IE904189A1 - Substituted Pyrimidobenzimidazole Derivatives - Google Patents

Abstract

The present invention relates to novel substituted pyrimidobenzimidazole derivatives of the general formula in which R<1> is hydrogen, halogen or amino, R<2> is halogen, R is a 4-pyridyl group which is substituted by lower alkyl or a group R<3>R<4>N- in which R<3> and R<4> in each case are hydrogen or lower alkyl or together are a group of the formula -(CH2)n-X-(CH2)m- or -(CH2)p-, each of 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 in each case are the number 1, 2 or 3, where n + m is not more than 5, p is the number 4, 5 or 6, X is an oxygen or sulphur atom or the group -NR'''-, R is hydrogen, lower alkyl, lower alkenyl, phenyl, or phenyl which is mono-, di- or trisubstituted by halogen, lower alkyl or hydroxyl, and R' and R'' in each case are hydrogen or lower alkyl, R''' is hydrogen, hydroxyl, lower alkyl or lower aminoalkanoyl, R<5> is hydrogen, halogen, lower alkoxy or amino, R<6> is lower alkyl, lower cycloalkyl, lower haloalkyl, phenyl, or phenyl which is mono-, di- or trisubstituted by halogen, lower alkyl, hydroxyl or lower alkoxy, R<7> is hydrogen, lower alkyl or carboxyl, R<8> is hydrogen, hydroxyl, lower alkoxy, amino, lower alkylamino or di-lower alkylamino, and Y is 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 be used for preventing or combating bacterial infections.

Description

RAN 4410/221 The present invention is concerned with novel substituted pyrimidobenzimidazole derivatives of the general formula wherein R1 signifies hydrogen, halogen or amino, R signifies halogen, R signifies a lower alkyl-substituted 4-pyridyl group or a group 4 3 4 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-(CH2)m- or -(CH2)pwhich is unsubstituted or substituted by lower alkyl. 25 amino, lower aminoalkyl, mono- or di(lower alkyl)a 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 is a maximum of 5. p 30 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. . 5 hydroxy, lower alkyl or lower ammoalkanoyl, R signifies hydrogen, halogen, lower alkoxy or amino, R6 signifies lower alkyl, lower cycloalkyl. lower Mn/25.9.90 - 2 haloalkyl. phenyl or phenyl which is mono-, di- or trisubstituted by halogen, lower alkyl, hydroxy or 7 . . . lower alkoxy. R signifies hydrogen, lower alkyl or g carboxy. R signifies hydrogen, hydroxy, lower alkoxy, amino, lower alkylamino or di-lower alkylamino and Y signifies an oxygen or eulphur 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 therapeutically active substances; a process and intermediates for 20 their manufacture, medicaments based on these novel substances; as well as the use of the novel compounds of formula I for the control or prevention of bacterial infections and for the manufacture of antibacterially-active medicaments.

The term lower used in the scope of the present description denotes residues and compounds having a maximum of 7. preferably a maximum of 4, carbon atoms. The term alkyl, taken alone or in combinations such as alkyl group and alkoxy, denotes straight-chain or branched saturated hydrocarbon residues such as methyl, ethyl, n-propyl. i-propyl. n-butyl. s-butyl. i-butyl and t-butyl. The term alkenyl denotes etraight-chain or branched hydrocarbon residues which contain at least one olefinic double bond, such as allyl and 2-butenyl. The terra ’’cycloalkyl denotes cyclic saturated hydrocarbon residues such as cyclopropyl. The term alkanoyl denotes residues of straight-chain or branched saturated fatty - 3 acids, such as acetyl. The term halogen denotes the four forms fluorine, chlorine, bromine and iodine. 2 Preferably. R and R each signify hydrogen. R 4 preferably signifies fluorine. R and R preferably together signify a group of the formula -(CH_) -X-(CH_) - or a group of the formula _ £» 11 & Ul _ 10 -(CH_) - which is substituted by the group -COORd, z p wherein n and m each signify the number 2, p signifies the a number 4, X signifies the group -NR'-, R signifies lower alkyl and R' signifies hydrogen, lower alkyl or 3 4 lower aminoalkanoyl. R R N- is preferably 1-pipera13 zinyl or 4-methyl-l-piperazinyl. R6 preferably signifies lower alkyl, especially ethyl, or lower cycloalkyl. ... especially cyclopropyl. R preferably signifies hydrogen 8 ... or carboxy. R preferably signifies hydrogen, hydroxy, amino, methylamino or dimethylamino. Y preferably signifies an oxygen atom. When 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: -Ethyl-8-fluor0-7-(4-methyl-l-piperazinyl)-pyrimido[1.6-a J benzimidazole-1.3(2H.5H)-dione. -cyclopropyl-8-fluoro-7-(1-piperazinyl)-pyrimido[1,6-a]benzimidazole-1.3(2H.5H)-dione. -ethyl-9-fluoro-3.5-dihydr0-8-(4-methyl-1-piperazinyl) -3-thioxopyrimidofl.6-a]benzimidazol-l(2H)-one, -cyclopropy1-8-fluoro-2-hydroxy-7-(1-piperazinyl)35 -pyrimido[1.6-a]benzimidazole-1,3(2H.5H)-dione. tert-butyl rac-1-[5-cyclopropy1-8-fluoro-2.3-dihydro-1.3-dioxopyrimido[l.6-a]benzimidazole-5(lH)-yl]-2-pyrrol idinecarboxylate. 7-(4-L-alanyl-l-piperazinyl)-5-cyclopropyl-8-fluoro-2-hydroxypyrimidofl,6-a]benzimidazole-l,3(2H.5H)-dione, 1- [5-cyclopropyl-8-fluoro-1.2,3.5-tetrahydro-2-hydroxy -1.3-dioxopyrimido[l,6-a]benzimidazol-7-yl]-L-proline tert-butyl ester, -ethy1-8-fluoro-7-(1-piperazinyl)pyrimidofl.6-a ]benzimidazole-1.3(2H.5H)-dione, -ethy1-8-fluoro-2-hydroxy-7-(4-methy1-1-piperazinyl)pyrimido[l.6-a]benzimidazole-1,3(2H,5H)-dione. -cyclopropyl-8-fluoro-1.2.3,4-tetrahydro-1,3-dioxo-7- (1-piperazinyl)pyr imido[1.6-a]benz imidazole-4-carboxylie acid. -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)pyrimidof1,6-a]benzimidazole-1.3(2H,5H)-dione, -cyclopropyl-8-fluoro-2-(methylamino)-7-(1-piperazinyl ) pyr imido[ 1. 6-a]benzimidazole-1,3(2H,5H)-dione and -cyclopropy1-2-(dimethylamino)-8-fluoro-7-(1-piperazinyl)pyrimidofl,6-a]benzimidazole-1,3(2H.5H)-dione.

The novel compounds of formula I and their pharmaceutically acceptable salts can be manufactured in accordance with the invention by a) reacting a compound of the general formula wherein R. Y. R1. R2. R5. R6. R7 and R8 II - 5 have the above significance, 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 ί 2 5 6 8 wherein R. 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, in the presence of a base with a compound of the general formula RaOOC-CHR7-COORa wherein Ra signifies lower alkyl and R has the above significance, with the proviso that a free carboxy group which may be present is in protected - 6 form, or c) reacting a compound of the general formula wherein Rb signifies a carboxy protecting group and 12 5 6 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 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.

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 present no difficulties to him. There come into consideration for the present purpose especially the protecting groups which are usually used in peptide chemistry.

An especially suitable amino protecting group is the t-butoxycarbonyl group which can be cleaved off readily, for example, by treatment with trifluoroacetic acid. - 7 dilute HCl/dioxan or sodium iodide/trimethylchlorosilane/ acetonitrile.

An especially suitable hydroxy protecting group is the benzyl group which can be cleaved off readily, for example, by reduction with elementary hydrogen on a suitable catalyst (e.g. palladium/carbon). Suitable 10 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 presence 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 Ν.N1-carbonyldiimidazole, with the last-named compound being particularly preferred. A tertiary amine such as triethylamine or a bicyclic amidine such as 1,8-diazabicyclo[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 tetrahydrofuran (THF). The reaction is preferably carried out in a temperature range of about room temperature to about 100°C.

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 - 8 a base. A lower alkali metal alcoholate such as sodium methanolate or potassium methanolate is preferably used as 5 the base. The corresponding lower alcohol, e.g. methanol, is preferably used as the solvent. This reaction is preferably carried out at room temperature. . 7 . .

Compounds of formula I in which R signifies IO 8 carboxy, R signifies hydrogen and Y signifies an oxygen atom can he manufactured in accordance with process variant c). The reaction of a compound of formula VI with 2 molar equivalents of chloroacetyl isocyanate is preferably carried out in an inert organic solvent, with 15 e.g. open-chain and cyclic ethers such as diethyl ether, t-butyl methyl ether and tetrahydrofuran coming into consideration for this purpose. The reaction is preferably carried out in a temperature range of 0°C to room temperature.

Pharmaceutically acceptable salts of compounds of formula I can be manufactured according to methods which are known per se and which are familiar to any person skilled in the art. Compounds of formula I which have a free carboxy group can be converted into such salts, for example, by treatment with a suitable base. Alkali metal salts such as the sodium and potassium salts can be mentioned as examples of such salts.

Compounds of formula I which have a basic amino group can be converted into acid addition salts, for example, by treatment with pharmaceutically acceptable acids. As acid addition salts there come into consideration not only salts with inorganic acids but also salts with organic acids, for example hydrochlorides, hydrobromides, sulphates, nitrates, citrates, tartrates, acetates, maleates. succinates, methanesulphonates. p-toluenesulphonates and the like. - 9 The compounds of general formulae II. IV and VI which are used as starting materials are novel and are also 5 objects of the present invention. These starting 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 materials.

The intermediates corresponding to formula I in which free 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 compounds 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. 171-180 (1983). The DNA-gyrase used was isolated from E. coli N4186 and from the sub-unit B of E. coli MK47 (Mitsuchi et al.. JBL 159. 9199-9201 (1984)). Relaxed pUC18 or pUC19 plasmid DNA was used as the substrate. The results determined in this test are compiled in the following Table, with the results being expressed as the MNC (maximum non-effective concentration) in ug/ml. - 10 Table Product from Activity Toxicity MNC in ug/miLD50 ln mg/kg 10 Example 1 2 - Example 2 0.45 30 (i.v.) Example 3 2 >2000 (p.o.) 15 Example 4 2 30 (i.v.) Example 8 1 >4000 (p.o.) The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form 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 capsules, solutions, emulsions or suspensions, rectally. e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The manufacture of the pharmaceutical preparations can be effected in a manner which is familiar to any person skilled in the art by bringing the products 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 - 11 materials and, if desired, the usual pharmaceutical adjuvants.

Suitable carrier materials 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 1° 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 carrier 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 suppositories 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 substances, solubilizers, colouring and coating agents and anti30 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 course, 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 - 12 consideration for adult patients. Depending on the dosage it is convenient to administer the daily dosage in several unit dosages.

The pharmaceutical preparations 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 sulphate 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 (105 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 (10 ml) and 10 percent sodium chloride solution - 13 (100 ml). The solution is dried over magnesium sulphate and evaporated. The residue is recrystallized from 5 n-hexane. There are obtained 102 g (84.2%) of 3'-chloro-N-ethy1-4'-fluoroacetanilide.

Microanalysis C^H^CIFNO: 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 dissolved in cone, sulphuric acid (300 ml). A solution of potassium nitrate (57 g. 0.564 mol) in cone, sulphuric acid (220 ml) is added dropwise thereto at 5°.

The solution obtained is stirred overnight, then poured on to ice/water and extracted with ethyl acetate (2x 200 ml). The organic phase is washed in succession with water (200 ml), saturated sodium bicarbonate solution (100 ml) and saturated sodium chloride solution (100 ml). The 20 organic phase is treated with active charcoal, filtered and dried over magnesium sulphate. The solvent is distilled off and the residue is recrystallized from ether/n-hexane. There are obtained 74.8 g (61%) of 5'-chloro-N-ethyl-4'-fluoro-2'-nitroacetanilide with a m.p. of 68°.

Microanalysis ciqhiOfc1N2°3: Calc.: C 46.08 H 3.87 N 10.75 Found: 45.99 3.92 10.82. d) 51-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 stirred at 60° for 2 hours. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate (250 ml) and washed in succession with water (3x 100 ml) and 10 percent sodium chloride solution (100 ml). The organic solution is dried over magnesium sulphate and evaporated. The residue is recrystallized from ethyl acetate/n-hexane. There are - 14 obtained 72.3 g (78.5%) of N-ethyl-41-fluoro-51 - (4-methyl-1-piperazinyl)-21-nitroacetanilide with a m.p. of 5 117-119°.

Microanalysis C,CH_.FN.O,: 21 4 3 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-l-piperazinyl)-2'-nitroacetanilide (20 g. 61 mmol) in methanol (160 ml) is treated with an aqueous potassium hydroxide solution (34.6 g. 616 mmol). The solution is heated to 80° for 3 hours and thereafter cooled to room temperature. The crystals 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-methylpiperazine with a m.p. of 149-150°.

Microanalysis C,_H,nFN.O_: 19 4 2 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-nitrophenyl)-4-methylpiperazine (10 g) in THF (200 ml) is 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 solution of sodium cyanate (230 mg) in water (50 ml) and the pH is adjusted to 3.5 with cone. 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 residue is extracted with methanol/ethyl acetate (1:4). The solution is filtered, decolorized with active charcoal and evaporated in a vacuum. The residue is taken up in warm ethyl acetate. After cooling the crystals are filtered off and dried. There is obtained 0.63 g (60%) of l-[2-(N-ethylamino)-5-fluor0-4-(4-methyl-1-piperazinyl]phenyl-urea - 15 Microanalysis C^H^F^O: Calc.: C 56.93 H 7.51 N 23.71 5 Found: 57.16 7.64 23.80. g) A solution of l-f2-(N-ethylamino)-5-fluoro-4-(4-methyl-l-piperazinyl]phenyl-urea (640 mg) in methanol is 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 ice and 2N HCl (50 ml). The methanol is evaporated and the aqueous phase is extracted with ethyl acetate (3x 100 ml) and methylene chloride (2x 100 ral). 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%) of 5-ethyl-8-fluoro-7-(4-methyl-1-piperazinyl)pyrimidofl. 6-a]benzimidazole-1,3(2H,5H)-dione.

MS: 345(M) Microanalysis (hydrochloride) ci7H21ClFN5°2: Calc.: C 53.47 H 5.54 N 18.34 Found: 52.97 5.52 18.12.

Example 2 a) l-Chloro-2.5-difluoro-4-nitrobenzene (3.69 g. 19 mmol) 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 is taken up in water (150 ml) and extracted with ethyl acetate. The organic phase is 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-2IE 904189 - 16 -nitroaniline with a m.p. of 73.5-75.5°.

Microanalysis C9HgClFN2O2: 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. .2 mmol) is heated with N-acetylpiperazine (3.89 g. 30.4 mmol) and triethylamine (2.3 g 22.8 mmol) while stirring vigorously and held at 60° for 12 hours. The mass obtained is 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 15 sulphate. After distillation of the solvent the residue is recrystallized from ethanol. There are obtained 4.57 g (93%) of l-acetyl-4-[5-(cyclopropylamino)-2-fluoro-4-nitrophenyl]piperazine with a m.p. of 142-143°.

Microanalysis C_, CH_, _FN.0. : 19 4 3 Calc.: C 55.89 H 5.94 N 17.38 Found: 55.66 5.94 17.35. c) 1-Acetyl-4-[5-(cyclopropylamino)-2-fluoro-4-nitrophenyl ] piperazine (17 g. 53 mmol) is dissolved 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 phase is washed in succession with water and sodium chloride solution and dried over magnesium sulphate. After distillation of the solvent the residue is dissolved in dioxan (100 ml) and treated with di-tert-butyl dicarbonate (13.8 g. 63.24 mmol) and an aqueous solution of sodium hydrogen carbonate (6.6 g. 79 mmol, in 60 ml of water). After stirring for 20 hours the suspension obtained is diluted with water. The crystals are filtered off. washed with water and recrystallized from ethanol. There are obtained 18.2 g (91%) of tert-butyl 4-[5-(cyclopropylamino)-2IE 904189 - 17 -fluoro-4-nitrophenyl)-l-piperazinecarboxylate with a m.p. of 159-160°.

Microanalysis Cn.HorFN.O.: 4 4 Calc.: C 56.83 H 6.62 N 14.73 Found: 56.92 6.70 14.89. d) tert-Butyl 4-[5-(cyclopropylamino)-2-fluoro-4-nitro10 phenylJ-l-piperazinecarboxylate (17.21 g, 45.2 mmol) is dissolved in methanol (500 ml) and hydrogenated with 5 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 is dried in a high vacuum, then dissolved in DMF (150 ml) and treated with ethyl 3-ethoxy-3-iminopropanoate hydrochloride (17.3 g. 88.4 mmol). The solution obtained is 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 is 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 recrystallized from ethyl acetate/hexane. There are obtained 15.5 g (78%) of ethyl 6-[4-(tert-butoxycarbonyl)-1-piperazinyl]3q -l-cyclopropyl-5-fluoro-2-benzimidazoleacetate with a m.p. Of 152-153°.

Microanalysis C23H3iFN4°4: Calc.: C 61.87 H 7.00 N 12.55 Found: 62.13 7.17 12.68. e) Ethyl 6-[4-(tert-butoxycarbonyl)-l-piperazinyl]-l-cyclopropyl-5-fluoro-2-benzimidazoleacetate (4.5 g, mmol) is dissolved in ethanol (100 ml) and treated with - 18 ammonium chloride (5.35 g. 100 mmol) and 25 percent 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 3-0 on silica gel (eluent: ethyl acetate/methanol 9:1). The product is recrystallized from ethyl acetate/n-hexane. There are obtained 2.22 g (53%) of tert-butyl 4-[2-(carbamoyImethyl)-1-cyclopropy1-5-fluoro-6-benzimidazolyl ]-l-piperazinecarboxylate with a m.p. of 15 219-220°.

Microanalysis Co1H_oFNc0,: Z1 Zo bo Calc.: C 60.42 H 6.76 N 16.78 Found: 60.26 6.88 16.31. f) tert-Butyl 4-[2-(carbamoylmethyl)-l-cyclopropyl-5-fluoro-6-benzimidazolyl]-l-piperazinecarboxylate (980 mg. 2.53 mmol) is suspended in THF (15 ml) and treated with 1.1'-carbonyldiimidazole (760 mg. 2 mmol) and 1.8-diazabicyclo[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 obtained 760 mg (73%) of tert-butyl 4-[5-cyclopropyl-8-fluoro-l.2.3.5-tetrahydro-l.3-dioxopyrimido30 [1.6-a]benzimidazol-7-yl]-l-piperazinecarboxylate.

Microanalysis C-_H_,FN_O. with 0.6 mol of ethanol: 26 5 4 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-l.2.3,5-tetrahydro-1. 3-dioxopyrimidofl.6-a]benzimidazol-7-yl]-1-piperazinecarboxylate (471 mg. 1 mmol) is dissolved in trifluoroacetic acid (2 ml). After 1 hour at 25° the - 19 trifluoroacetic acid is distilled off. The residue is taken up in water (10 ml), treated with sodium hydrogen 5 carbonate (168 mg. 2 mmol) and stirred at 25° for 2 hours. The suspension is cooled to 0°. The crystals are filtered off. washed in succession with in each case 5 ml of cold water and ethanol and recrystallized from ethanol/water (95/5). There are obtained 208 mg (60.6%) of 5-cyclo10 propyl-8-fluoro-7-(l-piperazinyl)-pyrimidof1.6-a]benzimidazole-1. 3(2H.5H)-dione trifluoroacetate.

Microanalysis C. ΗΊ-FNcO_»CF.COOH: X / 18 5 Z 3 Calc.: C 49.89 H 4.19 N 15.31 Found: 49.71 4.43 15.29.

Example 3 a) 1-[5-(Ethylamino)-2-fluoro-4-nitrophenyl]-4-methylpiperazine (2.8 g. 10 mmol) is dissolved in methanol 20 (200 ml) and hydrogenated with 5 percent palladium/carbon under hydrogen at normal pressure. The palladium/carbon is filtered off and the filtrate is evaporated under reduced pressure. The residue is 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 solvent is 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) 30 and chromatographed on silica gel (eluent: ethyl acetate/ methanol 6:4). The product is recrystallized from an ethyl acetate/acetonitrile mixture (9:1). There are obtained 1.17 g (39%) of l-ethyl-5-fluoro-6-(4-methyl-l-piperazinyl)-2-benzimidazoleacetonitrile with a m.p. of 204-206°.

Microanalysis cxgH20FN5: Calc.: C 63.77 H 6.69 N 23.24 Found: 63.65 6.54 23.31. - 20 b) l-Ethyl-5-fluoro-6-(4-methyl-l-piperazinyl)-2-benzs . . . . lmidazoleacetonitrlie (834 mg. 2.77 mmol) is dissolved in pyridine (20 ml) and triethylamine (2.8 g. 27.7 mmol). The solution is 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 30 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 13 recrystallized from ethyl acetate. There are obtained 745 mg (80%) of l-ethyl-5-fluoro-6-[4-methyl-l-piperazinyl]-2-benzimidazolecarbothioamide.

Microanalysis cx5H22FN5S-0.3 H2O: Calc.: C 56.38 H 6.68 N 20.55 20 Found: 56.32 6.76 20.41. c) l-Ethyl-5-fluoro-6-[4-methyl-l-piperazinyl]-2-benzimidazolecarbothioamide (120 mg. 0.36 mmol) is suspended in tetrahydrofuran (2 ml) and treated with carbonyldi25 imidazole (140 mg. 0.86 mmol). The reaction solution is 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 (16.9%) of 5-ethyl-9-fluoro-3.5-dihydro-β-(4-methyl-l-piperazinyl)-3-thioxopyr imidofl.6-a]benzimidazol-l(2H)-one.

Microanalysis C,_H_-FNCOS«0.7 H_O: X Z b Z Calc.: C 54.59 H 5.77 N 18.72 Found: 54.37 5.84 18.64. - 21 Example 4 a) tert-Butyl 4-[2-carbamoylraethyl)-l-cyclopropyl-5-£luoro-6-benzimidazolylJ-l-piperazinecarboxylate (703 mg. 1.68 mmol) is heated to 50° for 72 hours with O-benzylhydroxylamine 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 crystals obtained are filtered off, washed with water and dried in a high vacuum. The product is recrystallized from ethyl acetate. There are obtained 317 mg (36%) of tert-butyl 4-[2—[[(benzyloxy)carbamoyl]methyl]-l-cyclo15 propyl-5-fluoro-6-benzimidazolylJ-l-piperazinecarboxylate.

Microanalysis _FNrO.: 34 5 4 Calc.: C 64.23 H 6.55 N 13.38 Found: 64.35 6.83 13.35. b) tert-Butyl 4-(2-([(benzyloxy)carbamoyljmethylj-l-cyclopropyl-5-fluoro-6-benzimidazolylJ-l-piperazinecarboxylate (779 mg. 1.18 mmol) is dissolved in tetrahydrofuran (15 ml) and treated with N.N'-carbonyldiimidazole (480 mg. 2.96 mmol) and 1.8-diazabicyclo(5.4.0]25 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 is washed in succession 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-l.3-dioxopyrimido [1.6-aJ benzimidazo1-7-ylJ-l-piperazinecarboxylate.

Microanalysis C_nH__FNCOC: Z7 3Z b b Calc.: C 63.38 H 5.87 N 12.74 Found: 62.78 5.69 12.64. - 22 c) tert-Butyl 4-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-1,2.3,5-tetrahydro-l.3-dioxopyrimido[1.6-a]benzimidazo15 -7-yl]-l-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 10 combined filtrates are evaporated under reduced pressure. The residue is recrystallized from dimethylformamide.

There are obtained 619 mg (72%) of tert-butyl 4-[5-cyclopropyl-8-fluoro-1.2.3,5-tetrahydro-2-hydroxy-l,3-dioxopyr imido[1.6-a]benzimidazo1-7-yl]-1-piperaz inecarboxylate.

Microanalysis C__H_,FNCOC: zz zo □ □ 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-tetra20 hydro-2-hydroxy-l.3-dioxopyrimido[1.6-a]benzimidazo1-7-yl]-l-piperazinecarboxylate (350 mg. 0.76 mmol) is treated with a 2.5N hydrochloric acid solution in dioxan (4 ml), whereby a white precipitate forms immediately. The suspension is stirred 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)-pyrimidofl.6-a]benz imidazole-1.3(2H.5H)-dione hydrochloride.

Microanalysis C17HigFN5O3: Calc.: C 51.59 H 4.84 N 17.69 Found: 51.27 5.11 17.54. - 23 Example 5 5 a) 5-Chloro-N-cyclopropyl-4-fluoro-2-nitroaniline (460 mg. 2 mmol) is heated to 80° for 40 hours with L-proline tert-butyl ester (342 mg. 2 mmol) and 1.8-diaza bicyclo[5.4.O]undec-7-ene (304 mg. 2 mmol). The reaction mixture is then dissolved in a water/ethyl acetate mixtur (1:1, 100 ml). The 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 15 ether/n-hexane. There are obtained 94 mg (13%) of tert-butyl rac-1-[5-(eyelopropylamino)-2-fluoro-4-nitrophenyl]pyrrole-2-carboxylate with a m.p. of 142-143°.

Microanalysis CloH_.FN_0.: 24 3 4 Calc.: C 59.17 H 6.62 N 11.50 20 Found: 59.23 6.62 11.52. b) In analogy to Example 2d), from tert-butyl rac-l-[5-(eyelopropylamino)-2-fluoro-4-nitrophenyl]pyrrole-2-carboxylate there is obtained in a yield of 56% ethyl rac-6-[2-( tert-butoxycarbonyl)-l-pyrrolidinyl]-1-cyclopropyl-5-fluoro-2-benzimidazoleacetate with a m.p. of 93-96°.

Microanalysis C_.H_.FN_O.: 3 4 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)-l-pyrrolidinylJ-1-cyclopropy1-5-fluoro-2 -benzimidazoleacetate there is obtained in a yield of 34% tert-butyl rac-1-[2-(carbamoylmethyl)-l-cyclopropyl-5-fluoro-6-benzimidazolyl]-2-pyrrolidinecarboxylate with a m.p. of 176-178°. - 24 Microanalysis C„,H FNO : 2127 43 Calc.: C 62.67 H 6.76 N 13.92 5 Found: 62.40 6.86 13.60. d) In analogy to Example 2f). from tert-butyl rac-l-[2-(carbamoylmethyl)-l-cyclopropyl-5-fluoro-6-benzimidazolylJ -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]benzimidazo1-7(1H)-yl]-2-pyrrolidinecarboxylate with a m.p. of 226-227°.

Microanalysis C22H25FN4°4·0.25 THF Calc.: C 61.87 H 6.10 N 12.55 Found: 61.77 6.38 12.62.

Example 6 a) tert-Butyl 4-[2-(benzyloxy)-5-cyclopropyl-8-fluoro20 -l.2.3.5-tetrahydro-l.3-dioxopyrimido[1.6-a]benzimidazo1-7-yl]-l-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 water/ethanol mixture (2:1. ml). The pH is adjusted to 8 using IN sodium hydroxide solution, whereby white crystals separate. The crystals 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 C24H24FN5°3: 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 dicycloIE 904189 - 25 hexylcarbodiimide (103 mg. 0.5 mmol). After 30 minutes the crystals are filtered off and washed with a small amount 3 (30 ml) of dichloromethane. The filtrate is treated with a solution of 2-(benzyloxy)-5-cyclopropyl-8-fluoro-7-(l-piperazinyl)pyrimido[1.6-aJbenzimidazole-1.3(2H.5H)-dione (112 mg, 0.25 mmol) in DMF (5 ml). After 2 hours the solvent is distilled off. The residue is recrystallized 10 from methanol. There are obtained 142 mg (86%) of benzyl [(S)-l-[[4-[2-(benzyloxy)-5-cyclopropyl-8-fluor0-1.2,3,5-tetrahydro-1,3-dioxopyrimido[1.6-a]benzimidazol-7-yl]-l-piperazinyl]carbonyl]ethyl]carbamate.

MS: 653(M). c) Benzyl [(S)-l-[[4-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-l,2.3.5-tetrahydro-l.3-dioxopyrimido[1.6-a]benzimidazo1-7-yl]-l-piperazinyl]carbony1]ethyl]carbamate (127 mg. 0.194 mmol) is dissolved in DMF (15 ml) and 20 hydrogenated over 5 percent Pd/C. After completion of the reduction the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in methanol (50 ml) and treated with active charcoal. After filtering off the charcoal the filtrate is concentrated to a volume of ml. The separated crystals are filtered off. There are obtained 62 mg (84%) of 7-(4-L-alanyl-l-piperazinyl)-5-cyclopropy1-8-fluoro-2-hydroxypyrimido[1.6-a]benzimidazole -1,3(2H,5H)-dione.

Microanalysis C2OH23FN6°4·0*25 CH3OH: Calc.: C 55.47 H 5.52 N 19.17 Found: 55.15 5.76 19.18.

Example 7 a) A solution of ethyl rac-6-[2-(tert-butoxycarbonyl)-l-pyrro1idinyl]-l-cyclopropyl-5-fluoro-2-benzimidazoleacetate (1.647 g. 3.82 mmol) in ethanol (15 ml) is treated with a IN ethanolic solution of hydroxylamine (9.54 ml. - 26 9.54 mmol) and with a IN ethanolic sodium methylate solution (1.91 ml. 1.91 mmol). After one hour the solvent 5 is distilled off and the residue is dissolved in water.

The pH is adjusted to 5.5 with IN hydrochloric acid. This solution is extracted with ethyl acetate and the organic phase is washed with water, dried (magnesium sulphate) and concentrated. The residue is recrystallized from ethyl 30 acetate. The crystals obtained are dissolved in tetrahydrofuran (30 ml) and treated with 1,8-diazabicyclo[5.4.0]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 (magnesium sulphate) and concentrated. The residue is recrystallized from ether/n-hexane. There are obtained 643 mg (33%) of 1-f 2-[[(benzyloxy)carbamoyl]methyl]-l-cyclopropy1-520 -fluoro-6-benzimidazolyl]-L-proline tert-butyl ester.

Microanalysis C_oH__FN.0.: 33 4 4 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-[2-[[(benzyloxy)carbamoylJmethyl]-l-cyclopropyl-5-fluoro-6-benzimidazolyl] -L-proline tert-butyl ester there is obtained in a yield of 78% 1-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-1.2.3.5-tetrahydro-1,3-dioxopyrimidofl.6-aJ benzimidazo1-7-ylJ-L30 -proline tert-butyl ester.

MS: 534(M). c) In analogy to Example 4c). from 1-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-1.2,3.5-tetrahydro-l.3-dioxopyrimido fl.6-a]benzimidazol-7-yl]-L-proline tert-butyl ester there is obtained in a yield of 81% l-[5-cyclopropyl-8-£luoro-1,2,3,5-tetrahydro-2-hydroxy-l.3-dioxopyrimidof1,6-a]benzimidazol-7-yl]-L-proline tert-butyl ester. - 27 Microanalysis C^^H^FN,Or: 4 5 Calc.: C 59.45 H 5.67 N 12.61 5 Found: 59.03 5.54 12.51.

Example 8 a) In analogy to Example Id), from N-acetylpiperazine and 10 5'-chloro-N-ethyl-4'-fluoro-2'-nitroacetanilide there is obtained in a yield of 76% N-ethyl-4'-fluoro-5'-(4-acetyl-l-piperazinyl)-21-nitroacetanilide with a m.p. of 129-131°.

Microanalysis Cn,H_,FN.O.: 1 162144 15 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-51 -(4-acetyl-l-piperazinyl)-21-nitroacetanilide (8.4 g. 23.8 mmol) in 20 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]-l-piperazinecarboxylate with a m.p. of 155-157°. c) In analogy to Example 2d), from tert-butyl 4-[5-(ethylamino)-2-fluoro-4-nitrophenyl]-1-piperazinecarboxylate there is obtained in a yield of 67% ethyl - 28 6-[4-tert-butoxycarbony1)-1-piperazinyl]-l-ethy1-5-fluoro-2-benzimidazoleacetate with a m.p. of 131-133°.

Microanalysis C„H,,FN.O.: 31 4 4 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-[4-tert10 -butoxycarbonyl)-l-piperaz inyl]-l-ethy1-5-fluoro-2-benzimidazoleacetate there is obtained a yield of 36% tert-butyl 4-[2-carbamoyImethyl)-l-ethy1-5-fluoro-6-benzimidazolyl]-l-piperazinecarboxylate with a m.p. of 162-164°.

MS: 405(M). e) In analogy to Example 2f), from tert-butyl 4-[2- (carbamoyImethyl)-l-ethyl-5-fluoro-6-benzimidazolyl] -1-piperazinecarboxylate there is obtained in a yield of 67% 20 tert-butyl 4-(5-ethyl-8-fluoro-l,2.3,5-tetrahydro-l.3-dioxopyr imido[1.6-a]benzimidazo1-7-yl)-1-piperazinecarboxylate with a m.p. of 270-273°.

Microanalysis C_.H_,FNcO.: Z1 Zb □ 4 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-l.2.3,5-tetrahydro-l,3-dioxopyrimido[l,6-a]benzimidazol-7-yl)-l-piperazinecarboxylate there is obtained in a yield of 70% 5-ethyl-8-fluoro-7-(l-piperazinyl)pyrimido[1,6-a]benzimidazole-1.3(2H,5H)-dione with a m.p. of 264-266°.

Microanalysis C,,H._FNCO ·0.2 CH.OH: lo lo □ Z □ Calc.: C 57.61 H 5.61 N 20.74 Found: 57.44 5.49 20.85. - 29 Example 9 a) In analogy to Example 2d), from l-(5-ethylamino)-2-fluoro-4-nitrophenyl)-4-methylpiperazine there is obtained in a yield of 30% ethyl l-ethyl-5-fluoro-6-(4-methyl-l-piperazinyl)-2-benzimidazoleacetate with a m.p. Of 142-144°.

Microanalysis C,OH__FN.O_: 4 2 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 l-ethyl-515 -fluoro-6-(4-methy1-1-piperazinyl)-2-benzimidazoleacetate there is obtained l-ethyl-5-fluoro-6-(4-methyl-l-piperazinyl)-2-benzimidazoleacetamide. From this intermediate there is obtained in analogy to Example 4a) in a yield of 35% (over both steps) 2-[[(benzyloxy)carbamoyl]20 methyl]-l-ethyl-5-fluoro-6-(4-methyl-1-piperazinyl)-benzimidazole with a m.p. of 165-168° (ethyl acetate).

Microanalysis C__,H_aFN._O ' Z 3 Zo b Z Calc.: C 64.92 H 6.63 N 16.46 Found: 64.92 6.85 16.36. c) In analogy to Example 4b), from 2-[[(benzyloxy)carbamoylJmethyl]-l-ethyl-5-fluoro-6-(4-methyl-1-piperaziny1)-benzimidazole there is obtained in a yield of 54% 2-(benzyloxy)-5-ethyl-8-fluoro-7-(4-methyl-l30 -piperazinyl)pyrimidofl.6-aJ benzimidazole-1.3(2H.5H)-dione with a m.p. of 250-252° (methanol).

Microanalysis C24H26FN5°3: 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)pyrimidofl.6-a]benzimidazole-1.3 (2H, 5H)-dione there is obtained in a yield of - 30 53% 4-ethyl-8-fluoro-2-hydroxy-7-(4-methyl-l-piperazinyl)pyrimidoΓ1,6-a]benzimidazole-1,3(2H.5H)-dione.

Microanalysis CinH FNO »0.2 DMF: Xι ZQ b 3 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]-l-piperazinecarboxylate there is obtained in a yield of 44% p-nitrobenzyl 6-[4-(tert-butoxycarbonyl)-1-piperazinyl]-1-cyclopropyl-5-fluoro-2-benzimidazoleacetate.

Microanalysis C_oH__FN_0 : Zo 3Z b ο Calc.: C 60.75 H 5.83 N 12.65 Found: 60.81 6.11 12.54. b) A solution of p-nitrobenzyl 6-[4-(tert-butoxycar bonyl)-1-piperazinyl]-l-cyclopropyl-5-fluoro-2-benzimidazoleacetate (553 mg, 1 mmol) in THF (50 ml) is treated in succession at 0° with triethylamine (300 mg. 3 mmol) and chloroacetyl isocyanate (298 mg. 2.5 mmol).

After stirring for 20 hours the solvent is distilled 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 solvent is evaporated. The residue is 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-butoxycarbonyl)-1-piperaziny1]pyrimido[1.6-a]benzimidazole-435 -carboxylate.

Microanalysis C3OH31FN6°8: Calc.: C 57.87 H 5.02 N 13.50 Found: 57.50 5.04 13.38. - 31 c) A solution of p-nitrobenzyl 5-cyclopropyl-8-fluoro-1.2.3.4-tetrahydro-1,3-dioxo-7-[4-( tert-butoxycarbonyl)5 -1-piperazinyl]pyrimidof1,6-a]benz imidazole-4-carboxylate (1.758 g. 2.82 mmol) in acetonitrile (250 ml) is treated in succession with sodium iodide (846 mg, 5.65 mmol) and trimethylchlorosilane (1.23 g, 11.28 mmol). After one hour at 80° the suspension obtained is cooled to 0°. The 10 crystals are filtered off and taken up in an ethanol/water mixture (2:8. 250 ml). The pH is adjusted to 8.0 with a sodium bicarbonate solution. The suspension is cooled to 0° and the pale yellow crystals are filtered off. The filter residue is suspended in ethanol. The crystals are filtered off and washed with ether. There are obtained 1.10 g (75%) of p-nitrobenzyl 5-cyclopropyl-8-fluoro-1,2.3,4-tetrahydro-l,3-dioxo-7-(1-piperazinyl)pyr imido[1,6-a]benz imidazole-4-carboxylate.

Microanalysis C_rH__FNrO · Ζ ο Z J b b 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-l.3-dioxo-7-(1-piperazinyl)pyrimido25 [1,6-a]benzimidazole-4-carboxylate (122 mg, 0.234 mmol) in DMF (30 ml) is hydrogenated over 5 percent Pd/C. After completion of the hydrogenation the catalyst is filtered off and the filtrate is treated with fuller's earth, filtered and concentrated to a volume of 5 ml. The separated crystals are filtered off. There are obtained 62 mg (68%) of the sodium salt of 5-cyclopropyl-8-fluoro-1,2,3,4-tetrahydro-l.3-dioxo-7-(1-piperazinyl)pyrimido[1,6-a]benzimidazole-4-carboxylie acid.

MS: 343(M-CO2). 44 (CO2).

The crystals are taken up in DMF (10 ml) and treated with a saturated sodium bicarbonate solution (1 ml). The solvent is distilled off and the residue is chromato32 ΐε 904l8g graphed with water on a reversed phase (column RP8). There are obtained 39 mg (40%) of the above product.

MS: 343 (M-CO2), 44 (CO2).

Example 11 In analogy to Example 9. from tert-butyl 4-[210 - (carbamoylmethyl)-1-ethyl-5-fluoro-6-benzimidazolyl]-1-piperazinecarboxylate (from Example 8d) there is 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-(l-piperazinyl)pyrimidof1.6-a]benz15 imidazole-1,3(2H.5H)-dione hydrochloride.

Microanalysis Cn,Hn_C1FNCO_: io iy b 3 Calc.: C 50.07 H 4.99 N 18.25 Found: 50.94 5.22 18.47, Example 12 a) Ethyl 6—[4 —(tert-butoxycarbonyl)-l-piperazinyl]-l-cyclopropyl-5-fluoro-2-benzimidazoleacetate (1.8 g. mmol; from Example 2d) and tert.butyl carbazate (21 g. 16 mmol) are dissolved in pyridine (40 ml) and stirred at 115° under argon for 65 hours. The reaction solution is concentrated and triturated with 50 ml of ether. The separated product is filtered off under suction and dried. There is obtained tert-butyl 3-ff6-[4-(tert-butoxycar30 bony1)-1-piperazinyl]-l-cyclopropyl-5-fluoro-2-benzimidazolyl]acetyl]carbazate. Yield: 0.49 g (23%); m.p. 202-203°.

Microanalysis C_rH__FN,O,: Z b 3 / b b Calc.: C 58.63 H 7.00 N 15.78 Found: 58.44 7.15 15.66. b) tert-Butyl 3-(]6-(4-(tert-butoxycarbonyl)-l-piperazinyl]-1-cyclopropy1-5-fluoro-2-benzimidazolyl]acetyl]carba - 33 zate (0.40 g. 0.76 mmol) is dissolved in THF (15 ml) and treated with 1,1'-carbonyldiimidazole (0.24 g, 1.5 mmol) 5 and DBU (3 drops). The solution obtained is stirred at 60°C for 2 hours and thereafter concentrated on a rotary evaporator. The residue is dissolved in ethyl acetate and then chromatographed on silica gel (eluent: ethyl acetate/ hexane 4:1). The product is recrystallized from ethyl 10 acetate/ether. There is obtained tert-butyl 7-[4-(tert- . -butoxycarbonyl)-1-piperazinyl]-5-eyelopropy1-8-fluoro-3.5-dihydro-l.3-dioxopyrimido[l,6-a]benzimidazole-2(IH)-carbaraate. Yield: 85 mg (20%): m.p. 219-220°. Microanalysis Cnr,H_cFN,O, : 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-eyelopropy1-8-fluoro-3,5-dihydro-l.3-dioxopyrimido20 [l.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 is 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: CHCl3/EtOH/NH4OH 80:20:1) and recrystallized from ethanol. There is obtained 2-amino-5-cyclopropy1-8-fluor0-7-(1-piperazinyl)pyrimidof1.6-a]benz imidazole-1.3(2H.5H)-dione. Yield: 43 mg (46%); m.p. 232-234° .

Microanalysis C17HigFN6O2; 0.3 EtOH: Calc.: C 56.70 H 5.62 N 22.58 Found: 56.40 5.77 N 22.67. Example 13 a) In analogy to Example 12a). from ethyl 6-[4-(tertIE 904189 - 34 -butoxycarbonyl)-1-piperazinylJ-l-cyclopropy1-5-fluoro-2-benzimidazoleacetate and tert-butyl 2-methylcarbazate there is obtained in a yield of 33% tert-butyl-4-[2-(((2- (tert-butoxycarbonyl)-2-methylhydrazino]carbonyl]methyl]5 -1-eye1opropy1-5-fluor0-6-benzimidazolyl]-1-piperazine-carboxylate with a m.p. of 180-182°.

MS: 546 (M) ; 446 [M- ( isobutene + CC>2 ) ] . b) In analogy to Example 12b). starting from tert-butyl 4-[2-[[(2-(tert-butoxycarbonyl)-2-methylhydrazino]carbonyl] methyl]-l-cyclopropyl-5-fluoro-6-benzimidazolylJ-l-piperazinecarboxylate there is obtained in a yield of 59% tert-butyl 7-[4-(tert-butoxycarbonyl)-1-piperazinyl]-5-cyclopropy1-8-fluoro-3.5-dihydro-N-methyl-l,3-dioxopyrimido15 [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-cyclopropyl20 -8-fluoro-3.5-dihydro-N-methyl-l.3-dioxopyrimido[1,6-a]benzimidazole-2-carbamate there is obtained in a yield of 43% 5-cyclopropyl-8-fluoro-2-(methylamino)-7-(1-piperaziny1)pyrimido[1.6-a]benzimidazole-l,3(2H,5H)-dione with a m.p. of 228-230°.

Microanalysis C1OH FN O : X ο Z X ο Z 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)-1-piperazinyl]-1-eye1opropy1-5-fluoro-2-benzimidazoleacetate and hydrazine hydrate there is obtained tert-butyl 4-(2-[[(hydrazino)carbonyl]methyl]35 -l-cyclopropyl-5-fluoro-6-benzimidazolyl]-l-piperazinecarboxylate with a m.p. of 172-173°. - 35 Microanalysis C H FN O : 29 6 3 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-[[(hydrazino) carbonyl J methyl]-1-cyclopropyl-5-fluoro-6-benzimidazolylJ-l-piperazine-carboxylate (0.43 g) in methanol (22 ml) is stirred at 50° with a 35% aqueous formaldehyde solution (0.102 g); subsequently sodium borohydride (46 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-[2-[[[2-(dimethylhydrazino) carbonylJmethyl]-1-cyclopropyl-5-fluoro-6-benzimidazolylJ-1-piperazine-carboxylate are obtained with a m.p. of 179-181°.

MS: 460 (M) c) In analogy to Example 12b). starting from tert-butyl 4-[2-[[[2-(dimethylhydrazino)]carbonylJmethylJ-1-cyclopropyl-5-fluoro-6-benzimidazolyl]-1-piperazine-carboxylate there is obtained tert-butyl 4-[5-cyclopropyl-8-fluoro-1.2.3.5-tetrahydro-2-(dimethylamino)-1.3-dioxopyrimidofl, 6-aJbenzimidazol-7-ylJ-l-piperazine-carboxylate with a m.p. of 201-203°.

Microanalysis C H,FNO: 31 6 4 Calc.: C 59.25 H 6.42 N 17.27 Found: 59.13 7.10 17.73. d) In analogy to Example 12c), starting from tert-butyl 4-f 5-cyclopropyl-8-fluoro-1,2.3.5-tetrahydro-2-(dimethylamino )-1.3-dioxopyrimidof1.6-a J benzimidazo1-7-ylJ-l-pipera zine-carboxylate there is obtained 5-cyclopropyl-2-(dimethylamino) -8-fluoro-7-(1-piperazinyl)pyrimidof1.6-aJ 35 benzimidazole-1,3(2H,5H)-dione with a m.p. of 207-209°. - 36 Microanalysis C H FN O : 1923 62 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: -Cyclopropyl-8-fluoro-7-(1-piperazinyl)-pyrimidof1,6-a]- benzimidazole-1,3(2H,5H)-dione 200 mg Luviskol (water-soluble polyvinylpyrrolidone) 20 mg Mannitol 20 mg Talc 15 mg Magnesium stearate 2 mq 257 mg Example B Tablets containing the following ingredients are manufactured in the usual manner: -Cyclopropy1-8-fluoro-7-(125 -piperazinyl)-pyrimido[l,6-a]- benzimidazole-1,3(2H,5H)-dione 200 mg Starch 44 mg Calcium carboxymethylcellulose 30 mg Crystalline cellulose 40 mg Magnesium stearate 6 320 mq mg

Claims (45)

1. Compounds of the general formula R 8 wherein R signifies hydrogen, halogen or amino, 2. . . . ... R signifies halogen. R signifies a lower alkyl-substituted 4-pyridyl group or a group 3. 4 3 4 R R N- in which R and R each signify hydrogen or lower alkyl or together signify a group of the formula -(CH_) -X-(CH_) - or -(CH ) 2 η z m 2 p which is unsubstituted or substituted by lower alkyl. amino, lower aminoalkyl, mono- or di(lower alkyl)a 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 is a maximum of 5, p signifies the number 4. 5 or 6. X signifies an oxygen a 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 ammoalkanoyl. R signifies hydrogen, halogen, lower alkoxy or amino. R 6 signifies lower alkyl, lower cycloalkyl. lower haloalkyl. phenyl or phenyl which is mono-, di- or trisubstituted by halogen, lower alkyl, hydroxy or lower alkoxy. R signifies hydrogen, lower alkyl or Q carboxy. R signifies hydrogen, hydroxy, lower 4. * - 38 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 R signifies hydrogen, hydroxy, lower alkoxy, amino or lower alkylamino.

3. Compounds according to claim 2. wherein R . . 3 4 8 . . . signifies the group R R N- and R signifies hydrogen, hydroxy or lower alkoxy. 15 · 1

4. Compounds according to claim 3. wherein R and 5 R each signify hydrogen.

5. Compounds according to claim 3 or claim 4, . 2 . . . wherein R signifies fluorine.

6. Compounds according to any one of claims 3-5, 3 4 wherein R and R together signify a group of the formula -(CH ) -X-(CH ) - or a group of the 2 n 2 in formula -(CH ) - which is substituted by the group a 2 P 25 -COOR . n and m each signify the number 2. p signifies the number 4. X signifies the group -NR'-. R signifies lower alkyl and R' signifies hydrogen, lower alkyl or lower aminoalkanoyl. 30

7. Compounds according to claim 6. wherein 3 4 R R N- signifies the 1-piperazmyl group or the 4-methyl-l-piperazinyl group.

8. Compounds according to any one of claims 3-7, 35 wherein R 6 signifies lower alkyl or lower cycloalkyl.

9. Compounds according to claim 8. wherein R signifies ethyl. - 39

10. Compounds according to claim 8. wherein R 6 signifies cyclopropyl.

11. wherein Compounds according to any one of 7 . . . R signifies hydrogen or carboxy. claims 3-10. 10

12. wherein Compounds according to any one of 8 . . . R signifies hydrogen or hydroxy. claims 3-11.

13 . wherein Compounds according to any one of Y signifies an oxygen atom. claims 3-12. 15

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, 8 . . . wherein R signifies amino or methylamino.

16. Compounds according to any one of claims 1-14. 8 . . . wherein R signifies dimethylamino.

17. 5-Ethyl-8-fluoro-7-(4-methyl-l-piperazinyl)25 -pyrimidof1.6-a]benzimidazole-1.3(2H.5H)-dione.

18. 5-Cyclopropy1-8-fluoro-7-(1-piperazinyl)-pyr imido [1.6-a]benzimidazole-1,3(2H.5H)-dione. 30

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

20. 5-Cyclopropyl-8-fluoro-2-hydroxy-7-(135 -piperazinyl)pyrimidof1.6-a]benzimidazole-1.3(2H.5H)-dione

21. tert-Butyl rac-1-f5-cyclopropyl-8-fluoro-2.3-dihydro-l.3-dioxopyrimidofl,6-a]benzimidazol-5(lH)-yl]-2IE 904189 - 40 -pyrrolidinecarboxylate.

22. 7-(4-L-Alanyl-l-piperazinyl)-5-cyclopropy1-8-fluoro-2-hydroxypyrimidofl,6-a]benzimidazole-1,3(2H,5H)-dione.

23. 1-f 5-Cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-210 -hydroxy-1.3-dioxopyrimidof1.6-a]benzimidazol-7-yl]-L-proline tert-butyl ester.

24. 5-Ethyl-8-fluoro-7-(1-piperazinyl)pyrimidof1,6-a] benzimidazole-1.3(2H,5H)-dione.

25. 5-Ethyl-8-fluoro-2-hydroxy-7-(4-methyl-l-piperazinyl)-pyrimidof1,6-a]benz imidazole-1,3(2H,5H)-d ione.

26. 5-Cyclopropyl-8-fluoro-1.2.3,4-tetrahydro-l.3-dioxo-7-(1-piperazinyl)pyr imidofl.6-a]benz imidazole-4-carboxylic acid.

27. 5-Ethyl-8-fluoro-2-hydroxy-7-(1-piperaziny1) 25 pyrimidofl.6-a]benzimidazole-1.3(2H.5H)-dione.

28. 2-Amino-5-cyclopropyl-8-fluoro-7-(1-piperazinyl)-pyrimidof1.6-a]benzimidazole-1.3(2H.5H)-dione. 3Γ»

29. 5-Cyclopropyl-8-fluoro-2-(methylammo)-7-(l-piperazinyl)pyrimidof1.6-a]benzimidazole-1.3(2H,5H)-dione

30. 5-Cyclopropyl-2-(dimethylamino)-8-fluoro-7-(1piperazinyl)pyrimidof1.6-a]benzimidazole-1.3(2H,5H)-dione.

31. Compounds of the general formula - 41 Rl 1 2 5 6 7 8 wherein R. Y. R . R , R , R , R and R 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. R s ignif icance free hydroxy present are 1 t, 2 r, 5 t, 6 , „8 , , R . R . R and R have the given in claim 1. with the proviso , amino and carboxy groups which may in protected form. that be

33. Compounds of the general formula 30 wherein Rb signifies a carboxy protecting group and R. 12 5 6 R . R . R and R have the significance given in claim 1. with the proviso that free hydroxy, amino and carboxy groups which may be present are in 33 protected form.

34. Compounds of formula I in claim 1, which have at least one protected hydroxy, amino and/or carboxy group. 20

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 30 a) reacting a compound of the general formula χ 2 5 6 V 8 wherein R. Y. R . R . R . R , R and R 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 25 b) reacting a compound of the general formula IV wherein R, R significance given in claim 1. with the proviso that free hydroxy, amino and carboxy groups which may be present are in protected form. - 44 in the presence of a base with a compound of the general formula RaOOC-CHR 7 -COORa 10. Wherein Ra signifies lower alkyl and R 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 wherein Rb signifies a carboxy protecting group and 12 5 6 R, R . R . R and R 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. - 45

39. An antibacterially-active medicament, containing a compound in accordance with any one of claims 1-30 and a therapeutically inert carrier. 5

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 10 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. 20

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 25 effective amount of a compound in accordance with any one of claims 1-34 together with a therapeutically inert carrier material.