[go: up one dir, main page]

IL41146A - Derivatives of pyrroleacetic acids salts thereof and process for their preparation - Google Patents

Derivatives of pyrroleacetic acids salts thereof and process for their preparation

Info

Publication number
IL41146A
IL41146A IL41146A IL4114672A IL41146A IL 41146 A IL41146 A IL 41146A IL 41146 A IL41146 A IL 41146A IL 4114672 A IL4114672 A IL 4114672A IL 41146 A IL41146 A IL 41146A
Authority
IL
Israel
Prior art keywords
acid
chlorophenyl
dimethyl
salt
derivative
Prior art date
Application number
IL41146A
Original Assignee
Continental Pharma
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
Priority claimed from BE777207A external-priority patent/BE777207A/en
Priority claimed from BE785274A external-priority patent/BE785274R/en
Application filed by Continental Pharma filed Critical Continental Pharma
Publication of IL41146A publication Critical patent/IL41146A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Description

Derivatives of pyrroleacetic acids, salts thereof and their process of preparation This invention relates "s to new deri at ves of pyrroleacetic acids having the general formula (I) given hereinafter and to salts thereof, more particularly salts of alkali and alkaline-earth metals, of amino-alcohols and of amines, as well as to the syntheses and pharmaceutical uses of said derivatives and salts.
Said- formula I is as follows : wherein Ri is phenyl substituted by chlorine^fluorine,methyl o methoxy and R^ i8 hydrogen or "alkyi δί to 4 carbon atoms.
S mila^'^iIQRSSS&S^^ are already known of which the most important are described in the German Offenlegungsschrift 1.923.306 and in W. Herz, J. Org. Chem. 24.» 2°1 (1959) .
For example, the 1- (p-chlorophenyl) -2, 5-diphenylpyrrole- 3-acetic acid is known by said German Offenlegungsschr ift while the following compounds must be considered as known by the publi cation of Herz : -l-phenyl-2, 5-dimethylpyrrole-3-acetic acid. -1 n.butyl-2, 5-dimethylpyrrole-3-acetic acid. -1, 2, 5-trimethyl-3-pyrroleacetic acid.
Said known compounds are found inactive or very poorly active and cannot be considered as valid pharmaceutically products, especially as ant i-inflammatory and analgesic agents. have said acids of formula I by addition of non toxic bases, for example to metal salts, such as sodium, potassium, calcium, magnesium salts, or to salts with an organic base, such as an amino-alcohol or an amine for example.
When in general formula I, an asymmetrical carbon atom is present (R^ different from hydrogen), the enantiomer mixture can be resolved by traditional methods such as fo example formation of diastereoisomer salts with optically active bases, such as brucine, strychnine, quinine, cinchonidine , ephedrine and the like.
The compounds of formula I have excellent analgesic and anti- inflammatory activities which are associated with good antipyretic activity and a low toxicity. Thus, said compounds are an effective means for treatment of associated inflammatory conditions and painful syndromes, such as rheumatoid arthritis. The excellent detected analgesic effect allows to extend the uses to all painful phenomena whatever their origin may be.
The topical application of the compounds of the invention, in case of skin inflammation and. eczema, also allows ί to effectively treat this kind of affection.
Consequently, the present invention also concerns the use of said pyrroleacetic acid, derivatives and of salts thereof, as agents having an analgesic, anti- inflammatory and . antipyretic activity, and pharmaceutical compositions comprising said derivatives, the' latter or salts thereof being used alone having a similar or aiirerent activixy.
The active doses of said products are dependent on the affection treated; however daily dosages of 50 to 3000 mgr for humans can be advantageously used. . .. , The active compounds of the invention can be administrated according to the invention as a pharmaceutical composition, in association with various pharmaceutical excipients orally, parenterally, ectally or topically.
For oral administration, pills, granules, tablets, capsules, solutions, syrups, emulsions and suspensions containing excipients or additives which are usual in galenic pharmacy will be used.
Parenterally, salts of active products could be administrated as an aqueous solution for example.
For rectal administration, suppositories will be used and topically lotions, ointments or pomades can be used.
The active products can be used alone or combined with other active products having a similar or different activity.
Amongst compounds which give interesting results on a pharmaceutical point of view, those compounds of formula I can be mentioned, wherein represents a p-chlorophenyl , or p-bromophenyl , p-fluorophenyl , m-chlorophenylX'lower alkoxy or 2 ' , 3 ' -dimethylphenyl radical,,-?,^ Rn-d oaoh roprooont a- represents hydrogen or a methyl radical, the following compounds having to be more particularly mentioned: - l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid - 1-p-fluorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid '1 p fluorophonyl"2 mothyl 5 phenyl 3 pyrrolGaeetie acid - l-m-chloro hen l-2 5-dimeth l- 3- rroleacetic acid ln-ι m Γ ·■ ■ i l y ~J - 7 - me. L ι vi- 5-p T - jue Liiviphenvi- py T ΓΗΓΠ P P Γ1 - l-p-bromophenyl-2 , 5-dimethyl-3-pyrroleacetic acid - l-(2' ,3'-dimethylphenyl)-2 ,5-dimethyl-3-pyrro eacetic acid - l-p-methoxyphenyl-2 , 5-dimethyl- 3-pyrroleacetic acid wherein R^, } R^ and have the above given meanings and Y represents - CN, -COORc , -CONH. or C (=S) MR R , R, , Rc and Rn 5 t- b o o 6 7 being alkyl radicals of 1 to k ' carbon atoms, Rg and R^ can also form with the nitrogen atom a heterocycle of the piperidine or morpholine type.
This invention also relates to a process for preparing derivatives of formula I and salts of the latter.
This process is characterised in that said derivative of formula I and salts thereof are prepared by hydrolysis from a compound of formula II hereinbefore given. \ According to the invention, said hydrolysis is preferably carried out in an alcoholic or hydroalcoholic solvent at a temperature between room temperature and the reflux temperature of the solvent selected.
(R = lower alkyl), said hydrolysis can the most easily bt? made in the presence of a base, such as sodium or potassium hydroxide, in an alcoholic or hydroalcoholic solvent.
When in formula II, Y. = CONH, or C.( =S )NRCR„ , the derivatives of pyrroleacetic acids can be preferably obtained according to the known reaction of Willgerodt or Willgerodt-Kindler, the last step of which is a hydrolysis in basic or acid medium.
The compounds of general formula II can be easily obtained according to several different ways shortly resumed by the following schemes.
+ Pyr-CH2N(R7>2 — Pyr-CH2 R? ) 2I Pyr-CH2-CN scheme 1 Pyr-CHO Pyr-CH2OH Pyr-CH2X —> Pyr-CH2CN scheme 2 (X = halogen or tosyl) Pyr-CH2CN ·→ Pyr-CH-CN scheme 3 Pyr-CH2CN ~→ Pyr-CH2COORg — Pyr-CH-COORg scheme H R„ R I Pyr-CH2CN Pyr-CH-CN — Pyr-C Pyr-CH-CN scheme 5 I i °" COOC2H5 COOC_Hc c. o According to Scheme 1, a Mannich reaction is «S^?r^ied out on a 1, 2, 5-trisubstituted pyrrole, this being the most easily made by action of formaldehyde and a secondary amine (R^ = lower alkyl or forms with nitrogen, an unsaturated hetero-r. cycle of the piperidine or morpholine type) in a solvent such as ethanol, acetic acid or toluene. The . quaternary salt is the most easily obtained by action of an alkyl halide such as methyl iodide for example, in a solvent, such .as ethanol or acetone. The nitrile is obtained by action of alkali metal cyanide on the quaternary salt . according to a well- known method; this reaction is the most easily made in a solvent such as ' ethanol, isopropanol, dimethylsulfoxide or dimethylformamide at a temperature between 50 and 100° C.
According to Scheme 2, formylation of a 1, 2., 5-trisubstituted pyrrole is very easily made for example by action of dimethylformamide and phosphorus oxychloride in a solvent such as toluene or 1, 2-dichloroethane . The reduction of the aldehyde is made according to usual processes and the most easily by action of an alkali metal hydride such as sodium borohydride for example. The intermediate alcohol can also be obtained by reduction of a pyrrole of the Pyr-COOR type obtain-ed by condensation of a diketone of the R*-C0-CH2-CH- (C00Rg )C0^3 type with an amine R-^NH^ .
According to Scheme 3, the insertion of a R^ radical is the most easily made by treating the nitrile with a basic condensation agent such as sodium, sodium amide, sodium hydroxide, or the sodium hydride by an alkyl halide: R^X (X= halogen) in a solvent such as ammoniac, ether, tetrahy-drofuran, dimethylsulfoxide or dimethylformamide .
According to Scheme 4, the nitrile is transformed into ester by traditional methods;, the insertion of a radical According to Scheme 5, a selective monoalkylatRn . is made by prior carboethoxylation of the nitrile acpording to processes well known in literature.
The starting 1, 2, 5-trisubstituted pyrroles are^ ...... ■ obtained by Knorr-Paal condensation between a V-diketone of H3C- -CH3 ..' the ^-CO-iCI-^^CO^ ^ "type and an amine R^NH^ ; the condensation is very easily made in a solvent such as benzene, toluene or acetic acid.
Other details and features of the present invention, which do not limit the scope of the present invention, are given hereinafter by means of examples of preparation of several compounds of formula I and formula II, by means of pharmacological results of various of said compounds and by means of some formulations for tablets, ampules, suppositories and ointments.
Example 1 l-p-Chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid a) iodomethoxide of l-p-chlorophenyl-2 , 5-dimethyl-3-dimethyl- aminomethylpyrrole To 47 g (0.23 m) of finely ground 1-p-chlorophenyl-2 , 5-dimethylpyrrole , a solution of 47.5 ml of an aqueous solution of 40% dimethylamine , 57.5 ml of acetic acid and 27.5 ml of 35% formaldehyde is slowly added while stirring. The mixture is stirred overnight at room temperature and extraction is made with 2 x 100 ml of ether. To the aqueous phase, 700 m>L of' 20% NaOH are added and extraction is made with ether. The organic phase is dried on MgSO^, filtered and evaporated. To the j residue obtained, 60 ml of absolute ethanol are added, then dropwise while stirring 34.1 g of methyl iodide. The mixture is stirred for 1 hour, then the precipitate obtained is filtered; 85.9 are thus obtained. Yield: 92.5% - MP (melting point) hj i-p-Cniorophenyi-.: , o-dimerhyi-d-pyrroie acetonitriie .
To 166 g (0.41 m) of the preceding product in 600 ml of dimethylsulfoxide , 66.6 g of sodium cyanide are added and the. mixture is heated to 100°C with stirring and under- a- .. nitrogen stream for 3.5 hours. After cooling, the mixture is poured into 1500 ml of water and extracted with ether. The ethereal phase is washed with water, dried on MgSO^ and evaporated.
The residue is vacuum stripped; 62.1 g of a yellow oil are thus obtained, which rapidly solidifies and which is recrystallized from aqueous methanol. Finally 57.4 g of product are obtained. MP (°C): 86-88. BP (boiling point) (°C): 158-161 (0.4 mm) . Yield: 56%.
Centesimal analysis C H N Calculated, % 68.71. 5.35 11.45 Found, % 68.75 5.30 11.15 c) l-p-Chlorophenyl-2 , 5-dimethyl- 3-pyrroleacetic acid •To 64 g of the preceding nitrile, 64 g of K0H and 300 ml of ethanol are added and the mixture is refluxed for 15 hours. The alcohol is evaporated and one dilutes with 300 ml of water. The aqueous phase is washed with ether, then acidified with 20% HC1. The precipitate obtained is filtered and one washes with petroleum ether and a minimum of ether. 58.5 g of product are thus obtained. MP (°C): 99.5-101. Yield:, 85% .
The product can be recrystallized from dxisopropyl ether. MP (°C) 112-114 (form ft ) or from a diethyl ether-pentane mixture* MP (°C): 102-104.5 (form &< ) . · Centesimal analysis C H N Calculated, % 63.75 5.35 5.30 ... · .
Example 2 '": ; . ■' f ' ■■ ■ , l-p-Chlorophenyl-2 , 5-'dimethyl-3-pyrroleacet ic acid a) 1-p- ch1oropheny1-2 , 5 -dimethy1- 3-ace;ty1 yrro1e" , To 9.5. g of 3-acetyl-2 , 5-hexanedione in .50 ml of benzene, '7 ;7 g of p-chloroaniline are added and the mixture is refluxed for 5 hours with azeotropic 'removal of the water forme The excess solvent is evaporated and.' the residue ' is vacuum ^stripped: 12 g of an orange "oil which rapidly crystallises are . thus obtained: DP: 144-1M6°C ( 0.1 mm) . '.Yield : 80% . .
The product can be recrystallized from hexane . MP (°C) : '80-81. ' ,· ■ _ ' .
Centesimal analysis ' · ■ ' '.'. · c ' :, H ■.
Calculated,' % - ;. 67.88 5.70 ' 5.65 Found, % ' .,. ¾ 67.75 " 5.70 5.65 2, 4-dinitrophenylhydrazoae MP (°C) 239-241 CAcOH) k 1- P-c 1propheny. -2 , 5 -dimethy1 - 3-pyrrole c tic aci d To 5 g of the preceding ketone, 0.7 g of sulfur and 2.7 ml of morphol ne are added'and the. mixture is refluxed > for 5 hours. Then, 20 ml of an aqueous solution of 20% K0K are added and the mixture, is refluxed for 4 hours. The mixture is washed with ether, acidified with 20% HC1, then extracted with ether. The organic phase is extracted with a 10% bicarbonate solution which is acidified with 5% HC1.
The solid obtained is 'filtered and recrystallized several time's from a diethyl ether-pentane mixture. 1.1 g of prbduct is thus obtained. MP (°Q: 100-103. Yield: 20% Example 3 l-p-Fluorophenyl-2 , 5-dimethyl- 3-pyrroleacetic acid *>-·-' To 24 g of 1-p-fluorophenyl-2 , 5-dimethyl-3-pyrro.le- acetonitrile in 2Ί0 ml "of ethanol, 24 g of KOH are added and the mixture is refluxed for 6 hours. The solvent is evaporated 400 ml of water are added and extraction is made with 2 x 100 m of ether. The aqueous phase is acidified with 50% HC1. The product obtained is added and recrystallized from a benzene- petroleum ether mixture. 15 g of product are thus obtained.
MP (°C) : 125-127. . .. · . - , , ' , Centesimal analysis ' • C H N Calculated, % 68.00 5.71. 5.66 Found, % 68.10 . 5.75 5.80 Exam l ^4 l-p-Methylpheny 1-2 , 5-dimethyl-3-pyrroleacetic acid To 34 g of 1-p-methyIpheny1-2 , 5-dimethyl- 3-^ pyrroleacetonitrile in 340 ml of ethanol, 34 g of KOH are added and the mixture is refluxed for 7 hours. The. alcohol is evaporated and. one dilutes with 200 ml of water. The aqueous phase is washed with ether, then acidified with 50% HC1. , The product is filtered, dried and recrystallized from an ether- petroleum ether mixture. 24.7 g are thus, obtained. Yield 67% MP (*C) :' 110-112. · ' · Centesimal analysis s " '. , . ·!. ■ C " H N Calculated, % 74.05 7.04 5.76 Found, % ' 73.95 6.95 5.78 The following Tables I and II relate to the preparation, according to the invention of a series of compounds of general formula I.
TABLE I < Centesimal analysis Nr MP (°C) (1 ) Carbon Hydrogen Gale . Fd. Calc. Fd. Cal 69.50 69.30 6.60 6.65 5.4 63.75 63.60 5.35 5.26 5.3 of P) , 3 68.00 68.10 5.71 5.75 5.6 of P) 4 74.05 73.95 7.04 6.95 5.7 of P) m 59.16 59.02 6.52 6.40 8.6 64.90 65.05 5.80 5.80 5.0 m 60.26 60.30 6.84 6.70 8.2 63.75 63.90 5.35 5.40 5.3 of P) 64.87 64.70 5.81 5.75 5.0 Centesimal Nr MP (°C) (1) Carbon Hydrogen Calc. Fd. Calc. Fd. Calc. 10 67.08 66.557.95 7.95 9.20 11 69.48 69.456.61 6.60 5.40 of P) 12 56.40 56.704.39 4.55 4.70 of P) 13 56.40 56.354.40 4.45 4.70 of P) 14 74.00 74.307.00 7.05 5.75 of P) 15 74.70 74.607.45 7.50 5.45 16 64.85 64.655.80 5.75 5.00 17 66.40 66.606.60 6.85 4.80 18 64.85 64.705.80 5.90 5.05 41 Centesimal Analy Carbon Hydrogen Nr MP (°C) (1) Calc. Fd. Calc. Fd. 19 -Br CH3 CH- 128-130 54.56 54.32 4.58 4.62 (Et20-pentane) 20 5.35 21 6.55 22 7.60 23 4.35 24 7.60 25 4.65 26 4.50 Nr. MP (°C) (1) Centesimal a Carbon Hydrogen ~~Fd 0 ) the recrystallisation solvent is given between brackets. (2) melting point of the ethanolamine salt. 1 TABLE II . rne toiiowmg Table ill relates to pharmaceutical results for a series of compounds given in Tables I and II. The numbers of the first column of this Table III correspond to numbers, of the first column of Tables I and II in order t indicate the corresponding compounds.
'C\8 I CO' TABLE III.
Acute toxicity Ant i-inflammatorv .activity Analqesic activity Mouse, orally J" abscess (1) edemas (2) Siegmund (3) Randall LD50 mg/kg' 31 2250 (1406-3600.) :. +++ 0.14 · . - 100 95 (400 1 ++÷ 0.52 25 (13-48 ) 77 (400 .2. 780 (655-928) +++ , ' ' - 1.10 21.5 (15.9-29) 83 (50 3 740 (649-844) +++ 1,20 . 23 (15-34) 54 (50 2850 (2151-3776) . +++ 0.06 . 75 (34-165) · - ' t S3 (100 5 1650 (1320-2063) , 0,72 160 (67-38.4) 138 (40 6 1700 (1308-2210) ' ; +++ . 0, 10 ·. 46.5 (34-63) " . 56 (400 8 .1400 (966-2030) ■ +++ 0,90 49 (29-83) . . 80 (400 ... '., ··. . ' i • ' "'. ' - ' 14 1125 (833-1519) +++ 5 (35-100)' is;·" 1900 (1397-2584) +++'· 53 (34-82) · ■· "' ·· . . ! "19 1350 (1595-1728) +++ 46 (32-67) · ! ■ ' ' carragheenin abscess on rat; Benitz and Hall method; screening method ^simple dose 500 mg/k of weight reduction corresponding to +++ designates a net activity which is then appreciated butazone in' the test of carragheenin edemas carragheenin abscess on rat; the activity expressed with respect to phenylbutazone = 1.
Siegmund test : ED^0 in mg/kg per os on' mouse. . · - Randall and Selitto test : weight increase., of the inflamed paw of the rat; between brackets in mg/kg per os . borne particular examples or pharmaceu ical compflfcsi. tions for tablets, ampules, suppositories and ointments are given hereinafter. 1 - Tablets 250 mg . a) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid Magnesium oxide Avicel pH lOKmicrocrystalline cellulose) b) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid Starch · Lactose Magnesium oxide Gelatin c) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid Primo el (starch sodium glycolate) STA-RX 1500 (pretreated starch) Hydrog. Castor oil Magnesium oxide 2 - Ampules 250 mg a) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid-ethanolamine (acid) Benzyl alcohol Bidistil. water, q.s.ad. b) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid-ethanolamine (acid) p-chlorometacresol Sodium metabisulfite Bidistil. water, q.s.ad. c) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid-Na (acid) Thioglycolic acid Bidistil. water, q.s.ad. a - aupposmones -** a) l-p-chlorophenyl-2 ,5-dimethy1-3- pyrroleacetic acid 250 mg Polyoxyethylene sorbitan monostearate 2050 mg b) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid 250 mg Syndermin GMR (glycerin monoricinoleate) 115 mg Adeps solidus (mixture of mono-, di- and triglycerides of fatty acids) 1935 mg c) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid (acid) 250 mg Aerosdl. simple > j' "■" " 2030 mg Adeps solidus 2020 mg d) l-p-chlorophenyl-2 , 5-dimethyl- 3- pyrroleacetic acid 250 mg Dibucaine HC1 4 mg Adeps solidus 2046 mg . e) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid- a (acid) 250 mg Butylhydroxyanisole 0,4 mg Citric acid 0.2 mg Adeps .solidus 2049.4 mg f) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid-ethanolamine (acid) 250 mg dl- -tocopherol acetate 0.15 mg Adeps solidus 2049.85 mg 4 - Ointments , a) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid 5 g White petrolatum 85 g Lanoline 10 g dl- c -tocopherol acetate 0.075 g b) l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid . 5 g Liquid paraffin 11.25 g P o lene glycol y g Poly^ryethylene sorbltan monostearate 1.62 g Sorbitan monostearate 1.08 g Methyl p-oxybenzoate 0.18 g Propyl p-oxybenzoate .0.02 g dl- O -tocopherol acetate 0.075 g Distil, water 62.775 g c) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid 5.000 g Sodium lauryl sulfate 12.820 g Methyl p-oxybenzoate 0.095 g Glycerin , 9.500 g Distil, water 71.160 g d) l-p-chlorophenyl-2 , 5-dimethyl- 3- pyrroleacetic acid 5.000 g Amphocerin K (mixture of fatty alcohols, waxy esters and greases) 68.600 g Eutanol G (liquid saturated fatty alcohols prevalent in octyldodecanol ) 20.800 g Polyethylene glycol monoricinoleate 5.515 g dl- -tocopherol acetate 0.075 g Citric acid 0.010 g 5 - Gelules' 100 mg a) l-p-chlorophenyl-2 , 5-dimethyl- 3- pyrroleacetic acid 100 mg Lactose 75 mg Magnesium oxide 10 mg b) l-p-chlorophenyl-2 , 5-dimethyl-3- pyrroleacetic acid 100 mg STA-RX 1500 50 mg Magnesium oxide 30 mg c ) l-p-chlorophenyl-2 , 5-dimethyl- 3- pyrroleacetic acid 100 mg Avicel 50 mg TABLE IV.
This table groups the physical characteristics of nitriles which are intermediate products of formul a Ila in the preparation process of compounds of formula I.
The numbers given in the first col umn of said table correspond to those of the same column of table I, so that a compound of table IV, which has the same number as a compound of table I , is an intermediate product in the preparation process of said compound of table I .
Nr. MP or BP (°C) D 2"5 = 1 .5470 1.5670 1.5522 MP or BP (°C) finally, more complete pharmacological resul.ts relating to l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic ac are given hereinafter. 1 - Analgesic activity 1.1. Torsion test with acetic acid on mouse When orally administered 30 minutes before intraperitoneal injection of acetic acid, the 1-p-chlorophen 2 , 5-dimethyl-3-pyrroleacetic acid has an analgesic activity which is equal to that of alclofenac.- Produit ED (mg/kg per os) Slope Maximum obtained and confidence (% - dose) limits 0.95 1-p-chlorophenyl-2 , 5~dimethyl-3-pyrroleacetic acid 21.5(15.9-29) . 1.94 85 (50.) Alclofehac 25.0(16.6-38) ' 5.34 85 (200) Codeine 17.0(11.3-25.5) 3.80. 100 (80) 1.2. Randall and Selitto test The determinat on of painful threshold or response to a pressure exerted on the paw inflamed by intrapedious injection of yeast extract is carried out on Wistar rats. The response obtained after 30 minutes from the oral administration of l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid and of comparison standards is noted. The difference between the mean maximum weight (g) which is tolerated by rats treated and . control rats is given hereinafter 12.5 mg/kg 2.5 mg/kg 50 mg/kg 1-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid 43 60 83 Pentazocine 52 78 117 50 mg/kg 100 mg/kg 200mg/kg Alclofenac 22 47 102 1U mg/kg 1 mg/kg 40½ftg/kg Codeine 38 40 187 (depression of CNS) The . l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic aci reveals to be twice less active'than codeine, substantially equivalent to pentazocine, four times more active than alclofenac and five times more active than aminopyrine (highly significant difference). 2 - Anti-inflammatory activity The activity of the l-p-chlorophenyl-2 , 5-dimethyl- 3-pyrroleacetic acid is not distinguishable from that of. phenylbutazone in this test (activity ratio: 0.78-N.S.) (N.S. = non significant). - 2.2. Paw edema of the rat 2.2.1. Normal rat The activity of the l-p-chlorophenyl-2 , 5-dimethyl- 3-pyrroleacetic acid is compared to that of phenylbutazone in regard to the intrapedious injection/ of carragfeenin .. The 1-p-. chlorophenyl-2 , 5-dimethyl- 3-pyrroleacetic acid when administered per os at dosages of 20, 40 and 80 mg/kg one hour before injectbnof carragjaeenin shows the same activity as. equivalent dosages of ^phenylbutazone . The l-p-chlorophenyl-2 , 5-dimethyl-3-pyrrolea- cetic acid is equal to 1.1 times the phenylbutazone (M.S.). 2.2.2. Suprarenalectomised rat · The activity of l-p-chlorophenyl-2 , 5-dimethyl- 3-pyrroleacetic acid is maintained and remains comparable to that of phenylbutazone. 2.3. Granulomas Cotton pellets are implanted under the back skin of 160 rats. From da 3 to da 6 the rats are treated with 35 ctcid υΐ' llttliyIbu Lct-jUiiC v cr uo). Cit da 7, t e i"ci'L cii'vi kj.. Cd and the granulomas are taken off and dried till constant weight. Under these conditions, the anti-inflammatory activity of 1-p- -. · chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid, is. near to that .,, of phenylbutazone (l-p-chlorophenyl-2 , 5-dimethyl- 3-;pyrroleace,tic acid = 0,73 of phenylbutazone (N.S.). At the dosages tested, the products did not affect the weight of animals. 2.4. Arthritis with Freund adjuvent on rat Polyarthritis are induced on male Wistar rats of '. 400-500-g by intradermic injection, in the . paw root, ; of the Freund adjuvent comprised of a Mycobacterium butyricum (killed) suspension in paraffin oil (0.1 ml containing 0.7 mg of Mycobacterium per rat). 2.4.1. Preventive activity of l-p-chlorophenyl-2 , 5-dimethy - 3-pyrroleacetic acid When the l-p-chlorophenyl-2 , 5-dimethyl-3-pyrrolea-cetic acid is orally administered at dosages of 25 and 50 mg/kg per day, from day 1 to day 20, after intradermic injection of the adjuvent, it is seen that an important protection is exerted by the l-p-chlorophenyl-2 , 5-dimethyl- 3-pyrroleacetic acid in regard to the arthritis severity (see Table).
Treatment n dosage Score (mean/rat + S.E.) Gain of mg/kg/ ~ weight, g _ day day 14 day 17 day 21 + S.E. 12.18 12.89 13.36 -79 + 0,48 + 0.42 + 0.46 ± 1.08 ± 0.92 + 0.93 5.11** 3.78xx 3.00KX -38** + 0.84 + 1.79 + 0.50 Phenylbuta¬ x signir icantly distinct from controls at threshold^ =^T.Ub xx significantly distinct from controls at threshold 0(= 0.01 S.E. = standard error This protection is statistically significant (at threshold θ : 0.01) and is statistically identical with 25 or 50 mg/kg/day of l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid or 50 mg/kg of phenylbutazone. The weight loss remarked for controls is also reduced by the treatment : on this point of view, the differences remarked after treatment with the l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid and with phenylbutazone at the ratio of 50 mg/kg/day are statistically significant ( 0^ :0.01) and identical for both products. 2.4.2. Curative activity of the l-p-chlorophenyl-2 , 5-dimethyl- 3-pyrroleacetic acid When the l-p-chlorophenyl-2 ,5-dimethyl-3-pyrroleace-tic acid is administered per os at a dosage of 25 mg/kg from day 21 after intradermic injection of the adjuvent, it has been ascertained a reduction of the arthritis severity, which is as ~i important as in case of rats treated under the same conditions with 50 mg/kg/day of phenylbutazone. After 3-day treatment, the l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid significantly reduces the arthritis severity (p = 0.001), while no spontaneous significant evolution is noted for controls and while phenylbutazone (50 mg/kg/day ) has no significant effect. After a 15-day administration, the^ l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid (25 mg/kg/day) and phenylbutazone (50 mg/ kg/day) have reduced by half the importance of the arthritis. The l-p-chlorophenyl-2 ,5-dimethyl-3-pyrroleacetic acid is as active as phenylbutazone at a twice lower dosage. On the contrary, phenylbutazone significantly corrects ( {/^ =0.01\ the t s em r ed on c ntrols while the 1- -chloro hen l- connection (see following Table).
Arthritis by adjuvent - curative treatme (mean values + S.E.) Products Dose Scores at days Weight mg/kg gains of 21 _2_1 28. li ££ bod before treat .
Controls - 13.7 14.0 13.0 12.1 11.2 -22.6 + 0.6 + 0.6 + 0.6 + 0.7 + 0.6 + 8.7 1-p-chlo-rophenyl- 2,5-di- * methyl-3-pyrrolea-cetic acid 25 14.5 13.5 11.6 9.5* 6.9XH -19.0 + 0.6 + 0.6 + 0.6 + 0.7 + 1.2 + 5.6 Phenyl-r butazone 50 14.2 13.8 11.2 8.3KK 5.8K¾ +15.3K¾ + 0.7 + 0.9 + 1.1 + 0.8 + 0.9 + 5.0 2· 5. Conclusion of studies of ant i- inflammatory activity' The l-p-chlor'ophenyl-2 , 5-dimethyl-3-pyrroleacetic aci seems to be as active as phenylbutazone in regard to acute inflammations (edema by carragheenin on paw). While it is equivalent to phenylbutazone in the granuloma test with cotton pellets, the l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid is better than phenylbutazone in regard to arthritis by Freund adjuvent, as preventive agent as well as curative agent. The anti-inflammatory activity of l-p-chlorophenyl-2 , 5-dimethyl- 3-pyrroleacetic acid is not modified by suprarenalectomy . 3 - Antipyretic activity The l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid was tested at dosages of 50 and 200 mg/kg on rabbit rendered febrile by intravenous injection of antigonococcus vaccine. A effect-dosage relation is noted; the product reveals as being t. „ , - 1. Influence on cardio-vascular system The daily administration for 3 months to rat (orally) of dosages of 12?5, 25 and 50 mg/kg modifies neither arterial pressure nor cardiac rhythm. 4.2. Influence on central nervous system Search of an eventual tranquillizing power: the l-p-chlorophenyl-2 , 5-G¾ethyl-3-pyrroleacetic acid from a dosage of 50 mg/kg potentiates the sleep time induced by barbiturics. 4.3. Influence on digestive tract The l-p-chlorophenyl-2 , 5-dimethyl-3-pyrroleacetic acid causes no slowing-down of the intestinal transit on mouse till dosages of 100 mg/kg. At 200 mg/kg, there is a tendency to a slowing-down. 5 - Toxicology 5.1. Acute toxicity on oral administration Mice : 780 mg/kg (65-5-928) Rats : 560 mg/kg (439-714) 5.2. Tolerance on oral administration - test of 35 days on rat The l-p-chlorophenyl-2 ,5-dimethyl-3-pyrroleacetic acid when daily administered to rats at dosages of 12.5, 25 and · 50 mg/kg for 2 weeks causes no apparent toxicity sign; the dosage of 100 mg/kg/day seems also to be well tolerated. 5.3. Studies of sub-acute toxicity on oral administration 5.3.1. Test of 3 months on rat Dosages: 12.5; 25; 50 and 100 mg/,kg/day. The daily dosage of 12.5 and 25 mg/kg involves no toxic phenomenon. 5.3.2. Test of 3 months on monkey Dosages: 25; 50; 100 and ^ 100 mg/kg/day. The dosages of 25, 50 and 100 mg/kg/day were perfectly tolerated by animals and induce no toxicity on said species. —,, ; ; „-· - ■ - - . -_ci_ - e. ~ v - ~ Dosages: 25, 50 and 100 mg/kg/day. No embryotoxicity observed; no anomaly was detected on foetus issuing from female rate treated with said doses.

Claims (1)

1. 41146/2 WHAT IS CLAIMED IS: Λ 1· Pyrroleacetlo acids and salts of alkaline metals, alkalino-earth metals, amino-alcohols and amines of said acids the latter being represented by the formula wherein R^ represents a phenyl radical substituted by chlorine ^bromine fluo ine$ methyl or methoxy* R being hydrogen or an alkyl radical (C^-C^) and pharmaceutically acceptable salts thereof* 2« A salt of a derivative of pyrroleacetlo acid as claimed In claim 1* wherein said salt Is an alkali metal, alkaline earth metal, amino alcohol or amine salt* 3· l»(p-chlorophenyl)-2,5-dimethylpyrrole-*3-acetic acid. 4» A process for preparing a derivative of pyrroleaoetic acid as claimed In claim 1 or a salt thereof, which process comprises hydrolyslng a in which ¾ and ¾, are as defined In claim 1 and Y repreeente -CN, -COORj., -CONHg or being alkyl radicals of 1 to 4 carbon toms, while ^ and R^ can also form with the nitrogen atom a heterooyole of the kind piperidine or morpholine* 41146/2 5, A process as claimed in claim 4 wherein the compound ^ ο formula II Is subjected to hydrolysis In an alcoholic or aqueous alcoholic solvent at a temperature between room temperature and the reflu temperature of the solvent used* 6· A process as claimed in claim 4 or 5 wherein the starting compound of formula II is a derivative of pyrrole acetonltrile wherein Y =» -CN. 7· A derivative of pyrroleacetio acid as claimed in claim 1 or a salt thereof whenever prepared in a process as claimed in any one of claims 4 to 6« 3* A derivative of pyrroleacetio acid as claimed in claim 1 and hereinbefore specifically described or a salt thereof* 9· A pharmaceutical composition which comprises one or more active ingredients selected from a derivative of pyrroleacetio acid or a salt thereof as claimed In claim 1, 10. A pharmaceutical composition as claimed in claim 9 which composition also comprises one or more other therapeutic agents* P.O. Box 33116, TEL-AVIV, ISRAEL ·»4β**
IL41146A 1971-12-23 1972-12-22 Derivatives of pyrroleacetic acids salts thereof and process for their preparation IL41146A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BE777207A BE777207A (en) 1971-12-23 1971-12-23 3-pyrroleacetic acids - analgesics, antipyretics antiinflammatories prepd by hydrolysis of the corresp acid deriv
BE785274A BE785274R (en) 1972-06-22 1972-06-22 Pyrrole-3-acetic acids - useful as antiinflammatory analgesic and anti pyretic agents

Publications (1)

Publication Number Publication Date
IL41146A true IL41146A (en) 1977-03-31

Family

ID=25656964

Family Applications (1)

Application Number Title Priority Date Filing Date
IL41146A IL41146A (en) 1971-12-23 1972-12-22 Derivatives of pyrroleacetic acids salts thereof and process for their preparation

Country Status (19)

Country Link
JP (1) JPS5318507B2 (en)
AR (1) AR208494A1 (en)
AT (1) AT323727B (en)
AU (1) AU467602B2 (en)
CA (1) CA991193A (en)
CH (1) CH563364A5 (en)
DD (1) DD104976A5 (en)
DE (1) DE2261965A1 (en)
DK (1) DK134599B (en)
ES (1) ES409944A1 (en)
FR (1) FR2164857B1 (en)
GB (1) GB1406330A (en)
HU (1) HU165900B (en)
IE (1) IE37237B1 (en)
IL (1) IL41146A (en)
NL (1) NL7217521A (en)
OA (1) OA04523A (en)
PL (1) PL89071B1 (en)
SE (1) SE388853B (en)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2645234A1 (en) * 1976-10-07 1978-04-20 Basf Ag 2,5-DIALKOXY-3-AMINO-METHYLTETRAHYDROFURANS AND THE METHOD FOR THEIR PRODUCTION
US4248784A (en) * 1977-02-25 1981-02-03 Sterling Drug Inc. Pyrrole-3-acetamides
DE3026402A1 (en) * 1980-07-11 1982-02-04 Syntex Corp., Palo Alto, Calif. Non-steroidal antiinflammatory agents - for treatment of micro:vascular disease, e.g. diabetic retinopathy or diabetic nephropathy
US4973704A (en) * 1985-10-25 1990-11-27 Sandoz Pharm. Corp. Pyrrolyl intermediates in the synthesis of pyrrole analogs of mevalonolactone and derivatives thereof
AU598775B2 (en) * 1985-10-25 1990-07-05 Sandoz Ag Heterocyclic analogs of mevalonolactone
US4851427A (en) * 1985-10-25 1989-07-25 Sandoz Pharm. Corp. Pyrrole analogs of mevalonolactone, derivatives thereof and pharmaceutical use
DE3915450A1 (en) * 1989-05-11 1990-11-15 Gerd Prof Dr Dannhardt SUBSTITUTED PYRROL COMPOUNDS AND THEIR USE IN PHARMACY
US5260451A (en) * 1989-05-11 1993-11-09 Merckle Gmbh Substituted pyrrole compounds and use thereof in pharmaceutical compositions
EP0946507B1 (en) * 1996-12-10 2003-09-24 G.D. SEARLE &amp; CO. Substituted pyrrolyl compounds for the treatment of inflammation
WO2008014821A1 (en) * 2006-08-03 2008-02-07 Rottapharm S.P.A. 3-substituted-1,5-diarly-2-alkyl-pyrroles highly selective and orally effective cox-2 inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1228301A (en) * 1968-04-16 1971-04-15

Also Published As

Publication number Publication date
SE388853B (en) 1976-10-18
IE37237B1 (en) 1977-06-08
FR2164857B1 (en) 1976-03-05
DD104976A5 (en) 1974-04-05
HU165900B (en) 1974-12-28
DK134599B (en) 1976-12-06
PL89071B1 (en) 1976-10-30
CA991193A (en) 1976-06-15
JPS4868562A (en) 1973-09-18
IE37237L (en) 1973-06-23
ES409944A1 (en) 1976-03-16
DE2261965A1 (en) 1973-06-28
GB1406330A (en) 1975-09-17
DK134599C (en) 1977-05-09
AR208494A1 (en) 1977-02-15
AT323727B (en) 1975-07-25
CH563364A5 (en) 1975-06-30
FR2164857A1 (en) 1973-08-03
OA04523A (en) 1980-03-30
JPS5318507B2 (en) 1978-06-15
NL7217521A (en) 1973-06-26
AU5033872A (en) 1974-06-20
AU467602B2 (en) 1974-06-20

Similar Documents

Publication Publication Date Title
FI66368C (en) PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC ANVAENDBARA 6,1-DIHYDRO-11-OXODIBENS (B E) OXEPIN-2-ACETIC XRIDERATIVES
GB2200109A (en) Catechol derivatives
US4365076A (en) Process for the preparation of cycloalkylidenemethylphenylacetic acid derivatives
IE862616L (en) Control of intaglio printing
CH656800A5 (en) IMMUNOMODULATING AGENT.
IL41146A (en) Derivatives of pyrroleacetic acids salts thereof and process for their preparation
EP0085959B1 (en) Aromatic compounds
HU194796B (en) Novel process for preparing partly novel 2-substituted 1-naphthols
HU177531B (en) Process for producing azabicyclohexanes
US5288750A (en) Substituted β-diketones
US4034113A (en) Treatment of senile geriatric patients to restore performance
EP0334119B1 (en) Compounds for inhibiting the biosynthesis of lipoxygenase-derived metabolites of arachidonic acid
US4590205A (en) Antiinflammatory and/or analgesic 2,3-diaryl-5-halo thiophenes
US3709906A (en) 2-alkyl-4,5-diphenylpyrrole derivatives
US3453285A (en) Tetrazolyl alkanoic acids
AU611699B2 (en) Naphthalene propionic acid derivatives
US4116972A (en) Anti-inflammatory 1-oxo-isoindoline derivatives and processes for their preparation
CH633541A5 (en) Pharmacologically active substituted 1,2,4-triazines and medicaments containing these triazines
US4477463A (en) Antiinflammatory and/or analgesic 1-alkyl-4,5-diaryl-2-fluoroalkyl-1H-pyrroles
US4461912A (en) Phenylacetic acid derivatives, their preparation and compositions containing them
Holland et al. Cinnoline-3-propionic acids, a new series of orally active antiallergic substances
US4189607A (en) Anilionotropone derivatives
JPH037670B2 (en)
US4795758A (en) 5-[2-(pyrrolidin-1-yl)ethoxy]-p-cymene derivatives, the process for the preparation of the said derivatives and drugs in which the said derivatives are present
US3420839A (en) Aminomethyl pyrazolone derivatives of nicotinamide