CH628014A5 - Gamma-aryl-gamma-oxoisovaleric acids having antiphlogistic and antalgic properties - Google Patents

Description

The invention also relates to the salts of these compounds with therapeutically acceptable mineral or organic bases. The process of the present invention consists of a selective hydrogenation of the methylene group, in the presence of a catalyst, of the unsaturated derivatives of formula II below.

The catalysts used are preferably chosen from Raney nickel, platinum oxide or palladium on various supports and mainly on carbon.

By non-stereoselective reduction, the racemic compound (dl) is obtained which can be split.

The unsaturated starting materials are prepared by acylation of the aromatic substrate with itaconic anhydride according to the following reaction scheme:

H ',

have)

The present invention relates to new arylisovaleric acids, their preparation and pharmaceutical compositions containing them as active principles, endowed with analgesic and anti-inflammatory properties, useful for the treatment of inflammatory syndromes, in particular of acute inflammations, of degenerative rheumatisms. , low back pain, etc. They also have antiarthrosic properties.

In French patent N ° 74.10196 and its first certificate of addition N ° 75.04912, filed in the name of the holder, there have been described chemical compounds usable in therapy, which are unsaturated keto acids of formula:

C-CH2-C-G02H

The acylation reaction of the aromatic substrate with itaconic anhydride is described in the prior patents cited above.

The following new chemical compounds and their method of preparation are cited as examples. For convenience, each 55 compound will be designated by a code number.

Example 1:

Isochlorophenyl-4'phenyl-4'-4-oxo-4 isovaleric acid (F 1550). A suspension of 13 g of 10% palladium on carbon and 60,270 g of derivative of formula:

Rr

-J V-

-vs

I!

o

-CH = C

H.

COOH

C - CH2 - c

CH-

^ 2

COOH

R

3

628014

in 51 of dioxane and 1.81 of acetic acid is treated with stirring with hydrogen gas.

At ambient pressure and temperature, the hydrogen consumption is 201 in 3 h, that is to say approximately the theoretical quantity.

After removal of the catalyst, the reaction mixture is distilled to dryness.

The residue is dissolved in absolute alcohol while hot and then gradually cooled; F 1550 crystallizes in the form of fine needles. 185 g were recovered, ie a yield of approximately 70% of product of formula:

/ V / \

- CH2 - CH - COOH CH-

Cl

Organoleptic characters:

Thin light yellow needles.

Melting point: 172 ° C (Köfler bench).

Thin-layer chromotography:

Support: silica gel F 254 Merck Solvent: methanol / chloroform 20/80 Revelation: ultraviolet lamp and iodine vapor Rf: 0.79 Infrared spectrography:

Presence of characteristic absorption bands vc = 0 (acid) at 1705 cm -1 and vc = 0 (ketone) at 1680 cm -1 Ultraviolet spectrography:

In solution in ethanol at 95 ° GL 30

Xmax at 265 (x e = 17930

Analytical characteristics conforming to theory (alkalimetry,

elementary analysis)

Solubility characteristics:

Insoluble in water at 1% 35

Soluble at 1% in hot ethanol Very soluble in dimethylacetamide and N-methylpyrrolidone

By using Raney nickel as catalyst and as solvent a mixture of dimethylformamide and acetic acid, the product is obtained with a yield of 90%. With platinum oxide and as a solvent a mixture of dioxane and acetic acid, 4-orthochlorophenyl acid 4-phenyl-4 oxo-4 isovaleric is obtained with a yield of 85%.

45

Example 2:

(Dl) -phenyl-4 'acid 4-phenyl-4-oxo-isovaleric (F 1594).

By operating as before a catalytic reduction,

but starting from 4-phenyl-4-phenyl-4-oxo-2-methylene-butyric acid in solution in dioxane, the derivative F 1594 is obtained with a yield of 80% 50.

Expanded formula:

/ \ /

- CH., -

White crystals

Melting point: 216 ° C

Plate chromatography:

Support: silica F 254 Merck

Solvent: AcOH / dioxane / benzene 2/8/90

Revelation: ultraviolet lamp and iodine vapor

Rf: 0.38

Infrared spectrography:

vc = 0 acid at 1705 cm-1, and 1 vc = 0 ketone at 1680 cm-1 Solubility characteristics:

Insoluble in water at 1%, ethanol, propylene glycol Soluble at 5% in N-methylpyrrolidone Soluble at 12% in dimethylacetamide

Example 3:

Phenyl-4 '4-phenyl oxo-4 sodium isovalerate.

One mole of 4-phenyl-4-phenyl-4-oxo-isovaleric acid is treated with the stoichiometric amount of a sodium hydroxide solution (N). After stirring, filter and evaporate to dryness.

The sodium salt of the formula is recovered with a quantitative yield:

- CH_ - CH - CO, 2 I "

CH. "

® Ma®

CH - COOH

I

CH,

Organoleptic characters:

White crystals

Instant melting point: 210 ° C Solubility characters:

25% water soluble

Example 4:

(D) 4-phenyl-4'-phenyl-4-oxo-isovaleric acid.

Dissolve 200 g of F 1594 (0.745 m) in 11 of DMF at 60 ° C then add 45.2 g of (1) a-phenylethylamine (0.372 m).

Maintain stirring and temperature for 10 min, then leave to return to room temperature and leave overnight in the refrigerator.

After filtration and drying, 95 g of salt (d-1) are obtained.

This salt, suspended in water, is treated with a 10% hydrochloric acid solution to pH 2.

The crystals formed are recovered by filtration and recrystallized from methylcellosolve; 61 g of (d) 4-phenyl-4-phenyl-4-oxo-4-oxo-isovaleric acid which thus melts at 190 ° C. are thus obtained.

Example 5:

Preparation of calcium di (phenyl-4 'phenyl-4 oxo-4 isovalerate). . A suspension of 1 mol of 4-phenyl-4'-phenyl-4-oxo-isovaleric acid is neutralized with sodium hydroxide, then the solution is treated with a stoichiometric amount of calcium chloride hydrate in aqueous solution.

The calcium salt precipitates and the product of formula:

ff W

O

C - CH „-

There 2

O

CH - CO_

I 2

CH.,

It

628014

4

Preparation of aluminum tri (4-phenyl-4-phenyl-4-oxo-isovalerate).

A suspension of 1 mol of 4-phenyl-4'-phenyl-4-oxo-isovaleric acid is neutralized with sodium hydroxide.

To this solution is added dropwise an aqueous stoichiometric solution of aluminum nitrate.

Example 6:

Preparation of aluminum tri (4'-phenyl-4'-4-oxo-isovalerate).

A suspension of 1 mol of 4-phenyl-4'-phenyl-4-oxo-isovaleric acid is neutralized with sodium hydroxide.

To this solution is added dropwise an aqueous stoichiometric solution of aluminum nitrate.

The aluminum salt precipitates and the product of formula:

C - CH- - CH - CO-

Il 2 I 2

O CHj

Al "

Experiments:

The chemical compounds previously described have been the subject of experiments with a view to determining their pharmacological properties and the possibilities of application in therapy.

A) Toxicology:

Acute toxicity was sought in mice by the oral route, and the lethal dose 50 was calculated according to the method of Miller and Tainter. It is higher than 300 mg / kg for F1550 and F1594.

B) Pharmaeodynamics:

Analgesic properties superior to those of acetylsalicylic acid have been demonstrated with respect to the phenylbenzoquinone writhing test; the effective doses decreasing by 50% the number of contortions are:

Products of50

F 1550 F 1594 Acetylsalicylic acid

50 mg / kg 40 mg / kg 80 mg / kg

Anti-inflammatory properties are revealed by the test of edema caused by injection of carrageenan in the rat's paw.

The products were administered orally in suspension in the tween-water mixture, 1 h before the experiment.

The doses decreasing the volume of the leg by 50% are respectively: for F 1594 EDS0 = 25 mg / kg,

for F 1550 ED5D = 22.5 mg / kg.

With regard to the abscess to carrageenan, the doses decreasing by 30% the weight of the abscess are 7 mg / kg for F 1594 and F 1550.

On erythema caused by ultraviolet rays, the effective dose 50 is 4 mg / kg for F 1550 for example.

Intravenously at a dose of 10 mg / kg, the reduction in edema on the rat's paw is 60% for F 1550 and 75% for 30 F 1594.

The results obtained on granulomas with cotton pellets according to the technique of R. Meier, Schuler and Desaulles, "Experientia", 1950,6,469, make it possible to demonstrate a clear reduction in the weight of the granuloma from 10 mg / kg / d.

The results are recorded after 5 d and no change is observed, compared with the controls, as regards the weight development, the weight of the spleen, thymus and adrenal capsules.

On polyarthritis caused by Freund's adjuvant in the 40 rat according to B.B. Newbould, "Brit. J. Pharmacol. Chemother. ”, 1963, 21,127 (“ Freund's adjuvant arthritis in rats ”), the results obtained appear in the table and are expressed in comparison with the pathological controls.

Products

Daily doses in mg / kg

Arthritis reduction

Biochemical assays at the end of the primary secondary experience speed fibrinogen sedimentation paw injected paw not injected

F 1550

50

-40

-51

-37

-70

-23

30

-30

-44

-37

-50

-18

10

-21

-32

-40

-40

-10

F 1594

50

-41

-64

-72

-87

-45

30

-31

-51

-58

-83

-39

10

-25

-37

-50

-55

-30

C) Tolerance:

Several tests have been carried out in order to determine the good tolerance of the chemical compounds which are the subject of the invention. The gastric tolerance determined in the fasted rat (200 mg / kg / d for 5 d) or according to the stress test shows an ulceration index less than or equal to that of the control rats; the products F 1550 and F 1594 are very clearly less ulcerogenic than acetylsalicylic acid.

Subacute toxicity in rats for 3 weeks at doses of 100 mg / kg / d did not cause any mortality for 20 animals treated, no difference compared to the controls with regard to weight development, liver, kidneys. , thymus, adrenal glands, ulceration index, total proteins, urea and alkaline phosphatases. At the dose of 300 mg / kg for 21 d, the same parameters were examined and are unchanged

5

628014

notable; in only a few cases have we seen mild uricemia with no apparent kidney damage. This tolerance is much higher than that of known anti-inflammatory drugs.

D) Human clinical trials have been performed.

They confirmed the perfect tolerance of the new active ingredients and positive results in the treatment of inflammatory rheumatism, low back pain, trauma to the musculoskeletal system.

In the context of clinical trials carried out in particular in rheumatology and trauma, the compounds have been used either in the acid state or in the form of a pharmaceutically acceptable salt (sodium, potassium, calcium, aluminum, lithium salt , arginine, piperazine, dimethylaminoethanol, etc.). They were administered orally in the form of tablets, capsules or granules dosed from 50 to 1000 mg per unit. Other forms can be used for general administration and for local applications.

As an indication and not limiting are given some formulas of pharmaceutical preparations containing compounds object of the invention alone or in combination with other active ingredients useful for the complete treatment of the condition to be treated:

1) Film-coated tablets:

F 1594 Excipient qs

100 mg 1 tablet

2) Suppositories:

F 1550

N-butylhyoscin bromide Excipient qs

3) Cream:

F 1594 Mephenesin Excipient qs

4) Tablets:

F 1550 Ca salt Meprobamate Excipient qs

5) Injectable solution:

F 1550 sodium salt

Water for injection

6) Capsules:

F 1594 aluminum salt Excipient qs

200 mg 10 mg

1 suppository of 2 g

2g 10 g 100 g

300 mg 250 mg 1 tablet

30 mg 2 ml

200 mg 1 capsule

R

Claims (6)

628,014 2. Compound according to claim 1, characterized in that it consists of: - 4-orthochlorophenyl acid 4 'phenyl-4 iso-oxo-4, - 4-phenyl-4 'phenyl-4-oxo-isovaleric acid, - 4-paramethylphenyl-4 'phenyl-4 oxo-4 isovaleric acid, - 4-metamethoxyphenyl-4 'phenyl-4-oxo-4 isovaleric acid, - 4-phenyl '4-phenyl-4-oxo-isovalerate, The calcium di (4-phenylphenyl-4-oxo-4 isovalerate), and - the tri (4-phenylphenyl-4-oxo-4 isovalerate) of aluminum. 2 I. Therapeutically active isovalery y-aryl y-oxo acids corresponding to the general formula: Ç-CH2-CH 'cîî3 ® kCOOH in which X represents hydrogen, a halogen or an alkyl or alkoxy radical, as well as their salts with therapeutically acceptable organic or inorganic bases. 3 (i) "/ \ J S C-CH0-CH It 2 \ kCOOH ^ îCH2 di) COOH X having the same meaning as in claim 1. 3. Process for the preparation of the compounds according to one of claims 1 or 2, characterized in that a selective catalytic hydrogenation of derivatives of formula is carried out: S H, j- "r -x o ncooh = H, halogen, alkyl, alkoxy. By continuing the chemical investigations, starting from these unsaturated derivatives, by selective reduction of the ethylenic functions, new derivatives have been obtained, objects of the present invention, corresponding to the formula: CH, 4. Method according to claim 3, characterized in that the catalyst is palladium on carbon, Raney nickel or platinum oxide. 5. Pharmaceutical composition containing as active ingredient a compound according to one of claims 1 or 2. 6. Pharmaceutical composition according to claim 5, administrable by oral, rectal, parenteral or local application. X in which X represents hydrogen, a halogen or an alkyl or alkoxy radical.