4-PHENYLAMINOPYRIDINE DERIVATIVES, PROCESS OF THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: The present invention provides derivatives of 4-­ phenylaminopyridine of the general formula:- wherein X and Y are hydrogen atoms or hydroxyl groups, X being a hydroxyl group when Y is a hydrogen atom, whereas X is a hydrogen atom when Y is a hydroxyl group in one of the free positions of the aromatic nucleus and Z is a hydrogen atom or an alkyl radical containing up to 4 carbon atoms, which is optionally substituted by hydroxyl; and the pharmaceutically acceptable salts thereof. The present invention also provides a process for the preparation of these derivatives and pharmaceutical com­ positions containing them.

Description: BOEBRINGER MANNHEIM SMBH 4-Phenylaminopyridine derivatives, process of the preparation thereof and pharmaceutical compositions containing them The present invention is concerned with new derivatives of 4-phenylaoinopyridine, with a process for the preparation thereof and with pharmaceutical compositions containing them. Federal Republic of Germany Patent Specification No. 25 16 025 describes the compound 3-isopropyl carbamylBulphonamido-4-(3'-methylphenylamino)-pyridine, also known as torasemide, which has the following structural formula: EMI1.1 This compound has strong diuretic properties. We have now discovered that certain derivatives of 4-phenylaminopyridine, which are related to torasemide, also possess interesting diuretic properties which have proved to be superior to those of torasemide itself. Thus, according to the present invention, there are provided new derivatives of 4-phenylaminopyridine of the general formula: EMI2.1 wherein X and Y are hydrogen atoms or hydroxyl groups, X being a hydroxyl group when Y is a hydrogen atom, whereas X is a hydrogen atom when Y is a hydroxyl group in one of the free positions in the aromatic nucleus and Z is a hydrogen atom or an alkyl radical containing up to 4 carbon atoms which is optionally substituted by hydroxyl: and the pharmaceutically acceptable salts and conjugates thereof. Conjugates of compounds of general formula II are defined e.g. as esters of sulphuric acid or glucuronic acid. When the symbol z represents an alkyl radical, this is preferably a methyl, ethyl or isopropyl radical -GlU ren- the symbol z represents an alkyl radical containing hydroxyl, this is preferably a hydroxymethyl, 2-hydroxyethyl or hydroxyi sopropyl radical. Preferred compounds of general formula (II) according to the present invention include the following: I) a compound in which X is a hydrogen atom, Y is a hydroxyl group in the 4'-position and Z is an isopropyl radical, this compound having the following structural fonnula=- EMI3.1 2) a compound in which X is a hydroxyl group, Y is a hydrogen atom and Z is an isopropyl radical, this compound having the following structural formula: EMI3.2 3) a compound in which X and Y are both hydrogen atoms and Z is a hydroxyisopropyl radical, this compound having the following structural formula EMI4.1 4) a compound in which X, Y and Z are all hydrogen atoms, this compound having the following general formula: - EMI4.2 The compounds of general formula (11) according to the present invention have been tested on rats for their diuretic activity. The tests were carried out on male Wistar rats (IFFA CREDO, Belgium) having an average body weight of 180 g. and randomly divided up into groups of three animals. The test compounds were administered by gastric intubation at a standard dosage of 50 mg./kg. body weight in the form of an aqueous saline solution (30 rnl./kg. of body weight of a solution containing 154 millimoles of sodium chloride per litre). The comparative animals only received the aqueous saline solution (physiological saline) as a placebo. Two of the compounds according to the present invention were also tested at a dose of 5 mg./kg. of body weight1 administration being per os. Each group of three rats being subjected to the same treatment were placed in a metabolic cage and the urine was collected over a period of 4 hours. The volume of urine was precisely measured and expressed as per kg. of body weight of the animals. The augmentation of diuresis amongst the treated animals compared with the urinary excretion observed for the comparative animals indicates the diuretic activity of the tested compounds. The results of this test are given in the following Table I: TABLE I EMI6.1 <tb> <SEP> test <SEP> compound <SEP> diuresis <SEP> (ml./kg./4 <SEP> hours) <tb> <SEP> 50 <SEP> mg/kg. <SEP> p.o. <SEP> 5 <SEP> mg/kg. <SEP> p.o. <tb> none <SEP> (comparison) <SEP> 20.6 <SEP> 19.4 <tb> formula <SEP> IV <SEP> 50.0 <SEP> 20.8 <tb> formula <SEP> III <SEP> 104.3 <SEP> 85.7 <tb> formula <SEP> V <SEP> 102.6 <tb> formula <SEP> VI <SEP> 21.8 <SEP> <tb> torasemide <SEP> 109.3 <SEP> 75.0 <tb> This Table shows that at a dose of 50 mg./kg., two of the compounds according to the present invention have a diuretic activity approaching that of torasemide, whereas at a dose of 5 mg./kg., at least one of the compounds according to the present invention, namely that of formula III, has a diuretic activity which is superior to that of torasemide at the same dose level. The present invention also provides pharmaceutical campositions containing a diuretically efficacious amount of at least one compound of general formula (II) as active ingredient, together with an acceptable pharmaceutical excipient or vehicle. Thus, the compounds according to the present invention may be used in pharmaceutical compositions containing, as active ingredient, at least one compound of general formula (II) or an acid-addition salt thereof with, for example, hydrochloric or nitric acid, or a salt thereof with sodium or potassium hydroxide, admixed with a physiologically acceptable vehicle or excipient. The compositions according to the present invention may be administered, for example, in the form of dragees, tablets, capsules, suppositories or injection solutions, the daily dosage being from 5 to 50 mg. of active compound. The present invention also provides a process for the preparation of compounds of general formula (it), wherein a sulphonamidopyridine of the general formula: EMI7.1 wherein Z has the same meaning as above, is reacted with a phenylamine of the general formula EMI7.2 wherein X and Y have the same meanings as above, whereafter the product obtained is, if desired, converted into a pharmaceutically acceptable salt. The following Examples are given for the purpose of illustrating the present invention: Exawnle 1. 3-Isopropylcarbamylsulphonamido-4-(3'-methyl-4' hydroxyphenylamino)-pyridine (Formula III). 0.04 mole 3-isopropylcarbamylsulphonamido-4- chloropyridine is reacted with 0.04 mole 4-hydroxy-3methylaniline in 200 cc. acetone at ambient temperature for 72 hours. The precipitate obtained is filtered off, washed with acetone and then purified by dissolving in an aqueous solution of sodium carbonate, washing this alkaline solution with dichloromethane and precipitating the desired product by the addition of hydrochloric acid. The product thus obtained has a melting point of 192 - 1930C. Example 2. 3-Isoroylcarbamylsulphonamido-4-(3'-hydroxymethyl- phenylamino)-pyridine (Formula IV). This compound is prepared in the manner described in Example 1 but using 3-hydroxymethylaniline instead of 4-hydroxy-3-methylaniline m.p. 165 - 1680C. Example 3. 3- r 1- (Hvdroxymethv ethylcarbanvlsulphonamidol-4- (3' -methvlphenylamino )-pyridine (Formula V). This compound is prepared in the manner described in Example 1 but using 3-methylaniline and 3-±l (hydroxymethyl)-ethylcarbamylsulphonamido]-4-chloropyridine as starting materials. Example 4. 3-Carbamylsulhonamido-4-(3'-methylphenylarnino) pyridine (Formula VI). This compound is prepared in the manner described in Example 1 but using 3-carbamylsulphonamido-4chloropyridine and 3-methylaniline as starting materials.

Claims: Patent Claims 1. Derivatives of 4-phenylaminopyridine of the general formula EMI10.1 wherein X and Y are hydrogen atoms or hydroxyl groups, X being a hydroxy group when Y is a hydrogen atom, whereas X is a hydrogen atom when Y is a hydroxyl group in one of the free positions of the aromatic nucleus and Z is a hydrogen atom or an alkyl radical containing up to 4 carbon atoms, which is optionally substituted by hydroxyl: and the pharmaceutically acceptable salts and conjugates thereof. 2. 3-Isopropylcarbamylsulphonamido-4-(3 '-methyl- 4 '-hydroxyphenylamino)-pyridine. 3. 3-Isopropylcarbamylsulphonamido-4-(3'-hydroxy methylphenylamino)-pyridine. 4, 3-[l- (Hydroxymethyl )-ethylcarbamylsulphonamido] 4-(3'-methylphenylamino)-pyridine. 5. 3-Carbamylsulphonamido-4-(3'-methylphenylamino)- pyridine. 6. Process for the preparation of compounds according to claim 1, wherein a sulphonamidopyridine of the general formula: EMI11.1 in which Z has the same meaning as in claim 1, is reacted with a phenylamine of the general formula: EMI11.2 in which X and Y have the same meanings as in claim 1, whereafter, if desired, the product obtained is converted into a pharmaceutically acceptable salt or a conjugate. 7. Pharmaceutical compositions comprising at least one compound according to claim 1 in a diuretically efficacious amount as active component, together with a pharmaceutically acceptable excipient or vehicle. 8. Use of at least one compound according to claim 1 for the manufacture of a medicament with diuretic properties.

Inventors: DE SURAY, JEAN-MARIE, GHYS, ARLETTE, PARMANTIER, MICHEL
Applicants: BOEHRINGER MANNHEIM GMBH
Application year: 1985
Main classification: C07D213
IPC codes: A61P7, C07D213, A61K31