NEW COMPOUNDS WITH ANTIINFLAMMATORY AND ANTITUSSIVE ACTIVITY, PROCESS FOR THEIR PREPARATION AND RELATIVE PHARMACEUTICAL COMPOSITIONS

Abstract: N-Pyridil-amides of 1-phenyl-cyclopentancarboxylic acid having formula (I) wherein Py is the pyridine ring, eventually substituted with one or more methyl groups or chlorine atoms, endowed with interesting antiinflammatory and antitussive properties, and a process for the preparation thereof.

Description: New compounds with anti inflammatory and anti- tussive activity, process for their preparation and relative pharmaceutical compositions The present invention relates to a series of N-pyridyl-amides of 1-phenyl-cyclopentancarbo xylic acid having formula (I) EMI1.1 wherein Py is the pyridine ring, eventually substituted with one or more methyl groups or chlorine atoms0 Compounds (I) proved to be endowed with intere sting pharmacological properties, which make them suitable for the therapeutic use as antiinflammatory agents. The invention relates therefore also to pharmaceutical compositions with antiinflammatory activity containing as active principle one or more amides of formula (I). Object of the invention is finally provided by a process for the preparation of N-pyridylamides (I), characterized in that activated deriva tives of 1-phenyl-cyclopentancarboxylic acid, having general formula II , are reacted with aminopyridines III,according to the scheme: EMI2.1 In such a scheme, X is an halogen atom, or an alcoxy group, or a residue transforming (II) in a homogeneous or mixed anhydride; R and R', which can be the same or different, are hydrogen atoms, methyl groups or chlorine atoms. The reaction is preferably carried out with a nearly equimolar ratio between (II) and (III); it is possible to operate in the absence of sol vents, or preferably in solvents inert in the reaction conditions (such as ethyl ether, dioxa ne, chloroform, benzene or toluene), at tempera tures ranging from OOC and the solvent's boiling point. Whereas X is halogen, it is convenient to use an excess of aminopyridine Iii as a hydrohalogen acid acceptor, The same purpose can be achieved by operating in presence of alkaline or alkaline-earth metals carbonate or bicarbonate, or in presence of tertiary bases. The following examples illustrate the process ac cording to the invention. EXAMPLE 1 3-[(1-Phenyl)-cyclopentyl-carbonyl]aminopyridi ne 60 Mmoles of 3-aminopyridine, 50 ml of anhydrous benzene and 50 mmoles of anhydrous sodium carbonate, are placed in a three-necked flask with a stirrer, reflux condenser and dropping funnell; then, a solution of 50 mmoles of chloride of 1-phenyl-cyclopentancarboxylic acid, pre pared by reaction of thionyl chloride on the cor responding acid (J. Org. Chem. 4, 619 (1959)) in 50 ml of benzene, is added in small portions and under stirring. When the addition is comple te, the reaction mixture is left under stirring for one hour and is then refluxed for three hours. After hot filtration, benzene is removed under reduced pressure. The residue is re-crystallized from ethanol; m.p. 122-1230C (ethanol). Analytical and spectroscopical data agree with the teoretical data. EXAMPLE 2 2-/(1 -Phenyl )cyclopentyl-carbony-aminopyridine The reaction is carried out according to the exam ple 1, but using 2-aminopyridine instead of 3,ami nopyridine, and substituting sodium carbonate with triethylamine. The product obtained - whose structu re is confirmed by analytical and spectroscopical data- melts at 86-870C (methanol). Similar results are obtained using, instead of acid chloride, the corresponding mixed anhydride, obtained by 1-phenyl-cyclopentancarboxylic acid and ethyl chlorocarbonate in the presence of a tertiary base. Starting from such an anhydride, or by 1-phenyl- 1-chlorocarbonylcyclopentane, and from the suitable aminopyridine, the following compounds according to the invention are moreover obtained: - 2-[(1-phenyl)cyclopentyl-carbonyl]-amino-3-me thyl-pyridine; - 2-LTl -phenyl cyclopentyl-carbonyl7-amino-4-me thylpyridine; - 2-[(1-phenyl)cyclopentyl-carbonyl]-amino-6-me thyl-pyridine; - 2-[(1-phenyl)cyclopentyl-carbonyl]-amino-4,6 dimethyl-pyridine; - 2-[(1-phenyl)cyclopentyl-carbonyl]-amino-5-chlo ro-pyridine. The above compounds, whose characteristics are reported in the following table, show IR spectra having NH at 3300-3400 cm 1 and ÇCO at 16501700 cm and NMR spectra having multiplet band at 1.4-1.90 p.p.m. (cycloalkyl hydrogens) and a multiplet band at 6.60-8.20 p.p.m. (benzene and pyridine hydrogens). TABLE 1 EMI5.1 EMI5.2 Py <SEP> M.p. <SEP> Yield <SEP> Molecular <SEP> formula <SEP> Elementary <SEP> analysis <tb> <SEP> calc./found <tb> <SEP> C <SEP> N <SEP> H <tb> -N# <SEP> 86-87 C <SEP> 80 <SEP> C17H18N2O <SEP> 76.66 <SEP> 6.81 <SEP> 10.52 <tb> <SEP> (methanol) <SEP> 76.64 <SEP> 6.79 <SEP> 10.48 <tb> -#N <SEP> 122-123 C <SEP> 75 <SEP> C17H18N2O <SEP> 76.66 <SEP> 6.81 <SEP> 10.52 <tb> <SEP> (ethanol) <SEP> 76.69 <SEP> 6.74 <SEP> 10.54 <tb> CH3# <SEP> 106-108 C <SEP> 80 <SEP> C18H20N2O <SEP> 77.11 <SEP> 7.19 <SEP> 9.99 <tb> <SEP> -N# <SEP> (ethylacetate) <SEP> 7.06 <SEP> 7.17 <SEP> 9.94 <tb> EMI6.1 EMI6.2 Py <SEP> M.p. <SEP> Yield <SEP> Molecular <SEP> formula <SEP> Elementary <SEP> analysis <tb> <SEP> calc./found <tb> <SEP> C <SEP> N <SEP> H <tb> <SEP> #CH3 <SEP> 99-100 C <SEP> 83 <SEP> C18H20N2O <SEP> 77.11 <SEP> 7.19 <SEP> 9.99 <tb> -#N <SEP> (ethanol) <SEP> 77.10 <SEP> 7.17 <SEP> 10.11 <tb> -#N <SEP> 103-104 C <SEP> 78 <SEP> C18H20N2O <SEP> 77.11 <SEP> 7.19 <SEP> 9.99 <tb> <SEP> #CH3 <SEP> (ethanol) <SEP> 77.18 <SEP> 7.10 <SEP> 9.95 <tb> <SEP> #CH3 <SEP> 80-81 C <SEP> 85 <SEP> C19H22N2O <SEP> 77.52 <SEP> 7.53 <SEP> 9.52 <tb> -N# <SEP> (methanol) <SEP> 77.48 <SEP> 7.54 <SEP> 9.55 <tb> -N#-Cl <SEP> 99-101 C <SEP> 70 <SEP> C17H17ClN2O <SEP> 67.88 <SEP> 5.65 <SEP> 9.32 <tb> <SEP> (ethanol) <SEP> 67.90 <SEP> 5.69 <SEP> 9.40 <tb> The compounds according to the invention are endo wed with limited toxicity together with antiinflam matory, analgesic and antitussive properties. As an example, pharmacological data for 2-[(1-phe nyl)cyclopentyl-carbonyl]-amino-3-methylpyridine which will be also defined, for the sake of brevity, with the abbreviation MR 549, are reported. Acute toxicity The toxicity after single administrations of MR 549 has been studied in mice and rats by the oral and intraperitoneal routes. The LD50 values have been calculated according to the method of Litchfield and Wilcoxon (J. Pharm. Exp. Therap., 1949, 96, 99). From the results obtained, outlined in Table 2, it turned out that MR 549 has a very low acute toxicity, in the used experimental conditions. TABLE 2 - Acute toxicity of MR 549 EMI7.1 <tb> PECIES <SEP> ROUTE <SEP> LD50 <SEP> mg/kg <tb> mouse <SEP> Os <SEP> 550 <tb> <SEP> i.p. <SEP> 300 <tb> rat <SEP> os <SEP> 1100 <tb> <SEP> i.p. <SEP> 600 <tb> Pharmacological Activity Antitussive activity The antitussive activity of MR 549 has been studied in the rabbit according to the method of Boura and coll. (Prog. Brit. Pharmac. Soc., apr. 1970) by inducing cough with an aerosol administration of citric acid. MR 549 and an experimented antitussive agent, codeine, as a reference compound, have been administered by intraperitoneal route at equiponderant doses immediately before treat ing animals with oitric acid aerosol. Ih the 10 minutes following the end of treatment, cough strokes of each animal have been counted, oomputing the average for eaoh group and the percent inhibition in comparison with a control group. TABLE 3 - Antituasive activity of MR 549 EMI9.1 TREATMENT <SEP> DOSES <SEP> N <SEP> ANIMALS <SEP> % <SEP> INHIBITION <SEP> OF <SEP> STATISTICAL <tb> <SEP> mg/kg <SEP> COUGH <SEP> STROKES <SEP> SIGNIFICANCE <tb> <SEP> i.p. <SEP> IN <SEP> COMPARISON <SEP> (basal <SEP> minus <tb> <SEP> WITH <SEP> BASAL <SEP> VA- <SEP> final <SEP> values) <tb> <SEP> LUES <tb> CONTROLS <SEP> - <SEP> 12 <SEP> 13.7 <SEP> N.S. <tb> CODEINE <SEP> 50 <SEP> 12 <SEP> 79.5 <SEP> P <SEP> < <SEP> 0,01 <tb> MR <SEP> 549 <SEP> 50 <SEP> 12 <SEP> 63.5 <SEP> P <SEP> < <SEP> 0,01 <tb> From the obtained results reported in Table 3 it turns out that MR 549 has a marked antitussi ve activity, statistically significant in compa rison with control groups and with a very high percentage, comparable to a standard of proved ef ficacy such as codeine. Analgesic activity The analgesic properties of MR 549 have been studied with the test of whrithing by phenylquinone in mice according to the method of Siegmund et al. (Proc. Soc. Exp. Biol. Med. 1957, i2, .729): MR 549 has been administered by the oral route 30 minutes before of the phenylquinone injection at the dose of 50 mg/kg per os; acetylsalicylic acid, drug with proved analgesic activity has been used as preference drug at the dose of 100 m mg/kg per os. From the results obtained and shown in the Table 4 a potent analgesic activity of MR 549 is noticed, comparable to that of acetylsalicylic acid, in the used experimental conditions0 TABLE 4 - Analgesic activity of MR 549 - Whriting by phenylquinone EMI11.1 TREATMENT <SEP> DOSES <SEP> WEIGHT <SEP> g <SEP> N <SEP> CONTORSIONS <SEP> % <SEP> INHIBITION <SEP> N <SEP> WHRITING <tb> <SEP> mg/kg <SEP> X <SEP> # <SEP> e.s. <SEP> X <SEP> # <SEP> e.s. <SEP> IN <SEP> COMPARISON <SEP> ANIMALS/TO <tb> <SEP> WITH <SEP> CONTROLS <SEP> TAL <SEP> N & BR< CONTROLS <SEP> - <SEP> 26.6 <SEP> 19.1 <SEP> # <SEP> 3.24 <SEP> - <SEP> 20/20 <tb> <SEP> #0.58 <tb> ACETYL SALICYLIC <SEP> 100 <SEP> 25.8 <SEP> 3.9 <SEP> # <SEP> 1.93 <SEP> 79.6 <SEP> 12/20 <tb> ACID <SEP> #0.59 <tb> MR <SEP> 549 <SEP> 50 <SEP> 25.3 <SEP> 6.9 <SEP> # <SEP> 2.24 <SEP> 63.9 <SEP> 14/20 <tb> <SEP> #0.79 <tb> Antiinflammatory activity The antiinflammatory activity of MR 549 has been assessed by the carrageenin edema test in the rat according to the method of Winter et al.(Proc. Soc. Exp. Biol. Med., 1962, III, 544). The product under exam and indomethacin at equiponderant doses have been administered by the oral route 30 minutes before of the subplantar carragee ning injection; pletismographic measures of the edemas have been performed 3 hours after they had been induced. The results obtained are reported in Table 5. From the analysis of the obtained data it is poe sible to notice that MR 549 is endowed with a good anti inflammatory activity, slightly lower than that of indomethacin in the used experimental con ditions. TABLE 5 - Antiinflammatory activity - Edema by carrageenin EMI12.1 <tb> DRUG <SEP> DOSES <SEP> N <SEP> ANI <SEP> EDEMA <SEP> VOLUME <SEP> % <SEP> IN <tb> <SEP> mg/kg <SEP> MALS <SEP> Basal <SEP> Final <SEP> HIBI <tb> <SEP> value <SEP> value <SEP> TION <tb> CON- <SEP> - <SEP> 10 <SEP> 23.4 <SEP> 38.6 <SEP> <tb> TROLS <tb> INDO <tb> METHA <SEP> 50 <SEP> 10 <SEP> 22.5 <SEP> 29.6 <SEP> 53.2 <tb> CINE <tb> <SEP> NR <SEP> 549 <SEP> 50 <SEP> 10 <SEP> 22.6 <SEP> 31.8 <SEP> 38.1 <tb> Gastric tolerability The effect on gastric mucosa of MR 549 and of phenylbutazone as a reference drug has been asset sed with the method described by Pisanti and Volterra (II Farmaco Ed. pr. Vol. 25 (2), 105). Male rats of S-D strain, weighing 180-200 g and fasting for 48 hours with free access to water, have been used. The product under exam have been administered by intraperitoneal route: twice (after 24 and 31 hours - from the beginning of the fasting period) at the single dose of 100 mg/kg; or three times by oral route (9.24 and 31 hours after the beginning of the fasting period) at the single dose of 150 mg/kg. The solvent alone (1% carboxymethylcellulose) has been administered to a control group of animals. The results obtained, repor ted in the Table 6, show that MR 549 is endowed, both by parenteral and oral route, with a gastrolesive action clearly lower than phenylbutazone, according to the used method. TABLE 6 EMI14.1 <tb> TREAT- <SEP> DOSE <SEP> N <SEP> ANI <SEP> N <SEP> ANI- <SEP> % <SEP> ANI <tb> MENT <SEP> mg/kg <SEP> MALS <SEP> MALS <SEP> MALS <tb> <SEP> WITHE <SEP> UL <SEP> WITH <SEP> UL <tb> <SEP> CERS <SEP> CERS <tb> <SEP> CONTROLS <tb> <SEP> (1% <SEP> car <tb> boxymethyl <SEP> - <SEP> 12 <SEP> 0 <SEP> <tb> <SEP> cellulose) <tb> <SEP> Phenylbu- <SEP> 100 <SEP> mg <SEP> X <SEP> 2 <SEP> 12 <SEP> 10* <SEP> 83.30 <tb> <SEP> tazone <SEP> i.p. <tb> <SEP> Phenylbu- <SEP> <tb> <SEP> tazone <SEP> 150 <SEP> mg <SEP> X <SEP> 3 <SEP> 12 <SEP> 11** <SEP> 91.67 <tb> <SEP> Os <SEP> <tb> MR <SEP> 549 <SEP> 100 <SEP> mg <SEP> X <SEP> 2 <SEP> 12 <SEP> 3 <SEP> 25.00 <SEP> <tb> <SEP> i.p. <tb> MR <SEP> 549 <SEP> 150 <SEP> mg <SEP> X <SEP> 3 <SEP> 12 <SEP> 5 <SEP> 41.67 <tb> <SEP> os <tb> * an animal died during treatment ** two animals died during treatment. rotor activity The effect of MR 549 on the motor activity has been studied in the Swiss mouse, by placing two groups of animals in a box connected with a recorder detec ting spontaneous motility. On the basis of movements/minute recorded, MR 549 at the dose of 50 mg/kg i.p. has been administered to one group and the ac tivity has been recorded during the 2 hours following treatment; the second group, treated with the solvent alone, has been used as control group. The results obtained are reported in Table 7. From analysis of these data it turns out that MR 549 does'nt change the motor activity in the two hours following treatment. TABLE N. 7 EMI15.1 <tb> EATMENT <SEP> DOSE <SEP> N <SEP> recorded <SEP> movements/min. <tb> <SEP> Time: <SEP> 0 <SEP> 15' <SEP> 30' <SEP> 60' <SEP> 90' <tb> CONTROLS <SEP> - <SEP> 53 <SEP> 48 <SEP> 53 <SEP> 40 <SEP> 44 <tb> 549 <SEP> 50 <SEP> mg/ <SEP> 45 <SEP> 42 <SEP> 52 <SEP> 39 <SEP> 52 <tb> <SEP> kg <SEP> i.p <tb> The compounds (I) according to the present invention are therefore agents useful for the trea tment of cough and of inflammatory conditions, in the form of pharmaceutical compositions such as: - capsules, pills or tablets containing 100-500 mg of compounds (I); - syrup in such a concentration to deliver 300 1500 mg of compounds (I) a day, when administe red b.i.d., t.i0d. or more times; - suppositories containing 200-1000 mg of compo unds (I).

Claims: Claims: 1. N-Pyridyl-amides of 1 -phenyl-cyclopentan carboxylic acid having formula (I) EMI16.1 wherein Py is the pyridine ring, eventually substituted with one or more methyl groups or chlo rine atoms. 2. As a compound according to claim 1, 2phenyl)cyclopentyl-carbonyl]-aminopyridine. 3. As a compound according to claim 1, 3-Lt1- phenyl)cyclopentyl-carbonyl]-aminopyridine. 4. As a compound according to claim 1, 2-[(1- phenyl)cyclopentyl-carbonyl]-amino-4-methyl-py ridine. 5. As a compound according to claim 1, 2-[(1- phenyl)cyclopentyl-carbonyl]-amino-6-methyl-pyridine. 6. As a compound according to claim 1, 2-/t1- phenyl)cyclopentyl-carbonyl]-amino-3-methyl-py ridine. 7. As a compound according to claim 1, 2-Z(1- phenyl)cyclopentyl-carbonyl]-amino-4,6-dimethylpyridine. 8. As a compound according to claim 1, 2-Z(1- %phenyl)cyclopentyl-carbonyl]-amino-5-chloropyri dine. 9. Process for the preparation of compounds aocording to claims 1-8, characterized in that activated derivatives of 1-phenyl-cyclopentan-car boxylic acid, having general formula (it), are reacted with aminopyridines (III), according to EMI17.1 wherein X is an halogen atom, or an alcoxy group, or a residue transforming (II) in an homogeneous or mixed anhydride; R and R', which can be the sa me or different, are hydrogen atoms, methyl groups or chlorine atoms. 10. Pharmaceutical compositions endowed with anti tussive and antiinflammatory activity, charaoteri- zed by containing as an active principle a compound according to claims 1-8. Claims: 1. Process for the preparation of compounds having formula I EMI18.1 wherein Py is the pyridine ring, eventually sub stituted with one or more methyl groups or chlo rine atoms characterized in that activated derivatives of 1-phenyl-cyclopentan-carboxylic acid, having general formula (II), are reacted with aminopyridines (III), according to the sche mes EMI18.2 wherein X is an halogen atom, or an alcoxy group, or a residue transforming (II) in an homogeneous or mixed anhydride; R and R', which can be the sa me or different, are hydrogen atoms, methyl groups or chlorine atoms. 2. Process according to claim 1, characterized in that the reaction is carried out in inert solvents such as ethylether, dioxane, chloroform, benzene or toluene. 3. Process according to claim 1, characterized in that, when X is halogen, an hydroalogen acid acceptor or an excess of aminopyridine (III) are used.

Inventors: QUADRO, GIUSEPPE
Applicants: MEDEA RESEARCHES S.R.L.
Application year: 1982
Main classification: C07D213
IPC codes: C07D213