IE46192B1 - 1-(2-acylaminophenyl)imidazoles - Google Patents

Description

This invention relates to certain 1-(2-acylaminophenyl) imidazoles which, among other things, are useful as intermediates in the preparation of 4-substituted imidazo[l,2-a] quinoxalines which are useful for a variety of purposes. Some of them 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. Such 4-substituted imidazo[l,2-a] quinoxalines are described and claimed in Patent Specification No. 46191 The 4-substituted imidazo[l,2-a]quinoxalines encompassed in Patent Specification No. 46191 may be described by the formula: and pharmaceutically acceptable salts thereof wherein X is -R^ 2 or —'NHR wherein: 4619 2 (1) 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 group; and ' (2) R is a radical bonded to a nitrogen by a carbon to nitrogen linkage; said radical being an aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl or a monocyclic aryl-substituted aliphatic group.

The 1-(2-acylaminophenyl)imidazole reactants of the present invention are of the general formula: R is an aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl, or monocyclic aryl-substituted aliphatic group, bonded to the carbonyl carbon through a carbon 2 to carbon linkage; and R is a radical bonded to a nitrogen by a carbon-to-nitrogen linkage and is an aliphatic,cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl or a monocyclic aryl-substituted aliphatic group.

When R^ is an aliphatic group, it may be a straight chain - 4 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-tocarbon bondings e.g. ether linkages and carbon to halogen link5 ages. Ordinarily, it will contain from 1 to 18 carbon atoms, the most typical radicals of this group being the alkyl radicals having from 1 to 18 carbon atoms. Preferably R is an aliphatic group having 3 to 6 carbon atoms or a substituted phenyl group.

By way of illustrating the aliphatic groups that may be represented by R^, the following are given: CH3—; CH^CH^—; CH,CH.—CH.—; CH.(CH.) — in which nis 3, 4, 5, 6, 7, 8, 14 J z z j z n and 16 respectively;. (CH ) CH—CH—; CH (CH ) (CH CH )CH—, j Z Z j z CH2=CH—(CH2)8—, alkoxyalkyl in which the alkyl moieties have from 1 to 4 carbon atoms e.g. methoxymethyl; halogenoalkyl (i.e, - CH2C1—; CH3CHC1—; CHCl2—; CCl3—; CH2Br ; CF3).

When R is a cycloaliphatic radical it will most often be a cycloalkyl radical containing 3 to 8 carbon atoms or a cycloalkenyl radical containing 5 to 7 carbon atoms. By way of illustra ting the cycloaliphatic radicals that may correspond to R^ in formula I mention may be made of the eyelopropyl (i.e. hexenyl (i.e. ); cyclobutyl (i.e. ); cyclohexyl, eyeId); and norbornenyl (i.e.

When R is a substituted phenyl radical, the phenyl group may have from 1 to 5 substituents but will usually‘be mono, di or tri-substituted. Typical among the groups that may be contained in the phenyl group are (a) alkyl groups which are branched or straight chain containing 1 to 6 carbon atoms e.g. methyl, ethyl, tertiary butyl; (b) alkoxyl groups containing to 6 carbon atoms e.g. methoxy, ethoxy; (c, hydroxy; (d) acyloxy containing 1 to 18 carbon atoms; (e) halogen e.g. 1 or 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; in) acylthio containing 1 to 18 carbon atoms; (o) carboxyl; (p) carboalkoxyl containing 1 to 8 aliphatic carbon atoms; (q) phenyl; (r) phenoxy; (s) amido; (t) alkoxyphenoxy; (u) hydroxyphenoxy; and combinations thereof.

When r5 is a fused bicyclic aryl radical, it may be a . substituted or unsubstituted radical. These are exemplified by such fused bicyclic hydrocarbon radicals as 1-naphthyl and 2naphthyl.

When R5 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 - 6 2 2 The group R in the radical —NHR of formula IX above is exemplified by the same radicals given above in illustrating 5 2 the radical —R . Preferably R is a straight chain alkyl group containing 1 to 18 carbon atoms, or phenyl or substituted phenyl.

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 genera1 type: where R^ is as defined above, the 1-(2-aminophenyl)imidazole is reacted with the appropriate acid halide e.g. the acid chloride. equation: This can be expressed by the following - 7 5 in which R 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.

N wherein R is as defined above, these are prepared by reacting the aminophenylimidazole with the appropriate isocyanate. This can be expressed by the following equation: VIII 46182 - Β 2 in which R has the value ascribed to it above. The 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 the art.

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—TV below indicate the particular procedure used in the preparation of each compound as well as indicating the physio-chemical properties of the compound obtained. Melting points were obtained by the capillary tube method using a MelTemp melting point apparatus and are uncorrected. Ultraviolet spectra were obtained in ethanol solution using a Beckman U.V.

Acta III or a Beckman DBG. (Beckman is a Registered Trade Mark). 1-(2-aminophenyl)imidazole was prepared as reported by A.F. Pozharskii, A. M. Siminov and L. M. Sitkina, Khim. Geterotskl. Soedin., 5., 1916 (1969) [Chem. Abstra., 72, 11427& (1970), Table I below illustrates the preparation of the aliphatic cycloaliphatic and monocyclic aryl substituted aliphatic-aminophenylimidazoles of the present invention. Compound I is included for comparison purposes. 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 of excess pyridine on a steam bath for 45 minutes. The reaction - 9 mixture was then stirred into ice water and the crude product isolated according to one o' 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 chloroform. The chloroform was evaporated from the crude product which was crystal1O lized 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. 46183 - 10 c o « Eq •rl (fl VO rH o σ» CM •4* VO in o CM ro VO in ro CM rH *4* TV CM m in 6 Γ- VO cn VO CM VO CM vO rH ·? g < r u ) Q E vo in in H CO 41 VO H co vo in ro vo ro cm ro O tn VO •4* CM CM m in VO o CM ro ro ro ο» rl u S3 S3 o S3 a □ S3 Κ *4* vo ro u vo •vf CM rH rH Ci cn (J vo *4* CM rH rH TABLE I a o (fl •rl •P ns QJ N P H •rl G 0 pH bJ rH > ώ (4 rH Ό -P 0 •rl (fl ω g >1 •rl P X-. ϋ & Φ XJ CM Ό •rl g rH ω •rl a 0 *0 (6 •H 0 $ P x: t—I rd -P id H 1 0 a CM (fl H 1 rH ti P V •P rH G ftf Λ •P w P Φ -P I n cm ro m to cn io in h* (d I in CH3 (CH2)2- β 31..1 Toluene 108-110 C, 68.10 67-95 H, 6.59 6.52 N, 18.33 18.25 OH CM Π •4* (Continued) Pl η g Ό C (0 Ο •Η ω >1 ι-4 Λ ~ β Ό -% Η ft £ ύ ο •Η +J ftf -Ρ Ν G •rd φ Μ > rd rd πΐ Ο •Ρ W (0 >Ί Μ U β ο •Η 4J ιϋ f-4 Ο φ Η M· o [χ rd in ffl on M* ro O' in m rd 04 00 in Ol Ol © co O' ffl 01 rd o rd Γ0 <3* 04 0* O· Ol k0 u k0 Ol M* 01 ro ω υ rd ro m Ol O' ffl O- o* 0 (x 10 o O- tnr · co 03 CO ro ro co co in σ» o ffl o 01 k0 rd P* rd o- rd l rd O' rd O' rd [x rd 0* rd if [X ro 03 n CO in 03 03 rd 03 ro rd rd Ol σ» O' cn ffl O' rd o 03 o ff ro co CO in rd 0« 03 M1 υ CO GO ^f in σι m rd rd co cn O' jx o Φ O O> in rd co M* 04 CO Xf 04 * ro in 01 u ffl kJ σ» <0 rd [X O' rd o· rd rd O' rd O· co rd fx rd o· rd in k0 01 ι-4 04 rd σι ο* ο* k0 rd σι ο· ο» ffl rd ύ a a ό a a u a a u a a υ a a u a a o a a υ a a in in 04 o 03 o o o in rd 10 o r—l rd Ol rd 01 ffl cn rd 1 ro n ffl rd co 01 ffl 03 o σι o σι O' ci 01 rd rd rd Φ Ρ Φ p P p P P Φ Φ rd Φ Φ Φ Φ Φ β 43 >1 43 Λ 43 Λ nj -P 43 P •P •P Φ P P X Φ -P Φ Φ Φ β Φ Φ Φ Φ id XJ rd 0 rd rd rd X rd rd t J>1 P >1 >1 >1 >ί Φ >1 >1 Φ CU 0 ft & ft ft 43 ft ft c o rd 0 0 0 0 1 0 0 S p 40 p P P ϋ n 9 P p ft u ft ft ft (i ft ft r—l 0 ·Η 0 0 0 0 Λ 0 0 0 CQ P CQ CQ ω W P CQ ω •rl P •rl •rl •rl •rl Φ •H •rd ΪΛ rd ffl ro rd kO k0 Φ •H cn σι in in m o £ m in «f ffl rd ffl ω ο tn co 102-104 Φ β Φ Ν β Φ Λ οο ω Μ* Ό Ο χί Ρ φ S3 rfj « ffl offl ffl ϋ ffl u ffl u ffl co Oi ffl u ffl u ffl u ffl ϋ u ro ffl u ffl υ ι o ro ffl ffl u ffl a co O «-* C4 rd rd rd - 12 *0 Φ •rl 4-> s u TJ c Ο (fl Pm •rJ ω J? c _ < Ό o r-4 KJ O •rl μ (ϋ Ν •Η φ -μ ιη >4 μ υ •μ 3 φ > »—ι ο co Ό Λ Φ •rl >1 ίθ Ο Ο Ο νο Ο σι γ- Γ- νο ιη οο οο cn ID Ο Ο cm in η cn vo oo (4 fq C4 Η N rl 03 ιη cn cm σι co <η in sp vd cn vi > IT) σι in rH Γ*· [4 -tf r-S 14 00 CM rH VD 14 σι σι m 14 νη ιη Γ“1 14 in mt 1-1 νο rH [4 rH Ο ΙΟ ’«Ρ ιη CM CM r-i VO I—1 CM CM 14 m ιη m m 14 VD CM cn CM VD Π ιη r—1 00 cn cn 3 cn σι νο •Μ1 ι—4 (4 CM 14 CM in σ» νο Γ*' ι—ι 00 4* cn 00 CM VD σι σι <η ιη ιη VD cn -tf in νο Γ-1 Γ- i—l (4 r—1 14 f4 ι—1 £4 r—1 14 r-4 * * * «,K US0 υ a £ u as a u as a υ a a o a a u a Z O Γ4 14 f4 m CM M* VD o VD rH ι—1 σι < 14 1—1 CM r—1 CO in 1 CM m in in rH CM CM 01 14 vr O VD r-1 rH r-4 CM rH Φ 3 nJ rH tf ί>1 Φ Φ XJ +» Φ Φ Φ Q*XJ rH rH »—1 3 3 0 1 0 >4 0 Φ Φ Μ M 3 X! 3 N N Οι Φ 3 •μ 3 3 3 0 Λ x: φ Χί Φ Φ m -P · -μ Ή •μ Λ rQ •rl φ o φ τί Φ 00 00 CD σι 14 O ιη CM vo cn i—4 (4 cn CM m 14 ί*· CO 1 to to to O cn o o cn u tC 4» s S υ CM CM 1 CM c CM to to to to u u o u to m m II o ffi cn to CM cn II υ to o to to to 4* u 4* u u u υ rij in νο rH rH Γ» r-i οο σι Ο ι—1 rH CM - 13 Ό C ω Ο •Η fa 01 >1 Η (0 fi rij 7 o cn kf co cn r*· r-l LO CD CM > kF CO CO O > in > VO CD vo co m go M· r-l in co cm cn oo cn in 1 · · O vo in Γ- 00 r4 r> CO co vo o kF in ρ—1 kF • cn vo CM vO in r- r4 cn in vo kF i-4 VO vo r-l r* r4 co VO r—1 m CO r-l VO cn cn 1. r-l in i-4 o VO 95 ω ro VO r4 vO r4 co r- r·* kF vO CM KF co r4 VO r4 o r- CM m (0 cn in kF 03 m oo VO r- 1-4 m CM vO in VO r4 VO r-l VO r4 VO r-l r* r4 r4ss «. K «. u a z a a Z □ a a u a z u a z O a Z υ ο ά £ r- CO kF 1 O in 1 r—1 in in CM r4 in in I ' 1 VO vO co Γ- r4 cm in VO CD SF CO CO Ο in kF kF cn cn r4 r4 r4 CM r4 i-4 r4 r-l r4 (Continued) fi ο •Η +> (0 Ν 4J •Η β r4 φ > ίΟ Η 4-» Ο W W Ν k Ο Ό r4 ΐ? ω •Η ο ft ο •Η φ fi φ fi rd ο ΕΗ φ fi φ fi ι—I ο Η 1-4 Ο β d Λ +» Φ 00 r4 VO co vo cn r- o tn r- r4 kF r4 m VO CM CH Cl- Β 11.9 water 255(dec.) C, 56.OS 55.92 Η, 4.28 4.26 Ν, 17.83 17.72 > CM - 14 0 CO e Φ Λ u Ό Φ > r—( 0 Ui ω H Ό Ο •H ffl ω >1 ι—1 flX . Ο Ό ^'ϋ rH ιϋ ο ffl β rp CM CD *0* rp CM >· co o cn tn cn r—( O'» CM rp r-4 in CM tn rp r* ω cn in ffl i—l cn kd tn r-4 sP r—l CM in ι—I CM tn cn r—1 ffl ffl tn Γ-. ffl r* r-» co co cn cn tn CM r· r—1 rf r- sp KO cn cn in ffl i—l cn ffl in iP rp r—l CM in Γ—J □ cq a O « ffl μ o a ffl u in I ffl ffl in in r—l I I—l I cn m I CM in sp ·<· ffl to r-l ι—1 r—1 i—l 3 *3 0 Φ •rl 3 •P C rt «Ρ •rl N 3 •P •Η φ c r-( »> 0 r-l i—l Φ ϋ ca o 3 P co Φ Ui 3 H >1 I—l P 0 3 ffl U &ΐ π3 ι—4 0° Φ •Η φ α φ Ν β φ μ φ Λ Ρ Φ ¢4 •rl ui Φ P b >, +J w 3 Φ Φ 3 > « 0 iP •μ b 0 ϋ ω 3 • *3 b ω 0 ω Ρ « φ Οι ffl □ Κ Φ 0 φ »3 -P 3 m Ρ tn 0 0 c •rl 3 Φ <3 0 *3 cn Γ* CM CM cn ω Ο CM CM 0 •Ρ > 0 rt 0 ο Η Ρ rt r-l Οι φ •rl •Ρ 0 Ό ω ρ •Η ί* •Η *3 >1 S rt XJ Λ ffl 3 rt ι—1 Λ ο rt > -μ •Ηt •Η 0 £ Φ β β •3 *3 Ρ φ •rl 0 Ρ Φ Ρ m Ν *3 ι Ρ •Η >1 □ φ 1—1 Α •Η •Ρ rt 3 4J ιρ ρ rt Φ ί •Ρ □ 3 Φ purified by chromatography on alumina with ethyl acetate T3 Φ N Ή i—l «-J rt •P « >1 ri? a α cr ffl Ο CM 1—4 U ffl υ Pm O rt Φ Λ Ρ β • 3 •Ρ 0 0 σι ffl rt| φ Ρ rp 3 *γΊ 43 • Ψ1 σ rt ί>1 •Ρ γ—1 •Ρ 3 *—' ρ ffl 0 rt φ rp φ Φ 3 -Ρ Ρ rp +1 Ρ ffl 3 rt ffl (0 rt 1—1 ffl ? ffl 1—1 Φ φ ·. φ 3 Ρ μι 3 Ρ 0 Ui ffl >1 Ή ffl υ rt rt £ υ o co σι ffl CM CM o cn w Φ P ω •ιΗ tn >1 t—11 nJ Η Η W XJ (Ώ g rH u o CD *tf O CN CO co O O r-4 ro ’tf co m KD CO in m r- r—i Γ- r-i cn ω kD ΓΟ in m σ» © © KD •«tf r-l CN in CO m m > r—4 r- rH K * o E5 U S3 o o CN o Γ- 'tf «, ·» in «—I CN ι—I CN CN KD CN CN CN o in r-4 in t GO( O C-l -tf © r-4 rH rH Ό •rl fd •rl 4-> x ε rd 4J •rl N +J φ •rl a ih rH r-i φ X >1 r—1 > 0 rH C fd rH XJ 0 Φ -P 0 44 G XJ tn ω 0) d Ql >1 ε Λ 0 M •rl 4J ϋ Φ •rl ε rd r-4 Ό >1 p—i © r- M Φ • < •rl *tf CD 1 ix ’tf m CN ·—* 1 rH G 0 Ό •rl 0 4J x: fd 4-» rfj r-4 Φ 0 s « H - 16 Ό ω c •Η +> β Ο υ Η Η Η CQ co cn Is· CM CM CM ω in in γ-* w cn in in <0 «-4 m in tn Γ*·» r4 U B S3 O O Φ cn cn CM CM cn © 1*4 r4 GJ β OJ N β GJ £ > in rx cm cn «η m O cn cm r4 cn m co 10 10 10 i—i cn cm i-l U B S3 in I-1 I H in GJ β CD N β GJ Λ m in Sm '—i m* m in io cn tx «-4 r-t ω Γχ cm <□ CM O O cn o cn cm cm cn i-4 I C0 cn «•4 GJ Π) 4J GJ β Λ 4-> GJ cn cn C0 10 CO r- (M CM O o CM l cn I—ι β & o & o ω •r4 - 17 II (Continued) Ό β α (η Ο •Η ίΡ 03 r-4 β β «‘ο ρ4 β U β •Η +J β -Ρ Ν β Ή Φ > ι-4 ι-4 Μ Ο W +> 03 ηΙ ιο w >ι < Μ Η U ϊί ω •Η >< ίο ω Ο fx CM CM v0 8£ in 1-4 CM co CO CO • · · *4* t-4 6 fx m in --4 io co fx 10 CM fx o r-4 xT in CM «0 cm co φ H CO i—4 CO t—1 co in cn r-l Kf cn r4 co cm Γχ co CM ΓΧ O sf CM CM O cn CM O co cn r4 co σι r4 i-4 CO CO CM sj· CO CO cn cm cn CO CM CO CO CO cn o vr ci M1 «0 r-4 10 t-4 in i—l fx r-4 »0 r4 U ffi B υ s B B u B B d B B d B B **» a O O r~i O O O CO in O m •l « in — ·* Γχ o 10 0 74* «» cn 00 t-4 in r-4 co t-4 CM r-4 CM x CM x·* CM x1 © •0 cn in r-4 1 10 CM I in I * 1 CO CM 1 cn O cn cn O m f-4 CM r-4 r4 CM CM CM CM Φ Φ Φ Φ *0 V *d «Η ε Β Μ ρ4 t-4 XJ Ο -Ρ β φ β 6 Λ •Η +J *0 Φ Μ Ο γ4 ίΡ £ -Ρ ρ φ φ β ·Ρ •Η (Q Ό ί ΓΟ fx ω ο CM I in Ο CM 04 04 r-4 r-4 >1 >1 Φ λ β •P P -P P Φ Φ Φ φ Φ N β P β +J β •H β Ή β Φ TO § Tj £ rP r-4 fx t4* co 00 ΓΧ o 10 00 v0 tn - 18 IQ β rt 3 ra 0 th fc, I—1 (tf G tf Γ* ro ro O ro co ι—1 to1 GO CO O in in CM CM ro σ> · tf o in in 00 in tf r· O ro co σ» in . >3· . • · • • * • • * • · • in tf ro ro CM in ro cm tf <4· ro •4* ro tf VO i—l in l-t ro 1—1 ro pH ro rH TABLE II (Continued) Isolation % Crystallization Xmax. A Ar Method. Yield Solvent m.p.,°C. (Am) Calc* O rH r- ro ro GO ro tf co tf ro rH tf ro pH CM in tf rH in CM pH in CM in O i-H in o rH ro tf tf ro ro CM ro ro CM tf tf tf tf tf tf ro rH in pH ro «Η ro rH ro pH » ss o ffl ffl c ffl ffl υ ffl ffl o 53 ffl o ffl ffl rs o o o o o o o o r-4 rH rH ·. * s o o o CM co o rH ro ro i-4 tf CM in CM ro pH CM CM CM *-* CM 0 ro ro O tf ro in in CM rH cn I * t · I 1 1 σι O (Jl pH pH tf ro co © cn O O tf σι rH rH rH CM CM rH QJ •rl g QJ tf •rl g QJ V •rl ε τ! •rl g 4H ip MH m pH rH rH r-f >1 >t ix >1 H rH X! x: Δ Λ 0 0 P P •P •Ρ P -U C G Q) QJ QJ QJ QJ ra nJ (tf ε -p ε ε -p g Λ X •H (tf •*H •rl (tf •rf +J •P tf £ tf tf £ Ό 0) V 0) CM rH in ro • o co co m rQ tf ro ro - 19 0) •rl ω ih r—I d G Ό G G b ί? ά Φ ♦ G ε G •rl +J G G 0 0 U •rl +) d -P H N G H •Η φ r-l > W r-l ι—1 XI d 0 ffl •P co ω Eh ih Ό rH 0¾ 4) •rl >4 rH tf CN tn CO CO in rH co CN in in rH tf KO > CN CD tf © © O tf o KO in © CN rH co O rH CO CN O CN •tf cn CO ω CO co co CN © CO ό © in tf © in tf CO rH in rH in ι—1 tf rH KO rH KO rH tf CO rH in ’tf in m tf in CD rH o rH in ro • rH ΙΠ CO in O ι—1 co co KD co CO KO ro rH CD KO rH co KO rH CO •tf ’tf ’tf I*» ro CN r- CO CN © CO 6 © in tf © m tf CO rH in rH in rH ’tf rH KO rH IO rH k *, * K u 8 & u 8 8 ϋ 8 8 U as 8 □ w S3 u as S3 o O o O O r-\ i-H O o CD o o tf O r-H tf tf o — rH O KO in rH in CN m CD CO o ι-H - tf CN co CN co CN in CN CO CN CD in CN CN CN CN CN CN o > rH I rCO G d Λ X» Φ CN rH CN I O ι—I CN * 0) Ό •rl ε O m rH % Ρ M 0) ® ε +i •iH d Ό a r-l CO 1 1 in Γ- in in rH 1 rH | O co co © CD H CD CD CD ω tf Γ·* rH r-4 ι—1 rH rH rH Φ Ό •rl ε M M-4 rH ih X! •μ ε •rl Ό r-H G d x: -P φ o G d Qi ct ω •rH Φ Ό •rl ε M O m rH ih I •H P Φ -P CO CN © CO CN KO rH CN CD ro CN co tf in CD - 20 14.94 14.58 II (Continued) - 21 46192 II (Continued) ω τι 0 χί 44 tn Φ fi ε fi C •H 0 ♦ri rk tn •ri 0 fi 44 QJ 0 •rl U 44 0 £ d d 0 Φ fi fi f—1 k d 0 ι—I >1 cu 0 QJ □ t> 44 Λ O 44 Ul QJ •ri a XJ >1 Ul 44 Λ Φ k 44 fi 44 τι d 0 O φ •ri x: k k Φ d cu QJ fi a O QJ 0 k QJ k k 0 k CU Xl >1 cu CU 44 tQ 44 d fi Φ k •fi Φ k φ O φ > Φ xj 44 r4 £ 44 0 d 0 & Φ ω τι 4J k H fi 44 Φ H d tn 44 a H fi •0 d > Φ •ri C •k Φ r4 k d k a id r4 O fi ft fi A N •0 β 0 0 44 d d 0 k •rl β EH τι Ul •rl ft 44 d •ri QJ 44 ft d o £ k d d fi •η Ul »ri fi k •rl 04 Φ r4 44 44 Φ £ •rl fi Sh d r4 X3 k fi QJ fi k •ri 44 Φ tn r4 QJ QJ 44 44 •ri >1 xj & £ QJ Ul cu £ >1 O T3 a 0 QJ £ k k 3 c 44 44 Ό 0 r-l •«4 43 t-4 44 >1 £ xi QJ fi Φ a d 44 44 0 •H £ 0) d ϋ •ri • >1 0 Λ Φ Λ Φ 44 QJ r4 CL x: r4 d 4J τι 44 £ rk N d φ 0 r4 d 0 •H k 44 0 >1 44 Φ □ rk fi 44 r—1 O 44 r4 >1 Φ 0 Ul Ul fti XJ > τι N Ul d 44 •Η Φ QJ d 44 44 £ 01 £ k •fi β d >1 0) O< k •H fi 44 k Λ 0 g 0 C ϋ U 01 Ul •ri £ o fi 01 Ul eQ 1 d •ri •fi 44 d 0 d r4 44 0 □ «—ί *—' k fi k Φ Ό Ό 1 d r—i ft k Φ r4 β CM r4 0 •ri 44 d fi 1 0 ω Φ τι d •a 0 rk £ τι (-4 0 44 k t £ •ri fi QJ fi fi k Ul δ 0 r4 5* Φ ϋ •ri & u ril QJ fi f—1 QJ • • • 44 0 JZ d λ υ 0 44 44 to Η Ο in hot dimethylformamide and precipitated with water followed by τι φ Λ Ο υι ω Ή τι d 0} >ι k ϋ Φ 3 Φ ι—I >4 Φ Μ 3 r—I >1 3 Φ r3 Q< (Μ CM 00 ’Φ rH H r—t CM 3 CM cn m [4 VD in O O *4* co o o CO |4 Ό • » • a a • a * • 3 rH in VO CM MO <Φ cn VD m (4 rH η 3 νθ CM VD CM VO CM VD CM •Η 0 (0 h Ol cn cn CM O cn Ol CM Ol >1 ο cn rH in rH cn Ol VD oi O O VD rH νθ in Ol • a a a a • a • a (ύ • CM VD *4* cn VD CM in [4 rH 3 ι—1 in in VD CM VO CM vo CM C 'd VD CM X «, «, K * «1 * o w z υ ffl z U ffl z ϋ s s rH o ffl z r-S r-s r-s d o *—» o r—s o υ o o o o o o o o co o o o CM CM % <4* «. o CM CM in * in rH rH rH i—4 rH rH X »—* *s> •s_Z ssr> S o in co CM Ol o 00 rH Β sf rH Γ4 *Φ f4 mJ* 14 CM 4* CM CM CM CM CM CM in ϋ VD in rH vD ί 0 σι [4 rH rH rH I rH rH Q 1 1 m 1 Ol in , cn (4 cn rH £ rH rH rH rH RNCO I CM I r—i £ O •rl +J Λ , N -P •H 3 Η φ H > ni bi -P 0 to co >1 μ ϋ rH Ο ri ,3 •P Φ Φ φ rH >1 Λ 4J Φ μ ο rH Χ5 Ο •rl μ •μ φ φ rH >1 Λ μ Φ μ ο rH »3 ϋ •μ μ •μ ο Ε ο ϋ) Η vD cn cn VD t-4 14 Ol in CM n rtj ffl ffl ffl 1 CM ffl I u CM CM ffl ffl | o U CM CM CM $ ffl ffl I G U · υ cn cn cn cn ffl ffi ffl ffl u a D u *4· in VD |4 vO VD VD VD - 24 TJ ra β •H 3 (0 0 Λ* nJ . G TJ U rd (d O O CO ffl O 'sp 0* [x 01 ffl rd CO 01 O If) O fx IX fx 01 ffl rd □ ffl S o O o CM rd rd CM Ill (Continued) ft £ ffl ffl rd I ffl a •rl P id , Ν P •Ρ β rd φ H £ S3 tn ω >) u Φ TJ •id £ ρ o P rd >1 X P P § P g ffl ό in a _ ο Ό •h o SS Pi co co ffl CQ β nJ Tj •rl β id Φ 0) P P P tn β 3 Φ β β P 43 •rl id X P P & •rl Φ 0 o £ id 0 .fl φ CQ fl P P •rl 0 •id rd •id £ >1 >t P 45 P 0 TJ (d β Φ TJ Φ 43 Φ φ P CQ P P (d β id Φ Jj ft •rl •fl Φ P Ό P ft fl ft 0 id P • Φ ft IQ «. P ft Φ β Φ rd p 0 3 •rl Φ P P P id id > P P P H Φ P TJ ft rd Φ β £ •id rd id Φ P /3 P rd Φ >1 ft rd 43 43 *—* 0 P N id TJ s rd /5 Φ fi TJ P • ffl •P £ id P rd £ nJ p fl >< •rl Φ fl Φ Φ rd P ft > P >, CQ Φ rd 3 c IQ 0 rd ffl P IQ >1 JS id (fl β Qi nj Tj Φ 0 IQ g 43 fi P P ft •rl 3 P id £ 0 u u rd id 43 3 •P >1 TJ TJ rd Φ Φ 0 fl 0 43 Φ P •rl N P P ft d 43 Φ TJ P P Φ 43 •id 0 TJ P e Cn 3 •rd CQ fl P £ 1 P •rd u 0 rd β P P s-' 3 3 Φ P 1 Q *0 43 CM £ P tJ I id Φ Φ rd β TJ N >1 P Φ β •rl P id 3 id rd rtj rd rd rd Q 0 TJ Φ £ P φ P •id rd IQ 3 >1 0 >1 σ P 0 P ο TJ 0 ϋ Aryl-2- (1-imidazolyl) phenylureylenes - 25 Ή £. Η tf q *o q G fcj tf U TABLE IV (Continued) υ o ε c o •H XJ tf N •H rH XJ •-H q tf φ xj > Ul rH ih 0 p w ϋ φ 8 Ό rH •rl rH P rtj <ηιη co in > co r- in CN Ρ* r- kO p- o tf KO rH tf rHfP rH co tf CN © cn rH > tf 1—1 tf tf CN tn tf rH ©in O © m © © in © tf tf © tf tf © tf tf © ko ch co rH CD rH KD rH KO rH KO ι—I inn- co tf CN tf CN Γ- KO CN r—1 KO CN p- CO CN Γ* OO K CO in rH CO m rH CO tf © CO tf © co tf © ©in o © m © © m © tf tf CO tf tf co tf tf co φ CM CD rH KO rH KO rH KO rH - CO rH ·. *· - X UKZ u 8 8 u 8 8 o 8 8 o 8 8 o 8 8 r—. o o o o o o tf o o o o o KO tf CO in o rH X s * * Γ» cn in in ko m CN CN CN CN CN CN · *-»» CO GO KO rH cn rH in m m in in in CN CN CN CN CN CN . 46192 - 26 TABLE I (Continued) is Pound 61.57 4.12 to CM CO iP cn os rf tn r- m rf cm co co cn in 00 KO r* kd «ρ to in r*· to cn co o CM tn 10' CM tn h cn m iP rf rf to o s cm * 2 cn tn iP cn in cn m ip cn to iP ω rp tn cn iP in co rf O to GO O r· CO O n- co to CM r· nJ _ rf iP OS cn rf iP co > to co KD KO co lO to co rf os a ffl • « • • 1 • « • t • « • 00 < ’ ip rf > in cn KO m m in cn cn m cn cn in rf rf ϋ rP KO iP m rP in ip tn rP tn rp to iP rt X s * x X x x □ □ ffl a U ffi a ϋ ffl a u ffl a o ffl a - o ffl a ^-x o o o o O Q o o o o o O o KD Γ“» o σ» σι X X * * s cn ω r» KO O CM CM CM CM CM • cn cn *—· -· *-* CM 00 o cn rt fi co O m in KO in fi < tn KO CM CM CM CM (< CM CM tn ffl έ s CM I CM in in CM 00 rp m σι in o CM rf I rp cn O CM 1 m CM I CM 1 CM rf d co 1 I iP rf co rP CM o CM rP CM CM CM C •rl •P rt N •rf rp iP rt +i m ix ' P Φ ffl I Φ ffl I Cj ffl •P β ffl •rl β t Φ ffl •P fi ι φ ffl •P β P 0 0 0 Ο c ΨΙ m <Η tp Φ rp rp «Ρ rp > >1 >1 >1 >1 rp Λ 43 Λ 0 +i M •P Ρ •Ρ Ρ •Ρ w tt) 0) φ φ Φ Φ Φ E 4J fi •P S -Ρ ε •rl nJ •Ρ rt Ή rt •Η Ό £ ffl 2 ffl £ ffl O rt § P rp & +> u 0) tt) ε +i ffl rt '“J Ϊ& 0) s Γ·* ιΡ ο CM ip CM ΚΟ co ό in cn cn Γ·* ιη μ in co - 27 ti _ β Ό rH A U o Γ- O ro rH σ» O ro O o ro O rH in ro co CD > ro co O ro σι o o* in 00 00 ro in o ro CO O ro co h» rH in rH rH r- rH tf CM r-· ro co co r* CM σι r* CM cn co ro «-Η σι o rH ro σι CM ro cn CM σι in cn co ro ro d ro co o ro co ro rH ro rH > rH r- rH * «. % s d ffl ffl P ffl ffl o ffl ffl O ffl ffl o o o o rH rH co σι Γ- O ro ro o rH > σι CM ro CM CM o ro O co in in ro ro CM CM CM CM TABLE IV (Continued) O ά β ro o co rH CM r· I rH I ro I > ro ro rH rH CM in rH CM I CM rH CM CD CD rH I in co rH G •Η •P fit N •rH <0 •P ix P ϋ Φ ffl •P G Φ > H to tf rH Φ £ 76.2 dimethylformamide- 163.5-166 258(28,770) C, 70.57 70.52 water , H, 5.92 5.81 N, 18.29 17.94 - 28 Ό G g o •H fa ω r4 β c rii *ΰ o i—4 r4 Φ Xj* Φ in cm (Μ CM Μ* r-4 r4 CM φ ιη ιη Ο Η rl cn co cm CO r4 Ο in in co r-4 Φ < in φ sf 00 r4 CD • « in tx r-4 1-4 tx φ Φ t-4 r-4 φ Γχ tx t-4 φ φ in co γ4 φ r-4 η co Φ CO cn σ» CM CO [χ CM CO Γχ CM CO fx ω φ Γχ CM CM si* CM CM ι-4 CM CM r-4 CM CM r-4 t-4 φ Φ r—4 φ Γχ Φ in GO Φ in 00 Φ in 00 [χ ι-4 ΓΧ γ—ι Φ r-4 Φ r-4 Φ r-4 * * X ,, υ Ε Β □ Μ Β □ Β Β o B B u ffi B o o O o O CM CM co r-4 φ cn Φ Φ in tn cn lx O in si* CM CM r—} CM CM [x CM in CM o in ω 00 in Φ CM CM CM CM CM TABLE IV (Continued) o o ά β CM cn CM CM fx O I O r4 I CM 1 in CM cn I Φ d ω O Φ o o co o r-4 CM CM i-4 CM α ο Ή +J β Ν •Η 4J -μ η ω ο >ι w ρ ο φ Β Ό i?. <ΰ •Η ίχ -OCH CH 80.9 dimethylformamide- 190.5-193 259(27,180) , C, 67.07 66.80 water Η, 5.63 5.62 Ν, 17.38 17 .16 - 29 fi C fi W 0 •k Cm ω >1 rk β Ό CO Kf CM VO CO vO kF rk r—i r* co co kF vD CM 00 CO CM CM KF r- kF cn o vO CM O kF cn r* Γ- rk co co rk VO CM 00 cn cn cn kF kF rk GO VO vO in rk co r· rk VO i-4 in co cn kF O co «-« > > in cn rk kF in fO in co cn co cn rk c cn CM kF rk cn Kf GO GO co vo in • κΐ» in CM κί Γ* rk kF r- rk co Is» vO rk Γ* rk VO rk VO rk VO rk o’ d z d d a d d z d d s z ♦» o H W d r< o o O cn in co kF 00 rk * * VO m CM CM co CO s_z co cn CO m in r* CM CM CM fi QJ U fi < D fi * •k « +J ft c « 0 u •»_x £ > H fi 0 &3 •k P 44 « eC d N •k 44 rk fi rk 0) d > 44 rk ω o >1 W fi in in O σ» CM rk 1 cn !k in rk I J CO CM cn r· O co rk CM rk O rk CM O* co cn in CM in kF fk CM I m rk rk CM o co CM m CM S»Z CM in cm O rk CM I CO cn fi Λ rk QJ •k >* ϋ fi •k £ d QJ fi •k £ s QJ fi •k £ 3 £ fi £ fi £ fi O O O 4k 44 4k rk rk rk >1 >1 >, Xi Xi Λ +J fi 44 fi +> ri QJ QJ QJ QJ a> ai £ 44 £ -P £ 4J •k d •k d •π β fi > fi £ Ό £ i ω fi •k £ g k rk I QJ fi •k £ x: 4J I fi in rk rk » co cn cn kF in CM m VO r- VO - 30 TABLE IV (Continued) nd o O o © O O tf CO O © ω rH o P O q C0 in o p. p. ω co m © co O tf r- © © G • « • • • • • • • • • · U) 0 in cn co O| tf r- ρ- ω CO ω ω tf cn Ol tf •P Em in rH co rH ω rH ω rH ω rH w >1 iP in co tf co ω in o CO tf ω GO rH cn 00 rH d _ cn tf rH tf co rH rH co © co rH P· co rH Ρ» C Ό • • • • • • « « » • · < - in cn CO Ol tf P- co cn CO ω cn tf ω ω tf 0 in rH co rH ω rH in i—i ω i-H i-H d * V % «, ·» S X υ O a 8 u 8 8 □ 8 8 O 8 a □ 8 8 o o O d Ο co o ω ω ω • cn cn co tf cn X OJ i-H ω p· 10 ε rf cn cn OJ ω OJ ·—* » co co CD rH ω in m in co ω OJ oi CN OJ OJ Ol tf © OJ • cn cn tf o Ol Ol OJ Ol OJ 0 1 I cn 1 © in m OJ ω rH ( Qi Ol ρ- © © 1 o • cn ω Ol cn © ε Ol OJ OJ OJ rH a o •rl P d N •iH -p rH β rH Φ d > -P rH m o >ι ω ρ □ 0) Td rH ϊϊ ω •H ι o> Td ι QJ Td •rl ε I GJ τί •rl ε I QJ Td •ri ε I QJ *ΰ •rl ε m »P MH rH rH rH rH rH ih ih >1 ih Λ XJ Λ X3 x; •P P •P P -P P p P •P QJ QJ QJ QJ QJ QJ QJ QJ ε -p g «Ρ ε -p ε -ρ ε •r| d •h d • •r| d •rl Td g Td Td £ Td £ Td co P- o CO P- • tf o o ρ- O co P· r- ω ω 6192 - 31 IV (Continued) tf c ra 0 •rf fc, C Ό rH rt O u • Oj g G •rl «Ρ rt N •iH rH +J rH β rt QJ •P > 01 rH >1 0 ρ ω o φ ffl tf rH Φ •rl ί* o o tf ro o ι—1 rH Γ- r- CM t—1 ro tf rH tf rH rH cn o σι O > ro ro σι tf rH σι tf rH σι cn rH cn cn σι ro CM in CM in CM in rH tf in ro tf in ro tf in ro CM GO Γ- tf o ro tf o ro tf o ro > cn ro Ol tf rH σι tf rH σι tf rH ro cn σι in CM in CM in CM 1*- rH «. s υ ffl ffl υ ffl ffl υ ffl ffl □ ffl ffl o O o o o O rH co o r* O cn o O CM σι O tn * s co - o ro tf CM * ro CM ro ro rH in *>—· ' *—·> o {- r· ro CM tf ro ro cn in tf ro ro CM CM cn CM in 0 O 1 Λ 1 CM in in ro | CM r* σι ro co O ro ro in in in CM CM CM CM CM CM Λ ι φ tf •rl β Ό •rl g Φ tf •rH ε <1) tf •rl ε fc Ή .-, £ +> fc § “ a g P UH >1 ρ o UH £ fc ai φ E -fc •rl rt tf £ ρ o Uh rH >t rG •P Φ g •rl tf > CM CM tf tf tf cn tf cm in in cn 57.1 dimethylformamide- 254- 256(36,930) C, 60.53 60.26 water 256(Dec.) H, 4.48 4.34 N, 20.76 20.68 - 32 IV (Continued) »H nJ Ό ω cn Γ4 <31 in f4 o C4 d d 3 ω Η d O o f4 σι vo rH 3 « • a a a a a • 0 *Φ rH m [4 CM VD rt νο CM VO rH 14 rH in 1 CM CM σι co d σι m iH $ rH d d O O ’d* iH σι O d Τ3 « a « a a » a a • - > Μ* d Γ4 in 14 d 14 VD Ό νθ CM VO rH ¢4 iH m rH rt * υ υ ffl ffl a ffl ffl U ffl ffl u ο o o o «Η rH rH CM ιη (4 C4 01 £ (4 CM VO CM m d rH d Ο 14 CM σι σι CO m CM CM CM CM m σι • CM α CM VO CM 0 1 d d in CM CM ά Mf (4 d rH • SJ1 CM d d £ CM CM CM CM 1 Φ I Φ 1 Φ Φ Ό Π3 »d TJ U ffl ζ Ο •μ -Ρ nJ Ν •μ rH 4J -i 3 rt Φ •P £ ω *μ ο μ ω υ φ rt Ό rH Φ •μ MH »w <Η rH rH rH 5>i kH >1 XJ Λ XJ •Ρ μ •μ μ -μ φ Φ φ φ Φ Β X» Β 4J ε . •h rt •μ ρί •μ- Ό £ Ό £ «ϋ cn CO CM Γ4 cn ιη «Φ d d a g <Η ϊ rH ιΗ > ο Λ C +> id 0) Λ ε 4» •η ω ό ε

Claims (16)

CLAIMS:

1. A 1-(2-acylaminophenyl)imidazole of the formula 5 (1) R is an aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl, or monocyclic aryl-substituted aliphatic group, bonded to the carbonyl carbon through a carbonto-carbon linkage; and (2) R is a radical bonded to the nitrogen by a carbon IO to nitrogen linkage and is an aliphatic, cycloaliphatic, phenyl, substituted phenyl, fused bicyclic aryl, or monocyclic arylsubstituted aliphatic group. 2. 5

2. A compound according to Claim 1 in which -X is R .

3. A compound according to Claim 2 in which R is a 15 straight chain or branched chain saturated, mono-unsaturated or polyunsaturated aliphatic group containing from 1 to 18 carbon atoms, unsubstituted, substituted by halogen, or interrupted by an oxygen atom. - 34 5

4. A compound according to Claim 2 or 3 in which -R is an aliphatic· group containing from 3 to 6 carbon atoms.'

5. A compound according to Claim 2 in which -R 5 is substituted phenyl. 2 2 5

6. A compound according to Claim 1 in which -X is -NHR

7. A compound according to Claim 6 in which -R is an aliphatic group containing from 1 to 18 carbon atoms.

8. A compound according to Claim 7 in which -R is a straight chain alkyl group containing 1 to 18 carbon atoms.

9. 10 9. A compound according to claim 6 in which R is phenyl or substituted phenyl. 10. A process for preparing a 1-(2-acylaminophenyl)2 5 imidazole as defined in Claim 1 where -X is -R comprising reacting 1-(2-aminophenyl)imidazole with an acid chloride of 5 15 the formula R COCI.

10. 11. A process for preparing a 1-(2-acylaminophenyl)2 2 imidazole as defined in Claim 1 where -X is -NHR comprising reacting 1-(2-aminophenyl)imidazole with an isocyanate of the 2 formula R NCO. 20

11. 12. A compound as defined in Claim 1 substantially as described herein.

12. 13. A 1-(2-acylaminophenyl)imidazole according to claim 1 substantially as described herein with reference to any one of the preparations listed herein, other than preparation 1. 25

13. 14. A process according to Claim 10 or Claim 11 substantially as described herein.

14. 15. A process in accordance with Claim 10 or Claim 11 for preparing a 1-(2-acylaminophenyl)imidazole substantially as described herein with reference to any one of the preparations listed herein, other than preparation 1. according to Claim 1

15.

16. l-(2-acylaminop.,enyl) imidazoles'when prepared by theprocess of any one of Claims 10, 11, 14 and 15. Dated this the 3rd day of February^ 81. F. R. KELLY & CO. By:_Executive. 27 Clyde Road, Ballsbridge, Dublin 4.