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Publication numberUS3682949 A
Publication typeGrant
Publication dateAug 8, 1972
Filing dateJul 22, 1969
Priority dateJul 22, 1969
Publication numberUS 3682949 A, US 3682949A, US-A-3682949, US3682949 A, US3682949A
InventorsDavid W Henry, Dale R Hoff, Lewis H Sarett
Original AssigneeDale R Hoff, David W Henry, Lewis H Sarett
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
2-aryl-5(or 4-)nitroimidazoles
US 3682949 A
Abstract
1-Substituted-2-aryl-5-nitroimidazoles, 1-substituted-2-aryl-4-nitroimidazoles and related isoindoles and dihydroisoquinolines are prepared. The compounds are utilized as antiprotozoals, antibacterials, anthelmintics and the like. Further, the novel nitroimidazoles useful as intermediates in the preparation of the active parasiticides are prepared.
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Description  (OCR text may contain errors)

United States Patent Sarett et a].

[151 3,682,949 51 Aug. 8, 1972 [54] 2-ARYL-5(OR 4-)NITROIMIDAZOLES [22] Filed: July 22, 1969 [21] Appl. No.: 848,558

[52] US. Cl ..260/309, 260/ 141, 260/240 A, 260/240 G, 260/243 B, 260/247. 1, 260/247.2

R, 260/247.2 A, 260/247.2 B, 260/247.5 R, 260/247.5 B, 260/250 R, 260/256.4 N,

260/256.4 C, 260/256.4 H, 260/256.4 R,

260/256.5 R, 260/268 H, 260/268 BC,

260/268 N, 260/268 S, 260/287 R, 260/288 R, 260/293.7, 260/294.8 C, 260/294.8 G,

260/295 AM, 260/295 F, 260/295 H,

260/295 CA, 260/295 K, 260/295 R,

260/296 B, 260/296 R, 260/306.8 R,

[51] Int. Cl. ..C07d 49/36 [58] Field of Search ..260/309 [56] References Cited FOREIGN PATENTS OR APPLICATIONS 228,471 5/ 1958 Australia ..260/309 228,784 8/1958 Australia ..260/309 OTHER PUBLICATIONS Hazeldine et al. J. Chem. Soc. (London) V01. 125, pages 1431-41 (1924). QD1.C6

Ochiai et al. Chem Abst. Vol. 35, column 458 (1941). QD1.A51.

Primary Examiner-Natalie Trousof Attorney-.1. Jerome Behan, John Frederick Gerkens and Omri M. Behr ABSTRACT l-Substituted- 2-aryl-5-nitroimidazoles, l-substituted- 2-aryl-4-nitroimidazoles and related isoindoles and dihydroisoquinolines are prepared. The compounds are utilized as antiprotozoals, antibacterials, anthelmintics and the like. Further, the novel nitroimidazoles useful as intermediates in the preparation of the active parasiticides are prepared.

21 Claims, No Drawings 2-ARYL-5 (OR 4-)NITROIMIDAZOLES This application is a continuation application of U.S. Ser. No. 569,595 filed Aug. 2, 1966, now abandoned, which in turn was a continuation-in-part application of US. Ser. No. 350,639 filed Mar. 10, 1964, now US. Pat. No. 3,399,211.

This invention relates generally to new imidazoles and more particularly to new 2-aryl nitroimidazoles and to methods for their preparation. Still more specifically, it is concerned with l-substituted-2-aryl-5- nitroimidazoles, 1-substituted-2-aryl-4-nitroimidazoles, and structurally related isoindoles and dihydroisoquinolines, with the chemical synthesis of these new heterocyclic compounds, with compositions of such compounds and a carrier, and with the use of such compounds and compositions as parasiticides. More particularly, the invention is concerned with l-substituted- 2-aryl-5-nitroimidazoles, l-substituted-2-aryl-4- nitroimida-zoles, and related isoindoles and dihydroisoquinolines and their use as antiprotozoals, antibacterials, anthelmintics and the like. The inven tion is further concerned with novel nitroimidazoles useful as intermediates in the preparation of the active parasiticides and with methods for their preparation.

The compounds of this invention are effective against protozoal infections such as histomoniasis, trichomoniasis, amoebiasis, trypanosomiasis; helminths such as Heterakis and Ascarid species; bacteria such as Salmonella sp., Streptoccus sp. and Escherichia coli; and pleuro pneumonia like organisms (PPLO).

Histomoniasis is a poultry disease due to the protozoan parasite Histomonas meleagridis. This disease, also known as turkey blackhead or enteroheptatitis, is a serious economic problem in the turkey-raising industry. The infestation frequently spreads rapidly in turkey flocks and high mortality rates due to the disease are common. The compounds now commercially available for treating turkey blackhead are somewhat beneficial, but none have proven entirely satisfactory because they permit development of resistant strains of the infecting organism or lead to undesired side effects when ingested by the birds in quantities sufficient to treat the disease.

The protozoan disease trichomoniasis caused by T. vaginalis primarily infests the human vagina and is the etiological agent of very troublesome and prevalent form of vaginal infestation known as T. vaginalis vaginitis. Drugs heretofore available for treating this condition like those used for treating enteroheptatis have certain limitations and disadvantages.

One object of the present invention is to provide a new class of chemical compounds which have a high degree of antiparasitic activity. Another object is to provide new 1-substituted-2-aryl-5-nitroimidazoles, 1- substituted-2-aryl-4-nitroimidazoles, and structurally related isoindoles and dihydroisoquinolines. A further object is to provide processes for the preparation of the novel compounds. Still another object is the provision of new nitroimidazoles which are intermediate in the synthesis of such compounds. A further object is provision of processes for the preparation of these intermediates. A still further object is provision of antiparasitic compositions containing the novel compounds of this invention as active ingredients thereof. Further objects will become clear from the following description of the invention.

According to this invention, it has now been found that certain l-substituted-2-aryl-5-nitroimidazoles and l-substituted-2-aryl-4-nitroimidazoles are highly effective parasiticides. Generally, the l-substituted-2-aryl-5- nitroimidazoles are more effective parasiticides than the corresponding 1-substituted-2-aryl-4- nitroimidazoles, but both types of nitroimidazoles are particularly effective against the above-mentioned parsites and infections. An important feature of the compounds of this invention is that the substituent attached to the 2-position on the imidazole moiety of the active compounds be an aryl group. The aryl substituent may be unsubstituted or substituted at one or more of the positions on the ring. Ortho, meta and para substitution and combinations thereof are contemplated by the present invention. Hereafter, when the term aryl is used in referring to a substituent on the 2- position of the imidazole moiety such term is intended to embrace substituted aryl radicals, i.e. those having attached to the aryl nucleus groups other than hydrogen.

The novel 2-aryl-nitroimidazoles of this invention may be represented by the structural formula BUTT l R I? LR R1 J 3 where Ar represents phenyl or naphthyl;

R is hydrogen, chloro, bromo, loweralkyl, nitro,

lower-alkoxy or amino;

R is

hydrogen, loweralkyl, substituted loweralkyl wherein the substituent is carboxy, CONR R where R, and R are hydrogen or loweralkyl, and NR R represent morpholino, piperi-dino,

or pyrrolidino, loweralkoxycarbonyl, cyano or Z-phenyl where Z represents hydrogen, nitro, halo, loweralkyl or loweralkoxy, formyl alkyl, wherein alkyl has one to three carbon atoms, (CH ),,X where n is 2-4,

X is halo, hydroxy, loweralkoxy, lower-alkylthio, loweralkylsulfonyl, lower-alkylsulfinyl, or NR R where R R and NR R are as defined above,

where R R and NR R are as defined above,

wherein m is 0-2, or CH CB(CH H where H dis l-2,Bis Oor InInAo and e is 1-4;

R represents hydrogen, halo, nitro, cyano, or loweralkoxy, loweralkyl,

formyl, 5 loweralkanoyl, carboxy, loweralkoxycarbonyl,

M i N oll-1 where where Y is O or S and R R and NR R, are as defined above,

-0 ("J-NHOH,

cyanato, hydroxypseudoureido, L-phenylpseudoureido where L is hydrogen, halo, nitro or loweralkyl, loweralkyl, substituted loweralkyl wherein the substituent is loweralkanoylamino, loweralkanoyl, hydroxy,

H OC-NHOH where Y, R R and NR R are as defined above,

L-benzoylamino, L-phenoxycarbonyloxy or bphenoxythiocarbonyloxy where L is as above, formyl, loweralkanoyl,

defined where R, is hydrogen or loweralkyl,

l C=NNIICNR R where R is as defined above, M is O, S or NH, and R and R are hydrogen, loweralkyl or phenyl,

where R is as defined above and R and R are hydrogen, loweralkyl, phenyl, nitrophenyl, halophenyl, thiazolyl, pyridinyl, imidazolyl, thienyl, pyrimidinyl, loweralkanoyl, benzoyl, nitrobenzoyl, halobenzoyl, loweralkoxycarbonyl, thiazolecarbonyl, pyridinecarbonyl, imidazole-carbonyl, thenoyl, or pyrimidinecarbonyl, and NR R represents oxo-oxazolidinyl, oxo-imidazolidinyl,

oimidazolidinyl, piperidinyl, piperazinyl, morpholinyl or thiamorpholinyl, diloweralkanoyloxymethyl, carboxy, loweralkoxycarbonyl,

where M, R R and NR R are as defined above, imidazolinyl, N-loweralkylimidazolinyl, tetrahydropyrimidinyl, N-loweralkyltetrahydropyrimidinyl,

where R and R are hydrogen, loweralkyl, phenylloweralkyl or phenyl,

phenyl,

substituted phenyl wherein the substituent is halo,

nitro, carboxamido or cyano,

amino,

substituted amino wherein the substituent is loweralkyl, diloweralkyl, loweralkanoyl, haloloweralkanoyl, forrnyl, L-benzoyl where L is as defined above, carbamoyl or cyano,

where j is 1-6 and R R and NR R are as defined above, guanidino, biguanido, mercapto, substitutedthio wherein the substituent is loweralkyl, cyano, loweralkoxythiocarbonyl,

dioxwhere R R and NR R are as defined above,

T AlTRz represents tetrahydronaphthyl, indanyl, indenyl, quinolinyl or quinoxalinyl; and R and R represent hydrogen and nitro, provided one and only one of R and R is nitro.

The loweralkyl and loweralkoxy groups which R represents are preferably methyl, ethyl, methoxy, ethoxy and the like.

The symbol R may be hydrogen or a loweralkyl radical such as methyl, ethyl, n-propyl, isopropyl and the like; substituted loweralkyl such as carboxymethyl, carboxyethyl and the like; carboxamidomethyl, carboxamidoethyl, N-ethylcarboxamidomethyl, pyrrolidinocarbonylmethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl,

methoxycarbonylethyl, ethoxycarbonylethyl, methoxycarbonyl-n-propyl, and the like; cyano loweralkyl such as cyano methyl, cyano ethyl, cyano n-propyl, cyano isobutyl, and the like; phenylloweralkyl such as benzyl, phenethyl, and the like; substituted phenylloweralkyl such as p-nitrobenzyl, m-nitrophenethyl, p chlorobenzyl, p-fluorobenzyl, o-chlorophenethyl, loweralkylphenylloweralkyl such as p-ethylbenzyl and the like, or loweralkoxyphenylloweralkyl such as pmethoxybenzyl, and the like.

R also represents formylloweralkyl such as formylmethyl, formylethyl, formyl n-propyl, and the like; halo loweralkyl such as 2-chloroethyl, 2-fluoroethyl, 2- bromoethyl, 3-chloro-n-propyl, and the like; hydroxyloweralkyl such as 2-hydroxyethyl, 3-hydroxypropyl, and the like.

R also represents loweralkoxyloweralkyl such as 2- methoxyethyl, 3-methoxy-n-propyl, 3-eth0xy-n-propyl, and the like; loweralkylthioloweralkyl such as 2- methylthioethyl, 4-methylthio-n-butyl, and the like; loweralkylsulfonylloweralkyl such as 2,-methylsulfonylethyl, 2-ethylsulfonylethyl, and the like; loweralkylsulfinylloweralkyl such as 2-methylsulfinylethyl, 3- methylsulfinyl-n-propyl, and the like; aminoloweralkyl such as 2-aminoethyl, 3-amino-n-propyl, and the like; substitutedaminoloweralkyl such as 2-N- ethylaminoethyl, 2-N-N-dimethylaminoethyl, morpholino-n-propyl, piperidino-n-propyl, pyrrolidinoethyl, and the like; carbamoyloxy loweralkyl such as carbamoyloxyethyl, carbamoyloxy-n-propyl, carbamoyloxyisobutyl, and the like; or substituted carbamoyloxy loweralkyl such as 2-N,N-dimethylcarbamoyloxyethyl, 3 morpholinocarbonyloxy-n-propyl, 2piperidinocarbonyloxyethyl, Z-N-ethylcarbamoyloxyethyl, and the like.

The substituent at the 1-position of these imidazoles also represents a loweralkenyl group such as allyl, methallyl, and the like; loweralkylcarbonylloweralkyl such as methylcarbonylmethyl, ethylcarbonylethyl, and the like; or hydroxyloweralkyl such as 2-hydroxy-npropyl, 2-hydr0xy-n-butyl, and the like.

The substituent R represents hydrogen; halo such as bromo, chloro and fluoro; nitro; hydroxy; loweralkoxy such as methoxy, ethoxy, n-propoxy, and the like; substituted loweralkoxy such as chloroethoxy, bromoethoxy, chloropropoxy, carbamoylmethoxy, carbarnoylethoxy, N-methylcarbamoylethoxy, thiocarbarnoylethoxy, N-ethylthiocarbamoylethoxy, and the like; cyanato; hydroxypseudoureido; phenylpseudoureido; substitutedphenylpseudoureido such as nitrophenylpseudoureido, halophenylpseudoureido, e.g., chlorophenylpseudoureido and the like, and loweralkylphenylpseudoureido such as tolylpseudouriedo, ethylphenylpseudoureido, and the like; carbamoyloxy; substituted carbamoyloxy such as N- hydroxycarbamoyloxy, N-methyl-carbamoyloxy, N,N- dimethylcarbamoyloxy, pyrrolidinocarbonyloxy, piperidinocarbonyloxy, morpholinocarbonyloxy, and the like; thiocarbamoyloxy such as N-methylthiocarbamoyloxy, N,N-dimethylcarbamoyloxy, piperidinothiocarbonyloxy, pyrrolidionothiocarbonyloxy, morpholinothiocarbonyloxy, and the like; loweralkyl such as methyl, ethyl, n-propyl, isopropyl, nbutyl and the like; substituted loweralkyl such as loweralkanoylaminoloweralkyl, i.e. acetylaminomethyl, acetylaminoethyl, propionylaminoethyl and the like; cyanoloweralkyl such as cyanoethyl, cyanomethyl and the like; carboxyloweralkyl such as carboxymethyl, carboxyethyl, carboxy-n-propyl and the like; haloloweralkyl such as trifluoromethyl, trifluoroethyl, chloroethyl and the like; loweralkanolylloweralkyl such as acetylmethyl, acetylethyl, propionylmethyl, propionyl-n-butyl and the like; diloweralkanoylloweralkyl such as diacetylmethyl, and the like; or hydroxyloweralkyl such as hydroxymethyl, hydroxyethyl and the like.

Further substituted loweralkyl groups representing R include aminoloweralkyl such as aminomethyl, aminoethyl and the like; substituted aminoloweralkyl such as N-isopropylaminomethyl, diethylaminoethyl, pyrrolidinoethyl, morpholinomethyl, piperidino-npropyl and the like; carboxamidoloweralkyl such as carboxarnidomethyl, carboxamidoethyl and the like; substituted carboxamidoloweralkyl such as N-ethylcarboxamidomethyl, N,N-dimethylcarboxamido-n-propyl, piperidinocarbonylethyl, morpholinocarbonylethyl, pyrrolidinocarbonylethyl and the like; carbamoyloxyloweralkyl such as carbarnoyloxyethyl, carbamoyloxymethyl and the like; substituted carbamoyloxyloweralkyl such as N-ethylcarbarnoyloxyethyl, N,N-diethylcarbamoyloxyethyl, N-hydroxycarbamoyloxyrnethyl, pyrrolidinocarbonyloxymethyl, piperidinocarbonyloxy-npropyl, morpholinocarbonyloxyethyl, and the like; thiocarbamoyloxyloweralkyl such as thiocarbamoyloxymethyl, thiocarbamoyloxyethyl and the like; substituted thiocarbamoyloxyloweralkyl such as N-npropylthiocarbamoyloxyethyl, N,N-diethylthiocarbamoyloxymethyl, N-hydroxythiocarbamoyloxyethyl, piperidinothiocarbonyloxy-n-propyl, morpholinothiocarbonyloxyrnethyl, pyrrolidinothiocarbonylethyl, and the like; benzoylaminoloweralkyl such as benzoylaminomethyl,

benzoylaminoethyl and the like; substituted benzoylaminoloweralkyl such as pchlorobenzoylaminoethyl, p-

fluorobenzoylaminomethyl, o-nitrobenzoylamino-npropyl, toluolylaminomethyl, and the like; phenoxycarbonyloxyloweralkyl such as phenoxycarbonyloxyethyl, phenoxycarbonyloxymethyl, and the like; substituted phenoxycarbonyloxyloweralkyl such as pfluorophenoxycarbonyloxymethyl, m-chlorophenoxycarbonyloxyethyl, p-nitrophenoxycarbonyloxy-npropyl, p-ethylphenoxycarbonyloxyethyl, and the like.

Further substituents representing R in the above formula include phenyl; substituted phenyl such as nitrophenyl, halophenyl, such as chlorophenyl and fluorophenyl, cyanophenyl, carboxamidophenyl, and the like; fonnyl; carboxy; loweralkanoyl such as acetyl, propionyl and the like; or carboxyhydrazido and substituted carboxyhydrazido such as loweralkylcarboxyhydrazido, e.g., methylcarboxyhydrazido and the like, phenylloweralkylcarboxyhydrazido such as benzylcarboxyhydrazido and the like, or phenylcarboxyhydrazido.

Additional substituents represented by the symbol R have the structural formulas:

where R is hydrogen or loweralkyl, such as methyl, ethyl,

or propyl;

where R; is as defined above, M is O, S or NH, and

R and R are hydrogen, loweralkyl such as methyl or ethyl and the like, or phenyl; and

where R is as defined above and R and R are hydrogen, loweralkyl such as methyl, ethyl and the like, phenyl, nitrophenyl, halophenyl such as chlorophenyl or bromophenyl, heteroaryl such as thiazolyl, pyridinyl, imidazolyl, thienyl. pyrimidinyl and the like, loweralkanoyl such as acetyl or propionyl, benzoyl, nitrobenzoyl, halobenzoyl. such as chlorobenzoyl and the like, loweralkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and the like, heteroaroyl such as thiazolecarbonyl, pyridinecarbonyl, thenoyl, or pyrimidinecarbonyl and the like, and

NR, R represents oxo-oxazolidinyl, oxo-imidazolidinyl, dioxoimidazolidinyl, piperidinyl, piperazinyl, morpholinyl or thiamorpholinyl, and the like.

The substituent on the aryl group designated R also represents amino; substituted amino such as N- methylarnino, N-ethylamino, N-isopropylamino, N,N- dimethylarnino, N,N-diethylamino, morpholino, piperidino, pyrrolidino, and the like; ureido; loweralkanoylamino such as acetylamino, propionylamino and the like; haloalkanoylamino such as chloroacetylamino, dichloropropionamido, fluoropropionamido, bromopropionamido, and the like; carbamoylloweralkylarnino; substituted carbamoylloweralkylamino such as carbamoylmethylamino, carbamoylethylamino, N-ethylcarbamoylethylamino, N-methylcarbamoylethylamino, pyrrolidinocarbonyl-n-propylamino, piperidinocarbonyl-n-propylamino, morpholinocarbonyl-npropylarnino, and the like; guanidino; biguanido; cyanoamino; formylamino; benzoylamino; substituted benzoylamino such as p-fluorobenzoylamino, pchlorobenzoylamino, o-nitrobenzoylamino, ptoluoylamino, and the like; pseudothiourea; loweralkyl pseudothiourea such as N-methylpseudothiourea, N N -diethylpseudothiourea, and the like.

R further represents cyano; phosphondiamido; phosphonyl; halo alkylene such as 2-bromoethylene and 2-chloroethylene; thienyl; furyl; carboxamido; substituted carboxamido such as N-methylcarboxamido, N,N-dimethylcarboxamido, N,N-diethylcarboxamido, piperidinocarbonyl, morpholinocarbonyl, and the like; thiocarbamoyl; substituted thiocarbamoyl such as N- methylthiocarbamoyl, N,N-dimethylthiocarbamoyl, N,N-diethylthiocarbamoyl, morpholinothiocarbonyl, piperidinothiocarbonyl, pyrrolidinothiocarbonyl, and the like; amidino, substituted amidino such as N- methylamidino and the like; imidazolinyl, N-loweralkylimidazolinyl such as N-methylimidazolinyl and the like, tetrahydropyrimidinyl, N-loweralkyltetrahydropyrimidinyl such as N-ethyltetrahydropyrimidinyl, and the like; phenylaminodiazo; substituted phenylarninodiazo such as p-chlorophenylaminodiazo, p-bromophenylaminodiazo, ptolylaminodiazo, and the like; substituted phenyldiazo such as hydroxyphenyldiazo, N,N-dimethylaminodiazo, and the like.

Furthermore, the symbol R; on the aryl moiety of the nitroimidazole described above represents mercapto, substituted thio such as loweralkylthio, e.g., ethylthio, methylthio, isopropylthio, and the like; cyanothio;

loweralkylcarbamoylthio such as methylthiocarbamoylthio, ethylthiocarbamoylthio, and the like; diloweralkylthiocarbamoylthio such as N,N- dimethylthiocarbamoylthio, N,N-diethylthi0.car-

bamoylthio, and the like; thiocarbamoylthio; loweral' koxythiocarbonylthio such as methoxythiocarbonylthio, ethoxythiocarbonylthio, and the like; pyrrolidinothiocarbonylthio, morpholinothiocarbonylthio, and the like.

R also represents a loweralkylsulfonyl such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, and the like; loweralkyl sulfoxyl such as methylsulfoxyl, ethylsulfoxyl, and the like; sulfinyl; sulfonyl; sulfonamido; substituted sulfonamido such as N-methylsulfonamido, N-ethylsulfonamido, N,N-di-n-propylsulfonamido, morpholinosulfonyl, piperidinosulfonyl, pyrrolidinosulfonyl, and the like; phenylsulfonamido; substituted phenylsulfonarnido such as p-chlorophenylsulfonamido, p-nitrophenylsulfonamido, p-tolylsulfonamido, and the like.

The groups in the definition of R as set out earlier correspond with some of the substituents represented by the symbol R The above detailed description of the R substituents is applicable to the corresponding groups represented by R It should be understood that the l-unsubstituted nitroimidazoles discussed herein are compounds in which the nitro substituent is at either the 4 or 5 position on the imidazole nucleus. The hydrogen atom on a nitrogen in the imidazole ring is in the state of tautometric equilibrium and the result is an imidazole in which the 4 and 5 positions are equivalent. For convenience, these compounds are herein designated 4- nitroimidazoles.

In accordance with this invention, one method for preparing the novel l-loweralkyl-Z-aryl-S- nitroimidazoles described herein is depicted in the following flow diagram. R R and R are as hereinabove defined and R is loweralkyl.

Additional variations of the compounds set forth in the above Flow Diagram are represented by the formu- R4 N R2,,

where R represents hydrogen, nitro, halo, carboxamido,

sulfonamido or loweralkoxy; and a R represents hydrogen, loweralkyl, carboxy, phenyl, halo, hydroxy, amino, loweralkylamino, diloweralkylamino, nitro, sulfonamido, loweralkylsulfonamido, diloweralkylsulfonamido, loweralkoyl, loweralkylthio, cyano, carboxamido, loweralkylcarboxamido, diloweralkylcarboxamido, loweralkanoyl, loweralkanoylaminoloweralkyl, loweralkylaminoloweralkyl, diloweralkylaminoloweralkyl, N morpholinoloweralkyl, N'-piperidinoloweralkyl, N '-pyrrolidinoloweralkyl, hydroxyloweralkyl loweralkoxyiminocarbonyl, amidino, loweralkylamidino, diloweralkylamidino, carboxhydrazido, loweralkoxycarbonyl or loweralkylsulfonyl; and

R and R represent hydrogen or nitro, provided one and only one of R and R is nitro;

R is loweralkyl.

Further compounds which may be prepared in the above manner are those compounds having the formu- N J s OgN where R represents hydrogen, loweralkyl, carboxy, phenyl, halo, hydroxy, amino, loweralkylamino, diloweralkylamino, nitro, sulfonamido, loweralkylsulfonamido, diloweralkylsulfonamido, loweralkoxy, loweralkylthio, cyano, carboxamido, loweralkylcarboxarnido, diloweralkylcarboxamido, loweralkanoyl, loweralkanoylaminoloweralkyl, loweralkylaminoloweralkyl, diloweralkylaminoloweralkyl, N'- morpholinoloweralkyl, N'-piperidinoloweralkyl, N'-pyrrolidinoloweralkyl, hydroxyloweralkyl, loweralkoxyiminocarbonyl, amidino, loweralkylamidino, diloweralkylamidino, carboxhydrazido, loweralkoxycarbonyl or loweralkylsulfonyl.

An important feature of the present invention is concerned with the manner of nitrating the 2-aryl imidazole starting compounds. Selective introduction of a nitro substituent on to the imidazole moiety and substantial elimination of aryl radical nitration is usually desired. Certain reactants and reaction conditions have been found desirable in nitrating the starting compounds in the manner preferred. When nitration of a 2-aryl imidazole is carried out on a compound having an electronegative group on the aryl moiety thereof, it has been found that the use of a slight excess of concentrated nitric acid in sulfuric acid solvent affords a compound substituted only on the imidazole ring. For example, nitration using sulfuric and nitric acids produces a nitrosubstituted imidazole when a chloro, nitro or carboxamido substituent is affixed to the aryl radical of the starting aryl imidazole. Depending upon the particular reactants employed, reaction temperatures of the nitration may vary from about room temperature to a temperature as high as the reflux temperature of the acid mixture (about 150160 C. The reaction is normally completed in less than an hour and a 20 to 30 minute reaction time is often found to be sufficient. Temperature and reaction time are not critical when preparing these compounds according to the method described and it is only generally desirable to heat the reaction mixture in order that the rate of reaction be conveniently increased. When the formation of the desired nitroimidazole is complete, the product may be isolated and purified by known methods such as by filtration, extraction, removal of solvent under reduced pressure and crystallization of the residual heterocyclic compound.

The compounds which may be prepared according to the foregoing nitration procedure may be represented by the formula OzN N L R11 N Rm H where R represents chloro, bromo or nitro; R represents halo, nitro, cyano, formyl, loweralkanoyl, carboxy, loweralkoxycarbonyl,

where R R and NR R are as defined above, loweralkyl sulfonyl, loweralkylsulfoxyl, SO N(R where R is loweralkyl and N(R is pyrrolidino,

piperidino or morpholino; R represents halo, nitro, cyano, formyl, loweralkanoyl, carboxy, loweralkoxycarbonyl,

where Y, R R and NR R are as defined above, loweralkylsulfonyl, loweralkylsulfoxyl, sulfinyl, sulfonyl, SOgN(R1 )2 where R and N(R, are as defined above, and

represents quinolinyl or quinoxalinyl.

When in particular instances it is desired that nitration be etfected on both the aryl and imidazole moieties, concentrated sulfuric acid and concentrated nitric acid are employed. The reaction conditions are similar to those used when nitrating only the imidazole moiety except that at least 2 moles of nitric acid per mole of imidazole is preferably utilized. For example, when 2- 'phenyl imidazole or 2-(4-fluorophenyl)-imidazole is treated with sufficient nitric and sulfuric acids, there is obtained 2-(4'-nitrophenyl)-4-nitroimidazole or 2-(3- nitro-4'-fiuorophenyl)-4-nitroimidazole, respectively.

When a loweralkanoic acid or an anhydride thereof, such as acetic acid, propionic acid, butyric acid, acetic anhydride, propionic anhydride, butyric anhydride and the like is used in place of by acid as reaction medium in the above-described nitration reaction, those compounds, the aryl moiety of which would otherwise be nitrated, are selectively nitrated on the imidazole ring. Accordingly, the above-mentioned organic acids and anhydrides may be utilized when sulfuric acid as nitration solvent permits nitro substitution on the aryl moiety of the Z-aryl imidazole starting compounds. This change in reaction media permits a surprising degree of control over introduction of the nitro substituent to the imidazole ring. Substantially the same reaction conditions as those desired for the sulfuric acid medium are preferred. The tendency of a nitro group to attach to the imidazole rather than the aryl moiety is consequently effectively increased by the use of loweralkyl carboxylic acids or anhydrides thereof as solvents during nitration. It has been found that the organic compounds particularly useful as selective nitration solvents are acetic acid and acetic anhydride.

The compounds which may be prepared according to the above nitration procedure in which a lower alkanoic acid or a lower alkanoic anhydride is used as reaction medium may be represented by the formula O2N- N i-R2o m I AITRZI 11; TR

where Ar represents phenyl or naphthyl; R is hydrogen, chloro, bromo, nitro, loweralkoxy or loweralkyl;

R represents hydrogen, halo, nitro, cyano, loweralkoxy, loweralkyl, formyl, loweralkanoyl, carboxy, loweralkoxycarbonyl,

where I p R and N(R19) are as defined above, substituted amino wherein the substituent is loweralkanoyl, L- benzoyl where v L is as defined above, loweralkylsulfonyl, loweralkylpreferably nitronium tetrafluoborate, are useful for this sulfoxyl, purpose. The use of an inert solvent to bring the SO N(R where imidazole into solution is preferred. Solvents such as R, and N(R are as defined above; acetonitrile, chloroform, nitromethane, R represents 5 dichloroethane, tetramethylenesulfone and the like are hydrogen, halo, nitro, cyano, loweralkoxy, subsuitable for this purpose. The nitration may be constituted loweralkoxy wherein the substituent is carducted at temperatures between about 0 C. and room bamoyl, loweralkylcarbamoyl, or O( CH ),,T temperature and above, preferable at about -20 C. where The general formula below represents those com- T is halo and n is 2-4, loweralkyl, pounds which are preparable according to the nitronisubstituted loweralkyl wherein the substituent is um salt nitration procedure discussed above.

loweralkanoylamino, loweralkanoyl, hydroxy,

0 R2 "1N(Ri J 5 where Ar represents where phenyl or naphthyl;

R and N(R,,,) are as defined above, 20 R is L-benzoylamino where L is as defined above, hydrogen, chloro, bromo, nitro or loweralkyl;

formyl, R represents loweralkanoyl, hydrogen, halo, nitro, cyano,

diloweralkanoyloxymethyl, 25 loweralkyl,

carboxy, formyl,

loweralkoxycarbonyl, loweralkanoyl,

carboxy, o loweralkoxycarbonyl, %N(Rm)z II where C NRBRT R and N(R are as defined above, phenyl, substituted phenyl wherein the substituent is as 5 where defined above, R R and NR R are as defined above, substituted substituted amino wherein the substituent is amino wherein the substituent is loweralkanoyl or diloweralkyl, loweralkanoyl, haloloweralkanoyl, L-benzoyl where L is as defined above, loweralkyl- L-benzoyl where sulfonyl, loweralkylsulfoxyl, L is as defined above, substituted thio wherein the SO N(R where substituent is loweralkyl, loweralkysulfonyl, R is loweralkyl and N(R is pyrrolidino, loweralkylsulfoxyl, sulfinyl, sulfonyl, piperidino or morpholino; SO N(R where R represents R and N(R are as defined above, phosphonyl, hydrogen, halo, nitro, cyano, loweralkoxy, loweral- CH CH] where kyl,

J is as defined above; and substituted loweralkyl wherein the substituent is loweralkanoylamino, loweralkanoyl, halo, cyano, carboxy, NR R 5 where R R and NR R are as defined above,

formyl,

represents tetrahydronaphthyl, indanyl, indenyl, quinloweralkanoyl, olinyl or quinoxalinyl. diloweralkanoyloxymethyl,

According to an additional aspect of the invention, carboxy, nitronium perchlorate and certain nitronium metal loweralkoxycarbonyl fluorides have been found useful as nitrating agents in that they too cause nitro addition on the imidazole M moiety in preference to the aryl ring. Nitronium salts comprising anions in a high oxidation state such as nitronium tetrafluoborate, nitronium hexafluorophosphate, nitronium hexafluoroarsenate, where nitronium hexafluorosilicate, nitronium hexafluoroan- M is O or S and R R and NR R are as defined timonate, nitronium perchlorate and the like, above,

phenyl,

substituted phenyl wherein the substituent is halo,

nitro, carboxamido or cyano, substituted amino wherein the substituent is loweralkanoyl, haloloweralkanoyl, L-benzoyl where L is as defined above, substituted thio wherein the substituent is loweralkyl, loweralkylsulfonyl, loweralkylsulfoxyl, sulfinyl, sulfonyl, SO N(R where R is loweralkyl and N(R is pyrrolidino,

piperidino or morpholino, phosphonyl, CH CH] where J is as defined above, thienyl, fury]; and

represents tetrahydronaphthyl, indanyl, indenyl, quinolinyl or quinoxalinyl.

As illustrative of the compounds which may be prepared according to the foregoing nitration procedures, there may be mentioned 2-(4-chlorophenyl )-4-nitroimidazole, 2-( 2 '-(3 -nitrophenyl)-4- nitroimidazole, 2-(3,5'-dinitrophenyl)-4- nitroimidazole, 2-(4'-fluorophenyl)-4-nitroimidazole, N',N-dimethyl-2-(4'-carboxamidophenyl)-4- nitroimidazole, 2-(4'-nitrophenyl)-4-nitroimidazole, 2- phenyl-4-nitroimidazole, 2-( 2 ,4'-dichlorophenyl )-4- nitroimidazole, 2-( 3 '-nitro-4 -chlorophenyl )-4- nitroimidazole, 2-(2'-nitroimidazole, 4-nitroimidazole, 2-( 3 -nitrophenyl )-4-nitroimidazole, N ,N-dimethyl-2- (4-sulfonamidophenyl)-4-nitroimidazole, 2-(4'- acetylphenyl )-4-nitroimidazole, 2-( 3 -cyanophenyl )-4- nitroimidazole and 2-(2'-ethoxycarbonylphenyl)-4- nitroimidazole.

Certain of the compounds of the present invention lsubstituted at the l-position on the imidazole moiety with a loweralkyl group by alkylating the l-unsubstituted imidazoles with agents found useful for this purpose. Alkyl sulfates, preferably loweralkyl sulfates such as dimethyl sulfate, diethyl sulfate and the like, alkyl sulfonates, preferably loweralkyl sulfonates such as methyl benzenesulfonate, ethyl toluenesulfonate, methyl ethanesulfonate, and the like, and diazoalkanes, preferably diazoloweralkanes such as diazomethane, diazoethane and the like may be used in this regard. When preparation of l-substituted-Z-aryl-S- nitroimidazoles rather than l-substituted-2-aryl-4- nitroimidazoles is desired using these reactants, the conditions under which the reaction is run is critical. It has now been found that l-substituted-Z-aryl-S- nitroimidazoles may be prepared in substantial yields with the above reagents only when the reaction medium is substantially neutral or acidic. Accordingly, when dimethylsulfate is utilized to methylate 2-(2- nitrophenyl)-4-nitroimidazole, the reaction is conducted under neutral conditions in order that the 5- nitroimidazole be obtained. The alkylation reactions using alkyl sulfate or alkyl sulfonate are generally conducted at temperatures of from about 100200 C., either with or in the absence of solvent.

When solvent is used during alkylation with alkyl sulfonate, the solvent is preferably inert with respect to the particular reactants employed. Typical examples of 'solvents useful for such alkylation reactions are loweralkanoic acids such as formic acid, acetic acid and the like, or mixed solvents such as loweralkanoic acid and dimethylformamide and the like.

When a loweralkyl sulfate or loweralkyl sulfonate is employed to obtain l-loweralkyl-2-aryl-4- nitroimidazole, the reaction is run under basic conditions. The same considerations apply also when the substituent at the l-position is to be other than loweralkyl, e.g. hydroxyloweralkyl, loweralkoxyalkyl. Inasmuch as the l-substituted-2-aryl-5-nitroimidazoles of this invention display somewhat greater parisiticidal properties than the corresponding l-substituted-Z-aryl- 4-nitroimidazoles, a choice of reaction'conditions is an important aspect of this invention.

The l-loweralkyl-2-aryl-nitroimidazoles which may be prepared according to the above-described alkylation processes have the general formulas Ar is as previously defined;

R is loweralkyl;

R is hydrogen, chloro, bromo, nitro, loweralkoxy or loweralkyl;

R is hydrogen, halo, nitro, cyano, loweralkoxy,

loweralkyl, formyl, loweralkanoyl, loweralkoxycarbonyl,

R,,, R and NR R are as defined above, substituted amino wherein the substituent is loweralkanoyl, L- benzoyl where L is as defined above loweralkylsulfonyl,

SO2N(R19)2 Where R19 and N(R are as defined above; R23 is hydrogen, halo, nitro, cyano, loweralkoxy, substituted loweralkoxy wherein the substituent is carbamoyl, loweralkylcarbamoyl or O(CH ),,T where T is halo and n is 24, loweralkyl, substituted loweralkyl wherein the substituent is loweralkanoylamino, loweralkanoyl, hydroxy, halo,

cyano,

where.

"R R and NR R are as defined above, L-

benzoylamino where L is as defined above, formyl, loweralkanoyl, diloweralkanoyloxymethyl,

loweralkoxycarbonyl,

where R R and NR,,R are as defined above, phenyl,

substituted phenyl wherein the substituent is as defined above, substituted amino wherein the substituent is loweralkanoyl, haloloweralkanoyl, forrnyl, L-benzoyl where L is as defined above, carbamoyl', substituted thio wherein the substituent is loweralkyl,

loweralkoxythiocarbonyl,

where R and N(R are as defined above, loweralkylsulfonyl, loweralkylsulfoxyl, SO N(R, where R and N(R are as defined above, CH CH] where J is as defined above, thienyl, furyl; R is chloro,

bromo, loweralkyl, loweralkoxy or nitro;

' R represents hydrogen, halo, nitro, cyano, loweralkoxy, loweralkyl, formyl,

loweralkanoyl,

loweralkoxycarbonyl,

4 C-NRaRq where T and n are as defined above, cyanato, loweralkyl, substituted loweralkyl wherein the substituent is loweralkanoylamino, loweralkanoyl, hydroxy, a yano, QRW

- NR R -0 "J-NR,R,

where Y, R,,, R and W, are as defined above, L-

benzoylamino or L-phenoxycarbonyl where L is as defined above,

formyl, loweralkanoyl, diloweralkanoyloxymethyl, loweralkoxycarbonyl,

- N um,

where Y, R R and NR R are as defined above, phenyl, substituted phenyl wherein the substituent is as defined above, amino, substituted amino wherein the substituent is loweralkyl, diloweralkyl, loweralkanoyl, haloloweralkanoyl, formyl, L-benzoyl where L is as defined above, carbamoyl or cyano,

NH(oHz),-iiNmR where j, R R and NR R are as defined above, substituted thio wherein the substituent is loweralkyl, cyano, loweralkoxythiocarbonyl,

i CN(Riv)2 where R and N(R, are as defined above, loweralkylsulfonyl, loweralkylsulfoxyl, phosphondiamido, CI-[ CHJ where J is as defined above, thienyl, furyl, substituted diazo wherein the substituent is A-phenylamino where A is as defined above, D-phenylarnino where D is as defined above; and

T-Rzo 3TB. AFT-R27 and AlTRao R -R J 28 J 31 represent tetrahydronaphthyl, indanyl, or indenyl.

It has also now been discovered that 1-loweralkyl-2- aryl-S-nitroimidazoles are prepared in neutral medium from l-unsubstituted -2-aryl-4-nitroimidazoles when diazoalkane, preferably lower diazoalkane such as diazomethane, diazoethane and the like is used as alkylating agent. The reagent may be dissolved in inert organic solvent such as ethers, for example diethyl ester, 1,2-dimethoxyethane, tetrahydrofuran and the like, hydrocarbons such as benzene, toluene, xylene and the like, halogenated hydrocarbons such as chloroform and the like, and lower alkanols such as represent represent tetrahydronaphthyl, indanyl, or indenyl.

The l-loweralkoxyloweralkyl or l-hydroxyloweralkyl-2-aryl-5-nitroimidazoles defined by Formula (I) above may be prepared by reacting a 2-aryl-4- nitroimidazole and an appropriately substituted aryl sulfonate such as a loweralkoxyloweralkyl toluene sulfonate or the like at moderate temperature, preferably about 150 C. to about 200 C. Loweralkoxyloweralkyl sulfates are also useful reagents in this regard. Standard extraction methods may then be utilized to obtain the 1 -lowera.lkoxylowera1kyl-2-aryl-5-nitroimidazole. Hydrolysis of the 1-loweralkoxyloweralkyl-2-aryl-5- nitroimidazoles by treatment, for example, with a strong mineral oil acid such as sulfuric acid converts that compound to the corresponding l-hydroxyloweralkyl-Snitroimidazole. The l-substituted-Z-aryl- 4-nitroimidazoles are obtained when the reaction medium is basic. As illustrative of the aryl sulfonates useful in the above reaction, there may be mentioned methoxyethyltoluenesulfonate, ethoxyethyltoluenesulfonate, propoxyethyltoluenesulfonate, ethoxypropylbenzenesulfonate and the like, whereas among the loweralkoxyloweralkyl sulfates useful as reagents in the above-described process, there may be mentioned di(ethoxyethyl)-sulfate, di(ethoxypropyl)sulfate, di(methoxyethyl)sulfate and the like. Loweralkoxydiazoloweralkanes such as methoxydiazoethane, ethoxydiazoethane and the like are also useful in preparing the l-loweralkoxyloweralkyl and l-hydroxyloweralkyl-2-aryl-5-nitroimidazole in accordance with the above-described process.

The compounds prepared according to the lower-alkoxyalkylation and hydroxyalkylation I processes described above may be represented by the formulae Rai -Ru N l ArTRss OzN If TRau l ArTRas --R36 III J Ras substituted thio wherein the substituent is loweralkyl,

loweralkylsulfonyl, loweralkylsulfoxyl, SO2N(R19)2 Where R and N(R are as defined above; and

-Ral ATTR35 ao represents tetrahydronaphthyl, indanyl, indenyl, quinolinyl or quinoxalinyl.

As illustrative of some specific compounds which may be prepared according to the processes described above, there may be mentioned: l-(2- chloroethyl)-2-(4-chlorophenyl)-5- nitroimidazole, 1-(2-hydroxyethyl)-2-(4'- nitrophenyl )-5-nitroimidazole, 1 2 '-chloroethyl 2-phenyl-5 -nitroimidazole, 1-( 3 -hydroxypr0pyl)- 2-( 3 '-methylthiophenyl )-4-nitroimidazole, l-( 2 bromoethyl)-2-(biphenylyl)-5-nitroimidazole, l- 2 '-hydroxyethyl )-2-( 3 ',4'-dichlorophenyl )-5- nitroimidazole, l-(2'-fluoroethyl)-2-(4- fluorophenyl)-5-nitroimidazole, l-(2-hydroxyethyl)-2-(3 '-tolyl)-5-nitroimidazole, 1-(2'- hydroxyethyl )-2-( 2 '-nitrophenyl )-4- nitroimidazole, 1-(2-fluoroethyl)-2-(3-eth0xycarbonylphenyl)-5-nitroimidazole, 1-(2-hydroxyethy1)-2-(4 '-methylsulfonylphenyl )-5- nitroimidazole, l-(2'-chloroethyl)-2-(4-acetylaminomethylphenyl )-5-nitroimidazole, 1 2 chloroethyl)-2-(4'-carboxyphenyl)-5- nitroimidazole and l-(2-hydroxyethyl)-2-(3-formylphenyl)- 4-nitroimidazole.

The 1-hydroxyalkyl-2-aryl-4-nitroimidazoles are also obtainable from the corresponding l-unsubstituted-2- aryl-nitroimidazoles under basic conditions by use of a loweralkylene oxide as a reactant. This product is obtained when the reaction is conducted at a temperature of about 0-l 00 C., but temperatures from about room temperature to about 50 C. are more convenient and are accordingly preferred.

This reaction is carried out in solvent and water and organic solvents such as aromatic hydrocarbons, ethers, loweralkanols, dimethylformarnide and the like may be used. Any base strong enough to form a salt with the nitroimidazole would be adequate and basic alkali metal and alkaline earth metal salts such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydride and the like in particular are useful in the process.

The nitroirnidazoles prepared according to this hydroxyalkylation process have the formula OZN f AT+R39 Ll T where Ar and R are as previously defined; R is (Cl-l ),,OH where n is 2-4, (CH )BC,,( CHQ H where dis 1-2,Bis Oor H OH and e is 1-4; R represents hydrogen, halo, nitro, cyano, loweralkoxy, loweralkyl,

formyl, loweralkanoyl, loweralkoxycarbonyl,

ll C--N Rm where where Y, R R and NR R are as defined above, cyanato, loweralkyl,

the substituent is hydroxy,

substituted loweralkyl wherein loweralkanoylamino; loweralkanoyl, halo, cyano, NR R where Y, R,;, R and W, are as defined above,

L-benzoylamino or L-phenoxycarbonyl where L is as defined above,

formyl,

loweralkanoyl,

diloweralkanoyloxymethyl,

loweralkoxycarbonyl,

where M, R,, R and W, are as defined above, imidazolinyl, N-loweralkylimidazolinyl, tetrahydropyrimidinyl, N-loweralkyltetrahydropyrimidinyl,

where R and R are hydrogen, loweralkyl, phenylloweralkyl or phenyl, phenyl,

substituted phenyl wherein the substituent is as defined above,

substituted amino wherein the substituent is diloweralkyl, loweralkanoyl, haloloweralkanoyl, formyl, carbamoyl or L-benzoyl where L is as defined above, 15

Nmoumt l-Nmn,

where j, R,,, R and NR R are as defined above, substituted thio wherein the substituent is loweralkyl, cyano, loweralkoxythio carbonyl,

s I NRR1 where R R and NRQR'] are as defined above,

11m a r):

where each R is hydrogen or loweralkyl, loweralkylsulfonyl,

loweralkylsulfoxyl, v p 40 SO2N(R19)2 Where V R and N(R are as defined above, phosphondiarnido, I v ,CH CHJ where 1 l J is as defined above, thienyl, furyl, substituted diazowherein the substituent is A-phenylamino where A is as defined above; and

The l-unsubstituted nitroimidazoles are, by virtue of this invention, converted to the corresponding 1- loweralkoxycarbonylloweralkyl nitroimidazoles by treating the former with an appropriate diazo compound such as ethyldiazoacetate, methyldiazoacetate and the like, The reaction is preferably carried out at l00200 C. in the presence of a catalyst such as copper and the like.

These products are obtainable also from the l-unsubstituted nitroimidazole by treatment with a l-loweralkoxycarbonylloweralkyl halide in the presence of a strong base such as an alkali metal hydroxide or hydride, e.g. sodium hydride, sodium hydroxide, and the like. The product obtained, namely the l-loweralkoxy-carbonylloweralkyl-Z-aryl nitroimidiazole, may then be converted to the corresponding l-carboxyloweralkyl-2-aryl-nitroimidazole by hydrolysis with, for example, strong base in alcoholic solution, conveniently at ambient temperature. The l-carboxyloweralkyl derivative is converted to the acid halide by treatment, for example, with oxalyl chloride; the acid halide is then converted to a l-carboxamidoloweralkyl-Z-aryl-S-nitroimidazole by treatment with ammonia or an appropriate primary or secondary amine, e.g. ethyl amine, dimethyl amine, piperidine, pyrrolidine, morpholine, and the like. The l-carboxamidoloweralkyl-2-aryl-nitroimidazoles provide the corresponding l-cyanoloweralkyl derivative by treatment with a thionyl halide such as thionyl chloride at temperatures of from about 50-200 C. and neutralizing the cooled reaction mixture.

A haloalkyl group such as chloroethyl, 3- bromopropyl, and the like may be added to the l-unsubstituted nitroimidazole at the 1-position by treatment with a diazohaloloweralkane, in accordance with the procedure earlier described. The phenylloweralkyl or substituted phenylloweralkyl derivative is obtainable in much the same way by treating the l-unsubstituted nitroimidazole with phenyldiazoloweralkane or a substituted phenyldiazoloweralkane. In this way, the 1- position may be substituted with such groups as benzyl, phenethyl, chlorobenzyl, fluorobenzyl, ethylbenzyl, and the like' A ketone moiety is substituted on the l-position by treating the 2-aryl-4-nitroimidazole with a diazoketone such as diazoacetone, l-diazo-Z-butanone and the like. The resulting loweralkanone is converted to the corresponding alcohol function by treating the nitroimidazole with an alkali metal borohydride such as sodium borohydride in solvent such as a loweralkanol, e.g. ethanol.

An aminoloweralkyl group is added to the 1-position on the 1-hydroxyloweralkyl-2-aryl-4-nitroimidazoles by treating the latter, preferably at l to 20 C., with an aryl or alkyl sulfonyl halide such as p-toluene sulfonyl chloride, benzene sulfonyl chloride, or methane sulfonyl chloride and the like, and treating the resulting sulfonate ester, preferably at 50150 C., with ammonia or an appropriate amine such as ethylamine, dimethylamine, diethylamine, morpholine, piperidine or pyrrolidine, and the like. The above sulfonate ester is also convertible to the l-loweralkylthioloweralkyl nitroimidazole by treatment with an alkali metal salt of a loweralkanethiol such as methanethiol, ethanethiol, n-propanethiol, and the like. The sulfonate ester above mentioned is also converted to the corresponding 1- loweralkylsulfonylloweralkyl nitro-imidazole by treatment at about 50-150C. with an alkali metal sulfinate such as sodium methylsulfinate, potassium ethylsulfinate, sodium isopropylsulfinate, and the like. The corresponding l-loweralkylsulfinylloweralkyl nitroimidazole is obtained by oxidizing the earlier described 1-loweralkylthioloweralkyl nitroimidazole with a mild reducing agent such as monoperphthalic acid, nitrogen tetroxide, hydrogen peroxide, and the like.

The l-unsubstituted 2-aryl-nitroimidazoles of this invention are converted to the corresponding l-loweralkenyl derivatives by treatment with an alkenylsulfate or an alkenyl sulfonate in the manner and under the conditions earlier described for alkylating with an alkyl sulfate or sulfonate.

When a l-hydroxyloweralkyl-2-aryl imidazole is treated according to this invention with an aryl haloformate such as phenyl chloroformate and the resulting laryloxycarbonyloxyloweralkyl-2-aryl nitroimidazole is treated with ammonia or an appropriate primary or secondary amine, the corresponding l-carbamoyloxyloweralkyl-2-aryl-nitroimidazole is obtained. The lhydroxyloweralkyl starting material is also converted to the corresponding l-haloloweral kyl-2-arylnitroimidazole by treatment with a thionyl halide and it is converted also to the l-formylloweralkyl-Z-arylnitroimidazole by treatment with a dicycloalkylcarbodiimide such as dicyclohexylcarbodiimide in the presence of dimethyl sulfoxide and an acid catalyst such as trifluoroacetic acid or ortho-phosphoric acid. The above-mentioned 1-haloloweralkyl-2-arylnitroimidazole, when treated with an alkali metal tertiary butoxide such as sodium tertiary butoxide or potassium tertiary butoxide, provides the corresponding 1- alkenyl-2-aryl-nitroimidazole.

In accordance with the present invention, there are prepared 2-aminoaryl nitroimidazoles of the formula where Ar, R and R are as previously defined; R represents hydrogen, halo, nitro, cyano, hydroxy, loweralkoxy, substituted loweralkoxy wherein the substituent is thiocarbamoyl or O(CH ),,T where T and n are as defined above, loweralkyl, substituted loweralkyl wherein the substituent is carboxy, or NR R where R R and NR R are as defined above, formyl, loweralkanoyl, carboxy, phenyl, substituted phenyl wherein the substituent is halo or nitro, amino, substituted amino wherein the substituent is loweralkyl, diloweralkyl, loweralkanoyl, haloloweralkanoyl, L-benzoyl where L is as defined above, substituted thio wherein the substituent is loweralkyl, loweralkylsulfonyl, loweralkylsulfoxyl, SO NR R where R R and NR R are as defined above, L-phenylsulfonamido where L is as defined above; R represents hydrogen, halo, nitro, cyano, hydroxy, loweralkoxy, substituted loweralkoxy wherein the substituent is -O(CH ),,T where T and n are as defined above,

loweralkyl, substituted loweralkyl wherein the substituent is loweralkanoylamino, loweralkanoyl, hydroxy, halo, carboxy, NR R ll -C-NR5R1 where R R and NR R are as defined above, L-benzoylamino where L is as defined above,

formyl, loweralkanoyl, carboxy, loweralkoxycarbonyl,

I i) N R 5 R7 where R R and NR R are as defined above,

where R is hydrogen, loweralkyl, phenylloweralkyl or phenphenyl,

substituted phenyl wherein the substituent is halo or nitro,

amino,

substituted amino wherein the substituent is loweralkyl, diloweralkyl, loweralkanoyl, L-benzoyl where L is as defined above,

where j, R R and NR R are as defined above, guanidino, mercapto, substituted thio wherein the substituent is loweralkyl, loweralkylsulfonyl, loweralkylsulfoxyl, sulfinyl, sulfonyl, SO NR R where R R and NR R are as defined above,

, L-phenylsulfonamido where L is as defined above, phosphonyl, -CH CHJ where J is bromo or chloro; and R represents hydrogen, loweralkyl, substituted loweralkyl wherein the substituent is carboxy or Z- phenyl where Z represents hydrogen, nitro, halo, or loweralkyl or loweralkoxy,

formylalkyl, wherein alkyl has one to three carbon atoms, (CH ),,X' where n is as defined above and X is halo, hydroxy, loweralkoxy, loweralkylthio, loweralkylsulfonyl, loweralkylsulfinyl, or NR6R7 wherein R R and NR R are as defined above, (CH ),,,CH CH(CH ),,,H wherein m is as defined above, or (CH )BC (CH l-l where dis [-2, Bis Oor and e is 1-4.

When the preparation of a l-unsubstituted 2- (aminoaryl)-4-nitroimidazole of formula (H) is undertaken, it is obtained from a corresponding 2- (nitroaryl)-4-nitroimidazole by treatment with hydrogen sulfide and ammonia. The reaction temperature is not critical but a reaction temperature above about 50 C. is preferred to reduce reaction time. The reaction mixture is then acidified by convenient means preferably by addition of a strong mineral acid such as hydrochloric acid. The sulfur precipitate is then removed by filtration and the product is extracted by conventional means such as by use of inert organic solvent such as ethyl acetate. When this product is then to be substituted at the l-position, the amino group is acylated by use of a loweralkanoic acid or anhydride. The l-substituted -2-(aminoaryl)-nitroimidazole is then conveniently obtained by hydrolyzing the acylated aminoaryl compound with a mineral acid such as hydrochloric acid. The l-substituted and l-unsubstituted -2-aminoaryl nitroimidazoles of Formula (II) above are particularly valuable as intermediates in the preparation of additional novel active nitroimidazoles, as will be seen from the following discussion.

The Z-aminoaryl-nitroimidazole is, according to this invention, converted to a corresponding 2-cyanoaryl nitroimidazole by diazotization, preferably at Ol0 C. by use of sodium nitrate and treatment of the resulting 2-diazonium aryl nitroimidazole salt with a cyanide salt. This 2-cyanoaryl nitroimidazole is converted to the corresponding thiocarbamoylaryl nitroimidazole by treatment with an amide of the formula where R is as defined above. Examples of the amides useful in the above process are thioacetamide, thiopropionamide, and the like. The 2-cyanoaryl nitroimidazole is converted to the carboxamide aryl compound by standing in concentrated sulfuric acid overnight and pouring the mixture into ice water.

The 2-carboxamidoaryl-nitroimidazole which is oh- 5 tained by the above-described procedure is converted to the corresponding 2-cyan0aryl nitroimidazole by treatment with a thionyl halide such as thionyl chloride at a temperature of about 50-200 C., preferably 80l 50bL C.

The 2-diazonium aryl nitroimidazole salt obtainable from the 2-aminoaryl nitroimidazole depicted by Formula (11) above may be converted to the corresponding phenyl or substituted phenyl diazoaryl nitroimidazole by treatment with an appropriate aromatic compound, e.g., phenol or N,N-diloweralkyl aniline. The diazonium salt may also be converted to a 2-phenyl or 2-substituted phenylaminodiazoaryl nitroimidazole by treatment with aniline or a substituted aniline such as pfluoroaniline, o-chloroaniline, p-bromoaniline, pmethylaniline, p-isopropylaniline, and the like.

A 2-haloaryl nitroimidazole is also obtainable from the diazonium salt of the compound of Formula (II) by treatment with phosphorous trihalide and the like in the presence of catalyst such as cuprous bromide and cuprous chloride. When a hydrohalic acid is used in place of the phosphorous trihalide, the corresponding 2-haloaryl nitroimidazole is again prepared. The 2- diazonium aryl nitroimidazole salt is also converted to the 2-chloroethylaryl or 2-bromoethylaryl nitroimidazole by treatment with acetylene, preferably at temperatures between about C. to 50 C. in the presence of cupric halide. This process is also useful in obtaining the 2-furylaryl and Z-thienylaryl nitroimidazoles by replacing acetylene with furan or thiphene, respectively.

When a 2-aminoaryl nitroimidazole of Formula (II) is diazotized and the diazonium salt treated with a phosphorous trihalide, such as phosphorous trichloride, in the presence of catalyst such as cuprous bromide, cuprous chloride, and the like, and the resulting product hydrolyzed, e.g. with water, there is obtained the corresponding phosphonylaryl nitroimidazole. The reaction is preferably conducted at a temperature of 60-l80 C. When the phosphorous trihalide reaction product is treated with ammonium hydroxide, the 2-phosphondiamidoaryl nitroimidazole is obtained.

The Z-aminoaryl nitroimidazole earlier described is converted to the 2-formylarninoaryl nitroimidazole by treatment with formic acid at about 50-100 C. The 2- aminoaryl compound is also converted to the corresponding ureidoarylnitroimidazole by treatment with cyanate salt such as an alkali metal cyanato, e.g. potassium cyanate or sodium cyanate, at 0-l00 C. Said aminoaryl nitroimidazole is also converted to the loweralkanoylaminoaryl or haloloweralkanoylaminoaryl nitroimidazole by treatment with a compound of the formula CX H ,,,(Cl-l ),,COT where T is chloro, fluoro or bromo, n is 2-6 and m is 0-3, e.g. acetylchloride, dichloroacetylchloride, trifluoroacetylchloride, chloroacetylbromide, and the like. The reaction is preferably conducted at l0 to -50 C.

N-Methylated and N,N-dimethylated Z-aminoaryl nitroimidazoles are derived from the 2-aminoaryl compound of Formula (H) by treatment with formic acid and formaldehyde at 50-150 C.

The 2-aminoaryl nitroimidazoles of Formula (H) are converted to the corresponding 2-diloweralkylaminoaryl nitroimidazoles by treatment with a treatment with cyanogen chloride in the presence of triloweralkylamine such as triethylamine and the like. The reaction is preferably carried out at 10C to 30 C.

When the arninoaryl starting compound (II) is treated with a compound of the formula where T is halo, p is 1-5, and NR R and R R are as defined previously, there is obtained the corresponding 2- amino or substituted amino carbonylloweralkylarninaryl nitroimidazole. Temperatures from 20l00 C. are conveniently employed during this reaction.

The Z-guanidinoaryl derivative of a 2-aminoaryl nitroimidazole is obtained either by treatment of the latter with a methylisothiourea salt, such as the sulfate, at temperatures from about 50-200 C. or by treating the 2-arninoaryl nitroimidazole with cyanamide at about 5014 200 C. When dicyandiamide is used in place of cyanamide, the product obtained is the corresponding Z-biguanidoaryl nitroimidazole.

When a 2-cyanoarylnitroimidazole mentioned above is treated with a hydrohalide such as hydrogen chloride, and loweralkanol such as ethanol, the hydrohalic salt of the corresponding 2-loweralkoxyiminocarbonylaryl nitroimidazole is obtained. This compound may be converted to the amidinoaryl derivative by treatment with ammonia or an amine. with an alkali metal loweralkyl xanthate, the corresponding loweralkoxythiocarbonylthioaryl nitroimidazole is obtained. Reactants useful in this process include potassium methyl xanthate, sodium ethyl xanthate, and the like. The reaction is successfully carried out at cold temperatures, preferably at l0-l0 C. The above thiocarbonylthioaryl nitroimidazole may be converted to the corresponding 2-thioaryl nitroimidazole by hydrolysis with alkali metal hydroxide and neutralization with, for example, sulfuric acid.

The 2-thioaryl nitroimidazole may be converted to the corresponding 2-loweralkylthioaryl nitroimidazole by treatment with a loweralkylsulfate or sulfonate in basic medium. The reaction is conveniently carried out at room temperature. This loweralkylthioaryl nitroimidazole may be converted to two kinds of products within the scope of this invention. First, it may be converted to the corresponding loweralkylsulfoxylaryl compound by treatment with substantially a molar equivalent amount of mild oxidizing agent such as hydrogen peroxide, preferably at temperatures below room temperature. Secondly, it is converted to a loweralkylsulfonylaryl nitroimidazole by treatment with a substantial excess of mild oxidizing agent, such as hydrogen peroxide. This process is preferably conducted at about 0 C. to about room temperature. The 2-thioarylnitroimidazole, when treated with halogen such as bromine or chlorine in acidic medium, is converted to the corresponding sulfonyl halide which, when hydrolyzed, such as by treatment with base and strong acid, is converted to the 2-sulfonylaryl nitroimidazole.

According to the present invention, it has now been found that 2-sulfonamidoaryl-4-nitroimidazole is prepared from 2-aryl-4-nitroimidazole by treating the latter with chlorosulfonic acid at a temperature preferablyabove room temperature for a time greater than about 24 hours to get the chlorosulfonylaryl nitroimidazole intermediate. This intermediate is also obtained from the 2-diazoniumaryl nitroimidazole salt by treatment with sulfur dioxide and copper chloride at a temperature preferably of about C. to 100 C. The chlorosulfonylaryl intermediate is then treated with a source of ammonia, at a temperature of about 30 C. to about 100 C., preferably about 0 C. to about C. to obtain the desired 2-sulfonamidoaryl-4- nitroimidazole. Ammonium hydroxide, anhydrous ammonia and the like, preferably ammonium hydroxide are useful to supply the necessary ammonia. The use of loweralkyl substituted amines, e.g. dimethylamine or secondary amines such as morpholine, in place of an ammonia source give the corresponding 2-substituted sulfonylaminoaryl-4nitroimidazole.

The phenyl or substituted phenylsulfonylaminoarylnitroimidazoles of this invention are prepared bytreating the aminoarylnitroimidazole with a benzenesulfonyl halide or an appropriately substituted benzenesulfonylhalide such as p-toluene sulfonylchloride, ochlorobenzene sulfonylchloride, p-nitrobenzene sulfonylchloride, and the like. The reaction is preferably conducted at temperatures of about 10 to about 10 C. in solvents such as pyridine, dimethyl-formamide and the like. Corresponding loweralkylsulfonylaminoaryl compounds are prepared from the loweralkylsulfonyl halide.

When the above described phenyl or substituted phenyl sulfonylaminoaryl nitroimidazoles are treated with diloweralkylsulfate or halide, the corresponding phenyl or substituted phenyl sulfonyl N-loweralkylaminoarylnitroimidazole is obtained. This reaction is preferably carried out at 50-200C. in the presence of a strong base such as an alkali metal hydroxide. This compound is then converted to the loweralkylaminoaryl nitroimidazole by hydrolysis with strong mineral acid, .e.g. sulfuric acid.

The 2-diazoniumarylnitroimidazole salt discussed above is also converted to the corresponding thiocyanate by treatment with an alkali metal thiocyanate such as potassium or sodium thiocyanate in the presence of cuprous thiocyanate. The reaction is preferably performed below room temperature over a period of several hours.

The diazonium salt is converted to a thiocarbamoylthioarylnitroimidazole or an N-substituted thiocarbamoylthioarylnitroimidazole by treatment with an appropriate alkali metal dithiocarbamate such as sodium dithiocarbamate, potassium dithiocarbamate, sodium-N,N-diethyldithiocarbamate and the like. The reaction is preferably conducted at between 10-10 C.

An additional method for obtaining the thiocarbamoylthioarylnitroimidazoles is by treating a thioaryl nitroimidazole with thiophosgene and treating the intermediate with ammonia or a primary or secondary amine such as ethylamine, dimethylamine, morpholine, piperidine, pyrrolidine, and the like. The preferred reaction temperature is near room temperature for both steps of the reaction but lower temperatures may be used, particularly during the thiophosgene reaction. A still further method for obtaining the loweralkylthiocarbamoylthioarylnitroimidazoles is by treating the corresponding thioarylnitroimidazole with a loweralkylisothiocyanate at about 50-180 C. for about 1-20 hours in a suitable solvent.

The diazonium 2-aryl nitroimidazole salt (usually) the sulfate), a derivative of the 2-aminoarylnitroimidazole of Formula (II) above, is converted to the corresponding 2-hydroxyaryl nitroimidazole by heating an aqueous solution at a temperature above 50 C. and preferably below 200 C. This 2-hydroxyaryl nitroimidazole having the formula (III) where Ar, R and R are as previously defined and the 1-position and the Ar group may be substituted further, is then converted to the loweralkoxyaryl derivative by treatment with the appropriateloweralkylating agent such as diazoloweralkane such as diazomethane, diazoethane, and the like or by treating the sodium salt of the 2-hydroxyaryl derivative with an alkyl sulfate or halide at room temperature. This diazoalkane process is conducted below room temperature and preferably at between 10 to about 10 C. Said hydroxyaryl nitroimidazole of Formula (III) is also converted to the corresponding 2-cyanatoaryl nitroimidazole by treatment with a cyanogen halide such as cyanogen chloride, preferably at temperatures of about -15 to about 15 C. When this 2-cyanatoaryl nitroimidazole is treated with aniline or an aniline substituted with a halo, loweralkyl or nitro group, the corresponding phenyl or substituted phenyl pseudoureidoaryl nitroimidazole is obtained. The reaction is preferably carried out between 0l00 C. The 2-hydroxypseudoureidoaryl nitroimidazole is obtainable from the 2- cyanatoaryl compound by treatment at about -10 to about 15 C. with hydroxylamine.

The 2-hydroxyarylnitroimidazole of Formula (Ill) above is also converted to its corresponding 2-loweralkylcarbamoyloxyary] nitroimidazole by treatment in solvent at less than room temperature, Preferably 10 10 C., with a loweralkylisocyanate. The corresponding thiocarbamoyl compound is obtained by using an appropriate loweralkylisothiocyanate. Said hydroxyaryl nitroimidazole is. converted to a carbamoyl or thiocarbamoylloweralkoxyarylnitroimidazole derivative by treatment with a haloloweralkanoylamide or halothioloweralkyanoylamide such as chloroacetamide and the like at a temperature of about 0100 C. in the presence of a base such as sodium hydroxide.

The 2-carboxyaryl nitroimidazoles of this invention are obtained by treating a corresponding 2-methylaryl nitroimidazole with an oxidizing agent such as an alkali -halogenating agent such as thionylchloride, oxalyl chloride and the like, and treating said carboxylic acid halide with ammonia or the appropriate primary or secondary amide to obtain the corresponding carboxamide. Amines useful in this process include methylamine, dimethylamine, diethylamine, morpholine, piperidine, pyrrolidine, and the like. The halogenating step is performed at temperatures of about 50200 C. whereas the aminating step is con-,

veniently carried out at generally lower temperatures, e.g. room temperature. When hydrazine is used in place of ammonia in the above-described process, the 2-carboxyhydrazidoarylnitroimidazole is obtained.

The 2-carboxamidoarylnitroimidazole described above is converted to the 2-carboxyarylnitroimidazole by hydrolysis with strong acid such as mineral acid, e.g. hydrochloric acid and sulfuric acid, at temperatures above room temperature.

When a methylaryl nitroimidazole is treated with a loweralkanoic anhydride in the presence of the oxidizing agent, chromium oxide, the corresponding 2- diloweralkanoylmethylarylnitroimidazole, is obtained. The reaction is preferably performed at a temperature of 2015 C. This product is then converted to the corresponding formylaryl nitroimidazole by hydrolysis with strong acid, preferably strong mineral acid such as hydrochloric or sulfuric acids. The 2-loweralkanoylaryl and 2-formylaryl nitroimidazoles prepared according to the above described procedures may be represented by the formula where Ar, R R and R are as earlier defined and the 1-position and the aromatic moiety on the nitroimidazole may be further substituted.

The 2-formylaryl and 2-loweralkanoylaryl nitroimidazoles of Formula (IV) are particularly valuable as intermediates in the preparation of additional novel nitroimidazoles of this invention.

Additional compounds of our invention are obtained by reaction of the novel 2-formylaryl or 2-loweralkanoylaryl nitroimidazoles of Formula (IV) with hydroxylamine or alkoxylamine and the substituent on the aryl moiety may be represented by the structural formula where R, above is hydrogen or loweralkyl. These nitroimidazoles are produced by reacting together a 2- forrnylaryl or 2-loweralkanoy1aryl nitroimidazole of Formula (IV) above with hydroxylamine or alkoxylamine. These reagents are normally used in the form of acid addition salts, with the hydrohalide salts, and in particular the hydrochloride being preferred. Formation of the desired product takes place rapidly at temperatures in the range of 40-85C.

An additional type of aldehyde and ketone derivative within the scope of this invention is those having the following group on the aryl moiety:

where R,,, R and R are as defined above and M is oxygen,

sulfur or NH. These compounds are obtained by the reaction of the aldehydes and ketones described in Formula (IV) and a semicarbazide having the formula v where M, R R and NR R are as defined above. The reaction is preferably conducted at about 50"90 C.

A further group of 2-formylaryl and 2-alkanoylaryl nitroimidazole derivatives provided by the present invention are those having the following substituent on the aryl group where R has the same meaning as above and N-R R may be a 5- or 6-membered saturated heterocyclic ring in which the nitrogen is in the ring, while R and R together represent the remainder of the ring. Examples of compounds of this type are those where NR, R represents a morpholinyl, thiarnorpholinyl, piperidyl, piperazinyl, oxazolidinyl or imidazolidinyl ring, which rings may be substituted as with alkyl, or keto radicals. Those compounds where NR R is a 2-oxooxazolidinyl or 24 xo-imidazolidinyl moiety represent preferred embodiments of this aspect of the invention. Alternatively, R and R may be hydrogen, loweralkyl, phenyl, nitrophenyl, halophenyl, thiazolyl, pyridinyl, imidazolyl, thienyl, pyrimidinyl, loweralkanoyl, benzoyl, nitrobenzoyl, halobenzoyl,loweralkoxycarbonyl, thiazolecarbonyl, pyridinecarbonyl, imidazolecarbonyl, thenoyl, or pyrimidinecarbonyl. The reaction for obtaining these compounds is between an aldehyde or ketone and a compound of the formula where R, and R are as described above. The products areobtained in from -60 minutes at temperatures of about -100C. It is preferred to use a moderate excess of the amine reactant,'from 3-25 percent excess being satisfactory, and to carry out the reaction in a solvent such as a loweralkanol or an aqueous alkanol in the presence of a catalytic amount of mineral acid.

The 2-formylaryl nitroimidazoles of Formula (IV) are also converted to the corresponding hydroxymethylaryl nitroimidazole. This as accomplished by treatment with a mild reducing agent such as alkali metal borohydride, e.g. sodium borohydride or potassium borohydride, diborane and the like.

When the 2-hydroxyloweralkylaryl nitroimidazole described above is treated with halogenating agent such as thionyl halide, e.g. thionyl chloride, and then cyanide salt or ion, it is readily converted to the cor responding 2-cyanoloweralkylaryl nitroimidazole. This reaction is conveniently carried out at room temperature. The corresponding carboxamidoloweralkylaryl nitroimidazole is obtained upon hydrolysis with strong mineral acid such as hydrochloric acid, sulfuric acid and the like. Dependingvupon the strength of the acid, the time of hydrolysis and the temperature at which hydrolysis is conducted, the 2-carboxyloweralkylaryl nitroimidazole also is obtained by this process.

The intermediate formed upon treatment of the hydroxyloweralkylaryl nitroimidazole with thionyl halide is the haloloweralkylaryl nitroimidazole. This compound is converted to the aminoloweralkylaryl nitroimidazole by treatment with an alkali metal phthalimide such as potassium phthalimide, and reaction of the product with hydrazine. Both steps of this process may be carried out conveniently at room temperature.

A 2-hydroxyloweralkylaryl nitroimidazole derived from a 2-carboxyloweralkylaryl nitroimidazole is obtainable by treating the latter with a mild reducing agent such as diborane in ether solvent such as tetrahydrofuran or 1,2-dimethoxyethane. The reduction is conveniently carried out at room temperature.

This 2-hydroxyloweralkylaryl nitroimidazole is converted to the corresponding substituted aminoloweralkylaryl nitroimidazole by treannent in solvent with halogenating agent such as thionyl chloride, and the appropriate primary or secondary amine, e.g. ethylamine, diethylamine, morpholine, pyrrolidine, and the like. The temperature of the reaction is preferably maintained at about 0l00 C. This procedure provides nitroimidazole having at the 2-position a substituted loweralkylaryl group, the substituent on the loweralkyl group being represented by the formula where R and N(R are as earlier defined.

The hydroxyloweralkylaryl nitroimidazoles described earlier are converted to nitroimidazoles substituted on the aryl group at the 2-position by a radical represented by the structure where r is loweralkalene, and L and Y areas earlier defined by treating said hydroxyloweralkylaryl nitroimidazole with a phenyl or substituted. phenyl haloformate such as phenylchloroforrnade, p-nitrophenylchloroformade, ochlorophenylchloroformate or a corresponding thioformate, and the like. The reaction is preferably maintained at less than ambient temperature, e.g. -l0-l0 C. This product is in turn converted to the corresponding 2carbamoyloxyloweralkylaryl nitroimidazole or thiocarbarnoyloxyloweralkylaryl nitroimidazole by treatment with ammonia or an appropriate primary or secondary amine, such as ethylamine, dimethylamine, morpholine, pyrrolidine, piperidine or hydroxylamine and the like. The reaction is preferably carried out at a temperature of 20 to 50 C.

When a 2-trifluoromethylaryl nitroimidazole is desired, the compound is preparable from the corresponding 2-carboxyaryl or 2-carboxyloweralkyl compound by treatment with sulfur tetrafluoride in the presence of liquid anhydrous hydrogen fluoride at -200bL C. under pressure (e.g. in an autoclave.) The corresponding 2-trichloromethylaryl nitroimidazole is obtained from the 2-loweralkylaryl compound by treatment with N-chlorosuccinimide in trifluoroacetic acid.

Those 2-aryl imidazoles employed as starting materials in the present invention may be prepared according to synthetic methods presently known in the literature. One method for preparing those compounds involves reaction of an appropriately substituted aromatic nitrile such as benzonitrile with a loweralkanol, and a strong mineral acid. This reaction is preferably conducted at about O10 C. for up to about 14 days depending on the reactants used. The resulting product, a loweralkyl aryl imidate hydrochloride, is then treated with an amino acetaldehyde acetal in a suitable solvent, preferably a loweralkanol such as methanol at temperatures ranging from about 0 C. to room temperature. These temperatures are determined according to the particular reactants used. This reaction may be generally represented as follows:

where Ar R and R are as defined above; R represents hydrogen, halo, nitro, cyano, loweralkoxy, loweralkyl,

i JN1mt where R R and NR R, are as defined above, SO N(R, where R and N(R, are as defined above; and R represents hydrogen, halo, nitro, cyano, loweralkoxy,

loweralkyl,

forrnyl,

loweralkanoyl,

carboxy,

where R R and NR R are as defined above,

phenyl,

substituted amino wherein the substituent is loweralkanoyl, L-benzoyl where L is as defined above, substituted thio wherein the substituent is loweralkyl, loweralkylsulfonyl, loweralkylsulfonyl, SO N(R where R and N(R are as defined above.

The first step in preparing the above compounds involves reaction with a loweralkanol and hydrogen chloride. The reaction is preferably conducted at about 0-10 C. The resulting product is a loweralkyl ocyanoaryl irnidate hydrochloride which is then treated with amino acetal in solvent, preferably a loweralkanol such as methanol. The temperature is not critical but room temperature is preferred. The resulting ocyanoaryl amidine is then converted to the corresponding 2-(o-carboxyaryl) imidazole by treatment with a strong acid, preferably concentrated mineral acid such as sulfuric acid. This product is then nitrated on the imidazole ring using a nitrating agent such as fuming nitric acid in a mineral acid, preferably sulfuric acid. The process conditions are like those previously described for the nitric acid-sulfuric acid nitration. The carboxylic acid on the substituent is then reduced to hydroxymethyl by the use of a selective reducing agent such as diborane. Treatment of the 2-(2-hydroxymethylaryl)-4-nitroimidazole product with a halogenating agent such as thionyl chloride produces a 2-(2-halomethylaryl)-4-nitroimidazole which is then converted to the desired isoindole by heating at about 100 C. to 160 C. for about 130 minutes. Addition of a cyano substituent to the 2-halomethylaryl nitroimidazole intermediate according to procedures established in the art and further treatment according to the method above described produces 2-(2'- haloethylaryl)-4-nitroimidazole which upon cyclization gives a corresponding dihydroisoquinoline.

As illustrative of some of the isoindoles and dihydroisoquinolines preparable according to the above procedure, there may be mentioned 3-nitro-7( or 8 )-fluoroimidazo-[e42, 1 zal-isoindole, 3-nitro-7(or chloroimidazo[2,1:a]-isoindole, 3,7(or 8 dinitroimidazo-[2,1:a]-isoindole, 3-nitroimidazo-[ 2,1 :al isoindole, 3-nitro-7(or 8)-carboxamidoimidazo- [2,1:a]-isoindole, 3-nitro-7(or 8)-formylimidazo-[2,l zal-isoindole, 3-nitro-7(or 8)-methylimidazo-[2,1:a]- isoindole, 3-nitro-7(or 8)-sulfonamidoimidazo-[2,l :a]- isoindole, 3-nitro-5 ,6-dihydroimidazo-[ 2,1 zal-isoquinoline, 3-nitro-5,6-dihydro-8(or 9)-fluoroimidazo-[2,1 :a]-isoquinoline, 3-nitro-5,6-dihydro-8(or 9)- nitroimidazo-[2,1 :a]-isoquinoline and 3-nitro-5 ,6- dihydro-S-(or 9 )-phenylimidazo-[2, 1 :a]-isoquinoline.

The 1-substituted-2-aryl-S-nitroimidazoles, l-substituted-2-aryl-4-nitroimidazoles, and structurally related isoindoles and dihydroisoquinolines of this invention are effective in the control of enterohepatitis in turkeys. For this purpose they may be administered to turkeys mixed with an element of turkey sustenance, e.g. feed or drinking water. Good control of the disease is obtained when the imidazole compounds of the invention are incorporated in a turkey feed ration at levels of from about 0.003 to about 0.1 percent by weight and preferably from about 0.006 to 0.05 percent by weight of the feed. The optimum concentration will depend to a large extent on the age of the birds, the severity of the infection and the particular compound employed. With these feed levels good control of the disease is obtained with no or minimal side effects or growth retardation of the turkeys.

When the poultry feed or poultry ration is employed as carrier for the active compounds of the present invention, it is desired that the drug be uniformly mixed throughout the feed. This may be accomplished by first preparing a premix or feed supplement composition wherein the active ingredient is present in concentrations of from about 1 to about 50 percent by weight and wherein the carrier or diluent is a nontoxic orally ingestible carrier. It is preferred that the carrier be a nutritive one, for example corn distillers dried grains, corn gluten feed, corn cob meal, edible vegetable substances, condensed fish solubles, brewers yeast, whey, alfalfa, citrus meal, molasses solubles, soybean mill feed, antibiotic mycelia, toasted dehulled soya flour, soya grits, wheat shorts, wheat middlings, soybean meal, fermentation residues or corn meal. The supplements or premixes are then intimately and uniformly mixed with the remainder of the poultry ration by conventional techniques such as grinding or milling.

When the active compounds are administered by way of drinking water of the poultry which method is preferred when the birds are severely infected (the birds will normally continue to drink after they have stopped eating solid food), somewhat higher dose levels are employed than when administered with solid feed. The quantities of active agent which are useful are those in which from about 0.01 to about 0.1 percent by weight of water are utilized. Some of the nitroimidazoles of the invention are not highly water soluble and when such compounds are added to drinking water it is desirable that suspending or emulsifying

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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US5380865 *Jan 8, 1993Jan 10, 1995May & Baker LimitedHalogen substituents
US5616601 *Jun 5, 1995Apr 1, 1997Gd Searle & Co1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation
US6355665Jul 14, 1998Mar 12, 2002James Black Foundation Limited1H-4(5)-substituted imidazole derivatives, their preparation and their use as histamine H3 receptor ligands
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Classifications
U.S. Classification548/329.5, 544/133, 544/370, 544/60, 544/122, 544/58.5, 544/59, 534/560, 540/578, 544/58.6, 544/139, 544/131, 544/353, 548/119, 544/124
International ClassificationC07D233/92, C07D233/93, C07D233/95, C07D233/54
Cooperative ClassificationC07D233/64, C07D233/92, C07D233/95, C07D233/93
European ClassificationC07D233/92, C07D233/95, C07D233/93, C07D233/64