NO781556L - BENZIMIDAZOLE DERIVATIVES. - Google Patents

Description

Benzimidazole derivatives

The present invention relates to benzimidazole derivatives. More specifically, the invention relates to benzimidazole derivatives, a method for their production and pharmaceutical preparations containing them.

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

Where R represents a hydrogen atom or a lower alkyl group, R"*" represents a hydrogen atom or

' 2 a lower alkyl or lower cycloalkyl group, R represents a lower alkyl or lower cycloalkyl

3

group, R represents a hydrogen atom or a primary or secondary lower alkyl group Y represents an oxygen or sulfur atom,

and pharmaceutically acceptable acid addition salts thereof.

As used herein in the specification, the term "lower alkyl" means a straight or branched alkyl group preferably containing from 1 to 6 carbon atoms (e.g. methyl, ethyl,

n-propyl, isopropyl, n-butyl, sec.butyl, tert.butyl and the like). The term "lower cycloalkyl" means a cycloalkyl-

group which preferably contains from 3 to 8 carbon atoms (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like).

The benzimidazole derivatives with formula 1 above where Y represents a sulfur atom exist mainly in their tautomeric form with the general formula

12 3

wherein R, R , R and R have the meanings previously indicated.

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 such benzimidazole derivatives where R"<*>" represents a hydrogen atom, especially those where R<2>represents a lower alkyl group and especially a branched-chain lower alkyl group such as isopropyl or tert.butyl- the group.

Special benzimidazole derivatives which are provided by the present invention are those where Y represents an oxygen atom, R and R represent a hydrogen atom and R and R have the previously stated meaning, i.e. compound with the general formula 12 ' Where R and R has the aforesaid meaning.

Particular benzimidazole derivatives are those of formula Ia where R 1 represents a hydrogen atom and R 2 represents a lower cycloalkyl group or R 1 and R 2 each separately represent a lower alkyl or lower cycloalkyl group.

A further special class of benzimidazole derivatives provided by the present invention are those where Y represents an oxygen atom, R represents one lower

12 3

alkyl group and R , R and R have the previously stated meaning, i.e. compounds with the general formula

1 2 where R 1 represents a lower alkyl group and R , R and R 3 have previously indicated meanings. Another special class of benzimidazole derivatives provided by the present invention are those where Y represents a sulfur atom, R"*" represents a hydrogen atom 2 or a lower alkyl group, R represents one lower alkyl group and R and R 3 have the previously stated meaning, i.e. connect else with the general formula

Where R represents a hydrogen atom or a lower alkyl group, R 2' represents a lower alkyl group and R and R 3 have previously indicated meaning, 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-(dicyclo<p>entylamino)-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)<p>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,

1-(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 its hydrogen halides, especially the hydrochlorides.

According to the method provided by the present invention, the aforementioned benziminazole derivatives (i.e. compound of formula I above and their pharmaceutically acceptable acid addition salts) are prepared by a method comprising

a) reaction of a compound with the general formula

12 3 where R, R , R' and R have previously indicated meanings, with a compound of the general formula

where Z represents a chlorine atom or an amino group and Y has the previously stated meaning,

or

b) Compound of formula I in which Y represents an oxygen-12 3

atom and R, R , R and R have previously indicated meaning, is produced by reaction of epoxide with the general formula

3 where R and R have previously indicated meaning, with an amine of the general formula

12

where R and R have previously stated meaning,

or

c) resolution of a racemic compound of formula I in the optical isomers, and if desired to a compound obtained

of formula I in a pharmaceutically acceptable acid addition salt.

The reaction of the compound of formula III with phosgene or thiophosgene, i.e. one compound of formula IV where Z represents a chlorine atom, can be carried out according to methods known per se.

In a preferred embodiment, the reaction is carried out under acidic conditions. E.g. in connection with formula III, an aqueous mineral acid such as aqueous hydrohalic acid (e.g. aqueous hydrochloric acid) can be dissolved and treated with phosgene or thiophosgene, preferably in excess, which gives the corresponding acid addition salt of a compound of formula I which can is transferred to 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 an 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 where 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 presence of an inert organic solvent by fusing the reactants together under an 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 e.g. hydrocarbons, especially aromatic hydrocarbons such as benzene, toluene and the like, lower alkanols such as methanol, ethanol and the like, etc. When an inert organic solvent is used, the reaction is advantageously carried out at a higher temperature and at atmospheric pressure.

The starting materials of formula III are relatively unstable and, in a preferred embodiment of the present invention, they are reacted in situ (ie without processing or purification) with the compounds of formula IV.

The reaction of an epoxide of formula V with an amine of formula VI according to embodiment and form (b) of the method can be carried out

r presence or absence of an inert organic solvent.

When an inert organic solvent is used, this can e.g. be a lower alcohol such as methanol, ethanol or the like. Alternatively, an excess of an amine of formula VI may be used

and can thereby also serve as a solvent. The reaction is preferably carried out at a temperature from approx. 0°C to room temperature and under atmospheric pressure. Epoxides of formula V are relatively unstable and, in a preferred aspect of this embodiment, are reacted in situ (ie without workup or purification) with an amine of formula VI.

It will be clear that compound of formula I above contains an asymmetric carbon atom and may exist in racemic or optically active forms. The present invention includes the racemates as well as the optically active forms. A racemate can, if desired, be dissolved into the optical isomers according to methods known per se, e.g. by fractional crystallization of formed salts with optically active acids.

The compounds of formula I can be transferred into pharmaceutically acceptable acid addition salts and treatment with pharmaceutically acceptable organic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid etc.) and with pharmaceutically acceptable organic acids (e.g. acetic acid, tartaric acid, citric acid) , fumaric acid, maleic acid, malic acid, methanesulfonic acid, paratoluenesulfonic acid, etc.).

The starting materials of formula III above can be prepared, e.g.

2 3

according to the following formula nucleus A where R, R , R and R have the previously indicated meanings, R represents a hydrogen atom or the benzyl group and a lower alkyl or lower cycloalkyl group and R 30 represents a primary or secondary lower alkyl- group:

In step (i) in the preceding formula core A, a compound of formula VII is transferred into an epoxide of formula VIII by reaction with epihalohydrin, preferably epichlorohydrin. The reaction is preferably carried out in the presence of piperidine at a higher temperature (eg approx. 80°C) and the product obtained is then 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 dioxane. 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 suitably carried out in the presence of a water-miscible inert organic solvent such as a lower alkanol (e.g. methanol, ethanol or the like) at a temperature from approx. 0°C to room temperature, preferably around room temperature.

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

2 10

where R and R have the previously stated meanings •

to give a compound of formula IX. This reaction is carried out in the presence of an inert organic solvent, preferably a lower alkanol such as methanol, ethanol or the like. The reaction can be carried out at room temperature or at a higher temperature (e.g. a temperature up to reaction mix-

same boiling point). In certain circumstances, it may be advantageous to use an acid addition salt of an amine salt of formula XI (eg a hydrogen halide such as the hydrochloride) in this step and carry out the reaction in the presence of a suitable inorganic base (eg an alkali metal -carbonate such as potassium carbonate).

In step (iii) of formula A, a compound is hydrogenated

of formula IX to give a starting material of formula III wherein R"^ represents a hydrogen atom and where, when R"<*>"^ 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 (eg a palladium or platinum catalyst such as palladium-on-charcoal or platinum oxide), although other conventional hydrogenation catalysts such as Raney nickel, Raney cobalt and the like can also be used. the 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, ethanol or the like) and at room temperature and atmospheric pressure. According to a preferred method step (iii) is carried out in situ, i.e. without isolating a compound of formula IX from the medium in which it is produced.

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

In connection with formula X is then hydrogenated in step (v) in formula scheme A which gives a starting material of formula (III where R 3 represents a primary or secondary lower alkyl group and where, when R in the connection with formula X represents the benzyl 1 group, represents R"^ a hydrogen atom. The hydrogenation can be carried out essentially in the same way as described earlier in connection with the hydrogenation of a compound of formula IX.

When it is desired to produce starting material with formula III

1 2

where R represents a hydrogen atom and R represents a primary or secondary lower alkyl group, it is preferred to proceed via a corresponding compound of formula IX where represents the bensy1 group.

Preferred starting materials of formula III are those where R represents a lower alkyl group, especially the methyl group. Further preferred are such starting materials with formula III where R 1 represents a hydrogen atom, especially those where R<2> represents a lower alkyl group and especially a branched-chain lower alkyl group such as the isopropyl or tert-butyl group.

Special starting materials of formula III are those where R^ represents a hydrogen atom and R<2> represents a lower 1 2 cycloalkyl group or R and R each represent a lower alkyl or lower cycloalkyl group.

The epoxy starting materials with formula V above can be prepared, e.g. according to formula form B in the following where R and R<3> have the previously stated meanings.:

In formula B in step (i), a 2-methoxy-6-nitroaniline of formula XI is reduced to an o-diamine of formula XII. Reduce-

tion is often carried out using hydrogen in the presence of a noble metal catalyst (e.g. a palladium, platinum or rhodium catalyst such as palladium-on-tar coal, platinum oxide, rhodium-on-carbon or rhodium-alumina) although other conventional hydrogenation catalysts such as Raney nickel, Raney cobalt and the like can also be used. A palladium catalyst, especially palladium-on-charcoal, is preferably used. This catalytic hydrogenation is preferably carried out in the presence of an inert organic solvent (e.g. a lower alkanol such as methanol ethanol etc). It is preferred to carry out the catalytic hydrogenation at room temperature and atmospheric pressure.

In step (ii) in formula B, o-diamine is reacted with formula

XII with phosgene giving a 4-methoxy-2-benzimidazolinone

with formula XIII and the reaction is essentially carried out under the same conditions as described above in connection with the reaction of a diamine of formula II with phosgene. As o-diamines of formula XII are relatively unstable, they are preferably reacted in situ (ie without work-up or purification) with phosgene.

Step (iii) in formula scheme B' includes the transfer of the methoxy group in a 4-methoxy-2-benzimidazolinone of formula XIII to a hydroxy group whereby a corresponding 4-hydroxy-2-benzimidazolinone of formula XIV is obtained where R 3 represents a hydrogen -atom. This transfer is carried out according to methods known per se, e.g. by treatment with hydrogen bromide in acetic acid at a higher temperature (e.g. 80°C).

An alternative route to 4-hydroxy-2-benzimidazolinone of formula XIV consists of steps (iv), (v), (vi), (vii) and (viii) of Formula Scheme B.

In step (iv) a 3-nitrophenol of formula XV is nitrated in a manner known per se as by treatment with nitric acid in the presence

of sulfuric acid which gives the corresponding 2,3-dinitrophenol of formula XVI.

A 2,3-dinitrophenol of formula XVI is then reduced in step (v) which gives the corresponding o-diamine of formula XVII where

represents a hydrogen atom. This reduction is mainly carried out in the same way as previously described in connection with the reduction of et.2-methoxy-6-nitroaniline with the formula

XI.

Step (vi) in formula scheme B comprises the reaction of a 2,3-dinitrophenol of formula XVI with a primary or secondary lower alkylamine (eg methylamine, ethylamine, isopropylamine or the like) which gives a compound of formula XVIII. This reaction is usually carried out in the presence of an inert organic solvent, preferably a lower alkanol such as methanol, ethanol or the like. It is preferred to carry out this reaction at a higher temperature and atmospheric pressure.

A compound of formula XVIII is then hydrogenated in step (vii) of formula B which gives an o-diamine of formula XIV where R represents a primary or secondary lower alkyl group. The hydrogenation can be carried out in essentially the same way as previously described in connection with the hydrogenation of a compound of formula IX.

In step (viii), an o-diamine of formula XVII is reacted with phosgene, which gives the corresponding 4-hydroxy-2-benzimidazolinone of formula XIV. This reaction is carried out under essentially the same conditions as previously described in connection with the reaction of a diamine of formula II with phosgene. Furthermore, o-diamines of formula XVII are relatively unstable and are preferably reacted in situ (ie without work-up or purification) with phosgene.

A 4-hydroxy-2-benzimidazolinone of formula XIV which is obtained according to each of the aforementioned routes is transferred in step (ix) of formula scheme B into the desired epoxide starting material of formula V by reaction with an epihalohydride, preferably epichlorohydrin, in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. The reaction is preferably carried out in the presence of a water

miscible inert organic solvent such as a lower alkanol

(e.g. methanol, ethanol etc.) at a temperature from about 0 C to room temperature, preferably at about room temperature.

The amine starting material of formula IV above is known. Preferred amine starting materials of formula IV are those where R represents a hydrogen atom, especially those where R 3 represents a lower alkyl group and especially a branched lower alkyl group such as the isopropyl or tert.butyl group. Further preferred are such amine starting materials where R"^

2

represents a hydrogen atom, R represents a lower

12

cycloalkyl group or R and R each represent a lower alkyl or lower cycloalkyl group: The compounds of formulas V, VIII, IX, X, XIII and XIV above and the compounds of formula III above where R represents -12 3

represents a lower alkyl group and R , R and R have previously indicated meaning or R represents a hydrogen atom and R represents a lower alkyl group or lower cyclo-2 3

alkyl group and R and R have previously indicated meaning, are new and these compounds also form a component of the present invention.

The benzimidazole derivatives according to the present invention have (3-adrenoceptor blocking activity which, in such derivatives where R represents a lower alkyl group, is generally followed by low internal stimulating activity (ISA). The present benzimidazole derivatives can therefore be used for prophylaxis and treatment of diseases of the heart such as angina pectoris and cardiac arrhythmia.It can also be used as anti-hypertensive agents.

The 3-adrenoceptor blocking action of the present benzimidazole derivatives can be demonstrated by standard methods. The 3-adrenoceptor blocking activity in vitro is demonstrated using reserpinized kitten hearts according to the method described by Kaumann and Birnbaumer, J. Biol. Chem., 249 7874-7885, 1974. The results are expressed as I5Q values, namely the concentration in moles of substance being tested

required to inhibit by 50% the isoprenaline-stimulated

increase in adenylyl cyclase activity in the heart. The 3-adreno-

ceptor-blocking activity in vitro is demonstrated in mice by determining the dosage in mg/kg i.p. of substance being tested

which is necessary to give a 50% reduction in isoprenaline-dosed tachycardin, where this dosage is extracted as ED^q.

The test for ISA is performed using male rats that have had peripheral catecholamine stores depleted by treatment with res-erpine (5 mg/kg i.p.) according to the method described by Barrett and Carter, Br. J.Pharmac., 1970, 4_0, 373-381. The results are expressed as ED^g, namely the dosage of substance tested in mg/kg i.v. which gives an increase in the heart rate of 30 beats per my.

The results obtained in the preceding test using representative benzimidazole derivatives provided by the present invention and propanolol and pindolol, two well-known 3-adreOceptor blocking agents, are listed in the following tables:

Table II

ISA

Test substance - 3-blocking activity

T50 ( mol) ED- 50 ( mg/ kg i. p.) mg^ gi. v.)

4-[3-(tert.butyl-

amino) -2-hydroxy-

propoxy ]-7-methyl-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

Test substance 3-blocking activity ISA

I5Q( mol) ED5Q( mg/ kg i. p. ) ^ 30,^ . >v>)

1-(tert.butylamino)-

3-(2-mercapt.o-7-

methyl-4-benzimi-

dazolyloxy)-2-pro-

panol hydrochloride 1.8 x 10~<9>.0.01 >1.Q

propanolol 36 x 10~9 0 .29 -> 1.0

pindolol 5.2' x 10~ 9 0.01 0.005

It also appears that the pharmacological data for propanolol and pindolol are not identical in all three tables above. This is caused by the fact that the experiments were performed in different series.

The toxicity of the present benzimidazole derivatives is low, and the LDj-q generally does not exceed more than 200 mg/kg when administered orally to mice.

The benzimidazole derivatives provided by the present invention can be used as drugs, e.g. in the form of

pharmaceutical preparations containing them together with a tolerable pharmaceutical carrier. This carrier material can be an inert organic or inorganic carrier material which is suitable for enteral (eg oral) or parenteral administration. Examples of such carrier materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene glycols, petroleum "jelly" and the like. The pharmaceutical preparations can be prepared in a conventional manner and final dosage forms can be solid dosage forms (e.g. tablets, dragees, suppositories, capsules, etc.) or liquid dosage forms (e.g. solutions, suspensions, emulsions, etc.). The pharmaceutical preparations may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional auxiliary substances such as preservatives, stabilisers, wetting agents, buffers, salts for variation of osmotic pressure etc.

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

The following examples illustrate the method provided by the present invention. The term "(DSC)" used in the examples in connection with 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 was hydrogenated at room temperature and atmospheric pressure over 2.5 g of 10% palladium-on-carbon until hydrogen uptake stopped. 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 remaining. removed by a rapid stream of nitrogen and the precipitate collected, washed with water and crystallized from ethanol to give 7.7 g (79%) of 4-methoxy-2-benzimidazolinone mp 257°-259°C. Analysis for CgHgO2N2Calculated: 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) was heated at 80°C in a sealed tube for 20 hours. The resulting solution was evaporated to dryness in vacuo and the residue recrystallized from ethanol/chloroform which gave 10.95 g (60%). 4-hydroxy-2-benzimidazolinone with melting point 285°-287°C.

Analysis for C^HgC^^

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-dinitroph enol in 50 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 4 g of 10% palladium-on-carbon until hydrogen uptake 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 min. The precipitate formed was filtered off and recrystallized from ethanol/chloroform to give 4.8 g of 4-hydroxy-2-benzimidazolinone which, according to infrared, nuclear magnetic resonance and mass spectroscopic analysis, was identical to the compound obtained as described in part ( i) before.

(B) 4-[ 2- hydroxy- 3-( isopropylamino) propoxy]- 2- benzimidazolinone

A solution of 1.175 g (0.0294 mol) of sodium hydroxide in 16 ml of water was added to a solution of 4 g (0.0265 mol) of 4-hydroxy-2-benzimidazolinone in 24 ml of methanol. 4.16 g (0.045 mol) of epichlorohydrin was then added and the resulting solution was allowed to stand at room temperature for 17 hours. The bulk of the methanol was removed by evaporation in vacuo and the residue was extracted with ethyl acetate. The organic extracts were washed with water and evaporated to dryness in vacuo at room temperature to give 2.5 g of the epoxide, 4-(2,3-epoxypropoxy)-2-benzimidazolinone, which was immediately treated with an excess of isopropylamine (25 mL) . The mixture was allowed to stand at room temperature for 48 hours. The solution was evaporated to dryness in vacuo and the residue chromatographed on 250 g of silica gel in ethanol/triethylamine/isopropylamine/chloroform (100:40:1:259) which gave 0.19 g (2.7%) of 4-[-hydroxy -3-(isopropylamino)propoxy]-2-benzimidazolinone in the form of an oil. Treatment of this oil with ethanolic hydrochloric acid gave 4-(2-hydroxy-3-(isopropylamino)propoxy)-2-benzimidazolinone hydrochloride which was recrystallized from isopropanol/diethyl ether and which, according to infrared and mass spectroscopic analysis, was identical to the product obtained according to example 2 (B) below.

example 2

(A) 2,3-dinitrophenyl 2,3-epoxypropyl ether

30 g of 2,3-dinitrophenol, 90 g of epichlorohydrin and 2.5 ml of piperidine were heated at 80°C for 17.5 hours. The solution was evaporated to dryness in vacuo until the oil solidified. 90 ml of 2-N sodium hydroxide solution was then added to a vigorously stirred solution of the solid in 60 ml of dioxane and the resulting solution was stirred at room temperature for one hour. The precipitate was collected, washed well with water and dried in vacuum at 60°C.

35.0 g (89%) of crude 2,3-dinitrophenyl 2,3-epoxypropyl ether with melting point 86°-89°C was obtained 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 m.p. 95°-97°C.

Analysis for CgHg06N2

Calculated: C: 4 5.0; H: 3.4; N: 11.7%.

Found: C: 44.6; H: 3.3; N: 11.4%.

(B 4-[2-hydroxy-3-(-isopropylamino)propoxy]-2-benzimidazolinone hydrochloride 20 g (0.083 mol) of 2,3-dinitrophenyl 2,3-epoxypropyl ether was dissolved in 500 ml of hot ethanol and the solution was decanted from a small amount of insoluble residue. 18.4 g (0.123 mol) N-isopropylbenzylamine was added and the solution was heated at 50° C. for 16 hours. The cooled solution was hydrogenated at room temperature and atmospheric pressure above 7 g 10% palladium-on-carbon catalyst until hydrogen uptake ceased.The solution was filtered and the filtrate evaporated to dryness in vacuo to give the diamine, 3-(2,3-diaminophenoxy)-1-(isopropylamino)-2-propanol, found m/e 239,<c>i2H21°2<N>3 requires M'239^ which was immediately dissolved in 100 ml of 2-N hydrochloric acid.The solution was cooled to 0°C and stirred while a stream of phosgene was blown through for 45 min .The excess phosgene was removed by blowing through a strong stream of nitrogen into the solution which was then evaporated to dryness in vacuo.The residue was recrystallized from isopr opanol/diethyl ether yielding 11.27 g (45%) of 4-[2-hydroxy-3-(isopropylamino)propoxy]-2-benz imidazolinone hydrochloride with melting point (DSC) 232°C.

Analysis for C]_3Hi9°3N3-HCl

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- be. nzimidazolinone hydrochloride

20 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 400 ul of ethanol as described in example 2(B). 100 ml tart. butylamine was added and the solution was allowed to stand at room temperature for 18 hours. Evaporation of the solution in vacuo and crystallization of the residue from isopropanol gave 17.2 g (66%) of 1-(tert.butylamino)-3-(2,3-dinitrophenoxy)-2-propanol with melting point. 120°-122°C. |

t

Analysis for C]_3Hi9°gN3

Calculated: C: 49.8; H: 6.1; N: 13.4%.

Found: C: 49/9; H: 6.0; N: 13.5

5.1 g of 1-(tert.butylamino)-3-(2,3-dinitrophenoxy)-2-propanol in 100 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 2.5 g of 10% palladium-on-carbon catalyst until hydrogen uptake ceased. The solution was filtered, and the filtrate evaporated in vacuo and the residue, 1-(tert.butylamino)-3-(2,3-diamino-phenoxy)-2-propanol immediately dissolved in 50 ml of 2-N hydrochloric acid. The solution was cooled to 0°C and a slow stream of phosgene was blown through for 45 min. The excess phosgene was removed using a stream of nitrogen. The solution was evaporated to dryness in vacuo and the residue recrystallized from isopropanol/diethyl ether yielding 2.9 g (56.3%) of 4-[3-(tert.butylamino)-2-hydroxypropoxy]-2-benzimidazolinone hydrochloride with melting point (DSC) 263°C.

Analysis for C]_4H2i°3N3-HC1

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- benzimide. zolinone hydrochloride 10 g (0.042 mol) of 2,3-dinitrophenyl 2,3-epoxypropyl ether was dissolved in 250 ml of hot ethanol as described in example 2 (B). 7.56 g (0.0625 mol) of N-methylbenzylamine was added and the solution was allowed to stand at room temperature for 70 hours. The solution was then hydrogenated over 10% palladium-on-carbon as described in Example 2 (B) and the resulting diamine, 3-(.2,3-diaminophenoxy)--1-(methylamino)-2-propanol was immediately. reacted, in 100 ml of 2-N hydrochloric acid with phosgene likewise in the same way as described in example 2 (B). - The product was recrystallized from ethanol/diethyl ether which gave 5.36 g (47%) of 4-[2-hydroxy-3-(methylamino)-propoxy]-2-benzimidazolinone hydrochloride with melting point 218°-220° C.

Analysis for ci_]_<H>]_5°3<N>3-<H>C1

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 was dissolved in 250 ml of hot ethanol , as described in Example 2(B).

5.18 g (0.046 mol) of N-methylcyclohexylamine was added and the solution was allowed to stand at room temperature for 36 hours. The solution was then hydrogenated over 10% palladium-on-carbon as described in Example 2(B) giving 3-(2,3-diaminophenoxy)-1-(N-methylcyclohexylamino)-2-propanol which was immediately reacted in 100 ml. 2-N hydrochloric acid with phosgene, also in the same way as described in example 2(B). Recrystallization of the residue from isopropanol/diethyl ether gave 7.44 g (49%) of 4-[2-hydroxy-3-(N-methylcyclohexylamino)propoxy]-2-benzimidazolinone hydrochloride hemihydrate with melting point (DSC) higher than 288°C (decomposition point).

Analysis for<c>i7<H>25°3<N>3-<H>C1-°"5H2°

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- hemihydrate

8.5 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 250 ml of hot ethanol as 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 60°C 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 crystallized from chloroform/n-hexane which gave 6.2 g of 1-(dicyclopentylamino)-3-(2,3-dinitrophenoxy)-2-propanol with melting point 130°-133°C.

Analysis for<C>]_9<H>27<N>3°6

Calculated: C: 58.0; H: 6.9; N: 10.7%J M<+>393. j Found: , C: 57.9; H: 7.0; N: 10.6%; w/3 393.

5.05 g of 1-(dicyclo<p>entylamino)-3-(2,3-dinitropephenoxy)-2-propanol in 100 ml of ethanol were hydrogenated at room temperature and

atmospheric pressure above 2.0 g 10% palladium-on-carbon up to . hydrogen uptake ceased. The mixture was filtered and the filtrate evaporated in vacuo to give 3-(2,3-diaminophenoxy)-1-(dicyclopentylamino)-2-propanol 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 45 min., the excess phosgene was removed by means of a stream of nitrogen. The solution was evaporated to dryness in vacuo and the residue crystallized from isopropanol/diethyl ether, whereby 4.25 g (69.5%) of 4-[3-(diclyclopentylamino)-2-hydroxypropoxyJ-2-benzimidazolinone hydrochloride hemihydrate was obtained with melting point (DSC) higher than 308°C (decomposition point).

Analysis for C2QH2gN3O3.HC1.O5H20

Calculated: C: 5 9.3; 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 was dissolved in 100 ml of hot ethanol as described in example 2(B). The solution was treated with 6.1 g of diethylamine and the resulting solution was allowed 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 1 g of 10% palladium-on-carbon until hydrogen absorption ceased. The mixture was filtered and the filtrate evaporated in vacuo to give 3-(2,3-diamino-phenoxy)-1-(diethylamino)-2-pro<p>anol which immediately became. dissolved in 30 ml of 2-N hydrochloric acid, cooled to 0°C and treated with a slow stream of phosgene for 40 min, the excess phosgene was removed by means of a stream of nitrogen. Filtration of the solution, evaporation of the filtrate to dryness in vacuo<p>g recrystallization of the residue from ethanol/diethyl ether gave 2.6 g (49 4-[3-(diethyl-amino)-2-hydroxypropoxy]-2- benzimidazolinone hydrochloride with

melting point (DSC) 247°C.

Analysis for<c>i4<H>2i°3N3•HC1

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-hydroxypropoxy3-2-benzimidazolinone hydrochloride 5 g (0.021 mol) 2,3-dinitrophenyl 2,3-epoxypropyl ether were dissolved in 100 ml of hot ethanol as described in example 2 (B). The solution was cooled, treated with 12.25 g (0.124 mol) cyclohexylamino and allowed 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 hydrogen absorption 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 0°C and treated with a slow stream of phosgene for 45 min. as the excess phosgene was removed by means of a stream of nitrogen. Filtration, evaporation of the filtrate to dryness in vacuo and recrystallization of the residue from ethanol/diethyl ether gave 1.7 g (23.9%) of 4-[3-(cyclohexylamino)-2-hydroxypropoxy]-2-benzimidazolinone- hydrochloride with melting point (DSC) 224°C.

Analysis for C,,H0,0oNo.HC1

16 2 3 3 3

Calculated: C: 56.2; H: 7.1; N: 12.3; Cl: 10.4%.

Found: C: 55.9; H: 7.2; N: 11.9; Cl: 10.2%.

Example 9

4-[ 3-( cyclohexylamino)- 2- hydroxypropoxy]- 2- benzimidazolinone hydrochloride

5 g of 2,3-dinitrophenyl 2,3-epoxypropyl ether in ethanol was treated with 4.3 g of N-benzylcyclohexylamine and the solution was heated at 80°C for 48 hours. The solution was then hydrogenated as described in example 8 and the hydrogenation product was reacted with phosgene and worked up as described in example 8. im2id,a7 zog li(n3o7n,-5<%>)

hydrochloride which was shown by mass spectroscopic analysis to be identical to the product prepared as described in example 8.

Example 10

4- 1 2- hydroxy- 3-( n- propylamino) propoxy]- 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 allowed to stand at room temperature for 90 hours. The mixture was then hydrogenated as described in example 2(B) and the product, 3-(2,3-diaminophenoxy)-1-(n-propylamino)-2-propanol, immediately reacted with phosgene also as described in example 2(B) . The product obtained was recrystallized from ethanol/isopropanol which gave 3.4 g (64.5%) of 4-[2-hydroxy-3-(n-propylamino)propoxyj-2-benzimidazolinone hydrochloride with melting point 264°-267 °C.

Analysis for ci3Hi9°3<N>3-<H>Cl

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- epoxypropoxy)- 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 80°C for 20 hours. The solution was evaporated to dryness in vacuo and the residue dissolved in 60 ml of dioxane. To the vigorously stirred solution was added 90 ml of 2-N sodium hydroxide and the resulting solution was stirred for an additional 1 hour. The product was collected, washed well with water and air dried, whereby 40.2 g of 4-(2,3-epoxypropoxy)-2,3-dinitrotoluene with a melting point of 118°-120°C was obtained. A recrystallized sample from ethanol melted at 123°-125°C.

Analysis for c^oH10°6N2

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-dinitro-p-tolyloxy)-2-propanol 20 g 4-(2,3-epoxypropoxy)-2,3-dinitrotoluene. in 750 ml of ethanol was reacted with 100 ml. 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, which gave 22.6 g of 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol with a melting point of 117 °-119°C.

Analysis for C]_4H21^6<N>3

Calculated: C: 51.4; H: 6.45; N: 12.85%.

Found: C:.51,l;. H: 6.45; N: 12.8%.

( C) 4-[ 3-( tert. butylamino)- 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 was hydrogenated at room temperature and

atmospheric pressure above 1.5 g 10% palladiuro-on-carbon until hydrogen uptake ceased. The mixture was filtered and the filtrate evaporated to dryness yielding the unstable o-diamine, l-(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. A slow stream of phosgene was passed through the solution for 1 hour and the phosgene was then replaced with nitrogen and the solution was finally evaporated to dryness in vacuo. The solid residue was recrystallized from methanol/isopropanol to give 2.9 g 4-[3-(tert.butylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone hydrochloride with melting point 310°-312°C.

Analysis for ci5H23°3N3 ,H(~1

Calculated: C: 54.6; H: 7.35; N: 12.75; Cl: 10.75%.

Found: C: 54.5; H: 7.25; N: 12.9; D1: 10.6%'.

(b) 4.0 g of 1-(tert.butylamino)-3-(2,3-diamino-p-tolyloxy)-2-propanol was heated with 20 g of urea at 140°C 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. They combined

the ethyl acetate extracts were washed with 50 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 recrystallized from methanol/isopropanol to give 1.4 g of 4-[3-(tert.butylamino)-2-hydroxypropoxyj-

7-methyl-2-benzimidazolinone hydrochloride with 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 was treated with 4.55 g of N- benzylcyclopentylamine and the solution was heated at 60°C for 24 hours. The solution was evaporated to dryness in vacuo to give 1-(N-benzylcyclopentylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol which was dissolved in 150 ml of ethanol and hydrogenated in the presence of 1.5 g 10% palladium-on-carbon at room temperature and atmospheric pressure until hydrogen absorption. up-heard. Filtration and evaporation of the filtrate under reduced pressure gave a I-(cyclopentylamino)-3-(2,3-diamino-p-tolyloxy)-2-propanol which was treated with phosgene as described in Example 11(C) (a) which gave, after crystallization from ethanol containing a trace methanol, 4.8 g of 4-[3-(cyclopentylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone, m.p. 265°-266°C.

Example 13

(A) 1-(dicyclopentylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol

10 g of 4-(2,3-epoxypropoxy)-2,3-dinitrotoluene. in 150 ml of ethanol was treated with 9.05 g of dicyclopentylamine hydrochloride and 18 g of anhydrous potassium carbonate and the mixture was heated at 60°C

for 30 hours. The mixture was then evaporated to dryness. In vacuo 50 ml of water was 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;

night and evaporated to dryness in vacuo. Restem was recrystallized

separated from ethyl acetate and gave 5.9 g of 1-(dicyclopentylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol with melting point 119°-122°C.

Analysis for C2oH29°6N3

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-benz imidazolinone hydrochloride

5.4 g of 1-(dicyclopentylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol in 200 ml of ethanol was hydrogenated in the presence of 1.0 g of palladium-on-carbon at room temperature and atmospheric pressure. until hydrogen absorption had ceased. The solution was filtered and the filtrate evaporated to dryness in vacuo to give the unstable o-diamine 1-(dicyclopentylamino)-3-(2,3-diamino-p-tolyloxy)-2-propanol

which was immediately taken up in 2-N hydrochloric acid and reacted with phosgene as described in example 1(C) (a). The product was recrystallized from isopropanol which gave 1.8 g of 4-[3-(dicyclopentylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone hydrochloride with melting point 274°-276°C.

Example 14

7-[ 3-( tert. butylamino)- 2- hydroxypropoxy]- 1, 4- dimethyl- 2- benzimidazolinone hydrochloride

5.3 g of 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloxy)-2-propanol in 100 ml of ethanol was treated with 30 ml of a 33% solution of methylamine in ethanol and the resulting solution was heated at 50°C for 48 hours. The solution was then evaporated to dryness in vacuo to give 1-(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 1

10% palladium-on-carbon at room temperature and atmospheric pressure until hydrogen uptake had ceased. The mixture was filtered and the filtrate was evaporated to dryness in vacuo to give the unstable 1-(tert.butylamino)-3-(3-amino-2-methylamino-

in p-tolyloxy)-2-propanol which was taken up in 50 ml of 2-N hydrochloric acid j

and reacted with phosgene for 8 hours as described in example 11(C) (a). After recrystallization from ethanol containing traces of methanol, 1.8 g of 7-[3-(tert.butylamino)-2-hydroxypropoxy]-1,4-dimethyl-2-benzimidazolinone hydrochloride with melting point 290°-291° was obtained C. Example 15 1-(tert.butylamino)-3-(2-mercapto-7-methylbenzimidazolyloxy)-2-propanol hydrochloride 5 g 1-(tert.butylamino)-3-(2,3-dinitro-p -tolyloxy)-2-propanol in 100 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 1.5 g of 10% palladium-on-carbon until hydrogen uptake had ceased. The mixture was filtered and the filtrate 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 was added to the solution and the resulting mixture stirred vigorously under nitrogen at room temperature for 4 hours. The mixture was evaporated to dryness in vacuo and the residue was recrystallized from isopropanol to give 3.05 g of 1-(tert.butylamino)-3-(2-mercapto-7-methyl-benzimidazolyloxy)-2-propanol hydrochloride as pale -yellow crystals with melting point 203°-205°C (decomposition).

Analysis for C-^302N3S . 1.33HC1

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 was dissolved in 400 ml of hot ethanol and the solution was decanted from a small amount of insoluble residue. 100 ml of tert-butylamine was added and the solution was allowed to stand at room temperature for 18 hours. In-

evaporation of the solution in vacuo and crystallization of the residue

from isopropanol gave 17.2 g (66%) of 1-(tert.butylamino)-3-(2,3-dinitrophenoxy)-2-propanol with melting point 120O<->122°C.

Analysis for ci3H^9°6N3

Calculated: C: 49.8; H: 6.1; N: 13.4%.

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

10 g of 1-(tert.butylamino)-3-(2,3-dinitrophenoxy)-2-propanol in 150 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 4 g of 10% palladium-on-carbon catalyst until hydrogen absorption ceased. The solution was filtered, the filtrate was evaporated in vacuo and the residue, 1-(tert.butylamino)

-3-(2,3-diaminophenoxy)-r2-propanol was instantly dissolved

in 50 ml of 2-N hydrochloric acid. 10 ml of thiophosgene was 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 recrystallized from isopropanol to give 3.8 g of 1-(tert.butylamino)-3-(2-mercapto-4-benzimidazolyloxy)-2-propanol hydrochloride in the form of pale yellow crystals with melting point 145°-150°C (decomposition).

Analysis for c14<H>2i<0>2<N>3<S>'<1,>33HC1

Calculated: C: 48.9;. H: 6.55; N: 12.2; S: 9.35%.

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

Example 17

1-( tert. butylamino)- 3-( 2- mercaptol- 4- dimethyl- 7- benzimidazolyloxy)- 2- propanol- hydrochloride

4.75 g of 1-(tert.butylamino)-3-(2,3-dinitro-p-tolyloxy)-2--propanol in 100 ml of ethanol was treated with 25 ml of a 33% solution of methylamine in ethanol and the resulting solution

ning was heated at 50°C for 14 hours. The solution was then evaporated to dryness in vacuo giving 1-(tert.butylamino)-3-(2-methylamino-3-nitro-p-tolyloxy)-2-propanol in the form of an orange oil which was dissolved in 100 ml ethanol and hydrogenated

in the presence of a 10% palladium-on-carbon at room temp

and atmospheric pressure until hydrogen absorption ceased. Blahd-j

none was filtered and the filtrate was evaporated to dryness i

vacuum which gave the unstable 1-(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 vigorously stirred under nitrogen at room temperature for 2 hours and then evaporated to dryness in vacuo. The residue was recrystallized from isopropanol which gave 3.29 g of 1-(tert.butylamino)-3-(2-mercapto-1,4-dimethyl-7-benzimidazolyloxy)-2-propanol hydrochloride in the form of orange crystals with melting point 184°-185°C (decomposition).

Example 18

1-(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 amount of insoluble residue. The solution was treated with 11.2 g of diethylamine. and the resulting solution was allowed 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 hydrogen uptake ceased. The mixture was filtered and the filtrate was evaporated in vacuo to give 3-(2,3-diaminophenoxy)-1-(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 recrystallized from ethanol/isopropanol to give 1.8 g of 1-(diethylamino)-3-(2-mercapto-4-benzimidazolyloxy)-2-propanol hydrochloride as pale yellow crystals with melting point 249°-250°C (decomposition).

Analysis for<c>14<H>2i<0>2<N>3<S>- 1,33HC1

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 derivatives provided by the present invention:

Example A

A tablet formulation containing the following ingredients can be prepared in a conventional manner:

Example B

A capsule formulation containing the following ingredients can be prepared in a conventional manner:

This capsule formulation is filled in No. 4 hard gelatin capsules.

Claims (9)

1. Procedure for the preparation of a compound of the general formula .where R represents a hydrogen atom or a lower alkyl group, R^ represents a hydrogen atom or a 2 lower alkyl or lower cycloalkyl group, R represents a lower alkyl or lower cycloalkyl group, R 3 represents a hydrogen -atom or a primary or secondary lower alkyl group and Y represents an oxygen or sulfur atom, the thiol tautomers of these compounds of formula I where y represents a sulfur atom and pharmaceutically acceptable acid addition salts thereof, characterized in that mana) reacts with a compound of the general formula 12 3 Where R, R , R and R have previously indicated meanings : with a compound of the general formula j where.Z represents a chlorine atom or an amino group and Y has the meaning previously stated in the claim, or b) one prepares compounds of formula I where Y represents 12 3 centers an oxygen atom and R, R , R and R have previously given meanings, by reacting an epoxide with the general formula where R and R 3 have the meaning previously stated in the claim, with an amine of the general formula 12 where R and R have the meaning previously stated in the claim, or c) one dissolves a racemic compound of formula I in the optical isomers and, if desired, transfers an obtained compound of formula I into a pharmaceutically acceptable acid addition salt. 2. Method according to claim 1 characterized in that Y represents an oxygen atom, ■ R and R 3 represent a hydrogen atom and R 1 and R 2 have the meaning stated in claim 1 and where in method variant a) phosgene is used as compound of formula IV. 3. Method according to claim 1 or 2 characterized in that Y represents an oxygen atom, R oq 3 1 R represents a hydrogen atom and R represents a hydrogen atom and R 2 represents a lower cycloalkyl group 12 or R and R each represent a lower alkyl or lower cycloalkyl group. 4. Method according to claim 1 characterized in that Y represents an oxygen atom, R represents 12 3 a lower alkyl group and R , R and R have the meanings given in claim 1 and where only method variant a) is used. 5 . Method according to claim 1, characterized in that R^" represents a hydrogen atom or a lower 2 alkyl group, R represents a lower alkyl group and R and R 3 have the meaning stated in claim 1, and where thiophosgene is used as the compound of formula IV. 6. Method according to each of claims 1, 4 and 5, characterized in that R represents a lower alkyl group. 7. Method according to claim 6, characterized in that R represents the methyl group. 8. Method according to each of claims 1 to 7, characterized by . that R"*" represents a hydrogen atom.;9 . Method according to each of claims 1, 2 and 4 to 8, characterized in that R 2 represents a lower alkyl group.; 10. Method according to claim 9, characterized in that R 2 represents a branched lower alkyl group.; 11. Method according to claim 10, characterized in that R 2 represents the isopropyl or tert.butyl group.; 12. Method according to claim 1 or 2, characterized in that one prepares 4-[2-hydroxy-3-(methylamino)propoxy]-2-benzimidazolinone.;1 3. Method according to claim 1 or 2, characterized in that one prepares 4-[ 2-Hydroxy-3-(n-propylamino)propoxy]-2-benzimidazolinone.;14. Method according to claim 1 or 2, characterized in that 4-[2-hydroxy-3-(isopropylamino)propoxy]-2-benzimidazolinone is produced.;15. Process according to claim 1 or 2, characterized in that 4-[3-tert.butylamino)-2- hydroxypropoxy]-2-benzimidazolinone.;16. Process according to claim 3, characterized in that 4-[3-diethylamino)-2-hydroxypropoxy]-2-benzimidazolinone is produced.;17. Process according to claim 3, characterized in that 4-[3-(cyclohexylamino)-2-hydroxypropoxy]-2-benzimidazolinone is produced.;18. Process according to claim 3, characterized in that 4-[3-(dicyclopentylamino)-2-hydroxypropoxy]-2-benzimidazolinone is produced.;19. Process according to claim 3, characterized in that 4-[2-hydroxy-3-(N-methylcyclohexylamino)propoxy]-2-benzimidazolinone is produced.;20. Process according to claim 1 or 4, characterized in that 4-[3-(tert.butylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone is produced.;21. Process according to claim 1 or 4, characterized in that 4-[3-(cyclopentylamino)-2-! hydroxypropoxy]-7-methyl-2-benzimidazolinone.;22. Process according to claim 1 or characterized in that 4-[3-(dicyclopentylamino)- -2-hydroxypropoxy]-7-methyl-2-benzimidazolinone.;23. Process according to claim 1 or 4, characterized in that 7-[3-(tert.butylamino)-2-hydroxypropoxy]-1,4-dimethyl-2-benzimidazolinone is produced.;24. Method according to claim 1 or 5, characterized in that 1-(tert.butylamino)-3-(2-mercapto-7-methyl-4-benzimidazolyloxy)-2-propanol is produced.;25. Process according to claim 1 or 5, characterized in that 1-(tert.butylamino)-3-(2-mercapto-4-benzimidazolyloxy)-2-propanol is produced..;26. Process according to claim 1 or 5, characterized in that 1-(tert.butylamino)-3-(2-mercapto-1,4-dimethyl-7-benzimidazolyloxy-2-propanol) is prepared.; 27. Process according to claim 1 or 5 , characterized in that one prepares 1-(diethylamino)-3-(2-mercapto-4-benzimidazolyloxy)-2-propan.ol.; 28. Method according to claim 1, characterized in that one prepares a hydrohalide salt of a compound which is mentioned in one of the claims 12 to 27.; 29. Method according to claim 1, characterized in that a hydrochloride salt of a compound which is mentioned in one of the claims 12 to 27.; 30. Method according to each of claims 1 to 29, characterized in that a compound of formula III is reacted in situ with a compound of formula IV.; 31. Method according to each of claims 1 to 30 inclusive, characterized in that a compound of formula III is reacted with a compound with formula IV under acidic conditions and, if necessary, the resulting acid addition salt is transferred by a f starting compound of formula I to a free base of formula I.;32. Method according to each of claims 1 to 23, characterized in that the epoxides of formula V are reacted in situ with an amine of formula VI.; 33. Process for the preparation of preparations with (3-adrenoceptor-blocking properties, characterized in that a benzimidazole derivative of formula I as stated in claim 1 a thiol tautomer of a compound of formula I where Y represents a sulfur atom or a pharmaceutically acceptable acid addition salt thereof is mixed as active substance with non-toxic, inert, therapeutically tolerable solid or liquid carriers normally used in such preparations and/or excipients.; 34. Compositions with 3-adrenoceptor-blocking properties characterized in that they contain a benzimidazole derivative of the formula I as stated in claim 1, a thiol tautomer of a compound of formula I where Y represents a sulfur atom or a pharmaceutically acceptable acid addition salt thereof and a carrier.; 35. Diamines of the general formula; characterized in that R represents a hydrogen atom or a lower alkyl group, R"1" represents a hydrogen atom or a lower alkyl or ! lower cycloalkyl group, R 2 represents a lower alkyl or lower cycloalkyl group and R 3 represents a hydrogen atom or a primary or secondary lower alkyl group with the proviso that when R represents a hydrogen atom R.1 represents a lower alkyl or lower cycloalkyl group.;36. Compound of the general formula ; characterized by 8 R represents a hydrogen atom or or a lower alkyl group, R <2> represents a lower alkyl or lower cycloalkyl group, R represents a hydrogen atom or the benzyl group or a lower alkyl or lower cycloalkyl-30 group and R represents a primary or secondary lower alkyl group.;37. Compounds of the general formula ; characterized in that R represents a hydrogen atom or a lower alkyl group, R<2> represents a lower alkyl or lower cycloalkyl group and R represents a hydrogen atom or benzyl groups. or a lower alkyl or lower cycloalkyl group.;38. Compounds with the general formula ;characterized in that R represents a hydrogen atom or a lower alkyl group.;39. Compounds with the general formula ;characterized by åt R represents a hydrogen atom or a lower alkyl group and R 3 represents a hydrogen atom or a primary or a secondary lower alkyl group.;40. Compounds with the general formula characterized in that R represents a hydrogen atom or a lower alkyl group and R 3 represents a hydrogen atom or a primary or secondary lower alkyl group.;41. Compounds with the general formula ;characterized in that R represents a hydrogen atom or a lower alkyl group.;42. Compounds with the general formula i ■ j characterized by R representing a hydrogen atom or a lower alkyl group, R represents a hydrogen atom or a lower alkyl group 2 or lower cycloalkyl group, R represents a low ere alkyl or'lower cycloalkyl group, R 3 represents a hydrogen atom or a primary or secondary lower alkyl group and Y represents an oxygen or sulfur atom^ thiol tautomers of such compounds of formula I where Y represents a sulfur atom and pharmaceutically acceptable acid addition salts thereof.;43. Compounds according to claim 42 with the general formula; characterized in that R represents a hydrogen atom or a lower alkyl or lower cycloalkyl group and. R 2 represents a lower alkyl or lower cycloalkyl group, and pharmaceutically acceptable acid addition salts thereof.;44. Benzimidazole derivatives according to claim 43, characterized in that R 1 represents a hydrogen atom, R<2> represents a lower cycloalkyl group or R 1 and R 2 individually represent a lower alkyl or lower cycloalkyl group.;45. Compounds according to claim 42 with the general formula characterized in that R' represents a lower alkyl group", R"*" represents a hydrogen atom or a lower alkyl or lower cycloalkyl group, 2 R represents a lower alkyl or lower cycloalkyl group and R 3 represents a hydrogen atom or a primary or secondary lower alkyl group, and pharmaceutically acceptable acid addition salts thereof. 46. Compounds according to claim 42 with the general formula characterized in that R represents a hydrogen atom or a lower alkyl group, R 1 represents a hydrogen atom or a lower alkyl group 2' 3 R represents a lower alkyl group and R represents centers a hydrogen atom or a primary or secondary lower alkyl group, the thiol tautomers thereof and pharmaceutically acceptable acid addition salts thereof. |47. Compounds according to each of claims 42, 45 and 46, characterized in that R represents a lower alkyl group. 48. Compounds according to claim 47, characterized in that R represents the methyl group. 49. Compounds according to each of claims 42 to 48, characterized in that R represents a hydrogen atom. 50 - Compounds according to each of claims 42, 43, 45 to 49, characterized in that R 2 represents a lower alkyl group. 51. Compounds according to claim 50, characterized in that R<2> represents a branched lower alkyl group. 52. Compounds according to claim 51, characterized in that R 2 represents the isopropyl or tert.buty1 group. 5 3. 4-[2-hydroxy-3-(methylamino)propoxy]-2-benzimidazolinone. 54. 4-[2-hydroxy-3-(n-propylamino)propoxy]-2-benzimidazolinone. 55. 4-[2-hydroxy-3-(isopropylamino)propoxy]-2-benzimidazolinone. §6. 4-[3-tert.butylamino)-2-hydroxypropoxy]-2-benzimidazolinone. 57. 4-[3-(diethylamino)-2-hydroxypropoxy]-2-benzimidazolinone. 58. 4-[3-cyclohexylamino)-2-hydroxypropoxy]-2-benzimidazolinone. 59. 4-[3-Dicyclopentylamino)-2-hydroxypropoxy]-2-benzimidazolinone. 60. 4-[2-Hydroxy-3-(N-methylcyclohexylamino)propoxy]-2-benzimidazolinone. 61. 4-[3-(tert-butylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone. 62. 4-t 3-(cyclopentylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone. 6 3. 4-[3-(Dicyclopentylamino)-2-hydroxypropoxy]-7-methyl-2-benzimidazolinone. 64. 7-t 3-(tert.butylamino)-2-hydroxypropoxy]-1,4-dimethyl-2-benzimidazolinone. 65. 1-(tert.butylamino)-3-(2-mercapto-7-methyl-4-benzimidazolyloxy)-2-propanol. 66. 1-(tert.butylamino)-3-(2-mercapto-4-benzimidazolyloxy)- -2-propanol. . 67. 1-(tert.butylamino)-3-(2-mercapto-1,4-dimethyl-7-benzimidazolyloxy)-2-propanol. 68. 1-(Diethylamino)-3-(2-mercapto-4-benzimidazolyloxy)-2-propanol. 6 9. A hydrohalide salt of a compound according to each of claims 53 to 68 inclusive. 70 Hydrohalide salt of a compound according to each of claims 53 to 68.