4-substituted imidazo [1,2-a] quinoxalines, and intermediates, and process for preparing the same

938S This invention relates to certain 4-substituted imidazo [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 encompassed in the present invention may be described by the formula:

~N ~ X I ~ I and pharmaceutically acceptable salts thereof wherein X is -R or -NHR wherein:

(1) Rl is bonded to a ring carbon by a carbon-tocarbon linkage and is an aliphatic, cycloaliphatic, substituted phenyl, fused bicyclic aryl; or monocyclic aryl-substituted aliphatic; and 2 (2) R 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 3~ 385 T~ihen ~ is an aliphatic group, it ~ay ~e a straight chain or brancRed chain hydrocarbo~ Oroup which is saturated, monounsa'urated or ?olyunsaturated. It ~iay aiso comprise a strai~ht chain or branched chain grou? containing other than 5. carbon-to-carbon bondings e.g. ether lin'~ages, carbon to halogen linkages, etc. Ordir.arily, it will contain from about 1 to 1~ carbon atoms, the most ty?ical radicals o~ this group being the al~yl radicals having from 1 to 1~ carbon at oms .

10. 3y way of illustrating the aliphatic groups that may be represented by Rl, the following are given: CH3-;

H3 r2 ; C~3~H2~CH2~; CH3(CH2)n- 'n which n is 3, ~, 5, 6, 7, 8, 14 and 16 res?ectively; (CX3)2CH-CH2-; CH3(CEI2)3(C~3CX2)CH~CH2=CH-(CH2)~-, al~oxyalkyl in ~hich the al!~yl ~oieties 'na~e 15. from 1 to 4 carbon atoms e.g. e~hoc~methyl; halogenoalkyl (i.e. C~2Cl-; CX3CHCl-; CHC12-; CC13-; CH23r-; CF3).

When R- is a cyclcaliphat~c ra~ ical it Will most o~ter. be cycloalkyl radical containing 3 to 3 carbon atoms or a cycloalkenyl radical containing 5 to 6 c2rbon atoms. 3y ~ay of 20. illustrating the cycloalio'natic radicals that ~.ay correscond to R- in ~or~ula I ,mention may be rade of the cyclopro?yl (i.e. ~ ); cyclobutyl (i.e. O ); cyclohexyl, cyrlone~yer.

(i.e. ~ ); and norborneny~ e- ~ ) Tl'nen ~1 is a sllbsti~uted phenyl radical in or~ula I 25. above, tne ?henyl group .~ay 'nave from 1 to 5 substituentsbut will usually be ~or.o, di or trisubstituteà. ~ypical ar.,ong the ~rou?s tha~ ~ay be containe~ in the ?nenyl grou? are (a) al~yl grou?s ~Ihich are branched or str~ight chain containinO 1 to 5 carbon ato~s e.g. methyl, et'nyl, tertiary bu~yl; (b) 3- al'.~oxyl groups containing 1 vo ~ carbon a~oms e.~. me~hoxy, -- 2 - ~9~85 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 benzene ring is unsubstituted or monosubstituted, disubstituted or trisubstituted with alkyl groups containing 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 R1 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-naphtyl, 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, Cl ( ~ ~1 3 2 ~ The group R2 in the radical -NHR of formula I above is exemplified by the same radicals given above in illustrating the radical -R1. In addition, R2 may also be phenyl as in the case of the group -NH ~ .

~, ~ 9~5 ( I~ general, the com?o~ds included ln for~ula I above as well as the cases in for~ula I in which ~ is hydrogen or phenyl ~lay be prepared by heating the corresoonding 1-(2-acylamino?nenyl)imidazole at refl~Y in the ?resence of 5. cyclizi~g quantlties of a cycliz-ng agent e.g. polyphosohoric acid or phos?horous oxychloride, e~c. for sufficient ~i.me to cause significant cyclization of this reactant. ~1Iore particularly, the 1-(2-acylamlnophenyl)imidazole reactants that can be em?loyed in this process may be described by the general 10. formula:

II ~ W ~ Pl 2 r~ic-x in which x2 is R5 or -N~R2 wherein:

15. ~5 is an aliphatic, cycloaliphatic, phenyl or substitu~ed phenyl, fused bicyclic aryl or mor.ocyclic aryl suDstituted aliDhatlc radical and R2 has the sa.~.e values assignea to it in connection with for~ula I aoove.

The grou? ~5 in for~ula I- is iilus~r2~ed by the 20. sa~e grou?s ~hat illustra~e ~~ in for~ula . iowever, in addivion, ~5 ~y also be illustr2ted by t:~e ~heny' rad ^al.

Tne reaction cqn be de? c~Gd by ~r.e ~oll^wing ecuatio;l:

25. ~ ".So~orollS ~N~,~2 II_ ~ ~.C-~ Cx-rc^.lor~de ~ IN ~ U,Y . ~ _, ~V ~ ~ - 4 385 The process of equ tion III is preferably carried out in the presence of an e:ccess of a~n. organic amine solven~. A vari~ty of solvents ray be used for ~h-s Qur~ose among whicn mention ~ay be ~adç of the follo,Jing: ?~ridine, 2,6-dimethyl 5. pyridi~e, :~,N-dimethylaniline, tri,lethyla~ine, and ;~r-meth~lmorpholine, evc. However, the preferred org~nic solvent is pyridine.

The quantity of phos?horous oxychloride that is employed in the reaction can vary somewhat. Ge~er~lly, h~ever, 10. the pnos?horous oxychloride will be.employed in the rance of from about one-half ~ole JO about 6 moles and ore~_rably one-half mole to two moles per ~ole of compound II.

The desired product rv .~ay be recovered from the reaction mixture using any of the ordinary ~echniques well 15. known to tnose s~illed in this art The ti.me of reactior.

will vary de?ending u?on, among other things, the ?articular reactants or molar quantities of reactants employed. In general, the reaction ti~e will be from about 30 to 12C minutes.

20. The temperature employed in carrying out the reaction will also vary depending upon the particular reactar.ts selected, the solvent and other factors. Ordinarily, tne te perature employed will be the reflux ~emper~u-e of the reac'ion ~i;cture.

This generally will be in the ranOe of fro~ about ~5C 25. to 195C.

The method of preparing the 1-(2-acyl~minophenyl)imidazoles (compound II) will ~ary depending on the ?articular ty?e ~hat is oeir.g ~.ade. Thus, for exam?le, in pre?arir.g com?ound Of the general t~pe:

~r~ ~r~3R5 _ S _ 11 1~9~385 where R5 is aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicylic aryl or monocyclic aryl substituted aliphatic group, the l-(2-acylaminophenyl)imidazole is reacted with the appropriate acid halide e.g. the acid chloride.

This can be expressed by the following equation:

VI ~ / + Cl~ Rr ~ ~ ~ I~H2 ~ MHC-R5 in whieh R5 has the value ascribed to it above.

The reaetion 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 eompounds in question are of the phenylureylene type e.g.

~N ~ VII ~N O ~3,NH_C_M~IR2 wherein R is aliphatic, eycloaliphatic, phenyl, substituted phenyl, or fused bicyclie aryl, these are prepared by reaeting the aminophenylimidazole with the appropriate isoeyanate.

This ean be expressed by the following equation.

VIII ~,f NH2 > ~3~N~I-C-N~IRZ -- 6 ~i~93~35 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 equimolar 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[1,2-a]quinoxaline of the formula:

~ \)~X in which -X is -R or -NHR wherein:

~1) Rl is bonded to a ring carbon through a carbon-tocarbon 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, substituted phenyl, and fused bicyclic aryl, which process comprises reacting a 1-(2-acylaminophenyl)-imidazole of the formula:

.,,~, .~ ~9385 N N ~ NHC-X in which X is as defined above, with cyclizing quantities of a cyclizing agent. The cyclizing agent is preferably phosphorus oxychloride.

In another aspect of this invention there is provided a process for preparing a l-(2-acylaminophenyl)imidazole of the formula:

N N in which -X is -R or -NHR 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, 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) 93~3~ X' is a halide and R5 is as defined above; or ~ 2) when x is NHR, reacting 1-(2-aminophenyl)imidazole with an isocyanate of the formula: R2NCO wherein R is as defined above.

Preparation of 1-(2-Acylaminophenyl)Imidazoles The 1-(2-acylaminophenyl)imidazoles of this invention are prepared in accordance with the general procedures previously described. Tables I-IV below indicate the particular procedure used in the preparation of each compound as well as indicating the physio-chemical properties of the compound obtained. Melging 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 Beckman DBG. 1-(2minophenyl)~midazole was prepared as reported by A.F.

Pozharskii, A.M.

Siminov and L.M.

Sitkina, Khim.

Geterotskl. Soedin.,5, 1916 (1969) tChem.

Abstr., 72, 11427a (1970~].

Table I below illustrates the preparation of the aliphatic, cycloaliphatic and monocyclic aryl substituted aliphatic- amidophenylimidazoles of the present invention. Table II exemplifies the preparation of the aryl (including the fused ring aryl~ amidophenylimidazoles of this invention.

Except as noted in Tables I and II, the amides were prepared by reacting equimolar amounts of the appropriate acid chloride with 1-(2-aminophenyl)imidazole in the presence _ 7(b) ~,'' ~L.~ 35 of eYcess oyridine on a steam bath for 45 minutes. The reaction mixture was then stirred into ice water and the crude ?roduct isolated according to one of the ~oll~ling methods.

~le~hod A. If a solid was obtained, it was directl~ 5. crystallized from the solvent indicated in Table I.

`~Iethod 3. If an oil was ootair.ed, it was dissolved in a minimum amount of chloroform and oassed through an alumina column with the amount of alumina being aporoxi~ately t-~,tenty ti,mes the ~,teight of the crude solid; elution was with chlorolO. form. The chloroform was evaporated from the crude product which was crystalllzed as indicated in Table I.

Method C. If a solution was obtained in the ice water mixture, the pyridine~water azeotrooe ~as removed until the crude product se~arated. It was then trea~ec as ir.

Method 3 15. above.

~9385 ~D ~ O ~ ~ ~r ~D Ln O U~ ~ O r~ N 1` IY~ 1 0 ~1 5 ... ... ... ......

O ~ O~` ~D ~1--~D OD ~ ~ r-M ~4 ~ D tN ~1 U~ CO~ O Ln ~ ~ ~ ~ O _ . ~. . .. . . . . .. . . . .

U ~ ~ ~ u~ u~ O ~C Z O ~ Z ~ ~C Z C~ ~ Z O X Z U ~ ~ ~ O U~ O O X ~ ~`J ~1 ~1 ~ ~1 . l l l l l O t~ ~ ) 1~) . O D ~r O N Z~Z~ ~ \=~ o .,1 ~ ~1 a) C) a~ N ~ O ~ ~ C) / \ r~ O o ~ a) (~ N~1 ~1 ~ ~1 ~1 ~I X O ~,q 3 1 rl U~ E~ ~ ,i ~ ,1 ^O C) I O=C~ P; a rr + ~~ O~ ~ ~ G~ z e ~ ~ Z~Z ~ _I rl ~ ~ O 1~ ~ ~ ~ o ~ ~ m m o a~ U~ H 1~ 1~ I tN N (1~ r) ~C O C) I ~C C) -- _ ~C O ~ r) t~7 zl ~ ~ ~ ~ u~ 9385 a~ ~ ~ ~ ~ ~ ~ ~1 ~a) n ~ ~ ~D a:I` co ~ u~ ~ ~ o o o r~ ~ ~ o ~ o ~ 1~ D O ~r O O 1~ ~ o (_ ~ ~ o~ er ~ o~ ~~ ~0 ~ n a~ o ~9 o a~ U~ ... ... ... ... ... ... ... ... ...

O ' O 1--~D O 1--Lr~~ a~ ~r ~ o~ ~r ~ ) ~ In a~ o ~ o a~ ~ o ~ æ c) :~ z ~ æ ~ z~ ~ æ ~ z ~i~c z ci :c z o n ~ o er o o O ~ O In ~ ~ o o ~ ~ ~ ~ ~o~ a~ . I I I ~ I I I I I ~9 ~ ~ ~ ~r oo . o ~ o a~t~ ~ ~ o a s~ o ~ ~~ ~ ~ a -1 Q) ~ O~ ~ ~ ~ X oQ~ ~ Q~ ~ ~ ~ ~ a o o~ o o ~ o I o o u~ ~ ~h ~ hS~ .SI h S~ u~ Q~ C~ ~ Q. ~ ~ a)Q~ ~ N N ~ O -rl O O O O ~ O O h u) )~ ~n 0 u~ ~ 1 rl rl ~ rl rl R R ~ ~ ~ ~ u~ ~ ~ ~ ~ ~r 0~ a .,1 ~ ~ u~ In O ~ O o ~ ~ o ~1 ~ m ~ m m ~ o o U~ ~ H ~ ~ ~ ~ ~ N ~ C.) C~ O ~ a) ~ o ~1 ~ ~ ~r Z ~ ~ ~ ~ ~ -- 10 - ~9385 ~ ... ... ... ... ... ... ... ... ...

.,, U~ ,... ... ... ... ... ... ... ... ...

u ù~z ù~z ùxz ù~cz ùxz ù~:z ù~z ù~æ ù~:z U r~ ~-- r~ o ~ ~ ~9 ~ o ~ ~r I o . I I I I I o ~ ~ U~ D ~ ) r~ ~ ~ o~ r o ~D ~ ~ ~ O O h O ~ ~ S ~ N 1:: 0 ~ O .rl O ~1 X O S:~ a) ta O ~ O I O ~ O ~ ~ O u~ Q) ~ S U~ N Q, Q) 0 ~) 0 ~1 ~ O ~:: .C a) s ~ 1 0 C) U) ~ ~ rl ~ O O U~ U Q rl ~J O ~ a) E-l E-l -1 co o~ o c~ r~P ~ .~ ~ ~ ~ ~ r~ ~ ~ r~ o r~ r r~ ~O~ ~ O ~ s~ m ~ u u u ,¢ ,¢ ~ ~ o ~ u~ H r~ U ~ I ~ ::~ oa U _ N ~C ~ 3 U u u Ir ^ I _ U ~ U I I ,J { ~U U 1~ ~ 1 ~ Y 1~ r~ U ~ 0"1 ~ ~ o ~ o ~I N ~ ~ 9385 ~" O ~ ~ r ~ 1`co o ~ ~1 o ~1 ...... ~o~ O a~ o ~ D O Lr~ ~D ~ h h ^ X O _ ... ... ... ... ... .... ... .-- a~ZU U . U ~C Z ~ C Z U ~ Z C~ X Z ~ Z C~ X Z ~ ~C Z C~ ~ z 'r ~ R N rl ~_) ~ OD ~ 0 ~ r/ h o Il') I ~ O I o ~D ~9 ~ r-l . I I _ I I I O h ~1~1 ~1 ~1 ~1 ~1 ~1 ~1 ~ ~ ~ N O -,~ ~1 " C~ ~ ~ .

r~ O ,~ ¦ h .,1 . ~ h 3 N ~ I C) r~ G) O ` ~ h ,1 ~ ,~ o ~ ~ O ~ ~ o ~1 aJ s:: ~a o O a) ~:: h a) a) ~ ~ ~1 0 0 U~ ~ N n h O O J-\ ~ O ~ ~ h ~ O ~1 E~ ~ a) 3 E~ - Q m o rl O ~i 'O O ~ U ~) ~ ~ ~ O dP C) . . . . . . S U~ a h o ~a o ~ o a~ ~rl ro .,1 U~ .C O h ~ ~ ~ ~ ~ m o a , s u~ X H 0 X v a) td .,1 4~ h ~ 0 0 a h o ~ O h ,1;~ J~ a) ,~ Q C) ., U~ ~ I ~ rl ~ rl I O=C.) O ~ 0 3 ~i ~ Q O h I ~ X Q o ~ \/ \~ ~ ~ 4 ~ h ~ ~0 ~ ~ h O h ~::

h ~.) O . ..

O ~ ~ O ~ U~ Z '_ -,. ZO -- 12 - 9385 ~ ~ o o ,~ D ~ O ~ ~ 5 . . ... ... ... ... ...

U) O r~ In ~ ~ In ~ ~ u u~ ~ In u~ o ~ ~ u~ 0 ,1 _ ... ... ... ... ... ...

o ~ ~ z o :~ z ci x z c~ ~c z c~ ~ æ u ~c z O -- ~ O O _ ~ O ~ O O ~ t~ _ ~ ~ ,~ ~ O . ~ ~ U~ X _ _ ~ _ _ ~i U~ O ~ C~' ~g ~ t ¢ O 1 ~ r~ r~ r~r~ r~ r~ O=~ . l l l l l l Z ~ ~r a~ 1~ ~ ~ ' -- ~ r~ r~ r~r~ r~ r~ D7 æ ,,,~ \~ =J ~/ N a~ .~ r1 ~ O r~ d ~ S , a ~ o ~ a~a) c) ~ H r l a) 11:1 0 ~ 0 1~ ~ ~ H t ) ,5~ ~) ~ ID a) a) r~l R ~ 0~ N N N ~:1 0= y r1 ~ ) ~r~ ~ Q ,~ E~~ ,ra + I` r~ ~ O d~ ~ ~ rt ~r OC)~0 1` ~) O~ z _ ~ ~ U'~IS.In 11~ 1~ ZZ ~ r1 ~ ,1 ~ fC ~: m H r~ O ~ Z ~ i -- 13 - 93~5 Io ~ ~ ~ ~ o ~ ~ ~ o~ ~ ~r ~ a) o ~ a~ ~ ~r o u~ ~ ... ... ... ... ... ... ... ... .. .

U~ oo ~ ~ 1-- ~ ~ r` o ~;r ~ ~ o a~ ~ o ~ o ~ 1` ~ r~ , ... ... ... ... ... ... ... ... ...

~: z ~ z ~ x z ~ x z o ~ z o o o ~ o o o o ~ o ~ o o o o o o ~ ~ OD In O IS) ~~1 _ ~ I` ~ U ` o~ o ~ o x ~ r~ ~` ~D ~ ~ ~ ~ ~ Ln In ul L~ LO ~ o u~ ~ ~g o o~ ~ o ~ o o a~ o In ~ O C51 0 ~D . I I I I I I a~ I Q 0~ . ~ a~ n ~ o U r~ t~ ~ ~I h h h N ~ O O O O O O O O Q, ~1 ~ >1 ~ a) ~ ~ ~t O ~ ~ h~ ~ a) ~ S~ ~ ~ S~ u~ Q, a) ~ N a) o ~ tL) o ~ o .) -~1 ~ a) ~ 3 ~ 3~d 3 Q ":1 3 ~ ~ 3 ~11-- ~ ,~ ~ r t~ o ~ Q o o O ~rC ~ m o a ~n H ~ ~ 1~5 1 N~ ;~ ¢~ ~ ¢ ~/m o~ Z m .

O O ~ ~ ~ ~r In U:) I` 0 z ~, -- 14 - 3;~5 o Ln LnN ~ ~ ~ ~ ~ Ln ~ Ln ~ ~ ~ Ln Ln ~ ~ ~ N Ot) 1~ o ~a) ~ Ln ~ a~ ~ O er o ~ Ln ~ ~ ~l c~ oo o ~ ~ ~ o ~ cn o Ln ')~ r~l ~ ~ ~1 ~) ~0 ~ ~I r- ~ N a~ ~ O ~ ~ Ln er ~ Ln ~r ~ Ln ~ Ln ~Ln ~ e~ D ~ Ln ~ Ln Ln ~r Ln OD ~ O ~ ~ Ln ~ ~ Ln ~ ~D O O ~:1 ~ Ln O ~ILn o ~Ln o ~ o~ ~ ~ OD ~ ~ ~rl ~I CO ~D ~D ~ r~ ~D ~I r~ a) ~ o t) ~ ~ 'S''r ~ 'r'r 'r 'S' r~ ') N a~ ~ O ~ C~ Ln ~ ~ Ln ~r ~D Ln ~ ~1 ~D ~1 ~ ~ ~ ~Ln ~ Ln ~ ~ ~ ~ ~9 ~1 ~D ~1 ~D ~1 ~ ~) ~ ZU ~ Z ~ ~C Z C~ ~ Z ~ ~C Z U ~ Z H U ~: Z U ~C Z ~ Z o o o o o o ' o ~ o o ~o o o I` ~r o ,~ r o ~: ~ ~ o ~, ~ t~ ~ ~ ~ ~ o ~ S O . ~ ~ ~ .~ ~ ~ Ln U7 ~ X _ _ _ _ _ _ _ ~ ~ o LnLn Ln ~ ~~r ~D ~r ~ ~ Ln ~9 o~ N N ~ ~ Ln U ~~D O ~ ~ ~ ~1 o O ~ I`~ I I Ln1` Ln Ln . I I I I Q ~1~r 1`0 0 ~D ~~1 0 . o~r ~D~ C~ 0~ ~r-- ~ F~ Nr-l --1 ~`I ~I r l ~1 ~1 ~1 O . ~ ~i 'JJ ~ ~ ~ s~ N ~ O O O O O rl ~ ~U LU ~U ~ LU ~1 ~ ~ ~ ~ ~ ~1 ~1 ~1 ~ ~1~1 ~1 ~ ~ .

~ O S: O O O ~ ~ O O ~ u~ a) ~ a ~ o o N ~ ~ ~ ~ .C ~ ~ 1~ ~ 5: 0 ~ ~ ~ U ~ O au a) ~ 3 ~ 3 au rl~:1 3 R ~ I` Ln 1` dP ~ ~ ~~D Ln N ~D ~r Ln 0~~D o rl ~ O ~ ~ ~ m o a H U ~ O O a~ o ~1 ~ ~ ~ Ln Z ~r Ln Ln Ln Ln Ln Ln Ln Ln '~ -- 15 - ~L~ '3~3b~5 ~ O ~ ~D U~ ~ i--~ ~ ~ ~ ~ ~ 0~ ~ ~ r~ o Ln ~ o o~ u. J ~ o ~ 1 ~r u~ r ~ r~ r ~~ ~r ~ ~r ~ ~ ~ u~ ~ ~ .

r co~ o ~r o co o ~ D o o r~ ~ ~~r ~ o~ r ~ ~ o _ ... ... ... ... ... ... ... ...

u~ ~r ~ r ~ ~ r ~ ~z ~cz o~z c~z ~cz c~æ oxz o~z O O O O _ O _ ~ r o o o E ~r ~ c~ ~ ~ ` o _ u~ ~ o . ~ u ~ ~ Ln~ ~ o~ X _ _ _ _ _ _ 0 ~ ~ o~ r e 00 ~ ~ ~ ~ ~ ~ ~ ~_ ~ r ~9 ~ ~ I N .--1 1` 1` ~D o .

~- ~r~ ~ Ln In ~D ~r . ~ ~D~r o e ~ e e e ,, 0 0 ~ ~ h h ~ ~ ~ ~ h N ~ O O O O O O O 0 0 ~1 O ~ ~ O O O O 0~ ~ O u~ ~ h ~ hs~ h ~ h ~ a) ~:

u~ a) a) Q~ 0 ~ O N 0 ~ e~ e~ o o~ o o e S~ ~ rl 0 U~ U~ ~ U~ U~ 3 ~ 3~ ~ Q a~ CO OD O ~ r~ -- ~ O ~D ~ i-- 0~ ~ -~ 4 ~ a) . . . . . . . ~ e ~l ,1 ~ c~ ~ In ~ ~ co Ln h u~ ~ ~r ~ ~ ~r a) u, O h .,~ O 0 ~ ~ m ~ m ~ m ~ ~ ~ o o a U~ ~ ~ ~ H 0 ~u o h ~ o e c4~ fC ~ ~J 0~ 5 U r~ U . o ~ E~ O co ~ O --1 N ~ ~ ~1 0 Z u~ D ~ ~ ~ Z ,.

-- 16 - . . . . .

~1~9~85 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.

- 17 ~ . .

9385 ~I CO ~1~1 ~ N11'1 ~9 0 ~r O 00 0 CO ~ r ~ ~ o ~oc~ o 1-- ~D O ~r ~1 0 ~ U~ ~9 ~ ~D ~ ~ ~ ~ o ~ ~ ~ ~ ~ ~ o r.~ ~ ~ a~ co a~ o ~D Ln Ci) In ~1 ~ ~ ~ ~ o o ~ ~ o t~ ``` ``` ~ ; OXZ O ~O ~O ~O O O oO 00 oo O Ln O 1`0 0:~ 0 0 ~`I .

Ltl ~ ~` N ` Lt~ . ~ ~ ~~ ~ ,~ X _ _ __ _ _ _ ~_ O= O ~ O OD ~ O CO ~I r-l m Z ~: ~ N t~ Z ~ ~7 0 .

Q \ h a) al o ~ .~ 5~~ ~ ~ ~ ~I h QN ~: O a) - O O H ~ rl C) O O ~ ~1 H ~1~1 ~ h ~I td ~1 H ~~1 ~1~J 0 O r-l r~l O ~:

1:;1 0~ C~2~ 1 ~ h N U~ Il) U U Q aJ ~J a ~ ~ 1 rl U Ei ~ h E~ O ~ a) ~ ~ 3 æ r~ P~ + I ~ 0~O ~ ~~ O ~ ~~r ~ ~r .Y ,~\z ~ H ~ ~r:

~; 1~ C~ X ~ ~ .

~," -- 18 - .. . . .

~1~93~35 Aryl-2~ imidazolyl)phenylure yl2 nes (Table r~ ) were ~repared by reacting equimolar amounts of t~e aminophenylimidazo~e and the a~pro?riate arylisocyana~e in dry ~oluene during three hours at steam bath temperatures.

5. The reaction mixture was cooled and the crude ?roduct was separated by filtration, and washed with ether and crystallized from the indicated solvent.

. .

__ __ - i9 9385 ~1 ~ Ln ~ ~n r~ o~ r~ Lr) ~ r~ r~ ~D r~ o ~r ~ ... ... ... ... ... ...

O ~ Ln o ~ u~ ~ ~ ~ ~ ~r ~ ~ ~ ~ ~ ~r ~r a~ .,~ rn L~ r~ ~ ~r ~ r~~r ~ r~~9 N r~ r~ ~D ~ r~ . .

~1~D N ~ ~1 ~D ~1 ~D ~1 ~D r-l ~ ~ ~~ ~ z ~ z r ) ~ ~ c.) ~ z x o o o o o o ~ _ I~r o o o o o o= r~ ~ ~ ~rco Ln o ~ ~ ~ r~ .

x æ~ \=/ ~ ~ N rn r~ u~ o . o o I co I o O N a) . I . I . I ~ ~ ~ ~ ~ ~ ~ o ~ ~ o o o~ o o ~ H ~ a) a) a~ ~ o ~a ~1 .,, .~ rl ~1 8 rd ~ rd rd rd E~ æ N ~ ~I h ~d ~ a) O O O O ~ ~1 ~ 4 .~ td ~ ~ ~ ,~ ~ O ~ :~ + ~ ~n u~ O ~ O ~ ~ ~C :~ ~ ~ h ~ ~ rd a) a) rd O O O O a) O _, U S t~l ~1 ~ ~ . rd ~ rd ~ 3 3 Z r ~ r ':r ~D ~D r ~ u~ ~D r~ r~ r~ O ~ o ~ r~ ,~ ;r ~ ~D r~ r~ r~ r~ r~ -- 20 - ~1~938~ r~ ~ u~ ~ Ln ~ co ~ D Ln 0~ ~D ~ ~ O ~r o t--o ~ O ~ o Ln ~ ~ ~ er ~ CO ~ ~ D ~ O Ln ~~r ~r ~ ~ Ln ~ O ~ ...... ... ... ... ... ... ... ...

O ~1 ~D ~ ~ Ln ~ r~) Ln ~ ~ Ln ~ o Ln c~ ~ Ln O Ln CO U~ ~ ~D ~ Ln ~ Ln ,~ Ln ~ Ln ~ ~ ~ ~-- ~ Ln .,, U~ n ~ ~ Ln ~ ~r o ~ o r~ ~ o r :i ~ ~ r ~co Ln ~ ~ I~ ~I Ln ~ ~ ~,_ ... ... ... ... ... ... ... ... ...

. O ~ Ln ~ ~ ~ ~ Ln ~ ~ Ln ~ ~ Ln ~ ~ co a~ Ln a~ oo ~ ~ o Ln co _~ Ln ~ Ln ~1 Ln ~ Ln ~ ~ ~ ~D ~ Ln ~ t` ~ ~ ~ ::C Z C~ C Z C~ ~ Z t ) ~ 5 0 :~ 5 ~ :C z ~ Z o o o o o o o o o o o o o o o ~ ~ CO a~ o ~ 0 ~-- O Ln ~;

_ O ~ ~ CO 1` ~D O . ~ ~) N N N N N ~) X _, _ _ _ ~ _ ~, _ ~ ~ J O N CO O r~ O ~ O E~ Ln ~C) Ln Ln ~D Ln Ln Ln ~) N N N N N N N N ~1 Ln Ln Ln ~D Ln Cr~ o N O Ln ~ o ~r 7 ~ ~ I` I ~ O N N Ln Ln ~ N ~ ~ Ln Ln N . l l l l l l l e~ O N CO . O ~ a~ r-l N O ~~1 ~1 ~1 F~ N N r-l ~ N N N ~N N ~ a) o o a) o o Q) C) o ~ ~ ~ ~o ~ ~ ~ ~a N rl ~ 1~ S-l h h h ~1 ~ ~1 0 O O O O O O O O > L}~ Ll_/ L~ L~ L~ L~ L~ L~ O ~ 1 0 u~ ~q ~ rC ~ S ~ .S S S ~:

~ ~ ~1 ~ rl 0 ~1 0 ~1 0 ~ 0 rl 0 r~ 0 '~I ~ K ~ 3 ~ 3 ~ 3 ~ 3 ~ ~ 3 ~J 3 ~ 3 ~ 3 a) a~ . ,/, r` ~1 0 N ~I N 1 ~ oo o Ln ~ ~ .. dP r~ Ln t~ (` Ln oo Ln ~ I~ u O Ln ~ r~ co a~ O ~ N ~ Z I_ ,~ ,~ ,_ ~ oo GO 00 CO -- 21 - ~9;~5 ~a O ~D O ~ ~ ~r ~ ~D ~ ~ ~ ~ ~D u~ Lr) ~ ~ ~ ~ ~ CO O ~ ~D 0~ ~ ~ ~ r~) ~ O 1~ cr~ ~~D 1~ N~ r~ t~l 0~ ~1 ~1 C~ ~1 0 ~9 ~1 0~ ~) ~D ~ ~C) ~ ~D t~ '~ ~ z ~ ~ ~ ~ zo ~: z o ~ z o :c z ~ z t) ~ z o o o o o o o o o _ ~ oo a~ t-- o LO ~r t~ ~D . ~ ~ ~ ~ ~ ~ ~ ~ ~ x ~ ` ~ Ln ~ o ~ oo ~D O a~ c~ ço l l - o l o l r` o ~ u~ . l u~ r oo .

F~ ~ r-l ~ N t~ ~1 ~1 ~1 ~1 o ~ ~ ~ (~ 1~ t~ 0 0 (~ t~ 0 0 0 N ~ h h h h ~ h h h h ~ a) o o o o o o o o o 0 ~ ~ ~ ~ ~ ~ ~ ~ ~1 o u~ cq ~ .C ~ S :~ ~ h ~ S~ oa) a)o oa) G)O aJa) oa) a)o oa) Q)a) a) ~ 1 0 rl 0 rl 0 ~ rl 0 rl 0 ~1 0 D:; ~ 3 ~ 3 ~ 3 ~a 3 ~ 3 ~ 3 ~ 3 ~ 3 ~ 3 ,1 ~ ~ co ~ o o a~ 0 O~ ~r ~ O r~ U ~1 ~ U N U ~ ~C ~ U ~ 5: ~C U 5~ U O ~ o æ ~,~r J~ ~ 22 ~ 9385 ~ ~r ~ co ~ ~D ~ ~ ~ a~~ ~ co o o o ~ o o ~r ~D O ~ n ~ o r~ o c~ o r ~ a~ o r~ o ~r r- ~ ~ ~ ... ... ... ... ... ...

O ~ ~ o ~r r ~ ~ r~ tn ,.. ... ... ... ... ... ... ... ...

~) O t~ Z ~ 5 Z C~ ~ Z O ~ Z ~ X ~ ~ X ~ Z o o o o o o o o o ~ CO ~ ~ ~ ~ ~ ~D er _ Lr f~l O Ln ~ ~ U~ ~ ~ ~1 ~ I ~ N X _ _ _ _ _ _ _ _ _ rll ~ CO /:~ N 0~ ~ ~D ~1 U') O r~ O ~ I ~ I ~ I I ~ I O u~ ~ u~ ~ ~ In u~ . I I ~ I I . o oo ~ ~ c~ ~ ~ ~ ~ ~r o~ I a) ~ o o a) a) a) a) Q) O ~ ~ ~ ~ ~ ~ ~ ~ ~ J~ h ~ h h h ~ h ~ S~ a~ o o o o o o o o o ~ o ~ s ~ ~ ~c ~ ~ .c ~ ~ :~ ~ h ~ h ~ h ~ h ~ h ~ h ~ h ~ h ~ h V ~; ~ 3 ~ ~ ~a 3 ~ 3 ~ 3 ~ 3 ~ 3 ~ 3 ~ :~ ~ ~ ~ ~ ~ CO 1` 0 ~D 1` -~1 ~ ~ ~ o o 1-- o dP J~ W tn ~ - h I o ~ O ~ ~ 0 0 Z o~ -- 23 - 3~S o o ~r ~D O ~ ~ ~--t` ~ ~ ~ ~D ~ 0~ CO ~ 1-- a~ u, 1-- o 1` ~ ~ O r ~ ~ ~ o ~ o 1--~ ~ ~ ~ ~D CO ~ ~ ~ O O ~ ~ ~9 ~ ... ... ... ... ... ... ... O ~ ~ ~ a~ o ~ o 1~ ~ O 1~ U~ ~ U ) (~J Ln ~ U~ ~ W ~1 W N W ~I r` 1--l ~ ~;r o ~ ~ o ~D ~r o ~ ~ 7 ~ ~r o ~r ~ ~ o _ ~ a~ ~r ~ ~ ~ ~ ~ ~;r ~ ~ r~ o~ o ~ o 1~ ~ O ~ t~ ~ z ~ ~ z o ~ ~l o ~ z o ~ ~ c~ ~ z c~ ~: z o x ~ c) ~ z ~ - - - - - - - - o - o o o o o o o o o ~ - o ~ ~ co ~ ~ ~ ~ ~ _ o a~ o U O O ~ In ~ 1-- o~ -- ~ D O r~ W 1~ ~ D N X _ _ _ _ _ ~_ _ _ _ _ _ Ll~ W 0 ~-- W 0 , 1` ~ N Lr~ OD ~ . u~ a~ ~ o I a u~ o ~ U~ o~ ~ a er O ra ~ ~ ~ ~ ~ ~ ~ ~ N ~ O O O O O O O O 0 3 O, S~' S ~ S~ S~ S S~ S~ S~ h ~ S~ ~ h ~ ~ h a) a) O G) al ~; C) C) O O al G) C) O O Q) O S ~; ~ 3 'a 3 ~ 3 ~:) 3 ~ 3 ~ 3 ~ 3 'a 3 ,1 a) I` ~ t~) ~ ~1 ~) CO ~ N ~ ~r ~ u~ ~ ~ er d~ 0~ Z;

N Z C~ ~ ¢~Z ¢~ ~~ =~ O o o o o o o o Z ~ ,~ ,~ - 24 - ~9385 Preparation of 4-Substituted Imidazo[1,2-a~Quinoxalines m e 4-substituted imidazo-tl,2-a~quinoxalines of this invention are prepared in 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-Alkyl~midazo[1,2-a]quinoxalines (Table V) were prepared by refluxing the appropriate amide (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 MgS04, and chromatographed through an alumina column. The chloroform was evaporated and the product crystallized fro.m the indicated solvent - 25 ~1~9385 ~ ~ co o co c~ r o ~ er ~ ... ... ... ... ... ...

O N ~ ~ ~ 1~') ~J ~) ~ ~ ~ ~9 00 In [` 1-- ~ 1` ~D a ~ u ~ r- ~ o ~ o a~ ~r o ~ ~ ~xæ ~cz c xz ùxz ci~:z ~æ O O O O ~ O O )----\ ~ O O O O O O O \ ~ ~ O ~ / \ E~ ~ ~1 ~1 ~1 U~ O ~ ~ ~ ~ n 0 ~ ~r o h O ~t~ O f:~ ~~1 ~1 ~1 X ~ ~ O l O 1~1 ~ -rl h ) O ~ N ~ ~J E~ h O r O N u~,, ~ o a) ~ ,C :~ 51 0 X X X + X ~ ~ U~ 0=~ rl ~ ~ ~D ~ ~D ~ I` æ ~ ~ o\ ~D ~ ~ ~ ~1 ^N ~' ~ U ~ O I ~ X ~C ~ . a~ o O O æ ~ -- 26 - 93~j a ~ ~ o ~ ~r ~g r~~ ~ ~ ~r ~ ~ ~ ~ ~~r a~ ~r ~ oo ~D c;~ o o ~ u~ O u~ O o C~ o o u~ ... ... ... ... ... ... ... ... ...

c~ ~ zo ~ z o ~ zo ~: ~; ~ ~ zc~ x ~ ~ o o o o o o o o ~ o o o o o o o o o O ~D U~ ~ ~ 1-- CO - - ~ ~ ~ ~ ~ o ~ . a~ ~ ~1 x ~ - - - - - - - - ~ ~ ~ o ~ ~ ~ ~ o ~ ~ ~ ~ r~ ~ ~ ~ r~ o~ ~ O I` ~ t~ In ~1 n ~ ~ ~ Q I I I I I I ~ I o . ~ t~ co o ~ O h h h h S M ~ ~ I a,) h O O c) E~ ~1 ~ ~1 .C ~1 ~1 ~I h a ~1 ~ o O Q~ a) Q Ql U~Q, 4~ U~ U` O ~ O O C) O O ~ O :>1 h ~1 ~ h h ~ h h ~ ~:

h Q, ~ (~ Q Q, ~Ql O (~ (~ C) 0 5 X O O X O ~ X rC . u~ . .

. ~D . ~ ~) N O . ~ I I I ~ ~D 5 ~ X ~ ~0 ~ ~ m m m 5~ 5: ~ m m m c~ ~ m ~ ~ o o ,~ æ ~ ~ - 27 ~1~93t35 ~r~ .., ,,. ,.. ,,. -- -- o~4 d ' ` ` ` ` ` ` ` ` ` ` ` ` ` ` ` ` ` ` C~ $ ~; O ~ Z O ~C Z t,) 5: Z O P:~ Z 0 ~4 ~ ~ ~ _ O O ô o o o o C~ o o o o o o In ~ ~ ~ u~ In ~ t~ U~ ~ _ O O o ~1 ~1 ~ ,~ O x - - - - - - o ~ ~ ~ ~ o ~l ~ ~ o ~ 1-l ~1 CD ~I r-l ~I h .c ~ ~ ~ ~ ' O ~ a) a r) h ~ ~ o Ln ~ O O I~ U~ ~~ Ln _I ~ l- . 10 . ~ I I I ~ (~ . ~ D O O ~ ~ -- --1 ~iC~ ~ ~,1 ~ ~,1 ~ o ` U~ O h ~ a) a) ~a o ~ ~ rS a) .

N ~ t~ ~ O ~ X a) u~ rl --1 a) O h Id ~ ~ :~ O ~ O C~ ~1 0 ~ h s:: o ~ a) o o a) h ~1 ~ ~: X X O ~ Q a~ o ~ a) oa~ R ~ ~ ~4 .~ oo ~ I` o a) CO ~ -- o ~r 1-- 1-- . . rl ~P ~ o ~ U o ~1 ~r .

Il ~ ~ t~ H 1~ O X O I o ~ 0,-,1 ~ ~ <> b ~ O~i~k~ t_) ~ 3 3 ~ ~r . ~ R 0 ~n . ~ ~ O ,~ ' O ~ ~ ~ ~ ~ ~ O z ,_, ~, ~ ~, ,, ~ ~æ - 28 93~35 4-Arylimidazorl,2-a ~auino:calines (~able VI) were prepared and isolated according to the ~,eneral method described for the 4-alkylimidazorl~2~a~auinoxalines~ except as noted in Table VI.

__ d - 29 ~1'193~35 O CO O ~. CO 1` ~ ~ O ~ ~ ~ ~ o r~ ~ ~ a) o ~ u~ ,~ ~ ~ I` a~ o ~ co o ~ ~ ~ ... ... ... ... ... ...

U~ O00 ~ ~ n w oo ~ ~D ~ ~ U~ ~ ~ ~ Lr ~q 0 In ~ ~ ~o~r In O~ ~ O ~ O ~ ~ ~ ~ 0 ~1` 0 ~1` 0 ~~ r~ o ~ ~ ~:r UC~ ,U :~ ZO ~ ~ ~ Z o o o o o ,~ ._ ~ O U~ O O OD \, ~i /\ ~\ ~ ~~ Ul ~ ,` o ~I N . ~) ~ ~ ~ ~ ~ r~ S,, ~ I`o ~r o ~~r u~ ~, ~ ~7 O ~1 0 ~ ~ ~ ~ ~ ~1 ~ ~ o ll l l l l In a~ ~ o~ ~ X ~ ~r ~ --I X ~ E~ ,1~ ~1 O rJ H O rj~l O I 0~ I O ~ N .IJ O O O O C O rl E`: S N ~ ~ I~ O a) ~~ ~ Q~ Q la ~ ~ 1~ oo o o o ~ ,1 ~ O o o ~ V + ~ N ~ ~ Q. Q O OO O O O O a~ o u~ R ~ ,1~I-rl,1 ,1.,1 co o Z~ O ~ r~ ~;

-- 3 0 -.

3~5 er~ a~ ~ ~ w ~9~D CO ~~` 00 1` ~ U) a~ ~ ~ ~ In r~ Ln ~ o u~ D O ~n o ~ o1` ~ O ~ ... ...... ... ...... ... U~ O O~ r In O U~ ;r o ~ r~ o U~ O 10 ~1` U~ D O O NO O t~O O ~ ~ ~ I` I` ~ ~ 0 ~1 ~) O ~ ~ Z c~ ~ Z ~ Z ~ ~ ~ o ~ o o o o o ~D ~O ~ ~ O U~ O _ O ~ ~D ~ O ~r ~ ~ o ~ ~ ~ ~ ~ ~l ~ ~ ~ ~ x ~ o~ ~ o ~ ~ ~n r~ r~1 u~ .

I` o ~ u~ ~ C~ o In ~ I` ~D ~ ~ I` o ~ ~ ~ ~ ~ ~ ~ ~ u~ u~ . o ~r ~ I~ ~D ~ ~ ~9 ~D o ~ ~l ~1 ~I r-l h N ~ O O O ~ O ~1 a) :~ 0 a~ I a ~ Q) r-l ~ o ~ o ~ o o ~ a) o u~ ~ o s~ ai Q~ 0 N ~ r4 0 C) a) h X u~ ~0 u~ a) U~ ~0 S~ ~1 ~rl a) 5~ ~,1 ~ O O ~ 3 a~ ~1 1` ~ ~ U~ . . . . co . . ~r ~D ~ ~ ~ . n ~ . ~r ~ d u ~o~ ~, ~ ODO~ O ~ ~ ~ ~ U~ O Z ~ ~1~ ~ ~1 -- 31 - 93~5 O O 1` U~ I~ ~ ~ CO ~D ~ ~r ~ ~ ~ ~Y o ~ ~ ~ ~ ~ ... ... ... ... ... ... ... ... ...

0 0 a~ ~ ~ ~ ~r 1~7 o t~ ~ o ~D ~ ~ U~ ~ a~ I~ N ~ ~r) ~ ~ ~ ~ ~1 0 0 0 t` O O ~ O O ~ a~ O o~ ~ ~ ~ ~ no ~ ~ n ~ o ~ I~ ~ o ~ ~ t~ ~: z o o o o o ~ o o o O O O O U~ ~ C~ ~ o a~ N W ~r 00 _ N ~r CO ~r ~ Ln O ~ ~r . ~ ~ 1 ~ ~I N ~1 X ._ ~ ~ ~ ~ _. ~ _. ~ co ~ u~ o a~ N N N ~1~) eP ~r ~:1 N t N ~ ~ r'~ U~ U-) N N 11-) a~ ~) O ~ ~ l N N ~ ~ . I I - 0~ N r~ O 1` a~O N a~ ~) 00 0 . 1~ L~ '1N N ~ 00 o~ t' E~ _1 ~1 ~ N N N N N N ~I r-l a) a Ei ~ ~0 E~ ~ S ~ h N J_l O O O ~) O O O X a ~ ~ O o .c o ~ ~ s .c o ~ ~, s~ ~ ~ s~ ~: a) ~ ~ s~ ~ h 0 u~ a) a~ ~1 E~ ~ O .C h ~1 0 0 ~ I O ~ C~ ~ 3 ~ aJ ~ 3 N ~ ~ ~ 3 ~ 3 ra ~1 .,1 ~ ~ o ~ c~ f'~ Ln 1` a~ r~ ) ~ ~ O N IJ ) ~1 dP ~ . O ~ ¢~ ¢~ ~ ¢~ ~z~ O O Z 0 ~ O r-l N ~ ~ O ~ ~r ~r ~r It~ It~ Il 1 111 In Z ~ ,~ ,_, ~ ,_~ ~ ~1 ~1 ~1 ~ .

3 2 . . .

385 ~r o o ~r t~ ~r ~1 0 a~ r-l N ~ ~` N ~ ~ N ~Si ~ It~ ~ O ~ ~ ~IN O r-l O 1-- CO O 1-- 0 N ~ N r~ ~S 'd r~ D 00 N ~ ~ ) ~ N ~ ~~ ) ~ ~ ~ N ~7 ~ N ~) ~ N CO ~D O _ ... ... ... ... ... ...... ......

~ ~ ~ r` 00 ') ~ N ~ 1~1 ~ r~) N N ~ lS~) ~ ~r IO ~1 ~ ~ ~ ~ ~r co ~r 11~) ~ c~ :~ æ o ~c Z ~ ~; æ ~ ~c zu ~ z c~ z c~ ~: z O O O O O O O O O o u~ ~ E 1` ~7 o N (5~1~1 N ~ 00 _ ~ N ~ ~ r~ ~D 11~) ~1 . N ~ ~1 ~ 1 r-l ~I N N X _ _ _ _ _ _ _ _ _ N In _I N O ~ t~l O E ~r ~ N ~ ') N N In O O N ~ O ~ ~1 In N . I I I I I Q~ ~ r` In ~ N r~ ~r O F~; N N ~1 ~ ~1 ~I ~ I N a) (1) 0 3 ~ E, a ~ s~ N ~ (~ O O O ,E, o rl ~ ~ ~1 ~ 4 I S I ~:

~1 ~1 0 ~1 ~1 ~1 0 .c o ~ ~ o o ~ o O td O N Q~ X ,E. ~ ,~: ,E, ~,E, Y.~ o ~ J~ ~ ~rl 0 J- ~1 0~r~ 0 ~ ~ Q~ ~O C~ ~.C ~ 3 0 ~3 ~ 3 0 C.) Q ~, a) .,1 O tJ~ ~ ~D N . . . . Ir~ ~ ~D N ~r ~) N U:~ . . . . .

~P ~ ~I r~) In r` N O ~ In ~1 ~r N o [~ N O=c; ¢~1 m ~' 1 LO ~ ~) I~ C~ o ~I N O L~ æ ~ ~-;,r ,~ -- 33 - ., 385 ~ ... ... ... 0 0~ ~ ~ ~ In ~ ~ I~ a~ 0 0 0 ~: ~ ~ ~ a) ~r ~ ~ ~ o ~ ~ Lll ~ ~` ~ ~ O ~ ~ r~ ~ ~ ~ Ln 1--o ~ o~ ~ ~ In ~r ~ c~ z o ~ æ t~ O O O O O _ u~ O O ~r o ~ O~ ~_I 1 ;;

N . ~I -1 ~I t~l X e r~ n In O ~ ~ U~ ~ O ~ ~ I ~1 _I . I 1 11~ ~ I ~1 C~ ~ . ~ O . ~n ~ o u~ In ~ ~1 ~ a~ o N rl 1~ S~ ,_1 0 O a ~1 o o o o o O 0 ~ O S S S ~ S h ~ ~ ~J S ~ ~ U~ o .,1 ~ ~ ~D CO CO ~r o ~ I dP OD CO ~ U O ~ ~c ¢~ =~ =CO ~ m~ O m m v o=c~-- -- ~ o r~ ~ ~ m m m m O ~ :~ ~ ~ ~ ~ ~, - 33a - i7~, ',~ 5 N ~)N N ~ ~D ,~ r~ ~ C~ N O ~)N ~D N_ If \=~f N ~ ~ ~D ~ ~ ~ O (rl ~ i r~ ~ r~ a~ r-i ~ r~. r~ I~N t~ N ,~ ,~ . ~ C~ NN 0 L~ C~O ~ N u~ O :~ ~ O L~ r~ S: ~ ~ ~ ~ r~ D O ~ 0 ~1 IS~ ¢ ... ... ... ... ... ...

t~ r~ C~ N ~1 L~ ~ ~ ~ ~ ~1 ~ r~ v v~:~; vxz v~C~; v~C~ v~ vxæ ~ o o o o o o ¢ o o o o o o ~_ ~ . .~ X ~ ~I N tb N N N N N -o tr) ~-- ~) CO O~ Lr U-~ ' V o L~ ~-1 ~I r~ . 0 1 1 S:~ ~ ~ -. I ~ ~ 0 0 CO ~I r-l O I U~ ~ ~ ~ ~ ~I r-( r~l A CO ,-1 I Q) O .,1 ~ h N h ,~ a) o ~;3 ~ ;~:

cB r ~ h Q) a~ r-l ~ a.) S ~ O O ~:

S-~ tJ) ~ ~ N a3 0 :S ~) ~ S 5~ -I o a~ ~ ~ o E~ ,Q a~ Q) ~ ¦ N ~1 ~1 ~ N ~D C) CO ~ Lr~ ~r) CO N ~) ~) ~ N N C~I . ~:

bD h h H ~ V O r-l N _, G~ r-l N N N O~ ,- ~ r-( N N N N -3~ L _ ~9 3 8 5 Notos 0 I'~!a ~ ;

a. U.5.3,887,;66 d-sc-i~es this com?our.c as natrinS a r.t.p. oE 1;4-lsiC .

b. 'reparod ~y -efluxing e~uimola- æ~,ounta of l:ae 2-amir.o?henyl i~idazole an~ ph ~alic anlyd_ide in toluene or one anc` onehal~ hours. ~pon coollns, ~he ?roduct seearated out of solut_sn.

c. Pre?ared by c~talytic nydrogenalion wi.h 10~ ?allacium on car~on of a di~ethyl~o~amide solution or the nit~o an210s; cruc'e ?rocuc~ ?reci?itatec with water.

d. ~re~ared ~ir ~re-tting com?o~nd iS3 in oy-ici..e w~.. '~ie a?oropriate acic chloride ~ollowed by ?reciDitation wi~h ~a~er.

e. ~reDar2d ~y .. cieav~ge o^ comocu-.d ~o. 130.

'. ~re?a-~d by treating ~he lith~m sa't of compound ~;o. 162 wi~h the appropriate acid cnloride in DML~ 'ollowed Dy pre-ioitation w~th water.

S- ~rerared ~y .~eating cor~ound ~;o. lSl with ~he ae~ro?riace r~ucleo ~hile ac^ording to .ne ~ethod o~ Xorn~ et al, J.

Org.

Che~., ~', 1560 ~1~76) .

h, Prepared by H I cleavage of Compound 220, ~ 35 The 4-.~lk~yla;ninoimidazo~1,2-a ~quin3calines (Table were prepared by treating the corresponding al'~ylureylenes (Table III) with phosohorous ocychloride and pyrid7ne during one -`na lf hour at reif lux te mDe ra I ure s .

The rea c t ion mixture 5. was Qoured into cold water and the excess oyrid ne was removed by azeotropic distillation.

The crude product was dissolved in chlorofor~ and pass throuOh an alumina colu.-.a.

After evaporation of the chloroform, the solid was cr~rstallized ~rom the indicated solvent and obtained in the indicated yield.

;

~ 36 ~ 3r~s - L C O ~ ~ O O ~ r~, ~.

C .~, ~ ~ .` _, ~ o C ~; ~ r~ C Z ~ U _ Z C --I O ~, G \~_=/ xl ,~, _ _ ~ ~ :

ol ~ c ; ,, ~ O ~ I ,.

_L E C~ Z Z~ ~ -u ;~: ~ -~ _ _ r ~ 'J I ~ _~ ? ~ 5 4-~rylaminoimida7.orl,2-a~quinoxalines (Table VIII~ were prepared by treating the corresponding arylureylenes (Table ~) with an equ_molar amount of pnosprlorous oxychloride in refluxing pyridine during one hour. The cooled reaction 5. ~ixture~was stirred into cold wa~er, and ~he crude solid which separated was dissolved in cnlorofor~, dried and passed through an alu;nira colu.~n. The chlorofor~ was evaporated and the crude solid was crystallized as indicated in Table VIII.

.

38 ~1~9385 1~ D N~r 1` ~1 11~ N O a~ `D 1-- CO ~1 0 0 N N o 0 1-- C~ ~1 0 0 1` ~1 ~- .-.

U~ O N ~r O ~ lr) O ~ Ln O 1~1 ~1 ~ co ~ 1~ Gl ~r7 ~ ~I E4 ~` N ~-- N 1~ N ~ 1 Lt~ ~1 ~r ~( U) I` ~ ~ ~ N~) ~r N ~D 111 N CO ~ N ~D 1` r l I~ ~1 ~r _I ~~ ~ ~r N ~ O ~ O O r` C~ ~ _ ... ... ... ... ... ...

t~ N ~r ~1 ~r n O ~ Il~ O 11~ ~ ~ CO ~ t` ~ N ~1 1` N t` N l_ N U~ ~ ~ Z ~ W Z C~ ~ Z ~ ~ Z ~ ~ ~ CJ W Z P~ Z O O O O O -- ~ O O O O O O E~CO t-- N N D O ~;~r7 0 0 N ~ X~I N N N ~ ~r a~r ~ o o ~r N ~_ ~ O ~ ~ ~ ~ ~ / ~ ~ ~ ~ r~ a) L~ .~ o~ o Ln X C-~ N Ln ~:) O ~1 ~ILr) LO Lr) 1: O O ~ . ~ L~ LO t~ 1~ a~ S ~ H X N H O ~ rl ~U ~ h ,a N 3 1 ~ h ,5~ 1 a) I -1 0 r l O-1 0 ~ O I O ~ O ~ O ~O ~1~ 0 O o$ O s (~1 h 115 ~ h ~0 ~1 aJ ~1 S ~Lq ~q ~ S O ~ OS O S O ~ O ~ ~1 ~ S ~ ~ ~ ~1~ ~1 ~ ~ + ~ ~ ~ ~ s ~ s~ s ~ s~ $ ~ N 0=0 ~ N ~ -1 ~ O OD d~ I~ ~ ~ ~ ~!

~;

O -1 N ~r Ln ~D O Z ~ ~ ~ ~ ~ _~ -- 39 - 93~5 ~ ~ er r~ ~D O ~ ~ 0 a~ ~ O ~r o ~ ~9 ,~ In ~D ~ ~ ~1 ~ ~ ~ ~ ... ... ... ... ... ... ... ... ...

U~ O ~D r~ ~D ~ ~ ~D ~ ~ a) ~ ~r o cO ~ o c~ D O In a~, o u~ a~ U~ ~D ~ 10 ~9 ~ In ~ c, ~ o a~ ~ o a~ ~ o a~ ~ ~D ~ U~ ~ ~ ~ ~ 00 ~ ... ... ... ... ... ... ... ... ...

U u~ ~ o ~ ~ o cr~ ~ o ~ D O ~r ~ o ~ a~ o ~ c z ~ c z ~ ~ z o ~c æ c~ $ Z C.) X Z O ~ Z O o o o o o o o O O O O ,-1 ~ ~ E~ ~D r~ ~9 0 ~ O t- et~ _ ~D ~ ~ a~ o ~ ,~ ~ ~1 X _ ~ _ _ _ _ _ _. _ L~ Ul ~ I C~ ~ I I ~ o O In r~ r~ r~ . I I I I . ~ c~ r ~ ~ a) I a.) a) a .0 ~ ~ , , ,~ h E~ N ~ ~ O --1 0 0 0 0 0 ~ ~ ~ o ~ l ~ r~ ~ r~ O ~H ~ r~ rl Q~ o ~ o~ o ~ o o s O ~ 1~ h ~ ) h J~ :~ S~ ~ S h O O 1~ U ~ E~ U ~ 3 a) ~1 rl rl ~ 3 '~ 3 ~ 3 a) ~ 00 rl In O n o ~ ,~ ~ .

,~ In o ~ a~ d. '-1 '-I '~ '-I ,_1 ,_ 0~ ' ~ ~7 ~ L O l-- t-- ~` C~ CO oo oo CO o~ Z r.~ r-lr J r-l r l rl r-l r-l r~ /~l -- 40 - 385 ~ ~ ~ O~ CO ~ ~ ~ CO O ~ O ~D ~ O ~ r o ~ ... ... ......... ... ... ... ...

u~ o er o~ o ~ ~~ ~ ~ ~ ~ ~ u~ r In O ~ In cr~ ~ In c4 ~ In a~ U~ .... ... ... ... ... ... ... ... ...

U O er a~ o ~ ,~ ~ ~ ~ ~ ~ ~ ~ ~ In ~ In o ~r ~ a~ ~ In ~ ~7 U- o~ ~ ~ ~ z c~ z ~ ~ z ~ z ~ ~c æ o ~ z O O~_ O O O O O O ~r 1~o 1` o o o o o ~ U~ D ~ O ~ ~0 ~ _ CO O ~ ~ NCO 00 0 ~) . ~ 1CO N N--I~I N N X _ _ _ _ _ _ _ _ ~_ O OD U~O, r r~ U~ ~ ~1 ~ O ~D ~ ~ ~1 (~ .C ~ r~ U~ ~r C~ er 0~~ N I~r O r-l --1 N ~U'l_1 Il') t~ IJ~ . ~ I I I .I CO . ~ a~~r N ~) ,~ ~ ~ ~ ~ ~ ~ CO O E~ ~ ~ ~ e ~ ~ ~ h -1 0 ~-I h ~ h N ~ OO ~ O O O O O O O S OSS S S S S S S O ~ h ~ ~ ~ S-l~ ~1~) ~ ~ S~ ~ ~ h ~ S O ~ 3 -1 ~~ 3 ~ ~ 3~:5 3~ 'a 3 'O 3 aJ ~ ~ ~ a~ ~ .,1 ~1 ~ ~1 ~) ~ ~ N 00 . O . .U~ . . .

. ~ ~ ~1 . O If~ ~) 0~ 0~ 0~ ~ ~ ~ ~ o O o~ o z ~ ~ ~ ~ ~ ~ ~ ~ ~ -- 41 - s U~ _ ... ... ... ... ... ... ... ... ...

U U ~ iU ~ ~ ; U ~: Z U ~ fl U ~:: ~ U P:: Z; U ~: Z U P: ~ o o o o o o o o o ~ o o o o o o o o o ~ o ~ ~ _ ~ ~r o cs~ ~D O U~ x - - ~ - - - - - 0 In N O O ~1 1~ ~r r~ ~r ~ ~ ~ 'r r~ u) ~ i~ i~ i~ ~ o ~l ~ o ~ ~ ~ C~ a~ a~ I I ~ I I 1` O I ~ In u~ ~ Ln Q ~ i` O (~ CO ~ O . ~ CO ~ O O ~ i` i` I` i_ CO i Q) a) o , a) o o a o .,1 ~ 0 0 0 0 0 0 0 ~ h N ~ O ~ O O O O O O O ~ ~ 0 ~ o ~ ~ ~ ~ ~ ~ ~ 4~ ~ :~ ~ ~ o ~ o ~ ~ ~ ~ O 1-l ~10 i-l ~ S-l ~J ~ ~ S-l ~ ~1 ~ h ~ ~ ~ 0~ ~: rl 0 ~1 0 ~1 0 ~1 0 ~rl 0 r~ 0 rl 0 C~ ,1 3 ~ U ~ 3 ~a 3 ~ 3 ~a 3 ~:1 3 ~ 3 ~ 3 ~ ~ o o o~ ~1 1~ U7 Ll') ~ ~ ~ N --1 U~ ~I N o~,o ~ l N Ct) N ~t i` ~1 O O O O N N O N N S~' N N ~ 'I ~3 ~ ~ ^ ~ D ~ U U U ~ ,~, _ X C~ U ~ O O O O O O O O O O Z t`l N t`l N N N N N N - 42 9;~5 ~a~ LO o ~ o ~ ~ ~ c~In o ~ cn o ~ ~ o o ~ r U~ _ ,........ . ... ... ... ... ... ...

~ ~ ~ z c~ ~ z ~ ~ ù ~ ~ o o o o o o o - ~ o o o o o o o ~ ~ ~ ~r a~ ~r ~ I` . r-l N X _ _ _ _ _ _ _ ~ I` ~ ~ ~ ~r ~D . ~ I ~r ~ ~r ~r r~ Lf U~ ~ ~ O ~ O ~ 11'~ ~ ~ ~I N N C~ ~1 ~ ~ a~ a) a) a) o o a) aJ O '~ O E~ ~ ~ O O ~ ~ N ~J O O O O O O O O ~ o ~ o o a) S ~c) ~ ~ ~ ; ~ o c~ ~ 3 ~ 3 ~ 3 ~ ~ ~ 3~5 3 ~ oo . . ~ o ~ .

~ o . , . ~ . . .C o\o ~ ~ I~ r ~ O ~ ~ .

~ ~ ^Z~ .

$ . ~ N ~) ~r Ir) ~ ~ o o - l ~ ~ ~ ~ ~ ~ ~ z Z ~ ~J ~ ~ N tN 7 -- 43 - s Various com?ounds of this invention displa~ antifungal and anti-yeast activity. Thus, for e~ample, the~have been found to be effecti~e ag~inst such organisms as Candida albicans (~CC ~To. 10231), Candida trooicalis, .

5. Asoergillus niger (ATCC ~To. 10404), Trichochyton ~er.ta~roonytes (ATCC No. ~757 and 9129), Tricho?hyton rubr~m (ATCC rro. 10213 and 14001) and Tricho?hyton a~elloi.

The antifungal activity of compounds of this invention indicate tneir usefulness against der~atomycosis such 10. as tinea capitis, tinea favosa, tinea barbae, tinea corooris, tinea i.mbricata, tinea cruris, tinea ~edis, tinea ~anus, tinea unquiu~ and various tyoes of ca~didiasis such as glossitis, stom~titis, chelitis, ?erlèche, ~Jaginitis and balanitis.

15. t~hen tne com?ounds of the present invention are used for antifur.gal medical pur~oses, they will usually be incorpora'ed in a suitable pnarmaceutical carrier. These ar.tifungal preparations may take the form of solutions, lotions, creams, oint~ents, etc. ~he quantity of anti~ mgal 20. agent ~f this invention that will be contained in such preoarations ~ vary somewhat. Grdinarily, `nowev~r, it will constitute about 0.5~ to 10.0~ by weight based on the ~otal weight of the oreparation.

In Table I~ below are listed the an~ifungal activity 25. f a number of com?ounds encom?assed in the ?resent invenJion.

These were determiried by the agar dilution method as described in Cha?ters 2 and 3 of `fethods in Microbiolo~, Vol. 73, edited by J. ~. ~orris and ~ ibbons, Academic ~ress, Mew Yor~, 1972.

- 44 ~¢3;~85 ~ T.~3 ' c ~ .~ Anti'un$al ..c~i~ri~ ear:s Pa~ :lillion I~.:n~ ion~ o_ ~un~us anfi Yeast 5~ecias C~ound C. C. . ~. T. T. T.

~o. alDicanstrooicalisni e~2jel10i~.entacrooh~.csr~Sr 3 1~0 100 13 ~ 100 ~0 lC0 100 100 100 100 }6 39 100 100 133 . 100 100 8 8 8 13~ 100 16 13~ 100 13~ 100 ~ 00 13~ 100 ~ C0 142 10C 13~ 100 100 138 100 100 130 100 100 100 100 1' . 100 100 100 3 16 16 13 1~ 1~ 115 16 i6 1~' 16 16 109 12'3 32 11' 16 113 256 123 2 13 ' 16 2 1~0 &lt;~.5 51 119 8 120 ~ ~ 8 'S 4 2 1 iO 128 128 6~ 122 32 112 , lZ8 153 100 1~4 1C0 100 100 100 8 ;a loo lo~ loo 100 62 100 100 100 126 100 1~0 100 .

- 45 9385 T~ . C'`;iT ' d .

Co.. -o_~- C. , C. .~. T. 'r. T.

`'o. a!'~,iczns t-O~IiCal. is n~cj~r a j~lloi ~ LtaS_o?~n~ 3 r~rum 14; 100 100 1 00 i;9 ' 10~ 100 100 l~C 1(:10 100 lC)O 163 lOO 100 lOa 16~ lOO lOO lOO 16~ lOO ~ 00 100 lo? 100 lOO ' 00 l~o . lCtO lOO 1 00 1',~ 100 100 10~ 17 3 100 100 ~ ~0 ' ~ 100 100 100 la2 100 lB~ 100 100 }00 ~3; 100 lOO lCO a~ loo loo ' ~o a~ 100 ' CO ~ 37 lOO 1 0O - ~'' lo 1-~ 129 lo 1~ 3 - 46 A number of the com?ounds encomDassed in the ?resent invention have been found ~o have i~unosuporessant action.

Of ~hose tested, most of these are of the 4-substi~uted imidazo[l,2-a]quinoxaline t~?e described in ~orr,ula I above, 5. although a couple are of the 1-(2-acylamino?henyl)imidazole type shcwn in formula II. Because they exhibit tnis activity, they are i..dicated for use in the treat.ment of those diseases that the prior art recognizes may be helped by the ad~inistr_tion of im~unosup?ressants. These include such conditions lO. as: glomerulonephritis, serum sickn~ss, organ transplant, rheu.~atoid arthritis, systemic lupus erytheratosis, u1cerat_ve colitis, chronic active hepatitis, multiple sclerosis, heterografts or homogra~ts in burns, psoriatic arthritis, urticaria, resoiratory allergies, i.e. asth.~æ, ha~fever;

15. scleraclerra, mycosis fungoides, der-.a'om~ositis, osoriasis and contact der~titis (including ?oisor. ivy).

The dosage level for administering the i.mmunosu? ?ressants of the present invention will vary with the oarticular com?ound that is to be administered. In general, 20. th~s will be at about the sar.e le1tel of the prior art i.~unosuppressants. For the most ?ar~, T~hen the ?resent immunosuppressants are administered orall~ or intraveneouslJ~, the daily dose would be in the range of about 0.1 ~g. to 15 mg./per kilogram of body wei~ht. ~Then other .~ode o~ 25. administration are employed, e.g. de?ot injections, imoiants, etc. the dose .~ay be consider~bly higher i.e. u? to about 150 mg./'.~g of body t~eight in a single in~ection.

The immunosuppressant ac~ivities of the com?our.d~ o~ this in~JentiOn were deter~ined via the hemol~sin tes~ 30. in mice and by the delayed hypersensitivity test. The hemolysin test used is that described in ~!ethods in l.~munolo~y, edited b~ 3. ~..

Cam?be'l e~ al, i. .~ 3e ~amir., ~e.~ Yor'.~ 1903 ~ 47 ~ ~9~3~5 pa~es 172-175, and ~easures numeral or antibody response.

The delayed hy~ersensitivity test ~easures the effect of a test compound on the ability of a sub~ect mouse to mount a cell-mediated i.~mune response to the antigen, ~cobacterium . tuberculosis H37~a. The mouse is sensitized to the antigen by subcutaneous administration in the base of t`ne tail.

The de~elopment OL the delayed hy?ersensitivity res?orse may be measured at any time begirning si:c da~s after sensitization but is usually done on the ninth da~ as follows:

10. The right hind caw is in~ected with purifled protein derivative (tuberculin) while the left hind paw (control) receiv-es physiological saline. 30th ~a~,r volumes are r.e~sured after twenty-four hours and signi~icant increase in the volu~e of the right hind paw is taken as ~ measure of an 15. effective delayed hy?ersensitivity res~onse. ~11 com~ounds were ad.~inistered by the subcutaneous route.

The results of these studies are summ.arized i~ Table X bel~. The expression H1(ED50) mg.'kg. s.c. is an exprsssion of ~he nu.~ber of milligrams per kilogram o~ body 20. weight,o~ the drug administered subcutaneously required to reduce the antibody activity by 50~ when compared ~ith a control. In this case, the lot~er the HL(~D50) value ,o~ a drug the more effective immunosupcressant it is.

The D.H.S. (EDoO) mO-~kg. s.c. ~ lue a?~earing in ~5. colum~ 3 is an expression of tne efLectiveness of the drus in reducing the edema that accompanies the cell-mediated il~mune response. lt is a ~easure OL the nur.ber of milligr~..s ?er kilogr~m o body ~eight of the dr~lg adminis~ered subcutaneously ~Jhich is re~uired to reduce ~he edema o- the cell-me~iated 30. immune res?onse by 50$ when com?ared to the control. Agail, the lo~/er tne D.-.~.S. (~D60) value the ~ore effective is the cruO as an i~unosup~rossant for ~he ~ell-~.edi~te l~mur.e respcnse.

48 ~ T.`~L_ :~ C~r.?o~L~-d) D.:i.a. (~3~5) ?io.~.C,/.~'~,s.C. ~ .C.

,, ~ i~l 0.3 1.~2 ~~0 0.26 1.15 131 18 o~ 11~ >50 56 il7 >50 ~6 ~'3 >50 ~3 109 >50 >50 11 0 ~ 50 3 50 S0 46 >50 1~7 0.027 1.7 13~ 0.5 7.2 137 <0.1~ - 3-~ 13~ 0.033 0.~2 1,2 0.20 ~.2 136 2.7 >~0 1~3 0.75 32 133 3.0 >~ 13~ 0.72 2/ 127 >50 36 170 o.6 >50 1~0 22 >~0 1'3 0.3O 1.3 1l~ 0.21 '3.0 171 0.96 59.0 17~ 0.09 5.9 172 11 . 0 46. 0 1~6 0.~2 45 . O ~97 1.6 37 3 50.0 50.0 ~o~ ~6 >50.0 1~6 0. 11 3.1 11~3 1.2 ;.7 l'g O.lo 3.8 1~6 35.0 >;0.0 17, 13.0 >50.0 82 1.1 ---162 13.0 ~~~~ 173 ---- ~0 15~ 3.0 ~7 lôl 16.0 ---180 ~.6 ---183 0.39 15 15~ 1.0 7.o i57 0.39 ~2 218 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 ede~a of ,t e cell mediated-im~une-resp~nse by 60~. Since these values are higher than is of practical interest from a clinical poinf, of view, no further testin~ was done for these materials.

- 49 S .~ ~u~ber of compour.ds enco~?assed in the oresent inven'i~n dis?lay non-steroidal anti-in~lam.~atory ?ro?erties.

This apoears to oe generally the case for the 4-substituted imidazo[l,2-alquinoxalines o~ f~rmula 1 above and vhe 5. 1-(2-acylaminoohenyl)imidazoles of formula ~ ecause of this characteristic, they are i~dicared for use in the treatment of diseases that Ihe orior art recognizes ~y be hel?ed by t`ne administration of non-steroidal anti-infla~m,atory compounds. ~hese include suc:~ cond;tior.s as icht'~yosis, 10. osoriasis, alo?ecia, &amp;to~ic eczemas, etc.

The dosage level for ad~inistering t'ne antiinflammatory a~ents of the ~resent inver.tion ~ay trary somewh.av depending on the particular drug selected, t'ne disease bein~ treated and the mode of ad~i~istration.

In general, however, '5. w'nen used for tc?ic 1 a??lica'.ion, t~e co~?ounds are distr~'buted in a phar.~aceutical ve'nicle ~uitable for to?ical a??lication.

In t'nese compositions, the anti-inflam~atory agent of this inventi3n will comprise about 0.5~ to 15.0~ by weight b~sed on tne;total weight of the co~?osition.

20. - T~e ~nti-inflam~. tory agents of the present invention .~.ay also be administered orally, intraieneously, subcu aneous]y, i~tramuscularly, and intrader~lly.

Tn t'nese cases, vhe daily dosage will be in the rangP of fr-m 0.5 ~g. to 20 ~. oer '.~ilogram of body weight of t:~e ac'ive anvi-in~'~a~-ia'vory agents 25. of this invention.

The anti-ir.flam.~latory activi~y of reoresentati~e comrcur.ds o' this i.lvention was deter~ined by '~.e rat ~aw edsma assay both by iocal adml'nisvratiol (T~ble ~I below) and by oral dosing (Table '~lI below). ~or the oral dosir.g, the 30. Drocedure of C. .~ iinter, ~. ~. ~isley and ~ . ?iuss, ?roc.

Soc. -:C?. 3-'ol. :~ed. '1 ~ 54~ 62) was e~.?l~yed lith meas-1re-.e~t ta'.~en four r.ours afver the dru~ las ~dm-nis'ercd.

- 50 The local administratior. tests were carried out sililariy exce?t t'ae irritan~ (carrageenan) and the test co~?_und ~ere in~ected simultaneously a~ +i.me zero.

Tables XI and ~II recort the anti-infla~ atory 5. activity of the compounds tested as ~ differe.ce in the ede.~a or swelling as comcared with the cor.trol. T'.~ese Tables also give t;~e res?onse in r~ny instances of ~ore thar.

one dose level of the same drug.

- 51 93~5 Ti~3 L r Y I Rat ?aw ..d~ma .~ssa~, ~ocal .~minist a.ion (in ~ected direc ~.ly i rlto ?a~ ) 'e rencQ ~ 7~o~ Co r ~1 Ccmpound !~o. ~ ~ ~ ;, 1~0 mG/~ 1~3 -3 2 . 6 -i3 . ~ . 3 -39 109 -3 0 . ~3- 3 . g + 3 1 . o 114 -oi3 . 2 ~30 . O -13 1 . O 117 ll ~ ~7 122 -ol 7 - 2 5 1 -57 ~0 -78 - 52 1'1¢~ 5 ,~3L~ ?~t ~ E~em~ .~ssa~, 0-al 30~1n~ ~3if'e_2nce '~m Con~-ol ~~~?~nd `!o.100 mg/'.cc 400 mg/'.cg Indo.-.et~acln -6i i?her.y~u cazone_70 As?i_ in ~57 6 1 110 1'2 -61 ~a ,~ 49 -35 7 -52 51 -57 140 -35 131 -52 -30 39 -50 133 -17 137 -2~ 112 -17 -Oa 111 ~~3 1~1 -61 117 _39 13. _43 13~ -22 -25 132 -76 1~0 ~30 14~ -26 1~ +70 -2~ 117 -7 -1'3 123 1'6 +70~ -18 13~7 -9 -25 8 -22 -13 29 -24 -~i 1~ -52 ~59 '8 -~1 ~7 -3;

~0 -20 -33 -33 -~3 -5~ 37 -3;

1~ -28 - 53 s .A~L~ ~Tl C~n~ Cc3~c~ `.c. lGO m~ q 'G', 1 5 ;~ -2 52 -2~ ~ ~ .q3 23 -~6 -30 s~ -33 3~ -7 -o8 ~ _9 -2~ 2~ -17 -25 109 -17 71 -22 -30 Oa -26 -22 128 39 129 -30 - 54