US3607881A - Phenylbutazone derivatives - Google Patents

Phenylbutazone derivatives Download PDF

Info

Publication number
US3607881A
US3607881A US734528A US3607881DA US3607881A US 3607881 A US3607881 A US 3607881A US 734528 A US734528 A US 734528A US 3607881D A US3607881D A US 3607881DA US 3607881 A US3607881 A US 3607881A
Authority
US
United States
Prior art keywords
phenylbutazone
compounds
trimethoxybenzoate
percent
grams
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US734528A
Other languages
English (en)
Inventor
Miguel Izquierdo
Pedro Gomis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratorios Hosbon SA
Original Assignee
Laboratorios Hosbon SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Laboratorios Hosbon SA filed Critical Laboratorios Hosbon SA
Application granted granted Critical
Publication of US3607881A publication Critical patent/US3607881A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/28—Two oxygen or sulfur atoms
    • C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
    • C07D231/32—Oxygen atoms

Definitions

  • 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.
  • the present invention does provide a series of compounds with these advantageous properties.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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 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.
  • 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.
  • Acute Toxicity The LD by the oral method, expressed in mg./kg. for rats and mice, is as follows:
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US734528A 1967-06-06 1968-05-05 Phenylbutazone derivatives Expired - Lifetime US3607881A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR109213A FR6505M (en:Method) 1967-06-06 1967-06-06

Publications (1)

Publication Number Publication Date
US3607881A true US3607881A (en) 1971-09-21

Family

ID=8632382

Family Applications (1)

Application Number Title Priority Date Filing Date
US734528A Expired - Lifetime US3607881A (en) 1967-06-06 1968-05-05 Phenylbutazone derivatives

Country Status (10)

Country Link
US (1) US3607881A (en:Method)
BE (1) BE716160A (en:Method)
CH (1) CH476734A (en:Method)
DE (1) DE1767702A1 (en:Method)
DK (1) DK120491B (en:Method)
ES (1) ES353634A1 (en:Method)
FR (1) FR6505M (en:Method)
GB (1) GB1223875A (en:Method)
SE (1) SE361885B (en:Method)
SU (1) SU489325A3 (en:Method)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4117232A (en) * 1976-03-08 1978-09-26 Interx Research Corporation Transient pro-drug forms of phenylbutazone
FR2392979A1 (fr) * 1977-06-02 1978-12-29 Sterwin Ag Esters pharmacologiquement actifs de l'acide 2-acetoxy-benzoique avec des derives 4-alcoxyl-3,5-dioxo-pyrazolidine, procedes pour leur preparation et intermediaires utiles dans ces procedes
US5098477A (en) * 1988-12-14 1992-03-24 Ciba-Geigy Corporation Inks, particularly for ink printing

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4117232A (en) * 1976-03-08 1978-09-26 Interx Research Corporation Transient pro-drug forms of phenylbutazone
FR2392979A1 (fr) * 1977-06-02 1978-12-29 Sterwin Ag Esters pharmacologiquement actifs de l'acide 2-acetoxy-benzoique avec des derives 4-alcoxyl-3,5-dioxo-pyrazolidine, procedes pour leur preparation et intermediaires utiles dans ces procedes
US5098477A (en) * 1988-12-14 1992-03-24 Ciba-Geigy Corporation Inks, particularly for ink printing
US5686633A (en) * 1988-12-14 1997-11-11 Ciba Specialty Chemicals Corporation Inks, particularly for ink jet printing

Also Published As

Publication number Publication date
DK120491B (da) 1971-06-07
GB1223875A (en) 1971-03-03
SU489325A3 (ru) 1975-10-25
BE716160A (en:Method) 1968-11-04
SE361885B (en:Method) 1973-11-19
ES353634A1 (es) 1969-10-16
FR6505M (en:Method) 1968-12-02
DE1767702A1 (de) 1970-01-02
CH476734A (fr) 1969-08-15

Similar Documents

Publication Publication Date Title
US3505349A (en) 2-nitro-imidazolyl-1-acetamides
US2944061A (en) Acyl derivatives and process
US3349088A (en) Therapeutically valuable 1, 2-dihyro-1, 2, 4-benzotriazine derivatives and process for preparation thereof
US4031243A (en) 2-(4-Isobutyl phenyl)butyric acid, salts thereof, and pharmaceutical compositions containing the same
US3649679A (en) Substituted phenylalkanoic acid derivatives ii
US3957850A (en) Phenylacetic acid derivatives
IL23152A (en) Alkanoic acids are converted by aryl groups
US3249624A (en) Nu-beta, gamma-dihydroxy and diacetoxy-2, 4-dinitropyrroles
US3489793A (en) New benzamido butyric acid derivatives
US3607881A (en) Phenylbutazone derivatives
US3772319A (en) 5-amino-4-carboxamido-2-arylimidazoles
US4173577A (en) Phenylacetohydroxamic acids
US3812109A (en) Substituted indenyl glucoronide esters
US3976673A (en) 4-Cyclopropylmethyleneoxy-3-chlorophenylacetic acid and salts thereof
US3876800A (en) Pharmaceutical compositions and methods for treating inflammation and pain
FR2567520A1 (fr) Nouvelles phenyl-naphthyridines, leur procede de preparation, medicaments les contenant, notamment anti-ulceres
US3150047A (en) 4-[2'-(beta-dimethylaminoethoxycarbonyl)-phenylamino]-7-chloro-quinoline and its acidaddition salts
US3658989A (en) Antibacterial composition containing tetracycline sulfamate and derivatives thereof
US3290213A (en) Antibacterial nitrofurfurylidene derivatives and methods of using same
DK155936B (da) Analogifremgangsmaade til fremstilling af 2-amino-3-(halogenbenzoyl)-methylphenyleddikesyrer eller alkylestere eller metalsalte deraf
US4159986A (en) Novel thiophene-acetic acids
US4333951A (en) 2-Amino-6-biphenylacetic acids
US3313699A (en) Compositions for and method of treating the central nervous system
JPS6033373B2 (ja) １−ナフチル酢酸誘導体、その製造法ならびに１−ナフチル酢酸誘導体を含有する薬剤
US3637826A (en) Tetracycline derivative