CA1164877A - 1-(2-acyl-aminophenyl)imidazoles - Google Patents

Abstract

ABSTRACT

Novel 1-(2-acylaminophenyl) imidazole compounds of the formula:

in which -X2 is -R5 or -NHR2, wherein:
(1) R5 is an aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl or monocyclic aryl substituted aliphatic group bonded to the carbonyl carbon through a carbon-to-carbon linkage; and (2) R2 is a radical bonded to the nitrogen by a carbon to nitrogen linkage and selected from the group consisting of aliphatic, cycloaliphatic, phenyl, substituted phenyl and fused bicyclic aryl; and methods of making same from 1-(2-aminophenyl)imidazole are disclosed. These compounds are useful as intermediates in the preparation of certain 4-substituted imidazo [1,2-a] quinoxalines, which exhibit one or more of the following activities: immunosuppressant, anti-inflammatory and antifungal activity.

Description

This in~ention relates to certain 4-substituted imida~o-[1,2-a]quinoxalines and to processes for preparing the same.
It also concerns certain 1-(2-acylaminophenyl)imidazoles which among other things are useful as intermediates in the preparation of 4-substituted imidazo[l,2-a]quinoxalines. The aforesaid compounds are useful for a variety of purposes which will be described in more detail below. Some of these are useful as immunosuppressants; whereas, others are useful as anti-inflammatory agents or display antifungal activity. Moreover, some exhibit two or all three of these activities.
The 4-substituted imidazo~l,2-a]quinoxalines encom-passed in the present invention may be described by the formula:

~ ~
N ~ ~ X
I ~ J

and pharmaceutically acceptable salts thereof wherein X is _Rl or -NHR wherein:
(1) Rl is bonded to a ring carbon by a carbon-to-carbon linkage and is an aliphatic, cycloaliphatic, substituted phenyl, fused bicyclic aryl; or monocyclic aryl-substituted aliphatic; and

(2) R2 is a radical bonded to a nitrogen by a carbon to nitrogen linkage; said radical being selected from the group consisting of aliphatic, cycloaliphatic, phenyl, substituted phenyl, and fused bicyclic aryl - 1 - ~.

1 1 64~77 When Rl is an aliphatic group, it may be a straight chain or branched chain hydrocarbon group which is saturated, monounsaturated or polyunsaturated. It may also comprise a straight chain or branched chain group containing other than carbon-to-carbon bondings e.g. ether linkages, carbon to halogen linkages, etc. Ordinarily, it will contain from about 1 to 18 carbon atoms, the most typical radicals of this group being the alkyl radicals having from 1 to 18 carbon atoms.
By way of illustrating the aliphatic groups that may be represented by Rl, the following are given: CH3-;

3 2 3 2 CH2 ; CH3(CH2)n- in which n is 3 4 5 6 7 8, 14 and 16 respectively; (CH3)2CH-CH2-; CH3(CH2)3(CH3CH2)CH-, CH2=CH-(CH2)8-, alkoxyalkyl in which the alkyl moieties have from 1 to 4 carbon atoms e.g. methoxymethyl; halogenoalkyl (i.e. CH2C1-; CH3CHCl-; CHC12-; CC13-; CH2Br-; CF3).

When R is a cycloaliphatic radical it will most often be a cycloalkyl radical containing 3 to 8 carbon atoms or a cyclo-alkenyl radical containing 5 to 6 carbon atoms. By way of illustrating the cycloaliphatic radicals that may correspond to Rl in formula I mention may be made of the cyclopropyl (i.e. ~ ); cyclobutyl (i.e. ~ ); cyclohexyl, cyclohexenyl (i.e. ~ ); and norbornenyl (i-e- ~ ) -When R iS a substituted phenyl radical in formula I
above, the phenyl group may have from 1 to 5 substituents but will usually be mono, di or trisubstituted. Typical among the groups that may be contained in the phenyl group are (a) alkyl groups whiCh are branched or straight chain containing 30 1 to 6 carbon atoms e.g. methyl, ethyl, tertiary butyl; (b) alkoxyl groups containing 1 to 6 carbon atoms e.g. methoxy ~ 1 64~77 ethoxy; (c) hydroxy; (d) acyloxy containing 1 to 18 carbon atoms,(e) halogen e.g. 1 or 2 Cl, F, Br, I preferably in the meta and/or para position; (f) nitro; (g) amino; (h) acylamino in which the acylamino moiety is derived from an alkanoic acid containing 1 to 18 carbon atoms and benzamides in which the benze~e ring is unsubstituted or monosubstituted, disubstituted or trisubstituted with alkyl groups conta~ning 1 to 5 carbon atoms or halogen atoms; (i) polyhydroxyalkylamino groups containing

4 to 8 carbon atoms; (j) cyano; (k) trifluoromethyl; (1) mercapto;
~m) alkylthio; (n) acylthio containing 1 to 18 carbon atoms;
(o) carboxyl; (p) carboalkoxyl containing 1 to 8 aliphatic carbon atoms; (q) phenyl; (r) phenoxy, and combinations thereof.
When Rl is a fused bicyclic aryl radical, it may be a substituted or unsubstituted radical. These are exemplified by such fused bicyclic hydrocarbon radicals as l-naphthyl, 2-naphthyl etc.
When Rl is a monocyclic aryl substituted aliphatic radical, the monocyclic aryl moiety may be either of the substituted or unsubstituted variety. The aliphatic moiety of this group may be either of the saturated or unsaturated straight chain or branched chain hydrocarbon variety or it may contain other than carbon-to-carbon bonding. This may be illustrated by such groups as phenoxymethyl; benzyl, styryl, IH ( ~ ~ C- , ~

The group R2 in the radical -NHR of formula I above is exemplified by the same radicals given above in illustrating the radical -Rl. In addition, R2 may also be phenyl as in the case of the group -NH - ~ .

I 1 6~77 In general, the compounds included in formula I
above as well as the cases in formula I in which X is hydrogen or phenyl may be prepared by heating the corresponding 1-(2-acylaminophenyl)imidazole at reflux in the presence of cyclizing quantities ofa cyclizing agent e.g. polyphosphoric acid or phosphorous oxychloride, etc. for sufficient time to cause significant cyclization of this reactant. More particu-larly, the l-(2-acylaminophenyl)imidazole reactants that can be employed in this process may be described by the general N

10 formula: ~ \
~ \>
N o II ~ NHC-X

15 in which x2 is R5 or -NHR2 wherein:
R5 is an aliphatic, cycloaliphatic, phenyl or substituted phenyl, fused bicyclic aryl or monocyclic aryl substituted aliphatic radical and R2 has the same values assigned to it in connection with formula I above.
The group R5 in formula II is illustrated by the same groups that illustrate Rl in formula I. However, in addition, R5 may also be illustrated by the phenyl radical.
The reaction can be depicted by the following equation:

III N x2 Phosphorous ~ N ~ X2 P~eflux ~N

IV

1 1 64~77 The process of equation III is preferably carried out in the presence of an excess of an organic amine solvent.
A variety of solvents may be used for this purpose among which mention may be made of the following: pyridine, 2,6-dimethyl-pyridine, N,N-dimethylaniline, trimethylamine, and N-methyl-morpholine, etc. However, the preferred organic solvent is pyridine.
The quantity of phosphorous oxychloride that is employed in the reaction can vary somewhat. Generally, however, the phosphorous oxychloride will be employed in the range of from about one-half mole to about 6 moles and preferably one-half mole to two moles per mole of compound II.
The desired product IV may be recovered from the reaction mixture using any of the ordinary techniques well known to those skilled in this art. The time of reaction will vary depending upon, among other things, the particular reactants or molar quantities of reactants employed. In general, the reaction time will be from about 30 to 120 minutes.
The temperature employed in carrying out the reaction will also vary depending upon the particular reactants selected, the solvent and other factors. Ordinarily, the temperature employed will be the reflux temperature of the reaction mix-ture. This generally will be in the range of from about 95C
to 195C.
The method of preparing the 1-(2-acylaminophenyl)-imidazoles (compound II) will vary depending on the particular type that is being made. Thus, for example, in preparing compound of the general type:

N ~ 1l 5 NHCR

wnere RS is aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicylic aryl or monocyclic aryl substituted aliphatic group, the l-(2-acylaminophenyl)imidazole is reacted with t:he appropriate acid halide e.g. the acid chloride.
This can be expressed by the following equation:

VI ~ / + Cl- C - Rr > q ~ M~2 ~ MHC-R

in which R5 has the value ascribed to it above.
The reaction will usually be carried out employing equimolar amounts of the appropriate acid chloride and in the presence of excess solvent (e.g~ pyridine) at reflux.
When the compounds in question are of the phenyl-ureylene type e.g.

VII ~ 11 2 ~ NH-C-NHR

wherein R is aliphatic, cycloaliphatic, phenyl, substituted phenyl, or fused bicyclic aryl, these are prepared by reacting the aminophenylimidazole with the appropriate isocyanate.
This can be expressed by the following equation.

VIII ~ N ~ + R NCO ~ ~ ~ l NH2 ~ N~I-C-NHR

I 1 6~77 in which R has the value ascribed to it above. This reaction is preferably carried out in the presence of a solvent and at steam bath temperatures. A typical solvent that can be employed is toluene and the reactants are usually used in about equirnolar quantities. The products obtained from reactions VI
and VIII may be recovered using standard techniques well known to those skilled in this art.
In one aspect of this invention there is provided a process for preparing a 4-substituted imidazo[l,2-a]quinoxaline of the formula:

~NN\>~ X

\

in which -X is -Rl or -NHR2 wherein:
(1) Rl is bonded to a ring carbon through a carbon-to-carbon linkage and is an aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl or monocyclic aryl substituted aliphatic group; and (2) R2 is a radical bonded to the nitrogen by a carbon to nitrogen linkage and selected from the group consisting of aliphatic, cycloaliphatic, phenyl, substîtuted phenyl, and fused bicyclic aryl, which process comprises reacting a 1-(2-acylaminophenyl)-imidazole of the formula:

N

N

~ NHC-X

in which X is as defined above, with cyclizing quantities of a cyclizing agent. The cyclizing agent is prefexably phosphorus oxychloride.
In another aspect of this invention there is provided a process for preparing a l-(2-acylaminophenyl)imidazole of the formula:

~ N

in which _x2 is -R5 or -N~R2 wherein:
(1) RS is an aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl or monocyclic aryl substituted aliphatic group bonded to the carbonyl carbon through a carbon-to-carbon linkage; and (2) R2 is a radical bonded to the nitrogen by a carbon to nitrogen linkage and selected from the group consisting of aliphatic, cycloaliphatic, phenyl, substituted phenyl, and fused bicyclic aryl, groups, comprising:

(1) when x2 is R5, reacting 1-(2-aminophenyl)-imidazole with an acid halide of the formula: X'(Co)R5 wherein - 7(a) -` I 3 64~77 X' is a halide and R5 is as defined above; or (2) when x2 is NHR2, reacting 1-(2-aminophenyl)-imidazole with an isocyanate of the formula: R2NCO wherein R2 is as defined ab~ve.
Preparation of 1-(2-Acylaminophenyl)~midazoles The 1-(2-acylaminophenyl)~midazoles of this invention are prepared in accordance with the general procedures pre~iously described. Ta~les I-IV below indicate the pærticular procedure used in the preparation of each compound as well as indicating t~ physio-chemical properties of the compound obtained. Melting points were obtained by the capillary tube method using a Mel-Temp melting point apparatus and are uncorrected, Ultraviolet spectra were obtained in ethanol solution using a Beckman U,V, Acta III or a ~eckman DBG, 1-(2-aminophenyl)imidazole was prepared as reported by A.F, Pozharskii, A.M, Siminov and L.M. Sitkina, Knim, Geterotskl. Soedin., 1916 (1969) ~Chem, Abstr,, 72, 11427a (1970)~, Table I below illustrates the prepara$ion of the aliphatic, cycloal~phatic and monocyclic aryl substituted aliphatic- amidophenylimidazoles of the present invention, Table II exemplifies the preparation of the aryl (including the ~used ring aryl) amidophenylimidazoles of this in~ention.
Except as noted in Tables I and II, the a~ides were prepared by reacting equimolar amounts of the appropriate acid chloride with 1-(2-aminophenyl)imidazole in the presence _ 7(b) -r~ ' ,~.<., ~i ` i 1 1 6~77 of excess pyridine on a steam bath for 45 minutes. The reaction mixture was then stirred into ice water and the crude product isolated according to one of the following methods.
Method A. If a solid was obtained, it was directly crystallized from the solvent indicated in Table I.
Method B. If an oil was obtained, it was dissolved in a minimum amount of chloroform and passed through an alumina column with the amount of alumina being approximately twenty times the weight of the crude solid; elution was with chloro-form. The chloroform was evaporated from the crude product which was crystallized as indicated in Table I.
Method C. If a solution was obtained in the ice water mixture, the pyridine/water azeotrope was removed until the crude product separated. It was then treated as in Method B above.

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1 1 6~877 Alkyl-2-(1-imidazolyl)phenylureylenes (Table III) were prepared by the reaction of equimolar amounts of the aminophenylimidazole and the appropraite isocyanate in toluene solution at steam bath temperatures during two or three hours. Upon cooling,the crude product was collected by filtration and treated by one of the following methods:
(A) direct crystallization from the appropriate solvent or (B) dissolved in hot dimethylformamide and precipitated with water followed by crystallization.

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, 1 3 64~7 Aryl-2-(1-imidazolyl)phenylureylenes (Table IV) were prepared by reacting equimolar amounts of the amino-phenylimidazole and the appropriate arylisocyanate in dry toluene during three hours at steam bath temperatures.
The reaction mixture was cooled and the crude product was separated by filtration, and washed with ether and crystal-lized from the indicated solvent.

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I 1 6~77 Preparation of 4-Substituted Imidazorl,2-a~uinoxalines The 4-substituted imidazo-~l~2-a~quinoxalines of thi.s invention are prepared ln accordance with the general procedures previously described from the corresponding 1-(2-acylaminophenyl)imidazoles, Tables V-VIII below indicate the particular procedure used in the preparation of each compound as well as indicating the physio-chemical properties of the compound obtained, 4-Alkylimidazo[1,2-a~quinoxalines (Table V) were prepared by refluxing the appropriate a~ide (Table I, compounds 1-33) with phosphorous oxychloride in excess pyridine during one hour, The reaction mixture was stirred into water and sufficient azeotrope removed to form a viscous residue which was dissolved in chloroform, dried over MgS04J
and chromatographed through an alumina column, The chloroform was evaporated and the product crystallized from the indicated solvent, I 1 64~77 ~: ~ ~ o co o~ 7 r ~ ~ ~ ~ O ~D ~
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I 1 6~77 4-Arylimidazo[1,2-a]quinoxalines (Table VI) were prepared and isolated according to the general method described for the 4-alkylimidazo[1,2-a]quinoxalines, except as noted in Table VI.

X

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1 ~ 6~7 Notes To Table VI:

a. U.S. 3,887,566 describes this compound as having a m.p.
of 154-157C.
b. Prepared by refluxing equimolar amounts of the 2-aminophenylimidazole and phthalic anlydride in toluene for one and one half hours. Upon cooling, the product separated out of solution.
c. Prepared by catalytic hydrogenation with 10% palladium on carbon of a dimethylformamide solution of the nitro analog; crude product precipitated with water.
d. Prepared by treating compound 153 in pyridine with the appropriate acid chloride followed by precipitation with water.
e. Prepared by HI cleavage of compound No. 138.
f. Prepared by treating the lithium salt of compound No.
162 with the appropriate acid chloride in DMF followed by precipitation with water.
g. Prepared by treating compound No. 151 with appropriate nucleophile according to the method of Kornblum et al, J. Org. Chem., 41, 1560(1976).
h. Prepared by H I cleavage of Compound 220.

~ 1 6~77 The 4-.~lkyla~lnoi~idazo~1,2-2~quino.Yal~nes (Table VII) were prepared by treating the corresoonding alkylureylenes (Table I_I) wi~h phosohorous oYyc.hloride and ?yridine during ~r.e-hal~ hour at reflux te~Der~tures. The reaction ~ixture 5. was pou,ed into cold water and the excess oyrid,ne was re~oved by azeotropic distillatior.. The crude oroduc~ was dissolved in chlorofor~ ana pass throuOh an alu~ina colu~a. A.ter evaooration of the chloro~or~, the solid ~as crystalllzed ,ro~
the indicated so1vent and cbtained in the indicated yield.

-I 1 6~77 N Lr) 0 N ~1 ~1 ~ Ll~ O
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~ 1 64~77 4-Ary'aminoimida70rl,2-a,~quino.Yalines (TaDle VIII~
were prepared by treating the corresponding arylureylenes : (Table ~J) with an equimolar amount of phosp~orous ~xychloride in ref`luxing pyridir.e during one hour. The cooled reaction 5~ ~ixture was stirred into cold ~a'er, a~d ~he crude solid whic~ separ2ted was dissolved in chlorofor~, dried and passed throug`n a~ alu.~ir.a colu~.~. The chloroform was evaporated and the crude solid was crystallized as ind'cated in Table VIII.

/
//

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Z ~ N N ~ t``l N ~1 ~1 I 1 8~877 Various compounds of this invention display anti-fungal and anti-yeast activity. Thus, for example, they have been found to be effective against such organisms as Candida albicans (ATCC No. 10231), Candida tropicalis, Aspergillus niger (ATCC No. 16404), TrlchophYton menta~roPhytes (ATCC No. 8757 and 9129), Trichophyton rubrum (ATCC No. 10218 and 14001) and Trichophyton ajelloi.
The antifungal activity of compounds of this invention indicate their usefulness against dermatomycosis such as tinea capitis, tinea favosa, tinea barbae, tinea corporis, tinea imbricata, tinea cruris, tinea pedis, tinea manus, tinea unquium and various types of candidiasis such as glossitis, stomatitis, chelitis, perlèche, vaginitis and balanitis.
When the compounds of the present invention are used for antifungal medical purposes, they ~ill usually be incorporated in a suitable pharmaceutical carrier. These antifungal preparations may take the form of solutions, lotions, creams, ointments, etc. The quantity of antifungal agent of this invention that will be contained in such preparations may vary somewhat. Ordinarily, however, it will constitute about 0.5% to 10.0~ by weight based on the total weight of the preparation.
In Table IX below are listed the antifungal activity of a number of compounds encompassed in the present invention.
These were determined by the agar dilution method as described in Chapters 2 and 3 of Methods in Microbiology, Vol. 73, edited by J.R. Norris and D.W. Ribbons, Academic Press, New York, 1972.

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. " --4 6--A number of the compounds encompassed in the present invention have been found to have immunosuppressant action.
Of those tested, most of these are of the 4-substituted imidazo[l,2-a]quinoxaline type described in formula I above, S although a couple are of the 1-(2-acylaminophenyl)imidazole type shown in formula II. Because they exhibit this activity, they are indicated for use in the treatment of those diseases that the prior art recognizes may be helped by the administra-tion of immunosuppressants. These include such conditions as: glomerulonephritis, serum sickness, organ transplant, rheumatoid arthritis, systemic lupus erythematosis, ulcerative colitis, chronic active hepatitis, multiple sclerosis, heterografts or homografts in burns, psoriatic arthritis, urticaria, respiratory allergies, i.e. asthma, hayfever;
scleraclerma, mycosis fungoides, dermatomyositis, psoriasis and contact dermatitis (including poison ivy).
The dosage level for administering the immunosup-pressants of the present invention will vary with the particular compound that is to be administered. In general, 1 20 this will be at about the same level of the prior art immuno-! suppressants. For the most part, when thepresent ~nosuppressants are administered orally or intraveneously, the daily dose would be in the range of about 0.1 mg. to 15 mg./per kilogram of body weight. When other mode of administration are employed, e.g. depot injections, implants, etc., the dose may be j considerably higher, i.e. up to about 100 mg./kg of body weight ¦ in a single injection.
¦ The immunosuppressant activities of the compounds ! of this invention were determined via the hemolysin test in ! 30 mice and by the delayed hypersensitivity test. The hemolysin test used is that described in Methods in Immunology, edited by D.H. Campbell et al, W.A. Benjamin, New York 1963 I 1 64~77 pages 172-175, and measures humeral or antibody response.
The delayed hypersensitivity test measures the effect of a test compound on the ability of a subject mouse to mount a cell-mediated immune response to the antigen, Mycobacterium tuberculosis H37Ra. The mouse is sensitized to the antigen by subcutaneous administration in the base of the tail.
The development of the delayed hypersensitivity response may be measured at any time beginning six days after sensi-tization but is usually done on the ninth day as follows:
The right hind paw is injected with purified protein derivative (tuberculin) while the left hind paw (control) receives physiological saline. Both paw volumes are measured after twenty-four hours and significant increase in the volume of the right hind paw is taken as a measure of an effective delayed hypersensitivity response. All compounds were administered by the subcutaneous route.
The results of these studies are summarized in Table X below. The expression HL~ED50) mg./kg. s.c. is an expression of the number of milligrams per kilogram of body weight of the drug administered subcutaneously required to reduce the antibody activity by 50% when compared with a control. In this case, the lower the HL(ED50) value for a drug the more effective immunosuppressant it is.
The D.H.S. (ED60) mg./kg. s.c. value appearing in column 3 is an expression of the effectiveness of the drug in reducing the edema that accompanies the cell-mediated immune response. It is a measure of the number of milligrams per kilogram of body weight of the drug administered subcutaneously which is required to reduce the edema of the cell-mediated immune response by 60% when compared to the control. Again, the lower the D.H.S. (ED60) value ihe more effective is the drug as an immunosuppressant for the cell-mediate immune response.
_ y~._ I ~ 64877 TABLE X

Compound HL(ED50) D.H.S. (ED60) No.mg/kg,s.c. mg!kg,s.c.
151 0.3 1.52 140 0.26 1.15 116 >50 56 117 ~50 46 118 ~50 43 109 >50 >50 66 46 >50 147 0.027 1.7 134 0.5 7.2 137 <0.125 3.2 135 0.033 0.22 142 0.20 4.2 136 2.7 >50 133 0.75 32 139 3.0 >50 138 0.72 27 127 >50 36 170 6.6 >50 150 22 >50 143 0.36 1.3 174 0.61 8.0 171 0.96 59.0 175 0.09 5.9 178 11.0 46.0 196 0.42 45.0 197 1.6 37 3 50.0 50.0 169 46 >50.0 146 0.11 3.1 153 1.2 5.7 149 0.16 8.8 126 35.0 >50.0 177 13.0 >50.0 182 1.1 ----162 13.0 ----159 3.0 27 181 16.0 ----180 5.6 ----183 0.39 15 158 1.0 7.6 157 0.39 12 218 1.5 25 219 2.5 >32 220 2.3 11 221 1.0 >32 >50 means that it would take more than 50 mg./kg. of drug to reduce the humeral antibody activity by 50% or to reduce edema of the cell mediated immune response by 60%. Since these values are higher than is of practical interest from a clinical point of view, no further testing was done for these materials.
k -4g-' i ~ 1 648~7 A number of compounds encompassed in the present invention display non-steroidal anti-inflammatory properties.
This appears to be generally the case for the 4-substituted imidazo[l,2-a]quinoxalines of formula l above and the l-(2-acylami~ophenyl)imidazoles of formula II. Because of this characteristic, they are indicated for use in the treatment of diseases that the prior art recognizes may be helped by the administration of non-steroidal anti-inflammatory compounds. These include such conditions as ichthyosis, psoriasis, alopecia, atopic eczemas, etc.
The dosage level for administering the anti-inflammatory agents of the present invention may vary somewhat depending on the particular drug selected, the disease being treated and the mode of administration. In general, however, when used for topical application, the compounds are distributed in a pharmaceutical vehicle suitable for topical application.
In these compositions, the anti-inflammatory agent of this invention will comprise about 0.5% to 15.0% by weight based on the total weight of the composition.
The anti-inflammatory agents of the present invention may also be administered orally, intraveneously, subcutaneously, intramuscularly, and intradermally. In these cases, the daily dosage will be in the range of from 0.5 mg. to 20 mg. per kilogram of body weight of the active anti-inflammatory agents of this invention.
The anti-inflammatory activity of representative compounds of this invention was determined by the rat paw edema assay both by local administration (Table XI below) and by oral dosing (Table XII below). For the oral dosing, the procedure of C.A. Winter, E.A. Risley and G.W. Nuss, Proc. Soc.
Exp. Biol. Med. 111, 544 (1962) was employed with measurement taken four hours after the drug was administered.

i ~ 64~77 The local administration tests were carried out similarly except the irritant (carrageenan) and the test compound were injected simultaneously at time zero.
Tables XI and XII report the anti-inflammatory activity of the compounds tested as ~ difference in the edema or swelling as compared with the control. These Tables also give the response in many instances of more than one dose level of the same drug.

I 1 6~877 TABLE XI

Rat Paw Edema Assay, Local Administration (injected directly into paw) % Difference from Control Compound No. l~g lO~g lOO~g lOO mg/kg 148 -32.6 -53.5 - 14.3 _39 109 -30.8 - 3.9 + 31.6 114 -68.2 -30.0 -131.6 ~' '' 't -52-~ ~6~77 TABLE XII
Rat Paw Edema Assay, Oral Dosing % Difference from Control Compound No.100 mg/kg 400 mg/kg Indomethacin -65 ~ phenybutazone -76 : Aspirin -57 115 +70 -25 116 +104 -18 ,`~
; ~ -53-TABLE XI I Cont ' d Compound No . 100 mg /kg 400 mg /kg 2 -26 +43 +9 -33 128 _39 .

Claims (10)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a 1-(2-acylaminophenyl)imidazole of the formula:
in which -X2 is -R5 or -NHR2 wherein:
(1) R5 is an aliphatic; cycloaliphatic; phenyl; phenyl substi-tuted with one or more substituents selected from the group consisting of branched or straight chain alkyl, alkoxy, hydroxy, acyloxy, halogen, nitro, amino, acylamino, polyhydroxyalkyl-amino, cyano, trifluoromethyl, mercapto, alkylthio, acylthio, carboxyl, carboalkoxy, phenyl, phenoxy, and combinations thereof; fused bicyclic aryl or monocyclic aryl substituted aliphatic group bonded to the carbonyl carbon through a carbon-to-carbon linkage; and (2) R2 is a radical bonded to the nitrogen by a carbon to nitrogen linkage and selected from the group consisting of aliphatic, cycloaliphatic, phenyl, substituted phenyl and fused bicyclic aryl, comprising:
(1) when X2 is R5, reacting 1-(2-aminophenyl)imidazole with an acid halide of the formula: X'(CO)R5 wherein X' is a halogen and R5 is as defined above; or (2) when X2 is NHR2, reacting 1-(2-aminophenyl)imidazole with an isocyanate of the formula: R2NCO wherein R2 is as de-fined above.

2. A process according to claim 1 wherein X2 is R5.

3. A process according to claim 1 wherein R5 is an alkoxy alkyl group or a straight chain or branched chain saturated, mono-unsaturated or poly-unsaturated group containing from 1 to 17 carbon atoms in which one or more of the hydrogen atoms may be substituted by halogen.

4. A process according to claim 1 wherein X2 is NHR2.

5. A process according to claim 1 wherein R2 is an aliphatic group containing from 1 to 18 carbon atoms.

6. A 1-(2-acylaminophenyl)imidazole of the formula:
in which -X2 is -R5 or -NHR2 wherein:
(1) R5 is an aliphatic; cycloaliphatic; phenyl; phenyl substituted with one or more substituents selected from the group consisting of branched or straight chain alkyl, alkoxy, hydroxy, acyloxy, halogen, nitro, amino, acylamino, polyhydroxy-alkylamino, cyano, trifluoromethyl, mercapto, alkylthio, acyl-thio, carboxyl, carboalkoxy, phenyl, phenoxy, and combinations thereof; fused bicyclic aryl or monocyclic aryl substituted aliphatic group bonded to the carbonyl carbon through a carbon-to-carbon linkage; and (2) R2 is a radical bonded to the nitrogen by a carbon to nitrogen linkage and selected from the group consisting of aliphatic, cycloaliphatic, phenyl, substituted phenyl and fused bicyclic aryl, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

7. A compound according to claim 6 in which X2 is R5, when-ever prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

8. A compound according to claim 6 in which R5 is an alkoxy alkyl group or a straight chain or branched chain saturated, mono-unsaturated or poly-unsaturated group containing from 1 to 17 carbon atoms in which one or more of the hydrogen atoms may be substituted by halogen, whenever prepared by the pro-cess of claim 3 or by an obvious chemical equivalent thereof.

9. A compound according to claim 6 in which X2 is -NHR2, whenever prepared by the process of claim 4 or by an obvious chemical equivalent thereof.

10. A compound according to claim 6 in which R2 is an ali-phatic group containing from 1 to 18 carbon atoms, whenever prepared by the process of claim 5 or by an obvious chemical equivalent thereof.