Abstract:
This invention relates to new derivatives of biphenyl alkyl carboxylates, to a process for the preparation thereof and the use thereof as medicaments. 
     The new derivatives according to the present invention correspond to general formula (I): ##STR1## wherein X represents a hydrogen atom or a halogen atom, 
     R represents a hydrogen atom or an alkyl group, and 
     R 1  represents the following groups: ##STR2## These compounds will notably be used in the treatment of obstinate pains and inflammatory syndromes.

Description:
BACKGROUND OF THE INVENTION 
     This invention relates to new derivatives of biphenyl acetic acid, a process for the preparation thereof and the use thereof in therapeutics. 
     These new active principles have anti-inflammatory and pain-killing properties and are notably useful as medicaments for the treatment of various pains and types of rheumatism. 
     The invention also relates to pharmaceutical compositions containing these new compounds and the therapeutically acceptable salts thereof. 
     SUMMARY OF THE INVENTION 
     The compounds which are an object of the present invention correspond to the general formula (I): ##STR3## wherein 
     X represents a hydrogen atom or a halogen atom, 
     R represents a hydrogen atom or an alkyl group, and 
     R 1  represents the following groups: ##STR4## wherein 
     X 1  represents a hydrogen atom or a halogen atom or a CF 3  radical, and 
     Y represents an alkyl group or an aryl group optionally substituted by a halogen atom or by a CF 3  radical. 
     DETAILED DESCRIPTION 
     The term &#34;alkyl&#34; as used herein designates a linear or branched hydrocarbon radical containing from 1 to 4 carbon atoms. 
     The therapeutically acceptable salts of the compounds corresponding to the general formula (I) are mainly addition salts or salts of mineral or organic acids, such as hydrochloric acid, phosphoric acid, sulphuric acid, maleic acid, succinic acid, fumaric acid and citric acid etc. 
     The new derivatives of biphenyl acetic acid corresponding to the general formula (I) according to the present invention may be obtained, for example, by treating an acid corresponding to general formula (II): ##STR5## with a chloroacetylated derivative corresponding to general formula (III): ##STR6## in the presence of an alkaline carbonate and a catalyst, such as potassium iodide. 
    
    
     Some non-limiting Examples of the preparation of derivatives corresponding to the general formula (I) according to the present invention will be provided in the following simply by way of illustration. 
     EXAMPLE 1 
     Preparation of N-phenyl parabiphenylacetoxyacetamide 
     11 grammes (80 mmoles) of potassium carbonate are ground in the presence of 300 mg of potassium iodide. This mixture is added to 16.34 g (77 mmoles) of p-biphenylacetic acid in suspension in a solution of 11.9 g (70 mmoles) of chloroacetanilide in 200 ml of methylethylketone. 
     The reaction mixture is brought to reflux for 5 hours. After returning to ambient temperature, the mixture is poured into cold water. The organic phase is washed with an aqueous solution of sodium carbonate, then with water until neutral. It is dried over sodium sulphate in the presence of animal charcoal, and the insoluble matter is then removed by filtration. The solvent is evaporated under reduced pressure. The resulting crystals are recrystallised in a methylethylketone-hexane mixture (30/70). 73% of product corresponding to the following formula are recovered after filtration and drying: ##STR7## 
     Empirical formula: C 22  H 19  NO 3   
     Molecular weight: 345.4 
     Crystals: white 
     Melting point: 133° C. 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: ethyl acetate-petroleum ether 30/70, detection: UV and iodine, Rf: 0.35. 
     Infrared spectrum (KBr pellet): νC=O (ester) 1750 cm -1  ; νC=O (amide) 1660 cm -1 . 
     NMR spectrum (DMSO d 6 ): δppm: 3.85 (s, 2H, CH 2  --COO); 4.75 (s, 2H, ##STR8## 7-7.8 (m, 14H aromatic); 10.05 (s, 1H,N--H) 
     EXAMPLE 2 
     Preparation of N(metatrifluoromethylphenyl)parabiphenylacetoxyacetamide 
     55% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using metatrifluoromethyl chloroacetanilide: ##STR9## 
     Empirical formula: C 23  H 18  F 3  NO 3   
     Molecular weight: 413.4 
     Crystals: white 
     Melting point: 90° C. 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: ethyl acetate-petroleum ether 30/70, detection: UV and iodine, Rf: 0.35. 
     Infrared spectrum (KBr): νC=O (ester) 1740 cm -1  ; νC=O (amide) 1670 cm -1 . 
     NMR spectrum (DMSO d 6 ): δppm: 3.9 (s, 2H, CH 2  --CO 2 ); 4.75 (s, 2H, ##STR10## 7.2-7.8 (m, 13H aromatic); 10.4 (s, 1H, NH). 
     EXAMPLE 3 
     Preparation of 4-methyl-1-parabiphenylacetoxyacetyl piperazine hydrochloride 
     60% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using 4-methyl-1-chloroacetyl piperazine: ##STR11## 
     Empirical formula: C 21  H 25  ClN 2  O 3   
     Molecular weight: 388.9 
     Crystals: white 
     Melting point: 174°-176° C. 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: chloroform-methanol 90/10, detection: UV and iodine, Rf: 0.5. 
     Infrared spectrum (KBr): νC=O (ester) 1745 cm -1  ; νC=O (amide) 1670 cm -1 . 
     EXAMPLE 4 
     Preparation of 4-phenyl-1-parabiphenylacetoxyacetyl piperidine 
     65% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using 4-phenyl-1-chloroacetyl piperidine: ##STR12## 
     Empirical formula: C 27  H 27  NO 3   
     Molecular weight: 413.5 
     Crystals: white 
     Melting point: 93° C. 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: ethyl acetate-petroleum ether 50/50, detection: UV and iodine, Rf: 0.45. 
     Infrared spectrum (KBr): νC=O (ester) 1750 cm -1  ; νC=O (amide) 1660 cm -1 . 
     EXAMPLE 5 
     Preparation of 4-(metatrifluoromethylphenyl)-1-parabiphenylacetoxyacetyl piperazine hydrochloride 
     70% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using 4-(metatrifluoromethylphenyl)-1-chloroacetyl piperazine and hydrochloric acid as a salt-forming agent: ##STR13## 
     Empirical formula: C 27  H 26  ClF 3  N 2  O 3   
     Molecular weight: 518.9 
     Crystals: white 
     Melting point: slow decomposition between 100° and 110° C. 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: ethyl acetate-petroleum ether, detection: UV and iodine, Rf: 0.40. 
     Infrared spectrum (KBr): νC=O (ester) 1750 cm -1  and νC=O (amide) 1670 cm -1 . 
     EXAMPLE 6 
     Preparation of 4-phenyl-1-[(4-phenyl phenyl)acetoxyacetyl] piperazine: 
     71% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using 4-phenyl-1-chloroacetyl piperazine: ##STR14## 
     Empirical formula: C 26  H 26  N 2  O 3   
     Molecular weight: 414.5 
     Crystals: white 
     Melting point: 92° C. 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: ethyl acetate-petroleum ether 30/70, detection: UV and iodine, Rf: 0.65. 
     Infrared spectrum (KBr): νC=O (ester) 1740 cm -1  and νC=O (amide) 1650 cm -1 . 
     NMR spectrum (DMSO d 6 ): δppm: 2.9-3.2 (m, 4H, Ph--N--CH 2 ); 3.2-3.7 (m, 4H, ##STR15## 3.8 (s, 2H, Ph--CH 2  --CO); 4.7 (s, 2H, O--CH 2  --C═O ); 6.8-7.7 (m, 14H aromatic). 
     EXAMPLE 7 
     Preparation of 4-methyl-1-[(4-orthochlorophenyl phenyl) acetoxyacetyl] piperazine hydrochloride 
     83% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using orthochlorobiphenyl acetic acid and chloroacetyl piperazine, then forming a salt with hydrochloric acid: ##STR16## 
     Empirical formula: C 21  H 24  Cl 2  N 2  O 3   
     Molecular weight: 423.3 
     Crystals: white 
     Melting point: slow decomposition from 190° to 200° C. 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: chloroform-methanol 90/10, detection: UV and iodine, 
     Rf: 0.55. 
     Infrared spectrum (KBr): νC=O (ester) 1750 cm -1  and νC=O (amide) 1670 cm -1 . 
     EXAMPLE 8 
     4-phenyl-1-[(4-orthochlorophenyl)phenyl-acetoxyacetyl] piperazine hydrochloride 
     67% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using orthochlorobiphenyl acetic acid, and 4-phenyl chloroacetyl piperazine, then forming a salt with hydrochloric acid: ##STR17## 
     Empirical formula: C 26  H 26  Cl 2  N 2  O 3   
     Molecular weight: 485.4 
     Crystals: white 
     Melting point: 136°-140° C. 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: chloroform-methanol 95/5, detection: UV and iodine, RF: 0.55. 
     Infrared spectrum (KBr): νC=O (ester) 1750 cm -1  and νC=O (amide) 1670 cm -1 . 
     EXAMPLE 9 
     Preparation of 4-metatrifluoromethylphenyl-1-[4-(orthochlorophenyl)phenyl acetoxyacetyl] piperazine hydrochloride 
     62% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using orthochlorobiphenyl acetic acid and 4-phenyl chloroacetyl piperazine, then forming a salt with hydrochloric acid: ##STR18## 
     Empirical formula: C 27  H 25  Cl 2  N 2  O 3  F 3   
     Molecular weight: 553.4 
     Crystals: white 
     Melting point: 134° C. 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: chloroform-methanol 95/5, detection: UV and iodine, Rf: 0.61. 
     Infrared spectrum (KBr): νC=O (ester) 1755 cm -1  and νC=O (amide) 1670 cm -1 . 
     EXAMPLE 10 
     Preparation of 4-(metachlorophenyl)-1-[(4-orthochlorophenyl phenyl)acetoxyacetyl] piperazine hydrochloride 
     73% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using orthochlorobiphenyl acetic acid and 1-chloroacetyl-4-metachlorophenyl piperazine, then forming a salt with hydrochloric acid: ##STR19## 
     Empirical formula: C 26  H 25  Cl 3  N 2  O 3   
     Molecular weight: 519.8 
     Crystals: white 
     Melting point: 128° C. 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: chloroform-metahnol 95/5, detection: UV and iodine, Rf: 0.60. 
     Infrared spectrum (KBr): νC=O (ester) 1750 cm -1  and νC=O (amide) 1660 cm -1 . 
     EXAMPLE 11 
     Preparation of [2-(4-phenyl 1-piperazinyl)-2-oxo] ethyl 2-parabiphenyl propionate 
     50% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using 2-para-biphenylyl proprionic acid and N&#39;-phenyl-N-chloroacetyl piperazine: ##STR20## 
     Empirical formula: C 27  H 28  N 2  O 2   
     Molecular weight: 428.5 
     Crystals: white 
     Melting point: 92° C. 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: toluene/ethyl acetate 70/30, detection: UV and iodine, Rf: 0.38. 
     Infrared spectrum (KBr): νC=O (ester) 1740 cm -1  and νC=O (amide) 1660 cm -1 . 
     EXAMPLE 12 
     Preparation of 2-(4-methylpiperazino)-2-oxoethyl 2-(2&#39;-chloro-4-biphenylyl)propionate hydrochloride 
     62% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using 2-(4-orthochlorophenyl phenyl) propionic acid and 4-methyl-1-chloroacetyl piperazine, then forming a salt with hydrochloric acid: ##STR21## 
     Empirical formula: C 22  H 26  Cl 2  N 2  O 3   
     Molecular weight: 437.3 
     Crystals: white 
     Melting point: 210° C. (instantaneous) 
     Plate chromatography: support: silica gel 60 F. 254 Merck®, solvent: chloroform-methanol 90/10, detection: UV and iodine, Rf: 0.51. 
     Infrared spectrum (KBr): νC=O (ester) 1745 cm -1  and νC=O (amide) 1675 cm -1 . 
     NMR spectrum (DMSO d 6 ): δppm: 1.45 (d, 3H,CH 3  --C); 2.7 (s, 3H,CH 3  --N); 2.8-4.2 (m, 10H, (CH 2 ) 4 , exchangeable, CH--CH 3 ); 4.85 (s, 2H, O--CH 2  --CO); 7.35 (s,8H aromatic). 
     EXAMPLE 13 
     Preparation of 2-(4-phenylpiperazino)-2-oxoethyl 2-(2&#39;-chloro-4-biphenylyl)propionate 
     82% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using 2-(4-orthochlorophenyl phenyl)propionic acid and 1-phenyl chloroacetyl piperazine: ##STR22## 
     Empirical formula: C 27  H 27  ClN 2  O 3   
     Molecular weight: 462.9 
     Crystals: light beige 
     Melting point: 114° C. 
     Plate chromatography: support: silica gel 60 G 254 Merck®, solvent: chloroform-methanol 99/1, detection: UV and iodine, Rf: 0.51. 
     Infrared spectrum (KBr): νC=O (ester) 1745 cm -1  and νC=O (amide) 1650 cm -1 . 
     NMR spectrum (DMSO d 6 ): δppm: 2.95 (d,3H,CH 3  --C); 2.8-3.6 (m,8H,CH 2  piperazine); 3.6-4.2 (q,1H,CH 3  --CH); 4.8 (s,2H, O--CH 2  --C═O); 6.6-7.5 (m,13H aromatic). 
     EXAMPLE 14 
     Preparation of 2-(4-phenylpiperidino)-2-oxoethyl 2-(2&#39;-chloro-4-biphenylyl)propionate 
     75% of product corresponding to the following formula are obtained by a method similar to the one described in Example 1, but using 2-(4-orthochlorophenyl phenyl)propionic acid and 4-phenyl-1-chloroacetyl piperidine: ##STR23## 
     Empirical formula: C 28  H 28  ClNO 3   
     Molecular weight: 461.9 
     Crystals: white 
     Melting point: 74° C. 
     Plate chromatography: support: silica gel 60 F 254 Merck®, solvent: chloroform-methanol 99/1, detection: UV and iodine, Rf: 0.35. 
     Infrared spectrum (KBr): νC=O (ester) 1740 cm -1  and νC=O (amide) 1650 cm -1 . 
     EXAMPLE 15 
     Preparation of 2-(2-aminopyridine)-2-oxoethyl 2-(2&#39;-chloro-4-biphenylyl)propionate oxalate 
     A product corresponding to the following formula is obtained by a method similar to the one described in Example 1, but using 2-(4-orthochlorophenyl phenyl)propionic acid and 2-chloroacetylamino pyridine: ##STR24## 
     Empirical formula: C 24  H 21  ClN 2  O 7   
     Molecular weight: 484.89 
     Crystals: light beige 
     Melting point: instantaneous 160° C. 
     Plate chromatography: support: silica gel 60 F 254 Merck®, solvent: chloroform-acetone 90/10, detection: UV and iodine, Rf: 0.81 
     Infrared spectrum (KBr): νC=O (ester) 1735 cm -1  and νC=O (amide) 1630 cm -1 . 
     EXPERIMENTS 
     The above-described derivatives were the subject of pharmacological and toxicological experiments which have made it possible to demonstrate advantageous pain-killing and anti-inflammatory properties. 
     (A) Toxicology 
     A toxicity study was carried out on conventional mice weighing about 20 grams. 
     The compounds corresponding to the general formula I according to the present invention and the pharmaceutically acceptable salts thereof were administered orally. The DL 50  was calculated according to the method by L. C. Miller and M. L. Tainter--Proc. Soc. Exper. Biol. Med., 1944, 57,261. All of the administered compounds showed a very low toxicity and it will be particularly noted that the compounds of Examples 12 and 14 have a LD 50  greater than 500 mg/kg. 
     (B) Pharmacology 
     The pain-killing activity was studied according to Siegmund--J. Pharm. Exptl. ther., 1957, 119,453. 
     The compounds according to the present invention were administered orally 30 minutes before the injection of phenyl benzoquinone. 
     All of the administered compounds have an excellent pain-killing activity. In particular, the compounds of Examples 12 and 14 have a DE 50  respectively equal to 7 mg/kg and 5 mg/kg. 
     The anti-inflammatory properties were revealed in an oedema test by injecting carragenine into a rat&#39;s foot according to the technique of C. Winter, E. Ribley and G. Nuss--Proc. Soc. Exper. Biol. Med., 1962, 111, 544 547. 
     The products were administered orally in suspension in a Tween-water mixture 2 hours before the experiment. All the administered compounds have a good anti-inflammatory activity. It will particularly be noted that the compound of Example 14 has a DE 50  of 3 mg/kg. 
     For comparison purposes, the following Table shows the LD 50  and DE 50  values which were combined with some of the best known anti-inflammatory products. 
     
         ______________________________________                     DE.sub.50 (carragenine)Products  LD.sub.50 mg/kg p.o.                     mg/kg p.o.______________________________________Naproxen  400              5Ibuprofen 900             14Aspirin   1500            135Phenylbutanone     400             30Indometacine      20              4______________________________________ 
    
     (C) Therapeutic uses 
     Bearing in mind the perfect tolerance of the compounds according to the present invention, and their pharmacological properties, they may be used in human or animal therapeutics in the treatment of obstinate pains of an inflammatory nature for which prolonged treatment is applicable. 
     The clinical results have proved to be satisfactory in cases of inflammatory or degenerative rheumatism. 
     The pharmaceutical preparations containing these active principles may be administered orally, parenterally or rectally. The quantity in a doseage unit is generally from 25 to 150 mg. These pharmaceutical compositions may also contain other pharmaceutically and therapeutically acceptable active principles. 
     Some examples of pharmaceutical preparations containing the active principles used in the experiments are provided in the following in an illustrative, non-limiting manner. 
     (a) Tablets 
     2-(4-methylpiperazino-2-oxoethyl 2-(2&#39;-chloro-4-biphenylyl)propionate hydrochloride: 50 mg 
     excipient: lactose 
     (b) Capsules 
     2-(4-phenylpiperidino)-2-oxoethyl 2-(2&#39;-chloro-4-biphenyl)propionate: 25 mg 
     (c) Adult suppositories 
     2-(4-phenylpiperidino)-2-oxoethyl 2-(2&#39;-chloro-4-biphenylyl)propionate: 50 mg 
     Meprobamate: 100 mg 
     Semi-synthetic glycerides, quantity sufficient for 1 suppository of 1 g 
     (d) Injectable solution 
     2-(4-methylpiperazino)-2-oxoethyl 2-(2&#39;-chloro-4-biphenylyl)propionate hydrochloride: 10 mg 
     Water for injectable preparation: 2 ml.