New derivatives of aliphatic acids phényl, their preparation, their application like drugs, and the compositions containing them.

The present invention relates to novel phenyl aliphatic carboxylic acid derivatives, a process for their preparation and their use as drug and compositions containing them.

The present invention relates to the products of general formula I

wherein the three radicals methoxy are 3, 4, 3 or 2, 4, 6 or in position 2, 3, 5 or 2, 4, 5 or 2, 3, 6, wherein, or a and b together represent a double bond, or a represents a hydrogen atom and b represents a radical of HY droxy=, and wherein R represents a hydrogen atom or a radical alkylated. 1 to 5 containing carbon atoms, under the different forms possible stereoisomers, as well as the alkali, alkaline earth, or amines of the products of formula I wherein R represents a hydrogen atom "

The term alkyl containing 1 to 5 carbon atoms

can designate for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, terbutyle, pentyl.

The different stereoisomeric forms possible represent, for the products of formula I wherein a and b together represent a double bond, the E and Z geometric isomers (trans and the OIS), and for the products of formula I wherein a is a hydrogen atom and B represents a hydroxyl radical, the various racemic forms and•dede.ces optically active products.

The alkali or alkaline earth salts of the products of formula (I-) wherein R represents a hydrogen atom, can be, for example, salts of sodium th ^, potassium, lithium or calcium.

Amine salts of the products of formula (I-) wherein R represents a hydrogen atom, are the usual amine salts. Among the amines are usual, include monoalcoylamines, such as, for example, methylamine, 1' ethylamine, propylamine, bulky, such as, for example, dimethylamine, diethylamine, di-n-propylamine, the trialcoylamines, such as triethylamine. Also include piperidine, morpholine, piperazine and pyrrolidine.

The invention more particularly relates to O

- the products as defined by formula I, above, wherein confectioneries and b together represent a double bond, in the form of isomers, as well as the salts alkali, alkaline earth or amines of said products of formula I wherein R represents a hydrogen atom;

- the products as defined by formula I, above, wherein. A and b together represent a double bond, in the form of isomers, as well as the alkali, alkaline earth or amines of said products of formula I wherein R represents a hydrogen atom;

- the products as defined by formula I, above, wherein the three methoxy radicals are in position 3, 4, 5 or 2, 4, 5, in the form of isomers, as well as alkali lesles.sels, alkaline earth or amines of said products of formula I wherein R represents a hydrogen atom.

Among the products of the invention, examples more particularly;

. (I) 4 - Facide - (3, 4, 5 a-trimethoxy phenyl) 4 oxo 2-butenoic;

(i) acid - 4 - (2, 4, 5 a-trimethoxy phenyl) 4 oxo 2 a-buténolque.

According to the invention, the products of formula I above in the various possible stereoisomeric forms, as well as the alkali, alkaline earth or amines of said products of formula I wherein R represents a hydrogen atom, can be prepared by a process characterized in that the acid is reacted with glyoxylic - or its alkyl esters, of formula (III)'

CMB-COCR

(II)

wherein R represents a hydrogen atom or an alkyl radical containing 1 to 5 carbon atoms, with an acetophenone of formula (II):

HM

3% ^

HM,

HM,

T

- OH,

(III)

in which the radicals methoxy have the positions indicated above, to obtain a product of formula 1^corresponding to a product of formula (I-) wherein a represents a hydrogen atom and B represents a hydroxyl radical, or a product of formula (lg) corresponding to a product of formula (I-) wherein a and b together represent a double bond configuration (I) and that, if necessary, subjected to a dehydration agent a product of formula (I-), for obtaining a pro -

(I_) cut a formula (I) corresponding configuration, and that, Ω

if desired, the product of formula Cl bifurcates_WITH ) obtained by optically active isomers thereof, and that, if desired, isomerizing a compound of formula (lg) configuration (I) to a compound of formula (lg) configuration (Z-), and that, if desired, esterified or write tools is a product of formula (I-) obtained, wherein R represents a hydrogen atom, according to the usual methods.

By condensing a product of formula II and d>' a product of formula III, is obtained; by the process conditions, in particular, pH, temperature, heating time, a product of formula la or a product of formula IB or a mixture thereof.

According to the different possible combinations of pH, temperature and heating time, well known to the skilled artisan in this chemistry ^ of aldol condensation, is smaller or larger proportions of product la or lb of product.

The products of formula la are still forming in the first place and the products of formula IB are derived by dehydration.

In general, the proportion of the product of formula IB, which forms directly, increases when the operating conditions are such that the medium is more strongly acidic (of. e.g. Mathieu and was going, signatures of organic synthesis flight 3, on page 102, the passage about the chemistry of aldol condensation)

In preferential conditions for oeuvredu method of the invention, the above method is as follows:

a) when one tries to directly obtain a product of formula IB, the reaction of the product of formula II and formula III product in a high acid environment " the acidic medium may be obtained e.g. by an excess of d * glyoxylic acid or by the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or by adding the middle^- , d-reaction^F. water HG no. sodium sulfonate..

For the preparation of products lb;, it can be accomplished also for example in the presence of acetic anhydride to 130° C., according to a method similar to that described in Japanese Patent 7739020 published 3 October 1977 (OA is 88, P-37442)^? the MED J in drinking. Mal. 1972, YI flight, no. 9,918=22.

The glyoxylic acid can even be used, if desired, form of an alkaline salt, such as sodium salt, potassium.

When one tries to obtain products of formula IB: is preferably performed the ^. condensation of the product of formula II and the formuleîll product at a temperature between 120 and 150° C., and preferably, is heated for more than three hours.

It is well known that the "aldol" dewater is very easily in the corresponding unsaturated derivatives, either by heating, or by treatment in an acid medium and that this dehydration can be conducted either in minutes at high temperature, as described for example in US 3953, 463 (a àdeux minutes to 155° C.), either at a lower temperature during unterrps longer. ,

b) when one tries to obtain, products of formula la, is preferably performed, condensation of the product of formula II with the product of formula III at pH• > β. θ η performs this condensation preferably at a temperature below 100° C., and preferably less heating of three hours.

. When using the product of formula (III) wherein R represents, hydrogen, also advantageously be carried out at room temperature in the presence of a catalyst such as an alkali (sodium hydroxide) potassium hydroxide for example.

c) condensation of the product of formula II and of the product of formula III can be carried out without a solvent or in the presence of a solvent such as an aromatic or aliphatic hydrocarbon (benzene, toluene, heptane derivatives for example).

d) optional dehydration of a product of formula la Pro cut a formula IB can be produced for example by heat treating, in an acid medium.

Dehydrating agents' of suitable

for example hydrochloric acid, sulfuric acid, phosphoric acid, or an alkali such as hydrogénosulfonate 1' hydrogènosulfonate sodium or potassium.

e) is the resolution of products of formula. I-racemic in optically active isomers is carried out according to the usual methods.

f) is thethe LS alkali, alCa withtile-to-terreux or amines of the products of formula I may be prepared by a conventional method such as for example, by acting on said products of formula I by reaction of corresponding bases or ' double decomposition or by all customary methods known for this type of α β ethylenic carboxylic acids.

The salification reaction is performed, preferably, in a solvent or mixture of solvents, such as water, ethyl ether, acetone, ethyl acetate, tetrahydrofuran or dioxane.

g) the products of formula (I-) wherein R represents an alkyl radical containing 1 to 5 carbon atoms can be prepared from the products of formula (ii) wherein R represents a atcane of hvdrogene, conventionally, by action of an alcohol of the formula ROH, preferably in an acidic medium. The acid can be for example hydrochloric acid, phosphoric acid or paratoluene sulfonic acid.

h) the products of formula I wherein a and b together represent a double bond, in the form of Z isomers can be obtained by irradiation of the corresponding products of formula I, in the form of isomers, in the manner described in J 92. Mal. 13, 1948, p-284 - 286.

The products of formula I above in the various possible stereoisomeric forms, as well as the alkali, .

alkaline earth or amines of said products of formula I wherein R represents a hydrogen atom, have interesting pharmacological properties: they exhibit particularly significant anti-ulcer activity. In addition, brought into contact with the gastric mucosa,, exhibit both gastric antisecretory activity and cytoprotective.

Said properties makes their therapeutic application, and the invention also relates to, as medicaments, the products of formula I as defined above, under the different forms possible stereoisomers, as well as the alkali, alkaline earth or amines of said products of formula I wherein R represents a hydrogen atom.

The invention especially relates to, as medicaments the I

(i) acid - 4 - (3, 4, 5 a-trimethoxyphenyl) 4 oxo 2-butenoic;

(i) acid - 4 - (2, 4, 5 a-trimethoxyphenyl) 4 oxo 2-butenoic.

The set of products defined above form according to the invention, drugs very useful in human therapy, in particular for treating hyperchlorhydrias, gastric ulcers, and peptic, gastritis, of hiatal hernias, gastric disease of gastroduodenal and accompanying with gastric hyperacidity.

The dosage, variable according to the product used and the conditions in question can take for example between 0.05 and 2 g per day of adults orally.'

The present application also relates to pharmaceutical compositions containing, as active principle, at least one of the above drugs. These compositions are made so as to be administered by the digestive or parenteral route. *.

They may be solid or liquid and take

in the pharmaceutical forms commonly used in human medicine, for example, simple or sugar-coated tablets, capsules,, suppositories, injectable preparations? they are prepared according to the usual methods.

The active ingredient may be incorporated therein with excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, stearate, magnesium, cocoa butter, aqueous or non-vehicles, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

The products of formula II and III are known products.

The following examples illustrate the invention without however limiting same.

Example 1 : 4 Acid (2.4, 5 trimethoxyphenyl) 4 a-οχο-a 2 hydroxy butanolque.

19.3 G of heated glyoxylic acid to 50% by weight in water, down to about 80% removal of the water present, then after cooling, is introduced into the reaction medium 54.6 g of 2, 4, 5 a-trimethoxy acetophenone.

3 Hours at 90 °c is heated, under reduced pressure (· 2=: 50 mm/Hg at) distilling the wastewater has simultaneously.

After cooling, dü medium, is introduced:

toluene - 200 cm3

- 400 cm3 of water containing 7.5 g of sodium carbonate.

Decanted, washed the aqueous phase to toluene, then acidified to ph=1 with hydrochloric acid at half. The product sought is then extracted with ethyl acetate. After removing the solvent and recrystallization in 200 cm3 of dichloro 1.2-ethane, obtained 24.6 g acid 4 - (2, 4, 5 a-trimethoxyphenyl) 4 oxo 2 hydroxy butanoic acid. F=146 °C + 1 °C.

Analysis :

·· η..

' Calculated: C.% 5.67% 54.93 hr. ' Found; 54.9 5.7

NMR spectrum : In accordance with the structure "

Acidimetry : (expressed as percentage of theory):

100.5 + 0.5%. '

Example 2 : (I) acid 4 - (' 2, 4.5 and triméfhoxyphényl) 4 oxo 2-butenoic.

Heated to reflux 2 hours 30, 11 g acid 4 - (2, 4, 5 a-trimethoxyphenyl) 4 oxo 2 hydroxy butanoic acid obtained in the example 1, 30 cm3 acetic acid and 2 cm3 of concentrated hydrochloric acid (d=1.18).

The resulting solution is then cooled to room temperature, then after adding 100 cm3 of water, the precipitate formed is filtered to give 7 g of crude desired product "

=207 AND 208° FAHRENHEIT.

After recrystallization from 20 cm3 of acetic acid,

6.3 results grams of pure desired product. F.=210° GRAMS, Analysis ;

Calculated; C.% 58.64% 5.30 hr

Found; 58.6 5.3

NMR spectrum : The coupling constant of protons sinylic is of 16 Hertz, thereby indicating trans geometry "

Example 3 : 4 - Acid (3, 4, 5 a-trimethoxyphenyl) 4 - 2 - hydroxy-butanoic οχο.

29.6 G of heated glyoxylic acid to 50% by weight in water down to removal of 80% of the water present, then after cooling ., is introduced into the reaction medium 84.1 g of 3, 4, 5 a-trimethoxy acetophenone. 2 Hours is heated to 95 and 100 °C under reduced pressure (c 50 MM/mmHg) distilling the wastewater has simultaneously.

After cooling: medium, 120 cm3 introduced water containing 11.6 g of sodium carbonate and ether, decanted, washed the aqueous phase with ether then acidified aqueous phase to ph=1. with hydrochloric acid at half "

The product is•sought to ethyl acetate. After removing the extraction solvent and recrystallization in dichloro 1.2-ethane, obtained 31.5 grams product expected, f=119 - 120° C..

Analysis :

Calculated; C.% 5.67% 54.93 hr

Found:% 54.9 Η ¾ 5.7 C.

Acidimetry : (expressed as percentage of theory): 98.3%.

Example '4 acid (I)' 4 - (3.4 ', 5 tri 'm'éth'oxvphényl) 4 oxo 2-butenoic.

2 Hours 30 is heated to reflux, 15.8 g acid 4 - (3, 4, 5 a-trimethoxyphenyl) 4 oxo 2 hydroxy butanoï ' that obtained in the example 3, 20 cm3 of acetic acid and 20 cm3 of concentrated hydrochloric acid (d=1.18 ").

The reaction medium is cooled and precipitated by the water.

Filtering the precipitate formed. 12 G of product is obtained crude expected. F=140 °C.

After recrystallization from a mixture of 40 cm3 (1 - 1) ethanol-water, 10.5 g of product is obtained pure expected. F=144 °C.

Calculated: C.% 58.64% 5.30 hr

Found: 58.4 5.3

Acidimetry : (expressed as percentage of theory):

98.7 + 0.5%.

NMR spectrum : The coupling constant is vinyl protons of 16 Hertz, thereby indicating trans geometry.

Example 5 : (I) acid 4 - (2, 4, 6 a-triméthoxvphénvl) 4 oxo 2 a-buténoîque.

3.3 G of mixed potassium hydroxide pellets in 100 cm3 of absolute ethanol, then introduced 31.5 g of 2, 4, 6 a-trimethoxy acetophenone and then, dropwise, in 30 minutes at 20 °c, a solution of 4.6 g of glyoxylic acid to 80% ' in water in 50 cm3 of absolute ethanol.

The resultant solution is then chaugge during 6 hours at reflux, and then evaporated under pressure gut dry. The residue is taken up with 300 cm3 of water, filter, collects the filtrate that the acidified to ph=1 with concentrated hydrochloric acid. The product sought crystallizes, is wrung out, and is dried to constant weight at 60 °c under reduced pressure. 0.7 G of product is obtained which is recrystallized in expected methyl ethyl ketone. F=152 °C + 1 °C.

Analysis :^C ]_ 3^H i4⁰ 5 (266.30)

Calculated: C.% 58.64. HR % 5.30

Found: 58.7 5.5

NMR spectrum : The coupling constant is vinyl protons of 16 Hertz, thereby indicating trans geometry.

Example 6 : The ester 'methyl' I 'acid' (I) 4 - (3, 4, 5 a-trimethoxyphenyl) 4 oxo 2 a-buténoïcrue.

Is heated during 5 hours at reflux a mixture of 20 g of 4 - (I) acid (3, 4, 5 a-trimethoxyphenyl) 4 oxo 2-butenoic, 150 cm3 methanol and 0.15 g of toluenesulfonic acid. The resultant solution is cooled to room temperature, is added 0.2 g of sodium acetate and evaporated under reduced pressure. Added 200 cm3 of ' toluene at residue, washed with an aqueous solution of sodium bicarbonate followed by water. The solvent is removed under reduced pressure, the residue in a recrystallized with methanol-water mixture (1 - 1) and obtained 10.7 g of desired product melts at 94 °c.

Example 7 O Acid-morpholine salt (I) 4 - (3, 4, 5 a-trimethoxy phenyl) 4 oxo 2-butenoic.

50 Cm3 is poured ethyl ether containing 1,758 grams of morpholine in a solution containing 5, 375g acid (I) 4 - (3.4, 5 a-trimethoxyphenyl) 4 oxo 2-butenoic. The formed precipitate is filtered, washed with ethyl ether and dried under reduced pressure.

- 6.5 G of obtained desired product melts at 140 °c.

Example 8 O Acid sodium salt (I) 4 - (3, 4, 5 a-trimethoxyphenyl) 4 oxo 2 a-buténoïoue.

Introduced to 10 °c, 28 cm3 of an aqueous sodium hydroxide solution In in a mixture of 7.7 g acid (I) 4 - (3, 4, 5 a-trimethoxyphenyl) 4 oxo 2-butenoic 30 cm3 and water. Filtered and evaporated under reduced pressure. The solid obtained is taken up with acetone, filter, washed with acetone and dried under reduced pressure at 20 °c " 7 g of product is obtained desired flux to 250 °c.

Example 9 : Salt of piperidine acid (I) 4 - (3, 4, 5 a-triméthoxv phenyl) 4 oxo 2 a-buténoIgue.

50 Cm3 is added ethyl ether containing 1,988 g of piperidine in a solution of 6,215 g acid (I) 4 - (3, 4, 5 a-trimethoxyphenyl) 4 oxo 2-butenoic 1200 cm3 in ethyl ether. The formed precipitate is filtered, washed with ethyl ether and dried under reduced pressure. This gives 7.3 g of desired product melts at 124 °c.

Pharmaceutical forms.

Example 10 : Tablets.

Tablets were prepared corresponding to the following formula

(I) acid 4 - (3, 4, 5 a-trimethoxyphenyl) - 4 oxo - 2

- Q-s-carrier. for a tablet completed to ' 300 mg.

(Detail of the excipient: lactose-, wheat starch, processed starch, rice starch, magnesium stearate, talcum).

Example 11 capsules.>

Capsules were prepared corresponding to the following formula:

(I) acid 4 - (2, 4, 5 a-trimethoxyphenyl) - 4 oxo - 2

100 mg butenoic

Q.S. - carrier. for a nanocapsule terminated to 300 mg.

(Detail of the excipient: talcum, magnesium stearate, aerosil).

1) Determination of the antiulcer activity of the products of examples I to 4.

The technique used is described by SHAY and ai in gastro-enterology, j5, 43, (1945).

The " technique involves inducing SHAY ulcers on rats at the stomach by ligation of the pylorus.

The animals are anesthetized with ether. A longitudinal incision is made approximately 1 cm below the sternum, the glandular portion of the stomach and duodenum are updated and a ligature is placed several millimeters below the pylorus. Equals is left as it is and the skin is sutured by 2 staples.

The animals receive, immediately after, the dispersive or the substance to be analyzed, orally, in a volume of 0.5 α η 3/100 g and are held without food and drink until sacrifice carotid by bleeding that occurs about 16 hours after treatment.

Prior to withdrawing the stomach, a ligature is placed above the cardia.

The gastric fluid is collected for measuring the pK. The stomach is then opened as the greater curvature, rinsed in saline and spread on paper millimeter for review in the binocular magnifier.

Evaluated macroscopically severity of lesions that is listed for each stomach 0 to 4.

It is then determined for each batch of rats, the average intensity ulcerations and calculating the protection by relating the index through the group to the index means the control group.

Also determined the pH values of the gastric fluid for treated animals and control animals.

.2) Determination of the antiulcer activity of the products of examples 6 and 7..

The technique used is described by SHAY and ai in gastro-enterology, 5 ., 43, (1945), modified by w.w. GUTH in gastro-enterology, lè_, 88 (1976).

After a 48 hour jeunede, rats receive the dispersive or the substance to be examined orally in a volume of

3 - 1 α π / 100 grams.

One hour after, the animals are anesthetized with ether;

A longitudinal incision is made approximately 1 cm below the sternum, the glandular portion of the stomach and duodenum are updated and a ligature is placed a few millimeters below the pylorus - equals is sutured and the skin is stapled.

One hour later, 200 mg/kg of aspirin dispersed in a slurry to IX. methyl cellulose in water with added 150 millimoles of hydrochloric acid are administered orally in a volume of 0, 5 g to 100 / σ η 3.

Two hours after, the delivering, animals are. distressed 1' using carbon dioxide.

Prior to withdrawing the stomach, a ligature is placed above the cardia.

The gastric fluid is collected for measuring the pH, for the treated animals and control animals.

Having obtained the following results e

Was estimated LD50 dl50 derivatives examples 1 to 8 after oral administration in mouse.

The results obtained were the following: