IL31458A

IL31458A - Hydantoin derivatives

Info

Publication number: IL31458A
Application number: IL31458A
Authority: IL
Original assignee: Farmaceutici Italia
Priority date: 1968-01-26
Filing date: 1969-01-21
Publication date: 1972-06-28
Also published as: FR2000801B1; YU12569A; DE1902985A1; GB1174760A; IL31458A0; SE348732B; NL6900631A; YU33193B; AT281863B; CH513176A; ES362888A1; NO122976B; BR6905856D0; FR2000801A1; BE727366A; DE1966142A1

Description

HYDANTOIN DERIVATIVES The invention relates to. a new class of hydant'oin derivatives which have proved useful in therapy. The new compounds of the invention have the following structural formula: where R is hydrogen or a lower alkyl group; R' is hydrogen or.

R and R' together' form a ring of five or six atoms; and X is an amino group or a group of the formula The invention •"includes a process which can be represented by the following scheme': R' I 1 R* where R and R' have the meanings given above and R" is a lower alkyl radical. This process comprises reacting _p_-nitrophenyl chloroformate with the ester of a amino-acid having the formula II in an inert organic solvent and at a temperature of from -20 C to +30 C. The product III thus obtained s reacted in the warm with hydrazine hydrate, preferably in alcoholic solution, to obtain the corresponding product IV. This may be isolated as such or transformed into the corresponding nitrofurfurylidene derivative V by reaction with 5-nitro-2-furaldehyde preferably in the warm. al The new compounds of the invention show a good antibacterie activity against a high number of gram-positive and gram-negative bacteria and' antiprotozoic activity against, for example, Trichomonas foetus. They also have a low toxicity and therefore a high therapeutic index.

The acti ity of the new compounds of the invention has been determined by tests "in vitro" and "in vivo" in comparison with the antibacterial substance N-( 5-nitro-2-furfurylidene )-l-aminohydantoin. al The tests, of antibacterier activity "in vitro" have been carried out in & a nutrient medium (Difco-Registered Trade Mark) mixed with different concentrations of the substances under examination. After 24 hours incubation at 37 C the minimum inhibiting dose (DIM); expressed in Y/CC has been determined and the results are in Table 1.

TABLE 1 - DIM (†/cc) Strain l-methyl-3- D,L-2,4- 3-(5 '- (5 '-nitro- diketo-3- nitrofur- furfuryliden- ( '-nitro- furyliden- furfuryliden- amino) furfuryl- amino)- amino)- hydantoin amino- hydantoin hydantoi imidazo- (1,,5-a)- piperidine Staphylococcus aureus 209P 2.5 5 2.5 20 Bacillus substilis 5 10 5 10 Escherichia coli 5 10 5 20 Abortive equin salmonella 1.25 1.25 2 2 TABLE 1 continued Strain 1-sec .butyl-3- l-n-propyl-3- N-( 'nitro- ( 5-nitro-furfury- ( '-nitrofur- furfuryliden- lidenamino)- fury 1idenamino)- -1-amino)- hydantoin hydantoin hydantoin Staphy 1ocoOciis aureus 209P 0.6 1.25 2.5 Bacillus substilis 5 5 5 Escherichia coli 10 10 5 abortive equih salmonella 2.5 1.25 jl.25 Tests of antibacteri-e activity "in vivo" have been carried out on mice experimentally infected by intraperitoneal route with Staphylococcus aureus, Diplococcus pneumoniae, Escherichia coli and Shigella flexheri. The compounds have been administered per os at the doses- of 200, 100 and 50 mg/kg. In Table 2 are the results expressed as therapeutical doses, TD 50 (in mg/kg), and average death times, LT 50 (in days), after treatment with 200 mg/kg. In Table 2 there are also the average lethal doses, LD 50 (in mg/kg), mice obtained in mo%H3«.

TABLE 2 TABLE 2 continued The average lethal dose, LD 50, for l-n-propyl-3-(5 '-nitro- furfurylidenamino)-hydantoin is 5000 mg/kg. The antiprotozoic activity "in vitro" has been tested on Trichomonas foetus in a nutrient medium by adding the products under examination at a concentration of 100, 10 and 1 γ/cc. After 3 days incubation at 37 C there has been determined the DIM (in γ/cc), that is the minimum concentration inhibiting the growth of Trichomonas foetus and the ID 50 (in y/cc), that is the concentration inhibiting 50?£ of the growth. In Table 3 are reported the results obtained in comparison with those of N-(5-nitro-2-furfurylidene)-l-amino-hydantoin TABLE 3 Compound ID 3-(5 '-nitrofurfurylidenamino)- 10 0.5 hydantoin l-Isopropyl-3-( 5 '-nitrofurfurylidenamino)-hydantoin 0.1 1-sec .butyl-3- ( '-nitrofurfuryliden-amino )-hydantoin 20 0.1 l-n-propyl-3-( 5 '-nitrofurfuryliden-amino )-hydantoin 0.1 |N-(5-nitro-2-furfurylidene)-l- . aminohydantoin 0.2 The tests of antiprotozoic activity "in vivo" have been carried out mice on -mtrasre* experimentally infected by Trichomonas foetus. The compounds have been administered subcutaneous ly at doses of 50, .25 and 12.5 mg/kg. In Table 4 are the results expressed as percentage mortality^ average lethal time LT 50 (in days) and average therapeutic dose TD 50 (in mg/kg), TABLE 4 The clinical applications of the new compounds of the invention are infections of the genital-urinary apparatus and others: pyelonephritis, cystopyelitis , cystitis, urethritis, prostatitis, hydronephrosis ,■ infected calculosis, and post-operation infections. The new compounds of the invention may be administered by the oral or parenteral route. The therapeutic eompositionsof the invention contain one or more of the new compounds of the invention in admixture with a solid or liquid pharmaceutical vehicle. The compositions can be prepared in the form of solutions, syrups, tablets, pills. Suitable vehicles are starch, lactose, talc and their analogues.

The following Examples illustrate the invention: EXAMPLE 1 3-( '-nitrofurfurylidenamino)-hydantoin 41.25 g of ethyl glycinate are dissolved in 100 cc of absolute chloroform. The solution is cooled to -15°C and a solution of 53.64 of j)-nitro-phenyl chloroformate in 100 cc of absolute chloroform is dropped in with shaking so that the temperature is maintained at -5°C. After 2 hours at -5°C and overnight at room temperature the solution is filtered, diluted with chloroform and washed in the cold with 0.5N hydrochloric acid and then with water. After drying over sodium sulphate the. solvent is evaporated off under reduced pressure and the solid residue is crystallized from diethyl ether. 43.62 g.' of ethyl j)-nitro-phenyl-oxycarbonyl-glycinate , melting at 94°-96°C, are obtained. An analytical sample, recrystallized from diethyl ether, melts at 98°-100°C.

A solution of 10.56 g of this ethyl j3-nitro-pheny;l-oxycarbonyl-glycinate and 1.97 cc of 99-100 hydrazine hydrate in 100 cc of absolute ethanol is refluxed for 3 hours and then allowed to stand o overnight at 0 C. The precipitate is filtered off, washed with ethanol and then with diethyl ether. 1.99 g of 3-araino-hydantoin, melting at 195°-197°C,. are obtained. A suspension of 1.15 g of this 3-amino-hydantoi and 2.40 g of 5-nitro-2-furaldehyde diacetate in 140 cc of ap aqueous solution containing 8 of acetic acid and 12$ of concentrated sulphuric acid (by volume) and 14 cc of ethanol is shaken in the dark for 30 minutes on an oil bath warmed at 85°C.

After cooling, the precipitate is filtered off and washed with ethanol and then with* diethyl ether. 2.4 g of 3-(5 '-nitro-furfuryl-iden-amino)-hydantoin, melting at 165-175°C (with decomposition) are obtained. This is suspended in 10 cc of dimethylformamide and separated by filtration from an insoluble residue. The solution is diluted with ethanol and the precipitate is suspended in 30 cc of boiling acetic acid and filtered in the warm from an Undissolved part From the lukewarm acetic solution 1 g of the product, melting at 220°-221°C, is separated.

EXAMPLE 2 l-Methyl-3- ( ' -nitrofurfurylidenamino )-hydantoin 37.49 g of ethyl sarcosinate are dissolved in 100 cc of absolute chloroform, cooled to -15°C and a solution of 32.25 g of £-nitro-phenylfchloroformate in chloroform is dropped under shaking. Operati as in Example 1, 41.24 g of ethyl _p-nitro-phenyl-oxycarbonyl-sarcosinate f melting at 58°-59°C, are obtained by crystallization from diethyl ether-petroleum ether. A solution of 36.85* g ethyl _p_-nitro-phenyl-oxycarbonyl-sarcosinate in 300 cc of absolute ethanol and 6.40 cc of 99-100 hydrazine hydrate is refluxed for 8 hours. The solvent is evaporated off under reduced pressure and the oily residue is washed three times by decantation with boiling diethyl ether and the crystallize from ethanol-di ethyl ether. 10.20 g of l-methyl-3-amino-hydantoin melting at 93°-95°C are obtained. An analytical sample, recrystallized from methylene dichloride-petroleum ether, melts at 94°-96°C.

A suspension of 1.29 g of this l-methyl-3-amino-hydantoin and 2.40 g of 5-nitro-2-furaldehyde diacet'ate in 140 cc of an aqueous solution containing 8 of acetic acid and 12 of concentrated sulphuric acid (by volume) and 14 cc of ethanol is shaken in the dark for 30 minutes on an oil bath warmed at 85°C. After cooling the precipitate is filtered off, washed with ethanol and then with diethyl ether. 1.48 g of l-methyl-3-(5 '-nitro-furfurylidei?-amino)-hydantoin melting at 174°C are obtained. By crystallization from dimethylformamide-ethanol an analytical sample melting at 175°C is obtained.

EXAMPLE 3 DL-2 , 4-diketo-3- ( 5 ' -nitro-furfuryliden^-amino )-imidazo- (1 g 5-a)-piperidine . 3.235 g of j>-nitro-phenyl chloroformate are added,. with shaking at -5°C, to a solution of 5.188 g of DL-ethyl pipecolinate in 40 cc of absolute chloroform. After 40 minutes at room temperature a further 3.2j35 g of jD-nitro-phenyl chloroformate , are added at -5°C, followed by 4.58 cc of triethylamine. The solution is allowed to stand for 4 hours at room temperature. Then it is washed with 0.5 N hydrochloric acid and then with water. After drying over sodium sulphate the solvent is evaporated off under reduced pressure and the residue is crystallized from ethanol. 10 g of ethyl _p_-nitro-phenyl-oxycarbonyl-D,.L-pipecolinate, melting at 80°-82°C, are obtained.

A solution of 14.35 g of this ethyl _p_-nitro-phenyl-oxycarbonyl-D,L-pipecolinate in 32 cc of absolute ethanol and' 32 cc of 98$ hydrazine hydrate is refluxed for 6 hours'. The solvent is evaporated off under reduced pressure and the residue is taken up with chloroform. , The chloroform solution is separated by filtration from a red-orange insoluble residue and the solvent is evaporated off. The resulting oily residue is dissolved in 60 cc of water and the solution is refluxed for half an hour, The solvent is then evaporated off under reduced pressure and the residue is crystallized from diethyl ether-petroleum ether. 5.5 g of D,L-2,4-diketo-3-amino-imidazo-(l , 5-a)-piperidine melting at 98°-102°C are obtained.

A suspension bf 1.40 g of this D,L-2,4—diketo-3-amino-imidazo- ( 1 , -a)-piperidine and 2.00 g of 5-nitro-2— furaldehyde diacetate in 140 cc of an aqueous solution containing 8o of acetic acid jand 12fo of concentrated sulphuric acid (by volume) is then shaken in the dark for 1 hour at 8.5°C° After cooling the precipitate is filtered, washed with -2,4-water and recrystallized · from methanol-water (l:l). 2 g of D,L-¾iketo-3- ( '-nitro-furfuryliden¾-amino)-imidazo- ( 1 , -a)-piperidine melting at 169°-170OC, are obtained.

EXAMPLE 4 l-Isopropyl-3-(5 '-nitrofurfurylidenamino)-hydantoin.

To a solution of 7.25 g of ethyl N-isopropylglycinate in 45 cc of absolute chloroform are added in two lots, as in Example 3, 10.06 g of j)-nitro-phenyl chloroformate and 6.94 cc of triethylamine . Operating as in the previous Example 3, 15 g of ethyl jj-nitro-phenyl-oxycarbonyl-N-isopropyl-glycinate are obtained.

A solution of 3.10 g of this ethyl -nitro-phenyl-oxycarbonyl-N-is¾propyl-glycinate in 7.5 cc of absolute ethanol and 7.5 cc of 98$ hydrazine hydrate is refluxed for 6 hours . Operating as in Example 3, 1.1 g of l-isopropyl-3-aminohydantoin in oily form are obtained.

A suspension of 1.10 g of this l-isopropyl-3-amino-hydantoin and 2.43 g of 5-nitro~2-furaldehyde diacetate in 80 cc of an aqueous solution containing 8$ of acetic acid and 12$ of concentrated sulphuric acid (by volume) and 8 cc of ethanol is shaken for 1 hour, in the dark, at 85°C. Operating as in Example 3, by recrystallization from methanol-water (l:l), 1.6 g of l-isopropyl-3- ( 5 '-nitro-furfuryliden-amino)-hydan-toin, melting at 180°-182°C, are obtained.

EXAMPlfe 5 Operating as in Example 4, the following compounds have been prepared l-n-pr^pyl-3-( '-nitro-furfuryliden-amino)-hydantoin melting at 184-186°C; l-sec.itt¾ityl-3-(5 '-nitro-furfurylidei^amino)-hydantoin melting at 156-158°C l-isobutyl-3- ( 5 '-nitro-furfuryliden-amino)-hydantoin melting at 165-166°C; l-j;-butyl-3-(5 '-nitro-furfuryliden?-amino)-hydantoin melting at 194'j-1950C ; l-n-butyl-3-(5 '-nitro-furfuryliden?-amino)-hydantoin melting at 134-135°C.

Claims

is a lower alkyl radical, is reacted with p-nitro-phenyl chloroformate in an inertvorganic solvent at from -20°C and +30°C, the product is reacted in the warm with

P.Α» 31 58/ΙΙ hydrazine hydrate to obtain the corresponding 3-amino-hydantoin derivative, and where appropriate the product; is reacted with 5-nitrt>-2-fu.raldehyde to give the corresponding 3-(5'-nitro-furfarylidenainino)-hydantoin derivative.
2. A process according to Claim 1 in which the reaction with hydrazine hydrate is carried out in alcoholic solution*
3· A process of preparing a hydantoin derivative substantially as herein described in any of Examples 1 to ¾.
4. A hydantoin derivative prepared by a process according to any of the preceding Claims*
5. A hydantoin derivative having the structural formula I herein.
6. 3- (5 '-nitro-furfuryliden-amino)-hydantoin.
7. l-Methyl-3-(5 '-hitro-furfuryliden-amino)-hydantoin.
8. DL-2,4-diketo-3-(5 ' -nitro-furfurylideit-amino) -imidazo-(l , 5-a)-piperidine.
9. l-Isopropyl-3-(5 ' -nitro-furfuryliden^-amino) -hydantoin.
10. l-n-propy¾.-3-(5 '-nitro-furfuryliden-amino)-hydantoin.
11. 1-s ec . butyl-3- ( 5 ' -nitro-furfuryliden-amino ) -hydantoin.
12. l-isobutyl-3- ( 5 ' -nitro-furfuryliden-amino) -hydantoin.
13. l-t-butyl-3- ( 5 '-nitro-furfuryliden-amino )-hydantoin.
14. l-n-butyl-3- ( 5 '-nitro-furfurylideS-amino)-hydantoin.
15. A therapeutic composition containing one or more products of the claims 4 to 14 in admixture with a solid or liquid pharmaceutical vehicle. Attorneys for Applicant