CA1097684A - PROCESS FOR THE PREPARATION OF .gamma.ARYL .gamma.OXO ISOVALERIC ACIDS - Google Patents

Abstract

The invention relates to a process for the preparation of new isaryl y aryl y oxo acids of formula: in which X is a hydrogen, halogen, alkyl or alkoxy radical, characterized in that a selective hydrogenation of the methylene group is carried out in the presence of 'a catalyst for the products of formula: as well as the therapeutically acceptable salts of these acids with mineral or organic bases. The products obtained are useful for the treatment of inflammatory syndromes.

Description

1 ~ 7t; ~ 4 The subject of the present invention is a method of manufacture of new arylisovaleric acids of formula general I:

~ C; CH2 - C - C02H

o ~ X represents H, halogen, alkyl or alkoxy.
The derivatives obtained by this process and their salts with -therapeutically acceptable mineral or organic bases are useful as medicaments and more particularly for the treatment of inflammatory syndromes. They have in in addition to analgesic and anti-arthritis properties.
The process of the present invention consists of a selective hydrogenation of the methylene group in the presence of a catalyst, unsaturated derivatives of formula II according to the reaction:

C-CH2-C-C02H catalyzes> r ~ H
X II X
The preferred catalysts are Raney nickel, platinum oxide or palladium on various supports and prin-mainly on coal.
The corresponding mineral salts are obtained in causing acid I to react with appropriate mineral bases, for example, soda or trans-salification by treating the sodium salt by calcium chloride hydrate or aluminum nitrate and other similar bases.
The unsaturated starting derivatives are prepared by acylation of the aromatic substrate with itaconic anhydride according to the following r ~ action diagram:

~ k B

iog7684 ~ H2 1l CIH2 XX II
The following examples are given to illustrate the invention.

Orthochlorophenyl-4 'acid 4-phenyl-4 oxo-4 isovaleric ~ F 1550) A suspension of 13 9 of palladium on carbon at 10%
and 270 9 of derivative of formula:
~ 311 \ COOH ~ ~

in 5 liters of dioxane and 1.8 liters of acetic acid is treated with stirring with gaseous hydrogen.
At pressure and ambient temperature consumption of hydrogen is 20 liters in 3 hours, that is to say approximately the theoretical quantity. After elimination of the catalyst, the the reaction mixture is distilled to dryness. The residue is solubilized in hot absolute alcohol and then cooled gressively, orthochlorophenyl-4 'phenyl-4 oxo-4 isovaleric (F 1550) crystallizes in the form of fine needles.
~ We have recovered 185 9 or a yield of around 70% of formula product:

~ C - CH2 - fH COOH

Cl CH3 Organoleptic characteristics:
Thin light yellow needles.
Melting point: 172C (Kofle bench .
! '.:
, ~

10 ~ 7684 ... r.
Thin-layer chromotography:
- - Support: Merck F 254 silica gel - Solvent: Methanol - chloroform 20/80 ~, - Revelation: ultraviolet lamp and iodine vapor, - Rf: 0.79 ::
Infrared spectrography:
- Presence of characteristic absorption bands vc = O (acid) at 1705 cm ~ l and vc = O!, cetone) at 168Q cm ~
U7tra-violet spectrography:
- In solution in ethanol at 95 GL
~ max. a 265 m ~ = 17930 Analytical characteristics conforming to the theory (alkalimetry, elementary analysis) Solubility characteristics: Insoluble in water ~ 1%.
Soluble at 1% in hot ethanol. .
Very soluble in dimethyl aceta-mide and N-methyl pyrrolidone.
Using Raney nickel as a catalyst and as a solvent a mixture of dimethylformamide and acid acetic the product is obtained with a yield of 90%. With platinum oxide and as solvent a mixture of dioxane and, ,, acetic acid, orthochlorophenyl-4 'phenyl-4 oxo-4 acid:
; ~ oval is obtained with a yield of 85%.

4-phenyl-4 'phenyl-4-oxo-isovaleric acid (F 1594) By operating as previously a cataly-tick but from 4-phenyl-4-phenyl-4-oxo-methylene acid

2 butyric solution in dioxane, one obtains with a 80% yield of 4-phenyl-4-phenyl-4-oxo-isoval acid-risk (F 1594).

f`: ' ~ 768 ~

Developed formula:

Cl - CH2 - CH - COOH ~; r White crystals Melting point: 216C
Plate chromatography: ~:
- Support: silica F 254 Merck;:;
- Solvent: AcOH / Dioxanne / Benzene 2/8/90;. `~
- Revelation: ultraviolet lamp and iodine vapor: -:
- Rf: 0.38; ~
Infrared spectrography:
vc = O (acid) at 1705 cm 1 and vc O (cetone) at 1680 cm 1 Solubility characteristics: Insoluble in water at 1 hour, in `-;
ethanol, propyl ~ ne glycol. .: ~
Soluble at 5% in N-methyl.:~:
pyrrolidone has 12% in dimethyl.
acetamide.
EXAMPLE 3;
4-Phenyl-4-phenyl-4-oxo-isovalerate sodium A ~ ole of 4-phenyl acid 4-phenyl-4 oxo-isovaleri-20 that is treated by the stoichiometric amount of a solution ~.
soda (N). After stirring, filter and evaporate until siccite. The salt is recovered with a quantitative yield formula sodium:
O
H2 - CH - C2 ~ Na ~

Organoleptic characteristics ~
White crystals Instant melting point: 210C

~ 097684 .
Solubility characteristics: Soluble in water at 25%.

Preparation of di (phenyl-4 'phenyl) -4 oxo 4 isovalerate calcium.
A suspension of one mole of phenyl-4 'phenyl-4 acid iso-valer oxo-4 is neutralized with sodium hydroxide N, then treats the solution with a stoichiometric amount of hydrate of calcium chloride in aqueous solution. Calcium salt precipitate and recover quantitatively by filtration the formula product:

C - CH2 - CH - C02 ¦ Ca2 ol H 3 Preparation of sorting (phenyl-4 'phenyl) -4 oxo-4 isovalerate aluminum _ A suspension of one mole of 4-phenyl-4-phenyl acid;
isovaleric oxo-4 is neutralized by sodium hydroxide N. At this solution is added ~ e dropwise an aqueous solution alum nitrate stoichiometric; um. Aluminum salt precipitate and recover quantitatively by filtration the formula product:

C ~ CH2 ~ 1 ~ ~ C2 A13 EXPERIMENTATIONS:
The previously described chemical compounds have subject to experiments in order to determine their properties pharmacological studies and the possibilities of application in therapeutic.

... ... ...

lQg7684. . .

A) Toxicology;
Acute toxicity was sought in mice by orally and the lethal dose 50 was calculated according to the method of Miller and Tainter. It is greater than 300 mg / kg for F 1550 and F 1594.
B) Pharmacodynamics:
It has been demonstrated analgesic properties higher than those of acetyl salicylic acid vis-~ -vis du; ~
writhing test 3 phenyl benzoquinone; effective doses lO decreasing by 50% the number of contortions are: -DE50 Products F 1550 50 mg / kg -F 1594 40 mg / kg Acetyl salicylic acid 80 mg / kg anti-inflammatory properties, revealed by the edema caused by injection of carragenin in the paw rat. The products have been administered orally in .
suspension in the tween-water mixture, 1 hour before the experiment mentation.
Doses reducing the volume of the leg by 50% are respectively: .
for F 1594 ED50 - 25 mg / kg F 1550 ED50 ~ 22.5 mg / kg.
With regard to abscess to carrageenan, the doses decreasing the weight of the abscess by 30% are 7 mg / kg for the;
F 1594 and F 1550. On the erythemes provoked by the ultraviolet rays, the effective dose 50 is 4 mg / kg -for the F 1550 for example. Intravenous 3 dose 10 mg / kg, the reduction of edema on the rat's paw is 60% for the F 1550 and 75% for the F 1594. The results 109768 ~ a obtained on granulomas with cotton pellets according to the technology pic of R. Meier, Schuler and Desaulles, Experientia, 1950, 6, 469, make it possible to highlight a net reduction in granuloma weight from 10 mg / kg per day. The results tats are read after 5 days and no changes is observed, compared to the witnesses, with regard to the weight development, the weight of the spleen, thymus and adrenal capsules. On polyarthritis caused by the adju-of Freund in rats according to: BB Newbould - Brit. J.
Pharmacol. Chemother. 1963, 21, 127 - Polyarthritis ~ adjuvant of Freund in the rat, the results obtained appear in the table below and are expressed compared to the witnesses pathological. ``

Reduction of biochemical dosages Doses' arthritis at the end of e:: perience Products Journa- primary secondary speed fibri-lieres I
in mg / kg inject. inject ~. ti ~ nogene ~ -C) Tolerance:
Several tests have been carried out with a view to deter-undermine the good tolerance of the chemical compounds subject to the invention. The gastric tolerance determined in rats has fasting (200 mg / kg daily for 5 days) or according to the constraint shows an ulceration index less than or equal to . . -. .- -.

10 ~ 7684 that of control rats, the products F 1550 or F 1594 are very significantly less ulcerogenic than acetyl salicylic acid. The subacute toxicity in rats for 3 weeks at doses of 10 mg / kg per day did not cause death for 20 animals treated, no difference compared to the witnesses in as regards the weight development, the liver, the kidneys, the thymus, adrenal glands, ulceration index, total proteins, urea and alkaline phosphatases. To the dose of 300 mg / kg for 21 days, the same parameters have have been reviewed and are without notable modifications; in some case only we noticed a slight uricemia without apparent renal involvement. This tolerance is much higher to that of known anti-inflammatories.
D) Human clinical trials have been carried out. They have confirmed the perfect tolerance of the new principles active and positive results in the treatment of ruma-inflammatory forms, low back pain, trauma to the device locomotor. In the context of clinical trials carried out in particularly in rheumatology and trauma, the compounds were used either in the acid state or in the salt state pharmaceutically acceptable (sodium salt, potassium, calcium, aluminum, lithium, arginine, piperazine, dimethyl amino ethanol, etc.). They were administered by the way oral in the form of tablets, capsules or granules doses of 50 al, 000 mg per unit ~. Other forms can be used for general administration and for applications local tions.
For information and not limitation are given some formulas of pharmaceutical preparations containing compounds subject of the invention alone or in combination with other active ingredients useful in the complete treatment of the condition ~ treat:

-. . ., -. -10 "7684 1) Dandruff tablets:
F 1594 l00 mg Excipient qspl compresses 2) Suppositories:
F 1550 200 mg N- bromide:
butylhyoscinelO mg Excipient qsp1 suppository of 2 9

3) Cream:

M ~ phenesine 10 9 Excipient qsp100 9

4) _mprimes:
F 1550 Ca salt 300 mg Meprobamate 250 mg Excipient qs 1 tablet

5) Injectable solution:
F 1550 sodium salt 30 mg Water for preparation injectable 2 ml

6) Capsules:
F 1594 aluminum salt minimum 200 mg Excipient qs

Claims (15)

The embodiments of the invention about which an exclusive right of property or privilege is claimed, are defined as follows: 1. Process for the production of y aryl y oxo acids isovalerics of the general formula:

in which X is a hydrogen or halogen radical characteristic laughed at in that a selective hydrogenation of the methylene group in the presence of a catalyst, products of formula:

as well as the therapeutically acceptable salts of these acids with mineral or organic bases. 2. Method according to claim 1, characterized in what the catalyst uses is palladium on carbon. 3. Method according to claim 1, characterized in what the catalyst uses is Raney nickel. 4. Method according to claim 1, characterized in what the catalyst uses is platinum oxide. 5. Method according to claim 1, in which X
is chloro and the product obtained is orthochlorophenyl-4 '4-phenyl oxo-4 isovaleric. 6. The method of claim 1, wherein X is hydrogen and the product obtained is phenyl-4 'acid 4-phenyl iso-valeric 4-oxo. 7. The method of claim 6, wherein the acid obtained is reacted with sodium hydroxide and obtains 4-phenyl-4-phenyl-4-oxo-isovalerate sodium. 8. The method of claim 6, wherein react the sodium salt with the chloride hydrate of calcium and 4 (phenyl-phenyl) -4 oxo-4 is obtained calcium isovalerate. 9. The method of claim 6, wherein react the sodium salt with aluminum nitrate and one obtains the tri (4-phenylphenyl) -4 oxo-4 isovalerate aluminum. 10. Isaryl y aryl y oxo acids of general formula:

in which X is a hydrogen or halogen radical, when prepared by the process of claim 1 or by a process equivalent chemical. 11. Orthochlorophenyl-4 'phenyl-4 oxo-4 acid isovaleric, when prepared by the process of the claim cation 5 or by an equivalent chemical process. 12. 4-phenyl-4 'phenyl-4-oxo-isovaleic acid, when prepared by the process of claim 6 or by a equivalent chemical process. 13. 4-phenyl-4-phenyl-4-oxo-isovalerate sodium, when prepared by the process of claim 7 or by an equivalent chemical process. 14. The di (phenyl-4 'phenyl) -4 oxo-4 isovalerate calcium, when prepared by the process of claim 8 or by an equivalent chemical process. 15. Sorting (4-phenylphenyl) -4 oxo-4 isovalerate aluminum, when prepared by the process of claim 9 or by an equivalent chemical process.