4,5-Dihydro-4-oxo-2- [(2-trans-phenylcyclopropyl)amino]-3-furancarboxylic acids and derivatives thereof

Abstract: 4,5-dihydro-4-oxo-2-[(2- trans -phenylcyclopropyl)amino]- 3-furancarboxylic acids and derivatives are described.

Description: Background of the Invention This invention relates generally to 2-[(N-substituted) amino]-4,5-dihydro-4-oxo-3-furancarboxylic acids and more specifically to 4,5-dihydro-4-oxo-2-[(2- trans -phenylcyclopropyl) amino]-3-furancarboxylic acids and derivatives thereof. A series of 2-[(N-substituted)amino]-4,5-dihydro-4-oxo-3- furancarboxylic acids and their ethyl esters have been described in the literature, for example by Capuano et al in Chem. Ber. 109 , pp. 212-217 (1976). We have found that some of these compounds possess anti-inflammatory activity in the carrageenan-induced rat paw edema assay, but no antimicrobial activity. We have now prepared new 2-[(N-substituted)amino]- 4,5-dihydro-4-oxo-3-furancarboxylic acid derivatives which contain the ( trans -phenlycyclopropyl)amino moiety. The new compounds show antimicrobial activity against a variety of bacteria. Summary of the Invention In accordance with this invention there are provided 4,5- dihydro-4-oxo-2-[(2- trans -phenylcyclopropyl)amino]-3- furancarboxylic acids or derivatives thereof having the general formula: Where R is selected from hydroxy, lower alkoxy, anilino, and O-alkali metal; and where R¹ is selected from phenyl and substituted phenyl. Detailed Description The compounds of the invention are carboxylic acids and acid derivatives including alkali metal salts of the acid, esters formed from lower alkyl alcohols and amides containing the anilino group wherein the term "anilino" as used herein refers to radicals of aniline and aniline substituted in the phenyl ring with one or more of the following: lower alkyl, halogenated lower alkyl, nitro, halogen, and lower alkoxy. Examples of R¹ in the general formula include phenyl and substituted phenyl wherein the term "substituted phenyl" as used herein refers to phenyl substituted with lower alkyl and/or halogen (chlorine, fluorine, bromine, iodine), preferably chlor The terms "lower alkyl" and "lower alkoxy" as used herein refer to straight and branched chain alkylene groups having 1 to 8 carbon atoms. The compounds of the invention can be prepared as illustrated in the following diagram which involves a base-catalyzed cyclocondensation of ethyl-4- chloroacetoacetate I with an appropriate trans -phenylcyclopropyl isocyanate II to provide the esters III . Alkaline hydrolysis of esters III gives the corresponding free acids IV which in turn can be treated with anilines V in the presence of triethylamine and N,N-bis-(2-oxo-3-oxazolinyl) phosphordiamidic chloride (BOP-C1) to provide the amide derivatives VI . In addition, treatment of the free acids IV with sodium carbonate (or another alkali metal carbonate) gives the salts VII . Non-limiting examples of specific compounds according to the invention and their preparation are illustrated in the following examples. Example 1 4,5-Dihydro-4-oxo-2[2-( trans -phenylcyclopropyl)amino]-3- furancarboxylic Acid Ethyl Ester (1) . Under nitrogen atmosphere, triethylamine (4.5 ml) was added dropwise over 15 min. to a well-stirred solution of trans -phenylcyclopropyl isocyanate (5.45 grams) and ethyl 4-chloroacetoacetate (4.50 grams) in petroleum ether-ethyl acetate (10:1 by volume), at 5-10°C (ice/water bath). During the addition, a heavy precipitate formed. The reaction mixture was stirred at 0-5°C for 1 hours, and the precipitate was filtered off under vacuum. The solid was stirred for 1 hour in petroleum ether, filtered and stirred with 1 N hydrochloric acid. The filter cake was rinsed with water, then sucked dry on the filter. Recrystallization from isopropanol gave 5.54 grams of compound 1 as a white crystalline product melting at 140-142°C. This compound showed antimicrobial activity against several bacteria in broth and agar dilution tests. Example 2 4,5-Dihydro-4-oxo-2-[[2- trans -(4-chlorophenyl)cyclopropyl] amino]-3-furancarboxylic Acid Ethyl Ester (2) . Compound 2 was prepared by a similar process to that described in Example 1 with trans -4-chlorophenylcyclopropyl isocyanate being reacted with ethyl 4-chloroacetoacetate. Example 3 4,5-Dihydro-4-oxo-2-[[2- trans -(4-methylphenly)cyclopropyl] amino]-3-furancarboxylic Acid Ethyl Ester (3) . Compound 3 was prepared by a similar process to that described in Example 1 with trans -4-(methylphenyl)cyclopropyl isocycanate being reacted with ethyl 4-chloroacetoacetate. Example 4 4,5-Dihydro-4-oxo-2-[(2- trans -phenylcyclopropyl)amino]-3- furancarboxylic Acid (4) . 4,5-Dihydro-4-oxo-2-[(2- trans -phenylcyclopropyl)amino] -3-furancarboxylic acid ethyl ester (1) (15.50 grams, 54 mmol) was added to a solution of sodium carbonate (11,45 grams, 108 mmol) in 170 ml water. Steam was then passed through the mixture for 2 hours. After refluxing for 1 additional hour, the reaction mixture was cooled to 5-10°C and filtered in order to remove some solid impurities. Acidification to pH 1 was concentrated hydrochloric acid precipitated the free acid. The latter was recrystallized from ethanol to give 7.15 grams of compound 4 melting at 155-157°C. This compound showed antimicrobial activity against a variety of bacteria in broth and agar dilution tests. Examples 5 and 6 4,5-Dihydro-4-oxo-2-[[2- trans -(4-methylphenyl)cyclopropyl]amino] 3-furancarboxylic Acid (5) ; and 4,5-Dihydro-4-oxo-2-[[2- trans -(4-chlorophenyl)cyclopropyl]amino] 3-furancarboxylic Acid (6) . Compounds 5 and 6 were prepared by treatment of esters 3 and 2 respectively with sodium carbonate followed by precipitati with concentrated hydrochloric acid similar to the process of Example 4. Example 7 4,5-Dihydro-4-oxo-2-[(2- trans -phenylcyclopropyl)amino]-3- furancarboxylic Acid Sodium Salt (7) . The compound 4 , (5.05 grams, 19.5 mmol), was neutralized with sodium carbonate (2.56 grams, 24.2 mmol) in 150 ml water. The solution was warmed to 50°C, then filtered and concentrated to 50 ml under vacuum. The addition of a small amount of ethanol caused a rapid crystallization of the sodium salt 7 . Recrystallization from water provided 4.66 grams of pure sodium salt as the monohydrate. Example 8 N-(3-Methylphenyl)-4,5-dihydro-4-oxo-2-[(2- trans - phenylcyclopropyl)amino]-3-furancarboxamide (8) . Under nitrogen atmosphere, triethylamine (2.22 grams, 22 mmol) was added dropwise to a solution of 4,5-dihydro-4- oxo-2-[(2- trans -phenylcyclopropyl)amino]-3-furancarboxylic acid ( 4 ) (2.85 grams, 10 mmol) in 22 ml methylene chloride, at 0°C (ice/water bath). Then, m -toluidine (1.24 gram, 11.57 mmol) was added, the reaction mixture was allowed to warm to 10°C, and N,N-bis-(2-oxo-3-oxazolinyl)phosphordiamidic chloride (BOP-C1) (2.8 grams, 11 mmol) was added in one portion. The mixture was stirred at 10°C for 15 min, and at 20°C for an additional 2.5 hours. Water (25 ml) was added and the mixture was acidified to pH 1 with 4 N hydrochloric acid. The two layers were separated and the aqueous phase was extracted with methylene chloride. The combined extracts were washed sequentially with water and 5% aqueous sodium bicarbonate. After removal of the solvent and recrystallization of the resulting residue from ethanol, 3.33 grams of the crystalline amide 8 melting at 136-137°C were obtained. Examples 9-12 The following compounds were prepared by procedures similar to that of Example 8 using the appropriate aniline derivative in place of m-toluidine: N-(3-Nitrophenyl)-4,5-dihydro-4-oxo-2-[(2- trans - phenylcyclopropyl)amino]-3-furancarboxamide ( 9 ); N-(4-chlorophenyl)-4,5- dihydro-4-oxo-2-[(2- trans -phenylcyclopropyl)amino]-3- furancarboxamide ( 10 ); N-(3,4-dimethoxyphenyl)-4,5-dihydro-4-oxo-2- [(2- trans -phenylcyclopropyl)amino]-3-furancarboxamide ( 11 ); N-(3-trifluoromethylphenyl)-4,5-dihydro-4-oxo-2-[(2- trans - phenylcyclopropyl)amino]-3-furancarboxamide ( 12 ). The foregoing has described novel 4,5-dihydro-4-oxo-2[(2- trans -phenylcyclopropyl)amino]-3-furancarboxylic acids and derivatives thereof which are useful as antimicrobial materials.

Claims: 1. A 4,5-dihydro-4-oxo-2-[(2-trans-phenylcyclopropyl) amino]-3-furancarboxylic acid or derivative thereof having the general formula: where R is selected from hydroxy, lower alkoxy, anilino, and O-alkali metal; and where R¹ is selected from phenyl and substituted phenyl. 2. The compound of claim 1 wherein R is hydroxy. 3. The compound of claim 1 wherein R is lower alkoxy. 4. The compound of claim 1 wherein R is anilino. 5. The compound of claim 1 wherein R is O-alkali metal. 6. The compound of claim 1 wherein the compound is 4,5-dihydro-4-oxo-2-[(2-transphenylcyclopropyl)amino]-3- furancarboxylic acid ethyl ester. 7. The compound of claim 1 wherein the compound is 4,5-dihydro-4-oxo-2-[[2-trans-(4-chlorophenyl)cyclopropyl]amino] 3-furancarboxylic acid ethyl ester. 8. The compound of claim 1 wherein the compound is 4,5- dihydro-4-oxo-2-[[2-trans-(4-methylphenyl)cyclopropyl]amino-]- 3-furancarboxylic acid ethyl ester. 9. The compound of claim 1 wherein the compound is 4,5-dihydro-4-oxo-2-[(2-trans-phenylcyclopropyl)amino]-3- furancarboxylic acid. 10. The compound of claim 1 wherein the compound is 4,5-dihydro-4-oxo-2-[[2-trans-(4-methylphenyl)cyclopropyl] amino]-3-furancarboxylic acid. 11. The compound of claim 1 wherein the compound is 4,5-dihydro-4-oxo-2-[[2-trans-(4-chlorophenyl)cyclopropyl] amino]-3-furancarboxylic acid. 12. The compound of claim 1 wherein the compound is 4,5-dihydro-4-oxo-2-[(2-trans-phenylcyclopropyl)amino]-3- furancarboxylic acid sodium salt. 13. The compound of claim 1 wherein the compound is N-(3-methylphenyl)-4,5-dihydro-4-oxo-2-[(2-trans phenylcyclopropyl)amino]-3-furancarboxamide. 14. The compound of claim 1 wherein the compound is N-(3-nitrophenyl)-4,5-dihydro-4-oxo-2-[(2-trans- phenylcyclopropyl)amino]-3-furancarboxamide. 15. The compound of claim 1 wherein the compound is N-(4-chlorophenyl)-4,5-dihydro-4-oxo-2-[(2-trans- phenylcyclopropyl)amino]-3-furancarboxamide. 16. The compound of claim 1 wherein the compound is N-(3,4-dimethoxyphenyl)-4,5-dihydro-4-oxo-2-[(2-trans- phenylcyclopropyl)amino]-3-furancarboxamide. 17. The compound of claim 1 wherein the compound is N-(3-trifluoromethylphenyl)-4,5-dihydro-4-oxo-2-[(2-trans phenylcyclopropyl)amino]-3-furancarboxamide. C L A I M S for the Contracting State AT 1. A process for the production of a 4,5-dihydro-4- oxo-2-[(2-trans-phenylcyclopropyl)amino]-3-furancarboxylic acid or derivative thereof having the general formula where R is selected from hydroxy, lower alkoxy, anilino, and O-alkali metal; and where R¹ is selected from phenyl and substituted phenyl, characterized by preparing the ester derivatives, where R is lower alkoxy, by a base catalyzed cyclocondensation of a lower alkyl-4-chloroacetoacetate with a trans-phenylcyclopropyl isocyanate of the formula: where R¹ is as defined above, preparing the free acid where R is hydroxy, by alkaline hydrolysis of the ester derivatives, preparing the salt derivatives, where R is O-alkali metal, by reaction of the free acid with an alkali metal carbonate, and preparing the amide derivatives, where R is anilino, by reaction of the free acid with an aniline in the presence of triethylamine and BOP-Cl. 2. The process of claim 1 for the production of a compound wherein R is hydroxy. 3. The process of claim 1 for the production of a compound wherein R is lower alkoxy. 4. The process of claim 1 for the production of a compound wherein R is anilino. 5. The process of claim 1 for the production of a compound wherein R is O-alkali metal. 6. The process of claim 1 for the production of the compound 4,5-dihydro-4-oxo-2-[(2-trans-phenylcyclopropyl)- amino]-3-furancarboxylic acid ethyl ester. 7. The process of claim 1 for the production of the compound 4,5-dihydro-4-oxo-2-[[2-trans-(4-chlorophenyl)- cyclopropyl]amino]-3-furancarboxylic acid ethyl ester. 8. The process of claim 1 for the production of the compound 4,5-dihydro-4-oxo-2-[[2-trans-(4-methylphenyl)- cyclopropyl]amino]-3-furancarboxylic acid ethyl ester. 9. The process of claim 1 for the production of the compound 4,5-dihydro-4-oxo-2-[(2-trans-phenylcyclopropyl)- amino]-3-furancarboxylic acid. 10. The process of claim 1 for the production of the compound 4,5-dihydro-4-oxo-2-[[2-trans-(4-methylphenyl)- cyclopropyl]amino]-3-furancarboxylic acid. 11. The process of claim 1 for the production of the compound 4,5-dihydro-4-oxo-2-[[2-trans-(4-chlorophenyl)- cyclopropyl]amino]-3-furancarboxylic acid. 12. The process of claim 1 for the production of the compound 4,5-dihydro-4-oxo-2-[(2-trans-phenylcyclopropyl)- amino]-3-furancarboxylic acid sodium salt. 13. The process of claim 1 for the production of the compound N-(3-methylphenyl)-4,5-dihydro-4-oxo-2-[(2-trans- phenylcyclopropyl)amino]-3-furancarboxamide. 14. The process of claim 1 for the production of the compound N-(3-nitrophenyl)-4,5-dihydro-4-oxo-2-[(2-trans- phenylcyclopropyl)amino]-3-furancarboxamide. 15. The process of claim 1 for the production of the compound N-(4-chlorophenyl)-4,5-dihydro-4-oxo-2-[(2-trans- phenylcyclopropyl)amino]-3-furancarboxamide. 16. The process of claim 1 for the production of the compound N-(3,4-dimethoxyphenyl)-4,5-dihydro-4-oxo-2-[(2- trans-phenylcyclopropyl)amino]-3-furancarboxamide. 17. The process of claim 1 for the production of the compound N-(3-trifluoromethylphenyl)-4,5-dihydro-4-oxo-2-[(2- trans-phenylcyclopropyl)amino]-3-furancarboxamide.

Inventors: GEORGIEV, VASSIL STEFANO, KINSOLVING, CLYDE RICHARD, MACK, ROBERT ALLAN
Applicants: PENNWALT CORPORATION
Application year: 1985
Main classification: C07D307
IPC codes: C07D307