MXPA99001482A - Pharmaceutical composition containing 4-oxo-butynic acids - Google Patents

Abstract

The invention concerns a pharmaceutical composition containing, as active principle, a compound of formula (a) in which groups A and B are selected independently of each other among:a mono-cyclic, bi-cyclic or tri-cyclic aryl group having 6 to 14 carbon atoms;a heteroaraomatic group selected among the pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl groups;an alkyl group having 1 to 14 carbon atoms;a cycloalkyl group having 5 to 8 carbon atoms;a saturated heterocyclic group selected among thetetrahydrofuryl, tetrahydropyrranyl, piperidinyl and pyrrolidinyl groups;its solvate or a salt of this acid with a pharmaceutically acceptable base.

Description

Pharmaceutical composition containing 4-oxobutanoic acids The present invention relates to pharmaceutical compositions containing 4-oxobutanoic acids, which are useful in particular in the treatment of diabetes.

The subject of the present invention are thus pharmaceutical compositions containing, as an active principle, a compound of the formula: in which groups A and B are chosen, independently from each other, from: - a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms; - a heteroaromatic group chosen from the pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl groups; REF. : 29269 - an alkyl group having from 1 to 14 carbon atoms; - a cycloalkyl group having from 5 to 8 carbon atoms; - a saturated heterocyclic group selected from the groups tetrahydrofuryl, tetrahydropyranyl, piperidyl and pyrrolidinyl; it is possible that groups A and B have from 1 to 3 substituents chosen from a Ci-Cg alkyl group, Cj-Cg alkoxy group, C6-C14 aryl group, a heteroaryl group selected from pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl, an aryl (C6-C14) alkyl group (Cx-Cg), an aryl (C6-C14) alkyl group (Cx-Cg) aryl (C6-C14), halogen, a trifluoromethyl group, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxyl, alkoxycarbonyl (C: -C6), carbamoyl, alkylsulfonyl (Ci-Cg), sulfoamino, alkylsulfonylamino (Cx-Cg), sulfamoyl or alkylcarbonylamino (C1-C6), or two of the substituents that form a methylenedioxy group, its solvate or a salt of this acid with a pharmaceutically acceptable base.

In a preferred embodiment of the invention, the compositions comprise, as active ingredients, a compound of formula I wherein A and B are selected from aryl groups.

Examples of aryl groups that could be mentioned are phenyl, α-naphthyl, β-naphthyl and fluorophenyl groups.

The Cx-Cg alkyl groups could be linear or branched. Examples that could be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups.

The alkoxy groups could be similarly linear or branched.

Examples that could be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy groups.

The halogens could be chosen from fluorine, chlorine, bromine, and iodine.

The present invention encompasses compositions containing the tautomeric forms, the enantiomers, the diastereomers and the epimers of the compounds of formula I.

Examples of pharmaceutically acceptable salts that could be mentioned are sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminum, iron, bismuth, etc.).

In a preferred embodiment, the compositions according to the invention comprise a compound chosen from: - 2-benzyl-4- (4-methoxyphenyl) -4-oxobutanoic acid - 2-benzyl-4- acid. { 4-fluorophenyl} -4-oxobutanoic 2-cyclohexylmethyl and 1-4- (4-methoxyphenyl) -4-oxobutanoic acid - 2-benzyl-4-phenyl-4-oxobutanoic acid - 2- (ß-naphthylmethyl) -4-phenyl-4-oxobutanoic acid 2- [(4-chlorophenyl) methyl] -4- (4-methoxyphenyl) -4-oxo-butaoic acid - 2-benzyl-4- (4-methylphenyl) -4-oxobutanoic acid - 4- (4-fluorophenyl) -2- [(4-methoxyphenyl) methyl] -4-oxo-buo-ico acid - 2-benzyl-4- (3,4-methylenedioxyphenyl) -4-oxobutanoic acid - 2-benzyl-4-cyclohexyl-4-oxobutanoic acid 4-phenyl-2- [(2-tetrahydrofuryl) methyl] -4-oxobutanoic acid, the solvates and the salts of these acids with pharmaceutically acceptable bases.

Certain compounds of formula I are known (Bioor Chem 14, 148, 1986, Biochemistry 23, 2083, 1984, J.A.C.S. 100, 7750, 1978, EP-A-310918 and DE-A-3 839 401).

The subject of the present invention are also the novel compounds of formula I, ie the compounds of formula: in which groups A and B are chosen, independently from each other, from: - a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms; - a heteroaromatic group chosen from the pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl groups; - an alkyl group having from 1 to 14 carbon atoms; - a cycloalkyl group having from 5 to 8 carbon atoms; - a saturated heterocyclic group selected from the groups tetrahydrofuryl, tetrahydropyranyl, piperidyl and pyrrolidinyl; it is possible that groups A and B have from 1 to 3 substituents chosen from a C?-C6 alkyl group, C?-C6 alkoxy group, C 6 -C 14 aryl group, a heteroaryl group selected from pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl, an aryl (C6-C14) alkyl group (Cx-Cg), an aryl group (C6-C? 4) alkyl (C? -C6) aryl (C6-C? 4), halogen, a trifluoromethyl group, trifluoromethoxy , cyano, hydroxyl, nitro, amino, carboxyl, alkoxycarbonyl (C? -C6), carbamoyl, alkylsulfonyl (C? -C6), sulfoamino, alkylsulfonylamino (C? -C6), sulfamoyl or alkylcarbonylamino (C? -C6), or two of the substituents that form a methylenedioxy group, with the exclusion of the compounds of formula I in which B is an unsubstituted phenyl group and A is a phenyl, 4-methoxyphenyl, 4-chlorophenyl or cyclohexyl group, its sols and the salts of these acids with bases.

The new compounds include the salts of the acids with pharmaceutically acceptable bases or other bases that give salts that could serve to identify, purify or resolve the compounds of formula I.

The compounds of formula I could be prepared according to a malonic synthesis consisting of reacting a compound of the formula: wherein X is a halogen as defined above and A has the meaning given above, with a malonic derive of formula: wherein R and R 'are C? -C6 alkyl groups and B has the meaning given above, in the presence of an alkali metal hydride or an alkali metal alkoxide, to form a compound of the formula: wherein A, B, R and R 'have the meaning given above, and then saponifying the compound of formula IV, for example with a mixture of alkali hydroxide, water, tetrahydrofuran and / or ethanol, to form a compound of formula: and then decarboxylating the compound of formula V, in particular by heating to dryness, to give the compound of formula I.

The enantiomers of the compounds of formula (I) could be separated by successive recrystallization of the salt of the acid (I) with an optically active base in solvents such as acetone, ethyl acetate, isopropanol, etc., followed by displacement of the optically active acid of the salt by an inorganic or organic acid according to a standard method.

The compositions according to the present invention could be used in the treatment of diabetes, in particular insulin-independent diabetes, due to its hypoglucoemission effect and its absence of toxicity in active doses.

The pharmaceutical compositions according to the invention could be provided in forms intended for parenteral, oral, rectal, permucosal or percutaneous administration.

This will be in the form of multi-dose bottles or injectable solutions or suspensions, in the form of flat or covered tablets, sugar-coated tablets, wafer capsules, gelatin capsules, pills, pills, powders, suppositories, rectal capsules, solutions or suspensions, for percutaneous use in a polar solvent or for permucous use.

The excipients which are suitable for such administrations are cellulose derives or microcrystalline cellulose, alkaline earth metal carbonates, magnesium phosphate, starches, modified starches and lactose for solid forms.

For rectal use, cocoa butter or polyethylene glycol stearates are the preferred excipients.

For parenteral use, water, aqueous solutions, physiological and isotonic saline solutions are the most conveniently used vehicles.

The dosage may vary over a wide range depending on the therapeutic indication and the route of administration, as well as the age and weight of the patient.

The following examples illustrate the preparation of the compounds of formula I.

Example 1 Preparation of 2-benzyl-4- (4-methoxyphenyl) -4-oxobutanoic acid (product No. 2) A - Preparation of distyl 2-benzyl-2- £ 2- (4-methoxyphenyl) -2-oxoethyl] propandioate A mixture of 24 ml of diethyl 2-benzylmalonate, 3 g of 80% sodium hydride in oil (washed by hand beforehand with petroleum ether) and 150 ml of tetrahydrofuran is heated at 70 ° C for 1 hour. 24 g of 2-bromo-4 * -methoxy-acetophenone dissolved in 50 ml of tetrahydrofuran are added at + 5 ° C for 1 hour. After one night at room temperature, the reaction mixture is poured into 400 ml of water. After extraction with ethyl acetate, the organic solution is washed with brine, dried with magnesium sulfate and concentrated to dryness under reduced pressure. 40 g of a yellow oil is obtained which crystallizes. p.f. = 67 ° C (hexane) I.R. (KBr): v CO (ketone) = 1671 cm "1; v CO (ester) = 1735 era-1 XH NMR (DMSO / TMS) 1. 2 (6H, t, 2CH3); 3.35 (4H, d, 2CH2); 3.8 (3H, s, OCH3); 4.1 (4H, q.20CH2); 7.1 (7H, m, aromatic H); 7.85 (2H, d, aromatic H).

B - Preparation of 2-benzyl-2- [2- (4-methoxy-phenyl) -oxo-ethyl] propandioic acid g of diethyl 2-benzyl-2- [2- (4-methoxyphenyl) -2-oxo-yl] propandioate, 80 ml of 2N aqueous sodium hydroxide and 250 ml of tetrahydrofuran are mixed together with vigorous stirring.

After 5 days at room temperature, the reaction mixture is poured into 1 liter of ice water. The mixture is washed twice with 200 ml of ethyl acetate and then acidified with 60 ml of 3N aqueous hydrochloric acid.

The mixture is extracted 3.times with 200 ml of ethyl acetate. The organic phase is washed with 100 ml of neutral water, 100 ml of brine and then dried with magnesium sulfate and finally concentrated to dryness under reduced pressure. The fatty yellow solid is recrystallized from acetonitrile. 18 g of a white solid are obtained. p.f. = 175 ° C, decomp.

GO. (KBR): v CO (ketone) = 1660 crn "1; v CO (acid) = 1749 cm'1 : H NMR (DMSO / TMS) 3. 1 (4H, s, 2CHr); 3.8 (3H, s, OCH3); 7 (7H, m, aromatic H); 7.8 (2H, d, aromatic H); 13.7 (m, OH).

C - Preparation of 2-benzyl-4- (4-methoxy-phenyl) -4-oxobutanoic acid 17 g of 2-benzyl-2- [2- (4-methoxyphenyl) -2-oxo-ethyl] propandioic acid are heated with stirring until melted. When the evolution of gas has stopped, the heating stops and the material cools to room temperature. The yellow solid is recrystallized from ethyl acetate. 12 g of a white solid are obtained. p.f. = 131 ° C GO. (KBR): v CO (ketone) = 1664 cr1; v CO (acid) = 1729 cm "1 XH NMR (DMSO / TMS) 3. 1 (5H, m, CH and 2CH2); 3.8 (3H, s, OCH3); 7.1 (7H, m, aromatic H); 7.9 (2H, d, aromatic H); 13.5 (m, OH).

EXAMPLE 2 Preparation of (-) -2-benzyl-4- (4-methoxy-phenyl) -4-oxobutanoic acid (product No. 3) g of the acid obtained in Example 1 are dissolved in 200 ml of warm acetone. 8.12 g of S- are added. { -) -a-methylbenzylamine dissolved in 40 ml of acetone. The mixture is cooled and the white solid is filtered and drained. After successive recrystallization with isopropanol until the optical deviation of the salt is stable, 7.3 g of a salt are obtained, this product is treated with 100 ml of 2N hydrochloric acid and 50 ml of ethyl ether with vigorous stirring. The mixture is separated after the sedimentation has been carried out and the acidic aqueous phase is extracted again with 50 ml of ethyl ether. The combined ether solutions are washed once with neutral water and then once with brine. The organic solution is then dried with magnesium sulfate and concentrated to dryness under reduced pressure at room temperature. The residual oil crystallizes in pentane. 5.1 g of a white solid are obtained. p.f. = 94 ° C HPLC purity > 95%; [a] 22D = -18 ° 1 (c = 5, EtOAc).

EXAMPLE 3 Preparation of (+) -2-benzyl-4- (4-methoxy-phenyl) -4-oxobutanoic acid (product No. 4) The technique is the same as that used to separate the acid (-), except that R - (+) - a-methyl-benzylamine is used here. A white solid is obtained. p.f. = 93 ° C HPLC = 98%; [α] 19 D = + 17 ° 6 (c = 5, EtOAc). EXAMPLE 4 Preparation of 2-benzyl-4- (4-fluoro-enyl) -4-oxobutanoic acid (product No. 5) A - Preparation of ethyl 2-benzyl-2- [2- (4-fluorophenyl) -2-oxoethyl] propandioate The process is carried out in the same way as Example 1, step A. A copper yellow oil is obtained.

GO. (film): v CO (ketone) = 1687 crn-1; v CO (ester) = 1735 crn-1.

* H NMR (DMSO / TMS) = 1 .5 (6H, t, 2CH3); 3.5 (4H, d, 2CH2); 4.2 (4H, q.20CH2); 6.8-8 (9H, m, aromatic H).

B - Preparation of 2-benzyl-2- [2- (4-fluorophenyl) -2-oxoethyl] propandioic acid The process is carried out in the same way as Example 1, step B. A white solid is obtained. p.f. = 185-90 ° C (acetonitrile) GO. (KBR): v CO (ketone) = 1675 crn-1; v CO (acid) = 1747 cm "1. 2 H NMR (DMSO / TMS) = 3.3 (4H, d, 2CH 2); 6.7-8 (9H, m, aromatic H); 13 (m, OH).

C - Preparation of 2-benzyl-4- (4-fluoro-phenyl) -4-oxobutanoic acid The process is carried out in the same manner as Example 1, step C. A yellow solid is obtained, which is recrystallized from acetonitrile. The white solid thus obtained corresponds to the acid. p.f. = 140 ° C I.R. (KBR): v CO (ketone) = 1683 cm * 1; v CO (acid) = 1708 cm-1.

X H NMR (DMSO / TMS) = 3 (5H, m, CH and 2CH 2); 7-8.1 (9H, m, aromatic H); 12.2 (s, OH).

EXAMPLE 5 Preparation of (+) -2-benzyl-4- (4-fluorophenyl) -4-oxobutanoic acid (product No. 6) The same method is used as in Example 4. A white solid is obtained. p.f. = 88 ° C HPLC = 99.8%; [α] -P = + 9 ° 9 (c = 5, EtOAc).

EXAMPLE 6 Preparation of (-) -2-benzyl-4- (4-fluoro-enyl) -4-oxobutanoic acid (product No. 7) The same method is used as in Example 3. A white solid is obtained. p.f. = 89 ° C HPLC = 98.5%; [a] "D = -8 ° 9 (c = 10, EtOAc).

The characteristics of the compounds of formula I are compared in Table I below.

TABLE I TABLE I (continued) The results of pharmacological studies will be given below. 1 - . 1 - Study of antidiabetic activity in nOSTZ rats The antidiabetic activity of the compounds of formula I was determined orally in an experimental model of insulin-independent diabetes induced in rats by means of streptozocin.

The model of insulin-independent diabetes is obtained in rats by means of neonatal injection (on the day of birth) of streptozocin.

The diabetic rats used are 8 weeks old.

The establishment of the animals is carried out, from the day of their birth to the day of the experiment, in a domestic animal at a controlled temperature of 21 to 22 ° C, and is subjected to a fixed cycle of light (of 7.00 ha. 7:00 pm) and darkness (from 7:00 pm to 7:00 am). His diet consisted of a maintenance diet; water and food were supplied wad libitum ", with the exception of the 2-hour fasting period prior to testing, during which the food is removed (post-absorbent state).

The rats are treated orally during the day with the test product. 2 hours - after the final administration of the product and 30 minutes after anesthetizing the animals with sodium pentobarbital (Nembutal®), a blood sample of 300 μl is taken from the end of the tail.

Table II compares the main results obtained.

These results show the efficacy of the compounds of formula I in decreasing glycemia in diabetic animals.

Certain compounds of formula I also have an early short-acting insulin secretory effect.

TABLE II TABLE II (continued) 2 - . 2 - Study in non-diabetic rats On the day of the experiment, the non-diabetic rats are treated orally with the test product. Blood samples of 300 μl are taken from the end of the tails of the rats in the first ones. 30 minutes after the administration of the product.

As an example, the results obtained with the product No. 5 (200 mg / kg p.o.) will be given.

TABLE III A reduction in blood glucose is observed, without observing any significant increase in the level of insulin, but more than a decrease in this level. 3 - . 3 - Toxicity test Products Nos. 5 and 6 administered orally at a dose of 200 mg / kg did not induce a toxicity signal. 4 - . 4 - Action on glucagon secretion The experiments carried out in vi tro in infusion of pancreas of non-diabetic rats, isolated according to the technique of Sussman et al., (Diabetes 1_5: 466, 1 966) modified by Assan et al., (Na ture 239; 125, 1976) showed that in the absence of glucose, in the medium infusion, as well as in the presence of arginine, the secretion of glucagon was stimulated by the compounds of formula I. Under the same conditions, the sulfonylureas have a pronounced inhibitory effect . However, in the presence of a high concentration of glucose, the compounds of formula I do not modify the inhibition of glucagon secretion by glucose. The risks of hypoglycaemia associated with treatment with sulfonylureas will be avoided during the treatments with the compounds of formula I.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Having described the invention as above, property is claimed as contained in the following

Claims (4)

1. The pharmaceutical composition, characterized in that it comprises, as an active principle, a compound of the formula: in which groups A and B are chosen, independently from each other, from: - a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms; a heteroaromatic group chosen from pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl groups; - an alkyl group having from 1 to 14 carbon atoms; - a cycloalkyl group having from 5 to 8 carbon atoms; - a saturated heterocyclic group selected from the groups tetrahydrofuryl, tetrahydropyranyl, piperidyl and pyrrolidinyl; it is possible that groups A and B have 1 to 3 substituents selected from a C 1 -Cg alkyl group, C 1 -Cg alkoxy group, C 6 -C 14 aryl group, a heteroaryl group selected from pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl, a aryl group (C6-C14) alkyl (Cx-C, an aryl group (C6-C14) alkyl (Ci-C aryl (C6-C14), halogen, a trifluoromethyl group, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxyl , alkoxycarbonyl (Cx-C6), carbamoyl, alkylsulfonyl (C: -C6), sulfoamino, alkylsulfonylamino (C! -C6), sulfamoyl or alkylcarbonylamino group (Ci-C, or two of the substituents that form a methylenedioxy group, its solvate or a salt of this acid with a pharmaceutically acceptable base.

2. The pharmaceutical composition according to claim 1, characterized in that it comprises, as an active principle, a compound of formula I in which A and B are chosen from aryl groups.

3. The compositions according to claim 1, characterized in that they comprise, as an active principle, a compound chosen from the compounds of the formula: - 2-benzyl-4- (4-methoxyphenyl) -4-oxobutanoic acid - 2-benzyl-4- (4-fluorophenyl) -4-oxobutanoic acid 2-cyclohexylmethyl-4- (4-methoxyphenyl) -4-oxobutanoic acid - 2-benzyl-4-phenyl-4-oxobutanoic acid - 2- (ß-naft-il-yl-yl) -4-phenyl-4-oxobutanoic acid - 2-benzyl-4- (ß-naphthyl) -4-oxobutanoic acid - 2- [(4-chlorophenyl) methyl] -4- (4-methoxyphenyl) -4-oxo-butanoic acid - 2-benzyl-4- (4-methyl-phenyl) -4-oxobutanoic acid - 4- (4-fluorophenyl) -2- [(4-methoxyphenyl) methyl] -4-oxo-butaoic acid 2-benzyl-4- (3, -methylenedioxyphenyl) -4-oxobutanoic acid - 2-benzyl-4-cyclohexyl-4-oxobutanoic acid 4-phenyl-2- [(2-tet rahydrofril) ethyl] -4-oxobutanoic acid, the solvates and the salts of these acids with pharmaceutically acceptable bases.

4. Compounds of formula: in which groups A and B are chosen, independently of each other, from: - a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms; a heteroaromatic group chosen from pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl groups; - an alkyl group having from 1 to 14 carbon atoms; - a cycloalkyl group having from 5 to 8 carbon atoms; - a saturated heterocyclic group selected from the groups tetrahydrofuryl, tetrahydropyranyl, piperidyl and pyrrolidinyl; it is possible that groups A and B have from 1 to 3 substituents of a selected group of Cx-C6 alkyl, C: -C6 alkoxy group, C6-C14 aryl group, a heteroaryl group selected from pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl, an aryl (C6-C14) alkyl group (Ci-C, an aryl (C6-C14) alkyl group (Cx-Cg) aryl (C6-C14), halogen, a trifluoromethyl group, trifluoromethoxy, cyano, hydroxyl, nitro , amino, carboxyl, alkoxycarbonyl (Cj-Cg), carbamoyl, a 1 qu i 1 su 1 foni 1, sulfoamino, alkylsulphonylamino (Cx-Cg), sulfamoyl or alkylcarbonylamino (Ci-Cg), or two of the substituents that form a methylenedioxy group, with the exclusion of the compounds of formula I in which B is an unsubstituted phenyl group and A is a phenyl, 4-methoxyphenyl, 4-chlorophenyl or cyclohexyl group, its solvates and the salts of these acids with bases. SUMMARY n THE INVENTION The present invention relates to a pharmaceutical composition comprising, as an active principle, a compound of the formula: in which groups A and B are chosen, independently from each other, from: - a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms; - a heteroaromatic group chosen from the pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl groups; - an alkyl group having from 1 to 14 carbon atoms, " - a cycloalkyl group having from 5 to 8 carbon atoms; - a saturated heterocyclic group selected from the groups tetrahydrofuryl, tetrahydropyranyl, piperidyl and pyrrolidinyl; as well as its solvate or as a salt of this acid with a pharmaceutically acceptable base.