CA1148165A - Esters of arylpropionic acids endowed with an anti- inflammatory activity, process for their preparation, and related pharmaceutical compositions - Google Patents
Esters of arylpropionic acids endowed with an anti- inflammatory activity, process for their preparation, and related pharmaceutical compositionsInfo
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- CA1148165A CA1148165A CA000372274A CA372274A CA1148165A CA 1148165 A CA1148165 A CA 1148165A CA 000372274 A CA000372274 A CA 000372274A CA 372274 A CA372274 A CA 372274A CA 1148165 A CA1148165 A CA 1148165A
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- propionic acid
- phenyl
- tetraethylene glycol
- aryl
- group
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Abstract
ESTERS OF ARYLPROPIONIC ACIDS ENDOWED WITH AN ANTI-INFLAMMATORY ACTIVITY, PROCESS FOR THEIR PREPARATION, AND RELATED PHARMACEUTICAL COMPOSITIONS
ABSTRACT OF THE DISCLOSURE
The present invention concerns tetraethylene glycol monoesters with 2-arylpropionic acids (known as anti-inflammatory agents).
Said esters, while being endowed with the characteristics of low toxicity and gastric injuring effects shown by the related acids, differ advantageously from the latter because their anti-inflammatory activity is much more prolonged, and their bioavailability markedly better.
ABSTRACT OF THE DISCLOSURE
The present invention concerns tetraethylene glycol monoesters with 2-arylpropionic acids (known as anti-inflammatory agents).
Said esters, while being endowed with the characteristics of low toxicity and gastric injuring effects shown by the related acids, differ advantageously from the latter because their anti-inflammatory activity is much more prolonged, and their bioavailability markedly better.
Description
~148165 DESCRIPTIOII OF THE INVENTION
The present invention concerns new esters of aryl-propionic acids characterized by the general formula (I) CH
~ ' 3 R~ ~
R" (I) where R represents the -(CH2CH2O)3-CH-2CH2OH residue; R' may be a hydrogen atom, in which case R" represents the isobutyl, benzoyl, 2-tenoyl or 1-oxo-2-isoindolinyl residue or alternatively R' may be a phenyl group in which case R"
represents a fluorine atom or still R' and R" may together represent a benzene ring orthocondensated on the former and carrying a methoxyl group. Preferably, R' and R" are such that (I) represents esters of tetraethylene glycol with
The present invention concerns new esters of aryl-propionic acids characterized by the general formula (I) CH
~ ' 3 R~ ~
R" (I) where R represents the -(CH2CH2O)3-CH-2CH2OH residue; R' may be a hydrogen atom, in which case R" represents the isobutyl, benzoyl, 2-tenoyl or 1-oxo-2-isoindolinyl residue or alternatively R' may be a phenyl group in which case R"
represents a fluorine atom or still R' and R" may together represent a benzene ring orthocondensated on the former and carrying a methoxyl group. Preferably, R' and R" are such that (I) represents esters of tetraethylene glycol with
2-(4-isobutyl-phenyl)-, 2-[4-2-(tenoyl)-phenyl]-, 2-[4-(1-oxo-2-isoindolinyl)phenyl]-, 2-(3-benzoyl-phenyl)-, 2-(3-fluoro-4-phenyl-phenyl) and 2-(6-methoxy-2-naphthyl)-propionic acids, all known for their anti-inflammatory properties. The present invention also concerns the enantiomers of the esters of formula (I).
The compounds (I), comparable to the corresponding acids with respect to their properties of low toxicity and gastric injuring effects, present with an anti-inflammatory activity that, although showing an equivalent intensity, differs markedly for a more prolonged duration. This evidence represents a considerable advantage since the corres-ponding acids are characterized generally by a short-term - 1 - ~
~816S
action. Also pharmacokinetic investigations show a bio-availability markedly higher, even of a 100 percent rate, than that shown by the corresponding acids.
Therefore, a further object of the present invention is represented by pharmaceutical compositions endowed with an anti-inflammatory activity, containing as active ingredient at least one ester of formula (I), in the form of a racemus or of enantiomers.
A further object of the present invention is re-presented by a procedure for the preparation of the esters (I), that consists in reacting compounds of formula (II) CH-COX (II) R"
(where R' and R" have the above stated significance while X
represents either a hydroxyl group or preferably an activating group such as alkoxyl, Cl, l-imidanolyl group or still a residue apt to form an anhydride function with the remaining moiety of the molecule) with an excess of tetraethylene glycol. Preferably, the compounds (II) are reacied with tetraethylene glycol, in a molar ratio at least equivalent to 1:3.5, in order to ensure the maximum yield of monoester.
The below reported example illustrates the invention, con-stituting however no limitation to its scope.
EXAMPLE
Monoester o~ 2-(4-isobutyl-phenyl)propionic acid with tetra-ethylene glycol ~f~;
'~
The compounds (I), comparable to the corresponding acids with respect to their properties of low toxicity and gastric injuring effects, present with an anti-inflammatory activity that, although showing an equivalent intensity, differs markedly for a more prolonged duration. This evidence represents a considerable advantage since the corres-ponding acids are characterized generally by a short-term - 1 - ~
~816S
action. Also pharmacokinetic investigations show a bio-availability markedly higher, even of a 100 percent rate, than that shown by the corresponding acids.
Therefore, a further object of the present invention is represented by pharmaceutical compositions endowed with an anti-inflammatory activity, containing as active ingredient at least one ester of formula (I), in the form of a racemus or of enantiomers.
A further object of the present invention is re-presented by a procedure for the preparation of the esters (I), that consists in reacting compounds of formula (II) CH-COX (II) R"
(where R' and R" have the above stated significance while X
represents either a hydroxyl group or preferably an activating group such as alkoxyl, Cl, l-imidanolyl group or still a residue apt to form an anhydride function with the remaining moiety of the molecule) with an excess of tetraethylene glycol. Preferably, the compounds (II) are reacied with tetraethylene glycol, in a molar ratio at least equivalent to 1:3.5, in order to ensure the maximum yield of monoester.
The below reported example illustrates the invention, con-stituting however no limitation to its scope.
EXAMPLE
Monoester o~ 2-(4-isobutyl-phenyl)propionic acid with tetra-ethylene glycol ~f~;
'~
3 \ ~ CH3 CH-CH2 ~ / ~ CH-C-O(CH2CH2O)3-CH2CH2OH
20 grams (0.09 moles) of 2-(4-isobutyl-phenyl) propionic acid (ibuprofen) are dissolved in 250 ml of anhydrous CHC13. The resulting solution is added with 20 g of carbonyl-diimidazole (CDI, 0.12 moles, 33 percent excess) under agitation, at room temperature. As soon as the effervescence is terminated (30 minutes approximately), the reaction mixture is added with 55.2 ml of tetraethylene glycol (0.32 moles, 250 percent excess approximately), previously dried on CaSO4. The reaction is caused to occur in a thermostatized bath at 60C for 48 h.
The solution is concentrated in a rotary evaporator, and diluted thereafter with ethyl ether (250-300 ml). The ether solution is then washed two times with 100 ml of water, two times with 100 ml of 0.1 N HCl, two further times with 100 ml of water, two times with 100 ml of 0.1 N NaOH, and finally three times with 100 ml of water.
After drying on Na2SO4, the resulting solution is filtered and evaporated to dryness. The residue is purified by washing with anhydrous n-heptane (500 ml approximately), duly cooling in order to reduce to a minimum the solubility of the product, appreciable also in apolar solvents.
n-Heptane is then decanted, and the product is dried under vacuum (0.1 mmHg).80 percent yield.
On the basis of the NMR spectrum (see attached figure), the overall rate of esterification results to correspond to 50 percent approximately in weight of . ~
~14~3165 2-(4-isobutyl-phenyl) propionic acid likely to be liberated.
Sa:id datum is comparable with the one resulting from the indirect titration (theoretical:1.319 meq; practical:l.33 meq, equivalent to 50.4 percent of acid likely to be liberated);
moreover, the direct titration states the absence of unbound acid.
The resulting produ~t (that, for brevity's sake shall be indicated from now on with the code name MR-653) is practically insoluble in water, and soluble on the other hand in methanol, diethyl ether, acetone and chloroform.
The MeOH/CHCl3/glacial acetic acid (70:35:4) mixture was used for the elution on 60 Merck Kieselgel plates.
MR-653, the starting acid and tetraethylene glycol show the following retention coefficients:
Rf MR-653 0.8 Acid 0.78 Tetraethylene glycol 0.6 CHROMATOGRAPHIC TESTS
-A single spot characterizes the presence of MR-653.
TLC does not show in any case the presence of unbound 2-(4-isobutyl-phenyl) propionic acid. A related perfect reproducibility was observed repeating the preparations of the compound MR-653. This evidence also proved valid in all the cases in which the chloride of 2-(4-isobutyl-phenyl)-propionic acid or its mixed anhydride with ethyl chloro-carbonate are used in replacement of imidazolide.
The pharmacotoxicologic properties of the esters (I) are herein described on the basis of the example provided by MR-653.
~148~65 ACUTE TOXICITY: in the mouse, the oral LD 50 of MR-653 proved higher than 2000 mg/kg.
ANTI-INFLAMMATORY ACTIVITY
_ The anti-inflammatory activity of MR-653 was assessed versus the one of ibuprofen, i.e. 2-(4-isobutyl-phenyl)-propionic acid, at equimolar doses by the carrageenin edema test in the rat (Wistar males and females, bodyweight 160-200 g, twelve animals per compound and per experiment).
1 percent carrageenin in saline was given, at the rate of 0.1 ml subcutaneously, into the plantar area of the left paw.
Ibuprofen was given at doses of 100 mg/kg/os(in 5 percent gum arabic); MR-653 in doses equivalent to ibuprofen 100 mg/
kg/os, i.e. 200 mg/kg/os respectively.
The compounds were administered 1, 3 and 6 hours respectively before the carrageenin injection; the related values were always read 4 hours after the carrageenin injection, duly assessing the percent swelling of the paw versus the value at the time 0 (carrageenin inocula). The results are expressed as percent protection considering the swelling in the control group as equal to 100.
The protection exerted by the two compounds, versus the edema induced by carrageenin, proved rapid and effective.
A comparable peak of activity is observed for both treatments around the first hour; said peak, while undergoing in the case of ibuprofen a rapid and progressive decrease even starting from the second hour, proves on the contrary markedly slower in the.case of MR-653, with a typical action prolonged in the course of time, as results from the attached Table 1.
~48165 Table 1 - Percent protection from the carrageenin edema considering.the.control .gro.ups a.s eqN.al. to..l.00..
-Drug Detection after hours Ibuprofen 6044 28 24 20 ANALGESIC ACTIVITY
Abdominal squirmings were induced by an intraperitoneal injection in saline, given at the dose of 4 mg/kg/20 ml.
The compounds ibuprofen and MR-653 had been given one hour before, orally, at the dose of 100 mg/kg (equimolar doses).
In the course of the 20 minutes subsequent to the injection of phenylquinone, all animals were observed in order to detect any squirming: the animals, presenting with no squirming, were considered as protected. A 20 percent protection (10 animals per group), versus the control group.
Acetylcholine Test Squirmings were induced by an intraperitoneal injection of aCetylcholine (200 ml; 0.5 ml per mouse); both compounds were given orally one hour before the administration of acetylcholine at the dose of 10 mg/kg, in equimolar doses.
After the administration of acetylcholine the animals were observed for the subsequent 4 minutes, and considered protected when presenting with no squirming. The below reported results were obtained in comparison with the control group:
Ibuprofen: 50 percent protection MR-653 : 48 percent protection 11~8165 Gastric Injuring Effects The possible gastric injuring effect of MR-653, versus ibuprofen, was assessed on Wistar rats of either sex, bodyweight ranging between 160 and 200 g, fasted for 24 hours at the time of treatment. The compounds were given intra-peritoneally at the equimolar dose of 500 mg/kg.
The animals were killed 5 hours after the treatment in order to assess the conditions of the gastric mucosa, and the possible presence of bleedings and ulcers.
Results A punctiform ulcer was observed in 14 percent of the cases in the group given ibuprofen; stomachs were presenting with an almost normal mucosa with a fair quantity of a yellowish foamy secretion. A comparable percent incidence of ulcero-genic punctiform episodes ~16 percent), associated with the presence of a mildly hyperemic peritoneal exudate, was also observed in the group given MR-653.
PHARMACOKINETICS
The plasma kinetics of MR-653 was assessed, following oral administration, in the male albino rat, Wistar strain, bodyweight of 180-220 grams. Since said compound liberates in the body a certain amount of ibuprofen, the kinetics'of said latter drug, at the doses of 58.8 mg/kg and 19.2 mg/kg, was also assessed. In the direct case of ibuprofen plasma kinetics was also investigated after intraperitoneal administration to the purposes of being provided with an assessment of the rate of the intestinal absorption of this drug. The investigational drugs were given by oral gavage, suspended in 0.5 percent gum arabic; an analogous suspension was used in the case of the intraperitoneal administration.
:1148~65 Blood withdrawals from the experimental animals were made from a sublingual vein according to the procedure described by M. Ferro Milone and P. Barbiera (Atti della Soc.
It.Scienze Veterinarie, 1974, 28,394). The plasma deter-mination of ibuprofen was carried out by a gas chromatographic method, according to the procedure described by F.M. Runci and G. Segre (Recent Development in Chromatography and Electro-phoresis, A. Frigerio, L.Renoz Eds., Elsevier, Amsterdam, 1979, p. 199).
Table 2 shows the plasma kinetic patterns of ibu-profen after oral and intraperitoneal administration of 58.8 mg/kg.
If the intraperitoneal kinetics can be assimilated to the intravenous kinetics, it can be expressed by a biex-ponential equation, i.e.
X(T) = 468 e 2-1t+ 32 e-0.23t where X = concentration in mcg/ml and t = hours.
The half-life, calculated on the basis of the second component, results to be equivalent to 3 hours approximately.
The AUC (areas under the curves) are on first approximation (for times up to the 7th hour) equivalent-to 190 (os) and 325 (ip) with ratio equivalent to a 60 percent rate.
Table 2 also shows the kinetics of MR-653; the ibuprofen content is such that the dose used of MR-653 (128 mg/kg) corresponds to 58.8 mg/kg of ibuprofen.
On the basis of said content of ibuprofen, the plasma curves were compared with the curves provided by the administration of 58.8 mg/kg of ibuprofen.
1~8~6S
A line going through the peaks (at the first hour) of the plasma levels of ibuprofen ~as plotted in order to better compare the kinetic patterns. It could be therefore seen, on the basis of said line, that the value results to be markedly higher in the case of MR-653. Said compound, therefore, shows an increased bioavailability (ranging on a 100 percent level, as can be assumed by extrapolation).
PHARMACOKINETICS
TAsLE 2 - Plasma concentrations (mcg/ml) and standard deviation of ibuprofen in the male rat after intraperitoneal and oral administration, and of MR-653 given orally.
Com~ound Dose given hours mg/kg 0.5 1 2 5 7 Ibuprofen i.p. 58.8 215.2-33.4 104.7- 18.3- 6.2-12.4 11.0 2.4 Ibuprofen os 58.8 71.7- 32.2- 12.1- 9.1-23.6 7.7 22 1.5 MR-653 os 120 (x)118.4- 76.6- 45.2- 36.8-20.7 12.9 23.7 11.3 X correspondent to 58.8 mg of Ibuprofen It appears evident from the summation of the results that MR-653, compared with ibuprofen at equimolar doses exerts, although maintaining practically unchanged values of toxicity and gastric injuring effects, a better anti-inflam-matory activity that becomes evident with an earlier onset of effects while higher values are kept in the course of time, especially after the second hour. Actually, while in the case of ibuprofen the anti-inflammatory activity results to consist in a curve effect with highly marked drops, the activity of MR-653 proves quite prolonged with values still markedly high until the 6th hour, higher in fact, in a 48 per-g _ , ~
1~8165 cent rate, than those encountered in the case of ibuprofen.
Said higher efficacy, especially in the longint:ervals, is also confirmed by the tests of pharmacokinetics that demonstrate the higher bioavailability of MR-653 with respect to ibuprofen for an approximate 100 percent rate.
20 grams (0.09 moles) of 2-(4-isobutyl-phenyl) propionic acid (ibuprofen) are dissolved in 250 ml of anhydrous CHC13. The resulting solution is added with 20 g of carbonyl-diimidazole (CDI, 0.12 moles, 33 percent excess) under agitation, at room temperature. As soon as the effervescence is terminated (30 minutes approximately), the reaction mixture is added with 55.2 ml of tetraethylene glycol (0.32 moles, 250 percent excess approximately), previously dried on CaSO4. The reaction is caused to occur in a thermostatized bath at 60C for 48 h.
The solution is concentrated in a rotary evaporator, and diluted thereafter with ethyl ether (250-300 ml). The ether solution is then washed two times with 100 ml of water, two times with 100 ml of 0.1 N HCl, two further times with 100 ml of water, two times with 100 ml of 0.1 N NaOH, and finally three times with 100 ml of water.
After drying on Na2SO4, the resulting solution is filtered and evaporated to dryness. The residue is purified by washing with anhydrous n-heptane (500 ml approximately), duly cooling in order to reduce to a minimum the solubility of the product, appreciable also in apolar solvents.
n-Heptane is then decanted, and the product is dried under vacuum (0.1 mmHg).80 percent yield.
On the basis of the NMR spectrum (see attached figure), the overall rate of esterification results to correspond to 50 percent approximately in weight of . ~
~14~3165 2-(4-isobutyl-phenyl) propionic acid likely to be liberated.
Sa:id datum is comparable with the one resulting from the indirect titration (theoretical:1.319 meq; practical:l.33 meq, equivalent to 50.4 percent of acid likely to be liberated);
moreover, the direct titration states the absence of unbound acid.
The resulting produ~t (that, for brevity's sake shall be indicated from now on with the code name MR-653) is practically insoluble in water, and soluble on the other hand in methanol, diethyl ether, acetone and chloroform.
The MeOH/CHCl3/glacial acetic acid (70:35:4) mixture was used for the elution on 60 Merck Kieselgel plates.
MR-653, the starting acid and tetraethylene glycol show the following retention coefficients:
Rf MR-653 0.8 Acid 0.78 Tetraethylene glycol 0.6 CHROMATOGRAPHIC TESTS
-A single spot characterizes the presence of MR-653.
TLC does not show in any case the presence of unbound 2-(4-isobutyl-phenyl) propionic acid. A related perfect reproducibility was observed repeating the preparations of the compound MR-653. This evidence also proved valid in all the cases in which the chloride of 2-(4-isobutyl-phenyl)-propionic acid or its mixed anhydride with ethyl chloro-carbonate are used in replacement of imidazolide.
The pharmacotoxicologic properties of the esters (I) are herein described on the basis of the example provided by MR-653.
~148~65 ACUTE TOXICITY: in the mouse, the oral LD 50 of MR-653 proved higher than 2000 mg/kg.
ANTI-INFLAMMATORY ACTIVITY
_ The anti-inflammatory activity of MR-653 was assessed versus the one of ibuprofen, i.e. 2-(4-isobutyl-phenyl)-propionic acid, at equimolar doses by the carrageenin edema test in the rat (Wistar males and females, bodyweight 160-200 g, twelve animals per compound and per experiment).
1 percent carrageenin in saline was given, at the rate of 0.1 ml subcutaneously, into the plantar area of the left paw.
Ibuprofen was given at doses of 100 mg/kg/os(in 5 percent gum arabic); MR-653 in doses equivalent to ibuprofen 100 mg/
kg/os, i.e. 200 mg/kg/os respectively.
The compounds were administered 1, 3 and 6 hours respectively before the carrageenin injection; the related values were always read 4 hours after the carrageenin injection, duly assessing the percent swelling of the paw versus the value at the time 0 (carrageenin inocula). The results are expressed as percent protection considering the swelling in the control group as equal to 100.
The protection exerted by the two compounds, versus the edema induced by carrageenin, proved rapid and effective.
A comparable peak of activity is observed for both treatments around the first hour; said peak, while undergoing in the case of ibuprofen a rapid and progressive decrease even starting from the second hour, proves on the contrary markedly slower in the.case of MR-653, with a typical action prolonged in the course of time, as results from the attached Table 1.
~48165 Table 1 - Percent protection from the carrageenin edema considering.the.control .gro.ups a.s eqN.al. to..l.00..
-Drug Detection after hours Ibuprofen 6044 28 24 20 ANALGESIC ACTIVITY
Abdominal squirmings were induced by an intraperitoneal injection in saline, given at the dose of 4 mg/kg/20 ml.
The compounds ibuprofen and MR-653 had been given one hour before, orally, at the dose of 100 mg/kg (equimolar doses).
In the course of the 20 minutes subsequent to the injection of phenylquinone, all animals were observed in order to detect any squirming: the animals, presenting with no squirming, were considered as protected. A 20 percent protection (10 animals per group), versus the control group.
Acetylcholine Test Squirmings were induced by an intraperitoneal injection of aCetylcholine (200 ml; 0.5 ml per mouse); both compounds were given orally one hour before the administration of acetylcholine at the dose of 10 mg/kg, in equimolar doses.
After the administration of acetylcholine the animals were observed for the subsequent 4 minutes, and considered protected when presenting with no squirming. The below reported results were obtained in comparison with the control group:
Ibuprofen: 50 percent protection MR-653 : 48 percent protection 11~8165 Gastric Injuring Effects The possible gastric injuring effect of MR-653, versus ibuprofen, was assessed on Wistar rats of either sex, bodyweight ranging between 160 and 200 g, fasted for 24 hours at the time of treatment. The compounds were given intra-peritoneally at the equimolar dose of 500 mg/kg.
The animals were killed 5 hours after the treatment in order to assess the conditions of the gastric mucosa, and the possible presence of bleedings and ulcers.
Results A punctiform ulcer was observed in 14 percent of the cases in the group given ibuprofen; stomachs were presenting with an almost normal mucosa with a fair quantity of a yellowish foamy secretion. A comparable percent incidence of ulcero-genic punctiform episodes ~16 percent), associated with the presence of a mildly hyperemic peritoneal exudate, was also observed in the group given MR-653.
PHARMACOKINETICS
The plasma kinetics of MR-653 was assessed, following oral administration, in the male albino rat, Wistar strain, bodyweight of 180-220 grams. Since said compound liberates in the body a certain amount of ibuprofen, the kinetics'of said latter drug, at the doses of 58.8 mg/kg and 19.2 mg/kg, was also assessed. In the direct case of ibuprofen plasma kinetics was also investigated after intraperitoneal administration to the purposes of being provided with an assessment of the rate of the intestinal absorption of this drug. The investigational drugs were given by oral gavage, suspended in 0.5 percent gum arabic; an analogous suspension was used in the case of the intraperitoneal administration.
:1148~65 Blood withdrawals from the experimental animals were made from a sublingual vein according to the procedure described by M. Ferro Milone and P. Barbiera (Atti della Soc.
It.Scienze Veterinarie, 1974, 28,394). The plasma deter-mination of ibuprofen was carried out by a gas chromatographic method, according to the procedure described by F.M. Runci and G. Segre (Recent Development in Chromatography and Electro-phoresis, A. Frigerio, L.Renoz Eds., Elsevier, Amsterdam, 1979, p. 199).
Table 2 shows the plasma kinetic patterns of ibu-profen after oral and intraperitoneal administration of 58.8 mg/kg.
If the intraperitoneal kinetics can be assimilated to the intravenous kinetics, it can be expressed by a biex-ponential equation, i.e.
X(T) = 468 e 2-1t+ 32 e-0.23t where X = concentration in mcg/ml and t = hours.
The half-life, calculated on the basis of the second component, results to be equivalent to 3 hours approximately.
The AUC (areas under the curves) are on first approximation (for times up to the 7th hour) equivalent-to 190 (os) and 325 (ip) with ratio equivalent to a 60 percent rate.
Table 2 also shows the kinetics of MR-653; the ibuprofen content is such that the dose used of MR-653 (128 mg/kg) corresponds to 58.8 mg/kg of ibuprofen.
On the basis of said content of ibuprofen, the plasma curves were compared with the curves provided by the administration of 58.8 mg/kg of ibuprofen.
1~8~6S
A line going through the peaks (at the first hour) of the plasma levels of ibuprofen ~as plotted in order to better compare the kinetic patterns. It could be therefore seen, on the basis of said line, that the value results to be markedly higher in the case of MR-653. Said compound, therefore, shows an increased bioavailability (ranging on a 100 percent level, as can be assumed by extrapolation).
PHARMACOKINETICS
TAsLE 2 - Plasma concentrations (mcg/ml) and standard deviation of ibuprofen in the male rat after intraperitoneal and oral administration, and of MR-653 given orally.
Com~ound Dose given hours mg/kg 0.5 1 2 5 7 Ibuprofen i.p. 58.8 215.2-33.4 104.7- 18.3- 6.2-12.4 11.0 2.4 Ibuprofen os 58.8 71.7- 32.2- 12.1- 9.1-23.6 7.7 22 1.5 MR-653 os 120 (x)118.4- 76.6- 45.2- 36.8-20.7 12.9 23.7 11.3 X correspondent to 58.8 mg of Ibuprofen It appears evident from the summation of the results that MR-653, compared with ibuprofen at equimolar doses exerts, although maintaining practically unchanged values of toxicity and gastric injuring effects, a better anti-inflam-matory activity that becomes evident with an earlier onset of effects while higher values are kept in the course of time, especially after the second hour. Actually, while in the case of ibuprofen the anti-inflammatory activity results to consist in a curve effect with highly marked drops, the activity of MR-653 proves quite prolonged with values still markedly high until the 6th hour, higher in fact, in a 48 per-g _ , ~
1~8165 cent rate, than those encountered in the case of ibuprofen.
Said higher efficacy, especially in the longint:ervals, is also confirmed by the tests of pharmacokinetics that demonstrate the higher bioavailability of MR-653 with respect to ibuprofen for an approximate 100 percent rate.
Claims (14)
1. Process for the preparation of esters of aryl-propionic acids of the formula (I) (I) where R represents the residue -(CH2CH2O)3-CH2-CH2OH; R' may be a hydrogen atom, in which case R" represents the isobutyl, benzoyl, 2-tenoyl or 1-oxo-2-isoindolinyl residue, or altern-atively R' may be a phenyl group in which case R" represents a fluorine atom or still R' and R" may represent together a benzene ring orthocondensated on the first ring and carrying a methoxyl group, as well as their enantiomers, characterized by the fact that a reaction is caused between compounds characterized by the formula (II) (II) wherein R' and R" are as above defined, and X represents a hydroxyl group, or preferably an activating group such as an alkoxyl group, a C1 atom, a 1-imidazolyl group, or still a residue apt to form an anhydride function with the re-maining moiety of the molecule, with an excess of tetraethylene glycol, the molar ratio between (II) and tetraethylene glycol being at least 1:3.5.
2. Process according to claim 1, wherein the aryl-propionic acid is 2-(4-isobutyl-phenyl)propionic acid.
3. Process according to claim 1, wherein the aryl-propionic acid is 2-[4-(2-tenoyl)phenyl]propionic acid.
4. Process according to claim 1, wherein the aryl-propionic acid is 2-[4-(1-oxo-2-isoindolinyl)phenyl]propionic acid.
5. Process according to claim 1, wherein the aryl-propionic acid is 2-(3-benzoyl-phenyl)propionic acid.
6. Process according to claim 1, wherein the aryl-propionic acid is 2-(3-fluoro-4-phenyl-phenyl)propionic acid.
7. Process according to claim 1, wherein the aryl-propionic acid is 2-(6-methoxy-2-naphthyl)propionic acid.
8. Esters of arylpropionic acids of the formula (I) (I) where R represents the residue -(CH2CH2O)3-CH2-CH2OH; R' may be a hydrogen atom, in which case R" represents the isobutyl, benzoyl, 2-tenoyl or 1-oxo-2-isoindolinyl residue, or alternatively R' may be a phenyl group in which case R"
represents a fluorine atom or still R' and R" may represent together a benzene ring orthocondensated on the first ring and carrying a methoxyl group, as well as their enantiomers, whenever obtained by the process as claimed in Claim 1, or by an obvious chemical equivalent thereof.
represents a fluorine atom or still R' and R" may represent together a benzene ring orthocondensated on the first ring and carrying a methoxyl group, as well as their enantiomers, whenever obtained by the process as claimed in Claim 1, or by an obvious chemical equivalent thereof.
9. Tetraethylene glycol monoester with 2-(4-isobutyl-phenyl)propionic acid, whenever obtained by the process as claimed. in Claim 2, or by an obvious chemical equivalent thereof.
10. Tetraethylene glycol monoester with 2-[4-(2-tenoyl) phenyl]-propionic acid, whenever obtained by the process as claimed in Claim 3, or by an obvious chemical equivalent thereof.
11. Tetraethylene glycol monoester with 2-[4-(1-oxo-2-isoindolinyl)phenyl]propionic acid, whenever obtained by the process as claimed in Claim 4, or by an obvious chemical equivalent thereof.
12. Tetraethylene glycol monoester with 2-(3-benzoyl-phenyl)-propionic acid, whenever obtained by the process as claimed in Claim 5, or by an obvious chemical equivalent thereof.
13. Tetraethylene glycol monoester with 2-(3-fluoro-4-phenyl-phenyl)propionic acid, whenever obtained by the process as claimed in Claim 6, or by an obvious chemical equivalent thereof.
14. Tetraethylene glycol monoester with 2-(6-methoxy-2-naphthyl)propionic acid, whenever obtained by the process as claimed in Claim 7, or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000372274A CA1148165A (en) | 1981-03-04 | 1981-03-04 | Esters of arylpropionic acids endowed with an anti- inflammatory activity, process for their preparation, and related pharmaceutical compositions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000372274A CA1148165A (en) | 1981-03-04 | 1981-03-04 | Esters of arylpropionic acids endowed with an anti- inflammatory activity, process for their preparation, and related pharmaceutical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1148165A true CA1148165A (en) | 1983-06-14 |
Family
ID=4119375
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000372274A Expired CA1148165A (en) | 1981-03-04 | 1981-03-04 | Esters of arylpropionic acids endowed with an anti- inflammatory activity, process for their preparation, and related pharmaceutical compositions |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1148165A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5681964A (en) * | 1990-10-23 | 1997-10-28 | University Of Kentucky Research Foundation | Permeable, non-irritating prodrugs of nonsteroidal and steroidal agents |
| US6765019B1 (en) | 1999-05-06 | 2004-07-20 | University Of Kentucky Research Foundation | Permeable, water soluble, non-irritating prodrugs of chemotherapeutic agents with oxaalkanoic acids |
-
1981
- 1981-03-04 CA CA000372274A patent/CA1148165A/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5681964A (en) * | 1990-10-23 | 1997-10-28 | University Of Kentucky Research Foundation | Permeable, non-irritating prodrugs of nonsteroidal and steroidal agents |
| US6765019B1 (en) | 1999-05-06 | 2004-07-20 | University Of Kentucky Research Foundation | Permeable, water soluble, non-irritating prodrugs of chemotherapeutic agents with oxaalkanoic acids |
| US7214710B2 (en) | 1999-05-06 | 2007-05-08 | University Of Kentucky Research Foundation | Permeable, water soluble, non-irritating prodrugs of chemotherapeutic agents with oxaalkanoic acids |
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