This disclosure relates to a novel class of substituted dihydroimidazo[1,2-a]quinoxaline derivatives. The disclosure further relates to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions as anti-anaerobic agents.

This invention relates to a novel class of substituted 
dihydroimidazo[1,2-a]quinoxaline derivatives. The present invention 
further relates to pharmaceutical compositions containing such compounds 
and to the use of such compounds and compositions as anti-anaerobic 
agents. 
BACKGROUND OF THE INVENTION 
Parthasarathy, et al., Indian Journal of Chemistry Vol. 22B (December 1983) 
p.1250-1251, describe a class of substituted 
1,2-dihydroimidazo[1,2-a]quinoxaline 5-oxides that have antiamoebic 
activity against Entamoeba histolytica in intestinal and hepatic 
amoebiasis. Parthasarathy, et al., Indian Journal of Chemistry Vol. 22B 
(December 1983) p.1233-1235 describe certain N-oxides of 
2,3-dihydro-1H-pyrimido[2,1-h]pteridines; 
1,2-dihydroimidazo[2,1-h]pteridines; 
10-aza-2,3-dihydro-1H-pyrimido[1,2-a]quinoxalines; 
9-aza-1,2-dihydroimidazo[1,2-a]quinoxalines and 
7-aza-1,2-dihydroimidazo[1,2-a]quinoxalines which possess antiamoebic 
activity in particular against hepatic amoebiasis. Strauss, et al., J Org 
Chem, Vol 43, No 10, 1978 p.2041-2044 describe the preparation of 
quinoxaline and dihydroimidazoquinoxaline N-oxides. 
SUMMARY OF THE INVENTION 
The present invention relates to a class of novel compounds of the formula 
##STR1## 
wherein 
R.sup.1 is C.sub.1 -C.sub.6 alkyl, benzyl, phenyl, 
##STR2## 
wherein R.sup.4 is C.sub.1 -C.sub.6 alkyl, and R.sup.5 is C.sub.1 -C.sub.8 
alkyl, aminomethyl, pyridinyl, phenyl, halophenyl of a 
##STR3## 
wherein R.sup.6 is C.sub.1 -C.sub.6 alkyl; 
R.sup.2 is phenyl or substituted phenyl having 1 or 2 substituents selected 
from the class consisting of halo or C.sub.1 -C.sub.6 alkoxy. 
R.sup.3 is hydrogen or halogen; and 
X is --CH-- or --N--. 
The present invention further relates to pharmaceutical compositions 
containing such compounds and to the use of such compounds as 
anti-anaerobic agents. 
DETAILED DESCRIPTION OF THE INVENTION 
The "C.sub.1 -C.sub.8 alkyl" and "C.sub.1 -C.sub.6 alkyl" groups specified 
herein include straight chain or branched chain hydrocarbon radicals 
having from one to eight and from one to six carbon atoms respectively. 
Illustrative of such alkyl groups include methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, 
hexyl, isohexyl, octyl and the like. 
Illustrative of the groups represented by the term "C.sub.1 -C.sub.6 
alkoxy" include straight chain or branched chain alkoxy radicals having 
from one to six carbon atoms. Representative of such groups include, for 
example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, 
hexoxy and the like. 
The term "substituted phenyl" as used herein refers to phenyl moieties 
having one or two substituents selected from the class consisting of halo 
and C.sub.1 -C.sub.6 alkoxy. Illustrative of such substituted phenyl 
groups include 4-chlorophenyl, 2,4-dichlorophenyl, 3-bromophenyl, 
2-methoxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 
3,5-diethoxyphenyl, 2-chloro-4-methoxyphenyl and the like. 
As used herein the term "halogen or halo" refers to fluoro, chloro, iodo 
and bromo. 
The compounds of the present invention wherein R.sup.1 is hydrogen, C.sub.1 
-C.sub.6 alkyl, benzyl or phenyl may be prepared in accordance with the 
following general procedure: 
A dihydroimidazole of the formula 
##STR4## 
wherein R.sup.2 is above defined; is reacted with a substituted 
nitroaromatic of the formula 
##STR5## 
wherein Z is halo; and X and R.sup.3 are above defined; under basic 
conditions in an appropriate solvent such as isopropyl alcohol or 
acetonitrile, to yield a dihydroimidazo[1,2,-a]quinoxaline of the formula: 
##STR6## 
The dihydroimidazo[1,2,-a]quinoxaline of the formula (IV) is reacted with 
an N-substituted piperazine of the formula 
##STR7## 
wherein R.sup.7 is hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl or phenyl; in 
an appropriate solvent at a temperature of from 70.degree. C. to 
100.degree. C. to yield the compounds of the formula: 
##STR8## 
The product may be utilized as is or recrystallized using an appropriate 
solvent applying conventional techniques. 
To prepare the compounds of formula (I) wherein R.sup.1 is a 
##STR9## 
a compound of formula (VI) wherein R.sup.7 is hydrogen is reacted with a 
sulfonylhalide of the formula 
##STR10## 
wherein Y is halo and R.sup.4 is above defined; in an appropriate 
solution. 
To prepare the compounds of formula (I) wherein R.sup.1 is a 
##STR11## 
a compound of formula (VI), wherein R.sup.7 is hydrogen, is reacted with 
an acid of the formula: 
##STR12## 
wherein R.sup.5 is above defined; in the presence of a 
diphenylphosphorylazide. 
A preferred embodiment includes compounds of the formula 
##STR13## 
wherein X and R.sup.1 are above defined. 
A more preferred embodiment encompasses compounds of formula (IX) wherein 
R.sup.1 is C.sub.1 -C.sub.6 alkyl or benzyl and X is above defined and 
most preferred are compounds of formula (IX) wherein R.sup.1 is methyl and 
X is --N--. 
The appropriate solvents employed in the above reactions are solvents 
wherein the reactants are soluble but do not react with the reactants. The 
preferred solvents vary from reaction to reaction and are readily 
ascertained by one of ordinary skill in the art. 
The compounds of the present invention may be administered by any suitable 
route, preferably in the form of a pharmaceutical composition adapted to 
such a route, and in a dose effective for the treatment intended. 
Therapeutically effective doses of the compounds of the present invention 
required to prevent or arrest the progress of the medical condition are 
readily ascertained by one of ordinary skill in the art. 
Accordingly, the invention provides a class of novel pharmaceutical 
compositions comprising one or more compounds of the present invention in 
association with one or more non-toxic, pharmaceutically acceptable 
carriers and/or diluents and/or adjuvants (collectively referred to herein 
as "carrier" materials) and if desired other active ingredients. The 
compounds and composition may for example be administered intravascularly, 
intraperitoneally, subcutaneously, intramuscularly or topically. 
For oral administration, the pharmaceutical composition may be in the form 
of, for example, a tablet, capsule, suspension or liquid. The 
pharmaceutical composition is preferably made in the form of a dosage unit 
contained in a particular amount of the active ingredient. Examples of 
such dosage units are tablets or capsules. These may with advantage 
contain an amount of active ingredient from about 1 to 250 mg preferably 
from about 25 to 150 mg. A suitable daily dose for a mammal may vary 
widely depending on the condition of the patient and other factors. 
However, a dose of from about 0.1 to 300 mg/kg body weight, particularly 
from about 1 to 100 mg/kg body weight may be appropriate. 
The active ingredient may also be administered by injection as a 
composition wherein, for example, saline, dextrose or water may be used as 
a suitable carrier. A suitable daily dose is from about 0.1 to 100 mg per 
kg body weight injected per day in multiple doses depending on the disease 
being treated. A preferred daily dose would be from about 1 to 30 mg/kg 
body weight. 
The dosage regimen for treating an infectious disease condition with the 
compounds and/or compositions of this invention is selected in accordance 
with a variety of factors, including the type, age, weight, sex and 
medical condition of the patient; the severity of the infection; the route 
of administration; and the particular compound employed and thus may vary 
widely. 
For therapeutic purposes, the compounds of this invention are ordinarily 
combined with one or more adjuvants appropriate to the indicated route of 
administration. If per os, the compounds may be admixed with lactose, 
sucrose, starch powder, cellulose esters of alkanoic acids, cellulose 
alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, 
sodium and calcium salts of phosphoric and sulphuric acids, gelatin, 
acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, 
and thus tableted or encapsulated for convenient administration. 
Alternatively, the compounds may be dissolved in water, polyethylene 
glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, 
sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other 
adjuvants and modes of administration are well and widely known in the 
pharmaceutical art. Appropriate dosages, in any given instance, of course 
depend upon the nature and severity of the condition treated, the route of 
administration, and the species of mammal involved, including its size and 
any individual idiosyncrasies. 
Representative carriers, diluents and adjuvants include for example, water, 
lactose, gelatin, starches, magnesium stearate, talc, vegetable oils, 
gums, polyalkyline glycols, petroleum jelly, etc. The pharmaceutical 
compositions may be made up in a solid form such as granules, powders or 
suppositories or in a liquid form such as solutions, suspensions or 
emulsions. The pharmaceutical compositions may be subjected to 
conventional pharmaceutical operations such as sterilization and/or may 
contain conventional pharmaceutical adjuvants such as preservatives, 
stabilizers, wetting agents, emulsifiers, buffers, etc. 
As previously mentioned, the compounds and compositions of the present 
invention are effective as anti-anaerobic agents for the treatment of 
infectious diseases related to anaerobic bacteria. Representative of 
infectious diseases that may be treated with the compounds and 
compositions of the present invention include, for example, post operative 
sepsis following lower gastrointestinal surgery or female urinogenital 
surgery, pelvic inflammatory disease, ulcers and gangrene, trichomonal 
vaginitis, non-specific vaginitis, amoebiasis, giardiasis, periodontal 
disease, acne and the like.

The following Examples are intended to further illustrate the present 
invention and not to limit the invention in spirit or scope. In the 
Examples, all parts are parts by weight unless otherwise expressly set 
forth. 
EXAMPLE 1 
1,2-Dihydro-8-fluoro-4-phenylimidazo[1,2-a]quinoxaline 5-oxide 
A mixture of tolazoline (40 g, 0.25 mol), 2,4-difluoronitrobenzene (39.75 
g, 0.25 mol) and potassium carbonate (17.26 g, 0.125 mol) in isopropanol 
(500 ml) was heated to 50.degree. C. for a period of two days. The solvent 
was removed in vacuo from the mixture and the residue was dissolved in 
dichloromethane. The resulting solution was filtered and the solvent 
removed in vacuo to yield a yellow solid which was chromatographed on 
silica gel using 2% methanol/chloroform as the eluent to yield 
1,2-dihydro-8-fluoro-4-phenylimidazo[1,2-a]quinoxaline 5-oxide (38.5 g) as 
an orange solid, having a m.p. 188.degree.-193.degree. C., (Found: C, 
68.07; H 4.23; N 14.82%; C.sub.16 H.sub.12 FN.sub.3 O requires C 68.33; H 
4.27; N 14.95%) and represented by the structural formula 
##STR14## 
EXAMPLES 2-3 
The following compounds were prepared in accordance with the procedure of 
Example 1 utilizing the appropriate nitroaromatic in lieu of the 
2,4-difluoronitrobenzene. 
EXAMPLE 2 
1,2-Dihydro-7,8-difluoro-4-phenylimidazo[1,2-a]quinoxaline 5-oxide;--orange 
solid, m.p. 212.degree.-213.degree. C. (Found: C, 63.28; H, 3.65; N 
13.72%; C.sub.16 H.sub.11 F.sub.2 N.sub.3 0.0.2H.sub.2 O requires C, 
63.45; H, 3.76; N 13.88%) represented by the structural formula: 
##STR15## 
EXAMPLE 3 
8-Chloro-1,2-dihydro-4-phenylimidazo[1,2-a]pyrido[3,2-e]-pyrazine 
5-oxide;--yellow needles, m.p. 170.degree.-171.degree. C. (Found: C, 
60.14; H,3.61; N,18.52%; C.sub.15 H.sub.11 ClN.sub.4 O requires C,60.40; 
H, 3.69; N,18.79%) represented by the structural formula: 
##STR16## 
EXAMPLE 4 
1,2-Dihydro-8-(4-methylpiperazinyl)-4-phenylimidazo[1,2-a]-quinoxaline 
5-oxide; 
1,2-Dihydro-8-fluoro-4-phenylimidazo[1,2-a]quinoxaline 5-oxide (3.5 g, 
0.012 mol) and N-methylpiperazine (15 ml, 0.13 mol) were heated at 
100.degree. C. in isopropanol (5 ml) for 16 hrs. The solvent was removed 
in vacuo and the residue was dissolved in dichloromethane. The resulting 
solution was washed with saturated aqueous sodium hydrogen carbonate, 
dried over anhydrous magnesium sulphate and concentrated in vacuo to yield 
a dark oil which was chromatographed on silica gel in 2% 
methanol/chloroform to yield a red solid. The red solid was recrystallized 
from ethyl acetate to yield 
1,2-dihydro-8-(4-methylpiperazinyl)-4-phenylimidazo[1,2-a]quinoxaline 
5-oxide, (0.75 g), as deep red crystals m.p. 179.degree.-183.degree. C., 
(.delta.(CDCl.sub.3) 2.38 (3H,s) 2.58 (4H,m) 3.37 (4H,m) 3.95-4.24 (4H,m) 
6.08 (1H,d,J=3.5Hz), 6.62 (1H,dd,J=9 and 3.5Hz), 7.38-7.5 (3H,m), 7.84 
(2H,m), and 8.11 (1H,d,J=9 Hz)), represented by the structural formula: 
##STR17## 
EXAMPLES 5-10 
The following compounds were prepared in accordance with the reaction 
conditions employed in Example 4 using appropriate starting materials; 
EXAMPLE 5 
1,2-Dihydro-7-fluoro-4-phenyl-8-(4-phenylpiperazinyl)imidazo[1,2-a]quinoxal 
ine 5-oxide;--deep red crystals, m.p. 201.degree.-205.degree. C. (Found: 
C,70.99; H,5.30; N,15.81%; C.sub.26 H.sub.24 FN.sub.5 O requires C,70.75; 
H,5.44; N,15.87%) represented by the structural formula: 
##STR18## 
To prepare the compound of Example 5, the reaction in the procedure of 
Example 4 was conducted at a temperature of 70.degree. C. rather than at 
100.degree. C. 
EXAMPLE 6 
1,2-Dihydro-4-phenyl-8-(4-phenylmethylpiperazinyl)imidazo[1,2-a]quinoxaline 
5-oxide;--red needles, m.p. 205.degree.-210.degree. C. (Found: C,73.80; 
H,6.30; N,15.59%; C.sub.27 H.sub.27 N.sub.5 O requires C, 74.14; H 6.18; 
N,16.02%) represented by the structural formula: 
##STR19## 
To prepare the compound of Example 6 the reaction in the procedure of 
Example 4 required three days to go to completion rather than 16 hours. 
EXAMPLE 7 
8-(4-Acetylpiperazinyl)-1,2-dihydro-4-phenylimidazo[1,2-a]quinoxaline 
5-oxide;--red crystals, m.p. 145.degree.-147.degree. C. (Found: C,67.67; 
H,5.91; N, 17.90%; C.sub.22 H.sub.23 N.sub.5 O.sub.2 requires C,67.87: 
H,5.91; N;17.99%) represented by the structural formula: 
##STR20## 
To prepare the compound of Example 7 the reaction in the procedure of 
Example 4 required four days to go to completion rather than 16 hours. 
EXAMPLE 8 
1,2-Dihydro-4-phenyl-8-(4-phenylpiperazinyl)imidazo[1,2-a]quinoxaline 
5-oxide;--yellow solid, m.p. 243.degree.-244.degree. C. (Found: C,73.15; 
H,5.86; N,16.31%; C.sub.26 H.sub.25 N.sub.5 O.O.2H.sub.2 O requires C, 
73.13; H,5.86; N,16.40%) represented by the structural formula: 
##STR21## 
To prepare the compound of Example 8, the procedure of Example 4 was 
conducted utilizing neat N-phenylpiperazine in lieu of N-methylpiperazine 
in isopropanol and the reaction was conducted at a temperature of 
120.degree. C., for 3 hrs. 
EXAMPLE 9 
1,2-Dihydro-8-(4-methylpiperazinyl)-4-phenylimidazo[1,2-a]pyrido[3,2-e]pyra 
zine 5-oxide;--orange-red solid, m.p. 138.degree.-142.degree. C. (Found: 
C,66.04; H,6.07; N,22.95%; C.sub.20 H.sub.22 N.sub.6 O requires C,66.30; 
H,6.08; N,23.20%), represented by the structural formula: 
##STR22## 
To prepare the compound of Example 9 the reaction in the procedure of 
Example 4 was conducted at a temperature of 60.degree. C., for 30 min., 
rather than at 100.degree. C. for 16 hrs. 
EXAMPLE 10 
8-(4-Acetylpiperazinvl)-1,2-dihydro-4-phenylimidazo[1,2-a]pyrido[3,2-e]pyra 
zine 5-oxide; an orange solid, m.p. 252.degree.-254.degree. C. (Found: C, 
63.80; H, 5.62; N, 20.95%; C.sub.21 H.sub.22 N.sub.6 O.sub.2.O.3H.sub.2 O 
requires C, 63.73; H, 5.71; N, 21.24%), represented by the structural 
formula: 
##STR23## 
To prepare the compound of Example 10 the reaction in the procedure of 
Example 4 was conducted at a temperature of 85.degree. C. for three days 
rather than at 100.degree. C. for 16 hrs. In addition, one molar 
equivalent of triethylamine was added to the reaction mixture before 
heating commenced. 
EXAMPLE 11 
1,2-Dihydro-4-phenyl-8-piperazinylimidazo[1,2a]quinoxaline 5-oxide 
Under a nitrogen atmosphere, 
1,2-dihydro-8-fluoro-4-phenylimidazo[1,2-a]quinoxaline 5-oxide (40 g 0.142 
mol) and piperazine (122 g, 419 mol) were heated at 9.degree. C., for 3.5 
hrs. The solvent was removed in vacuo and the resulting residue was 
dissolved in dichloromethane. The resulting solution was washed with 
water, dried over anhydrous magnesium sulphate and concentrated in vacuo 
to yield an orange solid. The orange solid was recrystallized from 
chloroform-ethyl acetate to yield 
1,2-dihydro-4-phenyl-8-piperazinylimidazo[1,2-a]quinoxaline 5-oxide, (45 
g) as orange crystals, m.p. 209.degree.-211.degree. C. (Found: C, 68.56; 
H,6.06; N,19.99%; C.sub.20 H.sub.21 N.sub.5 O.O.2H.sub.2 O requires C, 
68.43; H,6.14; N,19.95%) represented by the structural formula: 
##STR24## 
EXAMPLE 12 
1,2-Dihydro-8-(4-octanoylpiperazinyl)-4-phenylimidazo[1,2-a]quinoxaline 
5-oxide 
To a stirred suspension of 1,2-dihydro-4-phenyl-8piperazinylimidazo 
[1,2-a]quinoxaline 5-oxide (1.5 g, 0.0043 mol) in dimethylformamide (20 
ml) under an atmosphere of nitrogen and cooled in an ice-bath, was added 
octanoic acid (0.67 g, 0.0043 mol.) and diphenylphosphorylazide (1.29 g, 
0.0047 mol). The reaction mixture was allowed to stand for 15 minutes. 
Triethylamine (0.95 g, 0.0047 mol) was added to the reaction mixture and 
the resulting mixture was allowed to stand for 1 hr, then warmed to room 
temperature over an additional 1 hr period. The solvent was removed in 
vacuo and the residue was dissolved in chloroform. The solution was washed 
with saturated aqueous sodium hydrogen carbonate and then water, dried 
over anhydrous magnesium sulphate and concentrated in vacuo to yield an 
orange solid. The orange solid was recrystallized from chloroform:ethyl 
acetate to yield 
1,2-dihydro-8-(4-octanoylpiperazinyl)-4-phenylimidazo[1,2-a]quinoxaline 
5-oxide, (1.6 g) as yellow crystals, m.p. 212.degree.-213.degree. C. 
(Found: C,70.72; H,7.44; N,14.77%; C.sub.28 H.sub.35 N.sub.5 O.sub.2 
requires C,71.01; H,7.45; N,14.78%), represented by the structural 
formula: 
##STR25## 
EXAMPLES 13-16 
The following compounds were prepared in accordance with the reaction 
conditions employed in Example 12 using appropriate starting materials. 
EXAMPLE 13 
1,2-Dihydro-4-phenyl-8-[4-(2-phenylacetyl)piperazinyl]imidazo[1,2-a]quinoxa 
line 5-oxide;--orange crystals, m.p. 144.degree.-146.degree. C. (Found: C, 
69.36, H, 5.64; N, 14.11%; C.sub.28 H.sub.27 N.sub.5 O.sub.2 Requires: C, 
69.55; H, 6.04; N, 14.48%) having the formula: 
##STR26## 
EXAMPLE 14 
1,2-Dihydro-8-[4-[N-[(1,1-dimethylethoxy)carbonyl]glycinyl]piperazinyl]-4-p 
henylimidazo[1,2-a]quinoxaline 5-oxide;--orange crystals, m.p. 
210.degree.-212.degree. C. C,64.09; H,6.37; N,16.37%; C.sub.27 H.sub.32 
N.sub.6 O.sub.4 requires C 64.40; H,6.20; N,16.69%) having the formula: 
##STR27## 
EXAMPLE 15 
8-(4-Benzoylpiperazinyl)-1,2-dihydro-4-phenylimidazo[1,2-a]quinoxaline 
5-oxide;--orange crystals, m.p. 225.degree.-230.degree. C. (Found: 
C,71.09; H,5.54; N,15.36%; C.sub.27 H.sub.25 N.sub.5 O.sub.2.O.3H.sub.2 O 
requires C,70.97; H,5.65; N,15.33%) represented by the structural formula: 
##STR28## 
EXAMPLE 16 
1,2-Dihydro-4-phenyl-8-[4-(2-pyridinecarbonyl)piperazinyl]imidazo[1,2-a]qui 
noxaline 5-oxide;--orange crystals, m.p. 230.degree.-235.degree. C. (Found: 
C,68.27; H,5.28; N,18.41%; C.sub.26 H.sub.24 N.sub.6 O.sub.2.O.3H.sub.2 O 
requires C,68.20; H,5.41; N,18.35%) represented by the structural formula: 
##STR29## 
EXAMPLE 17 
1,2-Dihydro-4-phenyl-8-(4-phenylmethylpiperazinyl)imidazo[1,2-a]pyrido[3,2- 
e]pyrazine 5-oxide 
8-Chloro-1,2-dihydro-4-phenylimidazo[1,2-a]pyrido[3,2-e]pyrazine 5-oxide (3 
g, 0.01 mol) and benzylpiperazine (3.6 g, 0.02 mol) were heated at 
80.degree. C., in isopropanol (100 ml) under an atmosphere of nitrogen for 
16 hrs. As the reaction mixture cooled to room temperature, a yellow solid 
precipitated. The yellow solid was collected by filtration, washed with 
cold isopropanol and recrystallized from isopropanol to yield 
1,2-dihydro-4-phenyl-8-(4-phenylmethylpiperazinyl)imidazo 
[1,2-a]pyrido[3,2-e]pyrazine 5-oxide (3.7 g), as orange needles, m.p. 
184.degree.-187.degree. C. (Found: C,71.03; H,6.02; N,19.30%; C.sub.26 
H.sub.24 N.sub.6 O.O.1H.sub.2 O requires C,70.92; H,6.00; N,19.09%), 
represented by the structural formula: 
##STR30## 
EXAMPLE 18 
1,2-Dihydro-8-(4-(methylsulphonyl)piperazinyl)-4-phenylimidazo[1,2-a]quinox 
aline 5-oxide 
A solution of methanesulfonyl chloride (0.33 g, 0.003 mol) in 
dichloromethane (20 ml) was cooled in an ice-bath. To this solution was 
added dropwise with stirring, a solution of triethylamine (0.29 g, 0.003 
mol) and 1,2-dihydro-4-phenyl-8-piperazinylimidazo[1,2-a]quinoxaline 
5-oxide (1 g, 0.003 mol) in dichloromethane (10 ml). The reaction mixture 
was stirred for an additional 15 minutes and then was allowed to warm to 
room temperature. The reaction mixture was washed with water, dried over 
anhydrous magnesium sulphate and then evaporated to dryness under reduced 
pressure to yield a yellow solid. Recrystallization from ethyl acetate 
yielded 
1,2-dihydro-8-(4-(methylsulphonyl)piperazinyl)-4-phenylimidazo[1,2-a]quino 
xaline 5-oxide (0.8 g), as yellow crystals, m.p. 252.degree.-253.degree. C. 
(Found: C,59.19; H,5.35; N,16.33%; C.sub.21 H.sub.23 N.sub.5 O.sub.3 S 
requires C,59.29; H,5.41; N,16.47%) having the formula: 
##STR31## 
EXAMPLE 19 
2-[4-(1,2-Dihydro-5-oxido-4-phenylimidazo[1,2-a]quinoxalin-8-yl)piperazinyl 
]acetamide 
Triethylamine (0.75 g, 0.0072 mol.) was added to a solution of 
iodoacetamide (0.59 g, 0.0032 mol.) and 
1,2-dihydro-4-phenyl-8-piperazinylimidazo[1,2-a]quinoxaline 5-oxide (1.0 
g, 0.0029 mol.) in ethanol (50 ml) and the reaction mixture stirred 
overnight at room temperature. The resulting precipitate was removed by 
filtration, washed with ethanol and then ether. Recrystallization from 
ethanol yielded 
2-[4-(1,2-dihydro-5-oxido-4-phenylimidazo[1,2-a]-quinoxalin-8-yl)piperazin 
yl]acetamide, (0.63 g) as bright yellow crystals, m.p. 
225.degree.-227.degree. C. (Found: C, 63.50; H, 5.89; N, 19.72%; C.sub.22 
H.sub.24 N.sub.6 O.sub.6.O.75H.sub.2 O requires C, 63.23; H, 6.11; N, 
20.12%) represented by the structural formula: 
##STR32## 
EXAMPLE 20 
The screening panel utilized in this Example consisted of 5 strains of 
Bacteroides fragilis. All assays were carried out in 96 well microtitre 
plates. If an isolate was obtained from either a culture collection or 
clinical source, the isolate was immediately inoculated into 
Wilkins-Chalgren broth (Oxoid) and incubated at 37.degree. C. in an 
anaerobic chamber in an atmosphere of 85% nitrogen, 10% carbon dioxide, 
and 5% hydrogen for 48 hours. At the end of this time, the viable count 
was about 10.sup.12 organisms/ml broth. A 1 ml aliquot of each culture was 
placed in an ampoule and quick frozen in acetone-dry ice mixture and 
stored in liquid nitrogen. When an inoculum was utilised in an assay, one 
of the ampoules was thawed and diluted with fresh broth to yield a 
suspension having a count of 5.times.10.sup.5 organisms/ml. A 100 .mu.l 
aliquot of the suspension was inoculated into each well of the microtitre 
plate. 
A 2 mg sample of the test compound was dissolved in 0.2 ml of a suitable 
solvent such as dimethylsulphoxide, polyethylene glycol 200 or methanol. 
The solution was then diluted with 4.8 ml of water to yield a solution 
having a concentration of 400 mg/L. Doubling dilutions of this stock were 
prepared to give a range of concentrations from 1.6-200 mg/L. 100 .mu.l of 
each concentration were then placed in the wells of the microtitre plate 
containing the inoculum, to produce a mixture having a final concentration 
in the range of 0.8-100 mg/L. Metronidazole was employed as a positive 
control and a solvent/water mixture was employed as a negative control. 
After addition of the test solution the final inoculum level was 10.sup.5 
cells/ml. The plates were incubated for 48 hours at 37.degree. C. in the 
anaerobic chamber. The Minimum Inhibitory Concentration (MIC) was read 
visually. The MIC is defined as the lowest concentration at which there is 
no detectable growth. The Minimum Bactericidal Concentration (MBC) was 
determined by taking 50 .mu.l aliquot from each well and placing it in 
fresh medium. The MBC is defined as the lowest concentration at which 
there is less than 5 colonies (i.e., 99.9% reduction in viable count) 
after 48 hours of incubation. The MIC and MBC values for each compound 
tested and the respective MIC and MBC value for metronidazole are 
indicated in Table 1. The MIC and MBC value for the negative control that 
was assayed along with each test compound was greater than 100 mg/L. The 
MIC and MBC values in Table 1 are expressed in mg/L. A blank in the table 
represented by a "-" indicates that the assay was not conducted using the 
strain indicated. 
The strains of Bacteroides fragilis utilized in the above procedure are 
identified by letter in accordance with the following legend: 
______________________________________ 
STRAIN ORGANISM 
______________________________________ 
A B. fragilis NCTC 10581 
B B. fragilis NCTC 9343 
C B. fragilis NCTC 9344 
D B. fragilis MZ-R ATCC 11295 
E B. fragilis WS-1* 
______________________________________ 
*Obtained from St. Thomas's Hospital Medical School, London, United 
Kingdom. 
TABLE 1 
__________________________________________________________________________ 
STRAIN 
COMPOUND OF 
A B C D E 
EXAMPLE NO. 
MIC MBC MIC MBC MIC MBC MIC MBC MIC MBC 
__________________________________________________________________________ 
1 3.1 3.1 3.1 3.1 1.5 1.5 0.8 1.5 3.1 3.1 
Metronidazole 
0.6 0.8 0.8 1.5 0.6 0.6 3.1 6.2 1.5 3.1 
2 0.6 0.6 0.15 
0.15 
0.6 0.6 0.08 
0.15 
0.6 0.6 
Metronidazole 
0.6 0.8 0.6 0.8 0.6 0.8 6.2 12.5 
1.5 1.5 
3 12.5 
12.5 
12.5 
12.5 
6.2 6.2 3.1 3.1 6.2 6.2 
Metronidazole 
&lt;0.8 
&lt;0.8 
&lt;0.8 
&lt;0.8 
&lt;0.8 
&lt;0.8 
6.2 12.5 
&lt;0.8 
&lt;0.8 
4 3.1 3.1 3.1 3.1 3.1 3.1 1.5 1.5 6.2 6.2 
Metronidazole 
0.8 0.8 1.5 3.1 0.8 0.8 12.5 
12.5 
0.8 0.8 
5 3.1 -- 1.5 -- 6.2 -- 0.8 -- 1.5 -- 
Metronidazole 
0.8 -- 0.8 -- 0.8 -- 6.2 -- 0.8 -- 
6 25 25 50 50 12.5 
25 25 25 25 25 
Metronidazole 
1.5 1.5 1.5 1.5 &lt;0.8 
&lt;0.8 
12.5 
12.5 
1.5 3.1 
7 6.2 6.2 3.1 3.1 6.2 6.2 1.5 1.5 6.2 6.2 
Metronidazole 
0.6 0.8 0.6 0.8 0.6 0.8 6.2 12.5 
1.5 1.5 
8 1.5 -- 1.5 -- &lt;0.8 
-- &lt;0.8 
-- 3.1 -- 
Metronidazole 
&lt;0.8 
-- &lt;0.8 
-- &lt;0.8 
-- 6.2 -- &lt;0.8 
-- 
9 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 -- -- 
Metronidazole 
0.8 0.8 0.8 1.5 0.8 0.8 6.2 2.5 -- -- 
__________________________________________________________________________ 
EXAMPLE 21 
Utilizing the procedures described in Example 20, the anti-anaerobic 
activity of certain compounds of the present invention was demonstrated 
utilizing an additional 10 strains of various anaerobic bacteria. 
The MIC values obtained are indicated in Table 2. A blank in the table 
represented by a "-" indicates that the assay was not conducted using the 
strain indicated. 
TABLE 2 
__________________________________________________________________________ 
MIC vs. PANEL OF ANAEROBES 
Compound of Example No. 
Organism (1) (2) (3) (4) 
(5) (6) (7) (8) MZ* 
__________________________________________________________________________ 
Clostridium 
3.1 6.2 6.2 6.2 
3.1 12.5 
1.5 1.5 &lt;0.8 
perfringens 
NCTC 523 
Clostridium 
3.1 6.2 25 12.5 
6.2 12.5 
3.1 3.1 1.5 
perfringens 
NCTC 8237 
Clostridium 
&lt;0.8 
&lt;0.8 
&lt;0.8 1.5 
&lt;0.8 &lt;0.8 
&lt;0.8 
&lt;0.8 &lt;0.8 
difficile 
NCIB 10666 
Clostridium 
&lt;0.8 
6.2 &lt;0.8 6.2 
&lt;0.8 3.1 &lt;0.8 
&lt;0.8 &lt;0.8 
difficile 
Cytotoxic 1 
Campylobacter 
2.5 12.5 
50 25 &gt;100 100 12.5 
&gt;100 &gt;100 
fetus ss.jejuni 
ATCC 29428 
Fusobacterium 
&lt;0.8 
3.1 6.2 6.2 
6.2 12.5 
3.1 3.1 6.2 
necrophorum 
ATCC 11295 
Bacteroides 
25 6.2 100 12.5 
&gt;100 50 6.2 &gt;100 &gt;100 
melanogenicus 
NCTC 9336 
Peptostreptococcus 
25 12.5 
50 12.5 
&gt;100 100 12.5 
&gt;100 &gt;100 
anaerobicus 
Propionebecterium 
50 25 &gt;100 25 &gt; 100 50 25 &gt;100 &gt;100 
acnes 
NCTC 737 
Propionebacterium 
50 25 100 25 &gt;100 50 12.5 
&gt;100 &gt;100 
acnes 
NCTC 7337 
__________________________________________________________________________ 
*MZ = Metronidazole 
EXAMPLE 22 
Determination of in vivo Anti-anaerobe activity--mouse hepatic necrosis 
500 ml volumes of basic anaerobe broth (nutrient broth No. 2 (LAB M) 28 
g/L, haemin 5 mg/L, vitamin K 0.5 mg/L, and cysteine hydrochloride 0.5 
g/L) were inoculated from a cooked meat broth stock culture of B. Fragilis 
ATCC 23745 which had been inoculated from the original cooked meat broth 
stock i.e. subculturing was kept to a minimum. Cultures were incubated 
anaerobically in an anaerobic chamber. When the broths reached a heavy 
turbidity (24-48 hours) they were aliquoted into small bottles, 
inactivated horse serum added to 10%, together with a few drops of 
neutralized ascorbate (100 mg/ml) before snap freezing and storing at 
-20.degree. C. The viable count was 10.sup.10 organisms/ml. 
Rat faeces or mouse bowel contents were mixed with a small volume of water 
and autoclaved then homogenised. After standing overnight they were 
autoclaved again and then freeze-dried in small batches. 
Stock inoculum was thawed and diluted to yield a viable count of 
5.times.10.sup.8 organisms/ml with fresh broth, and sterile faecal 
material was added to a final concentration of 2% w/v. Animals (groups of 
ten male BALBLc mice weighing 18-22 g) were inoculated intraperitoneally 
with 0.2 ml of the inoculum so that each receives 10.sup.8 B. fragilis. 
Test compounds were dissolved in polyethylene glycol 200 or 
dimethylsulphoxide and then diluted with water or saline to give the 
appropriate final concentration. The stock solution was used to prepare a 
two-fold dilution series having a final dose range of 2.5-40 mg/kg. The 
initial dose was given p.o. immediately after infection and twice daily 
thereafter for 2 days. Animals were sacrificed on the third day using 
carbon dioxide or cervical dislocation. Control animals received dosing 
vehicle only. Metronidazole was used as a positive control. 
At the end of the experimental period the animals' livers were removed 
aseptically with care not to puncture the bowel, and transferred to 
Universal bottles of peptone water and kept on ice. 
The livers were homogenized at low speed with care to prevent frothing and 
the bottles were gassed out again. Homogenate was diluted by transferring 
0.1 ml of the homogenate to a 10 ml aliquot of peptone water diluent, and 
the diluted homogenate was spread on basic anaerobic agar at 0.1 ml per 
petri-dish. The media used for this purpose must have either been prepared 
freshly, or stored in plastic bags in which the air has been replaced by 
anaerobic gas mixture, or stored in anaerobic jars. After the homogenate 
was spread on the petri-dishes, the petri-dishes were left exposed to air 
for the minimum possible time (and never more than 15 minutes) so that 
small numbers of Bacteroides were recovered and grown from the inoculum. 
Cultures were incubated anaerobically for 48 hrs. in a Forma Anaerobic 
Chamber at 37.degree. C. At the end of this period, the resultant colonies 
were counted using an AMS 40-10 Image Analyser. The mean number of viable 
organisms were calculated for each treatment group and the data analysed 
using Analysis of varience and two sample t-test for comparison of 
individual groups. Results were expressed as the reduction in log colony 
forming units/ml of liver homogenate for each treatment group compared to 
the untreated controls. From the dose response curves, the dose giving 1 
log (90%) reduction is calculated for each compound and the efficacy of 
the test compound relative to metronidazole is determined. 
Under these test conditions, metronidazole gives a reduction in B. fragilis 
of 3-3.5 log.sub.10 at 40 mg/kg (p.o.). 
The activities of the compounds described above are given in Table 3. 
TABLE 3 
______________________________________ 
Dose giving 1 log reduction 
Compound of 
Example No. mg/kg (mM/kg) Metronidazole 
______________________________________ 
(1) 7.57 (26.9) 1.64 (9.6) 
(2) &lt;40 2.8 (12.7) 
(3) &lt;40 1.79 (10.46) 
(4) 7.73 (22.0) 2.49 (15.0) 
(5) 11.73 (26.6) 1.89 (11.06) 
(6) 6.27 (14.34) 2.29 (13.41) 
(7) 11.3 (29.1) 2.18 (12.7) 
(9) 4.48 (12.4) 1.95 (11.4) 
(17) 3.59 (8.19) 2.94 (17.2) 
______________________________________ 
Although this invention has been described with respect to specific 
modification, the details thereof are not to be construed as limitations, 
for it will be apparent that various equivalents, changes and 
modifications may be restored and modification may be resorted to without 
departing from the spirit and scope thereof and it is understood that such 
equivalent embodiments are intended to be included therein.