GB1592997A

GB1592997A - Aroyl-pyrrole carboxylic acids and derivatives thereof

Info

Publication number: GB1592997A
Application number: GB4289877A
Authority: GB
Original assignee: Laboratoires Albert Rolland SA
Current assignee: Laboratoires Albert Rolland SA
Priority date: 1977-10-14
Filing date: 1977-10-14
Publication date: 1981-07-15
Also published as: PL114404B1; FR2405936B1; DK154292B; PT68644A; FR2405936A1; PL210272A1; ES474653A1; DK154292C; DK442878A

Description

(54) AROYL-PYRROLE CARBOXYLIC ACIDS AND DERIVATIVES THEREOF (71) We, ALBERT ROLLAND S.

A., a French Body Corporate of 49, rue Saint-Andre-des-Arts, 75006 Paris, France, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to new pyrrole derivatives, to a process for their preparation, and to their therapeutic applications, typically in the treatment of hyperuricemia, or also to their use as intermediates for the synthesis of other therapeutically valuable compounds.

The present invention relates to pyrrole carboxylic acid derivatives having the formula:

wherein Ar represents a phenyl group substituted with one or more C16 alkyl, C16 alkoxy or halogen subtituents; a naphthyl, which may be unsubstituted or substituted with one or more C16 alkyl, C16 alkoxy or halogen substituents; or a thienyl or furyl group; and Rl represents hydrogen atom or alkyl group, the group -COOR1 is at 2- or 3position and the group Ar-CO is at 4- or 5position on the pyrrole nucleus, and to the salts of the acids of the formula (I) with pharmaceutically acceptable bases.

The compounds of the formula (I) may be prepared by acylation of a pyrrole -2 or 3-carboxylic acid or an alkyl ester thereof under Friedel Crafts conditions with the chloride or anhydride of an acid ArCOOH in which Ar has the above-defined meaning. More particularly, acid chloride ArCOCl may be reacted with an ester of the pyrrole ~ carboxylic acid under usual Friedel-Crafts reaction conditions, if necessary with subsequent hydrolysis of the resulting ester with a base and conversion of the salt to the free acid.

The Friedel-Crafts reaction generally provides mixtures of two position isomers corresponding to - the acylation of the pyrrole nucleus at 4- or 5-position, which mixtures have a composition which is dependent on the operating conditions and the reagents present; said isomers are separated by elution chromatography through an adsorbent column, or by recrystallization.

The compounds of the formula (I) are useful in the synthesis of compounds of the formula (II):

in which: R is a C16 alkyl group or a benzyl group, and Rl is hydrogen or a C16 alkyl group.

Ar is as defined for formula (I).

Said compounds exhibit a useful uricosuric activity, and are inter alia described and claimed in copending Application 42105/77 (Serial No 1592996).

To prepare compounds of the formula (II), according to the present invention, a compound of the formula (I) is reacted with a halogenated derivative RX in which R represents a C16 alkyl or benzyl group and X represents a halogen atom, in the presence of an acid-binding agent. The reaction is preferably conducted in a polar aprotic solvent such as dimethylformamide or dimethylsulfoxide, for example, and in the presence of an alkali hydroxide and, when required, with subsequent hydrolysis of the ester.

Folfowing-ExampTes lM6 illustrate the preparation of compounds of the -formula (I). Examples 7 and 8 illustrate the use of compounds of the formula (I) in the synthesis of compounds of the formula (II).

EXAMPLE 1 5-(1 -Naphthoyl)-pyrrole-2 carboxylic acid (a) Methyl pyrrole-2-carboxyfate (io g) and naphthalene-l carboxylic acid chloride (15.2 g) are dissolved in 1,2-dichloro-ethane (700 ml), and aluminium chloride (12 g) is added thereto, while maintaining the reaction medium at about 0 C. After several hours at room temperature, the mixture is poured over crushed ice and the organic phase is decanted off. After washing with aqueous sodium hydroxide, the solvent is evaporated off. The residual oil is a mixture of methyl 4 - (1 naphthoyl) - pyrrole - 2 - carboxylate and of methyl 5 - (I - naphthoyl) - pyrrole 2 - carboxylate.

The two esters are separated by elution chromatography through a silica column, using 1,2 - dichloroethane as eluent.

The above procedure gives 3.3 g methyl 5 - (1 - naphthoyl) - pyrrole - 2 carboxylate (m.p.=140"C) and 9 g of its position isomer which does not crystallize.

(b) A solution of methyl 5 - (1 naphthoyl) - pyrrole - 2 - carboxylate (4.3 g) and potassium hydroxide (1.5 g) in 50% aqueous ethanol (60 ml) is maintained for 5 hours at its reflux temperature, after which the solvent is evaporated under reduced pressure. Water (100 ml) is then added and the solution is made acidic by addition of a concentrated aqueous hydrochloric acid solution. The final acid is extracted with ethyl ether.

Recrystallization from diisopropyl oxide gives 2.8 g 5 - (I - naphthoyl) - pyrrole 2 - carboxylic acid which melts at 1880C.

EXAMPLE 2 4-(1 -Naphthoyl)-pyrrole-2 carboxylic acid A solution of methyl 4 - ( I naphthoyl)pyrrole - 2 carboxylate (9 g obtained as described in Example la) and potassium hydroxide (4 g) in aqueous ethanol (200 ml) is refluxed for 6 hours.

After removal of the solvent, water (200 ml) is added to the reaction medium after which the solution is made acidic by addition of a 10% aqueous hydrochloric acid solution. The acid precipitates out.

Recrystallization from acetone gives 5 g of pure acid, m.p.=180 C.

EXAMPLE 3 4-(3-Chloro-benzoyl)-pyrrole-2 carboxylic acid (a) Methyl pyrrole - 2 - carboxylate (10 g) is slowly added, at about 50C, to a mixture of 3 - chloro - benzoic acid chloride (14 g) and alúnninium chloride (23.4 g) in 1,2 - dichloro - ethane (300 ml).

After stirring one hour at room' temperature, the reaction medium is poured over ice and the organic phase is decanted off. The dichloroethane solution is washed with an aqueous basic solution, after which it is dried and the solvent is evaporated off. The remaining solid is recrystallized from benzene, to give 14.5 g methyl 4 - (3 - chloro - benzoyl) pyrrole - 2 - carboxylate, m.p.=130 C.

(b) Hydrolysis of 4.5 g of the ester obtained in a above is effected in 100 ml aqueous ethanol with 1 g potassium hydroxide. Recrystallization from acetonewater (1:1) gives 3 g of acid, m.p.=219 C.

EXAMPLE 4 4-(4-chlorobenzoyl)pyrrole-2 carboxylic acid To a solution of 4 chlorobenzoylchloride (7,8 g) aluminium chloride (12 g) in 1,2 - dichloroethane is added pyrrole - 2 - carboxylic acid (5 g) suspended in 1,2 - dichloroethane (100 ml).

After 3 hours at room temperature, the mixture is poured over ice and hydrochloric acid. The precipitate is isolated.

Recrystallization from acetone gives 5 g of acid, m.p. : 260"C.

EXAMPLE 5 (a) Methyl 4-(2,3-dimethylbenzoyl) pyrrole-2 carboxylate This compound is obtained as described in example 1(a).

Crystallized in methanol, m.p.: 158"C.

(b) 4-(2,3-dimethylbenzoyl)pyrrole 2-carboxylic acid Hydrolysis of the methyl ester as described in example 1(b), gives this compound, m.p. : 2100C.

EXAMPLE 6 4-(2-thenoyl)-pyrrole-2 carboxylic acid This compound is obtained as described in example 1.

After recrystallization in 2-butanone, m.p. : 234"C.

EXAMPLE 7 Process for the preparation of 1methyl 4-(3-chloro-benzoyl)-pyrrole-2 carboxylic acid (a) To a solution of methyl 4 - (3 chloro - benzoyl) - pyrrole - 2 carboxylate (13 g) and potassium hydroxide (11.2 g) in dimethyl sulfoxide (100 ml) is added 15 g methyl iodide. After stirring for one hour, the solution is poured over three volumes water; the final product is extracted with chloroform.

Recrystallization from methanol gives 11 g methyl 1 - methyl - 4 - (3 - chloro benzoyl) - pyrrole - 2 - carboxylate. (b) 5 g of the above ester are hydrolyzed by action of 2 g potassium hydroxide in 60 ml of refluxing 50% aqueous ethanol. Removal of the solvent and acidification in aqueous medium give 4.7 g-of acid, m.p.=216 C.

EXAMPLE 8 Process for the preparation of l-benzyl 4-(3-chloro-benzoyl)-pyrrole-2 carboxylic acid To a solution of methyl 4 - (3 - chloro benzoyl) - pyrrole - 2 - carboxylate (3 g) and potassium hydroxide (2.4 g) in dimethyl sulfoxide (25 ml) is added 2.8 g benzyl chloride. After one hour at room temperature, the solution is poured over 500 ml icewater. The resulting material is made acidic by addition of hydrochloric acid and the final acid is extracted with chloroform.

Recrystallization from benzene gives 2.5 g of the pure acid, m.p.=140 C.

In addition, the pharmacological investigation of the compounds of the formula (I) has shown that they exhibit per se an uricosuric activity and, therefore, that they may also be used in the treatment of pathological hyperuricemia or of hyperuricemia induced by the administration of certain drugs.

The uricosuric activity of compounds of the formula (i) was evidenced in rats, according to a method disclosed in "J.

Med. Pharm. Chem., 5, 175 (1962)".

While the compounds of the formula (I) all exhibit in mice an oral LD50 in excess of 1000 mg/kg, their uricosuric activity is apparent from as low a dosage as 100 mg/kg.

Thus, the present invention relates also to therapeutic compositions comprising, as active ingredient, a compound of the formula (I) or a salt thereof with a pharmaceutically acceptable base in combination with a pharmaceutically acceptable excipient.

The therapeutic compositions of this invention may be administered to humans by the oral or parenteral route.

Said compositions may be formulated typically as capsules, tablets, coated tablets, or injectable suspensions or solutions.

WHAT WE CLAIM IS: 1. A compound of the formula I:

in which: Ar represents a phenyl group substituted with one or more C1 alkyl, C16 alkoxy or halogen substituents; a naphthyl group, which may be unsubstituted or substituted with one or more C16 alkyl, C16 alkoxy or halogen substituents; or a thienyl or furyl group; and Rl represents hydrogen atom or alkyl group; the group -COOR1 is at 2- or 3position and the group Ar-CO- is at 4- or 5-position on the pyrrole nucleus; and the salts of the acids of the formula (I) with pharmaceutically acceptable bases.

2. A process for the preparation of a compound as claimed in claim 1, wherein pyrrole - 2 or 3-carboxylic acid or its alkyl ester is reacted under Friedel-Crafts conditions with the chloride or anhydride of an acid of formula ArCOOH, wherein Ar has the meaning given in claim 1.

3. A pharmaceutical composition which comprises a therapeutically effective amount of a compound selected from compounds as claimed in claim 1 in combination with a pharmaceutically acceptable excipient.

4. A compound as claimed in claim 1, substantially as hereinbefore described in any one of Example 1 to 6.

5. A process, as claimed in claim 2, substantially as hereinbefore described with reference to Examples 1 to 6.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

Recrystallization from methanol gives 11 g methyl 1 - methyl - 4 - (3 - chloro benzoyl) - pyrrole - 2 - carboxylate. (b) 5 g of the above ester are hydrolyzed by action of 2 g potassium hydroxide in 60 ml of refluxing 50% aqueous ethanol. Removal of the solvent and acidification in aqueous medium give 4.7 g-of acid, m.p.=216 C.

EXAMPLE 8 Process for the preparation of l-benzyl

4-(3-chloro-benzoyl)-pyrrole-2 carboxylic acid To a solution of methyl 4 - (3 - chloro benzoyl) - pyrrole - 2 - carboxylate (3 g) and potassium hydroxide (2.4 g) in dimethyl sulfoxide (25 ml) is added 2.8 g benzyl chloride. After one hour at room temperature, the solution is poured over 500 ml icewater. The resulting material is made acidic by addition of hydrochloric acid and the final acid is extracted with chloroform.

Recrystallization from benzene gives 2.5 g of the pure acid, m.p.=140 C.

In addition, the pharmacological investigation of the compounds of the formula (I) has shown that they exhibit per se an uricosuric activity and, therefore, that they may also be used in the treatment of pathological hyperuricemia or of hyperuricemia induced by the administration of certain drugs.

The uricosuric activity of compounds of the formula (i) was evidenced in rats, according to a method disclosed in "J.

Med. Pharm. Chem., 5, 175 (1962)".

While the compounds of the formula (I) all exhibit in mice an oral LD50 in excess of 1000 mg/kg, their uricosuric activity is apparent from as low a dosage as 100 mg/kg.

Thus, the present invention relates also to therapeutic compositions comprising, as active ingredient, a compound of the formula (I) or a salt thereof with a pharmaceutically acceptable base in combination with a pharmaceutically acceptable excipient.

The therapeutic compositions of this invention may be administered to humans by the oral or parenteral route.

Said compositions may be formulated typically as capsules, tablets, coated tablets, or injectable suspensions or solutions.

WHAT WE CLAIM IS: 1. A compound of the formula I:

in which: Ar represents a phenyl group substituted with one or more C1 alkyl, C16 alkoxy or halogen substituents; a naphthyl group, which may be unsubstituted or substituted with one or more C16 alkyl, C16 alkoxy or halogen substituents; or a thienyl or furyl group; and Rl represents hydrogen atom or alkyl group; the group -COOR1 is at 2- or 3position and the group Ar-CO- is at 4- or 5-position on the pyrrole nucleus; and the salts of the acids of the formula (I) with pharmaceutically acceptable bases.
2. A process for the preparation of a compound as claimed in claim 1, wherein pyrrole - 2 or 3-carboxylic acid or its alkyl ester is reacted under Friedel-Crafts conditions with the chloride or anhydride of an acid of formula ArCOOH, wherein Ar has the meaning given in claim 1.
3. A pharmaceutical composition which comprises a therapeutically effective amount of a compound selected from compounds as claimed in claim 1 in combination with a pharmaceutically acceptable excipient.
4. A compound as claimed in claim 1, substantially as hereinbefore described in any one of Example 1 to 6.
5. A process, as claimed in claim 2, substantially as hereinbefore described with reference to Examples 1 to
6.