DE1902985A1 - Hydantoin derivatives - Google Patents

Description

PtOF. Mt OR. J. ftfnSTOTTW

MUNO. W. MNTE IMPMQ »< W, HAVDNtWAlIt I

Fire * Soc. Fareaceutici Italia, 1/2 Largo Guido Donegani - 2ol21 M a i l.a η d

Hydantoin derivatives

The present invention is directed to a new one Class of hydantoin derivatives used in the therapy of Nutsen are, and a process su their manufacture. In particular, the invention relates to new compounds of the general formula:

R »

R-H CsO

I I (D.

BATH ORIGINAL

009831/1960

where R denotes hydrogen or a lower alkyl group,

R * represents hydrogen or R and R 'together are cyclic Can form a ring with 5 or β atoms and X

a group NH ₂ or

. "CH- —- CH ■■ ■: ■: - · ■

It Il

-N = CH-C C-NO ,,

means.

The products of the present invention exhibit one good antibacterial and antiprotozoal activity and have a low toxicity fit.

The process of the present invention can be represented by the following reaction scheme: ^y '

RR *

I I

OCOCl ♦ HN - CH - COOR "

(ID

OCO - N - CH - COOR "-—- R-N

N-NH ₂ .

009831/1960

BATH

-J-

(V)

in which R and R * have the above meaning and R "represents a lower alkyl group. In particular, the process according to the invention consists in _{B for the} acid ester of the formula II in an inert organic solvent and at a temperature of - 20 to "> 30 ^o C" it p-Nitrophenylchloroforaiat is unset.

The bo obtained © iPpodukfc isr Worml III wiri la der · VtrBe nit Hydrasinhydpßfeg vs *? 3 «igswei @ ® iß alcoholic solution» uBgotst, whereby the enteppieshande product of the panel IV is obtained, which is insulated as solehee or by means of oiling 5 -Mitro-2-furÄldshyd, wherein voreugsweise worked in the wiMe _e can be converted into the entspreohend® NitrofurfurylidenderiTat of formula V. The products obtained according to the invention have a good antibacterial activity against a large number of graopoeitive and gram-negative bacteria and an antiprotozoic activity, for example against Trichoaonas fetus. They are also resistant to low toxicity and therefore have a high therapeutic index.

The 0 0 9 8 3 1/19 8 0 ^BAD ORIGINAL

DI® activity of the product "erfindungegemäß available was ^v sun through trial © Tin vitro" and "in vivo" compared known antibacterial product N ~ (§-nitro-2-fu? ^Fus> ylide «n) <l-aminohyd & ntoin hestitsat. The experiments with regard to the antibacterial activity "in vitro" were carried out in a study "Difeo", in which various consentrations of the substances to be tested were examined.

After 2 hours ¹ S Bebrutuitg at 37 ° C, the ainimale HewsungadoBis (DIM) "was expressed in jjp / ml '' is determined and the results obtained are given in Table I below.

Table I.

BAU ORJGif \! _Al /

0 & 9831 / 19S0

Tabel

I - DIM (

(O W

D O

■ z.

Stana l-ethyl-3-
(5 ^f -nitro-
furfcurylid
amino) -
hydantoin D, L-2,4-
Diketo-3
(5 * -nitro-
furfuryli-
denaaino-
iflddaso-
piperidine 3- (5 ^f -
Mitro-
for-
furylid
aaino) -
hydantoin 1-Ieo
pxopyl
3- (5 ^f -
nitro "
ftUP-
furylid
amino) -
hydantpin Butyl
3-C5 ¹ -
nitro-
for-
furylid
aadno) -
hydantoin 1-n.propyl
3- (5'-nitro-
for-
furylid
asiino) -
hydantoin M-C5 ¹ -
Nitro
for-
furylid
1-aiino) -
hydantoin aureue
2O9P 2.5 5 20th Q.6 1.25 2.5 Ba-
eillue
sttb-
»Tili« 5 10 5 10 5 5 5 Eaohe-
richia
coil 5 10 5 20th 10 10 5 Abor
tive
equine
eal-
monella 1.25 1.25 2 2 2.5 1.25

OO cn

The attempt "deeply antibacterial"? "In vivo" activity was carried out in mice when exposed to intraptritons All Welaβ "it Staphjloeoocus aureue, DiplocDccus pneumonia" _s Sohsriohia coil and Shigella flexneri had been infected. The compounds were administered orally at doses of 200, 100 and 50 µg / kg; in Table II the results obtained are given, expressed as therapeutic doses, TD 50 (in Bg / kgJ and mean mortality since, LT 50 (in days), after treatment hit 200 mg / kg.

Table II also shows the mean mortal dose results obtained in mice, LD 50 (in mg / kg) » specified.

Table II

BAD ORiGiNAL '

0 0983 1 / 198Q

O 1-methyl-3- (5'-
nltrofurjt ury Ii-
denamin) -
hydantoin ε.
coli S.flex-
neri 500 T a b β] E.
colt S.flex-
neri 700 L 1 e II ε.
coli S.fflex-
neri y 1000 1-Iaopropyl-3-
(>'nitrofur
fury lidenamino) -
hydantoin S.flec
neri I. E. £ _k 350 Infect
tion
verur
gently
by: OTTD 50
Cp (Tn ^ e)
O * after
hanri-
funny
with
200
mg / kg s.
aureue 50 200
7th D, L-2, l4-Diket_-3-
5 ■ -nitrofurfuryIi-
I enamino-imidazo-
(1,5-a) -
piperidine 50 200 • 200
7th s. te.
aureua coil 200
8th LD 50
("G / k")
03 > 200
5 S.
a ure Ui 3_ (5 «_Nitrofur-
fury lld en-
am InO) -hydantoin 2,500 50 k S.
aureue "> 200
7th N- (5'-nitro
furfury1Idon-
1-amino) -
lydantoin > 200 S ₄ ,
auareufl N200
5

33 G)

co CD

In addition, it was found that the mean lethal dose, LD 50, for In-Propyi-3- (5 ^T -nitrofurfurylideneamino) -hydantoin is 5000 mg / kg.

The "in vitro" antiprotozoal activity was tested on Trichomonas fetus in a nutrient medium, the products to be tested being added in concentrations of 100, -10 and 1 ^ f / ml. After 3 days incubation at 37 ⁰ C, the DIM (in £ / ml), ie the minimum Konsentration which inhibits the growth of Trichomonas fetus, and the ID 50 (in jf / _ml): that is, the concentration that is 50% of the Wach β turas} "" inhibits., Definitely.

In Table III the results obtained are in comparison given for N- (5-nitro-2-furfurylidene) ~ l-amino-hydantoin.

Tab el Ie-

III

links DIM
r / mi ID
if / ial 3- (5 * -Nit rofurf ury lidenamino) -
hydantoin 10 0.5 l-isopropyl-3- "(5'-nitrofurfury liden
amino) -hj'dant oin 1 0.1 1 sec buty1-3- (5 ^l -nitrofurfurylidene
amino) hydantoin 20th 0.1 ln-propyl-3- (5'-nitrofurfurylidene »
amino) hydantoin 1 K- (5-Mitro-2-furfurylidene) -l-amino-
hydantoin 2 0.2

BATH ORIGINAL

0 09131/1960

The experiments on antipiOtozoic activity "In vivo" were carried out on mice, which were experimentally had been infected with Trichomonas fetus. The connections were administered subcutaneously at doses of 50, 25 and 12.5 mg / kg; in Table IV are the results expressed as a percentage Mortality reported as mean mortality time, LT 50 (in days), and as mean therapeutic dose, TD 50 (in mg / kg).

Table IV '

groups Cans
mg / kg Mortal
in %
10 days 15 days LT 50
Days TD 50
mg / kg 15th Controls - 33 65 - 12.5 - 25th l-isopropyl
3- (5'-nitro-
furfurylid
amino} -
hydantoin 50
25th
12.5 0 0
0 8
16 41 > 20
> 20
15 ■ N- (5-nitro-2-
furfurylids) -
1-amino-
hydantoin 50
25th
12.5 8 8
8 25
33 50 50
27
16

The clinical applications are preferably carried out at all infections of the genitourinary tract and various other infections, such as pyelonephritis, cystopyelitis, Cystitis, urethitis, prostatitis, hydronephrosis, infectious Calculosis, poetoperative infections, The according to the invention.

available

009831/1960

BATH

- ίο -

Compounds obtainable can be administered orally or parenterally. The therapeutic composition consists of one or more of the products obtainable according to the invention with a certain amount of a solid or liquid pharmaceutical carrier. The compounds can be made in form of solutions, syrups, tablets and pills; suitable carriers are starch, lactose _, talc and the like.

The following examples are presented to the present invention explain in more detail, but without this being restricted to this.

EXAMPLE 1:

3- (5'-Nitrofurfurylideneamino) hydantoin

¹ Il, 25 g of ethyl glycinate were dissolved in 100 ml of absolute chloroform; the solution was cooled to -15 ° C and a solution of 53 »6 * 1 g of p-nitrophenyl chloroformate was dropped under shaking in 100 al absolute chloroform so that the temperature was maintained at -5 ⁰ C.

After 2 hours at ⁰ -5 C and a night at room temperature, the solution was filtered, diluted with chloroform and then washed in the cold with 0-5n Sale acid and with water. After drying over sodium sulfate, the solvent was evaporated off under reduced pressure and the solid residue was crystallized from ether.

It wurdenΊ3f62 g Xthyl-p-nitrophenyloxycarbonylglycinat obtained Pp 9 * 1 -. 96 ⁰ C, The analytical sample> urnkriataiiisiert from Xther, melting at 98 - 10O ⁰ C.

One 0 09831/1080 ~ "

A solution of 10.56 g Xthyl-p-nitrophenyloxyearbonylglyeinat and 1.97 al 99-100 Sige "Hydra * inhydrat in 100 al Absolute Xthanol was heated for 3 hours under reflux and then About Naoht at 0 ⁰ C allowed to stand.

The precipitate was filtered, washed with ethanol and then Bit Xthes ·. 1.99 g of 3-asdnohydantoin were obtained, melting point 195-197 ° C. A suspension of 1.15 g of 3-aainohydantoin and 2.40 g of 5-nitro-2-furaldehyde diaoetate in 140 ml of an aqueous solution containing 8 % acetic acid and 12% concentrated sulfuric acid (Vol *) and 14 ml of ethanol was obtained from Ib dark for 30 minutes on an oil bath that had been erwärat to 85 ⁰ C, shaken.

After cooling, the precipitate was filtered and washed with ethanol and then sife Sfefe-os? ¹ «pw & asheno 2.4 g of 3- (5 ^l -NitrofurfuiTliö © nasifi ©)» _i Qi? ⁱ 4aiitOin, SJp. 165 - 17§ ^e C (decomp.), Which were suspended in 10 Bl SiioS! As? Ifors! AMd and separated insoluble by filtration 70a © η MoSc * t * nd.

The solution was diluted with ethanol and the resulting lower sap was poured into 30 ml of boiling acetic acid

ia tor Wtem

suspended and Mureh Filtrier * «tob rivets dissolved file separately.

1 g of desiccant was added to the lukewarm sugar solution Product, melting point 220-22 ° C., separated off.

EXAMPLE 2;

1-methy 1- 3- (5'-nitrofurf urylidenaaino) hydantoin

37.49 g

00983 1/1910

BATH ORIGINAL

37.49 g xthylaarcQsinat were in 100 ml absolute Dissolved chloroform, cooled to -15 ° C and a solution of 32.25 g of p-nitrophenyl chloroformate were added dropwise with shaking.

The procedure was as in Example 1, whereby through Crystallization from ether-petroleum ether 11.24 g of ethyl p-nitrophenyloxycarbonyl sarcosinate, pp. 58-59 ° C., were obtained.

A solution of 36.85 g of ethyl p-nitrophenyloxycarbonyl sarcosinate in 300 al of absolute ethanol and 6.40 ml of 99 to 100 ffiges Hydraein hydrate was refluxed for 8 hours.

The solvent was evaporated under reduced pressure and the oily Rüokatand three times by decanting with washed with boiling ether, whereupon it was crystallized from ethanol-ether.

10.20 g of 1-methyl-3-aminohydantoin were obtained, melting point 93-95 ° C. Di * analytical sample, umkrlstalXislert from methylene chloride-petroleum ether, melted at 94-96 ⁰ C.

A suspension of 1.29 g l-methyl-3-aainohydantoin and 2.40 g of 5 ~ nitro-2-furaldehyddiaoetat in 140 ml of an aqueous solution containing 8 S acetic acid and 12% conc. Sulfuric acid ( % by volume) and 14 ml of ethanol were shaken in the dark for 30 minutes on an oil bath which had been heated ^{to 85 ° C.}

After cooling, the precipitate was filtered off with Ethanol and then washed with ether.

gg BAD ORfGfNAL 009831/1860

Eb 1 _a 48 g of l-llethyl-3- (5 ^f -nitrofurfurylideneamino) -hydantoln were obtained,? P. 174 ⁰ C.

The analytical Prob "has been by crystallization from dimethylformamide-Xthanol get Pp. 175 ⁰ C.

BBEXAMPLE 3:

D ₁ L-2 _t 4-Diketo-3- (5'-nltrofurftirylldena «lno) -imidaEO- (l, 5-a) ··

piperidine

3.235 g of p-nitrophenyl chloroformate were added with shaking at -5 ° C of a solution of 5.188 gDyL-Xthylpipecolinat in 40 ml of absolute chloroform were added.

After 40 minutes at room temperature there were more 3.235 g of p-nitrophenyl chloroformate at -5 ° C and thereafter 4.58 ml of triethylamine co-set. The solution was 4 hours left to stand at room temperature for a long time, then it was with. 0.5N hydrochloric acid and then washed with water. After drying The solvent was evaporated off under reduced pressure over sodium sulfate and the residue was crystallized from Xchanol. There were 10 g of ethyl p-nitrophenyloxycarbonyl-D.L-pipecolinat, received, ip. 80-82 ° C.

A solution of 14.35 g of ethyl p-nitrophenyloxycarbonyl-D, L-pipecolinate in 32 ml of absolute ethanol and 32 ml 98 ml of hydrasin hydrate was refluxed for 6 hours heated.

. The solvent was evaporated under reduced pressure and the residue was taken up in chloroform.

the

BADORlGlMAt

The ohloroforalsehe solution was · by filtering Separated a red-orange insoluble Hüokstand and that Solvent was evaporated.

The oily residue obtained was dissolved in 60 ml of water and the solution was refluxed for half an hour get.

The solvent was then evaporated off under reduced pressure and the residue from Xthar petroleum ether was crystal! alert.

5 »5 S D, L-2, * - diketo-3-amino-imida * o- (i, 5-a) -piperidine, pp. 98-102 ° C. were obtained.

A suspension of 1.110 g of D ", L-2,4-diketo-3-aminoimide!» O- (1,5-a) -piperidine and 2.0 g of 5-nitro-2-furaldehyde diacetate in 1 O ml of an aqueous solution containing 8% acetic acid and 12% sulfuric acid konsentrierte (Vol.J) was then shaken in the dark for 1 hour at 85 ⁰ C. After cooling, the precipitate was filtered, washed with water ".ND from methanol-water. (1: 1) recrystallized.

There were 2 g of D, L-diketo-3- (5 ^I -nitrofurfurylidenamino) -imidai5O- (l, 5-a) -piperidine obtained Pp I69 -. 170 ⁰ C.

EXAMPLE 4 : 1-IBopropyl-3 "(5 ¹ " nitrofurfuryl denaaino) hydantoin

10.06 g of p-nitrophenyl chloroformate and 6.9% of lacta were added twice, as in Example 3 , to a solution of 7.55% ethyl-H-isopropylglyciiiSt in 45% absolute chloroform.

There 009831/1960 * ~

- 15 -

Acid · proceed as in the previous example »whereby 15 g of ethyl-p-nitrophenyloxycarbonyl-N-ieopropylglyeinftt were obtained.

A solution of 3 * 10 g of ethyl p-nitrophenyloxycarbonyl-H-isopropyl glycinate in 7 »5 tables of absolute ethanol and 7.5« 1 98 l hydraein hydrate was refluxed for 6 hours.

The procedure was as in Example 3, with 1.1 g l-Iaopropyl-3-aninohydantoin were obtained in the form of an oil.

A suspension of 1.10 g. 1-isopropyl-3-aminohydantoin and 2, H3 g of tJ-nitro-α-furaldehyde diacetate in 80 ml of aqueous solution containing 8 % acetic acid and 12% concentrated sulfuric acid (Vol.S) and 8% alcohol was used for 1 hour in the dark shaken at 85 ^{° C.} The procedure was as in Example 3, "wherein by Ua & ristalllsieren from methanol-water (1: 1) 1.6 g of l-Isopropyl-3- (5 ^f -nitrofurfurylidenamino) hydantoin was obtained» mp I80 - 182 ⁰ C..

EXAMPLE 5-

The procedure was as in Example 4, with the following Products were made:

in-Propyl-3- (5'-nitrofurfuryldenamino) -hydantoin, mp. 18H-186 ° C, i-sec-butyl-3- (5 ^l -nitrofurfurylidenainino) -hydantoin, pp. 156-158 ⁰ C, 1- isobutyl-3- (5'-nitrofurfurylidenamino) hydantoin, mp. 165-166 ° C, 1-tert.Buty 1-3- (5 ^f -nitrofurfurylldenamino) hydantoin, Pp. 19 * I-195 ^O C _t in -Butyl-3 ~ (5 * -nltrofurfurylidenamino) -hydantoin, pp. 13 ^ 135 ⁰ C.

003831/1960 ORIGINAL BATHROOM

Claims (12)

1. Procedure for the establishment of new connections of the general formula R * R-N CxO Il 0 «C N-X where R is hydrogen or a lower alkyl group » R * represents hydrogen or R and R * represent a cyclic one Ring ait can form 5 or 6 atoms and X a group NHg or CH CH -N «CH-C means, thereby identified, that a connection of the general formula R R » Il ■ ■ HR-CH- COOR ", where R and R * have the above meaning and R "represents an alkyl group, is reacted with ρ-Mitropheny! chlorine formate in an inert organic solvent at a teaper"> tur tor -20 to 430 ⁰ C and the product thus obtained - in 009831/1980 BAt) ORIGINAL - 17 - in the warmth with hydrasin hydrate sum corresponding 3-aminohydantoin derivative is reacted, because «isolated as such or can be unset with 5-nitro-2-furaldehyde sum of the corresponding 3- (5'-hitrofurfurylidenaraino) -hydantoin derivative. 2. A compound of the general formula R » I. CH '\ R-M € «0 I. I. ObC- B-X wherein R, R ¹ and X have the meaning given in claim 1. 3. 3- (5'-Nitrofurfurylidenaeino) hydantoin. 4. i-Methyl-3- (5 * -nitrofurfurylideneamino) hydantoin. 5. D, L-2, H-diketo-3- (5 * -nitrofurfurylideneamino) -imidaso- (1,5-a) -piperidine 6. 1-Ieopropy1-3- (5'-nitrofurfurylideneamino) hydantoin. 7. 1-n-Propy1-3- (5 * -nitrofurfurylideneamino) -hydantoin. 8. L-sec-butyl-3- (5'-nitrofurfurylideneamino) hydantoin. 9. 1-1βobuty1-3- (5 * -nitrofurfurylideneamino) -hydantoin. 10. 1-tert · Buty1-3 '(5 * -Nitrofurfurylidenamino) -hydantoin, 11. l-n-Butyl-3- (5 * -nitrofurfurylideneamino) hydantoin. 009831/1960 ORIGINAL BATHROOM 12. Pharaoh's approval ait antibacterial and antlprotoaoiaeher activity, daduroh known as £ aie one or more products of claim 2 to 11 in Mieehung with a suitable carrier sur oral or parenteral administration contains BATH ORIGINAL 009831/1 ·· 0