AU640708B2 - Substituted pyrimidobenzimidazole derivatives - Google Patents

Description

640708 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION S F Ref: 146188

(ORIGINAL)

FOR OFFICE USE: Class Int Class

A.

A

.6 b4 S 6 4 AA r* 6 4 *1* Complete Specification Lodged: Accepted: Published: Priority: Related Art: Name and Address of Applicant: F.Hoffmann-La Roche AG 124 Grenzacherstrasse CH-4002, Basel

SWITZERLAND

Address for Service: Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Complete Specification for the invention entitled: Substituted Pyrimidobenzimidazole Derivatives The following statement is a full description of this invention, including the best method of performing it known to melus 5845/6 RAN 4410/221 Abstract The present invention is concerned with novel substituted pyrimidobenzimidazole derivatives of the general formula se e e R2 N N R R8

*R

00

R

6

R

7 wherein R 1 signifies hydrogen, halogen or amino, 2 R2 signifies halogen, R signifies a lower alkyl-substituted 4-pyridyl group or a group

R

3

R

4 N- in which R 3 and R 4 each signify hydrogen or lower alkyl or together signify a group of the formula -(CH m or 2 n m or p which is unsubstituted or substituted by lower alkyl, 25 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 is a maximum of 5, p signifies the number 4, 5 or 6, X signifies an oxygen or sulphur atom or the group R a 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, signifies hydrogen, hydroxy, lower alkyl or lower aminoalkanoyl, 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, R7 signifies hydrogen, lower alkyl or carboxy, R 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 *o0 used for the prevention or control of bacterial infections.

S. e o °e see* 0 S.

S

1B RAN 4410/221 The present invention is concerned with novel substituted pyrimidobenzimidazole derivatives of the general formula

R

1

R

SR signifies halogen, R signifies a lower alkyl-substituted 4-pyridyl group or a group *3 4 where4N- in which signiies3 and R hydrogeach signify the formula -(CH2)n-X-(CH2) m- or -(CH2) p which is unsubstituted or substituted by lower alkyl, Samino, lower aminoalkyl, mono- or di(lower alkyl)amino-lower alkyl, oxo or the group -COOR or -CONR'R", n and m a each signify the number 1 2 or 3, with the proviso that n m is a maximum of S, p signifies the number 4, 5 or 6, X signifies an oxygen or sulphur atom or the group 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, 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 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 carboxy, R 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 novel compounds of formula I above have valuable pharmacological properties. They display an inhibitory

S*

Saction on the DNA-gyrase activity in bacteria and can accordingly be used for the control or prevention of 15 bacterial infections.

*5 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 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 straight-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 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.

Preferably, R 1 and R 5each signify hydrogen.R2 preferably signifies fluorine. R3and R 4preferably together signify a group of the formula -C -C or a group of the formula a -(CH 2 p- which is substituted by the group -COOR wherein n and m each signify the number 2. p signifies the number 4. X signifies the group -NII- R asignifies lower alkyl and R"'I signifies hydrogen, lower alkyl or Dote lower aminoalkanoyl. R 3R 4N- is preferably 1-pipera- 15 zinyl or 4-methyl-l-piperazinyl. R 6preferably signifies W* lower alkyl, especially ethyl, or lower cycloalkyl, 7 especially cyclopropyl. R preferably signifies hydrogen too* or carboxy. R 8preferably signifies hydrogen. hydroxy, amino, methylamino or dimethylamino. Y preferably signifies an oxygen atom. When R signifies a lower to alkyl-substituted 4-pyridyl group, this is preferably the 3,5-dimethyl-4-pyriiyl 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-l-piperazinyl)-pyrimido- S [1*6-a]benzimidazole-1. 3 2H. 5-ethyl-$-fluoro-3.5-dihydro-1-(4-methyl-1-piperazinyl)- -3-thioxopyrimidotl.6-ajbenzimidazol-1(2H)-one, 5-cyclopropyl-8-fluoro-2-hydroxy-7--(l-piperazinyl)- -pyrimido[1,6-a]benzimidazole-l,3(12H.5H)-dione, tert-butyl rac-l-[5-cyclopropyl-8-fluoro-2,3-dihydro- -l,3-dioxopyrimidofl.6-albenzimidazole-7(lH)-yl-2- -pyrrolidinecarboxylate, -4 7- (4-L-alany'L--1-piperazinyl)-5--cyclopropyl-8-fluoro-2- 5-hydroxypyrimido[l.6-ajbenzixpidazole-1.3(2H,5H)-dione.

1-[B-cyclopropyl-8-fluoro-1. 2.3. 5-tetrahydro--2-hydroxy- 3-dioxopyrimido[1. 6-a]benzimidazol-7-ylj-L-proline tert-butyl ester, luoro-7-(l.-piperazinyl)pyrimido[l.6-a)benzimidazole-1.3(2H.5H)-dione.

luoro-2-hydroxy-7- (4-methyl-1-piperazinyl)pyriluido[l.6-ajbenzimidazole--1,3(2H.5H)-dione.

'064105-cyclopropyl-8-fluoro-1.2. 3,4-tetrahydro--1.3-dioxo-7- *too-(l-piperazinyl)pyrimido[1.6-a]benzimidazole-4-carboxylic acid, o 15 5-ethyl-8-fluoro-2-hydroxy-7- (l-piperazinyl)pyrimido- Ce.. [1,6-.ajbenzimidazole-l.3(2H,5H)-dione, eg 2-amino-5-cyclopropyl-8-fluoro-7- (1-piperazinyl)pyri- -cycl1o pr opy 1- 8- fluo (me thyl am ino) -7 p ipe ra zinyl)pyrimido[1.6-a~benzimidazole-1,3(2H.5H)-dione and 5-cyclopropyl-2- (dimethylamino)-8-f luoro-7- (l-piperazinyl)pyrimido[1.6-ajbenzimidazole-1.3(2H.SH)-dione.

The novel compounds of formula I and their pharmaceu- 25 tically acceptable salts can be manufactured in accordance with the invention by a) reacting a compound of the general formula

R

1 2 5 6 7 8 wherein R. Y. R R R R R and R 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

s e* wherein X signifies a leaving group, or S" b) reacting a compound of the general formula R1 N- NHRS I

:I

R 'H

S

R

5 R6 *0"0* 25 1 2 5 6 R S 2 5 wherein R. R 1

R

2 R 5 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-CHR 7 -COORa V 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

R

1 R2 V I

\VI

R Ra 5

R

6 COORb wherein Rb signifies a carboxy protecting group and

R

1

R

2 R and R 6 have the above S* 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 ofI.

and a compound of formula I obtained is, if d:sired, converted into a pharmaceutically acceptable salt.

*99** S 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 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 15 reduction witlh elementary hydrogen in the presence of a S* suitable catalyst 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 25 or NN'-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[4.1.0]- (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 100 0

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 the base. The corresponding lower alcohol, e.g. methanol, is preferably used as the solvent. This reaction is preferably carried out at room temperature.

Compounds of formula I in which R signifies carboxy, R signifies hydrogen and Y signifies an oxygen atom can be manufactured in accordance with process variant The reaction of a compound of formula VI with 9-b 2 molar equivalents of chloroacetyl isocyanate is ,preferably carried out in an inert organic solvent, with e.g. open-chain and cyclic ethers such a3 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 Itl 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-toluene- Bulphonates and the like.

9 The compounds of general formulae II, IV and VI which are used as starting materials are novel and are also 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 b) and 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 plC18 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 jg/ml.

10 Table Activity Toxicity MNC in LD50 in Product from yIg/ml mg/kg Example 1 2 Example 2 0.45 30 >2000 Example 3 2 Example 4 2 30 >4000 Example 8 1 '8 4 e 06, .4o ~4 B Q 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 otier 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 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, 0,1* 15 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, 20 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.

25 As pharmaceutical adjuvants there come into consideration the usual stabilizing, preserving, wetting and emulsifying agents, flavour-improving agen's, salts for varying the osmotic pressure, buffer substances, solubilizers, colouring and coating agents and anti- 30 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 e. a) A suspension of lithium aluminium hydride (44.1 g, 1.16 mmol) in absolute ether (700 ml) is treated dropwise 20 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 00 and treated with a Rochelle salt solution (350 ml). The crystals obtained are filtered off 25 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 of 3-chloro-N-ethyl-4-fluoroaniline as an amorphous material.

30 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 n-hexane. There are obtained 102 g of 3'-chloro-N- -ethyl-4'-fluoroacetanilide.

Microanalysis C1 H C1FNO: 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 conc. 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 15 The solution obtained is stirred overnight, then poured on to ice/wate" 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 s, 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 of 5 -chloro-N-ethyl-4 -fluoro-2 -nitroacetanilide with a 25 m.p. of 68°.

S" Microanalysis C0 H FC1N203 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 stirred at 600 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 iagnesium sulphate and evaporated. The residue is recrystallized from ethyl acetate/n-hexane. There are 14 obtained 72.3 g of N-ethyl-4'-fluoro-5'-(4-methyl- -1-piperazinyl)-2'-nitroacetanilide with a m.p. of 117-1190.

Microanalysis C 15

H

21

FN

4 0 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 800 for 3 hours and thereafter cooled to room 15 temperature. The crystals obtained are filtered off and washed with water. There are obtained 13.7 g of 1-(5-(ethylamino)-2-fluoro-4-nitrophenyl)-4-methylpiperazine with a m.p. of 149-1500.

Microanalysis C 3H19FN402 **13 19F~ 4 2 20 Calc.: C 55.31 H 6.78 N 19.85 Found: 55.16 6.95 19.81.

f) A solution of l-(5-(ethylamino)-2-fluoro-4-nitrophenyl)-4-methylpiperazine (10 g) in THF (200 ml) is 25 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. HC1 (2.5 ml). After stirring under argon 30 for two hours the pH is adjusted to 8 with 4N NaOH and the solution is evaporated under reduced pressure. The residue S* is extracted with methanol/ethyl acetate 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 of -ethylamino)-5-fluoro-4-(4-methyl-l-piperazinyl]phenyl-urea.

15 Microanalysis C14H22FN 0: 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 is treated with a freshly prepared methanolic solution of sodium methylate (from 150 mg of sodium) and heated unde.r 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 HC1 (50 ml). The methanol is evaporated and the aqueous 15 phase is extracted with ethyl acetate (3x 100 ml) and methylene chloride (2x 100 ml). After drying over magnesium sulphate the solvent mixture is evaporated and 8' a the residue is suspended in a small amount of cold ethyl acetate and filtered off. There are obtained 130 mg (17%) 6** 20 of 5-ethyl-8-f luoro-7-(4-methyl-1-piperazinyl)pyrimido- 6-abenzimidazole-1.3(2H,5H)-dione.

MS: 345(M) Microanalysis (hydrochloride)

C

17

H

21 C1FN 5 0 2 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 00 the suspension obtained is stirred at 250 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 of 5-chloro-N-cyclopropyl-4-fluoro-2- 16 -nitroaniline with a m.p. of 73.5-75.50.

Microanalysis C 9HC1FN202 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) 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 600 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 se@ 15 sulphate. After distillation of the solvent the residue is recrystallized from ethanol. There are obtained 4.57 g of 1-acetyl-4-[5-(cyclopropylamino)-2-fluoro-4- -nitrophenyl]piperazine with a m.p. of 142-1430.

Microanalysis C15H 19

FN

4 0 3 Get 15 19 4 3 20 Calc.: C 55.89 H 5.94 N 17.38 Found: 55.66 5.94 17.35.

c) l-Acetyl-4-[5-(cyclopropylamino)-2-fluoro-4-nitrophenyl]piperazine (17 g, 53 mmol) is dissolved in methanol 25 (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 S" succession with water and sodium chloride solution and 30 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 Zor 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 of tert-butyl 4-[5-(cyclopropylamino)-2- 17 -fluoro-4-nitrophenyl]-l-piperazinecarboxylate with a m.p.

of 159-160°.

Microanalysis C18H 25

FN

4 0 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-nitrophenyl]-1-piperazinecarboxylate (17.21 g, 45.2 mmol) is dissolved in methanol (500 ml) and hydrogenated with 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 Soo Sheated to 500 for 2 hours. The DMF is distilled off, the :o2. 20 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 S 25 sulphate. The solution is evaporated under reduced b pressure and the residue is chromatographed on silica gel (eluent: ethyl acetate). The product is then recrystal- Slized from ethyl acetate/hexane. There are obtained 15.5 g of ethyl 6-[4-(tert-butoxycarbonyl)-l-piperazinyl]- 30 -l-cyclopropyl-5-fluoro-2-benzimidazoleacetate with a m.p.

of 152-153.

Microanalysis

C

23

H

31

FN

4 0 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 is stirred at 500 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 The product is recrystallized from ethyl acetate/n-hexane.

There are obtained Z~.22 g of tert-butyl 4-[2- (carbamoylmethyl)-l-cyclopropyl-5-fluoro-6-benzimidazolylj-l-piperazinecarboxylate with a m.p. of 15 219-2200.

Microanalysis C 21H 28FN 503 Calc.: C 60.42 H 6.76 N 16.78 :**Found: 60.26 6.88 16.31.

f) tert-Butyl 4-[2-(carbamoylmnethyl)-1-cyclopropyl-5- -fluoro-6-benzimidazolyl]-l-piperazinecarboxylate (980 mg.

2.53 mmol) is suspended in THF (15 ml) and treated with 1.11-carbonyldiimidazole (760 mg. 2 mmol) and 1.8-diazabicyclo[5.4.Ojundec-7-ene (0.2 ml). The reaction mixture is heated to 600 for 2 hours. whereby white crystals separate. The suspension is then cooled to 00. The crystals are filtered off and recrystallized from ethanol.

There are obtained 760 mg of tert-butyl 5 propyl-8-fluoro-1.2,3. 5-tetrahydro-l. 3-dioxopyrimido- 30 [±L.6-a]benzimidazol-7-ylj.-l-piperazinecarboxylate.

*Microanalysis C 22H 26FN 50 4with 0.6 mol of ethanol: Caic.: 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-tetrahydro-1.3.-dioxopyrimido[1. 6-ajbenzimidazol-7-yl]-1- -piperazinecarboxylate (471 mg. 1 mmol) is dissolved in trifluoroacetic acid (2 mll. After 1 hour at 250 the 19 trifluoroacetic acid is distilled off. The residue is taken up in water (10 ml), treated with sodium hydrogen carbonate (168 mg, 2 mmol) and stirred at 250 for 2 hours.

The suspension is cooled to The crystals are filtered off, washed in succession with in each case 5 ml of cold water and ethanol and recrystallized from ethanol/water There are obtained 208 mg of 1o propyl-8-fluoro-7-(l-piperazinyl)-pyriAidotl,6-a]benzimidazole-l,3(2H.5H)-dione trifluoroacetate.

Microanalysis C 7H 1FN 0 2

.CF

3

COOH:

Calc.: C 49.89 H 4.19 N 15.31 Found: 49.71 4.43 15.29.

0 ~Example 3 oo :69 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 25 with ethyl cyanoacetate (2.26 g, 20 mmol). The solution is heated to 1600 for 4 hours. The solvent is then distilled off and the residue is taken up in an acetic acid/ether mixture (100 ml, 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 The product is recrystallized from an ethyl acetate/acetonitrile mixture There are obtained 1.17 g of l-ethyl-5-fluoro-6-(4-methyl-1- -piperazinyl)-2-benzimidazoleacetonitrile with a m.p. of 204-206°.

Microanalysis

C

1 6

H

2 0

FN

5 Calc.: C 63.77 H 6.69 N 23.24 Found: 63.65 6.54 23.31.

20 b) i-Ethyl-5-fluoro-6-(4-methyl-l-piperazinyl)-2-benzimidazoleacetonitrile (834 mg. 2.77 mmol) is dissolved in pyridine (20 ml) and triethylamine (2.8 g, 27.7 mmol). The solution is cooled to 00. Subsequently, hydrogen sulphide is introduced during 30 minutes. The thus-obtained deep green solution is heated to 450 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 The product is sa 15 recrystallized from ethyl acetate. There are obtained l"o" 745 mg of l-ethyl-5-fluoro-6-[4-methyl-l- '-piperazinyl]-2-benzimidazolecarbothioamide.

Microanalysis C 16

H

2 2

FN

5 S*0.3 Calc.: C 56.38 H 6.68 N 20.55 S* 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 carbonyldi- 25 imidazole (140 mg, 0.86 mmol). The reaction solution is G" heated to 680 for 6 hours, whereby white crystals separate. The suspension is cooled to The crystals are filtered off, suspended in methanol and, after one hour, again filtered off, washed with ether and dried in a high 30 vacuum. There are obtained 22 mg of -fluoro-3,5-dihydro-7-(4-methyl-l-piperazinyl)-3-thioxo- Spyrimidoll,6-a]benzimidazol-1(2H)-one.

Microanalysis C17H20FN5OS*0.7 Calc.: C 54.59 H 5.77 N 18.72 Found: 54.37 5.84 18.64.

21 Example 4 tert-Butyl 4-[2-carbamoyl-methyl)-l-cyclopropyl-5- -fluoro-6-benzimidazolyl]-l-piperazinecarbQcylate (703 mg.

1.68 mmol) is heated to 500 for 72 hourvs 4i1h O-benzylhydroxylamine hydrochloride (806 mg. 5.05 mmol) in a water/ethanol mixture (5 ml, The solvent is .Odistilled 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 of tert-butyl 4-[2-FC(benzyloxy)carbamoyljmethyl]-l-cyclopropyl-5-fluoro-6-benzimidazolylj-1-piperazinecarboxylate.

Microanalysis C 28H 34FN 504 Calc.: C 64.23 H 6.55 N 1.3.38 6 see Found: 64.35 6.83 13.35.

.0.

20 b) tert..Butyl 4-[2--[E(benizyloxy)carbamoylmethyl-1cyclopropyl-5-fluoro-6-benzimidazolyl 1-1-piperazinecarboxylate (779 mg. 1.1.8 mmol) is dissolved in tetrahydrofuran (15 ml) and treated with N.NI-carbonyldiimidazole (480 mg. 2.96 mmol) and 1.8-diazabicyclo[5.4.0Jundec-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 5 dried over magnesium sulphate. The solvent is evaporated 30 under reduced pressure and the residue is chromatoV-dI on silica gel (eluent: ethyl acetate/n-hexane The 5 product is crystallized from ethyl acetate/n-herane. There are obtained 42 mg of tert-butyl 4-[2-(benzyloxy)-5- -eyclopropyl-8-fluoro-1. 2 5-tetrahydro-1. 3-dioxopyrimido- 6-,iJbenzimidazol-7-yl]-1-piperazinecarboxylate.

Microanalysis C 29H 32FN 505 Calc.: C 63.38 H 5.87 N 12.74 Found: 62.78 5.69 12.64.

22 c) tert-Butyl 4-f2-(benzyloxy)-5-cyclopropyl-8-fluoro- -1,2.3.5-tetrahydro-1,3-dioxopyrimido[l,6-ajbenzimidazol- -7-yl]-l-piperazinecarboxylate (981 mg, 1.87 mmol) is dissolved in ethanol (250 ml) and hydrogenated with percent palladium/carbon (200 mg) under hydrogen at normal pressure. The palladium/carbon is filtered off and washed w, th dimethylformamide (100 ml) at 1000. The combined filtrates are evaporated under reduced pressure.

The residue is recrystallized from dimethylformamide.

There are obtained 619 mg of tert-butyl 4-[15-cyclopropyl-8-fluoro-1 2,3.5-tetrhydro-2-hydroxy-. 3-dioxopyrimido(l,6-albenzimidazol-7-yl]-l-piperazinecarboxylate.

o.,o 15 Microanalysis C 22

H

26

FN

5 0 5 Calc.: C 57.51 H 5.70 N 15.24 Foun 57.27 5.65 15.38.

so s* d) tert-Butyl 4-[5-cyclopropyl-8-fluoro-1,2.3.5-tetrahydro-2-hydroxy-1,3-dioxopyrimido[l,6-a]benzimidazol-7- -yl)-.-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 (250) 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 0 The separated crystals are filtered off, washed with ethanol and ether and dried in a high vacuum. There are obtained 30 176 mg of 5-cyclopropyl-8-fluoro-2-hydroxy-7-(l- -piperazinyl)-pyrimido[l,6-ajbenzimidazole-1,3(2H,5H)- -dione hydrochloride.

Microanalysis C17 H 19FN 03 Calc.: C 51.59 H 4.84 N 17.69 Found: 51.27 5.11 17,54.

23 Example 5-f-hloro-N-cyclopropyl-4-fluoro-2-nitroaniline (460 mg. 2 mmol) is heated to 800 for 40 hours with L-proline tert-1)utyl ester (342 mg. 2 mmol) and 1.8-diazabicyclo[5.4.0jundec-7-ene (304 mg. 2 mmol). The reaction m4&xture is then dissolved in a water/ethyl acetate mixture 100 ml). The ethyl acetate phase is washed with percent sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel (eluent: hexane/ ethyl acetate The product is crystallized from ether/n-hexane. There are obtained 94 mg of tert-butyl rac-1-[5-(cyclopropylamino)-2-fluoro-4,-nitrophenyljpyrrole-2-carboxylate with a m.p. of 142-1430.

Microanalysis C 18H 24FN 304 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 (cyclopropylamino) -2-f luoro-4--nitrophenyl )pyrrole-2- -carboxylate there is obtained in a yield of 56% ethyl rac-6-[2--(tert-butoxycarbonyl)-1-pyrrolidinyl)-1-cyclopropyl-5-fluoro-2-benzimidazoleacetate with a m.p. of 93-960.

Microanalysis C 2 H FN 0 4 Calc.: C 64.02 H 7.01 N 9.74 Found: 64.47 7.16 9.77.

In analogy to Example 2e). from ethyl rac-6-[2-(tert- -butoxycarbonyl)-1.-pyrrolidinyl]-l-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 176-1780.

24 Microanalysis C 21H 27FN 403 Caic.: C 62.67 H 6.76 N 13.92 Found: 62.40 6.86 13.60.

d) In analogy to Example 2f), from tert-butyl rac-l-[2- (carbamoylmethyl)-l-cyclbpropyl-5-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[l.6-ajbenzimidazol-7(lH)-yl]-2- -pyrrolidinecarboxylate with a m.p. of 226-2270.

Microanalysis C 22

H

25 FN 4 0 4 *.25 THF Caic.: C 61.87 H 6.10 N 12.55 Found: 61.77 6.38 12.62.

see* Example 6 :s.

*0 se a) tort-Butyl 4-[2-(bDenzyloxy)-5-cyclopropyl-8-fluoro- 20 -1.2.3.5-tetrahydro-1.3-dioxopyrimido[,6-abenzimidazolgoes-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 ,goose separated crystals are filtered off. washed with glacial 46,10 25 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 1N sodium hydroxide solution, whereby white crystals separate. The crystals 6 9 are filtered off, washed with water and dried in a high '44 30C vacuum. There are obtained 417 mg of 2-(benzyloxy)- -5-cyclopropyl-8-.fluoro-7-(l-piperazinyl)pyrimido(1, 6-a]- C benzimidazole-l. 3(2H. SH)-dione.

Microanalysis C 24

H

24 FN 5 03 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 00 with dicyclo- 25 hexylcarbodiimide (103 mg. 0.5 mmol After 30 minutes the crystals are filtered raff and washed with a small amount (30 ml) of dichioromethane. The filtrate is treated with a solution of 2-(Lenzyloxy)-5-cycloprupyl--fluoro-7-(l- -piperazinyl)pyrimidoll.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 from methanol. There are obtained 142 mg of benzyl [(S)-l-[4-[2-(benzyloxy)-5-cyclopropyl-8-fluoro-l.2,3,5- -tetrahydro-1,3-dioxopyrimido[l.6-a]benzimidazol-7-yl -l- -piperazinyl]carbonyl 1 ethyl j'arbamate.

MS: 653(M).

C) Benzyl ((S)-l-[4-[2-(benzyloxy)--5-cyclopropyl-B- -fluoro-l.2.,3.5-tetrahydro-l, 3-dioxopyrimido l.6-ajbenza imidazol-7-yl]-1-piperazinyl] car bonyllethylcarbamate a (127 mg. 0,194 mmol) is dissolved in DMF (15 ml) and hydrogenated over 5 percent Pd/C. After completion of the goes 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 a. 25 25 ml. The separated crystals are filtered off. There are obtained 62 mg of 7-(4-L-alanyl-l-piperazinyl)-5- -cyclopropyl-B-fluoro-2-hydroxypyrimidoE1.6-albenzimidazole- -1.3(2HR5H)-dione.

Microanalysis C 20 23

FN

6 0 40.25 CH*3OH: S. 30 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- -pyrrolidinyl]-1-cyclopropyl-5-fluoro-2-benzimidazoleacetate (1.647 g, 3.82 mmol) in ethanol (15 ml) is treated with a 1N ethanolic solution of hydroxylamine (9.54 ml.

26 9.54 mmol) and with a 1N ethanolic sodium methylate solution (1.91 ml, 1.91 mmol). After one hour the solvent is distilled off and the residue is dissolved ii water.

The pH is adjusted to 5.5 with 1N 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 ri~crystallized from ethyl 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 0449 15 (100 ml) and subsequointly with 10 percent sodium chloride tov* "solution (100 ml). The organic phase is dried (magnesium a S6a sulphate) and concentrated. The residue is recrystallized from ether/n-hexane. There are obtained 643 mg of 1-(2-t[(benzyloxy)carbamoyl]methyl]-1-cycloprop, -fluoro-6--benzimidazolylj-L-proline tert-.butyl es'er.

Micro~analysis C 28R3 FN 404 Caic.: C 66.13 H 6.54 N 11.01 Found: 65.99 6 86 11.14.

b) In analogy to Example 4b), from 1-t2-[[(benzyloxy)carbamoyl]me ,hylJ-l-cyclopropyl-5-fl~oro-6-benzimidazolyl] -L-proline tert-butyl ester ther- -a obtained in a yield of 78% 1.4[2-(benzyloxy)-5-cyclopropyl-8-fluoro-i.2.3.5- -tetrahydro-1.3-dioxopyrimido[1.6-a]benzimidazol,-7-ylJ-L- 30 -proline tert-butyl ester.

MS: 534(M.

c) In analogy to Example 4c), from 1-[2-(benzyloxy)-5- -cyclopropyl-8-fluoro-1. 2,355-tetrahydro-i. 3-dioxopyrimido- [1,6-a]benzimidazol-7-ylJ-L-proline tert-butyl ester there is obtained in a yield of 81% 1-[5-cyclopropyl-8.-fluoro- -i.2.3.5-tetrahydro-2-hydroxy-.1.3-dioxopyrimido[1.6-a]benzimidazol-7-ylJ-L-prolin,-e tert-butyl ester.

27 Microanaly.,is C 22H 25FN 405 Caic.: C 59.45 H 5.67 N 12.61 59.03 5.54 12.51.

Example 8 a) In analogy to Example id). f rom N-acetylpiperazine and 5'-chloro-N-ethyl-41'-fluoro-2'-nitroacetanilide there is.

obtained in a yield of 76% N-ethyl-41-fluoro-51-(4-acetyl- -l-piperazinyl)-2'-nitroacetanilide with a m.p. of 129-1310.

Microanalysis C 1 6

H

21

FN

4 0 4 C 54. 54 H 6. 01 N 15. Fou)xd: 54.33 6.18 15.80.

b) A solution of N-ethyl-4'-fluoro-5'--(4-acetyl-l- -piperazinyl)-2'--nitroacetanilide (8.4 g, 23.8 mmol) in methanol (100 ml) is treated with pcrtassium 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 129-1310).

&SO' suspended in dioxan/wiater 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 mil) and washed wit~h water (500 nil) and 10 p*.krcent sodium chloride solutjop_ The organic phase is dried over magnesium sulphate and concentrated. The sel residue is crystallized from eth~yl acetate/ n-.hexane. There 0: are obtained 6.33 g of tert-butyl -2-f luoro-4-nitrophenyl]-l-pir.oarazinecarboxylate with a m.p. of 155-1570.

c) In analogy to Example 2d), from tert-butyl (ethylamino) -2-f luoro-4-nitrophenyl ]-1-piperazinecarboxylate there is obtained in a yield of 67% ethyl 28 6- [4-tert-butoxycarbonyl )-1-piperazinyl]I-1-ethyl-5-fluoro- -2-benzimidazoleacetate with a m.p. of 131-1330.

Microanalysis C 22

H

31 FN 4 0 4 Cale.: C 60.81 H 7.19 N 12.89 Found: 60.73 7.44 12.88.

d) In analogy to Example 2e), from 6thyl 6-(4-tertbutoxycarbonyl)--piperazinyl)thl-ets....fluoro2benz imidazoleacetate there is obtained a yield of 36% tert- -butyl 4-2craolehl--ehl5fur--ez imidazolylj-1-piperazinecarboxylate with a m.p. of 162-1640.

sees 15MS: 405(M).

06#06e) In analogy to Example 2f), from tert-butyl 4-E2- Ccarbamoylmethyl)-i1-ethyl-5-f luoro-6-benzimidazolyl 1-1- ***-piperazinecarboxylate there is obtained in a yield of 67% tert-butyl 4-(5-ethyl-8-fluoro-.2.3.5-tetrahydro-1.3- -dioxopyrimido[1. 6-a~henzimidazol-7-yl)-l-piperazinecarboxylate with a m.p. of 270-2730.

Microanalysis C 21H 26FN 50 4.

ease Caic.: C 58.46 H 6.07 N 16.23 Found: 58.18 6.30 16.16.

j f) In analogy to Example 2g), from tert-butyl -8-fluoro-1.2.3,5-tetrahydro1.3dioxopyrimido(1,6.abenz imidazol-7-yJ.,-A-piperazinecarrboxylate there is obtained in a yield of 70% 5-ethyl-8-fluoro-7-C1-piperazinyl)pyrimido(1,6-a]benzimidazole-J..3(2HSH)-dione with a m.p.

of 264-2660.

Microanalysis C 16H 18FN 5 0 2 0.2 CH 3

OH

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 1-(5-ethylamino)-2- -fluoro-4-nitrophenyl)-4-ethylpiperazine there is obtained in a yield of 30t ethyl I-ethyl-5-fluoro-6-(4- -methyl-l-piperazinyl)-2-benzimidazoleacetate with a m.p.

of 142-1440.

Microanalysis C H FN 0 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 -fluoro-6-(4-methyl-1-piperazinyl)-2-benzimidazoleacetaie *06S* there is obtained 1-ethyl-5-fluoro-6-(4-methyl-l- -piperazinyl)-2-benzimidazoleacetamide. From this inter- 6694N mediate there is obtained, in analogy to Example 4a) in a yield of 35% (over both steps) 2-[[(benzyloxy)carbamoylj- 20 methyl)-l-ethyl-5-fluoro-6- (4-methyl-1-piperazinyl)-benzimidazole with a m.p. of 165-168 (ethyl acetate).

Microanalysis C 23H 28FM 0 Calc.: C 64.92 H 6.63 N 16.46 Found: 64.92 6.85 16.36.

0666 6066 C) In analogy to Example 4b), from 2-[[(benzyloxy)carbamoyljmethyl]-l-ethyl-5-fluoro-6-(4-methyl-l- -piperazinyl)-benzimidazole tt 're is obtained in a yield of 54% 2- (benzyloxy)-5-ethyl-B-f luoro.-7- (4-inethyl-l- -piperazinyl)pyrimido[1.6-ajbenzimidazole-l.3(2H,SH)-dione with a m.p. of 250-252 (methanol).

0:00 0: Microanalysis

C

2 4

H

2 6

FN

5 0 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 -8-fluoro-7-(4-methyl-1-piperazinyl)pyrimido[1.6-ajbenzimidazole-1.3(2H.5H)-dione there is obtained in a yield of 30 53% 5-ethyl-8-fluoro-2-hydroxy7..methyl1..piperazinyl).

pyrimido[l.6-abenzimidazole-1..3(2H.5H)-.dione.

Microanalysis C 17

H

20 FN 5 0 3 e0.2 DMF: Ca'4c.: C 56.22 H 5.74 N 19.37 Found: 56.05 5.90 19.40.

Example a) In analogy to Example 2d), from p-nitrobenzyl 3-ethoxy-3-iminopropanoate hydrochloride and tert-butyl (cyclopropylamino)-2-fluoro-4-iitrophenyl.1..

-piperazinecarboxylate there is obtained in a yield of 44% p-nitrobenzyl 6-[4-(tert-butoxycarbonyl)--piperazinyl.l- Microanalysis 0283 FN 0 2325 6 Calc.: C 60.75 H 5.83 N 12.65 Found: 60.81 6.11 12.54.

A solution of p-nitrobenzyl 6-[4-(tert-butoxycarbonyl )-1-piperazinyl]-1-cyclopropyl-fluoro2benzimidazoleacetate (553 mg. 1 mmol) in THF (50 ml) is treated in succession at 00 with triethylamine (300 mg.

25 3 mmol) and chioroacetyl isocyanate (29n mg. 2.5 mmol).

After stirring for 20 hours the solvent is distiLlled off and the residue is taken up in ethyl acetate and washed in se 0 0 succession with water (50 ml) and 10 percent sodium 0:...:chloride solution (50 ml). The organic phase is dried over magnesium sulphate and the solvent is evaporated. The S 9residue is recrystallized from ethyl acetate. There are 0:99.:obtained 373 mg of p-nitrobenzyl 5-cyclopropyl-8- -fluoro-1. 2.3 .4-tetrahydro-1. 3-dioxo-7-[4- (tert-butoxycarbonyl)-l-piperazinyl]pyrimido[1,6abenzimidazole4- -carboxylate.

Microanalysis C 30

H

31 FN 6 0 8 Cale.: C 57.87 H 5.02 N 13.50 Fouind: 57.50 5.04 13.38.

31 c) A solution of p-nitrobenzyl 5-cyclopropyl-8-fluoro- 2 4-tetrahydro-1, 3-dioxo-7- 4(ter t.butoxycarbonyl) -1-piperazinyljpyrimido[1. 6-a~benzimidazole-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 trimethylchlorosilaine (1.23 g. 11.28 mmol). After one hour at 800 the suspension obtained is cooled to 00. The crystals are filtered off and taken up in an ethanol/water mixture 250 ml). The pH is adjusted to 8.0 with a sodium bicarbonate solution. The suspension is cooled to 00 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 4100&0,1.10 g of p-nitrobenzyl 5-cyclopropyl-8-fluoro- 009.

-1.2.3.4-tetrahydro-1.3dioxo7(l.piperazinvl)pyrimidosees 6-ajbenzimidazole-4-carboxylate.

Microanalysis u 25

H

2 FN 0: 0* 20 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-(l-piperazinyl)pyrimido- *seeS [1.6,-abenzimidazole-4-carboxylate (122 mg. 0.234 minol) in go DMF (30 ml) is hydrogenated over 5 percent Pd/C. After completion of the hydrogenation the catalyst is filtered lose 0:off and the filtrate is treated with fuller's earth, %:*Seefiltered and concentrated to a volume of 5 ml. Th~e separated crystals are filtered off. There are obtained *62 mg of the sodium salt of S-cyclopropyl-8-fluoro- -1.2.3.4-tetrahydro-1.3-dioxo-7-(l-piperazinyl)pyrimido- [1.6-a]benzimidazole-4-carboxylic acid.

MS: 343(M-C 2 44 (CO0 2 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 chromato- 32 graphed with water on a reversed phase (column RP8). Thsi~e are obtained 39 mg of the above product.

343 (M-C 2 44z (CO0 2 Example 11 In analogy to Example 9. from tert-butyl 4-[2- -(carbamoylmethyl)--ethyl-5fluoro6benzimidazolyl.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), -8-fluoro-2-hydroxy-7-(l-piperazinyl)pyrimido[l.6a~benzimidazole-1,3(2H,5H)-dione hydrochloride.

*see Microanalysis C 16H 19ClFN 503 **so Caic.: C 50.07 H 4.99 N 18.25 Found: 50.94 5.22 18.47.

20 Example 12 a) Ethyl 6-[4-(tert-butoxycarbonyl)--piperazinylJ-l- -cyclopropyl-5-fluoro-2-benzimidazoleacetate (1.8 g, 4 mmo],; from Example 2d) and tert.butyl carbazate (21 g.

16 mmol) are dissolved in pyridine (40 ml) and stirred at under argon fot 65 hours. The reaction solution is concentrated and trituzated with 50 ml of ether. The separated product is filtered off under suction and dried.

There is obtained tert-butyl 3-[6-[4-(tert-butoxycaPease imidazolyljacetyljcarbazate. Yield: 0.49 g m-p.

202-2030.

Microanalysis C 26 H 7FN 60 Calc.: C 58.63 H 7.00 N 15.78 Found: 58.44 7.15 15.66.

b) tert-Butyl 3-H]6-[4-(tert-butoxycarbonyl)-1-piperazinylJ-1-cyclopropyl-5-fluoro-2-benzimidazolyl~acetyl]carba- 33 zate (0.40 g. 0.76 mmol) is dissolved in THF (15 ml) and treated with l,1'-carbonyldiimidazole (0.24 g. 1.5 mmol) and DBU (3 drops). The solution obtained is stirred at 0 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 The product is recrystallized from ethyl acetate/ether. There is obtained tert-butyl 7-[4-(tert- -butoxycarbonyl)-1-piperazinyl]-5-cyclopropyl-8-fluoro- -3,5-dihydro-1,3-dioxopyrimidoll,6-a]benzimidazole- -2(1H)-carbamate. Yield: Fj5 mg m.p. 219-2200.

Microanalysis C 7

H

35

FN

6 0 6 Calc.i C 58.05 H 6.32 N 15.04 .Found: 57.87 6.36 14.69.

eec.

c) tert-Butyl 7-(4-(tert-butoxycarbonyl)-1-piperazinyl]- -5-cyclopropyl-8-fluoro-3, 5-dihydro-1, 3-dioxopyrimido- [1,.6-a]benzimidazol-2(1H)-carbamate (0.145 g, 0.26 mmol) sis 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 H 2 0, adjusted to pH 8 with saturated aqueous NaHCO solution and stirred at CW@* 3 25 room temperature for 1 hour. The suspenv .n is cooled to 00 and suction filtered. The product is chromatographed on silica gel (eluent: CHC13/EtOH/N4 OH 80:20:1) and crecrystallized from ethanol. There is obtained *-cyclopropyl-8-fluoro-7-(1-piperazinyl)pyrimido(1.6-a benzimidazole-1.3(2H.5H)-dione. Yield: 43 mg m.p.

232-2340.

Microanalysis C 17 H1 FN602 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-(tert- 34 -butoxycarbonyl)-l-.piperazinyl] -l-cyclopropyl-5-fluoro-2- -benzimidazoleacetate and tert-butyl 2-methylcarbazate there is obtained in a yield of 33% tert-butyl-4-[2-[f[2- -Ctert-butoxycarbonyl)-2-methylhydrazino]carbonyljmethyl.

-l-cyclopropyl-5-fluoro-6-benzimidazoly......piperazine- -carboxylate with a m.p. of 180-1820.

MS: 546 446 [M-(isobutene CO 2 b) In analogy to Example 12b), starting from tert-butyl 4-[2-C[[[2-(tert--butoxycarbonyl)-2-methylhydrazino]carbonyl..

methyl] -1-cyclopropyl-5-fluoro-6-benzimidazolyl ]-l-pipera-.

zinecarboxylate there is obtained in a yield of 59% tert- -butyl 7-[4-(tert-butoxycarbonyl)-l-piperazinyl..s-cyclopropyl-8-fluoro-3, 5-dihydro-N-methyl-1. 3-dioxopyrimido- EJ1,6-albenzimidazole-.2--carbamate with a m.p. of 224-.2250.

MS: 573 (M+U) c) In analogy to Example 12c), starting from tert-butyl 7-[4-.(tert-butoxycarbonyl)-1-piperazinyl]-5-cyclopropyl- -8-fluoro-3,S-dihydro--methy1.3-dioxopyrimido~l.6-abenzimidazole-2-carbamate there is obtained in a yield of 43% 5-cyclopropyl-8-fluoro-2-(methylamino)-7-c1-piperazinyl)pyrimido[l.6-albenzimidazole-2.3(2H,5H)-dione with a m.p. of 228-.2300.

Microanalysis C H- FN 0 18 21 6 2 Caic.: 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--cyclopropyl-5-fluoro-2- -benzimidazoleacetate and hydrazine hydrate there is obtained tert-butyl 4-[2-[((hydrazino)carbonyl]methyl]- 1-cyclopropyl-S-fluoro-6-benz imidazolyl ]-1-piperazinecarboxylate, with a of 172-1730.

35 Microanalysis C 21H 29FN Caic.: C 58.32 H 6.76 N 19.43 Found: 57f! 6.92. 19.20.

b) A solution of tert-butyl 4-[2-[[(hydrazino)carbonyl]methyl) -l-cyclopropyl-5-f luoro-6-benzimidazolyl I-1-p iperazine-.carboxylate (0.43 g) in methanol (22 ml) is stirred at 500 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 ig evaporated and the raw material crystallized from ethyl acetate. 0.325 g of tert-butyl 4-.2-[(2-(dimethylhydrazino )carbonyl ]methyl -6-benzimidazolyl)-l)-piperazine-carboxylate are obtained with a m.p. of 179-1810.

MS: 460 (M) c) In analogy to Example 12b), starting from tert-butyl 20 4-[2-[C[2-(dimethylhydrazino)]carbonyl~methyl]--cyclopropyl-5--fluoro--6-benzimidazolyl 1-1-piperazine-carboxylate there is obtained tert-butyl -l 5 2,3,5-tetrahydro-2-(dimethylamino)-2.3-dioxopyrimido- 00.0 [1,6-ajbenzimidazol-7-yl]-1-piperazino-carboxylate with a :25 m.p. of 201-203-.

Microanalysis C 24H 31FN 604 Caic.: C 59.25 H 6.42 N 17.27 Found: 59.13 7.10 17.73.

3. 0 d) In analogy to Example 12c), starting from tert-butyl 4-(5-cyclopropyl-8-fluoro-1,2,3,5-tetrahydro-2-(dimethylaxuino)-2.3-dioxopyrimido1,6-a~benzimidazol-7-yl)-l-piperazine-carboxylate there is obtained 5-cyclopropyl-2-(dimethylamino)-8-fluoro-7-(1-piperazinyl)pyrimido[ 1, 6-s]benzimidazole-1,3(2H,5H)-dione with a m.p. of 201-2- 0 9 0 36 Micjoanalysis C 19H 23FN 602 Caic.: C 59.06 6.00 N 21.75 Fouind, 58.12 6 37 20.75.

Example A Gelatine capsules containing the following ingredients -are manufact,,red in the usual manner: 5-CycloproPy1-8-fluoro-7-(Ibenz imidazole-l, 3 (2f1, 51i-dii,e 200 mg Luviskol (water-soliu' 'e polyvinylpyrrolidone) 20 mg Mannitol 20 mg is Talc 15 mg Magneqiun stearate 2 mg 257 m g Example B Tablets contaiz7'ng the follo.wing ingredients are manufactured in the usual manner: 5-.Cyclopropy'l-8-f luoro-7- I- -piperazinyl)-pyrimido[1. 6-a]benzimidazo)e-1,3(2H.5H)-dioae, 200 mig Starch 44 mg Calcium carboxymethylcellu lose 30 mrg crystalline cellulose 40 mg 30 Magnesium steaflate 6 mci 0*00*-320 mg

Claims (19)

1. Compounds of the general formula R 5 R 6 R 7 1 wherein R signifies hydrogen, halogen or amino, SR 2 signifies halogen, R signifies a lower alkyl-substituted 4-pyridyl group or a group R R4N- in which R and R each signify hydrogen or lower alky] or together signify a group of 20 the formula -(CH 2 )n-X-(CH 2 or -(CH 2 )p which is unsubstituted or substituted by lower alkyl, amino, lower aminoalkyl, mono- or di(lower alkyl)- amino-lower alkyl, oxo or the group -COOR a 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 25 signifies the number 4, 5 or 6, X signifies an oxygen or sulphur atom or the group R signifies hydrogen, lower alkyl, lower alkenyl, phenyl or; phenyl which is mono-, di- or trisubstituted by halogen, 30 lower alkyl or hydroxy, R' and R" each signify hydrogen or lower alkyl, signifies hydrogen, hydroxy, lower alkyl or lower aminoalkanoyl, R signifies hydrogen, halogen, lower alkoxy or amino, R 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 7 signifies hydrogen, lower alkyl or carboxy. R 8 signifies hydrogen, hydroxy, lower 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 8 signifies hydrogen, hydroxy, lower alkoxy, amino or lower 1 alkylamino.

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

5. Compounds according to claim 3 or claim 4, 2 wherein R 2 signifies fluorine. Compounds'according to any one of claims wherein R 3 and R 4 together signify a group of the formula -(CH 2 )n-X-(CH 2 m or a group of the formula -(CH which is substituted by the group *25 _COOa 2 p 25 -COO a n and m each signify the number 2, p signifies the rumber 4, X signifies the group Rh signifies lower alkyl and signifies hydrogen, lower alkyl or o lower aminoalkanoyl.

7. Compounds accocding to claim 6, wherein S. 3 4 R N- signifies the l-piperazinyl group or the 4-methyl-l-piperazinyl group.

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

9. Compounds according to claim 8, wherein R 6 signifies ethyl. 39 Compounds according to claim 8, wherein R 6 signifies cyclopropyl.

11. Compounds according to any one of signifies hydrogen or carboxy.

12. Compounds according to any one of signifies hydrogen or hydroxy.

13. Compounds according to any one of signifies an oxygen atom.

14. Compounds according to any one of signifies the 3,5-dimethyl-4-pyridyl group. Compounds according to any one of 14, wherein R 8signifies amino or methylamin(

16. Compounds according to any one of claims 3 to 10, whereinR7 claims 3 to 11, wherein R 8 claims 3 to 12, wherein Y claims 2, 4 and 5, wherein R claims 2, 4 to 11, 13 and claims 1, 4 to 11, 13 and *0 0 *0*0 *000 000 D. 11 0 0 14, wherein ARsignifies di Imethylanin.. 15 17. 5-Ethy1-8--fluoro-7-.(4.-methyl-1-piperazinyl)-pyrimido[l benzimidazole-1,3(2H,5H)-dione.

18. 5-Cyclopropy-8-fuoro-7-(-piperaznyl)-pyrimido[1,6a.. benzirnidazole-1 ,3(2H-,5H)-dione.

19. 5-.Ethy-8-fluoro-3,5-dhydro-7-(4-methyl-1-plperaziny1)-3- thioxopyrimido[l ,6-ajbenzimidazol-l(2H)one. 5-Cyclopropyl-8-fluoro-2-hydroxy-7-(-pipyrazlnyl )pyrimi do- [1 ,6-albenzimidazole-1 ,3(2H,5H)-dione.

21. tert-Biltyl rac-1-[5-cyclopropyl-8-fluoro-2,3-dhydro-1 ,3-dloxo- pyrimidoll,6-albenzimldazo1-7(1H)-y1 SR 00 S *@R LMM/1 672u 40 -pyrrolidinecarboxylate.

22. 7-(4-L-Alanyl-l-piperazinyl)-5-cyclopropyl-8- -fluoro-2-hydroxypyrimido[1.6-ajbenzimidazole-1,3(2H.5H>.. -dione.

23. 1-[5-Cyclopropyl-8-fiuoro-1.2.3.5-tetrahydro-2- &-ii..rQxy-1. 3-dioxopyrimido[L. 6-a) benzimidazol-7-,yl -proline tert-butyl aster.

24. 5-Ethyl-8-fluoro-7-(1-piperazinyl)pyrimido1,6-a.. benzimidazole-1 3 (2H.

00625. 5-Ethyl--8-fluoro-2-hydroxy-7-(4--methyl-l- -piperazinyl)-pyrimido[1,6-ajbenzimidazole-1,3(2H.5H)- -dione. 20 26. 5-Cyclopropyl-8-fluoro-1,2,3.4-tetrahydro-1.3- a -dioxo-7-(l-piperazinyl)pyrimido(1,6-a~benzimidazole-4- -carboxylic acid. 27. 5-Ethyl-8-fluoro-2-hydroxy--7-(1-piperazinyl)- aaee 25 pyrimidorl,6-ajbenzimidazole-1.3(2H,H)-dione. 28. 2-Amino-5-cyclopropyl--8-fluoro-7--(l-piperazinyl)- S -pyrimido(1.6-ajbenzimidazole-1.3(2H.5H)-dione. 29. 5-Cyclopropyl-8-fluoro-2-(methylamino)-7-(l- -piperazinyl)pyrimido(1.6-abenzimidazole-1,3(2H,5I)-dione. 5-Cyclopropyl-2-(dimethylamino)-8-fluoro-7-(l- piperazinyl)pyrimido[1.6-ajbenzimidazole-1.3(2H,5H)-dione. Gemjpzunds ef the zczl oml 31. Compounds of formula I in claim 1, which have at least one protected hydroxy, amino and/or carboxy group. 32. A process for the manufacture of compounds according to any one of claims 1 to 30, which process comprises a) reacting a compound of the general formula e**o S |Prlv21\00100:KEH 41 of 2 J 5 1 N HN RIT R6 R7 1 2 5 6 7 8 wherein R. Y, R 1 R 2 R 5 R 6 R 7 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. e.g optionally in the presence of a base with a compound of the general formula *49 c X-CO-X III wherein X signifies a leaving group, or 25 b) reacting a compound of the general formula 3I H a, R 1 30 IV a6 wherein R. R 1 R 2 R R and R have the significance given in claim with the proviso that free hydroxy, amino and carboxy groups which may be present are in protected form, 4-3- in the presence of a base with a compound of the general formula RaOOC-CHR 7 -COORa V wherein Ra signifies lower alkyl and R 7 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 UitR R 6 COORb 25 wherein Rb signifies a carboxy protecting group and 1 2 5 6 R R 2 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. a whereupon any protecting groups present are cleaved off &able: a a and a compound of formula I obtained is, if desired, converted into a pharmaceutically acceptable salt. 33. A medicament containing a compound in accordance with any one of claims 1-30 and a therapeutically inert carrier. 44 34. Compounds as defined in claim 1, whenever prepared according to the process as defined in claim 32 or by an obvious chemical equivalent thereof. Substituted pyrimidobenzimidazole derivatives of the formula I as set out in claim 1, substantially as hereinbefore described with reference to any one of the Examples. 36. An antibacterially-active medicament, containing a compound in accordance with any one of claims 1 to 30, 34 or 35 and a therapeutically inert carrier. 37. A process for preparing substituted pyrimidobenzimidazole derivatives of the formula I as set out in claim 1, substantially as hereinbefore described with reference to any one of the Examples. 38. A method of preventing or treating a bacterial infection in a patient requiring such prevention or treatment, which method comprises administering to said patient an effective amount of a compound in accordance with any one of claims 1 to 30, 34 or or of a medicament in accordance with claim 36. Dated 23 June, 1993 F. Hoffmann-La Roche AG Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 99 9 9 9 99 9 9 9 9 9.. 9 9 .9 9 9 9 9 9 9 9. 99 9t a t~ 2~OO~E 44 of 2