HU198012B - Process for producing cyclic amino-acid derivatives and pharmaceutical compositions containing them - Google Patents

Description

The present invention relates to a process for the preparation of new 4-phenyl-4-oxybutenoylarylides of formula I

- azole in the formula (I)

R is hydrogen or C14 alkoxy

X can be any of the groups of formula (IV), (V), or (VI) in which the formula (I) is

R1 is a C14 straight or branched alkyl group.

Ős The double bond in the compounds of formula I allows two geometric isomers, so that the compounds of formula I can exist in the form of the E or Z isomers.

When the amino acid component of the compounds of formula (I) has a chiral center, the formula (I) may be any enantiomer or mixture of any of the enantiomers.

The compounds of formula (I) are potent cytoprotective agents and inhibitors of gastric acid secretion.

Compounds close to the scope and structure of the compounds of the present invention are described in British Patent No. 2,096,999.

Among the compounds claimed in the above patent, 4- (3,4,5-trimethoxyphenyl) 4-oxobutene is one of the most potent compounds obtained by the aldol adduct obtained by the aldol reaction of 3,4,5-trinethoxyacetophenone and glyoxylic acid. by dehydration. The aldol reaction takes place in 28% yield and the dehydration step in 71% yield giving a total yield of 20%.

It is an object of the present invention to provide novel therapeutic compounds which may be prepared in good yield from partially commercially available starting materials.

The present invention therefore relates to a process for the preparation of new compounds of the formula I

- in which formula

R is hydrogen or C 14 alkoxy,

X can be any of the groups of formula (IV), (V), or (VI) in which the formula (I) is

R 1 is a C 14 straight or branched alkyl group such that in a compound of formula II wherein X is as defined in the preceding formula, R 1 is a C 14 straight or branched carbon in formula (IV) or with a carboxyl-activated derivative thereof, which is a substituted butenic acid of formula (III) wherein R is as defined herein.

The starting compounds are either commercially available or prepared according to the literature. For example, the preparation of (E) -4-phenyl-4-oxo-2-butenoic acid is described in Org. Synth. Coll., Vol. 3, 109 (1955), and (E) 4- (4-methoxyphenyl) -4-o-buto-2-butenoic acid is described in Papa et al., J. Am. Chem. Soc. 3356, 1948. 1,2,3,4-Tetrahydro-O-carboline-1-carboxylic acid esters may be prepared according to Chem. Abstr. 92, 72679.

In our experiments, it was found that the reaction of the starting compounds was carried out in an average yield of 45-70%.

In the process of the present invention, a substituted butenoic acid of formula (III) or a carboxyl-activated derivative thereof, which may have the E or Z configuration according to the double bond geometry, is reacted with an amino acid derivative of formula (II) in an inert organic solvent. (The activated derivative of the compound of formula (III) may be the ester, acid halide or acid anhydride of the compound of formula (III) or a derivative thereof with an activating reagent known in the art. in case carbodiimide application of an inert organic solvent, preferably anhydrous dichloromethane is used and the reaction is carried out at 0-20 between ^ö C activating agent, a Diphenylphosp chloride may in this case inert organic solvent is ethyl acetate ^ lőnyösen and reaction. -. 10 DEG C. at a temperature as described in the literature (Houben-Weyl E5, 949 (1985)), i.e. a stoichiometric amount of base, preferably triethylamine or N-methylmorpholine, is added to bind the resulting hydrochloric acid.

If desired, the E or Z configuration isomers of the compounds of formula (I) may be converted into one another, for example, by converting the product of configuration E to Z in an inert organic solvent by UV light.

In pharmacological studies, compounds of formula I have been found to exhibit cytoprotective effects at lower doses (ED50 2-10 mg / kg orally) and, at higher doses (ED50 15-40 mg / kg), to inhibit gastric acid secretion. occurs.

For the study of cytoprotective activity, the method of A. Róbert (Gastroenterology, 77, 761767 (1979)) was used, whereby abs. ethanol, which causes long-term hemorrhages in the glandular part of the stomach. Cytoprotective agents prevent this deleterious effect.

The assay for inhibiting gastric acid secretion was assayed by the method of Shay et al., Gastroenterology, 5, 43-61, 1945, using pylorus ligature. Test substances were administered orally in 0.5 ml / 100 mg body weight Tween suspension 30 minutes prior to pylorus ligation to female Wistar rats fasted for 20 hours. After four OTs, the animals were sacrificed and the acid content of their stomach content was determined by titration with 0.01 N sodium hydroxide solution in a phenolphthalein indicator. Gastric pH was determined using a Radelkis OP-211/1 instrument.

The test results for one of the most potent lactated compounds (4- (4-methoxyphenyl) -4-oxo-2 (E) -butenoyl-4R) -thiazolidinecarboxylic acid methyl ester - see Example 3) are shown in Table 1. Statistical evaluation was performed by Student's t-test. Values of p <0.05 were considered significant. Mean values and ± S.E. are shown in the table.

The ED50 values of the substances of the invention are 2-40 mg / kg orally, while the toxicity values of the substances are very favorable as they do not cause toxic symptoms at a single dose of 1000 mg / kg orally.

Table 1

4- (4-Methoxyphenyl) -4-oxo-2- (E-butenoyl-4 H) -lazolidine carboxylic acid methylated by ^ED 50 ^{: 67.76} P · ° -

n The secreted juice the amount of acid inhibition %-in acidity uEq / l00g volume ml / lOOg 10 mg / kg 5 541.4 ± 98.7 5.0 ± 0.6 0 control 4 531.6 ± 50.1 5.1 ± 0.4 25 mg / kg 5 331.0 ± 73.4 5.4 ± 0.9 26.6 control 5 451.0 ± 108.7 4.3 ± 0.8 50 mg / kg 19 suspension of 280.7 ± 29.3 ' 5.7 ± 0 / 43.1 control 14 493.2 ± 44.8 4.3 ± 0.3 100 mg / kg 5 222.3 * ± 91.9 * 6.3 ± 0.7 58.2 control 4 531.6 fr 50.1 5.1 + 0.4

x: p <0.05

The invention is further illustrated by the following non-limiting Examples.

Example 1

4-phenyl-4-oxo-2- (E) -butenoyl-4- (R) -thiazolidine-carboxylic acid methyl ester

4-Phenyl-4-oxo-2- (E) -butenoic acid (1.85 g, 10.5 mmol) was dissolved in anhydrous dichloromethane (30 mL) followed by 4 (R) -thiazolidine (1.83 g, 10.0 mmol). methyl carboxylic acid hydrochloride is added. The solution was cooled to 0 ° C, N-methylmorpholine (0.01 g, 10.0 mmol) was added followed by small portions of NN-dicyclohexylcarbodiimide (2.06 g, 10.0 mmol) in dichloromethane (10 mL). solution is added dropwise. The solution was stirred at 0 ° C for 2 hours. The precipitated N, N-cyclohexylurea was removed by filtration, washed several times with dichloromethane and the filtrate was washed twice with 15 ml of 1N hydrochloric acid solution, once with 15 ml of water, twice with 15 ml of saturated sodium bicarbonate solution and finally once with 15 ml of chloride solution. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue was recrystallized from diethyl ether.

Yield: 2.34 g (77%) of the title compound. 110-112 ° C.

[aps 13O.2 ^ö C (c = 1, CH _? CU).

ElePi analysis

Calculated for C 50 N: 50.00% 4.95% 4.58% Found: 59.52% 5.33% 4.49%

Example 2

4-phenyl-4-oxo-2 (E) -butenoil- (S) -proline methyl ester

3.52 g (20 mmol) of 4-phenyl-4-oxo-2 (N-butenoic acid) and 3.14 g (18.0 mmol) of S-proline methyl ester hydrochloride are dissolved in 40 ml of anhydrous dichloromethane. After cooling to 0 ° C, a solution of 1.92 g (18.0 mmol) of N-methylmorpholine and 3.92 g (18.0 mmol) of Ν, Ν-dicyclohexylcarbodiimide in 10 ml of anhydrous dichloromethane are added. is added to the solution.

After stirring for two hours at 0 ° C, the precipitated dicyclohexylurea was removed by filtration and the filtrate was washed twice with 15 ml of 1N hydrochloric acid, 15 ml of water, twice with 15 ml of saturated sodium bicarbonate solution, and The reaction mixture was extracted with saturated sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue was crystallized from diethyl ether / petroleum ether.

Yield: 2.80 g (52%) of the title compound.

Mp 62-64 ° C.

Nf ⁵ -93.0 ° (c -1, CH ₂ Cl ₂ ).

ANALYSIS:

Calculated for C 66 N: 66.88% 5.96% 4.87% Found: 67.11% 6.29% 5.00%

Example 3 ⁴⁰ 4- (4-Methoxyphenyl) 4-oxo-2 (E) -butenoyl-4 (R) ·

thiazolidin-carboxylic acid methyl ester

2.16 g (10.5 mmol) of 4- (4-methoxyphenyl) -4-oxo-2 (N-butenoic acid) and 1.83 g (10.0 mmol) of 4 (R) -thiazolidinecarboxylic acid methyl ester hydrochloric acid was dissolved in 40 ml of anhydrous dichloromethane qq. The solution was cooled at 0 ° C to 1.01 g (10.0 mmol) of N-methylmorpholine, followed by 2.06 g (10.0 mmol) of NN-dicyclohexyl. A solution of dicyclohexylcarbodiimide in 10 ml of anhydrous dichloromethane is added. the reaction mixture was stirred at 0 ^° C for two hours, then the precipitated dicyclohexylurea is removed by filtration. the filtrate was washed twice with 10 ml of iN HCl, 15 mL water, twice with 15 ml of sodium bicarbonate solution The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated, and the residue was crystallized from ethyl acetate / diethyl ether.

-3198,012

Yield: 1.61 g (48%) of the title compound.

M.p. 83-85 ° C

119.4 ° (C ₁ , CH ₂ Cl ₂ ).

ANALYSIS:

CHN calcd: 57.30% 5.10% 4.17% found: 56.91% 5.15% 4.32%

Example 4

Ethyl 4-phenyl-4-oxo-2- (E) -butenoyl-1,2,3,4-tetrahydro-O-carboline-1 (R, S) -carboxylic acid. 2.88 g (16.3 mmol) of 4-phenyl-4-oxo-2 (E) -butenoic acid and 4.0 g (16.3 mmol) of 1,2,3,4-tetrahydro-1 H -carboline-1 The (R, S) -carboxylic acid ethyl ester was dissolved in 40 ml of anhydrous dichloromethane. The solution was cooled to 0 ° C and a solution of 3.37 g (16.3 mmol) of N, N-dicyclohexylcarbodiimide in 15 ml of anhydrous dichloromethane was added. The solution was stirred for two hours at 0 ° C and the precipitated dicyclohexylurea was removed by filtration. The organic layer was extracted with 1N hydrochloric acid (2 x 20 mL), water (20 mL), saturated sodium bicarbonate solution (2 x 20 mL), saturated sodium bicarbonate solution (20 mL), and brine (20 mL). The solution was dried over anhydrous magnesium sulfate, evaporated and the residue crystallized with diethyl ether.

Yield: 3.95 g (61%) of the title compound.

Mp 183-186 ° C.

ANALYSIS:

Calculated for CΗ N: 71.63% 5.51% 6.95% Found: 71.20% 5.91% 6.86%.

Claims (4)

A process for the preparation of 4-phenyl-4-oxo-butenoylamides of formula (I): wherein: R is hydrogen or C 14 alkoxy; X can be any of the groups of formula (IV), (V) or (VI) wherein R 1 is a straight or branched alkyl group of 14 carbon atoms, characterized in that a compound of formula (II) X is as defined herein, in formula (IV) (V) and (VI), R1 is a straight or branched alkyl group of 14 carbon atoms with a substituted butenoic acid of formula (111) wherein R is as defined herein ^. reacting with a carboxyl-activated derivative of the brain. Process according to claim 1, characterized in that the substituted butenoic acid of formula (III), wherein R is as defined in the foregoing, is a carbodiimide, Preferably, it is used in an activated form with dicyclohexylcarbodiimide. 3. A process according to claim 1 wherein the substituted butenoic acid of formula (III) wherein R is as defined in the foregoing is used as an activated derivative of an ester, an acid halide or an anhydride thereof. 4. A process for the preparation of a compound of formula (I) as an active ingredient 3q R is hydrogen or C 14 alkoxy, X can be any of the groups of formula (IV) (V) or (VI), wherein R 1 is a straight or branched alkyl group containing 14 carbon atoms, wherein the active ingredient of claim 1 is formulated in a pharmaceutical composition. in admixture with excipients and / or excipients used in the preparation of the active ingredient.