CA1041015A - Acetic acid derivatives pharmacological activity and compositions containing the same - Google Patents
Acetic acid derivatives pharmacological activity and compositions containing the sameInfo
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- CA1041015A CA1041015A CA229,907A CA229907A CA1041015A CA 1041015 A CA1041015 A CA 1041015A CA 229907 A CA229907 A CA 229907A CA 1041015 A CA1041015 A CA 1041015A
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- C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/08—Antiepileptics; Anticonvulsants
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Abstract
ABSTRACT OF THE DISCLOSURE
Acetic acid derivatives having the general formula:
(I) and their pharmaceutically acceptable alkali metal salts, wherein R represents a radical of the formula:
or
Acetic acid derivatives having the general formula:
(I) and their pharmaceutically acceptable alkali metal salts, wherein R represents a radical of the formula:
or
Description
This inven~ion relates to acetic acid derivatives hav-ing pharmacological activity, to pharmaceutical and veterinary compositions containing them and to ~ proce~s for preparing these derivative 9, Ihe pharmacologically active compounds with which the present invention is concerned arethe scetic acid derivatives re-presented by the general formula:
R_C-OH (I) -wherein R represents the radical 1\ 1~
CH (CH2)n CH or C=CH_ ~:R2 R3 R2 in ~hich R1 and R2 are the same or different and each represent an alkyl rsdical having from 1 to 4 carbon atoms, R3 represents a hydrogen atom or a methyl radical and n is an integer in the range - of from O to 3 inclusive, as well as the pharmaceutically accept-able alkali metal salts of these compounds.
In accordance with another aspect of the invention there i~ provided a pharmaceutical or veterinary composition comprising, aa an essential active ingredient, at least one acetic acid derivative of formula I, or a pharmaceutically acceptable alkali metal salt thereof, in association with a pharmaceutical carrier or e~cipient ~herefor, Aa will be described in greater detail further on, it has been found that the acetic acid derivatives of the general formula (I) are endowed with biochemical and pharmacological pro-perties likely to render them particularly u~eful in the treat-ment of pathological conditions due to disturbances of the central nervous system, 104~015 Pharmacological and biochemical tests have shown -that the compounds of formula (I) and their alkali metal salts can act as competitive inhibitors with respect to -the action of ~-amino-butyric ~-ketoglutaric transaminase and also as anticonvulsant and antianoxic agents. Consequently, these compounds will con-stitute particularly valuable agents for treating various kinds of central neurological disorders whether resulting or not from cerebral ischemia and including, in particular, convulsive states and seizures, in a host in need of such treatment.
Daily dosage will preferably be between 400 and 2000 mg of active principle by any route for a human being weighing 60 kg, for example about 1000 mg by oral or rectal route.
Amongst the compounds of formula (I), a certain number are known products. In this connection may be cited:
3-Methyl-butanoic acid, 3-methyl-pentanoic acid and 4-methyl-pentanoic acid which are cited in U.S. Patent no.2,484,486.
Furthermore, this same U.S. Patent also generically covers the whole of the compounds of formula I wherein R represents RlR2CH-(CH2)n-CHR3 in which Rl and R2 have the same meaning as in formula I, R3 represents hydrogen and n is 0.
3-Ethyl-pentanoic acid and 3-ethyl-2-pentenoic acid which are described in Berichte 42, 4710-4713.
3-n-Propyl-hexanoic acid which is cited in Chem.
Abstracts, 35, 47336 (1941).
4-n-Propyl-heptanoic acid which is mentioned in Ann.
Chem. 693, 90-98 (1966).
5-n-Propyl-octanoic acid which is disclosed in Physiol.
;- Chem. 282, 135-142 (1947).
3-n-Propyl-2-hexenoic acid and 3-isobutyl-5-methyl-2-hexenoic acid which are described in J. Chem. Soc., 129, 1549-1555 (1927).
The compounds of formula (I) in which R represents ~ - 2 -,: --(CH2)n-CHR3 wherein R1 and R2 each represent methyl or ethyl and R3 represent~ methyl with n equal to 0 ~rhich are covered by U,S Patent no 2,484,500.
However, as far a~ i9 known, no therapeutic activity has ever been ~ttributed to these compounds of formula (I) cited hereabove with the exception of 3-methyl-pentanoic acid which is included in the composition of officinal valerianic acid known for its sedative properties [MERCIER, ~es Médicament~ du système nerveux cérébro-spinal p. 171 (1959~
The other compounds of formula (I) can be considered as novel product~ In fact, searches have not revealed any publica-tion with respect to these other acids of formula (I) Similarly, the pharmaceutically acceptable alkali metal salts of the compounds of formula (I) can also be regarded as novel compounds.
In consequence, the invention also relates, as new com-pounds~ to the pharmaceutically acceptable alkali metal salts of the acid derivatives of formula ~I) and more particularly, a~
preferred compounds, to the pharmaceutically acceptable alkali metal salts corresponding to the general formula:
3 7 \ 1l 1 H_(CH2)n 2 . C3H7/
whRrein Me represents an alkali metal atom, for example lithium"
sodium or potassium, and n is an integer in the range of from 0 : to 2 inclusive. ~ -i~he acid derivatives of formula (I) and their pharmaceuti-- cally acceptable alkali metal salts can be obtained by various procedures in accordance ~ith their chemical structure Ihus, the compounds of formula (I) wherein R represents _3_ ' ' ' ' ,: ~, 1~4101S
R1R2CH-(CH2)n-CHR3 may be prepared a9 follows:
a) V~en n i9 O, by hydrogenating in an appropriate solvent such as for example absolute ethanol and in the presence of a catalyst 3uch as for example Raney's nickel~ a mixture of ethylenic acids ~ -obtained by dehydrating, for example with acetic anhydride, a~ - j hydroxy acid of the general formula:
1~
C_CH_C_OH (II) R2 OH ¦ , 3 ¦
wherein R1, R2 and R3 have the aforesaid meanings, which yields .the required compound of formula (I) in free acid form; when a l .
pharmaceutically acceptable alkali metal ~alt thereof is desired, the scid derivative obtained is further treated with an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, to provide the required salt. The hydrogenation is carried out under pressure and by heating the mixture of ethylenic acids in .~
question and the dehydration is preferably effected by heating the .;
reagents.
b) When n i9 1 to 3, by oxydizing, for examplè by means of chromic anhydride, in an appropriate solvent such a~ for example acetic acid, an alcohol of the general formula:
, , R1 / CH~(CH2)n~CH~CH2H (III) R2 3 .
wherein R1, R2 and R3 have the aforesaid meanings and n is an integer 10410~5 in the range of from 1 to 3 inclusive, to ~btain the required compound of formula (I) in free acid form; when a pharmaceutically acceptable alkali metal salt thereof i~ desired, the acid deriva-tive obtained i~ further treated with an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, to provide :~
the required ~alt.
The compound~ of formula (I) wherein R represents R~R2C=CH- can be obtained by dehydrating, for example by means of acetic anhydride, the appropriate ~-hydroxy acid derivative of formula II, corresponding to the general formula:
R1~
C_CH2_C_OH (IV) wherein R1 and R2 have the aforesaid meanings, to form the required ¢ompound of formula (I) in free acid form; when a pharmaceutically acceptable alkali metal salt thereof is desired, the acid deriva-tive obtained is further treated with an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, to provide the required salt.
~he dehydration may be effected by heating the reagents for exsmple under reflux, - ~he compounds of formula (II) can be prepared by react-ing a dianion obtained from an aromatic hydrocarbon such as naphtalene or anthracene, an alkali metal such as lithium, sodium or potassium and an acid of the general formula:
. O
R3~CH2~C~H ~) -wherein R3 ha~ the afore~sid meaning, with a ketone of the general formula:
Rl-C-R2 (VI ) wherein R1 and R2 have the aforesaid meanings, in an anhydrous ether such as ethyl ether, hydrolysing the alkali metal salt 90 obtained and subsequently acidifying the salt to form the required B -hydroxy acid derivative All the acids of formula (V) and ketones of formula (VI) are known and commercialized compounds.
Similarly, the compounds of formula III are either known compounds or can be prepared by the method described in Ann Chem. 1966, 693, 90-98, As alresdy mentioned, the acetic acid derivative~ of general formula (I) and their alkali metal salts have been found to possess valuable biochemical properties, and in particular a marked competitive inhibitory effect with respect to the action of ~ -aminobutyric a-ketoglutaric transaminase. These compounds also possess powerful pharmacological activity and more particularly marked antianoxic and snticonvulsant properties.
~ hese propertie~, when taken as a whole, are likely to render ~uch compounds useful for treating various kinds of central neurological disturbances whether resulting or not from cerebral i~chemia.
As an example of such central neurological disturbances or of disorders indlced by central neurologicsl dysfunction, the following may be cited: convulsive state~ and seiæures such as, for exsmple~ epilepsy, choreic states such as Huntington's chorea, difficulties with respect to memory, bala~ce and fixing the attention, as well a9 dizziness, decrease of arterial pressure, cephslslgia and comatose states.
~ -Aminobutyric acid or GABA i~ an important constituent of the brain of the vertebrates. At present, it represents the 1~410~
only known physiological inhibitor of the pre- and postsynaptic discharges which it has been possible to isolate in the brain.
Furthermore, this acid plays an all important role in the ease of choreic patients in whom cerebral depletion in GAsA has been observed.
The normal oxidative metabolism of the carbohydrates leads in particular to the production of a-ketoglutaric acid through the medium of the tricarboxylic cyele of KREBS. Fromthis point, a deviation oeeurs whieh results in the formation of GABA.
Various enzymes regulate by natural processes the pro-duetion and destruetion of this acid and of GABA itself whieh is re-transformed into ~-ketoglutarie acid, this latter aeid being taken up again in the KREBS' eyele. The activity of these enzymes ean itself be either aceelerated or inhibited by several substances.
It has been discovered, in aecordance with the invention, that the aeetie acid derivatives of formula (I) and their alkali metal salts are capable of produeing a eompetitive inhibitoryeffeet with respeet to the aetion of ~-aminobutyrie ~-ketoglutaric trans-aminase or GABA T which destroys GABA. Such an inhibitory effeet eonsequently produees an inerease in the GABA level inthe organism.
These bioehemieal properties are likely to produee more partieularly an antieonvulsant aetion in pharmaeology and in elini-eal use to exert antiepileptie and antiehoreic effeets.
Furthermore, the eompounds of formula (I) and their alkali metal salts have been found to be strong antianoxie agents eapable in partieular of delaying the onset of eerebral pain due to oxygen defieieney i.e. originating from eerebral isehemia.
Cerebral isehemia ean be provoked by numerous faetors sueh as, for example: eerebral vaseular defieieney due to senes-eenee, thrombosis or tumors. At present eerebral vasodilators areeommonly used in order to delay the onset of eerebral pain due to oxygen defieieney or to treat cerebral vascular deficiency and ,~
104:10~5 its resulting dlsorders for example central neurological dis-turbances such as those cited hereabove.
However, such drugs must be employed in accordance with the vascular state of the patient. Since these compounds act by mechanical means,namely by dilating the arterioles toincrease the blood flow and consequently the amount ofoxygen in the brain,they will be ineffective, for example in cases involving arteriosclerosis.
Furthermore, certain agents can provoke a marked cerebral vasodilation of the healthy parts which upsets the circulatory equilibrium. As a consequence of this, a decrease of irrigation in the ischemic parts can occur.
The compounds of formula (I) and their alkalimetal saltson the other hand do not present these disadvantages as they do not act by mechanical means but exert theireffectdirectly onthe meta-bolism of the nervous cells without affecting, theconditions of irrigation. Theydo, infact, act by bringing about aneconomy and a better use of oxygen in the nervous cells. These antianoxic pro-perties will also be useful for preventing convulsive seizures as it is well known that anoxia can induce such seizures.
In the light of these different properties, the compounds of formula (I) and their alkali metal salts will be likely to con-stitute valuable antianoxic agents, for exemple, for treating cen-tral neurological disturbances due to cerebral ischemia, particu-larly in cases where the classic drugs are ineffective.
In the field of diseases requiring anticonvulsant therapy and, in particular, epilepsy, there are numerous drugs of undeniable efficacy. However, these classic medicaments, such as the barbi-turates and molecules of similar structure cause an overall de-pression of the central nervous system, which moreover, explains their anticonvulsant effect.
For this reason, such drugs frequently cause undesirable side-effects such as difficulty in fixing the attention, reduction rA~ ~
104~015 in intellectual efficiency and somnolence as well as biological disorders of which the most serious are hematological.
The compounds of formula (I) do not present these dis-advantages since they do not act by provoking a general depression of the central nervous system but, on the contrary, the~ function by means of an enzymatic mechanism involving the metabolism of a neurotransmittor which is a physiological inhibitor namely -aminobutyric acid. Furthermore, certain well-known anticonvul-sant agents are toxic at relatively low doses while others are only useful for the treatment of one single type of epilepsy.
The compounds of formula (I) and their alkali metal salts do not present these disadvantages since they are relatively non-toxic and at the same time possess a very wide range of properties which are likely to render them useful in the treatment of an extremely broad variety of convulsive states.
Compounds of a similar chemical structure to that of the compounds of formula (I) and their alkali metal salts, namely dialkylacetic acid derivatives which possess anticonvulsant pro-perties have been published in U.S. Patent no. 3,325,361. A de-tailed study has been carried out with sodium di-n-propylacetate which is the preferred compound of the above-cited U.S. Patent.
This study, which is reported in J. of Neurochemistry, 1969, Vol. 16, pp. 869-873, showed that sodium di-n-propylacetate is capable of increasing the level of intracerebral GABA by in-hibiting GABA T. Up to present, no other therapeutic substance is known which possesses this property. This property endows sodium di-n-propylacetate with powerful anticonvulsant activity and a completely original mechanism of action.
Similarly, it has been demonstrated, as reported in Bull.
Soc. Sci. Vét. et Méd. comparée, Lyon, 1970, 72, pp. 303-325, that sodium di-n-propylacetate possesses very marked antianoxic pro-perties.
.
.-~ rAl ~ 9 , '. ~
-At present, sodium di-n-propylacetate is widely commercialized as an antiepileptic agent.
Ho~,7ever, it has been discovered in accordance with the present invention that the acetic acid derivatives of formula I
as well as their pharmaceutically acceptable alkali me-tal salts, possess the above-cited properties of sodium di-n-propylacetate but to different degrees which confer on them an originality of action as compared with this latter product.
Thus,pharmacologicaltests haveshown thatatleastone of the three biochemicalandpharmacologicalactivities citedhereabove is moreintense inthe caseof the compounds of formula (I) andtheir alkali metalsalts than in that of sodium di-n-propylacetate.
In therapeutic use this essential difference between sodium di-n-propylacetate and the compounds of formula (I) will be likely to render the latter more selective for the treatment of certain kinds of central neurological disorders whether result-ing or not from cerebral ischemia. For example, the compounds of ~ formula (I) and their alkali metal salts which have been found to - be more active than sodium di-n-propylacetate as competitive inhi-bitors of GABA T will be likely to be more effective, for example, - in the treatment of choreic states. On the other hand, the com-pounds of formula (I) and their alkali metal salts which have shown better antianoxic properties than sodium di-n-propylacetate will ~ be more active in the treatment of central neurological disorders - due to cerebral ischemia.
Disturbances and dysfunction of the central nervous system whether of ischemic origin or not are numerous and consti-tute one of the most widespread disorders at the present time.
For this reason, it is very difficult for the doctor to choose amongst the various drugs at his disposal, that which will be effective for the particular case under treatment. When faced with a case of chorea, epilepsy or other affection, the neurologist is often obliged to feel his way by trying several drugs one after the other vntil he discovers the most suitable medication.
104~015 From this point of view, acetic derivatives of formula (I) and their pharmaceutically acceptable alkali metal salts will constitute valuable additions to the therapeutic arsenal at the disposal of the doctor and, if necessary, will provide useful replacement medication for a drug which has become ineffective for any reason such as, for example, a change in the state of the patient or habituation.
The compounds which have been found to be particularly useful for the treatment of central neurological disturbances whether originating or not from cerebral ischemia and in particular epilepsy are:
3-n-Propyl-hexanoic acid 4-n-Propyl-heptanoic acid and 5-n-Propyl-octanoic acid as well as their pharmaceutically acceptable alkali metal salts.
Pharmacological trials have been undertaken with a view to determining the presence of a competitive inhibitory effect with respect to the action of r-aminobutyric a-ketoglutaric transaminase, as well as antianoxic and anticonvulsant properties which, taken together, are capable of rendering the compounds of formula (I) and their pharmaceutically acceptable alkali metal salts useful for treating central neurological disturbances whether originating or not from cerebral ischemia.
I. Inhibition of GABA T.
This test was undertaken "in vitro" in the absorption cell of a double-beam U.V. spectrophotometer.
The activity of GABA T was determined by coupling this enzyme with an excess of succinosemialdehyde dehydro~enase (NADP~) so that the rate of formation of the succinosemialdehyde dehy-drogenase coenzyme (NADPH) was limited by the activ ty of theGABA T. The coupling of the two reactions was as~follows:
GABA T
GABA ~ a-ketoglutarate ~ glutamate ~ succinosemialdehyde.
r -- 11 --In the presence of succinosemialdehyde dehydrogenase of which the active element is NADP~, the reaction became:
succinosemialdehyde ~ NADP~ + H2O ~succinate ~ NADPH ~ H~.
The overall reaction can be represented by the following equation:
GAsA t a-ketoglutarate ~ NADP ~ H2O >succinate + glutamate t NADPH ~ H~.
The activity of GAsA T was measured by following the reduction rate (v) of NADP~ which corresponds to the evolution of the optical density at 340 m,u on the spectrophotometer.
Determination of the activity rate of GABA T by the principle hereabove described can be effected with either limiting concentrations or a saturating concentration of one of the sub-strates, in the present case GAsA, in each instance, in the pre-sence of a saturating concentration of the second substrate namely a-ketoglutarate. Thus, it is possible to discover the activity rate of GABA T in relation to the concentration o~ GABA and in this way, to determine the affinity of GAsA T for GAsA.
Similar measurements of the activity of GABA T were then carried out in the presence of different concentrations (i) of an inhibitor namely a compound of formula (I) or a pharmaceutically acceptable alkali metal salt thereof, so as to evaluate the ef-fectiveness of the latter. This effectiveness is represented by the constant Ki or constant of inhibition which determines the affinity of the enzyme (GABA T) for the inhibitor.
This constant is expressed in units of concentration, in the present case, in m mol per ml and can be determined by plotting all the curves corresponding to 1 = f (i) for a saturating concen-tration of GAsA and for different limiting concentrations of GAsA.
The point of coincidence of these curves determines the Ki in question or the necessary concentration of inhibitor to arrest completely the activity of the GABA T. l'he lower the Ki value is, the greater is the effectiveness of the inhibition of GABA T by the compound tested.
The following experimental procedure wa~ used:
In the absorption cell (optical passage : 1 cm, volume :
about 1 ml) the ~ollowing solutions were introduced.
0.5 ml of a 1.5 molar solution of sodium ~ulphate 0.05 ml of a molar buffer solution of pH ~ 7.9 0.05 ml of a 0.1 molar solution of mercapto-ethanol 0,05 ml of a 20 mg/ml solution of NADP~
0.125 ml of a solution of G~BA
0,03 ml of a 40 mg/ml solution of GABASæ (namely a bacterial enzyme isolated from Pseudomonss fluorescens containing a mixture of Y -aminobutyric a-ketoglutaric transaminase and succinosemialde-hyde dehydrogenase).
0.125 ml of 8 solution of the compound to be studied, If the compound to be studied was in the form of a water-insoluble acid, its sodium salt was used after adjustment to a pH
of about 7,9 by adding a titrated solution of sodium hydroxide.
Different measurements of optical density were effected by varying the concentration of GABA and the concentration of the compound under study. Control assays were also effected by re-placing the solution of the compound to be studied by 0~125 ml of water, ~ he content of the absorption cell wa~ allowed to incu-bate for 10 minutes at 30C and then the enzymatic reaction was ~tarted by adding 0.1 ml of a 0.02 molar solution of ~-ketoglut~-rate in the absorption cell, The final volume was 1.03 ml, The réaction was then followed by spectrophotometric recording of the reduction rate of the NADP~ at 340 m~ and at 30C, The optical density was sutomatically registered every 30 seconds.
In accordance vnth the process hereabove described, the following compounds were studied. ~hese compounds were pre-~41015 ferably tested in the form of a pharmaceutically acceptable alkali metal salt~ for example the sodium salt.
The pharmaceutically acceptable alka-li metal salts of the acids of formula (I) such as the sodium salt, are in fact more advantageous than the acids them~elves. These salts have a much milder irritant effect upon the upper part of the digestive tract than the acids.
Thus, the pharmaceutically acceptable alkali metal salts of the acids of formula (I) present an undeniable superiority over the corre~ponding acids, This will serve to reduce considerably the undesirable side-effects when the salts are used in therapeutics.
3-n-Propyl-hexanoic acid (Compound A) 4-n-Propyl-heptanoic acid (Compound B) 5-n-Propyl-octanoic acid (Compound C) 3-Methyl_butanoic acid (Compound D) 3-Ethyl-pentanoic acid (Compound E) 3-n-Butyl-heptanoic acid (Compound F) 3-n-Propyl-2-hexenoic acid (Compound G) ~he following Ki were registered ~ith these different compound~:
~ABIE I
Com ound K (in m mol/~l) P
A 0,63 + 0.15 B 1.05 + 0.20 C 1.18 + 0,50 - 0.51 + 0.14 E 2.15 - 0.50 F 1,06 + 0,58 0.70 + 0.17 ,~ , A comparative test carried out, under the 3ame conditions with sodium di-n-propylacetate gave a Ki of 0.8 m mol/ml, This re~ult shows that Compounds A, D and G are more active than sodium di-n-propylacetate in this test while Compounds ~ and ~ are slightly less active in this testO
II, Antianoxic activi~.
.
Action on the anoxic seizure induced by gallamine triiodoeth~late.
____________ ___ ___________________ _____________________ ____ The injection of a sufficient dose of a synthetic curariform substance such a9 gallamine triiodoethylate provokes in the mouse paralysis of the diaphragm. The animal then dies through asphyxia, An intraperitoneal dose of the compound to be studied was administered to batches of 20 mice five minutes before the administration of 16 mg/kg of gallamine triiodoethylate by intra-peritoneal route, ~he dose of the compound to be tested W39 calculated 80 that each batch received a higher dose than the pre-ceding batch.
The period of survival of the trested ani-mals was noted in comparison with that of the controls which had not received the compound under study. The period of time of survival was registerea by controlling cardiac arrest by means of an electro-- cardiogram.
Under these conditions, an antianoxic effect produces an increase in the period of survival of the animal.
The following results were recorded:
., I
TABIE II
Compound Dose admir,istered% of increase in the in mg/kgperiod of survival in comparison with the contro~
. _ ; 30 D 250 73 . , .
¦ E 1 151O4 lO 1 5 ¦
A comparative trial undertaken with sodium di-n-propyl-acetate, under the same conditions, showed that a dose of 330 mg/kg of this product increases by 40% the period of survival of the animals in comparison with the controls.
Table II hereabove shows that Compounds D and E are appreciably more active than sodium di-n-propylacetate as anti-anoxic agents while at the doses studied Compounds A, F and G
appear to be slightly more active than sodium di-n-propylacetate.
III. Anticonvulsant activity.
This test is carried out on mice with a view to deter-mining whether the compounds of formula (I) and their pharmaceu-tically acceptable alkali metal salts, when given preventively by intraperitoneal route, are capable at certain doses of pro-tecting some of the animals against the epileptic seizure pro-duced by an adequate and predetermined dose of pentylenetetrazol which would be 100% fatal in the absence of the compound.
The test was carried out on batches of 10 mice. Each batch of animals received an intraperitoneal dose of the compound to be studied so that each batch received a higher dose than the preceding batch. Fifteen minutes after administration of the compound to be tested, the animals were each given 125 mg/kg of pentylenetetrazol by intraperitoneal route. The percentage of deaths was noted 3 hours after injection of this latter compound and the result was expressed as a percentage of protection.
The results obtained are given in the following Table:
- TABLE III
30Compound in mg/kg% of protection A 160 ~100 10~1015 F' 185 95 A comparative trial performed with sodium di-n-pro-pylacetate under the same conditions showed that a do~e of 250 mg/kg of this product protects 100~o of the animals against the pentylene-tetrazol-induced seizure.
~hese results indicate that Compounds A and F are more active, in this test, than sodium di-n-propylacetate.
0 A9 against this~ it was observed that Compound~ B and C
exert their action over a longer period of time than sodium di-n-propylacetate, Thus, 195 mg/kg of Compound ~ and 210 mg/kg of Compound C both of which offer about 100% protection against the pentylene-tetrazol-induced seizure, still protect 40~o and 70~o respectively of the animals one hour after ad-ministration As against this, a dose of 250 mg/kg of sodium di-n-propylacetate only offers, in this test, 20~o protection of the animals~ one hour after administration~
Furthermore~ additional trials performed in accordance with the process described hereabove have shown that a dose of Compound A as low as 105 mg/kg administered by intraperitoneal route, offers 85~o protection against the pentylenetetrazol-induced seizure, Similarly, it was found that a dose of 125 mg/kg of Compound C, also administered by intraperitoneal route, protects .- 65% of the mice against the pentylenetetrazol-induced seizure.
IV Acute toxicit~.
Acute toxicity was aetermined on the mouse. For this purpose, a dose of the compound to be tested was administered to batches of 5 mice, by intraperitoneal route, 90 that each batch received a higher dose than the preceding batch, 104~015 ~he following results ~rere obtained:
~om~ounds LD
Furthermore, the IDo of Compounds A and D, namely the maximum tolerated dose (~.T.D.) or the highest dose which pro-vokes no deaths amongst the trial animals was found to be greater than 400 mg/kg~ by intraperitoneal route, in the mouse.
It will be appreciated that for therapeutic use the acetic acid derivatives of formula (I) and their pharmaceutically acceptable alkali metal salts will normally be administered in the form of a pharmaceutical or veterinary composition in a dosage unit form appropriate to the required mode of administration, the composition compri~ing as active ingredient at least one acid derivative of formula (I) or a pharmaceutically acceptable alkali metal salt thereof in association with a pharmaceutical carrier or excipient therefor. For oral administration, the composition may take the form of, for example, a coated or uncoated tablet, a hard- or soft-gelatin cap~ule, a suspension or a syrup. The composition may alternntively take the form of a suppository for rectal administration~ or of a solution or suspension for parent-eral administration, ~ hen in dosage unit form, the compo~ition may contain from 200 to 500 mg of active ingredient per dosage unit for ora~
administration, from 400 to 1000 mg of active ingredient per dosage unit for rectal administration, or from 100 to 400 mg of active ingredient for parenteral administration.
~ hese therapeutic compositions will be prepared by associating at least one of the compounds of formula (I) or a ' .. . . .
. . .
0~1015 pharmaceutically acceptable alkali metal ~alt thereof ~ith at least one àppropriate carrier or excipient therefor. ~xamplex of suitable carriers or e~cipient~ are talc, magnesium stearate~
lacto~e, saccharose, colloidal silica, carboxymethylcellulose, ~tarches, kaolin, levilite, mannitol7 cocoa butter.
The follo~ing Examples illustrate the preparation of the compounds o~ formula (I) and their alkali metal salts, together with suitable therapeutic compositions:
FXAMPL~ 1 PreParation of 3-n-prop~l-hexanoic acid a) 3-n-Pro~1-3-hydroxy-heY.anoic acid _____ _ _____ ___ __________ __ In a 3-necked flask, an ionic radical solution was pre-psred by mixing 128 g (1 mol) of naphtalene, 6.9 g (1 mol) of lithium and 600 ml of tetrahydrofuran for 3 to 4 hours The mix-ture v~a~ then cooled to between -10 and -15C and 30 g (0.5 mol) of scetic acid for metalation dissolved in the same volume of tetrahydrofuran were added drop by drop. The reaction medium ~as heated to about 50-60C for 90 minutes The dianion 80 formed ~as brownish-coloured. This mixture was then quickly added to 57 g (0 5 mol) of 4-heptanone dissol~ed in 250 ml of anhydrous ether The mixture 90 formed was refluxed for 90 minutes and then hydrolysed with a minimum of water. The alkaline layer vas decanted and acidified. It was then extracted with ether, dried over anhydrous ~odium sulphate and filtered. The ether was evaporated out and the residue was distilled.
In thi~ manner, 49.6 g of 3-n-propyl-3-hydroxy-hexanoic acid ~re obtained in the form of a ~iscous liquid.
Yield : 59%
B,P. 10~-110C under 0.25 mmHg By following the same procedure a9 that described above but using the appropriate starting-products, the oompounds li~ed x~.r~
~ 04101~
hereunder were prepared :
~ompound 3-Ethyl-3-hydroxy-pentanoic acid used in crude form (yield : 52~) 3-n-~utyl-~-hydroxy-heptanoic acid used in crude form (yield : 35%) b) 3-n-Pro~l-hexanoic acid _____ ~ ___ ___________ ~he 3-n-propyl-3-hydroxy-hexanoic acid, obtained above, wa9 refluxed in a flask with 248 g of acetic anhydride (1 g of acid for 5 g of anhydride) for 120 to 150 minutes. After this period of time, the anhydride in excess was eliminated by means of a rotating evaporator. ~he mixture of ethylenic acids 90 obtained ~as mixed with 100 ml of distilled water for 30 to 60 minutes by heating under reflux. The mixture was then extracted ~ith ether. ~he ethereal phases were dried over anhydrous sodium - ~ulphate and the filtrate was evaporated. ~he residue so obtaincd, which was composed of the mixture of the isomeric acids was dis-- tilled and the higher fraction was eliminated. ~he new residue 80 obtained was formed with a mixture of 3-n-propyl-2-hexenoic and 3-n-propyl-3-hexenoic acids. ~hen 15.6 g (0.1 mol) of the !'' mixture of isomeric ethylenic acids dissolved in 150 ml of absolute ethanol were placed in a bomb-apparatus maintained at a temperature of 100C for 10 hours, under a pressure of 100 kg/cm2 and the presence of about 10 g of Raney~s nickel (i.e. a finely divided nickel catalyst obtained by dissol~ing out with alkali the alumin-, ., ium from a nickel-aluminium alloy) After cooling, the reaction mixture was filtered, the alcohol evaporated off and the residue ~a 9 distilled, In this manner, 9.6 g of ~0-n-propyl-hexanoic acid were obtained in the form of a colourless, slightly viscous liquid, in-~oluble in water and soluble in the organic solvents.
1~10~
Yield : 55% calculated from the mixture of ethylenic acids, .P. 131C under 15 ~mHg.
~ y following the same procedure a~ that described here-above, but with hydrogenation period~ up to 20 hours and using -the appropriate starting-product~, the following compounds were prepared:
Compound oiling ~oint in C
3_Methyl-butanoic acid 176 (760 mmHg) 3-Ethyl-pentanoic acid 85-8 (1 mmHg 3-n-Butyl-heptanoic acid 130 (4 mmHg) 3_N~thyl-pentanoic acid 196-200 (760 mmHg) EXAMPm 2 -PreParation of 5-n-~roP~ ~octanoic acid a) 5-n-Pro~-octanol In a flask, 150.4 g (0.8 mol) of 5-n-propyl-1,5-octanediol (B P, 142-144C under 3 mmHg) were reflux~d with 400 ml of acetic anhydride for 3 hours, The acetic acid 8~ formed and the acetic anhydride in excess were distilled off an~ the residue 90 formed - wa~ refluxed for a further 30 minutes. ~e acetyl derivative 90 obtained was then hydrogenated at room-te~perature and in glacial acetic acid to which palladium/barium sul~hate had been added.
he reaction ~ixture was then filtered ~he 5-n-propyl-1-octyl~
acetate (B P 108-110C under 3 mmHg) con~ained in the filtrate wa~ then saponified by adding a methanolic solution of potassium hydroxide.
In this manner, 5-n-propyl-octanol was obtained boiling at 105C under 0.1 mmHg, 104~V~S
b) 5-n-Pro~yl-octanoic acid _______ _______________ In a flask, 86 g (0 5 mol) OI the 5-n-propyl-octanol obtained above~ ~Jere added drop by drop to a previously cooled solution of 191 g of chromic anhydride in 1 7 l of glacial acetic acid containing 195 ml of water, care being taken to maintain the mixture at a temperature of 10C maximum. The reaction medium was then allol~ed to stand for about 2 hours at 0C and 24 hours at room-temperature. After -this time, 8 5 l of water were added and the mixture was extracted v~ith chloroform.
In this manner, 5-n-propyl-octanoic acid was obtaincd boiling at 136C under 3 mmHg, By following the same procedure as that described above but using the appropriate starting-products, the compounds here-under Y~ere prepared :
Compound Boilin~ ~oint C
4-Methyl-pentanoic acid 197 (750 mmHg) 4-n-Propyl-heptanoic acid 106-107 (1 mnHg) E X/~MPIE 3 Preparation of 3-n-pro~1-2-hexenoic acid In a flask, 15.6 g (O.l mol) of 3-n-propyl-3-hydroxy-hexanoic acid, obtained as in Example 1, was reflw~ed for1 20 to 150 minutes in 78 g of acetic anhydride (l g of acid for 5 g of anhydride) At the end of this time, the excess of acetic anhydride was removed by means of a rotating evaporator and the mixture of isomeric ethylenic acids was distilled. Ihe fraction ~hich distilled at 110C under a pressure of 0.6 mmHg was cooled to between -30 and -40C and the resulting acid cristallized. It was quickly filtered.
In this manner, 3-n-propyl-2-hexenoic acid was obtained, melting at 20C, .,, 'iE~
.
Preparation of sodium 4-n-propyl-heptanoa-te In a flask, 17.2 (0.1 mol) of 4-n-propyl-heptanoic acid, prepared as described in the above Example 2, were dissolved in a sufficient volume of water. ~fter that 4 g (0.1 mol) of a sodium hydroxide solution in water were added and the mixture was evaporated to dryness. The residue so obtained was rinsed with ethyl ether and maintained in a dessicator under vacuum.
In this manner, sodium 4-n-propyl-heptanoate was obtained. This product does not melt but decomposes when heated.
pH of a 0.1-molar solution in sodium 4-n-propyl-heptanoate :7.95 Bands of infra-red absorption of this 0.1-molar solution in the range of 1400-1600 cm 1 : 1580, 1550, 1470, 1430, 1415.
Following the same procedure as that described above, the compounds hereunder were prepared:
Compounds:
a) Sodium 3-n-propyl-hexanoate. pH of a 0.1-molar solution in sodium 3-n-propyl-hexanoate : 7.95.
Bands of infra-red absorption of this 0.1-molar solution in the range of 1400-1600 cm 1 : 1660, 1570, 1475, 1450, 1420.
b) Sodium 5-n-propyl-octanoate. pH of a 0.1-molar solution in sodium 5-n-propyl-octanoate : 7.95.
Bands of infra-red absorption of this 0.1-molar solution in the range of 1400-1600 cm 1 : 1590, 1570, 1470, 1450, 1430.
c) Sodium 3-n-butyl-heptanoate. pH of a 0.1-molar solution in sodium 3-n-butyl-heptanoate : 8.20.
Bands of infra-red absorption of this 0.1-molar solution in the range of 1400-1600 cm 1 : 1590, 1560, 1470, 1440, 1415.
, .
,~ ~ , .r ,~
Tablets containing the following ingredients were prepared in accordance with known pharmaceutical techniques:
Ingredients mg per tablet Sodium 4-n-propyl-hexanoate 200 Mannitol 138 Corn starch 120 Colloidal silica 24 Magnesium stearate 18 A suppository containing the following ingredients was prepared in accordance with known pharmaceutical techniques:
Ingredients mg 4-n-Propyl-hexanoic acid 400 Glycocoll 200 Cocoa butter 1 600
R_C-OH (I) -wherein R represents the radical 1\ 1~
CH (CH2)n CH or C=CH_ ~:R2 R3 R2 in ~hich R1 and R2 are the same or different and each represent an alkyl rsdical having from 1 to 4 carbon atoms, R3 represents a hydrogen atom or a methyl radical and n is an integer in the range - of from O to 3 inclusive, as well as the pharmaceutically accept-able alkali metal salts of these compounds.
In accordance with another aspect of the invention there i~ provided a pharmaceutical or veterinary composition comprising, aa an essential active ingredient, at least one acetic acid derivative of formula I, or a pharmaceutically acceptable alkali metal salt thereof, in association with a pharmaceutical carrier or e~cipient ~herefor, Aa will be described in greater detail further on, it has been found that the acetic acid derivatives of the general formula (I) are endowed with biochemical and pharmacological pro-perties likely to render them particularly u~eful in the treat-ment of pathological conditions due to disturbances of the central nervous system, 104~015 Pharmacological and biochemical tests have shown -that the compounds of formula (I) and their alkali metal salts can act as competitive inhibitors with respect to -the action of ~-amino-butyric ~-ketoglutaric transaminase and also as anticonvulsant and antianoxic agents. Consequently, these compounds will con-stitute particularly valuable agents for treating various kinds of central neurological disorders whether resulting or not from cerebral ischemia and including, in particular, convulsive states and seizures, in a host in need of such treatment.
Daily dosage will preferably be between 400 and 2000 mg of active principle by any route for a human being weighing 60 kg, for example about 1000 mg by oral or rectal route.
Amongst the compounds of formula (I), a certain number are known products. In this connection may be cited:
3-Methyl-butanoic acid, 3-methyl-pentanoic acid and 4-methyl-pentanoic acid which are cited in U.S. Patent no.2,484,486.
Furthermore, this same U.S. Patent also generically covers the whole of the compounds of formula I wherein R represents RlR2CH-(CH2)n-CHR3 in which Rl and R2 have the same meaning as in formula I, R3 represents hydrogen and n is 0.
3-Ethyl-pentanoic acid and 3-ethyl-2-pentenoic acid which are described in Berichte 42, 4710-4713.
3-n-Propyl-hexanoic acid which is cited in Chem.
Abstracts, 35, 47336 (1941).
4-n-Propyl-heptanoic acid which is mentioned in Ann.
Chem. 693, 90-98 (1966).
5-n-Propyl-octanoic acid which is disclosed in Physiol.
;- Chem. 282, 135-142 (1947).
3-n-Propyl-2-hexenoic acid and 3-isobutyl-5-methyl-2-hexenoic acid which are described in J. Chem. Soc., 129, 1549-1555 (1927).
The compounds of formula (I) in which R represents ~ - 2 -,: --(CH2)n-CHR3 wherein R1 and R2 each represent methyl or ethyl and R3 represent~ methyl with n equal to 0 ~rhich are covered by U,S Patent no 2,484,500.
However, as far a~ i9 known, no therapeutic activity has ever been ~ttributed to these compounds of formula (I) cited hereabove with the exception of 3-methyl-pentanoic acid which is included in the composition of officinal valerianic acid known for its sedative properties [MERCIER, ~es Médicament~ du système nerveux cérébro-spinal p. 171 (1959~
The other compounds of formula (I) can be considered as novel product~ In fact, searches have not revealed any publica-tion with respect to these other acids of formula (I) Similarly, the pharmaceutically acceptable alkali metal salts of the compounds of formula (I) can also be regarded as novel compounds.
In consequence, the invention also relates, as new com-pounds~ to the pharmaceutically acceptable alkali metal salts of the acid derivatives of formula ~I) and more particularly, a~
preferred compounds, to the pharmaceutically acceptable alkali metal salts corresponding to the general formula:
3 7 \ 1l 1 H_(CH2)n 2 . C3H7/
whRrein Me represents an alkali metal atom, for example lithium"
sodium or potassium, and n is an integer in the range of from 0 : to 2 inclusive. ~ -i~he acid derivatives of formula (I) and their pharmaceuti-- cally acceptable alkali metal salts can be obtained by various procedures in accordance ~ith their chemical structure Ihus, the compounds of formula (I) wherein R represents _3_ ' ' ' ' ,: ~, 1~4101S
R1R2CH-(CH2)n-CHR3 may be prepared a9 follows:
a) V~en n i9 O, by hydrogenating in an appropriate solvent such as for example absolute ethanol and in the presence of a catalyst 3uch as for example Raney's nickel~ a mixture of ethylenic acids ~ -obtained by dehydrating, for example with acetic anhydride, a~ - j hydroxy acid of the general formula:
1~
C_CH_C_OH (II) R2 OH ¦ , 3 ¦
wherein R1, R2 and R3 have the aforesaid meanings, which yields .the required compound of formula (I) in free acid form; when a l .
pharmaceutically acceptable alkali metal ~alt thereof is desired, the scid derivative obtained is further treated with an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, to provide the required salt. The hydrogenation is carried out under pressure and by heating the mixture of ethylenic acids in .~
question and the dehydration is preferably effected by heating the .;
reagents.
b) When n i9 1 to 3, by oxydizing, for examplè by means of chromic anhydride, in an appropriate solvent such a~ for example acetic acid, an alcohol of the general formula:
, , R1 / CH~(CH2)n~CH~CH2H (III) R2 3 .
wherein R1, R2 and R3 have the aforesaid meanings and n is an integer 10410~5 in the range of from 1 to 3 inclusive, to ~btain the required compound of formula (I) in free acid form; when a pharmaceutically acceptable alkali metal salt thereof i~ desired, the acid deriva-tive obtained i~ further treated with an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, to provide :~
the required ~alt.
The compound~ of formula (I) wherein R represents R~R2C=CH- can be obtained by dehydrating, for example by means of acetic anhydride, the appropriate ~-hydroxy acid derivative of formula II, corresponding to the general formula:
R1~
C_CH2_C_OH (IV) wherein R1 and R2 have the aforesaid meanings, to form the required ¢ompound of formula (I) in free acid form; when a pharmaceutically acceptable alkali metal salt thereof is desired, the acid deriva-tive obtained is further treated with an alkali metal hydroxide, for example lithium, sodium or potassium hydroxide, to provide the required salt.
~he dehydration may be effected by heating the reagents for exsmple under reflux, - ~he compounds of formula (II) can be prepared by react-ing a dianion obtained from an aromatic hydrocarbon such as naphtalene or anthracene, an alkali metal such as lithium, sodium or potassium and an acid of the general formula:
. O
R3~CH2~C~H ~) -wherein R3 ha~ the afore~sid meaning, with a ketone of the general formula:
Rl-C-R2 (VI ) wherein R1 and R2 have the aforesaid meanings, in an anhydrous ether such as ethyl ether, hydrolysing the alkali metal salt 90 obtained and subsequently acidifying the salt to form the required B -hydroxy acid derivative All the acids of formula (V) and ketones of formula (VI) are known and commercialized compounds.
Similarly, the compounds of formula III are either known compounds or can be prepared by the method described in Ann Chem. 1966, 693, 90-98, As alresdy mentioned, the acetic acid derivative~ of general formula (I) and their alkali metal salts have been found to possess valuable biochemical properties, and in particular a marked competitive inhibitory effect with respect to the action of ~ -aminobutyric a-ketoglutaric transaminase. These compounds also possess powerful pharmacological activity and more particularly marked antianoxic and snticonvulsant properties.
~ hese propertie~, when taken as a whole, are likely to render ~uch compounds useful for treating various kinds of central neurological disturbances whether resulting or not from cerebral i~chemia.
As an example of such central neurological disturbances or of disorders indlced by central neurologicsl dysfunction, the following may be cited: convulsive state~ and seiæures such as, for exsmple~ epilepsy, choreic states such as Huntington's chorea, difficulties with respect to memory, bala~ce and fixing the attention, as well a9 dizziness, decrease of arterial pressure, cephslslgia and comatose states.
~ -Aminobutyric acid or GABA i~ an important constituent of the brain of the vertebrates. At present, it represents the 1~410~
only known physiological inhibitor of the pre- and postsynaptic discharges which it has been possible to isolate in the brain.
Furthermore, this acid plays an all important role in the ease of choreic patients in whom cerebral depletion in GAsA has been observed.
The normal oxidative metabolism of the carbohydrates leads in particular to the production of a-ketoglutaric acid through the medium of the tricarboxylic cyele of KREBS. Fromthis point, a deviation oeeurs whieh results in the formation of GABA.
Various enzymes regulate by natural processes the pro-duetion and destruetion of this acid and of GABA itself whieh is re-transformed into ~-ketoglutarie acid, this latter aeid being taken up again in the KREBS' eyele. The activity of these enzymes ean itself be either aceelerated or inhibited by several substances.
It has been discovered, in aecordance with the invention, that the aeetie acid derivatives of formula (I) and their alkali metal salts are capable of produeing a eompetitive inhibitoryeffeet with respeet to the aetion of ~-aminobutyrie ~-ketoglutaric trans-aminase or GABA T which destroys GABA. Such an inhibitory effeet eonsequently produees an inerease in the GABA level inthe organism.
These bioehemieal properties are likely to produee more partieularly an antieonvulsant aetion in pharmaeology and in elini-eal use to exert antiepileptie and antiehoreic effeets.
Furthermore, the eompounds of formula (I) and their alkali metal salts have been found to be strong antianoxie agents eapable in partieular of delaying the onset of eerebral pain due to oxygen defieieney i.e. originating from eerebral isehemia.
Cerebral isehemia ean be provoked by numerous faetors sueh as, for example: eerebral vaseular defieieney due to senes-eenee, thrombosis or tumors. At present eerebral vasodilators areeommonly used in order to delay the onset of eerebral pain due to oxygen defieieney or to treat cerebral vascular deficiency and ,~
104:10~5 its resulting dlsorders for example central neurological dis-turbances such as those cited hereabove.
However, such drugs must be employed in accordance with the vascular state of the patient. Since these compounds act by mechanical means,namely by dilating the arterioles toincrease the blood flow and consequently the amount ofoxygen in the brain,they will be ineffective, for example in cases involving arteriosclerosis.
Furthermore, certain agents can provoke a marked cerebral vasodilation of the healthy parts which upsets the circulatory equilibrium. As a consequence of this, a decrease of irrigation in the ischemic parts can occur.
The compounds of formula (I) and their alkalimetal saltson the other hand do not present these disadvantages as they do not act by mechanical means but exert theireffectdirectly onthe meta-bolism of the nervous cells without affecting, theconditions of irrigation. Theydo, infact, act by bringing about aneconomy and a better use of oxygen in the nervous cells. These antianoxic pro-perties will also be useful for preventing convulsive seizures as it is well known that anoxia can induce such seizures.
In the light of these different properties, the compounds of formula (I) and their alkali metal salts will be likely to con-stitute valuable antianoxic agents, for exemple, for treating cen-tral neurological disturbances due to cerebral ischemia, particu-larly in cases where the classic drugs are ineffective.
In the field of diseases requiring anticonvulsant therapy and, in particular, epilepsy, there are numerous drugs of undeniable efficacy. However, these classic medicaments, such as the barbi-turates and molecules of similar structure cause an overall de-pression of the central nervous system, which moreover, explains their anticonvulsant effect.
For this reason, such drugs frequently cause undesirable side-effects such as difficulty in fixing the attention, reduction rA~ ~
104~015 in intellectual efficiency and somnolence as well as biological disorders of which the most serious are hematological.
The compounds of formula (I) do not present these dis-advantages since they do not act by provoking a general depression of the central nervous system but, on the contrary, the~ function by means of an enzymatic mechanism involving the metabolism of a neurotransmittor which is a physiological inhibitor namely -aminobutyric acid. Furthermore, certain well-known anticonvul-sant agents are toxic at relatively low doses while others are only useful for the treatment of one single type of epilepsy.
The compounds of formula (I) and their alkali metal salts do not present these disadvantages since they are relatively non-toxic and at the same time possess a very wide range of properties which are likely to render them useful in the treatment of an extremely broad variety of convulsive states.
Compounds of a similar chemical structure to that of the compounds of formula (I) and their alkali metal salts, namely dialkylacetic acid derivatives which possess anticonvulsant pro-perties have been published in U.S. Patent no. 3,325,361. A de-tailed study has been carried out with sodium di-n-propylacetate which is the preferred compound of the above-cited U.S. Patent.
This study, which is reported in J. of Neurochemistry, 1969, Vol. 16, pp. 869-873, showed that sodium di-n-propylacetate is capable of increasing the level of intracerebral GABA by in-hibiting GABA T. Up to present, no other therapeutic substance is known which possesses this property. This property endows sodium di-n-propylacetate with powerful anticonvulsant activity and a completely original mechanism of action.
Similarly, it has been demonstrated, as reported in Bull.
Soc. Sci. Vét. et Méd. comparée, Lyon, 1970, 72, pp. 303-325, that sodium di-n-propylacetate possesses very marked antianoxic pro-perties.
.
.-~ rAl ~ 9 , '. ~
-At present, sodium di-n-propylacetate is widely commercialized as an antiepileptic agent.
Ho~,7ever, it has been discovered in accordance with the present invention that the acetic acid derivatives of formula I
as well as their pharmaceutically acceptable alkali me-tal salts, possess the above-cited properties of sodium di-n-propylacetate but to different degrees which confer on them an originality of action as compared with this latter product.
Thus,pharmacologicaltests haveshown thatatleastone of the three biochemicalandpharmacologicalactivities citedhereabove is moreintense inthe caseof the compounds of formula (I) andtheir alkali metalsalts than in that of sodium di-n-propylacetate.
In therapeutic use this essential difference between sodium di-n-propylacetate and the compounds of formula (I) will be likely to render the latter more selective for the treatment of certain kinds of central neurological disorders whether result-ing or not from cerebral ischemia. For example, the compounds of ~ formula (I) and their alkali metal salts which have been found to - be more active than sodium di-n-propylacetate as competitive inhi-bitors of GABA T will be likely to be more effective, for example, - in the treatment of choreic states. On the other hand, the com-pounds of formula (I) and their alkali metal salts which have shown better antianoxic properties than sodium di-n-propylacetate will ~ be more active in the treatment of central neurological disorders - due to cerebral ischemia.
Disturbances and dysfunction of the central nervous system whether of ischemic origin or not are numerous and consti-tute one of the most widespread disorders at the present time.
For this reason, it is very difficult for the doctor to choose amongst the various drugs at his disposal, that which will be effective for the particular case under treatment. When faced with a case of chorea, epilepsy or other affection, the neurologist is often obliged to feel his way by trying several drugs one after the other vntil he discovers the most suitable medication.
104~015 From this point of view, acetic derivatives of formula (I) and their pharmaceutically acceptable alkali metal salts will constitute valuable additions to the therapeutic arsenal at the disposal of the doctor and, if necessary, will provide useful replacement medication for a drug which has become ineffective for any reason such as, for example, a change in the state of the patient or habituation.
The compounds which have been found to be particularly useful for the treatment of central neurological disturbances whether originating or not from cerebral ischemia and in particular epilepsy are:
3-n-Propyl-hexanoic acid 4-n-Propyl-heptanoic acid and 5-n-Propyl-octanoic acid as well as their pharmaceutically acceptable alkali metal salts.
Pharmacological trials have been undertaken with a view to determining the presence of a competitive inhibitory effect with respect to the action of r-aminobutyric a-ketoglutaric transaminase, as well as antianoxic and anticonvulsant properties which, taken together, are capable of rendering the compounds of formula (I) and their pharmaceutically acceptable alkali metal salts useful for treating central neurological disturbances whether originating or not from cerebral ischemia.
I. Inhibition of GABA T.
This test was undertaken "in vitro" in the absorption cell of a double-beam U.V. spectrophotometer.
The activity of GABA T was determined by coupling this enzyme with an excess of succinosemialdehyde dehydro~enase (NADP~) so that the rate of formation of the succinosemialdehyde dehy-drogenase coenzyme (NADPH) was limited by the activ ty of theGABA T. The coupling of the two reactions was as~follows:
GABA T
GABA ~ a-ketoglutarate ~ glutamate ~ succinosemialdehyde.
r -- 11 --In the presence of succinosemialdehyde dehydrogenase of which the active element is NADP~, the reaction became:
succinosemialdehyde ~ NADP~ + H2O ~succinate ~ NADPH ~ H~.
The overall reaction can be represented by the following equation:
GAsA t a-ketoglutarate ~ NADP ~ H2O >succinate + glutamate t NADPH ~ H~.
The activity of GAsA T was measured by following the reduction rate (v) of NADP~ which corresponds to the evolution of the optical density at 340 m,u on the spectrophotometer.
Determination of the activity rate of GABA T by the principle hereabove described can be effected with either limiting concentrations or a saturating concentration of one of the sub-strates, in the present case GAsA, in each instance, in the pre-sence of a saturating concentration of the second substrate namely a-ketoglutarate. Thus, it is possible to discover the activity rate of GABA T in relation to the concentration o~ GABA and in this way, to determine the affinity of GAsA T for GAsA.
Similar measurements of the activity of GABA T were then carried out in the presence of different concentrations (i) of an inhibitor namely a compound of formula (I) or a pharmaceutically acceptable alkali metal salt thereof, so as to evaluate the ef-fectiveness of the latter. This effectiveness is represented by the constant Ki or constant of inhibition which determines the affinity of the enzyme (GABA T) for the inhibitor.
This constant is expressed in units of concentration, in the present case, in m mol per ml and can be determined by plotting all the curves corresponding to 1 = f (i) for a saturating concen-tration of GAsA and for different limiting concentrations of GAsA.
The point of coincidence of these curves determines the Ki in question or the necessary concentration of inhibitor to arrest completely the activity of the GABA T. l'he lower the Ki value is, the greater is the effectiveness of the inhibition of GABA T by the compound tested.
The following experimental procedure wa~ used:
In the absorption cell (optical passage : 1 cm, volume :
about 1 ml) the ~ollowing solutions were introduced.
0.5 ml of a 1.5 molar solution of sodium ~ulphate 0.05 ml of a molar buffer solution of pH ~ 7.9 0.05 ml of a 0.1 molar solution of mercapto-ethanol 0,05 ml of a 20 mg/ml solution of NADP~
0.125 ml of a solution of G~BA
0,03 ml of a 40 mg/ml solution of GABASæ (namely a bacterial enzyme isolated from Pseudomonss fluorescens containing a mixture of Y -aminobutyric a-ketoglutaric transaminase and succinosemialde-hyde dehydrogenase).
0.125 ml of 8 solution of the compound to be studied, If the compound to be studied was in the form of a water-insoluble acid, its sodium salt was used after adjustment to a pH
of about 7,9 by adding a titrated solution of sodium hydroxide.
Different measurements of optical density were effected by varying the concentration of GABA and the concentration of the compound under study. Control assays were also effected by re-placing the solution of the compound to be studied by 0~125 ml of water, ~ he content of the absorption cell wa~ allowed to incu-bate for 10 minutes at 30C and then the enzymatic reaction was ~tarted by adding 0.1 ml of a 0.02 molar solution of ~-ketoglut~-rate in the absorption cell, The final volume was 1.03 ml, The réaction was then followed by spectrophotometric recording of the reduction rate of the NADP~ at 340 m~ and at 30C, The optical density was sutomatically registered every 30 seconds.
In accordance vnth the process hereabove described, the following compounds were studied. ~hese compounds were pre-~41015 ferably tested in the form of a pharmaceutically acceptable alkali metal salt~ for example the sodium salt.
The pharmaceutically acceptable alka-li metal salts of the acids of formula (I) such as the sodium salt, are in fact more advantageous than the acids them~elves. These salts have a much milder irritant effect upon the upper part of the digestive tract than the acids.
Thus, the pharmaceutically acceptable alkali metal salts of the acids of formula (I) present an undeniable superiority over the corre~ponding acids, This will serve to reduce considerably the undesirable side-effects when the salts are used in therapeutics.
3-n-Propyl-hexanoic acid (Compound A) 4-n-Propyl-heptanoic acid (Compound B) 5-n-Propyl-octanoic acid (Compound C) 3-Methyl_butanoic acid (Compound D) 3-Ethyl-pentanoic acid (Compound E) 3-n-Butyl-heptanoic acid (Compound F) 3-n-Propyl-2-hexenoic acid (Compound G) ~he following Ki were registered ~ith these different compound~:
~ABIE I
Com ound K (in m mol/~l) P
A 0,63 + 0.15 B 1.05 + 0.20 C 1.18 + 0,50 - 0.51 + 0.14 E 2.15 - 0.50 F 1,06 + 0,58 0.70 + 0.17 ,~ , A comparative test carried out, under the 3ame conditions with sodium di-n-propylacetate gave a Ki of 0.8 m mol/ml, This re~ult shows that Compounds A, D and G are more active than sodium di-n-propylacetate in this test while Compounds ~ and ~ are slightly less active in this testO
II, Antianoxic activi~.
.
Action on the anoxic seizure induced by gallamine triiodoeth~late.
____________ ___ ___________________ _____________________ ____ The injection of a sufficient dose of a synthetic curariform substance such a9 gallamine triiodoethylate provokes in the mouse paralysis of the diaphragm. The animal then dies through asphyxia, An intraperitoneal dose of the compound to be studied was administered to batches of 20 mice five minutes before the administration of 16 mg/kg of gallamine triiodoethylate by intra-peritoneal route, ~he dose of the compound to be tested W39 calculated 80 that each batch received a higher dose than the pre-ceding batch.
The period of survival of the trested ani-mals was noted in comparison with that of the controls which had not received the compound under study. The period of time of survival was registerea by controlling cardiac arrest by means of an electro-- cardiogram.
Under these conditions, an antianoxic effect produces an increase in the period of survival of the animal.
The following results were recorded:
., I
TABIE II
Compound Dose admir,istered% of increase in the in mg/kgperiod of survival in comparison with the contro~
. _ ; 30 D 250 73 . , .
¦ E 1 151O4 lO 1 5 ¦
A comparative trial undertaken with sodium di-n-propyl-acetate, under the same conditions, showed that a dose of 330 mg/kg of this product increases by 40% the period of survival of the animals in comparison with the controls.
Table II hereabove shows that Compounds D and E are appreciably more active than sodium di-n-propylacetate as anti-anoxic agents while at the doses studied Compounds A, F and G
appear to be slightly more active than sodium di-n-propylacetate.
III. Anticonvulsant activity.
This test is carried out on mice with a view to deter-mining whether the compounds of formula (I) and their pharmaceu-tically acceptable alkali metal salts, when given preventively by intraperitoneal route, are capable at certain doses of pro-tecting some of the animals against the epileptic seizure pro-duced by an adequate and predetermined dose of pentylenetetrazol which would be 100% fatal in the absence of the compound.
The test was carried out on batches of 10 mice. Each batch of animals received an intraperitoneal dose of the compound to be studied so that each batch received a higher dose than the preceding batch. Fifteen minutes after administration of the compound to be tested, the animals were each given 125 mg/kg of pentylenetetrazol by intraperitoneal route. The percentage of deaths was noted 3 hours after injection of this latter compound and the result was expressed as a percentage of protection.
The results obtained are given in the following Table:
- TABLE III
30Compound in mg/kg% of protection A 160 ~100 10~1015 F' 185 95 A comparative trial performed with sodium di-n-pro-pylacetate under the same conditions showed that a do~e of 250 mg/kg of this product protects 100~o of the animals against the pentylene-tetrazol-induced seizure.
~hese results indicate that Compounds A and F are more active, in this test, than sodium di-n-propylacetate.
0 A9 against this~ it was observed that Compound~ B and C
exert their action over a longer period of time than sodium di-n-propylacetate, Thus, 195 mg/kg of Compound ~ and 210 mg/kg of Compound C both of which offer about 100% protection against the pentylene-tetrazol-induced seizure, still protect 40~o and 70~o respectively of the animals one hour after ad-ministration As against this, a dose of 250 mg/kg of sodium di-n-propylacetate only offers, in this test, 20~o protection of the animals~ one hour after administration~
Furthermore~ additional trials performed in accordance with the process described hereabove have shown that a dose of Compound A as low as 105 mg/kg administered by intraperitoneal route, offers 85~o protection against the pentylenetetrazol-induced seizure, Similarly, it was found that a dose of 125 mg/kg of Compound C, also administered by intraperitoneal route, protects .- 65% of the mice against the pentylenetetrazol-induced seizure.
IV Acute toxicit~.
Acute toxicity was aetermined on the mouse. For this purpose, a dose of the compound to be tested was administered to batches of 5 mice, by intraperitoneal route, 90 that each batch received a higher dose than the preceding batch, 104~015 ~he following results ~rere obtained:
~om~ounds LD
Furthermore, the IDo of Compounds A and D, namely the maximum tolerated dose (~.T.D.) or the highest dose which pro-vokes no deaths amongst the trial animals was found to be greater than 400 mg/kg~ by intraperitoneal route, in the mouse.
It will be appreciated that for therapeutic use the acetic acid derivatives of formula (I) and their pharmaceutically acceptable alkali metal salts will normally be administered in the form of a pharmaceutical or veterinary composition in a dosage unit form appropriate to the required mode of administration, the composition compri~ing as active ingredient at least one acid derivative of formula (I) or a pharmaceutically acceptable alkali metal salt thereof in association with a pharmaceutical carrier or excipient therefor. For oral administration, the composition may take the form of, for example, a coated or uncoated tablet, a hard- or soft-gelatin cap~ule, a suspension or a syrup. The composition may alternntively take the form of a suppository for rectal administration~ or of a solution or suspension for parent-eral administration, ~ hen in dosage unit form, the compo~ition may contain from 200 to 500 mg of active ingredient per dosage unit for ora~
administration, from 400 to 1000 mg of active ingredient per dosage unit for rectal administration, or from 100 to 400 mg of active ingredient for parenteral administration.
~ hese therapeutic compositions will be prepared by associating at least one of the compounds of formula (I) or a ' .. . . .
. . .
0~1015 pharmaceutically acceptable alkali metal ~alt thereof ~ith at least one àppropriate carrier or excipient therefor. ~xamplex of suitable carriers or e~cipient~ are talc, magnesium stearate~
lacto~e, saccharose, colloidal silica, carboxymethylcellulose, ~tarches, kaolin, levilite, mannitol7 cocoa butter.
The follo~ing Examples illustrate the preparation of the compounds o~ formula (I) and their alkali metal salts, together with suitable therapeutic compositions:
FXAMPL~ 1 PreParation of 3-n-prop~l-hexanoic acid a) 3-n-Pro~1-3-hydroxy-heY.anoic acid _____ _ _____ ___ __________ __ In a 3-necked flask, an ionic radical solution was pre-psred by mixing 128 g (1 mol) of naphtalene, 6.9 g (1 mol) of lithium and 600 ml of tetrahydrofuran for 3 to 4 hours The mix-ture v~a~ then cooled to between -10 and -15C and 30 g (0.5 mol) of scetic acid for metalation dissolved in the same volume of tetrahydrofuran were added drop by drop. The reaction medium ~as heated to about 50-60C for 90 minutes The dianion 80 formed ~as brownish-coloured. This mixture was then quickly added to 57 g (0 5 mol) of 4-heptanone dissol~ed in 250 ml of anhydrous ether The mixture 90 formed was refluxed for 90 minutes and then hydrolysed with a minimum of water. The alkaline layer vas decanted and acidified. It was then extracted with ether, dried over anhydrous ~odium sulphate and filtered. The ether was evaporated out and the residue was distilled.
In thi~ manner, 49.6 g of 3-n-propyl-3-hydroxy-hexanoic acid ~re obtained in the form of a ~iscous liquid.
Yield : 59%
B,P. 10~-110C under 0.25 mmHg By following the same procedure a9 that described above but using the appropriate starting-products, the oompounds li~ed x~.r~
~ 04101~
hereunder were prepared :
~ompound 3-Ethyl-3-hydroxy-pentanoic acid used in crude form (yield : 52~) 3-n-~utyl-~-hydroxy-heptanoic acid used in crude form (yield : 35%) b) 3-n-Pro~l-hexanoic acid _____ ~ ___ ___________ ~he 3-n-propyl-3-hydroxy-hexanoic acid, obtained above, wa9 refluxed in a flask with 248 g of acetic anhydride (1 g of acid for 5 g of anhydride) for 120 to 150 minutes. After this period of time, the anhydride in excess was eliminated by means of a rotating evaporator. ~he mixture of ethylenic acids 90 obtained ~as mixed with 100 ml of distilled water for 30 to 60 minutes by heating under reflux. The mixture was then extracted ~ith ether. ~he ethereal phases were dried over anhydrous sodium - ~ulphate and the filtrate was evaporated. ~he residue so obtaincd, which was composed of the mixture of the isomeric acids was dis-- tilled and the higher fraction was eliminated. ~he new residue 80 obtained was formed with a mixture of 3-n-propyl-2-hexenoic and 3-n-propyl-3-hexenoic acids. ~hen 15.6 g (0.1 mol) of the !'' mixture of isomeric ethylenic acids dissolved in 150 ml of absolute ethanol were placed in a bomb-apparatus maintained at a temperature of 100C for 10 hours, under a pressure of 100 kg/cm2 and the presence of about 10 g of Raney~s nickel (i.e. a finely divided nickel catalyst obtained by dissol~ing out with alkali the alumin-, ., ium from a nickel-aluminium alloy) After cooling, the reaction mixture was filtered, the alcohol evaporated off and the residue ~a 9 distilled, In this manner, 9.6 g of ~0-n-propyl-hexanoic acid were obtained in the form of a colourless, slightly viscous liquid, in-~oluble in water and soluble in the organic solvents.
1~10~
Yield : 55% calculated from the mixture of ethylenic acids, .P. 131C under 15 ~mHg.
~ y following the same procedure a~ that described here-above, but with hydrogenation period~ up to 20 hours and using -the appropriate starting-product~, the following compounds were prepared:
Compound oiling ~oint in C
3_Methyl-butanoic acid 176 (760 mmHg) 3-Ethyl-pentanoic acid 85-8 (1 mmHg 3-n-Butyl-heptanoic acid 130 (4 mmHg) 3_N~thyl-pentanoic acid 196-200 (760 mmHg) EXAMPm 2 -PreParation of 5-n-~roP~ ~octanoic acid a) 5-n-Pro~-octanol In a flask, 150.4 g (0.8 mol) of 5-n-propyl-1,5-octanediol (B P, 142-144C under 3 mmHg) were reflux~d with 400 ml of acetic anhydride for 3 hours, The acetic acid 8~ formed and the acetic anhydride in excess were distilled off an~ the residue 90 formed - wa~ refluxed for a further 30 minutes. ~e acetyl derivative 90 obtained was then hydrogenated at room-te~perature and in glacial acetic acid to which palladium/barium sul~hate had been added.
he reaction ~ixture was then filtered ~he 5-n-propyl-1-octyl~
acetate (B P 108-110C under 3 mmHg) con~ained in the filtrate wa~ then saponified by adding a methanolic solution of potassium hydroxide.
In this manner, 5-n-propyl-octanol was obtained boiling at 105C under 0.1 mmHg, 104~V~S
b) 5-n-Pro~yl-octanoic acid _______ _______________ In a flask, 86 g (0 5 mol) OI the 5-n-propyl-octanol obtained above~ ~Jere added drop by drop to a previously cooled solution of 191 g of chromic anhydride in 1 7 l of glacial acetic acid containing 195 ml of water, care being taken to maintain the mixture at a temperature of 10C maximum. The reaction medium was then allol~ed to stand for about 2 hours at 0C and 24 hours at room-temperature. After -this time, 8 5 l of water were added and the mixture was extracted v~ith chloroform.
In this manner, 5-n-propyl-octanoic acid was obtaincd boiling at 136C under 3 mmHg, By following the same procedure as that described above but using the appropriate starting-products, the compounds here-under Y~ere prepared :
Compound Boilin~ ~oint C
4-Methyl-pentanoic acid 197 (750 mmHg) 4-n-Propyl-heptanoic acid 106-107 (1 mnHg) E X/~MPIE 3 Preparation of 3-n-pro~1-2-hexenoic acid In a flask, 15.6 g (O.l mol) of 3-n-propyl-3-hydroxy-hexanoic acid, obtained as in Example 1, was reflw~ed for1 20 to 150 minutes in 78 g of acetic anhydride (l g of acid for 5 g of anhydride) At the end of this time, the excess of acetic anhydride was removed by means of a rotating evaporator and the mixture of isomeric ethylenic acids was distilled. Ihe fraction ~hich distilled at 110C under a pressure of 0.6 mmHg was cooled to between -30 and -40C and the resulting acid cristallized. It was quickly filtered.
In this manner, 3-n-propyl-2-hexenoic acid was obtained, melting at 20C, .,, 'iE~
.
Preparation of sodium 4-n-propyl-heptanoa-te In a flask, 17.2 (0.1 mol) of 4-n-propyl-heptanoic acid, prepared as described in the above Example 2, were dissolved in a sufficient volume of water. ~fter that 4 g (0.1 mol) of a sodium hydroxide solution in water were added and the mixture was evaporated to dryness. The residue so obtained was rinsed with ethyl ether and maintained in a dessicator under vacuum.
In this manner, sodium 4-n-propyl-heptanoate was obtained. This product does not melt but decomposes when heated.
pH of a 0.1-molar solution in sodium 4-n-propyl-heptanoate :7.95 Bands of infra-red absorption of this 0.1-molar solution in the range of 1400-1600 cm 1 : 1580, 1550, 1470, 1430, 1415.
Following the same procedure as that described above, the compounds hereunder were prepared:
Compounds:
a) Sodium 3-n-propyl-hexanoate. pH of a 0.1-molar solution in sodium 3-n-propyl-hexanoate : 7.95.
Bands of infra-red absorption of this 0.1-molar solution in the range of 1400-1600 cm 1 : 1660, 1570, 1475, 1450, 1420.
b) Sodium 5-n-propyl-octanoate. pH of a 0.1-molar solution in sodium 5-n-propyl-octanoate : 7.95.
Bands of infra-red absorption of this 0.1-molar solution in the range of 1400-1600 cm 1 : 1590, 1570, 1470, 1450, 1430.
c) Sodium 3-n-butyl-heptanoate. pH of a 0.1-molar solution in sodium 3-n-butyl-heptanoate : 8.20.
Bands of infra-red absorption of this 0.1-molar solution in the range of 1400-1600 cm 1 : 1590, 1560, 1470, 1440, 1415.
, .
,~ ~ , .r ,~
Tablets containing the following ingredients were prepared in accordance with known pharmaceutical techniques:
Ingredients mg per tablet Sodium 4-n-propyl-hexanoate 200 Mannitol 138 Corn starch 120 Colloidal silica 24 Magnesium stearate 18 A suppository containing the following ingredients was prepared in accordance with known pharmaceutical techniques:
Ingredients mg 4-n-Propyl-hexanoic acid 400 Glycocoll 200 Cocoa butter 1 600
2 200 ':
: Bi . .
: Bi . .
Claims (6)
1. A pharmaceutical or veterinary composition having a competitive inhibitory activity with respect to .gamma.-aminobutyric .alpha.-ketoglutaric transaminase and antianoxic and anticonvulsant actions, comprising as an essential active ingredient at least one acetic acid derivative of the general formula:
wherein R represent a radical of the formula:
or in which R1 and R2 are the same or different and each represent an alkyl radical having from 1 to 4 carbon atoms, R3 represents a hydrogen atom or a methyl radical and n is an integer in the range of from 0 to 3 inclusive, or a pharmaceutically acceptable alkali metal salt thereof, in association with a pharmaceutical carrier or excipient therefor.
wherein R represent a radical of the formula:
or in which R1 and R2 are the same or different and each represent an alkyl radical having from 1 to 4 carbon atoms, R3 represents a hydrogen atom or a methyl radical and n is an integer in the range of from 0 to 3 inclusive, or a pharmaceutically acceptable alkali metal salt thereof, in association with a pharmaceutical carrier or excipient therefor.
2. Composition according to claim 1, wherein the active ingredient is 3-n-propyl-hexanoic acid or a pharmaceutically acceptable alkali metal salt thereof.
3. Composition according to claim 1, wherein the active ingredient is 4-n-propyl-heptanoic acid or a pharma-ceutically acceptable alkali metal salt thereof.
4. Composition according to claim 1, wherein the active ingredient is 5-n-propyl-octanoic acid or a pharma-ceutically acceptable alkali metal salt thereof.
5. Composition according to claim 1, wherein the alkali metal is lithium, sodium or potassium.
6. Composition according to claims 2, 3 or 4, wherein the alkali metal is sodium.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB28416/74A GB1485269A (en) | 1974-06-26 | 1974-06-26 | Pharmaceutical compositions containing acetic acid derivatives |
Publications (1)
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CA1041015A true CA1041015A (en) | 1978-10-24 |
Family
ID=10275286
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA229,907A Expired CA1041015A (en) | 1974-06-26 | 1975-06-23 | Acetic acid derivatives pharmacological activity and compositions containing the same |
Country Status (21)
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JP (1) | JPS6041058B2 (en) |
AR (2) | AR205748A1 (en) |
AT (1) | AT341490B (en) |
CA (1) | CA1041015A (en) |
CH (2) | CH609668A5 (en) |
DE (1) | DE2528025A1 (en) |
DK (1) | DK288775A (en) |
ES (1) | ES438905A1 (en) |
FI (1) | FI66834C (en) |
FR (1) | FR2276036A1 (en) |
GB (1) | GB1485269A (en) |
HU (1) | HU174772B (en) |
IE (1) | IE42947B1 (en) |
IT (1) | IT1049449B (en) |
NL (1) | NL7507253A (en) |
NO (1) | NO146905C (en) |
NZ (1) | NZ177837A (en) |
OA (1) | OA05039A (en) |
SE (2) | SE427926B (en) |
YU (2) | YU40439B (en) |
ZA (1) | ZA753800B (en) |
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FR2558154B1 (en) * | 1984-01-16 | 1986-08-29 | Pf Medicament | C10 TO C20 BRANCHED FATTY ACIDS USEFUL AS MEDICAMENTS, AND PROCESS FOR THEIR PREPARATION |
GB2323706B (en) * | 1997-03-13 | 2002-02-13 | United Microelectronics Corp | Method to inhibit the formation of ion implantation induced edge defects |
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US2484486A (en) * | 1946-05-15 | 1949-10-11 | Eastman Kodak Co | Preparation of carboxylic acids by the reduction of beta lactones |
US2484500A (en) * | 1947-10-28 | 1949-10-11 | Eastman Kodak Co | Preparation of propionic acids by reduction of beta propiono lactones |
FR2442M (en) * | 1962-10-17 | 1964-04-06 | Henry Eugene | Dipropylacetic acid and its derivatives as new central nervous system depressants. |
-
1974
- 1974-06-26 GB GB28416/74A patent/GB1485269A/en not_active Expired
-
1975
- 1975-01-01 AR AR259339A patent/AR205748A1/en active
- 1975-06-12 IE IE1323/75A patent/IE42947B1/en unknown
- 1975-06-13 FR FR7518489A patent/FR2276036A1/en active Granted
- 1975-06-13 ZA ZA00753800A patent/ZA753800B/en unknown
- 1975-06-16 NZ NZ177837A patent/NZ177837A/en unknown
- 1975-06-18 HU HU75LA870A patent/HU174772B/en unknown
- 1975-06-18 NL NL7507253A patent/NL7507253A/en not_active Application Discontinuation
- 1975-06-23 CA CA229,907A patent/CA1041015A/en not_active Expired
- 1975-06-24 DE DE19752528025 patent/DE2528025A1/en not_active Withdrawn
- 1975-06-25 AT AT487575A patent/AT341490B/en not_active IP Right Cessation
- 1975-06-25 DK DK288775A patent/DK288775A/en not_active Application Discontinuation
- 1975-06-25 IT IT24734/75A patent/IT1049449B/en active
- 1975-06-25 YU YU1629/75A patent/YU40439B/en unknown
- 1975-06-25 NO NO752270A patent/NO146905C/en unknown
- 1975-06-25 SE SE7507297A patent/SE427926B/en not_active IP Right Cessation
- 1975-06-26 OA OA55538A patent/OA05039A/en unknown
- 1975-06-26 JP JP50079960A patent/JPS6041058B2/en not_active Expired
- 1975-06-26 FI FI751888A patent/FI66834C/en not_active IP Right Cessation
- 1975-06-26 CH CH325278A patent/CH609668A5/en not_active IP Right Cessation
- 1975-06-26 ES ES438905A patent/ES438905A1/en not_active Expired
- 1975-06-26 CH CH832675A patent/CH609667A5/en not_active IP Right Cessation
- 1975-11-24 AR AR261324A patent/AR212236A1/en active
-
1979
- 1979-09-21 SE SE7907843A patent/SE435275B/en not_active IP Right Cessation
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1983
- 1983-03-11 YU YU598/83A patent/YU41539B/en unknown
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