Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3607881 A
Publication typeGrant
Publication dateSep 21, 1971
Filing dateMay 5, 1968
Priority dateJun 6, 1967
Also published asDE1767702A1
Publication numberUS 3607881 A, US 3607881A, US-A-3607881, US3607881 A, US3607881A
InventorsMiguel Izquierdo, Pedro Gomis
Original AssigneeHosbon Sa Lab
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Phenylbutazone derivatives
US 3607881 A
Images(4)
Previous page
Next page
Description  (OCR text may contain errors)

United States Patent [72] Inventors Miguel lzquierdo;

Pedro Gomis, both of Barcelona, Spain [21] Appl. No. 734,528

[22] Filed June 5, 1968 [45] Patented Sept. 21, 1971 [73 I Assignee Laboratorios Hosbon S.A.

Barcelona, Spain [32] Priority June 6, 1967 [33 1 France [54] PHENYLBUTAZONE DERIVATIVES 2 Claims, No Drawings [52] U.S. Cl 260/310 A, 424/273 [51 Int. Cl C07d 49/04 [50] Field of Search 260/310, 310 A, 31 l [56] References Cited UNITED STATES PATENTS 2,562,830 7/195] Stenzl 260/310A 2,905,694 9/1959 Pinson 260/3 10 3,123,616 3/1964 Mayer et al .1 260/310A OTHER REFERENCES Chemical Abstracts Vol. 68, Subject lndex (P- Z) Page 3I93S(1968)QDI.A51

Klosa German Application 1,200,309, 9/1965 (l2p-8/l0) (3 page spec.) 260 3 l0 Sala et al., Chemical Abstracts Vol. 68, Abstract 9575lm (May 20,1968)QD1.A51

Primary ExaminerNatalie Trousof Attorney-Craig, Antonelli and Hill desired pyrazolone derivative.

PHENYLBUTAZONE DERIVATIVES The present invention relates to new phenylbutazone derivatives. More particularly, it relates to antiinflammatory medicaments or drugs having beneficial therapeutic effects and a reduced toxicity. Even more particularly, the invention relates to orally, rectally or parenterally administrable pharmaceuticals having as the active ingredient novel phenylbutazone derivatives which display antiinflammatory, analgesic and antipyretic properties while maintaining a low toxicity and good tolerance.

The pharmaceutical industry is constantly seeking chemical derivatives which have beneficial therapeutic properties while at the same time being compounds of low toxicity which can be well tolerated. Such derivatives are difficult to provide. However, the present invention does provide a series of compounds with these advantageous properties.

Accordingly, one of the objects of the present invention is to provide a new series of phenylbutazone derivatives which avoid the disadvantages of the prior art.

Another object of the present invention is to provide a process for the preparation of useful phenylbutazone derivatives which may be carried out in an effective and advantageous manner.

Still another object of the present invention is to provide pharmaceutical compositions comprising phenylbutazone derivatives which have an excellent tolerance and a reduced toxicity.

A further object of the invention is to provide antiinflammatory. analgesic and antipyretic pharmaceuticals of low toxicity and good tolerance.

Yet another object of the present invention is the provision of the administration of the novel phenylbutazone derivatives described herein by various routes to achieve excellent therapeutic eifects.

These and other objects and advantages of the present invention will become apparent to those skilled in the art from a consideration of the following specification and claims In accordance with the present invention, it has been found that pharmaceutical compositions having an antiinflammatory action can be obtained utilizing compounds having the general formula:

OCH;

wherein R is a butyl or 3-oxobutyl group. These compounds are thus enolic esters formed either from trimethylgallic acid or 3, 4, S-trimethoxybenzoic acid with the following two antiinflammatory compounds having a pyrazolone nucleus: 4- butyl-l, 2-diphenylpyrazolidine-3, S-dione or phenylbotazone and 4-( 3-oxobutyl)-l, 2-diphenylpyrazolidine-3, 5-dione or 'yketophenylbutazone.

In both cases, the therapeutic effects of these substances are integrally preserved while their toxicity is reduced. which is not attained by simply admixing them with 3. 4, S-trimethoxybenzoic acid Accordingly, a better tolerance is achieved in prolonged treatments, particularly in chronic rheumatic syndromes.

The compounds of the present invention may be prepared by reacting an alkaline enolate of the desired pyrazolone compound with 3, 4, S-trimethoxybenzoyl chloride (and this enolate may be prepared in situ by neutralization with alkaline hydroxides) in a solution mixed in water and in a solvent havmg an average polarity at a temperature between ambient temperature and 40 C. while stirring continually during the reaction. The resultant product is thereafter isolated by filtering, washed and dried at a temperature of from about 40 to 60 C. at either normal or reduced pressure.

Another method of preparing the compounds of the present invention involves reacting 4-butyl-l, 2diphenylpyrazolidine- 3, S-dione, or its 4-(3-oxobutyl) derivative, in a slightly polar solvent such as chloroform with 3, 4, S-trimethoxybenzoyl chloride, either in the free form or in solution, in a solvent having the same characteristics described above (which may or may not be the same solvent) in the presence of a tertiary organic base, such as pyridine or triethylamine. The reaction is normally effected at the boiling temperature of the solvent during a period of time varying from 30 to 120 minutes according to the particular case. The products are isolated by washing the reaction liquid with aqueous solutions of mineral acids, and the solvent is eliminated at either normal or reduced pressure after having been dehydrated by means of a suitable agent, such as sodium sulfate or magnesium sulfate.

In the two processes described hereinabove, the ratio of acyl chloride and pyrazolone derivative is 1:1 or slightly higher, for example, 1 10:1 or b 1.05:1. The amount of amine utilized in the second process is normally in excess. Irrespective of whether the first or the second process is employed, the products may thereafter be subjected, if necessary, to a purification which consists in washing them with very slightly polar solvents (such as petroleum ether or hexane) or recrystallizing them in solvent mixtures, for example, a mixture of acetone and water or a mixture of acetone and petroleum ether.

The following examples are given merely as illustrative of the present invention and are not to be considered as limiting. Unless otherwise noted, the percentages therein and throughout the application are by weight.

EXAMPLE 1 Added to a solution of 6 l68 grams (0.02 mole) of 4-butyll, 2-cliphenylpyrazolidine-3, 5-dione in 20 cc. of l N sodium hydroxide and 20-30 cc. of acetone, dropwise and while stirring within a time of 10 minutes, is a solution of 4.77 grams (0.0205 mole) of 3. 4, S-trimethoxybenzoyl chloride in 20 cc. of acetone. The reaction mixture has a temperature of 2025 C. After the addition is completed, stirring is continued for 1 hour during which a crystalline precipitate is formed. The mixture is then cooled to about 35 C. either while still stirring or while leaving it at rest in a refrigerator.

The crystals which are formed are filtered, washed with 60 percent acetone (3 times with 10 cc. each) and dried in an oven in vacuo at 4050 C Obtained is 8.55 grams (a theoretical yield of percent) of 4-butyl-l, 2-diphenyl-3-(3, 4, S-trimethoxybenzoyloxy)-pyrazolinone in the form of small white crystals. The product is tasteless, odorless, insoluble in water, soluble in alcohols, acetone, chloroform, halogenated solvents and benzene, slightly soluble in ethyl ether and insoluble in petroleum ether and hexane It is insoluble both under cold and under hot conditions in aqueous alkalies, but the product dissolves and saponifies in hydroalcoholic solutions of alkaline hydroxides present in excess amount. When the solution obtained is acidified by means of mineral acids, 4- butyl-l, 2-diphenylpyrazolidine-3, S-dione and 3, 4, 5- trimethoxybenzoic acid are isolated, proving that an ester is formed between the two reactants in question.

The resultant ester has a melting point of 1 15-1 16 C. (Kofler) (acetonezwater). The infrared spectrum (KBr pastille) has the typical band at 5.72p., which characterizes the C=O of the enolic ester, and bands at 6.311. and 7 72;; present in any trimethoxybenzoic ester The ultraviolet spectrum shows a maximum of 278.5mp. (E ,""'=507 in alcohol) and in alkaline alcohol it has a maximum of 258mp..

Upon saponification with excess alcoholic KOl-l and titration with HCl, the following contents are found on different samples: 99.68 percent, 99.3 percent, 98.85 percent EXAMPLEZ 32. 24 grams (0.1 mole) of l, 2-diphenyl-4-(3oxobutyl)- pyrozolidine-3, S-dione is dissolved while stirring in 100 cc. of l N sodium hydroxide. Added to this alkaline enolate solution of the pyrazolone compound is 135 cc. of acetone, and added to the mixture thus obtained, dropwise and while stirring, is a solution of 23.87 grams (1.035 moles) of 3, 4, S-trimethoxybenzoyl chloride in 100 cc. of acetone. The reaction mixture is at ambient temperature. After the addition is completed and while stirring is continued, the liquid obtained is heated to 35 -40 C. and held at that temperature for 15 minutes. Then it is allowed to cool again to ambient temperature while stirring is continued, whereby the ester precipitates. The latter is finally caused to crystallize in the refrigerator.

Obtained is 41.9 grams (a theoretical yield of 81.5 percent) of 1, 2-diphenyl-4-(3-oxobutyl)-3-(3, 4, S-trimethoxybenzoyloxy)-pyrazolinone, a white, crystalline, odorless and tasteless powder. It has a melting point of 135-138 C. (Kofler) (acetone:water) and solubility characteristics very similar to those of the compound obtained according to example l.

The infrared spectrum shows bands at 5.72, 6.3 and 7.72,.L, as has already been mentioned for the compound described hereinabove. The E "=S03.5 at 279 mp.(95 percent alcohol). Obtained by saponification and acidification in a manner similar to example 1 are l, 2-diphenyl-4-(3-oxobutyl)- pyrozolidine-3, S-dione and trimethylgallic acid. The following contents are found upon saponification and acid titration: 99.1 percent, 98.8 percent.

EXAMPLE 3 Added to a solution of 6.168 grams (0.02 mole) of 4-butyl- 1, 2-diphenylpyrazolidine-3, S-dione and of 3.04 grams (0.03 mole) of triethylamine in 30 cc. of very pure chloroform, dropwise and within minutes while stirring, is 4.84 grams (0.021 mole) of 3, 4, S-trimethoxybenzoyl chloride dissolved in cc. of very pure chloroform. Stirring is continued for to minutes at ambient temperature, and, thereafter, heating is effected to the boiling temperature of the mixture while maintaining it at reflux for 30 minutes.

The cooled solution is washed withSO cc of 2 N HCl (2 times of 25 cc.) and with distilled water (3 times of 20 cc.). The solution is thereafter dried on anhydrous sodium sulfate and filtered. The solvent is eliminated at reduced pressure. Then, recrystallization is carried out by means of a mixture of ethyl ether and petroleum ether, and the crystals obtained are washed with ethyl ether and with petroleum ether. Obtained by drying at reduced pressure is 8.05 grams (a theoretical yield of percent) of the same trimethoxybenzoic ester of 4- butyl-l, 2-diphenylpyrazolidine-3, 5-dione that was obtained in example 1.

EXAMPLE 4 By means of a process identical to that described in example 3, and starting from 6.45 grams (0.02 mole) of 1. Z-diphenyl- 4-(3-oxobutyl)-pyrazolidine-3, S-dione and from 4.84 grams (0.021 mole) of 3, 4, S-trimethoxybenzoyl chloride, 8.53 grams (a theoretical yield of 82.7 percent of 1. 2-dipheny1-4- (3-oxobutyl)-33, 4, S-trimethoxybenzoyloxy)-pyrazolinone is obtained. This compound has the same characteristics as the product of example 2.

The products obtained by either one or the other of the procedures described in the preceding examples may be purified in the manner set forth hereinabove, according to the degree of purity with which they are respectively obtained each time.

Given hereinafter strictly by way of illustration and in a nonlimitative manner are the results of toxicological and pharmacological tests which were carried out on compositions containing as the active constituent the aforementioned compounds.

1. Acute Toxicity The LD by the oral method, expressed in mg./kg. for rats and mice, is as follows:

Rat Mouse phenylbutazone trimethoxybenzoate 1,700 980 'y-kclo-pheynlbutazone trimethoxybenzoale 1,620 890 phenylbutazone 1,000 680 The 1.D,, of a mixture of trimethoxybenzoic acid and phenylbutazone or y-keto-phenylbutazone has also been determined; the result is approximately the sarne as for phenylbu- 'tazone or y-keto-phenylbutazone. It may thus be deduced therefrom that the trimethoxybenzoates mentioned above are actually less toxic than the simple mixtures of trimethoxybenzoic acid and phenylbutazone or 'y-keto-phenylbutazone 2. Chronic Toxicity The equivalent in phenylbutazone of 0.04 percent was administered to groups of 12 rabbits in their daily food intake for a period of 6 months, during which the quantity of ingested food, the weight curve and, periodically, the hemogram were checked.

During this period of time, no modifications in the weight of the animals, the quantity of ingested nourishment, or in the hematic constants studied were observed. At the end of the experiment, an anatomical-pathological and histological study of the viscera of the animals treated was carried out; no modifications were observed.

3. Antiphlogistic Activity This activity has been rendered evident by the method of plethysmornetry of the paw of the rat after injection of carrageen and by treating the animals with different doses of the substances to be studied. The findings were made 5 hours after the administration of the product in doses of 50 and mgJkg.

The inhibition percentages of the edema thus produced with regard to the sample group are indicated in table 1.

TABLE 1 50 mgJkg. 100 mgJkg I) phenylbutazone 33.4% 42.51 (2) 'y-keto-phenylbutazone 34.391- 40% (3) phenylbutazone trimethoxybenzoate 35.2% 45.8% (4) 'y-keto-pl'ienylbutazone trlmethoxybenzoaie 35% 39.1%

4. Analgesic Activity This activity has been determined by the method which con sists in measuring the time relative to the response to the cu taneous thermalstimulation of the rat on a heated plate.

Table 11 indicates the extension of the latency period, expressed in percentage (reflex of licking the front paws).

TABLE [I phenylbutazone 'y-keto-phenylbutazone phenylbutazone trimethoxybenzoate 'y-keto-phenylbulazone trimethoxybenzoaie 47.4 percent 46.2 percent 46.9 percent 5 6.2 percent Doses bf 400-800 mg. (expressed as the equivalent of phenylbutazone) were administered to the patients orally or rectally, in dragees of 100 and 200 mg. or in the form of sup positories of 250 mg. for a period of time of between 4 days and 2 months, the doses being spaced by 8 or 12 hours.

The patients were divided into two groups. The first group of 39 was treated with phenylbutazone trimethoxybenzoate, and the second group of 26 was treated with y-keto-phenylbutazone trimethoxybenzoate. In all the cases observed, a good tolerance to the medication was observed without symptoms of inflammation of the gastric or rectal mucous. The highest doses were administered orally at the beginning of the treatment, and the rectal administration as well as a lower posology were reserved for periods of support in chronic syndromes.

The clinical results are good. No changes in the blood are found in the hemograms carried out periodically. Also, a rapid reduction of the tumefaction in the joints or inflamed zones, a decrease of the pain and of the other symptoms of phlogosis several hours after the beginning of the treatment are observed.

7. Formulations Four nonlimitative pharmaceutical formulations of the medicine proposed by the present invention are given hereinbelow for purposes of illustration.

Phenylbutaeone Trimethoxybenzoate Suppositories phenylbutazone trimethoxybenzoate I63 mg. excipieiit (Massafsrzarinuin B) quantity sufficient for l suppository phenylbutazone trimethoxybenzoate 408 mg. cxcipient (Mam: Eslearinum 8). quantity sufi'rcient for l suppository -y-Keto-Phenylbutazone Trimethoxybenzoate The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications are intended to be included within the scope of the following claims.

We claim:

1. 4-Butyl-1, 2-diphenyl-3-(3, 4, 5-trimethoxybenzoyloxy)- pyrazolinone.

2. l, 2-Diphenyl-4-(3-oxo-butyl)-3-(3, 4, S-trimethoxybenzoyloxy)-pyrazolinone.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4117232 *Mar 14, 1977Sep 26, 1978Interx Research CorporationTransient pro-drug forms of phenylbutazone
US5098477 *Dec 8, 1989Mar 24, 1992Ciba-Geigy CorporationAromatic ether derivatives as light stabilizers for organic materials
US5686633 *Dec 31, 1991Nov 11, 1997Ciba Specialty Chemicals CorporationInks, particularly for ink jet printing
Classifications
U.S. Classification548/367.1, 514/916
International ClassificationC07D231/22, C07D231/32
Cooperative ClassificationC07D231/32, Y10S514/916
European ClassificationC07D231/32