CA2028530A1

CA2028530A1 - Substituted pyrimidobenzimidazole derivatives

Info

Publication number: CA2028530A1
Application number: CA002028530A
Authority: CA
Inventors: Christian Hubschwerlen; Ivan Kompis; Jean-Luc Specklin
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1989-11-21
Filing date: 1990-10-25
Publication date: 1991-05-22
Also published as: EP0433648A1; NZ236109A; AU640708B2; JPH03170481A; IE904189A1; AU6670090A

Abstract

Abstract The present invention is concerned with novel substituted pyrimidobenzimidazole derivatives of the general formula wherein R1 signifies hydrogen, halogen or amino, R2 signifies halogen, R signifies a lower alkyl-substituted 4-pyridyl group or a group R3R4N- in which R3 and R4 each signify hydrogen or lower alkyl or together signify a group of the formula -(CH2)n-X-(CH2)m- or -(CH2)p-which is unsubstituted or substituted by lower alkyl, amino, lower aminoalkyl, mono- or di(lower alkyl)-amino-lower alkyl, oxo or the group -COOR2 or -CONR'R", n and m each signify the number 1, 2 or 3, with the proviso that n + m is a maximum of 5. p signifies the number 4, 5 or 6, X signifies an oxygen or sulphur atom or the group -NR"'-, Ra signifies hydrogen, lower alkyl, lower alkenyl, phenyl or phenyl which is mono-, di- or trisubstituted by halogen, lower alkyl or hydroxy, R' and R" each signify hydrogen or lower alkyl, R"' signifies hydrogen, hydroxy, lower alkyl or lower aminoalkanoyl, R5 signifies hydrogen, halogen, lower alkoxy or amino, R6 signifies lower alkyl, lower cycloalkyl, lower haloalkyl, phenyl or phenyl which is mono-, di- or trisubstituted by halogen, lower alkyl, hydroxy or lower alkoxy, R7 signifies hydrogen, lower alkyl or carboxy, R8 signifies hydrogen, hydroxy, lower alkoxy, amino, lower alkylamino or di-lower alkylamino and Y signifies an oxygen or sulphur atom, and pharmaceutically acceptable salts thereof.

The products have an inhibitory action on the DNA-gyrase activity in bacteria. They can accordingly be used for the prevention or control of bacterial infections.

Description

5 ~ ~

The present invention is concerned with novel sub6tituted pyrimidobenzimidazole derivatives of the general formula Rl 15 R2 ~ ~ R8 wherein Rl signifies hydrogen, halogen or amino, R signifies halogen, R signifies a lower alkyl-substituted 4-pyridyl group or a group R R N- in which R and R each signify hydrogen or lower alkyl or together signify a group of the formula ~(CH2)n~X~ICH2)m~ or -(CH2) ~
which is unsubstituted or substituted by lower alkyl, amino, lower aminoalkyl, mono- or di(lower alkyl)-amino-lower alkyl, oxo or the group -COOR or -CONR'R", n and m each signify the number 1, 2 or 3, with the proviso that n ~ m i~ a maximum of 5, p gignifies the number 4, 5 or 6, X signifies an oxygen or sulphur atom or the group -NR"'-, R signifies hydrogen, lower alkyl, lower alkenyl, phenyl or phenyl which is mono-, di- or trisubstituted by halogen, lower alkyl or hydroxy, R' and R" each signify hydrogen or lower alkyl, R"' signifies hydrogen, hydroxy, lower alkyl or lower aminoalkanoyl, R
signifies hydrogen, halogen, lower alkoxy or amino, R signifies lower alkyl, lower cycloalkyl, lower Mn/25.9.90 3 ~

haloalkyl, phenyl or phenyl which is mono-, di- or tri6ub~tituted by halogen, lower alkyl, hydroxy or S lower alkoxy, R7 signifie~ hydrogen, lower alkyl or carboxy, R ~ignif ies hydrogen, hydroxy, lower alkoxy, amino, lower alkylamino or di-lower alkylamino and Y signifie6 an oxygen or sulphur atom, and pharmaceutically acceptable salts thereof.

The novel compounds of formula I above have valuable pharmacological properties. They display an inhibitory action on the DNA-gyrase activity in bacteria and can accordingly be used for the control or prevention of bacterial infections.

Objects of the present invention are: the above compounds of formula I per se and for use as therapeu-tically active substance6; a proces6 and intermediates for their manufacture, medicament6 based on these novel 6ubstances; a6 well as the use of the novel compounds of formula I for the control or prevention of bacterial infections and for the manufac~ure of antibacterially--active medicament&.
The term "lower" used in the scope of the present description denotes residue6 and compounds having a maximum of 7, preferably a maximum of 4, carbon atoms. The term "alkyl", taken alone or in combination6 such as "alkyl group" and "alkoxy", denotes straight-chain or branched saturated hydrocarbon residue~ such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl and t-butyl. The term "alkenyl" denotes ~traight-chain or branched hydrocarbon residues which contain at least one olefinic double bond, such as allyl and 2-butenyl. The term "cycloalkyl" denotes cyclic saturated hydrocarbon residues such as cyclopropyl. The ~erm "alkanoyl" denotes residues of straight-chain or branched saturated fat~y 2 ~

acids, such as acetyl. The term ~halogen~ denotes the four forms fluorine, chlorine, bromine and iodine.

Preferably, Rl and R5 each signify hydrogen. R
preferably signifies fluorine. R3 and R4 preferably together signify a group of the formula -(CH2)n-~-(CH2)m_ or a group of the formula -(CH2)p- which i~ substituted by the group -COORa, wherein n and m each signify the number 2, p signifies the number 4, X signifies the group -NR"'-, R ~ignifies lower alkyl and R"~ signifies hydrogen, lower alkyl or lower aminoalkanoyl. R3R4N- is preferably l-pipera-zinyl or 4-methyl-1-piperazinyl. R6 preferably signifies lower alkyl, especially ethyl, or lower cycloalkyl, especially cyclopropyl. R preferably signifies hydrogen or carboxy. R preferably signifies hydrogen, hydroxy, amino, methylamino or dimethylamino. Y preferably signifies an oxygen atom. W~en R signifies a lower alkyl-substituted 4-pyridyl group, this is preferably the 3,5-dimethyl-4-pyridyl group.

The compounds listed hereinafter are representative members of the novel class of substance defined by general formula I:

5-Ethyl-8-fluoro-7-(4-methyl-1-piperazinyl)-pyrimido-[1,6-a]benzimidazole-1,3(2H,5H)-dione, 5-cyclopropyl-8-fluoro-7-(1-piperazinyl)-pyrimido-tl~6-aJbenzimidazole-l~3(2H~5H)-dione~
5-ethyl-9-fluoro-3,5-dihydro-8-(4-me~hyl-1-piperazinyl)--3-thioxopyrimido[1,6-a]benzimidazol-1(2H)-one, 5-cyclopropyl-8-fluoro-2-hydroxy-7-(1-piperazinyl)-35 -pyrimido~1,6-a]benzimidazole-1,3(2H,5H)-dione, tert-butyl rac-l-[5-cyclopropyl-8-fluoro-2,3-dihydro--1,3-dioxopyrimido[1,6-a]benzimidazole-5(1H)-yl]-2--pyrrolidinecarboxylate, 2~2~53~

7-(4-L-alanyl-l-pipera2inyl)-S-cyclopropyl-8-fluoro-2--hydroxypyrimido[1,6-a]benzimidazole-1,3(ZH,5H)-dione, 1-[5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-2-hydroxy--1,3-dioxopyrimido[1,6-aJbenzimidazol-7-yl~-L-proline tert-butyl ester, 5-ethyl-B-fluoro-7-(1-piperazinyl)pyrimido[1,6-a]-benzimidazole-1,3(2H,5H)-dione, 5-ethyl-8-fluoro-2-hydroxy-7-(4-methyl-1-piperazinyl)-pyrimido[l,6-a]benzimidazole-1,3(2H,5~)-dione, 5-cyclopropyl-8-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-7--(l-piperazinyl)pyrimido[1,6-a~benzimidazole-4-carboxylic acid, 5-ethyl-8-fluoro-2-hydroxy-7-(1-piperazinyl)pyrimido-[1,6-a]benzimidazole-1,3(2H,5H)-dione, 2-amino-5-cyclopropyl-8-fluoro-7-(1-piperazinyl)pyri-midorl,6-a]benzimidazole-1,3(2H,5H)-dione, 5-cyclopropyl-8-fluoro-2-(methylamino)-7-(1-pipera-zinyl)pyrimido[l,6-a]benzimidazole-1,3(2H,5H)-dione and 5-cyclopropyl-2-(dimethylamino)-a-fluoro-7-(1-pipera-zinyl)pyrimido[l,6-a]benzimidazole-1,3(2H,5H)-dione.

The novel compounds of formula I and their pharmaceu-tically acceptable 6alt6 can be manufactured in accordance with the invention by a) reacting a compound of the general formula ~1 ~ ~ ~ R8 II

~ R6 R7 wherein R Y Rl R2 R5 R6 R7 d R8 2 ~ 3 ~

have the above fiignificance, with the proviso that free hydroxy, amino and carboxy groups which may be present are in protected form, optionally in the presence of a ba~e with a compound of the general formula X-CO-X III

wherein X signifies a leaving group, or b) reacting a compound of the genecal formula Rl ~ ¦ HN NHR8 IV

R ~ 'H

wherein R, R , R , R , R and R8 have the above ~ignificance, with the proviso that free hydroxy, amino and carboxy group~ which may be present are in protected form, in the pre~ence of a base with a compound of the general formula RaOOC-CHR7-COORa V

wherein Ra signifie~ lower alkyl and R has the above significance, with the proviso that a free carboxy group which may be present ifi in protected 2~2~3~

form, or c) reacting a compound of the general formula ~,1 R2 ~ Vl ~5 ~6 COORb wherein Rb signifies a carboxy protecting group and R, R , R , R and R have the above significance, with the proviso that free hydroxy, amino and carboxy groups which may be present are in protected form, with 2 molac equivalents of chloroacetyl isocyanate, whereupon any protecting groups present are cleaved off and a compound of formula I obtained is, if desired, converted into a pharmaceutically acceptable salt.
In the above processes the reactive free hydroxy, amino and carboxy groups which may be present in the starting materials must be blocked by protecting groups.
These instances will be readily recognisable by a person skilled in the art and the choice of the respective suitable protecting groups will also pre6ent no difficulties to him. There come into consideration for the present purpose e6pecially the protecting groups which are usually used in peptide chemistry.

An especially suitable amino protecting group i8 the t-butoxycarbonyl group which can be cleaved off readily, for example, by treatment with trifluoroacetic acid, dilute HCl~dioxan or sodium iodide/trimethylchlorosilane/
acetonitrile.

An especially suitable hydroxy protecting group is the benzyl gcoup which can be cleaved off readily, for example, by reduction with elementary hydrogen on a suitable catalyst (e.g. palladium/carbon). Suitable solvents for this are, for example, lower alcohols such as ethanol and dimethylformamide.

An especially suitable carboxy protecting group is the p-nitrobenzyl group which also can be cleaved off by reduction with elementary hydrogen in the pre~ence of a suitable catalyst (e.g. palladium/carbon). Suitable solvents for this are also lower alcohols such as ethanol and dimethylformamide.

In accordance with process variant a) the compounds of formula I can be manufactured by reacting a compound of formula II with a compound of formula III optionally in the presence of a base. As the compound of formula III
there is preferably used phosgene or a precursor'thereof or N,N'-carbonyldiimidazole, with the last-named compound being particularly preferred. A tertiary amine such as triethylamine or a bicyclic amidine such as 1,8-diazabi-cyclo~5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN) is preferably used as the base. Suitable solvents are, for example, open-chain and cyclic ethers such as diethyl ether, t-butyl methyl ether and tetra-hydrofuran (THF). The reaction is preferably carried out in a temperature range of about room temperature to about 100C.
In accordance with process variant b) the compounds of formula I can be manufactured by reacting a compound of formula IV with a compound of formula V in the presence of f~ h ~ 3 3 a base. A lower alkali metal alcoholate 6uch as sodium methanolate or potas6ium methanolate is preferably used as the base. The corresponding lower alcohol, e.g. methanol, i6 preferably used as the solvent. This reaction is preferably carried out at room temperature.

Compound6 of formula I in which R7 signifie6 carboxy, R8 signifiefi hydrogen and Y signifie6 an oxygen atom ean be manufactured in accordance with proce6s variant c). The reaction of a compound of formula VI with 2 molar equivalent6 of chloroacetyl isocyanate is preferably carried ou~ in an inert organic solvent, with e.g. open-chain and cyclic ethers such as diethyl ether, t-butyl methyl ether and tetrahydrofuran coming into consideration for thi6 purpose. The reaction i6 preferably carried out in a temperature range of 0C to room temperature.

Pharmaceutically acceptable 6alts of compound6 of formula I can be manufactured according to method6 which are known per 6e and which are familiar to any per60n 6killed in the art. Compound6 of formula I which have a free carboxy group can be converted into such salt6, for example, by treatment with a suitable base. Alkali metal salts such as the sodium and potassium salt~ can be mentioned as examples of such salts.

Compounds of formula I which have a bafiic amino group can be converted into acid addition 6alts, for example, by treatment with pharmaceutically acceptable acids. As acid addition salt6 there come into consideration not only salts with inorganic acids but also salts with organic acids, for example hydrochloride~, hydrobromides, sulphates, nitrates, citrates, tartrates, acetates, maleates, succinates, methanesulphonates, p-toluene-sulphonates and the like.

'~2~3~

The compounds of general formulae II, IV and VI which are used as starting materials are novel and are al~o objects of the present invention. These ~tarting materials can be prepared according to methods which are known per se and which are familiar to any person skilled in the art. The Examples which follow below contain detailed information concerning the preparation of these starting 10 materialS-The intermediate~ correEponding to formula I in whichfree hydroxy, amino and/or carboxy groups present are in protected form, which are obtainable according to process variants a), b) and c), are also objects of the invention.

As mentioned earlier, the compound~ of formula I in accordance with the invention and their pharmaceutically acceptable salts display an inhibitory action on the DNA-gyrase activity in bacteria. They can accordingly be used for the prevention or control of bacterial infections.

The inhibitory action on the DNA-gyrase activity in bacteria can be determined, for example, by means of the supercoiling method described by R. Otter and N.R. Cozzarelli in Methods in Enzymology, Vol. 100, pp. 171-lBO tl983). The DNA-gyrase used was isolated from E. coli N4186 and from the sub-unit B of E. coli MK47 (~itsuchi et al., JBL 159, 9199-9201 (1984)). Relaxed pUC18 or pUCl9 pla~mid DNA was used as the substrate. The results determined in this test are compiled in the following Table, with the results being expressed a~ the MNC (maximum non-effective concentration) in ~g/~l.

2 ~ 3 ~

Table Activity Toxicity MNC in LD50 in Product from ~g~ml mg/kg _ Example 1 2 Example 2 0.45 30 (i.v.) >2000 (p.o.) Example 3 2 _ lS Example 4 2 30 (i.v.) >4000 (p.o.) Example 8 The compounds of formula I and their pharmaceutically acceptable salt6 can be used as medicaments, e.g. in the focm of pharmaceutical preparations for enteral or parenteral application. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsule6, solution6, emulsions or fiuspen6ions, rectally, e.g. in the form of 6upposi~0ries, or parenterally, e.g. in the form of injection 601utions.
30 The manufacture of the pharmaceutical preparations can be effected in a manner which i6 familiar to any person skilled in the art by bringing the product6 in accordance with the invention, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier 2Q~3~

materials and, if desired, the usual pharmaceutical adjuvants.

Suitable carrier material~ are not only inorganic carrier materials, but also organic carrier materials.
Thus, lactose, maize starch or derivatives thereof, talc, stearic acid or its salts can be used, for example, as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules).
Suitable Carrie materials for the manufacture of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppo~itorie6 are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.

As pharmaceutical adjuvants there come into consideration the usual stabilizing, preserving, wetting and emulsifying agents, flavour-improving agents, salts for varying the osmotic pressure, buffer fiubstances, solubilizers, colouring and coating agents and anti-oxidants.

The dosage of the compounds of formula I can vary within wide limits depending on the bacterial infection to be controlled, the age and the individual condition of the patient and on the mode of administration and will, of cour6e, be fitted to the individual requirements in each particular case. A daily dosage of about 0.05 g to about 4 g, especially about 0.1 g to about 2 g, comes into 2~2~53~

consideration foc adult patients. Depending on the dosage it is convenient to administer the daily dosage in several unit dosages.

The pharmaceutical p~eparations conveniently contain about 25-2000 mg, preferably 50-1000 mg, of a product in accordance with the invention.

The following Examples serve to illustrate the present invention in more detail. However, they are not intended to limit its scope in any manner. All temperatures are given in degrees Celsius.
Example 1 a) A suspension of lithium aluminium hydride (44.1 g, 1.16 mmol) in absolute ether (700 ml) is treated dropwise with a solution of 3'-chloro-4'-fluoroacetanilide (BE
Patent No. 891537; 109 g, 0.576 mol) in absolute THF
(350 ml). The suspension obtained is stirred for 2 hours, then cooled to 0 and treated with a Rochelle salt solution (350 ml). The crystals obtained are filtered off and washed with ether. The organic solution is dried over magnesium fiulphate and the solvent is distilled off under reduced pressure. There are obtained 97.5 g (97.5%) of 3-chloro-N-ethyl-4-fluoroaniline as an amorphous material.

b) A solution of 3-chloro-N-ethyl-4-fluoroaniline (97.4 g, 0.56 mmol) in glacial acetic acid (225 ml) is treated at 5 with acetic anhydride tlO5 ml, 1.12 mol).
The solution is stirred for one hour, then poured on to ice/water (250 ml) and extracted with ethyl acetate (2x 200 ml). The combined phases are washed in succession with water (100 ml), 2N sodium hydroxide solution (100 ml), saturated sodium bicarbonate solution (100 ml), water tlO ml) and 10 percent sodium chloride solution 2~28~3~

(100 ml). The solution i8 dried over magnesium 6ulphate and evaporated. The residue i6 recrystallized from n-hexane. There are obtained 102 g (84.2%) of 3'-chloro-N--ethyl-4'-fluoroacetanilide.
Microanalysi6 CloHllClFNo:
Calc.: C 55.70 H 5.14 N 6.50 Found: 55.04 5.43 6.57.

c) 3~-Chloro-N-ethyl-4~-fluoroacetanilide (101 g, 0.468 mmol) is di~solved in conc. 6ulphuric acid (300 ml).
A solution of potas6ium nitrate (57 g, 0.564 mol) in conc.
6ulphuric acid (220 ml) is added dropwi6e thereto at 5.
The solution obtained i~ 6~irred overnight, then poured on to ice/water and extracted with ethyl acetate (2x 200 ml).
The organic phase i6 washed in succession with water (200 ml), saturated sodium bicarbonate solution (100 ml) and saturated sodium chloride solution (100 ml). The organic phase is treated with active charcoal, filtered and dried over magnesium sulphate. The ~olvent is distilled off and the re6idue is recry6tallized from ether/n-hexane. There are obtained 74.8 g (61~) of 5'-chloro-N-ethyl-4'-fluoro-2'-nitroacetanilide with a 25 m.p. of 680.
Microanalysis CloHloFClNzO3:
Calc.: C 46.08 H 3.87 N 10.75 Found: 45.99 3.92 10.82.

30 d) 5'-Chloro-N-ethyl-4'-fluoro-2'-nitroacetanilide (74 g, 0.284 mmol) is treated with N-methylpiperazine (126 ml, 1.13 mol) and the solution obtained is ~tirred at 60 for 2 hours. The reaction mixture i6 evaporated, the re6idue is dissolved in ethyl acetate (250 ml) and wa~hed in 35 6uccession with water (3x 100 ml) and 10 percent sodium chloride 601ution (100 ml). The organic solution is dried over magne~ium sulphate and evaporated. The residue is recry6tallized from ethyl acetate/n-hexane. There are ~2~3~

obtained 72.3 g (78.5%) of N-ethyl-4'-fluoro-5'-(4-methyl--l-piperazinyl)-2'-nitroacetanilide with a m.p. of Microanalysis C15H21FN4O3 Calc.: C 55.50 H 6.53 N 17.27 Found: 55.47 6.73 17.14.

e) A solution of N-ethyl-4'-fluoro-5'-(4-methyl-1--piperazinyl)-2'-nitroacetanilide (20 g, 61 mmol) in methanol (160 ml) is treated with an agueous pota6sium hydeoxide 601ution (34.6 g, 616 mmol). The solution is heated to 80 foc 3 hourE and thereafter cooled to room temperature. The crystal6 obtained are filtered off and washed with water. There are obtained 13.7 g (78.7~) of 1-(5-(ethylamino)-2-fluoro-4-nitrophenyl)-4-methyl-piperazine with a m.p. of 149-150.
Microanalysi6 C13HlgFN4O2:
Calc.: C 55.31 H 6.78 N 19.85 Found: 55.16 6.95 19.81.

f) A solution of 1-(5-(ethylamino)-2-fluoro-4-nitro-phenyl)-4-methylpiperazine (10 g) in THF (200 ml) i6 hydrogenated over 5 percent Pd/C under hydrogen. At the end of the reduction the catalyst is filtered off, the filtrate is treated directly with a ~olution of sodium cyanate (230 mg) in water (50 ml~ and the pH is adjusted to 3.5 with conc. HCl (2.5 ml). After stirring under argon for two hours the pH is adjusted to 8 with 4N NaOH and the solution is evaporated under reduced pressure. The re6idue is extracted with methanol/ethyl acetate (1:4). The solution i8 filtered. decolorized with active charcoal and evaporated in a vacuum. The residue iE taken up in warm ethyl acetate. After cooling the crystals are filtered off and dried. There i~ obtained 0.63 g (60~) of 1-[2-(N--ethylamino~-5-fluoro-4-t4-methyl-1-piperazinyl]phenyl-urea.

2028~30 Microanalysis C14H22FN5O:
Calc.: C 56.93 H 7.51 N 23.71 Found: 57.16 7.64 23.80.

g) A solution of 1-[2-(N-ethylamino)-5-fluoro-4-(4--methyl-l-piperazinyl]phenyl-urea (640 mg) in methanol i6 treated with a freshly prepared methanolic solution of sodium methylate (from 150 mg of sodium) and heated under reflux for a short time. After cooling the solution is treated with diethyl malonate and stirred for 6 hours. The solution obtained in poured into a mixture of ise and 2N
HCl (50 ml). The methanol is evaporated and the aqueous phase is extracted with ethyl acetate (3x 100 ml) and methylene chloride (Zx 100 ml). After drying over magnesium sulphate the solvent mixture is evaporated and the residue is suspended in a small amount of cold ethyl acetate and filtered off. There are obtained 130 mg (17%) 20 of 5-ethyl-8-fluoro-7-(4-methyl-1-piperazinyl)pyrimido--tl~6-a]benzimidazole-l~3(2H~5H)-dione.
MS: 345(M) Microanalysis (hydrochloride) C17H21ClFN5O2:
Calc.: C 53.47 H 5.54 N 18.34 25 Found: 52.97 5.52 18.12.

ExamPle 2 a) l-Chloro-2.5-difluoro-4-nitrobenzene ~3.69 g, 19 mmol) 30 is treated at 0 with diethylamine (2.3 g. 23 mmol) and cyclopropylamine (1.3 g, 23 mmol). After 1 hour at 0 the suspension obtained is stirred at 25 for 16 hours. The reaction mixture i6 ~aken up in water (150 ml) and extracted with ethyl acetate. The organic phase i6 washed with 10 percent sodium chloride solution and dried over magnesium sulphate. After distillation of the solvent the residue is recrystallized from ethanol (50 ml). There are obtained 3.5 g (79%) of 5-chloro-N-cyclopropyl-4-fluoro-2-3 ~

-nitroaniline with a m.p. of 73.5-75.5.
Microanalysis CgH8ClFN202 Calc.: C 46.87 H 3.50 N 12.15 Found: 46.59 3.64 12.15.

b) 5-Chloro-N-cyclopropyl-4-fluoro-2-nitroaniline (3.5 g.
15.2 mmol) i6 heated with N-acetylpiperazine (3.89 g, 30,4 mmol) and triethylamine (Z.3 g 22.8 mmol) while stirring vigorously and held at 60 for 12 hours. The mass obtained i6 dissolved in water (200 ml) and extracted with ethyl acetate. The organic phase is washed with 10 percent sodium chloride solution and then dried over magnesium sulphate. After distillation of the solvent the residue is recrystallized from ethanol. There are obtained 4.57 g (93~) of 1-acetyl-4-[5-(cyclopropylamino)-2-fluoro-4--nitrophenyl]piperazine with a m.p. of 142-143.
Microanalysis C15HlgFN403:
Calc.: C 55.89 H 5.94 N 17.38 Found: 55.66 5.94 17.35.

c) l-Acetyl-4-t5-(cyclopropylamino)-2-fluoro-4-nitro-phenyl]piperazine (17 g, 53 mmol) is di6solved in methanol (250 ml), treated with potassium hydroxide (29.6 g, 527 mmol) and heated under reflux for 3 hours. The methanol is distilled off, the residue is dissolved in ethyl acetate and the organic pha6e is wa~hed in succe6sion with water and sodium chloride olution and dried over magnesium sulphate. After distillation of the solvent the residue i6 dissolved in dioxan (100 ml) and treated with di-tert-butyl dicarbonate (13.8 g, 63.24 mmol) and an aqueou6 solution of sodium hydrogen carbonate (6.6 g, 79 mmol, in 60 ml of water). After stirring for 20 hours the su6pension obtained is diluted with water. The cry6tals are filtered off, washed with water and recrystallized from ethanol. There are obtained 18.2 g (91%) of tert-butyl 4-[5-(cyclopropylamino)-2-3 û

-fluoro-4-nitrophenyl]-1-pipeeazinecarboxylate with a m.p.
of 159-160.
Microanalysis C18H25FN404 Calc.: C 56.83 ~ 6.62 N 14.73 Found: 56.9Z 6.70 14.89.

d) tert-Butyl 4-~5-(cyclopropylamino)-2-fluoro-4-nitro-phenyl]-l-piperazinecarboxylate (17.21 g, 45.2 mmol) i6 dissolved in methanol (500 ml) and hydrogenated with S percent Pd/C (500 mg) under hydrogen at normal pressure.
The hydrogen uptake amounts to 3.04 1. The palladium/
carbon is filtered off under an inert gas and the methanol is distilled off under reduced pressure. The residue i6 dried in a high vacuum, then dissolved in DMF (lS0 ml) and treated with ethyl 3-ethoxy-3-iminopropanoate hydro-chloride (17.3 g, 88.4 mmol). The 601ution obtained i6 heated to 50 for 2 hours. The DMF is distilled off, the residue is dissolved in water and the pH is adjusted to 8.0 with saturated sodium bicarbonate solution. The solution is extracted with ethyl acetate and the organic phase i6 washed in succession with water. 10 percent sodium chloride solution and then dried over magnesium sulphate. The solution is evaporated under reduced pressure and the residue is chromatographed on silica gel (eluent: ethyl acetate). The product is then recrystal-lized from ethyl acetate/hexane. There are obtained lS.S g (78%) of ethyl 6-~4-(tert-butoxycaebonyl)-1-piperazinyl]--1-cyclopeopyl-S-fluoro-2-benzimidazoleacetate with a m.p.
of 152-153.
Microanalysis C23H31FN404:
Calc.: C 61.87 H 7.00 N 12.55 Found: 62.13 7.17 12.68.

e) Ethyl 6-[4-(tert-butoxycarbonyl)-1-piperazinyl]-1--cyclopropyl-S-fluoro-2-benzimidazoleacetate (4.5 g, 10 mmol) is dissolved in ethanol (100 ml) and treated with 2~2~30 ammonium chloride (5.35 g, 100 mmol) and 25 percen~
ammonium hydroxide solution (50 ml). The suspension obtained is stirred at 50~ for 18 hours and thereafter evaporated under reduced pressure. The residue is suspended in ethyl acetate (150 ml) and the insoluble ammonium chloride is filtered off. The filtrate is concentrated to a volume of 50 ml and then chromatographed on silica gel (eluent: ethyl acetate/methanol 9:1). The product i8 recrystailized from ethyl acetate/n-hexane.
There are obtained 2.22 g (53%) of tert-butyl 4-[2--(carbamoylmethyl)-l-cyclopropyl-5-fluoro-6-benz-imidazolyl]-l-piperazinecarboxylate with a m.p. of 219-~2oo~
~icroanalYsis C21H28FN503 Calc.: C 60.42 H 6.76 N 16.78 Found: 60.26 6.88 16.31.

f) tert-Butyl 4-r2-(carbamoylmethyl)-1-cyclopropyl-5--fluoro-6-benzimidazolyl]-1-piperazinecarboxylate (980 mg, 2.53 mmol) is suspended in THF (15 ml) and treated with l,l'-carbonyldiimidazole (760 mg, 2 mmol) and 1,8-diaza-bicyclo[5.4.0]undec-7-ene (0.2 ml). The reaction mixture is heated to 60 for 2 hours, whereby white crystals separate. The suspension is then cooled to 0. The crystals are filtered off and recrystallized from ethanol.
There are obeained 760 mg (73~) of tert-butyl 4-t5-cyclo-propyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido-[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate.
Microanalysis C22H26FN504 with 0.6 mol of ethanol Calc.: C 59.41 H 6.67 N 14.69 Found: 59.15 6.33 14.87.

g) tert-Butyl 4-[5-cyclopropyl-8-fluoro-1,2,3,5-tetra-hydro-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-1--piperazinecarboxylate (471 mg, 1 mmol) is dissolved in trifluoroacetic acid (2 ml). After 1 hour at 25 the 20~3~

trifluoroacetic acid is distilled off. The residue i8 taken up in water (10 ml), treated with sodium hydrogen carbonate (168 mg, Z mmol) and ~tirred at 25 for 2 hours.
The suspension is cooled to 0. The crystals are filtered off, washed in 6uccession with in each case S ml of cold water and ethanol and recrystallized from ethanol/water (95/5). There are obtained 208 mg (60.~%) of 5-cyclo-propyl-8-fluoro-7-(1-piperazinyl)-pyrimido~1,6-a]benz-imidazole-1,3(2H,5H)-dione trifluoroacetate.
Microanalysis C17HlgFNsO2 CF3 Calc.: C 49.89 H 4.19 N 15.31 Found: 49.71 4.43 15.29.

Example_3 a) l-t5-(Ethylamino)-2-fluoro-4-nitrophenyl]-4-methyl-piperazine (2.8 g, 10 mmol) is dissolved in methanol (zoo ml) and hydrogenated with 5 percent palladium/carbon under hydrogen at hormal pressure. The palladium/carbon is filtered off and the filtrate is evaporated under reduced pressure. The residue i8 dried in a high vacuum, dissolved in diethyl glycol ethyl ether (10 ml) and then treated with ethyl cyanoacetate (2.26 g, 20 mmol). The solution is heated to 160 for 4 hours. The ~olvent i~ then distilled off and the residue is taken up in an acetic acid/ether mixture (100 ml, 1:2). The crystals obtained are filtered off, dissolved in an ethyl acetate/methanol mixture (6:4) and chromatographed on silica gel (eluent: ethyl acetate/
methanol 6:4~. The produc~ is recrystallized from an ethyl acetate/ace~onitrile mixture (9:1). There are obtained 1.17 g (39%) of 1-ethyl-5-fluoro-6-(4-methyl-1--piperazinyl)-2-benzimidazoleacetonitrile with a m.p. of 204-206.
Microanalysis C16H20FN5:
Calc.: C 63.77 H 6.69 N Z3.24 Found: 63.65 6.54 23.31.

2a28~30 b) l-Ethyl-5-fluoro-6-(4-methyl-1-piperazinyl)-2-benz-imidazoleacetonitrile (834 mg, ~.77 mmol) is dissolved in pyridine (20 ml) and triethylamine (2.B g, 27.7 mmol). The solution i8 cooled to 0~. Subsequently, hydrogen sulphide is introduced during 30 minutes. The thus-obtained deep green solution is heated to 45 for 2 hours. The solvent is distilled off and the residue is dried in a high vacuum and then crystallized from acetonitrile. The crystals are filtered off, dissolved in an ethyl acetate/methanol mixture (10 ml, 1:1) and then chromatographed on silica gel (eluent: ethyl acetate/methanol 6:4). The product is recrystallized from ethyl acetate. There are obtained 745 mg (80%) of 1-ethyl-5-fluoro-6-t4-methyl-1--piperazinyl]-2-benzimidazolecarbothioamide.

Calc.: C 56.38 H 6.68 N 20.55 Found: 56.32 6.76 20.41.

c) l-Ethyl-5-fluoro-6-[4-methyl-1-piperazinyl]-~-benz-imidazolecarbothioamide (120 mg, 0.36 mmol) is su6pended in tetrahydrofuran (2 ml) and treated with carbonyldi-imidazole (140 mg, 0.86 mmol). The reaction solution i~heated to 68 for 6 hours, whereby white crystals separate. The suspension is cooled to 0. The crystals are filtered off, suspended in methanol and, after one hour, again filtered off, washed with ether and dried in a high vacuum. There are obtained 22 mg (16.g%) of 5-ethyl-9--fluoro-3,5-dihydro-8-~4-methyl-1-piperazinyl)-3-thioxo-pyrimidorl,6-a]benzimidazol-1(2H)-one.
Microanalysis C17H20FN5S- 7 H2O
Calc.: C 54.59 H 5.77 N 18.72 35 Found: 54.37 5.84 18.64.

~2~3~

ExamPle 4 a) tert-Butyl 4-[2-carbamoylmethyl)-1-cyclopcopyl-5--fluoro-6-benzimidazolyl~-1-piperazinecarboxylate (703 mg, 1.68 mmol) is heated to 50 for 72 hours with 0-benzyl-hydroxylamine hydrochloride (806 mg, 5.05 mmol) in a water/ethanol mixture (5 ml, 1:1). The solvent is distilled off and the residue is stirred in water (20 ml).
The crystal~ obtained are filtered off, washed with water and dried in a high vacuum. The product i6 recrystallized from ethyl acetate. There are obtained 317 mg (36%) of tert-butyl 4-[2-[[(benzyloxy)carbamoyl]methyl]-1-cyclo-propyl-5-fluoro-6-benzimidazolyl]-1-piperazinecarboxylate.
Microanaly6is C28H34FN504:
Calc.: C 64.23 H 6.55 N 13.38 Found: 64.35 ~.83 13.35.

b) tert-Butyl 4-12-[[(benzyloxy)carbamoyl]methyl~-1-~cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazine-carboxylate (779 mg, 1.18 mmol) is dissolved in tetra-hydrofuran (15 ml) and treated with N,N'-carbonyldi-imidazole (480 mg, 2.96 mmol) and 1,8-diazabicyclo~5.4.0]-undec-7-ene (225 mg, 1.48 mmol). The suspension obtained is poured into water (200 ml) and then extracted with ethyl acetate. The organic phase i~ washed in 6uccession with water and 10 percent sodium chloride solution and dried over magnesium sulphate. The solvent is evaporated under reduced pressure and the residue is chromatographed on silica gel (eluent: ethyl acetate/n-hexane 8:2). The product is crystallized from ethyl acetate/n-hexane. There are obtained 42 mg (5%) of tert-butyl 4-[2-(benzyloxy)-5--cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido-[1,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate.
Microanalysis C29H32FN505:
Calc.: C 63.38 H 5.e7 N 12.74 Found: 62.78 5.69 12.64.

2~2~3~

c) tert-Butyl 4-[2-(benzyloxy)-5-cyclopropyl-B-fluoro--1,2,3,5-tetrahydro-1,3-dioxopyrimidorl,6-a~benzimidazol--7-yl]-1-piperazinecarboxylate (981 mg, 1.87 mmol) is dissolved in ethanol (250 ml) and hydrogenated with 5 percent palladium/carbon (200 mg) under hydrogen at normal pressure. The palladium/carbon is filtered off and washed with dimethylformamide (100 ml) at 100. The combined filtrates are evaporated under reduced pressure.
The residue is recrystallized from dimethylformamide.
There are obtained 619 mg (72%) of tert-butyl 4-[5-cyclo-propyl-8-fluoro-1,2,3,5-tetrahydro-2-hydroxy-1,3-dioxo-pyrimido[l,6-a]benzimidazol-7-yl]-1-piperazinecarboxylate.
lS Microanaly6is C22H26FN55 Calc.: C 57.51 H 5.70 N 15.24 Found: 57.27 5.65 15.38.

d) tert-Butyl 4-[5-cyclopropyl-8-fluoro-1,2,3,5-tetra-hydro-2-hydroxy-1,3-dioxopyrimidorl,6-a~benzimidaZol-7--yl]-l-piperazinecarboxylate (350 mg, 0.76 mmol) i8 treated with a 2.5N hydrochloric acid solution in dioxan (4 ml), whereby a white precipitate forms immediately. The suspension is ~tirred at room temperature (25) for 18 hours. The separated crystals are filtered off and dissolved in water (10 ml). The solution is treated with active charcoal, then filtered and cooled to 0. The separated crystals are filtered off, washed with ethanol and ether and dried in a high vacuum. There are obtained 176 mg (58%) of 5-cyclopropyl-8-fluoro-2-hydroxy-7-(1--piperazinyl)-pyrimidorl,6-a]benzimidazole-1,3(2H,5H)--dione hydrochloride.
Microanaly6is C17HlgFN503:
Calc.: C 51.59 H 4.84 N 17.69 35 Found: 51.27 5.11 17.54.

202~3~

ExamPle 5 a) 5-Chloro-N-cyclopropyl-4-fluoro-2-nitroaniline (460 mg, 2 mmol) i6 heated to 80 for 40 hours with L-proline tert-butyl ester (342 mg, 2 mmol) and 1,8-diaza-bicyclo[5.4.0]undec-7-ene (304 mg, 2 mmol). The reaction mixture is then dissolved in a water/ethyl acetate mixture (1:1, 100 ml). ~he ethyl acetate phase is washed with 10 percent sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel (eluent: hexane/
ethyl acetate 8:2). The product is crystallized from ether/n-hexane. There are obtained 94 mg (13%) of tert-butyl rac-1-[5-(cyclopropylamino)-2-fluoro-4-nitro-phenyl]pyrrole-2-carboxylate with a m.p. of 142-143.
Microanalysis C18H24FN304:
Calc.: C 59.17 H 6.62 N 11.50 Found: 59.23 6.62 11.52.

b) In analogy to Example 2d), from tert-butyl rac-1-[5--(cyclopropylamino)-2-fluoro-4-nitrophenyl]pyrrole-2--carboxylate there i6 obtained in a yield of 56~ ethyl rac-6-[2-(tert-butoxycarbonyl)-1-pyrrolidinyl]-1-cyclo-propyl-5-fluoro-2-benzimidazoleacetate with a m.p. of 93-96.
Microanalysis C23H30FN304:
Calc.: C 64.02 H 7.01 N 9.74 Found: 64.47 7.16 9.77.

c) In analogy to Example 2e), from ethyl rac-6-[2-(tert--butoxycarbonyl)-1-pyrrolidinyl]-1-cyclopropyl-5-fluoro-2--benzimidazoleacetate there is obtained in a yield of 34%
tert-butyl rac-1-[2-(carbamoylmethyl)-1-cyclopropyl-5--f luoro-6-benzimidazolyl]-2-pyrrolidinecarboxylate with a m.p. of 176-178.

~8~3~

Microanalysis C21H27FN4O3:
Calc.: C 6Z.67 H 6.76 N 13.92 Found: 62.40 6.86 13.60.

d) In analogy to Example 2f), from tert-butyl rac-1-[2--(carbamoylmethyl)-l-cyclopropyl-s-fluoro-6-benzimidazolyl]--2-pyrrolidinecarboxylate there is obtained in a yield of 60% tert-butyl rac-1-~5-cyclopropyl-8-fluoro-2,3-dihydro--1,3-dioxopyrimido~1,6-a]benzimidazol-7(1H)-yl]-2--pyrrolidinecarboxylate with a m.p. of 226-227.
Y 22 25 N404 0.2s THF
Calc.: C 61.87 H 6.10 N 12.55 Found: 61.77 6.38 12.62.

ExamPle 6 a) tert-Butyl 4-t2-(benzyloxy)-5-cyclopropyl-8-fluoro--1,2,3,s-tetrahydro-1,3-dioxopycimido[l,6-a]benzimidazol--7-yl]-1-piperazinecarboxylate (580 mg, 1.05 mmol) is treated with 33 percent hydrobromic acid in glacial acetic acid (5 ml). After 18 hours at room temperature the separated crystals are filtered off, washed with glacial acetic acid and recrystallized from methanol. The crystals are then dissolved in a watertethanol mixture (2:1, 50 ml). The pH is adjusted to B using lN sodium hydroxide solution, wheLeby white crystals separate. The crystaIs are filtered off, washed with water and dried in a high vacuum. There are obtained 417 mg (88%) of 2-(benzyloxy)--5-cyclopropyl-8-fluoro-7-(1-piperazinyl)pyrimido~1,6-a]-benzimidazole-1,3(2H,5H)-dione.
Microanalysis C24H24FN5O3:
Calc.: C 64.13 H 5.38 N 15.58 Found: 63.81 5.68 15.54.

b) Z-(L)-Alanine (223 mg, 1 mmol) is dissolved in dichloromethane (10 ml) and treated at 0 with dicyclo-2~2~.~3~

hexylcalbodiimide (103 mg, 0.5 mmol). After 30 minutes the cry6tal6 a~e filtered off and washed with a 6mall amount (30 ml) of dichloromethane. The filtrate i6 treated with a solution of 2-(benzyloxy)-5-cyclopropyl-B-fluorQ-7-(1--piperazinyl)pylimidorl,6-a]benzimidazole-1,3(2H,5H)-dione (112 mg, 0.25 mmol) in DMF (5 ml). After 2 hours the solvent i6 di6tilled off. The re6idue i6 recry6tallized from methanol. There are obtained 142 mg (86%) of benzyl t(S)-l-t[4-[2-(benzyloxy)-5-cyclopropyl-g-fluolo-1~2~3~5--tetrahydlo-1,3-dioxopyrimido[l,6-a]benzimidazol-7-yl]-1--piperazinyl]calbonyl]ethyl]calbamate.
MS: 653(M).
c) Benzyl [(S)-l-r[4-~2-(benzyloxy)-5-cyclopropyl-8--fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido[1,6-a]benz-imidazol-7-yl]-1-piperazinyl]calbonyl~ethyl]carbamate (127 mg, 0.194 mmol) i6 di6601ved in DMF (15 ml) and hydrogenated over 5 percent Pd/C. After completion of the reduction the catalyst i6 filtered off and the filtrate i6 evaporated. The residue i6 taken up in methanol (50 ml) and treated with active charcoal. After filtering off the charcoal the filtrate i6 concentrated to a volume of 25 ml- The 6eparated ceystal6 are filtered off. There are obtained 6Z mg (84%) of 7-(4-L-alanyl-l-piperazinyl)-5--cyclopropyl-B-fluo~o-2-hydloxypyrimido[1,6-a]benzimidazole--1,3(2H,5H)-dione.
Y 20H23FN64 0.25 CH30H:
Calc.: C 55.47 H 5.52 N 19.17 Found: 55.15 5.76 19.18.

Exam~le 7 a) A ~olution of ethyl rac-6-t2-(tert-butoxycalbonyl)-1--pyrlolidinyl]-l-cyclopropyl-5-fluoro-2-benzimidazole-acetate (1.647 g, 3.82 mmol) in ethanol (1~ ml) i6 treated with a lN ethanolic solution of hydroxylamine (9.54 ml, 202~30 9.54 mmol) and with a lN ethanolic sodium methylate 601ution (1.91 ml, 1.91 mmol). After one hour the solvent is distilled off and the residue is dissolved in water.
The pH is adjusted to 5.5 with lN hydrochloric acid. This solution i8 extracted with ethyl acetate and the organic phase is washed with water, dried (magnesium sulphate) and concentrated. The residue is recrystallized from ethyl acetate. The crystals obtained are dissolved in tetra-hydrofuran (30 ml) and treated with 1,8-diazabicyclo-r5.4.0]undec-7-ene (377 mg, 2.5 mmol) and benzyl bromide (462 mg, 2.7 mmol). After 4 hours the reaction solution is diluted with ethyl acetate (150 ml) and washed with water (100 ml) and subsequently with 10 percent sodium chloride solution (100 ml). The organic phase is dried (magne6ium sulphate) and concentrated. The residue is recrystallized from ether~n-hexane. There are obtained 643 mg (33%) of l-r2-[r(benzyloxy)carbamoyl]methyl]-1-cyclopropyl-5--fluoro-6-benzimidazolyl]-L-proline tert-butyl ester.
Microanalysis C28H33FN404:
Calc.: C 66.13 H 6.54 N 11.01 Found: 65.99 6.86 11.14.

b) In analogy to Example 4b), from l-t2-rr(benzyloxy)-carbamoyl~methyl]-l-cyclopropyl-5-fluoro-6-benzimidazolyl]--L-proline tert-butyl ester there is obtained in a yield of 78% 1-r2-(benzyloxy)-5-cyclopropyl-8-fluoro-1,2,3,5--tetrahydro-1,3-dioxopyrimidorl,6-a]benzimidazol-7-yl]-L--proline tert-butyl ester.
MS: 534(M).

c) In analogy to Example 4c), from 1-t2-(benzyloxy)-5--cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimido-tl~6-a]benzimidazol-7-yl]-L-proline tert-butyl ester there is obtained in a yield of 81% 1-r5-cyclopropyl-8-fluoro--1,2,3,5-tetrahydro-2-hydroxy-1,3-dioxopyrimido[1,6-a]-benzimidazol-7-yl]-L-proline tert-butyl ester.

2 ~ 3 ~

Microanalysis C22H25FN405 Calc.: C 59.45 H 5.67 N 12.61 ~ound: 59.03 5.54 12.51.

Example 3 a) In analogy to Example ld~, from N-acetylpiperazine and 5'-chloro-N-ethyl-4l-fluoro-2l-nitroacetanilide there is-obtained in a yield of 76% N-ethyl-4'-fluoro-5'-(4-acetyl--l-piperazinyl)-2'-nitroacetanilide with a m.p. of 129-131.
Microanalysis C16H21FN4O4:
Calc.: C 54.54 H 6.01 N 15.90 Found: 54.33 6.18 15.80.

b) A solution of N-ethyl-4'-fluoro-5'-(4-acetyl-1--piperazinyl)-2'-nitroacetanilide (8.4 g, 23.8 mmol) in methanol (100 ml) is treated with potassium hydroxide solution (13.3 g, 238 mmol in 20 ml). The solution is heated under reflux for 3 hours and then poured on to ice.
The separated crystals are filtered off (m.p. 129-131), suspended in dioxan/water 1:1 (200 ml) and treated with di-tert-butyl dicarbonate (4.44 g, 20.35 mmol) and sodium bicarbonate (1.71 g, 20.35 mmol). After 24 hours the reaction mixture is evaporated. The residue is taken up in ethyl acetate (500 ml) and washed with water (500 ml) and 10 percent sodium chloride solution. The organic phase is dried over magnesium sulphate and concentrated. The residue is crystallized from ethyl acetate/n-hexane. There are obtained 6.33 g (72%) of tert-butyl 4-[5-(ethylamino)--2-fluoro-4-nitrophenyl]-1-piperazinecarboxylate with a m.p. of 155-157.
c) In analogy to Example 2d), from tert-butyl 4-r5--(ethylamino)-2-fluoro-4-nitrophenyl]-1-piperazine-carboxylate there is obtained in a yield of 67% ethyl 2~28~3~

6-[4-tert-butoxycarbonyl)-1-piperazinyl]-1-ethyl-5-fluoro--2-benzimidazoleacetate with a m.p. of 13]-133.
Microanaly6iB c22H3lFN4o4 Calc.: C 60.81 H 7.19 N 12.89 Found: 60.73 7.44 12.88.

d) In analogy to Example 2e), from ethyl 6-t4-tert--butoxycarbonyl)-1-piperazinyl]-1-ethyl-5-fluoro-2-benz-imidazoleacetate there is obtained a yield of 36% tert--butyl 4-[2-carbamoylmethyl)-1-ethyl-5-fluoro-6-benz-imidazolyl]-l-piperazinecarboxylate with a m.p. of 162-164.
MS 405(M).

e) In analogy to Example 2f), from tert-butyl 4-[2.
-(carbamoylmethyl)-l-ethyl-5-fluoro-6-benzimidazolyl]-1--piperazinecarboxylate there is obtained in a yield of 67%
tert-butyl 4-(5-ethyl-8-fluoro-1,2,3,5-tetrahydro-1,3--dioxopyrimido[1,6-a]benzimidazol-7-yl)-1-piperazine-carboxylate with a m.p. of 270-273.
Microana ly6i s C21H26FN504 Calc.: C 58.46 H 6.07 N 16.23 Found: 58.18 6.30 16.16.

f) In analogy to Example 2g), from tert-butyl 4-(5-ethyl--8-fluoro-1,2,3,5-tetrahydro-1,3-dioxopyrimidorl,6-a]benz-imidazol-7-yl)-1-piperazinecarboxylate there i8 obtained in a yield of 70% S-ethyl-8-fluoro-7-(1-piperazinyl)-pyrimidorl,6-a]benzimidazole-1,3(2H,SH)-dione with a m.p.
of 264-266.
Microanalysis C16H18FN52- 2 CH30H:
Calc.: C 57.61 H 5.61 N 20.74 35 Found: 57.44 5.49 20.85.

2~28~3a ExamPle 9 S a) In analogy to Example 2d), from 1-(5-e~hylamino)-2--fluoro-4-nitrophenyl)-4-methylpiperazine thece i8 obtained in a yield of 30% ethyl 1-ethyl-5-fluoro-6-(4--methyl-l-piperazinyl)-2-benzimidazoleacetate with a m.p.
of 142-144.
Microanalysis Cl~H25FN402:
Calc.: C 62.05 H 7.23 N 16.08 Found: 61.68 7.31 16.09.

b) In analogy to Example 2e), from ethyl 1-ethyl-5--fluoro-6-(4-methyl-1-piperazinyl)-2-benzimidazoleacetate there i8 obtained 1-ethyl-5-fluoro-6-(4-methyl-1--piperazinyl)-2-benzimidazoleacetamide. From this inter-mediate there is obtained in analogy to Example 4a) in a yield of 35% (over both ~teps) 2-[[(benzyloxy)carbamoyl]-methyl]-1-ethyl-5-fluoro-6-(4-methyl-1-piperazinyl)-benz-imidazole with a m.p. of 165-168 (ethyl acetate).
Microanalysis C23H28FN502:
Calc.: C 64.92 H 6.63 N 16.46 Found: 64.92 6.85 16.36.
c) In analogy to Example 4b), fcom 2-[ r (benzyloxy)-carbamoyl]methyl]-l-ethyl-5-fluoro-6-(4-methyl-1--piperazinyl)-benzimidazole there i8 obtained in a yield of 54% 2-(benzyloxy)-5-ethyl-8-fluoro-7-(4-methyl-1--piperazinyl)pyrimidorl,6-a]benzimidazole-1,3(2H,5H)-dione with a m.p. of 250-252 (methanol).
Microanalysis C24H26FN503:
Calc.: C 63.85 H 5.80 N 15.51 Found: 63.64 6.13 15.43.
d~ In analogy to Example 4c~, from 2-(benzyloxy)-5-ethyl--8-fluoro-7-(4-methyl-1-piperazinyl)pyrimido[1,6-a]benz-imidazole-1,3(2H,5H)-dione there is obtained in a yield of 2 ~ 3 ~

53% 4-ethyl-8-fluoro-2-hydroxy-7-(4-methyl-1-piperazinyl)-pyrimido[l,6-a]benzimidazole-1,3(2H,5H)-dione.
Y 17 20 5 3 2 DMF:
Calc.: C 56.22 H 5.74 N 19.37 Found: 56.05 5.90 19.40.

ExamPle 10 a) In analogy to Example 2d), from p-nitrobenzyl 3-ethoxy-3-iminopropanoate hydrochloride and tert-butyl 4-[5-(cyclopropylamino)-2-fluoro-4-nitrophenyl]-1--piperazinecarboxylate there is obtained in a yield of 44%
p-nitrobenzyl 6-r4-(tert-butoxycarbonyl)-1-piperazinyl]-1--cyclopropyl-5-fluoro-2-benzimidazoleacetate.
Microanalysis C28H32FN506:
Calc.: C 60.75 H 5.83 N 12.65 Found: 60.81 6.11 12.54.

b) A solution of p-nitrobenzyl 6-t4-(tert-butoxy-carbonyl)-l-piperazinyl]-l-cyclopropyl-5-fluoro-2-benz-imidazoleacetate (553 mg, 1 mmol) in THF (50 ml) is treated in succession at 0 with triethylamine (300 mg, 3 mmol) ar.d chloroacetyl isocyanate (298 mg, 2.5 mmol).
After stirring for 20 hours the solvent i6 di~tilled off and the residue is taken up in ethyl acetate and washed in succession with water (50 ml) and 10 percent sodium chloride solution (50 ml). The organic phase is dried over magnesium sulphate and the 601vent is evaporated. The residue i8 recrystallized from ethyl acetate. There are obtained 373 mg (59%) of p-nitrobenzyl 5-cyclopropyl-8--fluoro-1,2,3,4-tetrahydro-1,3-dioxo-7-[4~(tert-butoxy-carbonyl)-l-piperazinyl]pycimido[1,6-a]benzimidazole-4--carboxylate.
Microanalysis C30H31FN608:
Calc.: C 57.87 H 5.02 N 13.50 Found: 57.50 5.04 13.38.

29~30 c) A 601ution of p-nitrobenzyl 5-cyclopropyl-8-fluoro--1,2,3,4-tetrahydro-1,3-dioxo-7-[4-(tert-butoxycarbonyl)--1-piperazinyl]pyrimidotl,6-a]benzimidazole-4-carboxylate (1.758 g, 2.82 mmol) in acetonitrile (Z50 ml) i8 treated in succe66ion with 60dium iodide (846 mg, 5.65 mmol) and trimethylchlorosilane (1.23 g, 11.28 mmol). After one hour at 80 the sufipen6ion obtained i6 cooled to 0. The cry6tals are filtered off and taken up in an ethanol/water mixture (2:8, 250 ml). The pH is adju6ted to 8.0 with a 60dium bicarbonate 601ution. The 6u6pen6ion i6 cooled to 0 and the pale yellow cry6tal6 are filtered off. The filter residue i6 su6pended in ethanol. The cry6tals ace filtered off and wa6hed with ether. There are obtained 1.10 g (75%) of p-nitrobenzyl 5-cyclopropyl-8-fluoro--1,2,3,4-tetrahydro-1,3-dioxo-7-(1-piperazinyl)pyrimido-[1,6-a]benzimidazole-4-carboxylate.
Microanaly6i6 C25~23FN66 Calc.: C 57.47 H 4.44 N 16.08 Found: 57.13 4.48 15.97.

d) A solution of p-nitrobenzyl 5-cyclopropyl-8-fluoro--1,2,3,4-tetrahydro-1,3-dioxo-7-tl-piperazinyl)pyrimido-~1,6-a]benzimidazole-4-carboxylate (122 mg, 0.234 mmol) in DMF (30 ml) i6 hydrogenated over 5 percent Pd/C. After completion of the hydrogenation the catalyst is filtered off and the filtrate i6 treated with fuller'6 earth, filtered and concentrated to a volume of 5 ml. The 6eparated cry6tals are filtered off. There are obtained 62 mg (68%) of the 60dium 6alt of 5-cyclopropyl-8-fluoro--1,2,3,4-tetrahydro-1,3-dioxo-7-(1-piperazinyl)pyrimido-[1,6-a]benzimidazole-4-carboxylic acid.
MS: 343(M-C02), 44 (C02).

The crystals are taken up in DMF (10 ml) and treated with a saturated sodium bicarbonate ~olution (1 ml). The 601vent is distilled off and the residue i6 chromato-2~2~3~

graphed with water on a rever6ed phase (column RP8). Thereare obtained 39 mg (40%) of the above product.
MS: 343 (M-C02), 44 (C02).

ExamPle 11 In analogy to Example 9, fcom tert-butyl 4-t2--(carbamoylmethyl)-1-ethyl-5-fluoro-6-benzimidazolyl]-1--eipecazinecarboxylate (from Example 8d) there i~
obtained, after cleaving off the tert-butoxycarbonyl group using 2.5N HCl~dioxan (in analogy to Example 4d), 5-ethyl--8-fluoro-2-hydroxy-7-(1-piperazinyl)pyrimido~1,6-a]benz-imidazole-1,3(2H,5H)-dione hydrochloride.
Microanalysis C16HlgClFN503:
Calc.: C 50.07 H 4.99 N 18.25 Found: 50.94 5.22 18.47, ExamPle 12 a) Ethyl 6-t4-(tert-butoxycarbonyl)-1-piperazinyl]-1--cyclopropyl-5-fluoro-2-benzimidazoleacetate (1.8 g, 4 mmol; from Example 2d) and tert.butyl carbazate (21 g, 16 mmol) are dis801ved in pycidine (40 ml) and s~irred at 115 under argon for 65 hours. The reaction solution is concentrated and triturated with 50 ml of ether. The separated product i6 filtered off under suction and dried.
There is obtained tert-butyl 3-[t6-[~-(tert-butoxycar-bonyl)-1-piperazinyl]-1-cyclopropyl-5-fluoro-2-benz-imidazolyl~acetyl]carbazate. Yield: 0.49 g (23%); m.p.
202-203.
Microanaly6is C26H37FN605:
Calc.: C 58.63 H 7.00 N 15.78 Found: 58.44 7.15 15.66.

b) tert-Butyl 3-[]6-t4-(tert-butoxycacbonyl)-1-pipera-zinyl]-l-cyclopropyl-5-fluoro-2-benzimidazolyl]acetyl]carba-2 ~ 3 0 zate (0.40 g, 0.76 mmol) is dissolved in THF (15 ml) andtreated with l,l'-carbonyldiimidazole (0.24 g, 1.5 mmol) and DBU (3 drops). The solution obtained is &tirred at 60C for 2 hours and thereafter concentrated on a rotary evaporator. The residue i8 dissolved in ethyl acetate and then chromatographed on silica gel (eluent: ethyl acetate/
hexane 4:1). The product is recrystallized from ethyl acetate/ether. There is obtained tert-butyl 7-~4-(tert-butoxycarbonyl)-l-piperazinyl]-5-cyclopropyl-8-fluoro--3,5-dihyd~o-1,3-dioxopyrimido[1,6-a]benzimidazole--2(1H)-carbamate. Yield: B5 mg (20%): m.p. 219-Z20.
Microanalysis C27H35FN606 Calc.: C 58.05 H 6.32 N 15.04 Found: 57.87 6.36 14.69.

c) tert-Butyl 7-[4-(tert-butoxycarbonyl)-1-piperazinyl]--5-cyclopropyl-8-fluoro-3,5-dihydro-1,3-dioxopyIimido-tl~6-a]benzimidazol-2(lH)-carbamate (0.145 g, 0.26 mmol) is dissolved in 1 ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The reaction solution i6 concentrated, treated with 1 ml of H2O, adjusted to pH 8 with saturated aqueous NaHCO3 solution and stirred at room temperature for 1 hour. The suspension is cooled to 0 and suction filtered. The product is chromatographed on silica gel (eluent: CHC13/EtOH/NH40H 80:20:1) and reccystallized from ethanol. There is obtained 2-amino-5--cyclopropyl-8-fluoro-7-(1-piperazinyl)pyrimido[1,6-a]benz-imidazole-1,3(2H,5H)-dione. Yield: 43 mg (46%); m.p.
232-234.
Mic~oanalysis C17HlgFN6O2: 0.3 EtOH:
Calc.: C 56.70 H 5.62 N 22.58 Found: 56.40 5.77 N 22.67.
ExamPle-l3 a) In analogy to Example 12a), from ethyl 6-[4-(tert-202~3~

-butoxycarbonyl)-l-piperazinyl]-l-cyclopropyl-5-fluoro-2--benzimidazoleacetate and tert-bu~yl 2-methylcarbazate there is obtained in a yield of 33% tert-butyl-4-[2-~2--(tert-butoxycarbonyl)-2-methylhydrazino]carbonyl]methyl]--1-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazine--carboxylate with a m.p. of 18C-182.
MS: 546 (M); 446 ~M-(isobutene + C02)].

b) In analogy to Example 12b), starting from tert-butyl 4-~2-~2-(tert-butoxycarbonyl)-2-methylhydrazino]carbonyl]-methyl]-l-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-pipera-zinecarboxylate there is obtained in a yield of 59% tert--butyl 7-~4-(tert-butoxycarbonyl)-1-piperazinyl]-5-cyclo-propyl-8-fluoro-3,5-dihydro-N-methyl-1,3-dioxopyrimido-~1,6-a]benzimidazole-2-carbamate with a m.p. of 224-225.
MS: 573 (M+H) .

c) In analogy to Example 12c), starting from tert-butyl 7-~4-(tert-butoxycarbonyl)-1-piperazinyl]-5-cyclopropyl-20 -8-fluoro-3~5-dihydro-N-methyl-l~3-dioxopyrimido~l~6-a]-benzimidazole-2-carbamate there is obtained in a yield of 43% 5-cyclopropyl-8-fluoro-2-(methylamino)-7-(1-pipera-zinyl)pyrimido~l,6-a]benzimidazole-1,3(2H,SH)-dione with a m.p. of 228-230.
25 Microanalysis C18H21FN602:
Calc.: C 58.05 H 5.68 N 22.57 Found: 57.95 5.81 22.18.

Example 14 a) In analogy to Example 12a), from ethyl 6-~4-(tert--butoxycarbonyl)-l-piperazinyl]-l-cyclopropyl-5-fluoro-2--benzimidazoleacetate and hydrazine hydrate there is obtained tert-butyl 4-~2-~[(hydrazino)carbonyl]methyl]-35 -1-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazine-carboxylate with a m.p. of 172-173.

Microanalysis C21H29FN603:
Calc.: C 58.32 H 6.76 N 19.43 Found: 57.86 6.91 19.20.

b) A solution of tert-butyl 4-[2-rr(hydrazino)carbonyl]-methyl]-l-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-pipera-zine-carboxylate (0.43 g) in methanol (22 ml) i6 stirred at 50 with a 35% agueous formaldehyde solution (0.102 g) subsequently sodium borohydride (~6 mg) is added. This procedure is carried out 3 times. The reaction mixture is evaporated and the raw material crystallized from ethyl acetate. 0.325 g (70%) of tert-butyl 4-r2-rrr2-(dimethyl-hydrazino)carbonyl]methyl]-l-cyclopropyl-5-fluoro--6-benzimidazolyl]-1-piperazine-carboxylate are obtained 15 with a m.p. of 179-181.

MS: 460 (M) c) In analogy to Example 12b), starting from tert-butyl 20 4-r2-rrr2-(dimethylhydrazino)]carbonyl]methyl]-1-syclo-propyl-5-fluoro-6-benzimidazolyl]-1-piperazine-carboxylate there is obtained tert-butyl 4-r5-cyclopropyl-8-fluoro--1,2,3,5-tetrahydro-2-(dimethylamino)-1,3-dioxopyrimido-rl,6-a]benzimidazol-7-yl]-1-piperazine-carboxylate with a 25 m.p. of 201-203.
Microanalysis C24H31FN604:
Calc.: C 59.25 H 6.42 N 17.27 Found: 59.13 7.10 17.73.

30 d) In analogy to Example 12c), starting from tert-butyl 4-[5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-2-(dimethyl-amino)-1,3-dioxopyrimidorl,6-a]benzimidazol-7-yl]-1-pipera-zine-carboxylate there is obtained 5-cyclopropyl-2-(di-methylamino)-8-fluoro-7-(1-piperazinyl)pyrimido~1,6-a]-35 benzimidazole-1,3(2H,5H)-~ione with a m.p. of 207-209.

20~30 Microanalysis ClgH23FN602:
Calc.: C 59.06 H 6.00 N 21.75 Found: 58.12 6.17 20.75.

ExamPle A

Gelatine capsules containing the following ingredients are manufactured in the usual manner:

5-Cyclopropyl-8-fluoro-7-(l--piperazinyl)-pyrimido[1,6-a]-benzimidazole-1,3(2H,5H)-dione 200 mg Luviskol (water-soluble polyvinylpyrrolidone) 20 mg Mannitol 20 mg 15 Talc 15 mg Magnesium stearate 2 mq 257 mg ExamPle B
Tablet6 containing the following ingredients are manufactured in the usual manner:

5-Cyclopropyl-8-fluoro-7-(1-25 -piperazinyl)-pyrimido r 1,6-a]-benzimidazole-1,3(2H,5H)-dione 200 mg Starch 44 mg Calcium carboxymethylcellulose 30 mg Crystalline cellulose 40 mg 30 Magnesium 6tearate 6 mq 320 mg

Claims

1. Compounds of the general formula I

wherein R1 signifies hydrogen, halogen or amino, R2 signifies halogen, R signifies a lower alkyl-substituted 4-pyridyl group or a group R3R4N- in which R3 and R4 each signify hydrogen or lower alkyl or together signify a group of the formula -(CH2)n-X-(CH2)m- or -(CH2)p-which is unsubstituted or substituted by lower alkyl, amino, lower aminoalkyl, mono- or di(lower alkyl)-amino-lower alkyl, oxo or the group -COORa or -CONR'R", n and m each signify the number 1, 2 or 3, with the proviso that n + m is a maximum of 5, p signifies the number 4, 5 or 6, X signifies an oxygen or sulphur atom or the group -NR"'-, Ra signifies hydrogen, lower alkyl, lower alkenyl, phenyl or phenyl which is mono-, di- or trisubstituted by halogen, lower alkyl or hydroxy, R' and R" each signify hydrogen or lower alkyl, R"' signifies hydrogen, hydroxy, lower alkyl or lower aminoalkanoyl, R5 signifies hydrogen, halogen, lower alkoxy or amino, R6 signifies lower alkyl, lower cycloalkyl, lower haloalkyl, phenyl or phenyl which is mono-, di- or trisubstituted by halogen, lower alkyl, hydroxy or lower alkoxy, R7 signifies hydrogen, lower alkyl or carboxy, R8 signifies hydrogen, hydroxy, lower alkoxy, amino, lower alkylamino or di-lower alkylamino and Y signifies an oxygen or sulphur atom, and pharmaceutically acceptable salts thereof.

2. Compounds according to claim 1, wherein R8 signifies hydrogen, hydroxy, lower alkoxy, amino or lower alkylamino.

3. Compounds according to claim 2, wherein R
signifies the group R3R4N- and R8 signifies hydrogen, hydroxy or lower alkoxy.

4. Compounds according to claim 3, wherein R1 and R5 each signify hydrogen.

5. Compounds according to claim 3 or claim 4, wherein R2 signifies fluorine.

6. Compounds according to any one of claims 3-5, wherein R3 and R4 together signify a group of the formula -(CH2)n-X-(CH2)m- or a group of the formula -(CH2)p- which is substituted by the group -COORa, n and m each signify the number 2, p signifies the number 4, X signifies the group -NR"'-, Ra signifies lower alkyl and R"' signifies hydrogen, lower alkyl or lower aminoalkanoyl.

7. Compounds according to claim 6, wherein R3R4N- signifies the 1-piperazinyl group or the 4-methyl-1-piperazinyl group.

8. Compounds according to any one of claims 3-7, wherein R6 signifies lower alkyl or lower cycloalkyl.

9. Compounds according to claim 8, wherein R6 signifies ethyl.

10. Compounds according to claim 8, wherein R6 signifies cyclopropyl.

11. Compounds according to any one of claims 3-10, wherein R7 signifies hydrogen or carboxy.

12. Compounds according to any one of claims 3-11, wherein R8 signifies hydrogen or hydroxy.

13. Compounds according to any one of claims 3-12, wherein Y signifies an oxygen atom.

14. Compounds according to any one of claims 2-5 and 8-13, wherein R signifies the 3,5-dimethyl-4-pyridyl group.

15. Compounds according to any one of claims 2-14, wherein R8 signifies amino or methylamino.

16. Compounds according to any one of claims 1-14, wherein R8 signifies dimethylamino.

17. 5-Ethyl-8-fluoro-7-(4-methyl-1-piperazinyl)--pyrimido[1,6-a]benzimidazole-1,3(ZH,5H)-dione.

18. 5-Cyclopropyl-8-fluoro-7-(1-piperazinyl)-pyrimido-[1,6-a]benzimidazole-1,3(2H,5H)-dione.

19. 5-Ethyl-9-fluoro-3,5-dihydro-8-(4-methyl-1--piperazinyl)-3-thioxopyrimido[1,6-a]benzimidazol-1(2H)--one.

20. 5-Cyclopropyl-8-fluoro-2-hydroxy-7-(1--piperazinyl)pyrimido[1,6-a]benzimidazole-1,3(2H,5H)-dione.

21. tert-Butyl rac-1-[5-cyclopropyl-8-fluoro-2,3--dihydro-1,3-dioxopyrimido[1,6-a]benzimidazol-5(1H)-yl]-2--pyrrolidinecarboxylate.

22. 7-(4-L-Alanyl-l-piperazinyl)-5-cyclopropyl-8--fluoro-2 hydroxypyrimido[l,6-a]benzimidazole-1,3(2H,5H)--dione.

23. 1-[5-Cyclopropyl-8-fluoro 1,2,3,5-tetrahydro-2--hydroxy-1,3-dioxopyrimido[1,6-a]benzimidazol-7-yl]-L--proline tert-butyl ester.

24. 5-Ethyl-8-fluoco-7-(1-piperazinyl)pyrimido[1,6-a]-benzimidazole-1,3(2H,5H)-dione.

25. 5-Ethyl-8-fluoro-2-hydroxy-7-(4-methyl-1--piperazinyl)-pyrimido[1,6-a]benzimidazole-1,3(2H,5H)--dione.

26. 5-Cyclopropyl-8-fluoro-1,2,3,4-tetrahydro-1,3--dioxo-7-(1-piperazinyl)pyrimido[1,6-a]benzimidazole-4--carboxylic acid.

27. 5-Ethyl-8-fluoro-2-hydroxy-7-(1-piperazinyl)-pyrimido[1,6-a]benzimidazole-1,3(2H,5H)-dione.

28. 2-Amino-5-cyclopropyl-8-fluoro-7-(1-piperazinyl)--pyrimido[1,6-a]benzimidazole-1,3(2H,5H)-dione.

29. 5-Cyclopropyl-8-fluoro-2-(methylamino)-7-(1--piperazinyl)pyrimido[1,6-a]benzimidazole-1,3(2H,5H)-dione.

30. 5-Cyclopropyl-2-(dimethylamino)-8-fluoro-7-(1-piperazinyl)pyrimido[1,6-a]benzimidazole-1,3(2H,5H)-dione.

31. Compounds of the general formula II

wherein R, Y, R1, R2, R5, R6, R7 and R8 have the significance given in claim 1, with the proviso that free hydroxy, amino and carboxy groups which may be present are in protected form.

32. Compounds of the general formula IV

wherein R, R1, R2, R5, R6 and R8 have the significance given in claim 1, with the proviso that free hydroxy, amino and carboxy groups which may be present are in protected form.

33. Compounds of the general formula VI

wherein Rb signifies a carboxy protecting group and R.
R1, R2, R5 and R6 have the significance given in claim 1, with the proviso that free hydroxy, amino and carboxy groups which may be present are in protected form.

34. Compounds of formula I in claim 1, which have at least one protected hydroxy, amino and/or carboxy group.

35. Compounds according to any one of claims 1-30 for use as therapeutically active substances.

36. Compounds according to any one of claims 1-30 for use as antibacterially-active substances.

37. A process for the manufacture of compounds according to any one of claims 1-30, which process comprises a) reacting a compound of the general formula II

wherein R, Y, R1, R2, R5, R6, R7 and R8 have the significance given in claim 1, with the proviso that free hydroxy, amino and carboxy groups which may be present are in protected form, optionally in the presence of a base with a compound of the general formula X-CO-X III

wherein X signifies a leaving group, or b) reacting a compound of the general formula IV

wherein R, R1, R2, R5, R6 and R8 have the significance given in claim 1, with the proviso that free hydroxy, amino and carboxy groups which may be present are in protected form, in the presence of a base with a compound of the general formula RaOOC-CHR7-COORa V

wherein Ra signifies lower alkyl and R7 has the significance given in claim 1, with the proviso that a free carboxy group which may be present is in protected form, or c) reacting a compound of the general formula VI

wherein Rb signifies a carboxy protecting group and R, R1, R2, R5 and R6 have the significance given in claim 1, with the proviso that free hydroxy, amino and carboxy groups which may be present are in protected form, with 2 molar equivalents of chloroacetyl isocyanate, whereupon any protecting groups present are cleaved off and a compound of formula I obtained is, if desired, converted into a pharmaceutically acceptable salt.

38. A medicament containing a compound in accordance with any one of claims 1-30 and a therapeutically inert carrier.

39. An antibacterially-active medicament, containing a compound in accordance with any one of claims 1-30 and a therapeutically inert carrier.

40. The use of compounds in accordance with any one of claims 1-30 in the control or prevention of illnesses.

41. The use of compounds in accordance with any one of claims 1-30 in the control or prevention of bacterial infections.

42. The use of compounds in accordance with any one of claims 1-30 for the manufacture of antibacterially--active medicaments.

43. Compounds as defined in claim 1, whenever prepared according to the process as defined in claim 37 or by in obvious chemical equivalent thereof.

44. The novel compounds, intermediates, formulations, processes and methods substantially as described herein.

45. A method of preventing or treating an infectious disease in a patient which comprises administering an effective amount of a compound in accordance with any one of claims 1-34 together with a therapeutically inert carrier material.