GB1595316A - 4-(3-amino-2-hydroxy-propoxy)-benzimidazole derivatives and pharmaceutical compositions containing them - Google Patents

Description

(54) 4-(3-AMINO-2-HYDROXY-PROPOXY)-BENZIMIDAZOLE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM (71) WE, ROCHE PRODUCTS LIMITED, a British Company of Broadwater Road, Welwyn Garden City, Hertfordshire, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to benzimidazole derivatives. More particularly, the invention is concerned with benzimidazole derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same.

The benzimidazole derivatives provided by the present invention are compounds of the general formula

wherein R represents a hydrogen atom or a lower alkyl group, R' represents a hydrogen atom or a lower alkyl or lower cycloalkyl group, R2 represents a lower alkyl or lower cycloalkyl group, R3 represents a hydrogen atom or a primary or secondary lower alkyl group and Y represents an oxygen or sulphur atom, and pharmaceutically acceptable acid addition salts thereof.

As used in this specification, the term "lower alkyl" means a straight-chain or branched-chain alkyl group which contains from 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl and tert.butyl. The term "lower cycloalkyl" means a cycloalkyl group which contains from 3 to 8 carbon atoms (e.g.

cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "primary or secondary lower alkyl" means a lower alkyl group in which the carbon atom attached to the ring nitrogen atom carries at least one hydrogen atom.

The benzimadazole derivatives of formula I hereinbefore, wherein Y represents a sulphur atom mainly exist in their tautomeric form of the general formula

wherein R, R' R2 and R3 have the significance given earlier.

Preferred benzimidazole derivatives provided by the present invention are those in which R represents a lower alkyl group, especially the methyl group. Also preferred are those benzimidazole derivatives in which R' represents a hydrogen atom, particularly those in which R2 represents a lower alkyl group and especially a branched-chain lower alkyl group such as the isopropyl or tert.butyl group.

Particular benzimidazole derivatives provided by the present invention are those in which Y represents an oxygen atom, R and R3 represent a hydrogen atom and R1 and R2 have the significance given earlier, i.e. compounds of the general formula

More particular benzimidazole derivatives are those of the formula Ia hereinbefore in which R' represents a hydrogen atom and R2 represents a lower cycloalkyl group or R' and R2 each individually represent a lower alkyl or lower cycloalkyl group.

A further particular class of benzimidazole derivatives provided by the present invention are those in which Y represents an oxygen atom, R represents a lower alkyl group and R', R2 and R3 have the significance given earlier, i.e. compounds of the general formula

wherein R' represents a lower alkyl group.

Still a further particular class of benzimidazole derivatives provided by the present invention are those in which Y represents a sulphur atom, R2 represents a hydrogen atom or a lower alkyl group, R2 represents a lower alkyl group and R and R3 have the significance given earlier, i.e. compounds of the general formula

wherein R" represents a hydrogen atom or a lower alkyl group and R2' represents a lower alkyl group, and the thiol tautomers thereof.

Examples of benzimidazole derivatives provided by the present invention are: 4-[3 - (Tert.butylamino) - 2 - hydroxypropoxy] - 7 - methyl - 2 benzimidazolinone, 4 - [3 - (cyclopentylamino) - 2 - hydroxypropoxy] - 7 - methyl - 2 benzimidazolinone, 4 - [3 - (dicyclopentylamino) - 2 - hydroxypropoxy] - 7 - methyl - 2 benzimidazolinone, 7 - [3 - (tert.butylamino) - 2 - hydroxypropoxy] - 1,4 - dimethyl - 2 benzimidazolinone, 4 - [2-hydroxy - 3 - (methylamino)propoxy] - 2 - benzimidazolinone, 4 - [2 - hydroxy - 3 - (n - propylamino)propoxy] - 2 - benzimidazolinone, 4 - [2 - hydroxy - 3 - (isopropylamino)propoxy] - 2 - benzimidazolinone, 4 - [3 - (tert.butylamino) - 2 - hydroxypropoxy] - 2 - benzimidazolinone, 4 - [3 - (diethylamino) - 2 - hydroxypropoxy] - 2 - benzimidazolinone, 4 - [3 - (cyclohexylamino) - 2 - hydroxypropoxy] - 2 - benzimidazolinone, 4 - [3 - (dicyclopentylamino) - 2 - hydroxypropoxy] - 2 - benzimidazolinone, 4- [2 - hydroxy - 3 - (N - methylcyclohexylamino)propoxy] - 2 benzimidazolinone, 1 - (tert.butylamino) - 3 - (2 - mercapto - 7 - methyl - 4 benzimidazolyloxy) - 2 - propanol, I - (tert.butylamino) - 3 - (2 - mercapto - 4 - benzimidazolyloxy) - 2 - propanol, 1 - (tert.butylamino) - 3 - (2 - mercapto - 1,4 - dimethyl - 7 benzimidazolyloxy) - 2 - propanol and 1 - (diethylamino) - 3 - (2 - mercapto - 4 - benzimidazolyloxy) - 2 - propanol, and the hydrohalides thereof particularly the hydrochlorides.

According to the process provided by the present invention, the benzimidazole derivatives aforesaid (i.e. the compounds of formula I hereinbefore and their pharmaceutically acceptable acid addition salts) are manufactured by a process which comprises a) reacting a compound of the general formula

wherein R, Rr, R2 and R3 have the significance given earlier, with a compound of the general formula Z2C=Y IV wherein Z represents a chlorine atom or an amino group and Y has the significance given earlier, or b)for preparing compounds of formula I in which Y represents an oxygen atom and R, R', R2 and R3 have the significance given earlier, reacting an epoxide of the general formula

wherein Rand R3 have the significance given earlier, with an amine of the general formula

wherein R' and R2 have the significance given earlier, or c) resolving a racemic compound of formula I into its optical isomers and, if desired, converting a compound of formula I obtained into a pharmaceutically acceptable acid addition salt.

The reaction of a compound of formula III with phosgene or thiophosgene, i.e.

a compound of formula IV in which Z represents a chlorine atom, can be carried out in accordance with methods known per se. In a preferred embodiment, the reaction is carried out under acidic conditions. For example, a compound of formula III can be dissolved in an aqueous mineral acid such as an aqueous hydrohalic acid (e.g. aqueous hydrochloric acid) and treated with phosgene or thiophosgene, preferably in excess, to give the corresponding acid addition salt of a compound of formula I which can be converted into a free base of formula I in a conventional manner if desired. The reaction is advantageously carried out at room temperature or below room temperature and at atmospheric pressure. It is preferred to carry out the reaction with thiophosgene under the atmosphere of an inert gas such as nitrogen or argon.

The reaction of a compound of formula III with urea or thiourea, i.e. a compound of formula IV in which Z represents an amino group, can be carried out in the presence or absence of an inert organic solvent. In a preferred embodiment, the reaction is carried out in the absence of an inert organic solvent by melting the reactants together under the atmosphere of an inert gas such as nitrogen or argon.

When the reaction is carried out in the presence of an inert organic solvent, suitable solvents include, for example, hydrocarbons, particularly aromatic hydrocarbons such as benzene and toluene, and lower alkanols such as methanol and ethanol. By the term "lower alkanols" as used herein we mean alkanols containing from 1 to 6 carbon atoms. When an inert organic solvent is used, the reaction is advantageously carried out at an elevated temperature and at atmospheric pressure.

The starting materials of formula III are relatively unstable and, in a preferred embodiment of the present process, are reacted in situ (i.e. without working-up or purification) with the compounds of formula IV.

The reaction of an epoxide of formula V with an amine of formula VI in accordance with embodiment (b) of the process can be carried out in the presence or absence of an inert organic solvent. When an inert organic solvent is used, this can be, for example, a lower alkanol such as methanol or ethanol. Alternatively, an excess of an amine of formula Vl can be used and can thereby also serve as the solvent. The reaction is preferably carried out at a temperature of from 0 C to room temperature and under atmospheric pressure. The epoxides of formula V are relatively unstable and, in a preferred aspect of this embodiment, are reacted in situ (i.e. without working-up or purification) with an amine of formula VI.

It will be appreciated that the compounds of formula I hereinbefore contain an asymmetric carbon atom and can occur in racemic or optically active form. The present invention includes within its scope the racemates as well as the optically active forms. A racemate can, if desired, be resolved into the optical isomers in accordance with methods known per se; for example, by frictional crystallization of salts formed with optically active acids.

The compounds of formula I can be converted into pharmaceutically acceptable acid addition salts by treatment with pharmaceutically acceptable inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and with pharmaceutically acceptable organic acids (e.g. acetic acid, tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, methanesulphonic acid and paratoluenesulphonic acid).

The starting materials of formula III hereinbefore can be prepared, for example, according to the following Formula Scheme A in which R, R', R2 and R3 have the significance given earlier, R'O represents a hydrogen atom or the benzyl group or a lower alkyl or lower cycloalkyl group and R30 represents a primary or secondary lower alkyl group: FORMULA SCHEME A

In step (i) of the foregoing Formula Scheme A, a compound of formula VII is converted into an epoxide of formula VIII by reaction with an epihalohydrin, preferably epichlorohydrin. The reaction is preferably carried out in the presence of piperidine at an elevated temperature (e.g. about 80"C) and the product obtained is subsequently treated with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. This treatment is preferably carried out in a water-miscible inert organic solvent such as dioxan.

Alternatively, a compound of formula VII can be reacted with an epihalohydrin in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. The reaction is conveniently carried out in the presence of a water-miscible inert organic such as a lower alkanol (e.g.

methanol or ethanol) at a temperature of from 0 C to room temperature, preferably at about room temperature.

In step (ii) of the Formula Scheme A, an epoxide of formula VIII is reacted with an amine of the general formula

wherein Ra and R'O have the significance given earlier, to give a compound of formula IX. This reaction is advantageously carried out in the presence of an inert organic solvent, preferably a lower alkanol such as methanol or ethanol. The reaction can be carried out at room temperature or at an elevated temperature (e.g.

a temperature up to the boiling point of the reaction mixture). In certain circumstances it may be advantageous to use an acid addition salt of an amine of formula XI (e.g. a hydrohalide such as the hydrochloride) in this step and to carry out the reaction in the presence of a suitable inorganic base (e.g. an alkali metal carbonate such as potassium carbonate).

In step (iii) of the Formula Scheme A, a compound of formula IX is hydrogenated to give a starting material of formula III in which R3 represents a hydrogen atom and in which, when R'O in the compound of formula IX represents the benzyl group, R' represents a hydrogen atom. The hydrogenation can be carried out in the presence of a noble-metal catalyst (e.g. a palladium or platinum catalyst such as palladium-on-charcoal or platinum oxide), although other conventional hydrogenation catalysts such as Raney-nickel and Raney-cobalt can also be used. This catalytic hydrogenation can be carried out in a conventional manner; for example, in an inert organic solvent such as a lower alkanol (e.g.

methanol, or ethanol) and at room temperature and atmospheric pressure.

According to a preferred procedure, step (iii) is carried out in situ, that is to say, without isolating a compound of formula IX from the medium in which it is prepared.

Step (iv) of the Formula Scheme A comprises the reaction of a compound of formula IX with a primary or secondary lower alkylamine (e.g. methylamine, ethylamine, or isopropylamine) to give a compound of formula X. This reaction is advantageously carried out in the presence of an inert organic solvent, preferably a lower alkanol such as methanol, or ethanol. It is preferred to carry out this reaction at an elevated temperature and at atmospheric pressure.

A compound of formula X is then hydrogenated in step (v) of the Formula Scheme A to give a starting material of formula III in which R3 represents a primary or secondary lower alkyl group and in which, when R'O in the compound of formula X represents the benzyl group, R' represents a hydrogen atom. The hydrogenation can be carried out in essentially the same manner as described earlier in connection with the hydrogenation of a compound of formula IX.

When it is desired to prepare a starting material of formula III in which R' represents a hydrogen atom and R2 represents a primary or secondary lower alkyl group, it is preferred to proceed via a corresponding compound of formula IX in which R'O represents the benzyl group.

Preferred starting materials of formula III are those in which R represents a lower alkyl group, especially the methyl group. Also preferred are those starting materials of formula III in which R' represents a hydrogen atom, particularly those in which R2 represents a lower alkyl group and especially a branched-chain lower alkyl group such as the isopropyl or tert.butyl group.

Particular starting materials of formula III are those in which R' represents a hydrogen atom and R2 represents a lower cycloalkyl group or R' and R2 each individually represent a lower alkyl or lower cycloalkyl group.

The epoxide starting materials of formula V hereinbefore can be prepared, for example, according to Formula Scheme B hereinafter in which R and R3 have the significance given earlier: FORMULA SCHEME B

Having regard to Formula Scheme B, in step (i) a 2-methoxy-6-nitroaniline of formula Xl is reduced to give an o-diamine of formula XII. The reduction is suitably carried out using hydrogen in the presence of a noble-metal catalyst (e.g. a palladium, platinum or rhodium catalyst such as palladium-on-charcoal, platinum oxide, rhodium-on-carbon or rhodium-on-alumina), although other conventional hydrogenation catalysts such as Raney-nickel and Raney-cobalt may also be used.

A palladium catalyst, especially palladium-on-charcoal, is preferably used. This catalytic hydrogenation is conveniently carried out in the presence of an inert organic solvent (e.g. a lower alkanol such as methanol, or ethanol). It is preferred to carry out the catalytic hydrogenation at room temperature and atmospheric pressure.

In step (ii) of Formula Scheme B, an o-diamine of formula XII is reacted with phosgene to give a 4-methoxy-2-benzimidazolinone of formula XIII, this reaction being carried out under essentially the same conditions as described hereinbefore in connection with the reaction of a diamine of formula II with phosgene. Since the o-diamines of formula XII are relatively unstable, they are preferably reacted in situ (i.e. without working-up or purification) with phosgene.

Step (iii) of Formula Scheme B involves the conversion of the methoxy group of a 4-methoxy-2-benzimidazolinone of formula XIII into a hydroxy group, there being obtained a corresponding 4-hydroxy-2-benzimidazolinone of formula XIV in which R3 represents a hydrogen atom. This conversion is carried out in accordance with methods known per se; for example, by treatment with hydrogen bromide in acetic acid at an elevated temperature (e.g. 80"C).

An a!ternative route to the 4-hydroxy-2-benzimidazolinones of formula XIV comprises steps (iv), (v), (vi), (vii) or (viii) of Formula Scheme B.

In step (iv), a 3-nitrophenol of formula XV is nitrated in a manner known per se such as by treatment with nitric acid in the presence of sulphuric acid to give the corresponding 2,3-dinitrophenol of formula XVI.

A 2,3-dinitrophenol of formula XVI is then reduced in step (v) to give the corresponding o-diamine of formula XVII in which R3 represents a hydrogen atom.

This reduction is carried out in essentially the same manner as described earlier in connection with the reduction of a 2-methoxy-6-nitroaniline of formula XI.

Step (vi) of the Formula Scheme B comprises the reaction of a 2,3-dinitrophenol of formula XVI with a primary or secondary lower alkylamine (e.g.

methylamine, ethylamine, or isopropylamine) to give a compound of formula XVIII. This reaction is advantageously carried out in the presence of an inert organic solvent, preferably a lower alkanol such as methanol, or ethanol. It is preferred to carry out this reaction at an elevated temperature and a atmospheric pressure.

A compound of formula XVIII is then hydrogenated in step (vii) of the Formula Scheme B to give an o-diamine of formula XIV in which R3 represents a primary or secondary lower alkyl group. The hydrogenation can be carried out in essentially the same manner as described earlier in connection with the hydrogenation of a compound of formula IX.

In step (viii) an o-diamine of formula XVII is reacted with phosgene to give the corresponding 4-hydroxy-2-benzimidazolinone of formula XIV. This reaction is carried out under essentially the same conditions as described earlier in connection with the reaction of a diamine of formula II with phosgene. Moreover, the odiamines of formula XVII are relatively unstable and are preferably reacted in situ (i.e. without working-up or purification) with phosgene.

A 4-hydroxy-2-benzimidazolinone of formula XIV obtained according to either of the aforementioned routes is converted in step (ix) of Formula Scheme B into the desired epoxide starting material of formula V by reaction with an epihalohydrin, preferably epichlorohydrin, in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. The reaction is conveniently carried out in the presence of a watermiscible inert organic solvent such as a lower alkanol (e.g. methanol or ethanol) at a temperature of from 0 C to room temperature, preferably at about room temperature.

The amine starting materials of formula IV hereinbefore are known. Preferred amine starting materials of formula IV are those in which R' represents a hydrogen atom, particularly those in which R2 represents a lower alkyl group and especially a branched-chain lower alkyl group such as the isopropyl or tert.butyl group. Also preferred are those amine starting materials in which R' represents a hydrogen atom and R2 represents a lower cycloalkyl group or R' and R2 each individually represent a lower alkyl or lower cycloalkyl group.

The compounds of formulae V, VIII, IX, X, XIII and XIV hereinbefore and the compounds of formula III hereinbefore in which R represents a lower alkyl group and R', R2 and R3 have the significance given earlier or R represents a hydrogen atom and R' represents a lower alkyl or lower cycloalkyl group and R2 and R3 have the significance given earlier, are novel.

The benzimidazole derivatives provided by the present invention possess p- adrenoceptor blocking activity which, in the case of those derivatives in which R represents a lower alkyl group, is generally accompanied by low intrinsic stimulant activity (ISA). The present benzimidazole derivatives may accordingly be used for the prophylaxis and treatment of diseases of the heart such as, for example, angina pectoris and cardiac arrhythmias. They may also be used as antihypertensive agents.

The A-adrenoceptor blocking activity of the present benzimidazole derivatives can be demonstrated using standard test procedures. The p-adrenoceptor blocking activity in vitro is demonstrated using a reserpinised kitten heart in accordance with the procedure described by Kaumann and Birnbaumer, J. Biol. Chem., 249, 7874-7885, 1974. The results are expressed as 150 values, namely the concentration in moles of substance being tested required to inhibit by 50% the isoprenalinestimulated increase in adenylyl cyclase activity in the heart. The ,B-adrenoceptor blocking activity in vivo is demonstrated in mice by determining the dosage in mg/kg i.p. of substance being tested required to produce a 50% reduction in isoprenaline-induced tachycardia, this dosage being expressed as the ED50 The test for ISA is carried out using male rats, which have been depleted of peripheral catecholamine stores by treatment with reserpine (5 mg/kg i.p.), according to the procedure described by Barrett and Carter, Br. J. Pharmac., 1970, 40, 373--381. The results are expressed as the ED30, namely the dosage of substance being tested in mg/kg i.v. which produces an increase in heart rate of 30 beats per minute.

The results obtained in the foregoing tests using representative benzomidazole derivatives provided by this invention and propanolol and pindolol, two wellknown p-adrenoceptor blocking agents, are compiled in the following Tables: TABLE I

-Blocking activity Test substances 150(moles) | EDs0(mg/kg i.p.) 4-[2-Hydroxy-3-(isopropyl amino)propoxy]-2-benzimi- dazolinone hydrochloride 1,2 x 10-8 0,007 4{3{tert.Butylamino)-2- hydroxypropoxyl -2 -benz imidazolinone hydrochloride 0,9 x 10 8 0,0017 4-[3-(Diethylamino) -2 hydroxypropoxy]-2-benz imidazolinone hydrochloride 9,0 x 10-9 4-[3-(Dicyclopentylamino)- 2 -hydroxypropoxy] -2-benz- imidazolinone 6,0 x 10-'0 Propanolol 12,0 x 10-8 0,29 Pindolol 2,0 x 10-8 0,01 TABI,E ll

-Blocking activity ISA ED30 Test substance Iso (moles) EDSn (mg/kg i.p.) (mg,'kg i.v.) 4-[3-(Tert.butyl amino)-2-hydroxy propoxy]-7nethyl-2- benzimidazolinone hydrochloride 3,4 x 10-9 0,06 > 10 Propanolol 36 x 10-9 0,29 > 10 Pindolol 5,2 x 10-9 0,01 0,005 TABLE III

Blocking activity ISA ED30 Test substance I50 (moles) ED50 (mg/kg i.p.) (mg/kg i.v.) 1-(Tert.butylamino)-3- (2-mercapto-7-me thyl-4- benzimidazolyloxy)-2 propanol hydrochloride 1,8 x 10-9 0,01 > 1,0 Propanolol 36 x 10-9 0,29 > 1,0 Pindolol 5,2 x 10-9 0,01 0,005 It is appreciated that the pharmacological data for propanolol and pindolol are not identical in all three above Tables. This is caused by the fact that the experiments were effected in different runs.

The toxicity of the present benzimidazole derivatives is slight, the LD50 generally amounting to more than 200 mg/kg in the case of oral administration to mice.

The benzimidazole derivatives provided by the present invention can be used as medicaments; for example, in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material.

This carrier material can be an inert organic or inorganic carrier material suitable for enteral (e.g. oral) or parenteral administration. Examples of such carrier materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkyleneglycols and petroleum jelly. The pharmaceutical preparations can be produced in a conventional manner and finished dosage forms can be solid dosage forms (e.g. tablets, drag es, suppositories and capsules) or liquid dosage forms (e.g. solutions, suspensions and emulsions).

The pharmaceutical preparations may be subjected to conventional pharmaceutical operations such as sterilisation and/or may contain conventional adjuvants such as preservatives, stabilisers, wetting agents, buffers and salts for varying the osmotic pressure.

The benzimidazole derivatives provided by the present invention are conveniently administered to adults in an amount of 5-100 mg per day. It will be appreciated that this dosage range is given by way of example and that it can be varied upwards or downwards depending on factors such as the particular benzimidazole derivative being administered, the route of administration and the needs and requirements of the patient as determined by the attending physician.

The following Examples illustrate the process provided by the present invention. The expression "(DSC)" used in the Examples in relation to melting points means that the melting points were determined by "Differential Scanning Calorimetry".

Example 1.

(A) 4-Hydroxy-2-benzimidazolinone (i) 10 g of 2-methoxy-6-nitroaniline in 160 ml of ethanol were hydrogenated at room temperature and atmospheric pressure over 2.5 g of 10% palladium-oncarbon until the uptake of hydrogen ceased. The mixture was then filtered and the filtrate evaporated in vacuo to give the unstable o-diamine, 2,3-diaminoanisole, which was immediately dissolved in 50 ml of 2-N hydrochloric acid and cooled to 0 C., A slow stream of phosgene was passed through the solution for 2 hours, excess phosgene was removed by means of a rapid stream of nitrogen, and the precipitate was collected, washed with water and crystallised from ethanol to give 7.7 g (79%) of 4-methoxy-2-benzimidazolinone of melting point 2570-2590C.

Analysis for CeHoO2N2 Calculated: C: 58.5; H: 4.9; N: 17.0%.

Found: C:58.4; H: 5.2; N: 17.2%.

20 g of 4-methoxy-2-benzimidazolinone in 40% hydrogen bromide/acetic acid (200 ml were heated at 800C in a sealed tube for 20 hours. The solution obtained was evaporated to dryness in vacuo and the residue recrystallised from ethanol/chloroform to give 10.95 g (60%) of 4-hydroxy-2-benzimidazolinone of melting point 2850-2870C.

Analysis for C,H802N2 Calculated: C: 56.0; H: 4.0; N: 18.7%.

Found: C: 55.6; H: 3.9; N: 18.4%.

(ii) 10 g of 2,3-dinitrophenol in 50 ml of ethanol were hydrogenated at room temperature and atmospheric pressure over 4 g of 10% palladium-on-carbon until the uptake of hydrogen ceased. The solution was filtered and the filtrate concentrated in vacuo to give the unstable o-diamine, 2,3-diaminophenol, which was dissolved in 30 ml of 2-N hydrochloric acid. A slow stream of phosgene was passed through the solution for 40 minutes a vigorously stirred solution of the solid in 60 ml of dioxan and the resulting solution was stirred at room temperature for I hour. The precipitate was collected.

washed well with water and dried in vacuo at 60"C. There were obtained 35.0 g (89%) of crude 2,3-dinitrophenyl 2,3-epoxypropyl ether of melting point 860-890C which was sufficiently pure for use in the next step. A sample was recrystallized from chloroform/diethyl ether to give 2,3-dinitrophenyl 2,3-epoxypropyl ether of melting point 950-970C.

Analysis for CgHssOeN2 Calculated: C: 45.0; H: 3.4; N: 11.7%.

Found: C: 44.6; H: 3.3; N: I 1.4%.

(B) 4-[2-Hydroxy-3-( isopropylamino}propoxyl.2-benzimidazollnone hydrochloride 20 g (0.083 mol) of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 500 ml of hot ethanol and the solution was decanted from a small quantity of insoluble residue. 18.4 g (0.123 mol) of N-isopropylbenzylamine were added and the solution was heated at 500C for 16 hours. The cooled solution was hydrogenated at room temperature and atmospheric pressure over 7 g of 10(/^ palladium-on-carbon catalyst until uptake of hydrogen ceased. The solution was filtered and the filtrate evaporated to dryness in vacuo to give the diamine, 3-(2,3 diaminophenoxy)- I .(isopropylamino).2-propanol, (found m/e 239; C,2H2,O2N3 requires M, 239), which was immediately dissolved in 100 ml of 2-N hydrochloric acid. The solution was cooled to OOC and stirred while a slow stream of phosgene was passed through for 45 minutes. Excess phosgene was removed by passing a vigorous stream of nitrogen through the solution which was subsequently evaporated to dryness in vacuo. The residue was recrystallised from isopropanol/diethyl ether to give 11.27 g (45%) of 4-[2-hydroxy-3 (isopropylamino)propoxyl -2-benzimidazolinone hydrochloride of melting point (DSC) 2320C.

Analysis for C,3H,903N3.HCI Calculated: C: 51.8; H: 6.7; N: 13.9; Cl: 11.8%.

Found: C: 51.9; H: 6.9; N: 13.6; Cl: 12.2%.

Example 3.

4- [3 - (tert.Butylamino)- 2 - hydroxypropoxy]- 2 - benzimidazolinone hydrochloride 20 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 400 ml of ethanol in the manner described in Example 2(B). 100 ml of tert.butylamine were added and the solution was left to stand at room temperature for 18 hours.

Evaporation of the solution in vacuo and crystallisation of the residue from isopropanol gave 17.2 g (66%) of l-(tert.butylamino)-3-(2,3-dinitrophenoxy)-2- propanol of melting point 1200--122"C.

Analysis for C,3H,90"N3 Calculated: C: 49.8; H: 6.1; N: 13.4%.

Found: C: 49.9; H: 6.0; N: 13.5%.

5.1 g of l-(tert.butylamino)-3-(2,3-dinitrophenoxy)-2-propanol in 100 ml of ethanol were hydrogenated at room temperature and atmospheric pressure over 2.5 g of 10% palladium-on-carbon catalyst until the uptake of hydrogen ceased. The solution was filtered, the filtrate evaporated in vacuo and the residue, l-(tert.butylamino)-3-(2,3-diaminophenoxy)-2-propanol, immediately dissolved in 50 ml of 2-N hydrochloric acid. The solution was cooled to OOC and a slow stream of phosgene was passed through for 45 minutes. Excess phosgene was removed by means of a stream of nitrogen. The solution was evaporated to dryness in vacuo and the residue recrystallised from isopropanol/diethyl ether to give 2.9 g (56.3%) of 4 [3-(tert.butylamino)-2-hydroxypropoxy]-2-benzimidazolinone hydrochloride of melting point (DSC) 263"C.

Analysis for C,4H2tO3N3.HCI Calculated: C: 53.3; H: 7.0; N:13.3; Cl: 11.2%.

Found: C: 53.1; H: 7.3; N: 13.4; Cl: 11.6%.

Example 4.

4 - [2 - Hydroxy - 3 - (methylamino)propoxy] - 2 - benzimidazolinone hydrochloride 10 g (0.042 mol) of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 250 ml of hot ethanol in the manner described in Example 2(B). 7.56 g (0.0625 mol) of N-methylbenzylamine were added and the solution was left to stand at room temperature for 70 hours. The solution was then hydrogenated over 10% palladium-on-charcoal in the manner described in Example 2(B) and the resulting diamine, 3-(2,3-diaminophenoxy)- I -(methylamino)-2-propanol, was immediately reacted in 100 ml of 2-N hydrochloric acid with phosgene also in the manner described in Example 2(B). The product was recrystallized from ethanol/diethyl ether to give 5.36 g (47%) of 4-[2-hydroxy-3-(methylamino)propoxy]-2-ben zimidazolinone hydrochloride of melting point 218"--220"C.

Analysis for C"H,503N3HCI Calculated: C: 48.3; H: 5.9; N: 15.4%.

Found: C: 48.2; H: 5.9; N: 15.3%.

Example 5.

4 - [2 - Hydroxy - 3 - (N - methylcyclohexylamino)propoxy] - 2 - benzimidazolinone hydrochloride hemihydrate 10 g (0.042 mol) of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 250 ml of hot ethanol in the manner described in Example 2(B). 5.18 g (0.046 mol) of N-methylcyclohexylamine were added and the solution was left to stand at room temperature for 36 hours. The solution was then hydrogenated over 10% palladium-on-carbon in the manner described in Example 2(B) to give 3 - (2,3 diaminophenoxy) - 1 - (N - methylcyclohexylamino) - 2 - propanol which was immediately reacted in 100 ml of 2-N hydrochloric acid with phosgene, also in the manner described in Example 2(B). Recrystallisation of the residue from isopropanol/diethyl ether yielded 7.44 g (49%) of 4 - [2 - hydroxy - 3 - (N methylcyclohexylamino)propoxy] - 2 - benzimidazolinone hydrochloride hemihydrate of melting point (DSC) greater than 288"C (decomposition point).

Analysis for C17H25O3N3.HCl.0.5H2O Calculated: C: 55.9; H: 7.5; N: 11.5%.

Found: C: 55.9; H: 7.3; N: 11.3%.

Example 6.

4 - [3 - (Dicyclopentylamino)-2-hydroxypropoxy]-2-benzimidazolinone hydrochloride hemihvdrate 8.5 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 250 ml of hot ethanol in the manner described in Example 2(B). 15 g of potassium carbonate and 7.5 g of dicyclopentylamine hydrochloride were added and the solution was heated at 600C for 18 hours. The solution was filtered, the filtrate evaporated to dryness in vacuo and the residue extracted with chloroform. The chloroform extract was washed with water, dried and evaporated to dryness in vacuo. The residue was crystallised from chloroform/n-hexane to give 6.2 g of l-(dicyclo pentylamino)-3-(2,3-dinitrophenoxy)-2-propanol of melting point 1300--133"C.

Analysis for C19H27N3O0 Calculated: C: 58.0; H: 6.9; N: 10.7%; M+ 393.

Found: C: 57.9; H: 7.0; N: 10; My 393.

6.05 g of 1-(dicyclopentylamino)-3-(2,3-dinitrophenoxy)-2-propanol in 100 ml of ethanol were hydrogenated at room temperature and atmospheric pressure over 2.0 g of 10% palladium-on-carbon until the uptake of hydrogen ceased. The mixture was filtered and the filtrate evaporated in vacuo to give 3-(2,3-diamino phenoxy)-l -(dicyclopentylamino)-2-propanol which was immediately dissolved in 50 ml of 2-N hydrochloric acid and cooled to OOC. A slow stream of phosgene was passed through the solution for 45 minutes, excess phosgene being removed by means of a stream of nitrogen. The solution was evaporated to dryness in vacuo and the residue crystallised from isopropanol/diethyl ether, there being obtained 4.25 g (69.5%) of 4-[3-dicyclopentylamino)-2-hydroxypropoxy]-2-benzimidazolinone hydrochloride hemihydrate of melting point (DSC) greater than 308"C (decomposition point).

Analysis for C20H29N3O3.HCl.0.5H2O Calculated: C: 59.3; H: 7.7; N: 10.4; Cl: 8.8%.

Found: C: 59.5; H: 7.8; N: 10.4; Cl: 9.5%.

Example 7.

4 - [3 - (Diethylamino) - 2 - hydroxypropoxy] - 2 - benzimidazolinone hydrochloride 4.0 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 100 ml of hot ethanol in the manner described in Example 2(B). The solution was treated with 6.1 g of diethylamine and the resulting solution left to stand at room temperature for 24 hours. The solution was then evaporated to dryness in vacuo and the residue was hydrogenated in 50 ml of ethanol at room temperature and atmospheric pressure over I g of 10% palladium-on-carbon until the uptake of hydrogen ceased. The mixture was filtered and the filtrate evaporated in vacuo to give 3-(2,3-diaminophenoxy)-l-(diethylamino)-2-propanol which was immediately dissolved in 30 ml of 2-N hydrochloric acid, cooled to OOC and treated with a slow steam of phosgene for 40 minutes, excess phosgene being removed by means of a stream of nitrogen. Filtration of the solution, evaporation of the filtrate to dryness in vacuo and recrystallisation of the residue from ethanol/diethyl ether yielded 2.6 g (49%) of 4 - [3 - (diethylamino) - 2 - hydroxypropoxy] - 2 - benzimidazxolinone hydrochloride of melting point (DSC) 247"C.

Analysis for C,4H2,O3N3.HCI Calculated: C: 53.2; H: 7.0; N: 13.3%.

Found: C: 53.5; H: 6.9; N: 13.5%.

Example 8.

4 - [3 - (Cyclohexylamino) - 2 - hydroxypropoxy] - 2 - benzimidazolinone hydrochloride 5 g (0.021 mol) of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 100 ml of hot ethanol in the manner described in Example 2(B). The solution was cooled, treated with 12.25 g (0.124 mol) of cyclohexylamine and left to stand at room temperature for 24 hours. The solution was evaporated to dryness in vacuo and the residue hydrogenated in 100 ml of ethanol at room temperature and atmospheric pressure over 3.5 g of 10% palladium-on-carbon until the uptake of hyrogen ceased. The mixture was filtered and the filtrate evaporated to dryness in vacuo to give 1 - (cyclohexylamino) - 3 - (2,3 - diaminophenoxy) - 2 - propanol which was immediately dissolved in 50 ml of 2-N hydrochloric acid, cooled to OOC and treated with a slow stream of phosgene for 45 minutes, excess phosgene being removed by means of stream of nitrogen. Filtration, evaporation of the filtrate to dryness in vacuo and recrystallisation of the residue from ethanol/diethyl ether gave 1.7 g (23.9%) of 4 - [3 - (cyclohexylamino) - 2 - hydroxypropoxy] - 2 benzimidazolinone hydrochloride of melting point (DSC) 2240 C.

Analysis for C10H23O3N3.HCl Calculated: C: 56.2; H: 7.1; N: 12.3; Cl: l0.40,u.

Found: C: 55.9; H: 7.2; N: 11.9; Cl: l0.20,u.

Example 9.

4 - [3 - (Cyclohexylamino) - 2 - hydroxypropoxjl - 2 - benzimidazolinone hydrochloride 5 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether in ethanol were treated with 4.3 g of N-benzylcyclohexylamine and the solution was heated at 80"C for 48 hours.

The solution was then hydrogenated in the manner described in Example 8 and the hydrogenation product was reacted with phosgene and worked-up, likewise as described in Example 8. Crystallisation of the resulting product from ethanol/diethyl ether yielded 2.7 g (37.5%) of 4 - [3 - (cyclohexylamino) - 2 hydroxypropoxy] - 2 - benzimidazolinone hydrochloride which was shown by mass spectrum analysis to be identical with the product prepared as described in Example 8.

Example 10.

4 - [2 - Hydroxy - 3 - (n - propylamino)prnpoxyl - 2 - benzimidazolinone hydrochloride 4.2 g (0.0175 mol) of 2,3-dinitrophenyl 2,3-epoxypropyl ether and 4.1 g (0.0275 mol) of n-propylbenzylamine were dissolved in 100 ml of ethanol and the mixture was left to stand at room temperature for 90 hours. The mixture was then hydrogenated in the manner described in Example 2(B) and the product 3 - (2,3 diaminophenoxy) - I - (n - propylamino) - 2 - propanol, immediately reacted with phosgene, also in the manner described in Example 2(B). The product obtained was recrystallised from ethanol/isopropanol to give 3.4 g (64.5%) of 4 [2 - hydroxy - 3 - (n - propylamino)propoxy] - 2 - benzimidazolinone hydrochloride of melting point 2640--2670C.

Analysis for C13H10O3N3.HCl Calculated: C: 51.8; H: 6.6; N: 13.9%.

Found: C: 51.5; H: 6.7; N: 13.5%.

Example 11.

(A) 4-(2 ,3-Epoxyprnpoxy)-2 3-dinitrotoluene 34.8 g of 2,3-dinitro-p-cresol in 100 g of epichlorohydrin and 3 ml of piperidine were heated at 800C for 20 hours. The solution was evaporated to dryness in vacuo and the residue was dissolved in 60 ml of dioxan. To the well-stirred solution were added 90 ml of 2-N sodium hydroxide and the resulting solution was stirred for a further I hour. The product was collected, washed well with water and air-dried, there being obtained 40.2 g of 4-(2,3-epoxypropoxy)-2,3-dinitrotoluene of melting point 1 l80-l200C. A sample recrystallized from ethanol melted at 1230--1250C.

Analysis for C10H10O6N2 Calculated: C:47.25; H:3.95; N: 11.0%.

Found: C: 47.1; H: 3.95; N: 10.9%.

(B)1-(Tert. butylamino)-3-(2 ,3-dinitrnp-tolyloxy)-2prnpanol 20 g of 4-(2,3-epoxypropoxy)-2,3-dinitrotoluene in 750 ml of ethanol were reacted with 100 ml of tert.butylamine at room temperature for 48 hours. The solution was evaporated to dryness in vacuo and the crystalline product obtained was recrystallized from isopropanol to give 22.6 g of l-(tert.butylamino)-3-(2,3- dinitro/p/tolyloxy)-2-propanol of melting point 1170--1190C Analysis for C,4H2,OeN3 Calculated: C:51.4; H: 6.45; N: 12.85%.

Found: C:51.1; H:6.45; N: 12.8%.

(C) 4 - [3 - (Tert.butylaniino) - 2 - hydroxypropoxy]- 7- methyl - 2 - benzimidazolinone hydrochloride (a) 4.7 g of 1 - (tert.butylamino) - 3 - (2,3-dinitro - p - tolyloxy) - 2 propanol in 75 ml of ethanol were hydrogenated at room temperature and atmospheric pressure over 1.5 g of 10% palladium-on-carbon until the uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated to dryness to give the unstable o-diamine, l-(tert.butylamino)-3-(2,3-diamino-ptolyloxy)-2-propanol, which was immediately dissolved in 50 ml of 2-N hydrochloric acid at room temperature. A slow stream of phosgene was passed through the solution for 1 hour, the phosgene was then replaced by nitrogen and the solution was finally evaporated to dryness in vacuo. The solid residue was recrystallized from methanol/isopropanol to give 2.9 g of 4- [3 (tert.butylamino) - 2 - hydroxypropoxy] - 7 - methyl - 2 - benzimidazolinone hydrochloride of melting point 3l00-3l20C.

Analysis for Cs5H2SO3N3.HCl Calculated: C: 54.6; H: 7.35; N: 12.75; Cl: 10.75%.

Found: C: 54.5; H: 7.25; N: 12.9; Cl: 10.6%.

(b) 4.0 g of I - (tert.butylamino) - 3 - (2,3 - diamino - p - tolyloxy) - 2 propanol were heated with 20 g of urea at 1400C for 5 hours under nitrogen. The cooled product was dissolved in 100 ml of water and extracted with three 50 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with 20 ml of water, dried over potassium carbonate and evaporated to dryness. The residue was treated with an excess of ethanolic hydrogen chloride and the resulting hydrochloride was recrystallised from methanol/isopropanol, there being obtained 1.4 g of 4 - [3 - (tert. - butylamino) - 2 - hydroxypropoxy] - 7 - methyl - 2 benzimidazolinone hydrochloride of melting point 303"--305"C.

Example 12.

4 - [3 - (Cyclopentylamino) - 2 - hydroxypropoxy]-7-methyl-2-benzimidazolinone 6 g of 4-(2,3-epoxypropoxy)-2,3-dinitrotoluene in 200 ml of ethanol were treated with 4.55 g of N-benzylcyclopentylamine and the solution was heated at 60 C for 24 hours. The solution was then evaporated to dryness in vacuo to give 1 (N - benzylcyclopentylamino) - 3 - (2,3 - dinotro - p - tolyoloxy)-2-propanol which was dissolved in 150 ml of ethanol and hydrogenated in the presence of 1.5 g of 10% palladium-on-carbon at room temperature and atmospheric pressure until the uptake of hydrogen ceased. Filtration and evaporation of the filtrate under reduced pressure gave 1 - (cyclopentylamino)- 3 - (2,3 - diamino - p tolyloxy) - 2 - propanol which was treated with phosgene in the manner described in Example 11(C) (a) to give, after crystallisation from ethanol containing a trace of methanol, 4.8 g of 4 - [3 - (cyclopentylamino) - 2 - hydroxypropoxy] - 7 methyl - 2 - benzimidazolinone of melting point2650-2660C.

Example 13.

(A) 1 - (Dicyclopentylamino) - 3 - (2,3 - dinotro - p - tolyloxy) - 2 - propanol 10 g of 4-(2,3-epoxypropoxy)-2,3-dinitrotoluene in 150 ml of ethanol were treated with 9.05 g of dicyclopentylamine hydrochloride and 18 g of anhydrous potassium carbonate and the mixture was heated at 600C for 30 hours. The mixture was then evaporated to dryness in vacuo, 50 ml of water were added and the resulting solution was extracted with two 50 ml portions of chloroform. The combined chloroform extracts were washed with water, dried over potassium carbonate and evaporated to dryness in vacuo. the residue was recrystallised from ethyl acetate to give 5.9 g of I - (dicyclopentylamino) - 3 - (2,3 - dinitro - p tolyloxy) - 2 - propanol of melting point ll90-1220C.

Analysis for C2oH29OeN3 Calculated: C: 58.95; H: 7.2 N: 10.3%.

Found: C: 59.0; H: 7.3; N: 10.25%.

(B) 4 - [3 - (Dicyclopentylamino) - 2- hydroxypropoxy] - 7- methyl - 2 benzimidazolinone hydrochloride 5.4 g of 1 - (dicyclopentylamino) - 3 - (2,3 - dinitro - p - tolyloxy) - 2 propanol in 200 ml of ethanol were hydrogenated in the presence of 1.0 g of 10% palladium-on-carbon at room temperature and atmospheric pressure until the uptake of hydrogen ceased. The solution was filtered and the filtrate was evaporated to dryness in vacuo to give the unstable o-diamine, I-(dicyclo pentylamino)-3-(2,3-diamino-p-tolyloxy-2-propanol, which was immediately taken up in 2-N hydrochloric acid and reacted with phosgene in the manner described in Example l(C) (a). The product was recrystallised from isopropanol to give 1.8 g of 4 - [3 - (dicyclopentylamino) - 2 hydroxypropoxy] - 7 - methyl - 2benzimidazolinone hydrochloride of melting point 274"--276"C.

Example 14.

7 - [3 - (Tert.butylamino) - 2 - hydroxypropoxy] - 1,4 - dimethyl - 2 - benzimidazolinone hydrochloride 5.3 g of I - (tert.butylamino) - 3 - (2,3 - dinitro - p - tolyloxy) - 2 - propanol in 100 ml of ethanol were treated with 30 ml of a 33% solution of methylamine in ethanol and the resulting solution was heated at 500C for 48 hours. The solution was then evaporated to dryness in vacuo to give I - (tert.butylamino) - 3 - (2 methylamino - 3 - nitro - p - tolyloxy) - 2 - propanol in the form of an orange oil which was dissolved in 100 ml of ethanol and hydrogenated in the presence of I g of 10% palladium-on-carbon at room temperature and atmospheric pressure until uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated to dryness in vacuo to give the unstable l-(tert. - butylamino) - 3 - (3 amino - 2 - methylamino - p - tolyloxy) - 2 - propanol which was taken up in 50 ml of 2-N hydrochloric acid and reacted with phosgene for 8 hours in the manner described in Example 11 (C) (a). After recrystallisation from ethanol containing a trace of methanol, there were obtained 1.8 g of 7 - [3 - (tert.butylamino) - 2 hydroxypropoxy] - 1,4 - dimethyl - 2- benzimidazolinone hydrochloride of melting point 290"--291"C.

Example 15.

I - (Tert.butylamino) - 3 - (2 - mercapto - 7 - methyl - benzimidazolyloxy) - 2 propanol hydrochloride 5 g of 1 - (tert.butylamino) - 3 - (2,3 - dinitro - p - tolyloxy) - 2 - propanol in 100 ml of ethanol were hydrogenated at room temperature and atmospheric pressure over 1.5 g of 10% palladium-on-carbon until the uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated to dryness to give the unstable o-diamine, 1 - (tert.butylamino) - 3 - (2,3 - diamino - p - tolyloxy 2 - propanol, which was immediately dissolved in 50 ml of 2-N hydrochloric acid at room temperature. 5 ml of thiophosgene were added to the solution and the resulting mixture was stirred vigorously under nitrogen at room temperature for 4 hours. The mixture was evaporated to dryness in vacuo and the residue was recrystallised from isopropanol to give 3.05 g of I - (tert.butylamino) - 3 - (2 mercapto - 7 - methyl - benzimidazolyloxy) - 2 - propanol hydrochloride in the form of pale yellow crystals of melting point 2030 2050C (decomposition).

Analysis for C,sH2302N3S. 1.33 HCI Calculated: C: 50.5; H: 6.6; N: 11.75%.

Found: C: 50.25; H:6.8; N: 11.35%.

Example 16.

1 - (Tert - butylamino) - 3 - (2 - mercapto - 4 - benzimidazolyloxy) - 2 - propanol hydrochloride 20 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 400 ml of hot ethanol and the solution was decanted from a small quantity of insoluble residue.

100 ml of tert.-butylamine were added and the solution was left to stand at room temperature for 18 hours. Evaporation of the solution in vacuo and crystallisation of the residue from isopropanol gave 17.2 g (66%) of 1 - (tert.butylamino) - 3 (2,3 - dinitrophenoxy) - 2 - propanol of melting point 1200--1220C.

Analysis for Cr3HXgOeN3 Calculated: C: 49.8; H: 6.1; N: 13.4%.

Found: C: 49.9; H: 6.0; N: 13.5%.

10 g of I - (tert.butylamino)-3-(2,3-dinitrophenoxy)-2-propanol in 150 ml of ethanol were hydrogenated at room temperature and atmospheric pressure over 4 g of 10% palladium-on-carbon catalyst until the uptake of hydrogen ceased. The solution was filtered, the filtrate was evaporated in vacuo and the residue, I (tert.butylamino) - 3 - (2,3 - diaminophenoxy) - 2 - propanol, was immediately dissolved in 50 ml of 2-N hydrochloric acid. 10 ml of thiophosgene were added to the solution and the resulting mixture was stirred vigorously under nitrogen at room temperature for 3 hours. The mixture was evaporated to dryness in vacuo and the residue was recrystallised from isopropanol to give 3.8 g of I (tert.butylamino) - 3 - (2 - mercapto - 4 - benzimidazolyloxy) - 2 - propanol hydrochloride in the form of pale yellow crystals of melting point l450-I500C (decomposition).

Analysis for C14H2rO2N3S. 1.33 HCI Calculated: C: 48.9; H: 6.55; N: 12.2; S: 9.35%.

Found: C:48.75; H:6.5; N: 11.7; S: 9.85%.

Example 17.

1 - (Tert.butylamino) - 3 - (2 - mercapto -1,4 - dimethyl - 7 - benzimidazolyloxy) 2 - propanol hydrochloride 4.75 g of I - (tert.butylamino) - 3 - (2,3 - dinitro - p - tolyloxy) - 2 propanol in 100 ml of ethanol were treated with 25 ml of a 33% solution of methylamine in ethanol and the resulting solution was heated at 500C for 14 hours.

The solution was then evaporated to dryness in vacuo to give I (tert.butylamino) - 3 - (2 - methylamino - 3 - nitro - p - tolyloxy) - 2 - propanol in the form of an orange oil which was dissolved in 100 ml of ethanol and hydrogenated in the presence of I g of 10% palladium-on-carbon at room temperature and atmospheric pressure until uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated to dryness in vacuo to give the unstable I - (tert.butylamino) - 3 - (3 - amino - 2 - methylamino - p - tolyloxy) 2 - propanol which was taken up in 50 ml of 2-N hydrochloric acid and treated with 5 ml of thiophosgene. The mixture was stirred vigorously under nitrogen at room temperature for 2 hours and then evaporated to dryness in vacuo. The residue was recrystallized from isopropanol to give 3.29 g of I - (tert.butylamino) 3 - (2 - mercapto - 1,4 - dimethyl - 7 - benzimidazolyloxy) - 2 - propanol hydrochloride in the form of orange crystals of melting point 1840--185"C (decompositon).

Example 18.

I - (Diethylamino) - 3 - (2 - mercapto - 4 - benzimidazolyloxy) - 2 - propanol hydrochloride 7 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 200 ml of hot ethanol and the solution was decanted from a small quantity of insoluble residue.

The solution was treated with 11.2 g of diethylamine and the resulting solution was left to stand at room temperature for 48 hours. The solution was then evaporated to dryness in vacuo and the residue was hydrogenated in 100 ml of ethanol at room temperature and atmospheric pressure over 3.5 g of 10% palladium-on-carbon until the uptake of hydrogen ceased. The mixture was filtered and the filtrate was evaporated in vacuo to give 3 - (2,3 - diaminophenoxy) - I - (diethylamino) - 2 propanol which was immediately dissolved in 50 ml of 2-N hydrochloric acid and treated with 5 ml of thiophosgene. The mixture was stirred vigorously under nitrogen at room temperature for 3 hours. The solution was evaporated in vacuo and the residue was recrystallised from ethanol/isopropanol to give 1.8 g of 1 (diethylamino) - 3 - (2 - mercapto - 4- benzimidazolyloxy) - 2 - propanol hydrochloride in the form of pale yellow crystals of melting point 2490-2500C (decomposition).

Analysis for C,4H2,O2N3S. 1.33 HCI Calculated: C: 48.9; H: 6.55; N: 12.2; S: 9.3%.

Found: C: 49.0; H: 6.5; N: 12.3; S: 9.8%.

The following Examples illustrate typical pharmaceutical preparations containing the benzimidazole derivative provided by the present invention: Example A.

A tablet formulation containing the following ingredients can be produced in a conventional manner: Ingredient Per tablet Benzimidazole derivative 5 mg Lactose 103 mg Starch 61 mg Magnesium stearate 1 mug Total weight 170 mg Example B.

A capsule formulation containing the following ingredients can be produced in a conventional manner: Ingredient Per capsule Benzimidazole derivative 5 mg Lactose 106 mg Starch 20 mg Talc 9 mg Total weight 140 mg This capsule formulation is suitably filled into No. 4 hard gelatin capsules.

WHAT WE CLAIM IS: 1. Compounds of the general formula

wherein R represents a hydrogen atom or a lower alkyl group, R' represents a hydrogen atom or a lower alkyl or lower cycloalkyl group, R2 represents a lower alkyl or lower cycloalkyl group, R3 r

Claims (66)

**WARNING** start of CLMS field may overlap end of DESC **. The following Examples illustrate typical pharmaceutical preparations containing the benzimidazole derivative provided by the present invention: Example A. A tablet formulation containing the following ingredients can be produced in a conventional manner: Ingredient Per tablet Benzimidazole derivative 5 mg Lactose 103 mg Starch 61 mg Magnesium stearate 1 mug Total weight 170 mg Example B. A capsule formulation containing the following ingredients can be produced in a conventional manner: Ingredient Per capsule Benzimidazole derivative 5 mg Lactose 106 mg Starch 20 mg Talc 9 mg Total weight 140 mg This capsule formulation is suitably filled into No. 4 hard gelatin capsules. WHAT WE CLAIM IS:

1. Compounds of the general formula

wherein R represents a hydrogen atom or a lower alkyl group, R' represents a hydrogen atom or a lower alkyl or lower cycloalkyl group, R2 represents a lower alkyl or lower cycloalkyl group, R3 represents a hydrogen atom or a primary or secondary lower alkyl group and Y represents an oxygen or sulphur atom, the thiol tautomers of those compounds of formula I in which Y represents a sulphur atom and pharmaceutically acceptable acid addition salts thereof.

2. Compounds as claimed in claim I of the general formula

wherein R' and R2 are as defined in claim I, and pharmaceutically acceptable acid addition salts thereof.

3. Benzimidazole derivatives as claimed in claim 2, wherein R' represents a hydrogen atom and R2 represents a lower cycloalkyl group or R' and R2 each individually represent a lower alky or lower cycloalkyl group.

4. Compounds as claimed in claim I or the general formula

wherein R' represents a lower alkyl group, Rs, R2 and R3 are as defined in claim 1, and pharmaceutically acceptable acid addition salts thereof.

5. Compounds as claimed in claim I of the general formula

wherein R'' represents a hydrogen atom or a lower alkyl group, R2' represents a lower alkyl groupand R and R3 are as defined in claim 1, the thiol tautomers thereof and pharmaceutically acceptable acid addition salts thereof.

6. Compounds as claimed in claim 1 or 5, wherein R represents a lower alkyl group.

7. Compounds as claimed in claim 4 or 6, wherein R' or R represents the methyl group.

8. Compounds as claimed in any one of claims 1 to 7, wherein R' or R'' represents a hydrogen atom.

9. Compounds as claimed in any one of claims 1 to 8 wherein R2 or R2, represents a lower alkyl group.

10. Compounds as claimed in claim 9, wherein R2 or R2' represents a branched-chain lower alkyl group.

Il. Compounds as claimed in claim 10, wherein R2 or R2, represents the isopropyl or tert.butyl group.

12. Compounds as claimed in any one of claims I to 7 or 9 to 11, wherein R' and R2, or R1, and R2' are lower alkyl or lower cycloalkyl groups.

13. 4 - [2 - Hydroxy - 3 - (methylamino)propoxy] - 2 - benzimidazolinone.

14. 4 - [2 - Hydroxy - 3 - (n - propylamino)propoxy] - 2 benzimidazolinone.

15. 4 - [2 - Hydroxy - 3 - (isopropylamino)propoxy] - 2 - benzimidazolinone.

16. 4 - [3 - (Tert.butylamino) - 2 - hydroxypropoxy] - 2 - benzimidazolinone.

17. 4 - [3 - (Diethylamino) - 2 - hydroxypropoxy] - 2 - benzimidazolinone.

18. 4 - [3 - (Cyclohexylamino) - 2 - hydroxypropoxy] - 2 benzimidazolinone.

19. 4 - [3 - (Dicyclopentylamino) - 2 - hydroxypropoxy] - 2 benzimidazolinone.

20. 4 - [2 - Hydroxy - 3 - (N - methylcyclohexylamino)propoxy] - 2 benzimidazolinone.

21. 4 - [3 - (Tert.butylamino) - 2 - hydroxypropoxy] - 7 - methyl - 2 benzimidazolinone.

22. 4 - [3 - (Cyclopentylamino) - 2 - hydroxypropoxy] - 7 - methyl - 2 benzimidazolinone.

23. 4 - [3 - (Dicyclopentylamino) - 2 - hydroxypropoxy] - 7 - methyl - 2 benzimidazolinone.

24. 7 - [3 - (Tert.butylamino) - 2 - hydroxypropoxy]l,4 - dimethyl - 2 benzimidazolinone.

25. 1 - (Tert.butylamino) - 3 - (2 - mercapto - 7 - methyl - 4 benzimidazolyloxy) - 2 - propanol.

26. I - (Tert.butylamino) - 3 - (2 - mercapto - 4 - benzimidazolyloxy) - 2 propanol.

27.1 - (Tert.butylamino) - 3 - (2 - mercapto - 1,4 - dimethyl - 7 benzimidazolyloxy) - 2 - propanol.

28. I - (Diethylamino) - 3 - (2 - mercapto - 4 - benzimidazolyloxy) - 2 propanol.

29. A hydrohalide salt of a compound as claimed in any one of claims 12 to 28.

30. A hydrochloride salt of a compound as claimed in any one of claims 12 to 28.

31. A process for the manufacture of the benzimidazole derivatives claimed in claim I, which process comprises a) reacting a compound of the general formula

wherein R, R', R2 and R3 have the significance given in claim 1, with a compound of the general formula Z2C=Y IV wherin Z represents a chlorine atom or an amino group and Y has the significance given in claim 1, or b) for the manufacture of a compound of formula I in which Y represents an oxygen atom and R, R', R2 and R3 have the significance given in claim 1, reacting an epoxide of the general formula

wherein R and R3 have the significance given in claim 1, with an amine of the general formula

wherein R' and R2 have the significance given in claim 1, or c) resolving a racemic compound of formula I into its optical isomers and, if desired, converting a compound of formula I obtained into a pharmaceutically acceptable acid addition salt.

32. A process according to claim 31, wherein Y represents an oxygen atom, R and R3 each represent a hydrogen atom and R' and R2 have the significance given in claim I and wherein in process embodiment a) phosgene is used as the compound of formula IV.

33. A process according to claim 31 or claim 32, wherein Y represents an oxygen atom, R and R3 each represent a hydrogen atom and R' represents a hydrogen atom and R2 represents a lower cycloalkyl group or R' and R2 each individually represent a lower alkyl or lower cycloalkyl group.

34. A process according to claim 31, wherein Y represents an oxygen atom, R represents a lower alkyl group and R', R2 and R3 have the significance given in claim 1 and wherein only process embodiment a) is used.

35. A process according to claim 31, wherein R' represents an hydrogen atom or lower alkyl group, R2 represents a lower alkyl group and R and R3 have the significance given in claim I and wherein thiophosgene is used as the compound of formula IV.

26. A process according to any one of claims 31, 34 and 35, wherein R represents a lower alkyl group.

37. A process according to claim 36, wherein R represents the methyl group.

38. A process according to any one of claims 31 to 37, wherein R' represents a hydrogen atom.

39. A process according to any one of claims 31 to 38 inclusive, wherein R2 represents a lower alkyl group.

40. A process according to claim 39, wherein R2 represents a branched-chain lower alkyl group.

41. A process according to claim 40, wherein R2 represents the isopropyl or tert.butyl group.

42. A process according to any one of claims 31 to 37, or 39 to 41, wherein R' and R2 are lower alkyl or lower cycloalkyl groups.

43. A process according to claim 31 or claim 32, wherein 4 - [2 - hydroxy - 3 (methylamino)propoxy] - 2 - benzimidazolinone is manufactured.

44. A process according to claim 31 or claim 32, wherein 4 - [2 - hydroxy - 3 (n - propylamino)propoxy] - 2 - benzimidazolinone is manufactured.

45. A process according to claim 31 or claim 32, wherein 4 - [2 - hydroxy - 3 (isopropylamino)propoxy] - 2 - benzimidazolinone is manufactured.

46. A process according to claim 31 or claim 32, wherein 4 - [3 (tert.butylamino) - 2 - hydroxypropoxy] - 2 - benzimidazolinone is manufactured.

47. A process according to claim 33, wherein 4 - [3 - (diethylamino) - 2 hydroxypropoxy] - 2 - benzimidazolinone is manufactured.

48. A process according to claim 33, wherein 4 - [3 - (cyclohexylamino) - 2 hydropropoxy] - 2 - benzimidazolinone is manufactured.

49. A process according to claim 33, wherein 4 - [3 - (dicyclopentylamino) 2 - hydroxypropoxy] - 2 - benzimidazolinone is manufactured.

50. A process according to claim 33, wherein 4 - [2 - hydroxy - 3 - (N methylcyclohexylaminopropoxy] - 2 - benzimidazolinone is manufactured.

51. A process according to claim 31 or claim 34, wherein 4 - [3 (tert.butylamino) - 2 - hydroxypropoxy] - 7 - methyl - 2 - benzimidazolinone is manufactured.

52. A process according to claim 31 or claim 34, wherein 4 - [3 (cyclopentylamino) - 2 - hydroxypropoxy] - 7 - methyl - 2 - benzimidazolinone is manufactured.

53. A process according to claim 31 or claim 34, wherein 4 - [3 (dicyclopentylamino) - 2 - hydroxypropoxy] - 7 - methyl - 2 - benzimidazolinone is manufactured.

54. A process according to claim 31 or claim 34, wherein 7 - [3 (tert.butylamino) - 2 - hydroxypropoxy] - 1,4 - dimethyl - 2 - benzimidazolinone is manufactured.

55. A process according to claim 31 or claim 35, wherein 1 - (tert.butylamino) - 3 - (2 - mercapto - 7 - methyl - 4 - benzimidazolyloxy - 2 propanol is manufactured.

56. A process according to claim 31 or claim 35, wherein I - (tert.butylamino) - 3 - (2 - mercapto - 4 - benzimidazolyloxy) - 2 - propanol is manufactured.

57. A process according to claim 31 or claim 35, wherein I - (tert.butylamino) - 3 - (2 - mercapto - 1,4 - dimethyl - 7 - benzimidazolyloxy) 2 - propanol is manufactured.

58. A process according to claim 31 or claim 35, wherein 1 - (diethylamino) - 3 - (2 - mercapto - 4 - benzimidazolyloxy) - 2 - propanol is manufactured.

59. A process according to claim 31, wherein a hydrohalide salt of a compound named in any one of claims 43 to 58 is manufactured.

60. A process according to claim 31, wherein a hydrochloride salt of a compound named in any one of claims 43 to 58 is manufactured.

61. A process according to any one of claims 31 to 60, wherein a compound of formula III is prepared and then reacted in situ with a compound of formula IV.

62. A process according to any one of claims 31 to 61, wherein a compound of formula III is reacted with a compound of formula IV under acidic conditions and, where required, the resulting acid addition salt of a compound of formula I is converted into a free base of formula I.

63. A process according to any one of claims 31 to 54, wherein the epoxide of formula V is prepared and the reacted in situ with an amine of formula VI.

64. A process for the manufacture of the benzimidazole derivatives set forth in claim 1, substantially as hereinbefore described with reference to any one of Examples I to 18.

65. Benzimidazole derivatives as set forth in claim 1, when manufactured by the process claimed in any one of claims 31 to 63 inclusive or by an obvious chemical equivalent thereof.

66. A pharmaceutical preparation containing a compound of formula I given in claim I, a thiol tautomer of a compound of formula I in which Y represents a sulphur atom or a pharmaceutically acceptable acid addition salt thereof in association with a compatible pharmaceutical carrier material.