81401299T patent/ATE21099T1/en not_active IP Right Cessation
- 1981-08-13 DE DE8181401299T patent/DE3175030D1/en not_active Expired
- 1981-08-13 EP EP81401299A patent/EP0046707B1/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 DK DK378781A patent/DK378781A/en not_active Application Discontinuation
- 1981-08-26 JP JP56132669A patent/JPS5772949A/en active Pending
- 1981-08-26 ES ES505004A patent/ES8206445A1/en not_active Expired
- 1981-08-26 NO NO812890A patent/NO156608C/en unknown
Also Published As
Publication number | Publication date |
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JPS5772949A (en) | 1982-05-07 |
EP0046707B1 (en) | 1986-07-30 |
AU547392B2 (en) | 1985-10-17 |
ES505004A0 (en) | 1982-08-16 |
DE3175030D1 (en) | 1986-09-04 |
PT73558B (en) | 1982-11-03 |
AU7425981A (en) | 1982-03-04 |
NO812890L (en) | 1982-03-01 |
FR2489319A1 (en) | 1982-03-05 |
NO156608B (en) | 1987-07-13 |
ATE21099T1 (en) | 1986-08-15 |
CA1208230A (en) | 1986-07-22 |
NO156608C (en) | 1987-10-21 |
DK378781A (en) | 1982-02-28 |
IE811835L (en) | 1982-02-27 |
PT73558A (en) | 1981-09-01 |
IE52415B1 (en) | 1987-10-28 |
EP0046707A1 (en) | 1982-03-03 |
GR75299B (en) | 1984-07-13 |
FR2489319B1 (en) | 1984-04-06 |
ZA815662B (en) | 1982-08-25 |
ES8206445A1 (en) | 1982-08-16 |
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