BE715405A - - Google Patents

Description

  

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 EMI1.1
 



  This invention relates to a dtu \ d.li method. 3.1 '.- d; 4 -.- certain chemical compounds having interesting pharmacodynamic action, and therapeutic compositions incorporating such compounds, More particularly, the invention relates to a method of administering
 EMI1.2
 tion of certain aromatic and heteroaromatic pyrrol-3-yl ketones having anti-inflammatory, analgesic and antipyretic properties, and therapeutically useful compositions incorporating such substances.



  Various aromatic and heteroaromatic pyrrol-3-yl ketones have already been described by Gardner, Wenis and Lee (J. Org. Chem. 33, 823 195 /). Such compost has been reported as "of no pharmacological or chemotherapeutic interest.



  The therapeutically active compounds of this invention are of the formula
 EMI1.3
 wherein R1 is hydrogen, or a lower alkyl, lower alkenyl or cycloalkyl radical having not more than 6 carbon atoms
 EMI1.4
 bono, bonzylo, bonzoyl, phenyl, or bonzyl, bonzoylo or phenyl halo, lower alkoxy- or lower alkyl-substituted, wherein the lower alkoxyl and lower alkyl sub- stitutes have no more than four carbon atoms;

   
 EMI1.5
 R2 # 11 and R are the same or different and are 3.hydro or lower alkyl, lower alkylene, or cycloalkyl, having not more than 6 carbon atoms, phenyl, ph6nyl-lower alkyl in which 'has no more than four carbon atoms,
 EMI1.6
 phenyl or ph6nyl-alkyloinferior halo-, lower-alkoxy-or lower-alkyl: r:

  ieur..fJubstit.ué in which the lower alkoxyl and the lower alkoxyl have not more than four carbon atoms and
R5 is a phenyl, naphthyl, biphenyl or phenyl radical,
 EMI1.7
 naphthyl, or mono, di-, or tri-substituted biphenyl, in which the substituents are hydroxyl, lower alkoxyl, lower alkyl, lower alkylene dioxide, phenoxide, nitro, fluorine, chlorine,
 EMI1.8
 bromine, iodine, amine, lower alkanoyl amine, benzylidane amine, lower alkyl amine, lower ditleoyl amine, di talcay.

   lower) amineN-oxide, ureidc, mercapto, lower alkyl thio, phenylthio, lower alkyl halo, lower alkanoyl, lower alkyl-sulfonyl, lower alkyl-sulfinyl, sulfamyl, cyano, carboxamide, lower carbalkoxyl or thio-hydroxyl, pyryl-oxyl, pyryl-oxyl, oxyhydrazide pyrazolyl,> hi.a'ki: aa, v3, oxazolyl, thiazolyl, pyrazinyl, pyridyl, imidazolyl,: 4x: .y., isoxazolyl, pyrimidinyl, triazolyl or '

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 isothiazolyl, unsubstituted and mono-, di- or tri-substituted;

   'in which said substituents are the same or different and are hydrogen, a halogen, or a nitro, amine, hydroxyl, phenyl, sulfamoyl, carbamoyl, cyano, trifluoromethyl, mercapto, lower alkyl, lower alkyl thio, lower alkoxyl or alkyl group lower amine, di- (lower alkyl) amine, lower alkanoyl amine, lower carbalkoxyl, or phenyl-lower alkyl, the carbon chains of the substituted aliphatic substituents having from one to six carbon atoms.



   Throughout this description all the symbols have the same meaning as that which has just been defined, unless otherwise specified.



   In the most interesting of this invention R5 is the phenyl radical; one of the substituents of an aromatic ring is fluorine; and R1, R2, R3 and R4 are hydrogen or an alkyl group having not more than two carbon atoms:
R5 is a 2- or 3-furyl group, whether it is unsubstituted or substituted as mentioned above, the preferred co-radical substituents being chosen from the group formed by halogen, nitro, amine, or lower alkyl, lower alkoxyl, or lower alkyl thio having no more than four carbon atoms in their aliphatic chains.



   It is further preferred to employ as active compounds those in which R1 is hydrogen and each of the radicals R2, R3 and R4 may be selected from the group of hydrogen, halogens, or lower alkyl or cycloalkyl radicals not having more than six carbon atoms. It is particularly desirable to incorporate such substituents in the active compounds used according to this invention, when the heterocyclic part of the compound consists of the preferred radicals: 2- or 3-furyl; 2- or 3-thienyl; pyrrol-2-yl or pyrrol-3-yl; or 1, '2,5-oxadiazol-3-yl or 1,2,4-oxadiazol-3-yl.



   Most unexpectedly, and contrary to the revelations of the prior art already cited, it has been found, according to the present invention, that the reported category of compounds possessed remarkable anti-inflammatory, analgesic and antipyretic properties. Such compounds are of particular interest in alleviating the symptoms of rheumatic, arthritic, allergic, and other inflammatory conditions.



   In comparison with other non-steroidal anti-inflammatory compounds known in the art, the compounds employed according to the present invention are remarkable for their effectiveness, for their ability to alleviate deep pain, as evidenced by their action in the analgesic test of hot plate, and in their ability to nullify an inflammatory condition experimentally induced in

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 animals.
 EMI3.1
 Iral Effects of Anti-Inflammatory Compounds'
 EMI3.2
 DE Anti- DE Analge- Dose AntiPy- LD50 Infiant. siqQe retic Compound - (mct mctlkg) (merlkct) ¯ .., ¯ (ma / kc
 EMI3.3
 
<tb>
<tb> 2-Furyl <SEP> 2,5dimethyl-pyrrol-
<tb>
 
 EMI3.4
 3-yl ketone Il (6) -1 32 (10) 20 (6) 4.

   201
 EMI3.5
 
<tb>
<tb> 3-Furyl <SEP> 2,5dimethyl-pyrrol-
<tb> 3-yl <SEP> ketone <SEP> 23 <SEP> (6) <SEP> -
<tb> 5-Bromo-2-furyl
<tb>
 
 EMI3.6
 2, 5-dimethylpyrrol
 EMI3.7
 
<tb>
<tb> -3-yl <SEP> celons <SEP> 20 <SEP> (6) <SEP> 28 <SEP> (10) <SEP> 45 <SEP> (6) <SEP>> 300
<tb> 2,5-Dimethylpyrrol-3-yl <SEP> 2thienyl <SEP> ketone <SEP> 25 <SEP> (6) <SEP> 64 <SEP> (10) <SEP> -
<tb> 2,5-Dimethylpyrrol-3-yl
<tb> 1-methylpyrrol- <SEP> '
<tb> 2-yl <SEP> ketone <SEP> 75 <SEP> (6) <SEP> 47 <SEP> (10) <SEP>> 300
<tb> 2,5-Dimethylpyrrol-3-yl
<tb> pyrrol-2-yl
<tb> ketone <SEP> 35 <SEP> (6) <SEP> 72 <SEP> (10)
<tb> 4-Methyl-1,2,5oxadiazol-3-yl
<tb> 2,5-dimethylpyrrol-3-yl
<tb> ketone <SEP> 40 <SEP> (6) <SEP> 49 <SEP> (10)
<tb> Ph6nylbutazone <SEP> 25 <SEP> (4) <SEP> 32 <SEP> (10) <SEP> 100 <SEP> (6) -Aspirin <SEP> 125 <SEP> (4) <SEP> 92 <SEP> (10) <SEP> 250 <SEP> (6)

   <SEP> 1100
<tb>
 
 EMI3.8
 z- Il1 payingMc number c; 1 'nimIH'K tilia6 "fiar level of therefore,

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   Oral Effects of Potential Anti-Inflammatory Compounds in Various Tests on Rodents
 EMI4.1
 
<tb> DE <SEP> 50 <SEP> Anti-Inflam. <SEP> DE <SEP> 50 <SEP> Analgesic <SEP> Dose <SEP> Antipyré- <SEP> LD50
<tb>
 
 EMI4.2
 Compound J (mg / kg) tick "150 EN-236? (MgJkg) (mqJkq) (mgJkg) 'mqJkq) EN-2367 - (mcr / kcj)
 EMI4.3
 
<tb> 2,5-Dimethylpyrrol-3-yl
<tb> phenyl <SEP> ketone <SEP> 19 <SEP> 1'10) <SEP> IL <SEP> 8 <SEP> (10) <SEP> 100 <SEP> (6) <SEP> 530
<tb> EN-2497
<tb>
 
 EMI4.4
 2-Pluorophenyl-2,5-dimethyl-
 EMI4.5
 
<tb> pyrrol-3-yl <SEP> ketone <SEP> 14 <SEP> (la) <SEP> 17 <SEP> (10) <SEP> 22 <SEP> (6) <SEP> 650
<tb> EN-2720
<tb> 4-Trifluoromethylphenyl
<tb> 2,

  5-dimethylpyrrol-3-yl <SEP> ketone <SEP> 14 <SEP> (4) <SEP> 44 <SEP> (10) <SEP> 25 <SEP> (5) <SEP> 600
<tb> Phenylbutazone <SEP> 25 <SEP> (4) <SEP> 32 <SEP> (10) <SEP> 100 <SEP> (5) <SEP> -Aspirin <SEP> 125 <SEP> (4) < SEP> 92 <SEP> (10) <SEP> 250 <SEP> (5) <SEP> 1100
<tb> # <SEP> Between <SEP> parentheses, <SEP> number <SEP> of animals <SEP> used <SEP> by <SEP> <SEP> level of <SEP> dose.
<tb>
 

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 Methodology (1) Anti-Inflammatory Test (Rat)
Subplantar injection of carrageenan (0.1 ml of a 1% suspension) into the hind paw of the rat causes the formation of edema which is inhibited by premedication with anti-inflammatory agents.

   The ED 50 values represent the calculated doses for which 50% of the animals show a reduction in swelling greater than two standard deviations from a control mean (n = 87).



     (2) Analgesic Test (Mouse)
The intraperitoneal injection of phenylquinone (i.e., phenyl-p-benzoquinone, Eastman), causes contortions in mice. This phenomenon is inhibited by premedication with analgesic agents. ED 50 values were calculated from the percentage of animals, at each dose level, which exhibited at least 50% less writhing than control animals, in the 30 minute observation period.



   (3) Antipyretic Test (Rat)
Rats injected subcutaneously with 1 ml of 15% brewer's yeast have elevated body temperatures the next day. The dose of the test compound required to reduce the body temperature by 1.65 C in three hours was arbitrarily considered to be the effective antipyretic dose, and is thus shown in the Table.



   (4) LD50 (Mouse)
Groups of 10 animals received oral doses of test compounds, and LD50 values were calculated by standard statistical methods.



   Indomethacin, phenylbutazone and aspirin suppress the inflammation but only the compounds of the present invention cancel the inflammations already produced. In the "cotton pellet granuloma" test, many of the compounds of this invention have activity equal to that of hydrocortisone.



   The compounds are therapeutically useful when administered to mammals orally, parenterally, or rectally.



  The oral route is preferred. Although they can be administered as neat compounds, the limited water solubility of many of the compounds employed in the practice of this invention makes them advantageous in combination with pharmaceutically acceptable excipients such as starch, sugar. , talc, and the like, to form powders which can be used directly or inserted into gelatin capsules, or even made into tablets.

   Suitable lubricants such as magnesium stearate,

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 Binders such as gelatin, and disintegrating agents such as sodium carbonate in combination with teric acid, can be used to form tablets, they can also be formulated as suspensions or emulsions in excipients. suitable liquids.



   Compounds of formula:
 EMI6.1
 wherein R1 is hydrogen or a lower alkyl, lower alkenyl or cycloalkyl radical having not more than 6 carbon atoms, benzyl, benzoyl, phenyl, or benzyl, benzoyl or phenyl halo-, lower alkoxy- or lower alkyl- substituted, wherein the lower alkoxyl and lower alkyl substituents have no more than four carbon atoms.



   R, R3 and R are the same or different and are hydrogen or a lower alkyl, lower alkenyl or cycloalkyl radical having not more than six carbon atoms, phenyl, phenyl lower alkyl in which the alkyl n ' has not more than four carbon atoms, phenyl or phenyl-lower alkyl halo-, lower alkoxy- or lower alkyl-substituted, wherein the lower alkoxyl and lower alkyl have not more than four carbon atoms;

   and
R5 is a mono-, di- or tri-substituted phenyl, naphthyl, biphenyl, or phenyl, naphthyl, or biphenyl radical, in which the substituents are hydroxyl, lower alkoxyl, lower alkyl, lower alkylenedioxide, phenoxide, nitro, fluorine, chlorine, bromine, iodine, amine, lower alkanoyl amine, benzylideneamine, lower alkyl amine, di (lower alkyl) ami @, di (lower alkyl) amine-N-oxide, ureid, mercapto, lower alkyl thio, phenylthio , halo lower alkyl, lower alkanoyl, lower alkyl sulfonyl, lower alkyl sulfinyl, sulfamyl;

     cyano, carboxamide, lower carboalkoxyl, or carboxhydrazide; furyl, pyrryl, thienyl. oxadiazolyl, pyrazolyl, thiadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyridyl, imidazolyl, tetrazolylo, isoxazolyl, pyrimidinyl, triazolyl, or unsubstituted and mono-, di- or trisubstituted isothiazolyl;

   wherein said substituents are the same or different and are hydrogen, halogen, or a nitro, amine, hydroxyl, phenyl, sulfamoyl, cyano, trifluoromethyl., mercapto, lower alkyl, lower alkyl tiiio, lower alkoxyl, lower alkyl amine, di (lower alkyl) amine, lower alkanoyl amine,

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   lower carbalkoxyl, or phenyl-lower alkyl, the carbon chains of the substituted aliphatic substituents having 1 to 6 carbon atoms, can be prepared by reacting compounds of the formula:

     
 EMI7.1
 with a compound capable of providing the radical
 EMI7.2
 or else with its equivalent, in the presence of a FriedelCrafts catalyst, R1, R2, R3, R4 and R5 being as defined above.



   Many of the compounds of this invention can also be prepared by reacting an acid chloride with a Grignard derivative of a suitable pyrrole.



   Alternatively a compound of formula I can be prepared by a variant of the Vilemoier-Haack method as described by Kleinspehn and Briod [J. Org. Chem., 26, 1652 (196117. Interaction of a suitable pyrrole with an N, N-disubstituted arylamide, eg, a morpholide having the desired aryl structure, in the presence of POCl3, provides the desired ketone.



   The Friedel-Crafts reaction, which constitutes a new and preferred synthetic method, is carried out under the best conditions with aluminum chloride as catalyst, in an inert solvent such as tetrachloroethane.



     Other Friedel-Crafts catalysts can be employed, such as boron trifluoride etherate and stannic chloride.



   Other solvents, such as nitromethane, can be used successfully in the reaction. methylene chloride, benzene and nitrobenzene. Mixtures of solvents can also be used, tetrachloroethane mixed with nitromethane has given good results.



   It will be understood that furyl-phenyl, pyridyl and thienyl-2,5di (lower alkyl) pyrrol-3-yl ketones are outside the scope of the novel compounds of this invention.



   The following examples are provided to serve as non-limiting illustrations of therapeutic compositions prepared according to preferred embodiments of the present invention. In the following examples, just as above, all parts and percentages are given by weight and all temperatures in degrees C, unless otherwise indicated.

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 Example
 EMI8.1
 FLUOROPHENYL 2.5-DIMETHYLPYRROIr3-Yh CETONE To a Grignard solution prepared from 17.5 g of magnesium, 79.2 g of ethyl bromide and 300 ml of ether, was added,
 EMI8.2
 dropwise with stirring, 57.1 g of 2, 5-dimethyl-pyrrole in 50 ml of ether. Stirring was continued for 20 minutes after the addition was complete.

   Then, 100 g of 4-fluorobenzoyl chloride in 200 ml of dry benzene was added over a period of 15 minutes.



  Stirring was then continued for a further two hours.



   100 ml of 25% aqueous ammonium chloride was added to quench the reaction. The organic layer was collected, washed with water, with 10% aqueous sodium bicarbonate, again with water, and dried. Concentration provided 115 g (88% yield) of product, m.p. 120-125 C. Recrystallization from benzene raised the m.p. to 129-130.



   Using 2,5-diethylpyrrole in place of 2,5-dimethylpyrrole, the previous method is used to prepare 2,5-diethyl-pyrrol-3-yl 4-fluorophenyl ketone.



   Example 2
 EMI8.3
 By the method of Example 1, using the appropriate acid-wenides in place of ¯;: orobenzoyl chloride, the following products were prepared: 2,5-D.methylgyrraJ- ., - ''; 4nyl ketone, PF 132-133, from the chloride 11 ""> <1.-GY.e *: ..,. ': .. Jrophenyl 2,5-dimethylpyrrol-3-yl ketone , Mp h56-158, from 4-chlorobenzoylo chloride.



   2-Fluorophenyl 2,5-dimethylpyrrol-3-yl ketone, m.p. 143-145, from 2-fluorobenzoyl chloride.



   3-Fluorophenyl 2,5-dimethylpyrrol-3-yl ketone, M.P., 141, from 3-fluorobonzoyl chloride.
 EMI8.4
 



  2,4-Dichlorophenyl 2,5-dimdthylpyrrol-3-yl ketone, m.p. 1% - 195 from 2,4-dichlorobenzoyl chloride. ,
3,4-Dichlorophenyl 2,5-dimethylpyrrol-3-yl ketone, P. F, 219-220, from 3,4-dichlorobenzoyl chloride.



     2,6-Dimethoxyphenyl 2,5-dimethylpyrrol-3-yl ketone, @ .F.



    232-233, from 2,6-dimethoxybenzoyl chloride.
 EMI8.5
 



  3,4,5-Trimethoxyphenyl 2,5-dimethylpyrrol-3-yl cetftai 3'.F.



  155-k56, from 3,4,5-trimethoxybenzoyl chloride. , 2,5-Dimethylpyrrol-α-yl 1-naphthyl ketone, m.p. 6u 367, from 1-naphthoyl chloride.



   The method of Example 1 is also used to prepare
 EMI8.6
 the following 2,5-dimethylpyrrol-3-yl ketones rt-benzyloxyphenyl ketone from 4- chloru

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   benzyloxybenzoyl.



   2-allyloxyphenyl ketone from 2-allyl-oxybenzoyl chloride.



   4-Phenylthiophenyl ketone from 4-phenylthiobenzoyl chloride.



   2-Butylphenyl ketone from 2-butylbenzoyl chloride.



   Example 3
 EMI9.1
 215.-DIMETHYLPYRROL-3-YL 3-NITROPHENYL CETONE
Has a solution of 113.6 g of boron trifluoride etherate, 100 ml of anhydrous benzene and 74.2 g of 3-nitroben- chloride
 EMI9.2
 zoyl, 38.1 g of 2,5-im6thyl-pyrrole were added. The reaction vessel was fitted with a desiccant tube, and the mixture was allowed to stand for 72 hours. The contents of the container were poured onto 200 g of ice and water, and the product crystallized. It was collected by filtration, dissolved in benzene, decolorized by passing through a short alumina column, and recovered by removing the benzene. Recrystallization from ethanol gave 50.0 g (52.4% yield) of product, m.p. 223-224.



   Example 4
By the method of the Example, using the halides
 EMI9.3
 Suitable acids instead of 3-nitrobenzoyl chloride the following products were prepared: 2-Methylphenyt 2,5¯dimethylpyrxa.-3-yl ketone, m.p. 146-1470. 3-Methylphenyl 2,5-dimethylpyrrol-3-yl ketone, m.p. 172-174 ", 4-mdthylphdnyl 2/5-dimethylpyrrol-3-yl ketone, m.p. 137-139.



  3-Tx'βluoromethylphenyX, 2,5-dimethylpyxrol-3-yl ketone, m.p. 145-146.



   2-Methoxyphenyl 2,5-dimethylpyrrol-3-yl ketone .. @ 1410.



   4-Methoxyphenyl 2,5-dimethylpyrrol-3-yl ketone, m.p. 102-103 '.
 EMI9.4
 2-Naphthyl 2,5-dimethylpyrrol-3-yl ketone, m.p. z.81-182 '.



     2,5-Dimethylpyrrol-3-yl 4-nitrophenyl ketone, m.p. 195-196.



   The method of Example 3 is also used to prepare the following 2,5-dimethylpyrrol-3-yl ketones:
 EMI9.5
 4-Phenoxyphenyl ketone, 3,4-methylene-dioxypheny, ce.tone, 4-methylthiophenyl ketone, 2- (N, 1T-dimethylcarboxamidophenyl) ketone, 4-methylsulfonylphenyl ketone, o-, m - and p-biphenyl
 EMI9.6
 ketones, 4-propionylphenyl ketone, 4-carbethoxyphenyl ketone, 4-oyanophenyl ketone, and 2-dimethylaminophenyl ketone.



  Example 5 2-HYDROXYPHENYL 2j, 5-DITiETI3YhPYRRaIr-3-YL KETONE

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A rapid stream of hydrochloric gas was passed through 20 ml of pyridine until reflux ceased. A 5.0 g portion of 2-methoxyphenyl 2,5-dimethylpyrrol-3-yl ketone was added. The resulting mixture was heated at 175-180 for two hours, then poured into 40 ml of water. The aqueous solution was extracted five times with 20 ml portions of ethyl acetate. The combined ethyl acetate extracts were evaporated. The residue was extracted with 10% aqueous aoudo. The resulting alkaline solution was treated with charcoal, filtered and acidified. The phenolic product precipitated.

   It was recrystallized from ethanol and melted at 110.5-111.5.



   Example 6
 EMI10.1
 4- liNOPHENYL 2.5-DTP: ': 1'I3YLPYRROL-3-YL CETONE
A 10 g portion of 2,5-dimethylpyrrol-3-yl 4-nitrophenyl ketone, 300 ml of ethanol and 1.0 g of 10% palladium on charcoal, were combined and shaken under a 20.4 atmosphere. kilograms of hydrogen for 20 minutes. Filtration of the catalyst and evaporation of the solvent left the product crystalline, m.p. 152-153.



    Example 7.
 EMI10.2
 



  11- FOnM1 \ HtDOPI, ENYL 2, 5- Dn1ETINLPYmOL-: S- YL KETONE
The product of Example 6 was heated for five minutes with formic acid, and the resulting solution was poured into water. The crude formamide compound crystallized, and after recrystallization from dimethylformamide and water, it melted at 210-212.
 EMI10.3
 



  Example tI-DEN7.YLïDI: NEAMINOPFII; luYL 2,5-DihtlâTIiYLEYRitOIr3-'iL CITOh? L
The product of Example 6 was heated in ethanol with an equimolar amount of benzaldehyde in the presence of a drop of sulfuric acid. Concentration provided the benzylidene derivative.



   Example 9
 EMI10.4
 -BENZYIa "3I'IINOPfiEi: YL 25-DTIIï; THYLPYI", I: f3.-3-'YL KETONE
The benzylidene compound of Example 8 was reduced with hydrogen in the presence of 10% palladium on carbon, by the method of Example 6, to produce the benzyl derivative.



   Example 10
 EMI10.5
 Z. 5-DII2I: TFIYLPYRItOIr 3-YL 4-UREIDOPHENYL CETONE 4-aminophenyl 2,5-dimethylpyrrol-3-yl ketone can be dissolved in dilute hydrochloric acid and heated with aqueous potassium cyanate to form the derivative, (ureid .



   Example 11
 EMI10.6
 1.2.5-TRIATtIYLiYP.rOL-3-l'L PH -'- NYL CETOl1E A mixture of 56.8 g of boron trifluoride etherate, 28.11 g of benzoyl chloride, 21.8 g of 1,2,5-trimethylpyrrole

 <Desc / Clms Page number 11>

 and 50 ml of dry benzene, was allowed to stand for 72 hours in the absence of moisture. It was then stirred in 150 g of ice and water. The organic layer was collected and concentrated. The residue. was stirred for 30 minutes with aqueous soda to remove unconverted benzoic acid. The organic product was extracted into benzene. The benzene solution was dried and decolorized by passing through an alumina column.

   The concentration of the solution
 EMI11.1
 Bon6niquQ and cooling gave 36% of crude product which, after recrystallization from benzene, melted 90-91.



   Example 12 @
 EMI11.2
 2, 5-DTbIETHYIrl-PFiENYLPYIROTr-3-YL PiIENYL CETONE 2,5-dimdthyl-1-phenylpyrrole, PF 50-51, was reacted with benzoyl chloride under the conditions of Example 11, The product melted at 129-130.



   Example 13
 EMI11.3
 l-CYCLOHBXYL-2, S-DIMETHYLPYRROL - YL PHENYL CETONE
Cyclohexylamine (1.1 mole) and acetonylacetone (1.0 mole) were heated under reflux in benzene in the presence of a few drops of concentrated sulfuric acid, until it did not dissolve.
 EMI11.4
 formed more water. Distillation afforded 1-oyclohoxyl-2,5-dimethylpyrrole, m.p. 47-48. The latter was converted to the product, m.p. 127-127.5 ", by treatment with benzoyl chloride under the conditions of Example 11.



   Example 14 thread
 EMI11.5
 1-BEN? YIr2 5-D h1E'L'iIYLPYRROIr-3-YL P13ED1YL CEMNE Benzylamine (1.1 mole) and .'tc4tonylac6tone (1.0 mole) were heated to reflux in benzene in the presence of '' a catalytic amount of concentrated sulfuric acid, until it does not
 EMI11.6
 more water is formed. Distillation afforded 1-benzyx-2,5-dimethyl-pyrrole, m.p. 48-49. The latter was converted to the product, m.p. 67-68, by treatment with benzoyl chloride under the conditions of Example 11.



   Likewise, starting from suitably substituted benzylamines, the following compounds can be prepared
 EMI11.7
 1- 2-Chlorobenxyl) .- 2.5-ai.methylpyxrol-3-yl phenyl ketone.



    1- (4-Butylbenzyl) -2,5-dimethylpyrrol-3-yl 2-chlorophenyl ketone.
 EMI11.8
 



  1- (3-Ethoxµbenzyl) -2,5-dimethylpyrrol-3-yl phenyl ketone.



  Example 15 2, h5-TRIN'HYLPYRROL-3-YL PHENYL CETONE A solution of 32.4 g of benzoylacetone and 20.2 g of
 EMI11.9
 2,3-butanodione monoxime in 250 ml of acetic acid and 30 ml of water, was treated with 40 g of zinc powder. Heat has been released

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 and the mixture began to boil. When the initial reaction subsided, the mixture was stirred and heated under reflux for 20 minutes.



  It was then poured onto ice. The precipitated product was collected and recrystallized from toluene; M.p. 174.



   Example 16 2,4-DIMETHYL-5-PROPYLPYRROL-3-YL PHENYL KETONE
100 g of ethyl 5-propyl-2,4-dimethylpyrrole-3-carboxylate was suspended in 800 ml of 60% phosphoric acid, and heated with stirring in a nitrogen atmosphere. The ester liquefied at 1300 and at the same time decarboxylated. Heating was continued at 103-108 for 30 minutes when the evolution of carbon dioxide ceased.

   The solution was poured onto ice, neutralized with ice-cold ammonia, the oil which separated was taken up in ether, dried, and after evaporation of the solvent the residue was distilled off in vacuo; obtained 55 g of 5-propyl-2,4-dimethylpyrrole, PE16nm 86-80. The pyrrole was benzoylated with benzoyl chloride and an etherate of boron trifluoride in benzene, according to the method of Example 3, to give the product, m.p. 152-153.



   Example 17
 EMI12.1
 2-BENZYIr4,5-DTIIETHYLPYRROïr-3-YL 2-FLUOROPHENYL KETONE Methyl 2-benzyl.-4,5-dimethylpyrrole-3-carboxylate, mp 115-115.5, was decarboxylated as described in Example 16 , to give 2-benzyl-4,5-dimethylpyrrole, mp 51-52. The latter was converted into 2-fluorophenyl ketone using 2-fluorobenzoyl chloride by the method of Example 1.



   Example 18
 EMI12.2
 2 L4DIMETHYLPYRR01, -3-YL PHENYL CETONE 4-Benzoyl-3,5-dimethylpyrrole-2-carboxylic acid, PF 185-186Q (decomposition), was decarboxylated in a nitrogen atmosphere bringing it to its depletion point. merge until the release of. carbon dioxide-, has ceased. The residual oil was diluted with toluene and cooled to give the product, m.p. 129-130.
 EMI12.3
 2-METHYL-5-PHENYLPYRROL-3-YL PHENYL KETONE
2-Methyl-5-phenylpyrrole was treated with boron trifluoride and benzoyl chloride in benzene, by the method of Example 3, to provide the desired product, of PF 206-207 after crystallization in. ethanol.



   In a similar way 2- (4-chlorophenyl) -5-methylpyrrole,
M.p. 125-126, leads to 5- (4-chlorophenyl) -2-methylpyrrol-3-yl
 EMI12.4
 phenyl ketone, and 2,4-dimthβ1-5-phenylpyrro7.e, P.F. '7, produces 2,4-dimethyl-5-phenylpyrrol-3-yl phenyl ketone.
Example 20
 EMI12.5
 .-I SOPROPYL-2 5-DiMETHYLPYRROL-3-YL PI-1NYL KETONE

 <Desc / Clms Page number 13>

 
A mixture of 233 g of 2,5-dimethylpyrrole, 500 ml of isopropanol, 225 g of 85% potassium hydroxide and 10 ml of water, was heated in a bomb for 20 hours between 200 and 250. After cooling, the contents of the bomb were concentrated and diluted with water and ether.

   The ethereal layer was distilled to give 250 g of 3-ispropyl-2, S-dimethylpyrrole, P.E. 195-205. The latter was converted into the phenyl ketone by reaction with benzoyl chloride, by the method of Example 3; P.F. 183-184,
Example 21
 EMI13.1
 4-ISOBUTYIo-2,5-DIaIETHYLPYRROL-3-YL PHENYL CETONE
This compound was prepared by the method of Example 20 using isobutanol in place of isopropanol. It melts at 190-1910.



   Example 22
 EMI13.2
 4-IiEXYL-2 5-DIMETHYLPYRROL-3-YL 4-FLUOROPHENYL CETONE
This compound was prepared by the method of Example 20 using hexanol in place of isopropanol and 4-fluorobenzoyl chloride in place of benzoyl chloride.



   Example 23 4-CYCLOHEXYL-2,5-DIMETHYLPYRROL-3-YL PIIENYL CETONE
2,5-Dimethylpyrrole was reacted with cyclohexanol
 EMI13.3
 as described in Example 20, to produce 3Lcyclohexyl-2,5-di.methyl-pyrrole, mp 118-119 C. The latter was converted to the desired product by reaction with benzoyl chloride according to the method of Example 3.



   Example 24
 EMI13.4
 2-CHLOROBENZOYL -2 5-DIME r'YLPYRROL-3-YL 2-CHLOROPHENYL CETONE
When the method of Example has been carried out with 2-chlorobenzoyl chloride, a by-product, boiling at 240-250 under 0.25 mm Hg., Melting at 112-114 after crystallization from ethanol , was obtained in addition to the compound of Example 25. It was found to be the 1- (2-chlorobenzoyl) derivative of 2-ehlorophenyl 2,5-dimethylpyrrol-3-yl ketone.



    Example 25
 EMI13.5
 2-CHLOROPHIENYL 2,5-DIMETHYLPYRROL-3-YL KETONE
The product of Example 24 was refluxed for five hours with excess aqueous alcoholic soda. Dilution with water precipitated the product, m.p. 141-142.



   Example 26

 <Desc / Clms Page number 14>

 
 EMI14.1
 Inctrêdient Diqiloml2rimé 2 "Fluoï'ophényl 2,5-diinâthylpyrrol-
 EMI14.2
 
<tb>
<tb> 3-yl-ketone
<tb> Lactose <SEP> USP <SEP> 100
<tb> Magnesium <SEP> <SEP> stearate <SEP> 1.2
<tb> Polyvinylpyrrolidone
<tb> Alcohol <SEP> absolute <SEP> to <SEP> will
<tb>
 
Combine drug and lactose, sift through a 40 mesh sieve, and mix well. Dissolve PVP in alcohol and granulate the pulverized mass, sieve through a 12 sieve, dry at 43-49 C to a moisture content of 1.5%.

   Sieve through a 16 mesh sieve and add the magnesium stearate (previously sieved through a 40 mesh sieve). Mix well and compress into tablets.



   Example 27
 EMI14.3
 Ingredient Mg / capsule 2,5-Dimethylpyrrol-3-yl p1) enyl keto 50
 EMI14.4
 
<tb>
<tb> Lactose <SEP> 150
<tb> Cab-0-Sil <SEP> (Brand <SEP> of <SEP> Factory <SEP> Registered) <SEP> 2.5
<tb>
 Mix well, sift through a 60 mesh sieve and amal-
 EMI14.5
 gamer in hard gelatin capsules doyblq, qyo;% U ::; a Example 28
 EMI14.6
 
<tb>
<tb> Ingredient <SEP> Quantity / 100 <SEP> ml
<tb> Hydrochloride <SEP> of <SEP> 4-aminophenyl <SEP> 2,5-dimethylpyrrol-3-yl <SEP> ketone <SEP> 1.5 <SEP> g
<tb> Solution <SEP> of <SEP> sorbitol <SEP> 25 <SEP> ml
<tb> Perfume <SEP> qs
<tb> Colorant <SEP> qs
<tb> <SEP> sugar <SEP> syrup <SEP> USP <SEP> qs
<tb> Water <SEP> to <SEP> will
<tb>
 
Dissolve the drug in a minimum amount of water.



  Add the sorbitol solution, the coloring and the fragrance and top up with sugar syrup.



   Example 29 ingredient Mg / suppository 4-Methylphenyl 2,5-dimethylpyrrol-
3-yl ketone 100 mg Cocoa butter cs
The drug and cocoa butter are combined, thoroughly mixed, and made into 2 gram suppositories.



   Example 30
 EMI14.7
 2-FURYL 2 5-DMETIiYLPYitROIr3-YL KETONE
A 12-liter flask was fitted with a mechanical stirrer, an internal thermometer, a solid addition tube, a

 <Desc / Clms Page number 15>

 reflux condenser with a desiccant tube, and a gas addition tube,
Dry nitrogen was bubbled through the mixture d. operate! throughout the reaction.



   Eight liters of 1,1,2,2-tetrachloroethane, 475 g (5 moles) of 2,5-dimethylpyrrole and 655 g (5 moles) of 2-furcyl chloride, were poured into the flask and stirred. has begun. While cooling to maintain the temperature below 30, 655 g (5 moles) of aluminum chloride were added over 30 minutes. The ice bath was then removed, replaced with a heating jacket, and the internal temperature was raised to 90-95. This temperature range was maintained for 7.5 hours, with continuous stirring.



   At the end of this time, the reaction mixture was cooled to room temperature and poured into 5 liters of ice and water with vigorous stirring. After stirring for one hour, the layers were separated and the aqueous part was further extracted with two 1000 ml portions of tetrachloroethane. All the organic layers were combined, washed successively with two portions of 1000 ml of 10% aqueous sodium hydroxide and two portions of 1000 ml of water, then dried on a 4A molecular sieve.



   After separating the desiccant by filtration, the solvent was evaporated under reduced pressure, keeping the bath temperature below 60. Stirring the residual oil with four successive 2000 ml portions of hexane gave a brown solid which weighed 570 g after filtration.



   The solid was carefully extracted with ether, and a dark insoluble residue was separated. The ethereal solution was decolorized with neutral alumina. After concentration and cooling to -30, 495 g of 2-furyl 2,5-dimethylpyrrol-3-yl ketone, M.P.



  97-98.



   The indicated compound is also prepared by reacting the Grignard derivative of 2,5-dimethylpyrrole with 2-furoyl chloride. Initially, the Grignard reagent is prepared by placing 3.6 g of magnesium in a round bottom flask in a device protected from humidity, and the device is then purged with dry nitrogen. a sufficient quantity of anhydrous ether is then added to cover the magnesium (20 ml).



   Then 2 g of methyl iodide is added to initiate the reaction. As soon as the reaction begins, a solution of 14.3 g of methyl iodide in 25 ml of dry ether is added, with stirring, at a rate sufficient to maintain reflux. Once the addition is complete, reflux and stirring are continued for one hour.

 <Desc / Clms Page number 16>

 



   The external heating is then stopped and a solution of 9.5 g of 2,5-dimethylpyrrole in 10 ml of dry ether is added dropwise at a rate sufficient to maintain reflux. Stirring is continued for a further 30 minutes, during which time a heavy precipitate forms.



   30 ml of dry benzene are added and the reaction mixture is cooled to above -10. While stirring, slowly added a solution of 14.3 g of 2-furoyl chloride in 20 ml of benzene, maintaining the internal temperature between -la and -50. Stirring was continued for a further two hours while the reaction mixture returned to room temperature.



   The reaction mixture is then cooled in an ice bath, and 30 ml of 25% aqueous ammonium chloride is added, followed by 100 ml of water. The layers are then separated ot the organic layer is washed successively with water, with two portions of 50 ml of 10% aqueous sodium hydroxide, and again with water. After drying, the solvent is removed under reduced pressure and the residue is triturated with five 20 ml portions of hexane, then filtered. The product is dissolved in benzene and decolorized by passing through a short column of alumina. Concentration of the benzene eluate provides 14 g of pure product, m.p. 98-99.



   The compound thus prepared is incorporated into the following composition intended to serve as a capsule:
 EMI16.1
 
<tb>
<tb> ingredient <SEP> Mg / Capsule
<tb>
 
 EMI16.2
 2-Furyl 2,5-dimethylpyrrol-3-yl ketone 15
 EMI16.3
 
<tb>
<tb> Lactose <SEP> 150
<tb> Cab-0-Sil <SEP> (<SEP> colloidal <SEP> silica) <SEP> 2.5
<tb>
 
The above mixture is mixed well, sieved through a 60 mesh screen and amalgamated into double-core hard gelatin capsules.
 EMI16.4
 



  Analogous anti-inflammatory compounds are prepared using the method of the previous Example, reacting other suitable acid halides in place of the 2-furoyl chloride reagent. In this way the following compounds are prepared which can be administered by capsule or otherwise.
 EMI16.5
 



  4,5-Dibromo-2-furyl 2, s-dimévhy.pyrrol .-? - yl ketone 5-Bromo-4-isopropyl-2-furyl 2,5-dimethylpyrrol-3-yl ketone 4-Bromo-5-methyl -2-furyl 2,5-dimethylpyrrol-3-yl ketone
 EMI16.6
 3-Chloro-2-furyl 2, j-dimethylpyrrol-3-yl ketone 5-Nethoxy-2-furyl 2,5-dimethylpyrroy-3-yl ketone 3,5-Dichloro-2-furyl 2 ,, 5-dimé, 'aylpfrxoi-3-yl ketone 5-Acetyl-2-furyl 2 <5-in; -: hylpyrrul-s-'. 5-ri-hoxyrnethyl-2-furyl ketone 2,! :: - dimethylpyrrol; ', ;;

  "yI ketone 5-Isopropoxy-2-furyl 2, S-dimethylpyrrol-3-yl ketone

 <Desc / Clms Page number 17>

   5-Methyl-4-sulfamoyl-2-furyl 2,5-dimethylpyrrol-3-yl ketone
 EMI17.1
 2,5-Dimethylpyrrol-3-yl 5-piperidirO-2-furyl ketone 1 5-Ethylthio-2-furyl 2,5-dimethylpyrrol-3-yl ketone. Example 31
 EMI17.2
 Tablets containing 5-bromo-2-furvl 2 5-dimeth rrol-3- 1 ketone
The above active compound is prepared by reacting 5-bromo-2-fqroyl chloride with the Grignard derivative of 2,5dimethylpyrrole.

   In order to form the Grignard reagent, 19.02 g of
 EMI17.3
 C, 5-diniethylpyrrolo are added dropwise with stirring to a Grignard solution prepared from 5.84 g of magnesium and 26.4 g of ethyl bromide in 200 ml of anhydro ether. The mixture is stirred for 30 minutes after the addition is complete. A solution of
 EMI17.4
 50.3 g of 5 ± bromo-2-uroyl chloride in 150 ml of anhydrous benzene is added, and the reaction mixture is stirred for 2 hours, then heated under reflux for 0.5 hour. 35 ml of 25% aqueous ammonium chloride is added to quench the reaction. The organic layer is separated, washed with water, with 10% aqueous sodium bicarbonate, and with water, then dried.

   After concentration a solid is obtained, m.p. 165-167. The product is recrystallized from ethyl acetate / benzene (1: 1) to give yellow crystals, m.p. 166-167.



   The compound thus prepared is incorporated into the following composition for tabletting s
 EMI17.5
 Têdient Mc, (Compr3.rné 5-Bromo-2- ùryl 2,5-dimethylpyrrol-
 EMI17.6
 
<tb>
<tb> 3-yl <SEP> ketone <SEP> 25
<tb> Lactose <SEP> USP <SEP> 100
<tb> Magnesium <SEP> <SEP> stearate <SEP> 1.2
<tb>
 
 EMI17.7
 Polyvinylpyrrolidone 6
 EMI17.8
 
<tb>
<tb> Ethnol <SEP> absolute <SEP> to <SEP> will
<tb>
 
The ketone product is first mixed with the lactose, the mixture is sieved through a 40 mesh screen, and remixed. The PVP is dissolved in alcohol and used to granulate the powdered mass, after which the mixture is sieved through a 12 sieve, and dried at 43-49 C to a moisture content of 1.5%.

   The mass is then sieved through a 16 sieve, and to it is added magnesium stearate (which has been previously sieved through a 40 mesh sieve). The composition is mixed and compressed into tablets.



   Example 32
 EMI17.9
 suppositories containing 3-furvl 2,5-dimethvlpvrrol-3-vl ketone The above product is prepared by reaction of chloride of

 <Desc / Clms Page number 18>

 3-furoyl with the Grignard reagent of 2,5-dimethylpyrrole. Initially, 3-furoyl chloride is prepared by heating a mixture of 20 g of 3-furoic acid and 30 g of thionyl chloride in a steam bath for 8 hours. The excess thionyl chloride is evaporated, and the residue is extracted twice with benzene, then distilled to
 EMI18.1
 give 3-furoyo 'chloride. P.E, 4fi, 5 under 15 mm.



   Then 3.43 g of 2,5-dimethylpyrrole is added to a Grignard solution prepared from 0.9 g of magnesium and 4.07 g of ethyl bromide in 30 ml of ether. The mixture is stirred for 30 minutes after the addition is complete. A solution of 4.4 g of 3-furoyl chloride in 15 ml of anhydrous benzene is added, and the mixture is stirred under nitrogen for two hours, then heated to reflux.
 EMI18.2
 for 0.5 hour. 5 ml of 1 ammoii.4- = chloride are added. * .qut-ux- a lez to calm the reaction. The organic layer is separated, washed with water, with 10% aqueous sodium bicarbonate, and with water, then dried. After concentration, a solid of m.p. 90-95 is obtained.



  The product is decolorized on an alumina column, recrystallized twice from benzene and dried under vacuum to give a solid, P.P.



  99-100.



     The active compound thus prepared is thoroughly mixed with cocoa butter to provide 2 g suppositories of the following composition:
 EMI18.3
 ingredient PzcrfSunpositoire 2-Furyl 2 $ 5-dimethylpyrrol-3-yl ketone 100 qs cocoa butter
Analogous therapeutically active compounds are prepared by reacting other acid halides in place of 3-furoyl chloride, employing the method of the previous Example. The following compounds are thus prepared:

   
 EMI18.4
 5-hcetyl-3-furyl 2,5-dimthylpyrro, -3-y3, ketone 2,5-Dimethyl-3-furyl 2,5-dimethylpyrrol-3-yl ketone 2-liethyl-s-phenyl-3-furyl 2 , 5-dimethylpyrrol-3-yl ietone 5-Bromo-3-furyl 2,5-dimethylpyrrol-3-yl ketone
Example 33
 EMI18.5
 2,5-dimethylpyrroi-3-VI 2-thienyl ketone suspension
The above active compound is prepared by reacting 2-thiophene carboxylic acid chloride with the Grignard derivative of
 EMI18.6
 2,5-dimethylpyrrole.



   The Grignard reagent is first prepared by adding 16.14 g of 2,5-dimethylpyrrole to a Grignard solution prepared from 4.12 g of magnesium and 10.7 g of ethyl bromide in 150 ml of Anhydrous ether. The mixture is stirred for 30 minutes after the end of the addition.

 <Desc / Clms Page number 19>

 Then an aolution of 25 g of acid chloride is added.
 EMI19.1
 2-thiophenacqrboxyliqu in 100 ml of anhydrous benzene. The reaction mixture is stirred for two hours, then refluxed for 30 minutes. 30 ml of aqueous ammonium chloride is added to quench the reaction.

   The organic layer is separated, washed with water, with bicar-
 EMI19.2
 bonn% o da aqueous sodium t 10%, at nvoa do oau, puin cÓoh6Q. 1lxn -concentration we obtain two products. The second product gives yellow needles, m.p. 124.5-125, after recrystallization from benzene.



   The compound thus prepared is dispersed in a PVP solution having the following composition:
Ingredient
 EMI19.3
 , B.imâthylpyrra3 .-. By9. 2-thienyl ketone 15 mg / LI Carboxymethylcellulose sodium 7 MSP 1% pa, yviny.pyrrolidona (Plasdone, Brand of
 EMI19.4
 
<tb>
<tb> Factory <SEP> Registered) <SEP> 1 <SEP>%
<tb> Tween <SEP> 80 <SEP> (<SEP> sorbitan monooleate <SEP>) <SEP> 0.1-0.5 <SEP>%
<tb>
 
 EMI19.5
 Mdthylparabon (methyl p-hydroxybenzoate) 0.1E3% Propylparaben (propyl p-hydrdxybonzoate) 0.02%
 EMI19.6
 
<tb>
<tb> Water <SEP> qs
<tb>
 
 EMI19.7
 tA ç1i1Qt'tJ1Qn tint 1 ") f6f1nt'Î $ c on {11!; 1AQlvnt;

   10 methyl paraben and propyl paraben in boiling water, allowing the solution to cool, adding the sorbitan monooleate, and mixing well. PVP and CNC are dissolved separately in water, after which the active ketone product is dispersed in the solution.
 EMI19.8
 tion of PVP, and the two solutions are well mixed.



   Analogous active ketones are prepared as described in Example 33, using other thiophenecarboxylic acid chloride reagents. In this manner, the following ketones are prepared 1
 EMI19.9
 , 5-Dimethylpyrrol-3-yl-3-methylthio) -2-thienyl ketone 2,5-Dimethylpyrrol-3-yl 4-methyl-2-thienyl ketone 2,5-Dimethylpyrrol-3-yl S-methoxy-2- thienyl ketone 2,5-Dimethylpyrrol-3-yl 3-thienyl ketone
 EMI19.10
 2,4,5-Trirnethylpyrrol-3-yl 5-nitro-3-thienyl ketone 2,5-Dimethylpyrrol-3-yl 2,5-di-tort-butyl-3-thienyl ketone.



  Example 34 Emulsions containing 2,5-Dimethylpvrrol-1-methylpyrrol-2-21 ketone The above active compound is prepared by reacting chlo-
 EMI19.11
 rura of, -methylpyrrolQ-2-caxbonyl with the Grignard derivative of 2,5-dim6thylpyrrole. The acid chloride reagent is first obtained by adding 60 g of thionyl chloride with stirring to a solution-

 <Desc / Clms Page number 20>

 58 g of 1-methylpyrrole-2-carboxylic acid and 102 g of triethylamine in 100 ml of anhydrous benzene. The mixture is refluxed for one hour, then it is filtered and evaporated to remove the solvents.



  After distillation, 40 g of 1-methylpyrrole-2-carbonyl chloride, m.p. 72-74, under 1.0 mm are obtained.



   Then 10.03 g of 2,5-dimethylpyrrole is added, dropwise with stirring, to a Grignard solution prepared from 5.84 g of magnesium and 26.4 g of ethyl bromide in 200 ml of Anhydrous ether. The mixture is stirred for 30 minutes after the end of the addition. A solution of 31 g of 1-methylpyrrole-2-carbonyl chloride in 100 ml of anhydrous benzene is added, and the reaction mixture is stirred. for two hours, then heated to reflux for 0.5 hour. 35 ml of 25% aqueous ammonium chloride is added to quench the reaction. The organic layer is separated, washed with water, with 10% aqueous sodium bicarbonate, and with water, then dried. After concentration, 32 g of product, m.p. 120-125, are obtained in two harvests.

   The product is recrystallized twice from benzene and then dried under vacuum to give 31 g (80%) of a solid, m.p. 138.5-140.



   The compound thus prepared is emulsified in the following composition:
 EMI20.1
 
<tb>
<tb> Ingredient <SEP> Gram $ / Liter
<tb> 2,5-Dimethylpyrrol <SEP> 1-methylpyrrol-2-yl <SEP> ketone <SEP> la, 0
<tb> <SEP> Oil <SEP> Mats <SEP> 500
<tb> Polyoxyethylene <SEP> Sorbitan <SEP> <SEP> monostearate <SEP> 50
<tb> Monooleate <SEP> of <SEP> Sorbitan <SEP> 50
<tb> Sucrose <SEP> USP <SEP> 50
<tb> Methylparaben <SEP> USP <SEP> they
<tb> Propylparaben <SEP> USP <SEP> 0.2
<tb> Solution <SEP> of <SEP> Sorbitol <SEP> 5.0
<tb> Perfume <SEP> qs
<tb> Colorant <SEP> qs
<tb> Water <SEP> qsp <SEP> 1000 <SEP> ml
<tb>
 
The active drug is first dissolved in corn oil with the help of gentle heating.

   The oil is then mixed with polyoxyethylene sorbitan monostearate and sorbitan monooleate, and warmed to 50 C, The mixture of sucrose and parabon is dissolved in water heated to 60 C, and the resulting aqueous phase is added to the oily phase with stirring. The sorbitol solution is then added, and the emulsion is allowed to cool, after which the perfume is added. Q.S. and mix well.



   0.05% butylated hydroxyanisole can be added to corn oil as an antioxidant.

 <Desc / Clms Page number 21>

 



   The following examples illustrate the preparation of other heteroaromatic pyrrol-3-yl ketones which demonstrate therapeutic action according to the present invention. Such substances can be administered to mammals in various formulations described above or, alternatively, they can be incorporated into other pharmaceutically acceptable excipients suitable for oral, parenteral, or rectal administration; Example 35 3,4,5-Trichloro-2-furyl 2,5-dimethyl-pyrrol-3-yl ketone
Chlorine gas is passed through rapidly stirred methyl 2-furoate for three hours.

   The product which distils from the reaction mixture at 137-147 under 14 mm is hydrolyzed using 40% aqueous sodium hydroxide. The reaction is exothermic and the sodium salt of 3,4,5-trichloro-2-furoic acid precipitates. The mixture is acidified and extracted with ether. The ethereal solution is evaporated to give 3,4,5-trichloro-2-furoic acid, m.p. 176-177. 10 g of the acid and 50 ml of thionyl chloride are heated in a steam bath until no more sulfur dioxide or hydrochloric acid is released. The mixture is evaporated twice from benzene, and the residue is distilled to give 3,4,5-trichloro-2furoyl chloride, m.p. 112-116 under 14 mm.



   6.34 g of 2,5-dimethylpyrrole are added to a Grignard solution prepared from 1.7 g of magnesium and 7.7 g of ethyl bromide in 70 ml of anhydrous ether. The mixture is stirred for 30 minutes after the end of the addition, a solution of 11.2 g of 3,4,5-trichloro-2-furoyl chloride in 70 ml of anhydrous bensene is added, and the reaction mixture is added. stirred for two hours then refluxed for 0.5 hour. 12 ml of 25% aqueous ammonium chloride is added to quench the reaction. The organic layer is separated, washed with water, with aqueous sodium bicarbonate :. at 10%, and with water, then dried. After concentration, 5 g of solid are obtained, m.p. 195-200.

   The product is subjected to chromatography on alumina and recrystallized twice from benzene to give yellow platelets which melt at 202-203 after drying in vacuo.



   - Example 36 2,5-Dimethylpyrrol-3-yl 5-Nitro-2-Furyl ketone
13.3 g of 2,5-dimethylpyrrole are added to a solution of 32 g of boron trifluoride etherate and 26 g of 5-nitro-2-furoyl chloride in 50 ml of benzene. After standing at room temperature for 72 hours, the reaction mixture is poured onto 60 ml of ice and water, and the solid is collected by filtration. After purification, it melts at 209-210.

 <Desc / Clms Page number 22>

 Example 37
 EMI22.1
 5-Amino-2-Furyl 2 ,,, 5-Dimethylbrrrol-3-vl ketone
A 10 g portion of 2,5-dimethylpyrrol-3-yl 5-nitro-2furyl ketone, 300 ml of ethanol, and 1.0 g of 10% palladium on charcoal, are combined and shaken under an atmosphere of 20. , 4 kilograms of hydrogen for 20 minutes.

   Filtration of the catalyst and evaporation of the solvent gives the crystalline product.



   Example 38
 EMI22.2
 5-FormamidoPhénvl 2,5-DiméthvlPvrrol-3-vl ketone
The product of Example 37 is heated for five minutes with formic acid, and the resulting solution is poured into water. The crude formamide crystallizes and is purified by recrystallization from dimethylformamide and from water.



   Example 39
 EMI22.3
 2-Furvl 1,2.5-Trimethyln, yrrol-3 = yl ketone
A mixture of 56.8 g of boron trifluoride etherate, 26.0 g of 2-furoyl chloride, 21.8 g of 1,2,5-trimethylpyrrole and 50 ml of anhydrous benzene is left at rest for 72 hours in the absence of moisture. It is then stirred in 150 g of ice and water. The organic layer is collected and concentrated. The residue is stirred for 30 minutes with aqueous sodium hydroxide to remove 2-furolque acid. The organic product is extracted into benzene. The solution
 EMI22.4
 tion bong4g ', that have <3iami <So for ttonnof the pr.ciy.L.



  Example 40 2-Furvl 2,5-Dimethvl-1-Phénvlpvrrol-3-vl keton 2,5-dimethyl-1-ph6nylpyrrolo, P.P. 50-51, with 2-furoyl chloride under the conditions of Example 39 to obtain the product, m.p. 154-155, in a yield of 54%.
 EMI22.5
 



  Likewise, 1-cyclohexyl-2,5-dim6thylDyrrole, m.p. 47-48, is converted to 1-cyclohemyl-2,5-dimethylpyrroX-3-yl 2-furyl ketone; 1-Benzyl-2,5-dimethylpyrrole, m.p. 48-49, is converted to 1-benzyl-2,5-dim6thylpyrrol-3-yl 2-furyl ketone; and 1-allyl-2,5dimethylpyrrole is converted to 1-allyl-2,5-dim6thylpyrrol-3-yl 2-furyl ketone by the corresponding methods.
Example 41
 EMI22.6
 3-Isobutvl-2,5-Dimethrrrol-3-Y1 2-Puryl ketone
33 g of 3-isobutyl-2,5-dimethylpyrrole are added to a Grignard solution prepared from 5.7 g of magnesium and 34 g of methyl iodide in 100 ml of anhydrous ether. The mixture is stirred for 30 minutes after the addition is complete. 31 g of 2-furoyl chloride, dissolved in 100 ml of benzene, are added and the mixture is stirred for two hours.

   75 ml of 25% aqueous ammonium chloride is added to quench the reaction. The layers are

 <Desc / Clms Page number 23>

 separated and the organic layer is washed with water and sodium hydroxide. The organic layer is dried over calcium carbonate and evaporated to give 30 g of solid, m.p. 220-224. After two recryst.ailizations in ethanol, the product melts at 224-225.



   By the method of Example 41, using appropriate pyrroles in place of 3-isobutyl-2,5-dimethylpyrrole, and appropriate acid halides in place of 2-furoyl chloride, the following compounds are prepared :
 EMI23.1
 3-Butyl-2,5-dimethylpyrrol-3-yl, S-methyl-2-furyl keto 3-isoprolyl-2,5-dimethylpyrrol-3-yl 2,, 5-trimethyl-3-furyl ketone
4-Bromo-5-methoxy-2-furyl 2,5-diethylpyrrol-3-yl ketone 3-Ethyl-2-methyl-5-phenylpyrrol-3-yl 5-tert-butyl-2-furyl ketone
 EMI23.2
 2-Methyl-5-phenylpyrrol-3-y1 5-sulfamoyl-2-furyl ketone 4-Cyclohexyl-2,5-dimethylpyrrol-3-yl 5-propargyl-2-furyl ketone.

   Example 42
 EMI23.3
 2,5-Dimeth-vlpyrrol-3-vl Pvrrol-2-vl ketone
A solution of 44.4 g of pyrrole-2-carboxylic acid and 40.8 g of triethylamine in 100 ml of anhydrous benzene is added dropwise, over 20 minutes, to a solution of 43.2 g of chloroformate d ethyl in 100 ml of anhydrous benzene at 0 C. The mixture is filtered after standing for 20 minutes more at 0. The ethyl ester of carbonic acid and 2-pyrrole carboxylic acid anhydride collected is dissolved in 50 ml of anhydrous benzene containing 113.6 g of boron trifluoride etherate. 38.1 g of 2,5-dimethylpyrrole are added to the solution which is maintained at room temperature for 72 hours. The reaction mixture is poured into 100 ml of ice water.



   The organic layer is separated, washed twice with water, dried and evaporated to give an oil which is treated with water.
 EMI23.4
 40% aqueous soda for one hour. The mixture is diluted with water and extracted twice with ethor ,. After evaporation of the dried ethereal fractions, an oil is obtained which crystallizes after tritura-
 EMI23.5
 tion with oyclohexane-benzene mixture, to give a solid, m.p. 140-147, which is recrystallized twice from benzene and dried in vacuo to give crystals at m.p. 156-157.



   By the method of Example 42, using the appropriate acids, the following compounds are prepared:
 EMI23.6
 5-16thyl-2-pyrazolin-5-yl 2,5-dimethylpyrrol-3-yl ketone, 3-Isobutyl-4-mdthyl-2-pyrazolin-4-yl 2,5-dimethylpyrrol- sayl ketone Di (2,5 -dimethylpyrrol-3-yl) ketone 1 ..it

 <Desc / Clms Page number 24>

 
 EMI24.1
 2, 5-D3.methylpyrxol-3-y. 4-benzy, -2.5-d3methyl, pyrro, -3-yl ketone
Example 43
 EMI24.2
 5-Dimdth 1 rral-3- 1 4-Pyridvl ketone A solution of 59.40 g of ethyl chlorsr'srmate in 100 ml of anhydrous benzene at 0 is added, with stirring, to a solution of 67.65 g of isonicotinic acid and 56.1 g of triethylamine in 100 ml of anhydrous benzene. The mixture is stirred at 0 for 20 minutes then filtered.

   The ethyl ester of carbonic acid anhydride and pyridin-4-carboxylic acid collected is dissolved in 15 ml of anhydrous benzene and set aside.



   47.5 g of 2,5-dimethylpyrrole are added dropwise with stirring to a Grignard solution prepared from 13.4 g of magnesium and 60.53 g of ethyl bromide in 500 ml. anhydrous ether. The mixture is stirred for 30 minutes after the end of the addition.



  The benzene solution of the ethyl ester of carbonic acid anhydride and pyridin-4-carboxylic acid is added, and the mixture is refluxed for three hours. The reaction is quenched with water. The organic layer is separated and treated with dilute hydrochloric acid, then extracted with ether. The aqueous layer is treated with 40% aqueous sodium hydroxide and then extracted with ether. The ethereal extract is dried and evaporated to give a solid, mp 192-193, which is subjected to chromatography on alumina with benzene, then recrystallized twice from benzene and dried under vacuum to give crystals at mp 197-198. .



   Similarly, pyrazinotque acid produces 2,5-
 EMI24.3
 dim6thylpyrrol-3-yl pyrazinyl ketone, 3-pyridinecarboxylic acid produces 2,5-dimethylpyrrol-3-yl 3-pyridyl ketone, and pyri-midin-2-carboxylic acid produces 2,5-dimethylpyrrol-3 -yl pyrimidin-2-yl ketone.



   Example 44
 EMI24.4
 2-Methvl-5-Phénvlpvrrol-3-vl 3-Thienyl ketone
2-Methyl-5-phenylpyrrole is treated with boron trifluoride and 3-thiophenccarboxylic acid chloride in benzene, by the method of Example 39, to give the desired product.
 EMI24.5
 



  Similarly, 2-% 4-chlorophenyl) -5-methylpyrrole, PF 125-126, leads to 5- (4-chlorophenyl) -2-methylpyrrol-3-yl 3-thienyl ketone, and 2 , 4-dimethyl-5-phenylpyrrole, PF 74, produces 2,4-dimethyl-5-phenylpyrrol-3-yl phenyl ketone.



   Example 45
 EMI24.6
 2- (2-Chlorophenyl) -5-Methvl-4-Isoxazolvl 2, -5-Dimethyl-Pyrrol-3-yl ketone
28.5 g of 2,5-dimethylpyrrole are added to a Grignard solution prepared from 8.5 g of magnesium and 38.5 g of

 <Desc / Clms Page number 25>

 ethyl bromide in 300 ml of anhydrous ether. The mixture is stirred for 30 minutes after the end of the addition. 87 g of chloride are added
 EMI25.1
 3- (2-clilarophenxl) -5-methyh4-, soxaxolecarbonyl, and the reaction mixture is stirred for two hours, then refluxed for 30 minutes. 50 ml of 25% aqueous ammonium chloride is added to quench the reaction. The organic layer is separated, washed with water; with 10% aqueous sodium bicarbonate, and with water, then dried. After concentration, the product crystallizes.

   After discoloration
 EMI25.2
 on a short column of alumina, recrystallization from benzene and drying in vacuo, a solid was obtained at mp 7a, 5-1-9. by the method of Example 45, in. using the appropriate acids, the following compounds are prepared 2-Benzyl-5-methyl-4-oxazolyl 2,5-dimethylpyrrol-3-yl ketone
5-Methyl-2-phenyl-4-oxazolyl 2,5-dimethylpyrrol-3-yl ketone 4-Methyl-5-oxazolyl 2,5-dimethylpyrrol-3-yl ketone
 EMI25.3
 3-soxazo71.2,4,5-trimethylpyrrol-3-yl ketone 5-Methyl-4-isoxazolyl 2,5-dimethylpyrrol-3-yl ketone 2-Mercapto-1-methylimidazol-5-yl 2,5-dimethylpyrrol- 3-yl ketone I-Benzylimidazol-2-yl 2,5-dimethylpyrrol-3-yl ketone
 EMI25.4
 3-Methyl-5-isothiazolyl 2,

  5-Dimethylpyrrol-3-yl ketone 2,5-Dimethylpyrrol-3-yl tetrazol-5-yl ketone 5-Acetamido-2-thiazolyl 2,5-dimethylpyrrol-3-yl ketone
 EMI25.5
 2-Hydroxy-4-methyl-5-thiazolyl 2,5-dimethylpyrrol-3-yl ketone
Example 46
 EMI25.6
 -Meth l-1 2 5-Qxadiazol-3- 2,5-Diméthv1pvrrol-3-vl ketone 14.6 g of 4-methyl-l, 2,4-oxadiazole-3carboxylic aid monohydrate are distilled at z6otrop. ', Quite with benzene to remove one mole of water, 20.4 g of triethylamine is added, and the mixture is cooled. 23.6 g of thionyl chloride are added, and the mixture is stirred for two hours, then filtered. The filtrate is diluted with benzene and evaporated twice to give the chloride of
 EMI25.7
 4-methyl-1,2,5-oxadiazole-3-carbonyl.



   8.07 g of 2,5-dimethylpyrrole are added to a Grignard solution prepared from 2.06 g of magnesium and 9.35 g of ethyl bromide in 75 ml of anhydrous ether. The mixture is stirred for 30 minutes after the end of the addition. A solution of 11.9 g of 4-methyl-1,2,5-oxadiazole-3-carbonyl chloride in 40 ml of anhydrous benzene is added. The mixture is stirred for two hours and then refluxed for 30 minutes. 15 ml of 25% aqueous ammonium chloride is added to quench the reaction.

   The organic layer is separated, washed with water, with 10% aqueous sodium bicarbonate,

 <Desc / Clms Page number 26>

 and with water, then dried, After concentration we obtain a total
 EMI26.1
 of 14.2 g t83 6) of solid, PF 130-1439, The product is decolorized on an alumina column, recrystallized twice from benzene and dried under vacuum to give yellow plates, PF 144-145 .



   By the method of Example 46, using the appropriate acids, the following compounds are prepared: 5-Methyl-1,2,4-oxadiazol-3-yl 2,5-dimethylpyrrol-3-yl ketone
 EMI26.2
 5-Benzyl-1,2,4-oxadiazol-3-yl 2,4,5-trimethylpyrrol-3-yl ketone
4-Carbamoyl-1,2,5-thiadiazol-3-yl 2,5-dimethylpyrrol-3-yl ketone
 EMI26.3
 5-Ac6tamido-1,3,4-thiadiazol-2-yl 2,5-dimethylpyrrol-3-yl ketone 5-Cyano-v-triazol-4-yl 2,5-dimethylpyrrol-3-yl ketone
 EMI26.4
 1-enzyl-5-mercapto-1, H-1,2,3-triazox - y. 2,5-dimethylpyrrol- 3-yl ketone
It will be appreciated that various modifications can be made to the preferred embodiments described above, without departing from the scope of the methods and compositions of the present invention.

   Consequently, it is understood that the preceding description should be considered in an illustrative and non-limiting sense.

 

Claims (1)

CLAIMS 1, Compounds of formula! EMI27.1 wherein R1 is hydrogen or a lower alkyl, lower alaenyl, or cycloalkyl radical having not more than six carbon atoms, benzyl, benzoyl, phenyl ,. or halo-, lower alkoxy- or lower alkyl-benzyl, -benzoyl or-substituted phenyl, the lower alkoxyl and lower alkyl components having no more than four carbon atoms; R2 'R3 and R4 are the same or different and are hydrogens or lower alkyl, lower alkenyl, or cycloalkyl radicals having not more than six carbon atoms, phenyl, phenyl-lower alkyl in which the alkyl n' has not more than four atoms of carbon, halo-, lower alkoxy- or lower alkyl-phenyl or -phenyl-substituted lower alkyl in which the lower alkoxyl and lower alkyl have not more than four atoms of carbon; and R5 is a phenyl, naphthyl, biphenyl, or phenyl, naphthyl or biphenyl mono-, 'di- or tri-substituted radical in which the substituents are hydroxyl, lower alkoxy, lower alkyl, lower alkylene dioxide, phenoxide, nitro, fluorine, chlorine, bromine, iodine, amine, lower alkanoyl-amine, bonzylidene-amine, lower alkyl-amine, di (lower aleoyl) -amine, di (lower alkyl) -amine-N-oxide, ureide, mcrcapto, lower alkyl-thio, phenylthio, lower haloalkyl, lower alkanoyl, lower alkyl -aulfonyl, lower alkyl-sulfonyl, sulfamyl, cyano, carboxamide, carbo-lower alkoxyl, or carboxhydrazide; furyl, pyrryl, thienyl, oxadiazolyl, pyrazolyl, thiadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyridyl, imidazolyl, tetrazolyl, isoxazolyl, pyrimidinyl, triazolyl or isothiazolyl unsubstituted and mono-, di- or tri-substituted in which said substituents are the same or different and are hydrogen, halogen, a nitro, amine, hydroxyl, phenyl, sulfamoyl, carbamoyl, cyano, trifluoromethyl, mercapto, lower alkyl, lower alkyl-thio, lower alkoxyl group , lower alkyl-amine, di (lower alkyl) amine, lower alkanoyl-amine, lower carbalkoxyl, or phenyl-lower alkyl, the carbon chains of the substituted aliphatic substituents having from one to six carbon atoms, provided that, when R2 and R4 are lower alkyl radicals and R5 is a pyridyl or phenyl radical, <Desc / Clms Page number 28> furyl or thienyl, there is at least one substituent other than hydrogen on the heteroaromatic part. 2. A process for preparing the compounds of formula: EMI28.1 wherein R1 is hydrogen or a lower alkyl, lower alkenyl, or cycloalkyl radical having not more than six carbon atoms, benzyl, benzoyl, phenyl, or halo-, lower alkoxy- or lower alkyl-benzyl, -benzoyl or substituted phenyl, the lower alkoxyl and lower alkyl substituents having no more than four carbon atoms; R2 'R3 and R4 are the same or different and are hydrogens or lower alkyl, lower alkenyl, or cycloalkyl radicals having not more than six carbon atoms, phenyl, phenyl-lower alkyl in which the alkyl has no more than four carbon atoms, halo-, lower alkoxy- or lower alkyl-phenyl or -phenyl-substituted lower alkyl in which the lower alkoxyl and lower alkyl have not more than four carbon atoms; and R5 is a mono-, di- or tri-substituted phenyl, naphthyl, biphenyl, or phenyl, naphthyl or biphenyl radical in which the substituents are hydroxyl, lower alkoxyl, lower alkyl, lower alkylene dioxide, phenoxide, nitro, fluorine, chlorine, bromine, iodine, amine, lower alkanoyl-amine, benzylideneamine, lower alkyl-amine, di (lower alkyl) -amine, di (lower alkyl) -amine-N-oxide, ureid, mercapto, lower alkyl-thio, phenylthio, lower haloalkyl, lower alkanoyl, lower alkyl -sulfonyl, lower alkyl-sulfinyl, sulfamyl, cyano, carboxamide, carbo-lower alkoxyl, or carboxhydrazide; furyl, pyrryl, thienyl, oxadiazolyl, pyrazolyl, thiadiazolyl, oxazolyl, thiazolyl, pyrazinyl, pyridyl, imidazolyl, tetrazolyl, isoxazolyl, pyrimidinyl, triazolyl or isothiazolyl unsubstituted and mono-, di- or trisubstitué wherein said substituents are the same or different and are hydrogen, halogen, nitro, amine, hydroxyl, phenyl, sulfamoyl, carbamoyl, cyano, trifluoromethyl, mercapto, lower alkyl, lower alkyl-thio, lower alkoxyl, lower alkyl -amine, di (lower alkyl) amine, lower alkanoylamine, lower carbalkoxyl, or phenyl-lower alkyl, the carbonaceous chains of substituted aliphatic substituents having from one to six carbon atoms, <Desc / Clms Page number 29> characterized by reacting compounds of formula! EMI29.1 with a compound capable of providing the @ 0 radical R5-C- or with its equivalent in the presence of a Friedel-Crafts catalyst, R1, R2, R3, R4 and R5 being as defined above. 3. A pharmaceutical composition containing a) a compound of formula: EMI29.2 in which R1 is hydrogen or a lower alkyl, lower alkenyl, or cycloalkyl radical having not more than six carbon atoms, benzyl, benzoyl, phenyl, or halo-, lower alkoxy- or lower alkyl-benzyl, - benzoyl or substituted phenyl, the lower alkoxyl and lower alkyl substituents having not more than four carbon atoms; R2, R3 and R4 are the same or different and are hydrogens or lower alkyl, lower alkenyl, or cycloalkyl radicals having not more than six carbon atoms, phenyl, phenyl lower alkyl in which the alkyl has no more of four carbon atoms, halo-, lower alkoxy- or lower alkyl-phenyl or -phenyl-substituted lower alkyl in which the lower alkoxyl and lower alkyl have not more than four carbon atoms, - and R5 is a mono-, di- or tri-substituted phenyl, naphthyl, biphenyl, or phenyl, naphthyl or biphenyl radical in which the substituents are hydroxyl, lower alkoxyl, lower alkyl, lower alkylene dioxide, phenoxide, nitro, fluorine, chlorine, bromine, iodine, amine, lower alkanoyl-amine, benzylidene-amine, lower alkyl amine di (lower alkyl) -amine, di (lower alkyl) -amine-N-oxide, ureide, mercapto, lower alkyl-thio, phenylthio, halo lower alkyl, lower alkanoyl, alkyl <Desc / Clms Page number 30> EMI30.1 lower-sulfonyl, lower alkyl-sulfinyl, sulfamyl, cyano, EMI30.2 carboxamide, lower carboalkoxyl, or carboxhydrazide; fur = le, pyrryl, thienylot oxadiazolyl, pyrazolyl, thiadiazolylo, oxazolyl, thiazolyl, pyrazinylo, pyridyl, imidazolyl, t6trazolyl, isoxazolyl, pyrimidinyl, triazolyle ou isothiazolyle unsubstituted tri-ouitud and mono-, dibat; in which said substituents are identical EMI30.3 or different and are 3 hydrogen, a halogen, a nitro group, EMI30.4 aminohydroxyl, phdnylo, sulfamoyl, uarbumoylo, cyano, trifluoromdthylo, morcapto, lower aleoyio, alkyl 1, nf6dc \\ r..thio, aleoxylo in "f4rieur, lower alkyl-amino, di (inf6louran-carbohydrate-aminoyl) mino, nf6dc \\ r..thio infériour, or ph6nyl-alcoylo in; Óriur, the chains eacbendaa of the subatitUlAn1: 11 submtitti6m ir, nt from one to six carbon atoms, lat (b) an excipiont pharmacQut1quomsnt acacp; n>; 1;:.