FR2503163A1 - Analgesic 4:quinolinyl amino thiophene carboxylic ester(s) - with 1:methyl 4:hydroxy piperidine - Google Patents

Abstract

Quinolinyl thiophene carboxylates of formula (I) and their salts are new. (where X is in position 5,6,7 or 8 and is H, halogen, CF3, CF3S, CF30, linear alkyl or 1-4C, branched alkyl of 3-5C, or 1-4C alkoxy). In the pref. prepn. cpd. (II) is reacted with (III). (Where R=H or 1-4C alkyl). Alternatively a reactive derivative of (II; R=H may be used esp. an anhydride or halide. (I;X=8-CF3) is specifically claimed. (I.HC1; X = 8-CF3) has AD50 of 10mg/kg p.o. in the analgesic test of Koster et al (Fred.Proc.1959,18,412).

Description

 The present invention relates to new derivatives of the 3/4-quinolinyl-amino / 2-thiophene carboxylic acid, their preparation process and their use as a medicament.

dans laquelle F en position 5, 6) 7 ou 8 sur le noyau benzénique représente un atome d'hydrogène, un atome d'halogène, un radical trifluorométhyle, un radical trifluorométhylthio, un radical trifluorométhoxy, un radical alcoyle linéaire renfermant de 1 à 4 atomes de carbone, un radical alcoyle ramifié renfermant de 3 à 5 atomes de carbone ou un radical alcoxy renfermant de 1 à 4 atomes de carbone, ainsi que leurs sels d'addition avec les acides organiques ou minéraux.The subject of the invention is the compounds of formula (I)

in which F in position 5, 6) 7 or 8 on the benzene nucleus represents a hydrogen atom, a halogen atom, a trifluoromethyl radical, a trifluoromethylthio radical, a trifluoromethoxy radical, a linear alkyl radical containing from 1 to 4 carbon atoms, a branched alkyl radical containing from 3 to 5 carbon atoms or an alkoxy radical containing from 1 to 4 carbon atoms, as well as their addition salts with organic or inorganic acids.

 When X1 represents a halogen atom, it is preferably a chlorine or bromine atom.

 When X1 represents a linear alkyl radical, it is preferably a methyl, ethyl or n-propyl radical.

 When X1 represents a branched alkyl radical, it is preferably the isopropyl or isobutyl radical.

 When X1 represents an alkoxy radical, it is preferably a methoxy, ethoxy or n-propoxy radical.

 Among the addition salts with acids, there may be mentioned those formed with mineral acids, such as hydrochloric, hydrobromic, sulfuric or phosphoric acids as well as those formed with sulfonic acids such as alkyl or arylsulfonic acids, for example l methane sulfonic or paratoluenesulfonic acid.

 X1 can be in position 5, 6, 7 or 8 but the invention relates more particularly to the compounds for which X1 is in position 7 or 8.

 A more particular subject of the invention is the compounds of formula (I) for which X1 represents a trifluoromethyl radical as well as their addition salts with organic or mineral acids.

 A very particular subject of the invention is the compound of formula (I) for which Xi represents a trifluor radical oromethy'een at position 8 as well as its addition salts with acids.

 The compounds of formula (I) as well as their salts have interesting pharmacological properties and in particular a remarkable analgesic activity.

 These properties justify the use of the products of formula (T) and their salts in therapy.

 The subject of the invention is therefore, as medicaments, the compounds of formula (I) as defined above as well as their salts with pharmaceutically acceptable acids.

 The invention is naturally quite particularly aimed, as a medicament, at the product of Example 1 as well as its addition salts with pharmaceutically acceptable acids.

 The medicaments of the invention can be used in the treatment of muscle, joint or nerve pain, dental pain and migraines.

 The invention extends to pharmaceutical compositions containing, as active principle, the medicaments defined above.

 These pharmaceutical compositions can be administered by the oral, rectal, parenteral or local route by topical application to the skin and mucous membranes.

 These compositions can be soliaes or liquids and is presented in the pharmaceutical forms commonly used in human medicine such as, for example, tablets, simpies or sugar-coated, capsules, granules, suppositories, injections, ointments, creams, gels and aerosol preparations; they are prepared according to the usual methods. The active principle can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.

 The dosage varies in particular depending on the route of administration, the condition treated and the subject concerned.

 For example, in adults, it can vary between 20 mg and 2 g of active principle per day, orally for the product of Example 1.

dans laquelle F conserve sa signification précédente et R représente un atome d'hydrogène, ou un radical alcoyle renfermant de 1 à 4 atomes de carbone, à l'action de la 4-hydroxy N-méthyl pipéridine de formule (III)

pour obtenir le composé de formule (I) correspondant que l'on soumet, si désiré, à l'action d'un acide pour en former le sel.The subject of the invention is also a process for preparing the compounds of formula (I) and their salts, characterized in that a compound of formula (II) is subjected

in which F retains its previous meaning and R represents a hydrogen atom, or an alkyl radical containing from 1 to 4 carbon atoms, to the action of 4-hydroxy N-methyl piperidine of formula (III)

to obtain the corresponding compound of formula (I) which is subjected, if desired, to the action of an acid to form its salt.

 In a preferred embodiment of the process of the invention, a compound for which R represents an alkyl radical is used as compound of formula (fui), the process then consists of a conventional transesterification reaction and the procedure is carried out presence of an alkaline agent such as an alkali hydride, an amide or an alkali alcoholate.

It is naturally possible to use the conventional esterification processes to prepare the compounds of formula (I), by reacting a product of formula (II) in which
R represents a hydrogen atom or a functional derivative of this acid, for example, an anhydride or an acid halide with the alcohol of formula (III). The formation of salts is preferably carried out by adding acids.

 The compounds of formula (II) used as starting materials are generally known and can be prepared according to the process described in French patent 2,132,545.

 The following examples illustrate the invention without, however, limiting it.

EXAMPLE -7: 3- / 8- (trifluoromethhl) 4-auino llinsl-amino / 2-thiophene carboxvlate hydrochloride of 1-methyl 4-piperinyl
A) Formation of the base.

 6.94 g of 4-hydroxy N-methyl piperidine are added to a suspension containing 10 g of 4- (2-methoxy carbonyl thienyl 3-amino) 8-trifluoromethyl quinoline and 100 cm3 of toluene. The reaction mixture is heated at reflux for 2 hours. It is cooled and 25 mg of sodium hydride is added all at once and the mixture is refluxed again for 3 hours. Toluene is distilled. The residue is taken up in 100 cm3 of ethyl ether with 20 cm3 of methylene chloride. The organic phase is washed with a batten, dried and concentrated to dryness. 20.2 g of product are obtained which crystallizes; the product is stirred, obtained00 cm3 of isopropyl ether, drained, washed with isopropyl ether and dried under reduced pressure.

10.2 g of product melting at 1640C are thus obtained.

 B) Formation of chlorhvdrate.

 5.2 g of the base prepared in Stage A are dissolved in 15 cm 3 of ethanol. 2 cm3 of an ethanolic hydrochloric acid solution (5.7N) are added to the solution obtained.

The hydrochloride is concreted with anhydrous ethyl ether. The hydrochloride is drained, washed with ethyl ether and dried in an oven at 800C. 5.6 g of the desired hydrochloride, melting at 1700C, are obtained.

EXAMPLE 2
Dharmacologiaue study.

 Analgesic activity.

 The test used is based on the fact reported by R.KOSTER et al. (Fred. Proc., 1959, 18, 412) according to which the intraperitoneal injection of acetic acid causes, in mice, repeated movements of stretching and twisting which can persist for more than six hours. Analgesics prevent or reduce this syndrome which can therefore be considered as the exteriorization of diffuse abdominal pain.

 Using a 1% acetic acid solution in water, the dose triggering the syndrome is under these conditions 0.01 cm 3 / g, ie 100 mg / kg of acetic acid.

 The product studied is administered orally half an hour before the injection of acetic acid, the mice having been fasting since the day before the experiment.

Stretching is observed and counted for each safety during a fifteen minute observation period starting immediately after the injection of acetic acid.

The result expressed by means of the DA50, that is to say the dose which makes it possible to obtain a reduction of 50% in the number of stretches compared to the control animals, is as follows
Product of Example 1 (hydrochloride): DA50 10 mg / kg
Conclusion: The product of Example 1 has significant analgesic activity.

EXAMPLE 3:
Tablets corresponding to the formula were prepared - Product of Example 1 (hydrochloride) ........... 50 mg - Excipient qs for a tablet finished at ....... 350 mg ( Details of excipient: lactose, talc, starch, magnesium stearate).

Claims (7)

1 / - The compounds of formula (I):

 in which X1 in position 5, 6, 7 or 8 on the benzene nucleus represents a hydrogen atom, a halogen atom, a trifluoromethyl radical, a trifluoromethylthio radical, a trifluoromethoxy radical, a linear alkyl radical containing from 1 to 4 carbon atoms, a branched alkyl radical containing from 3 to 5 carbon atoms or an alkoxy radical containing from 1 to 4 carbon atoms, as well as their addition salts with organic or inorganic acids. 2 / - The compounds of formula (I) as defined in claim 1 for which X1 is in position 7 or 8 as well as their addition salts with acids. 3 / - The compounds of formula (I) as defined in claim 1 or 2 for which X1 represents a trifluoromethyl radical as well as their addition salts with organic or mineral acids. 4 / - The compound as defined in claim 3 for which X1 represents a trifluoromethyl radical in position 8 as well as its addition salts with acids. 5 / - As medicaments, the compounds of formula (I) as defined in any one of claims 1 to 4 as well as their addition salts with pharmaceutically acceptable acids. 6 / - Pharmaceutical compositions containing as active principle at least one of the drugs defined in claim 5. 7 / - Process for the preparation of compounds of formula (I) as defined in any one of claims 1 to 4, characterized in that a compound of formula (II) is subjected

 in which X1 retains its previous meaning and R represents a hydrogen atom, or an alkyl radical containing from 1 to 4 carbon atoms, to the action of 4hydroxy N-methyl piperidine of formula (III)

 to obtain the corresponding compound of formula (I) which is subjected, if desired, to the action of an acid to form its salt.