DE2219408A1 - Substituted benzimidazole derivatives - Google Patents

Description

Patent attorneys
Dr. Ing.Walter Abitz
Dr. DioicrF. Morf
Dr. Hans - A. Brauns

8 Munich 86, Plera «ieuemlr, 2 |

20th ArR, 1972

CASE: 14108

MERCK ge CO., IHC. Rahway, Hew Jersey / USA

Substituted benzimidazole derivatives

The invention relates to benzimidazoles and derivatives thereof as well Process for their manufacture. It relates in particular to 2-ethylbenzimidazoles in which the ethyl group is in the 2-position with a benzoxazolyl, benzothiazolyl, indolyl or a quinazolinonyl group which may optionally be substituted. The benzimidazole derivatives thus formed have been shown to be effective compounds for the treatment of viral infections.

The benzimidazoles of the present invention and theirs according to the invention Derivatives can be best described by the following

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14108

Represent structural formula:

(D

in each of which R stands for lower alkoxy, cyclonic lower alkoxy, halo lower alkoxy, Medrigalkyl, lower alkylthio, halogen and lower alkenyl;

R ₁ denotes hydrogen or lower alkyl; each R _{2 represents} hydrogen or hydroxyl; X represents a carbonyl group;

A is an oxygen, sulfur, nitrogen or carbon atom

means;

η stands for zero or 1 and m for mull, 1 or 2 and in which the dotted line indicates that the double bond is in either of the two available between A and N. Positions can be located.

When "low" is used in the present invention, as it is used in lower alkoxy or lower alkyl, so it is meant that the carbon chain has 1 to 5 carbon atoms contains, which can be arranged linearly or branched.

Representatives of the lower alkoxy groups of the present invention are methoxy, ethoxy, propoxy, butoxy, amyloxy and branched Isomers thereof such as isopropoxy, sec-butoxy or isoamyloxy. Representatives of the lower alkyl groups are methyl, ethyl, propyl,

7 0 9844/1250

Butyl, amyl or branched isomers thereof, such as isopropyl, tert-butyl or isoamyl.

The compounds of the present invention are generally as the mono- or di-acid addition salts isolated, these salts are because of their ease of handling and their greater tendency to dissolve in water are preferred and therefore make the compounds more diversified in administration forms accessible. The non-toxic acid addition salts of both the inorganic and organic types are preferred, such as hydrohalides, e.g., hydrochlorides, hydrobromides and the same; Sulfates, nitrates, phosphates and the like as examples of the inorganic salts and Citrates, tartrates, maleates as representatives of the organic Salts.

The object of the present invention is to provide products which are useful for combating viruses of the RMA type are useful. This includes the creation of processes to produce the desired benzimidazole derivatives, the have the selected combinations of substituents, and the creation of processes for the preparation of special substituted benzimidazoles. Finally, it is also part of the object of the invention to provide preparations, which contain the compounds useful for treating rhinoviruses.

One aspect of the preferred embodiments of the present invention can be represented by the following structural formula represent:

14108

(H)

in which each radical R is lower alkoxy, halo-lower alkoxy or lower alkyl, or in which, when m is 2, the R groups can together form a methylenedioxy group; R ^ is hydrogen or lower alkyl; each R _{2 represents} hydrogen or hydroxyl, A. represents oxygen, sulfur or carbon and m represents zero, 1 or 2. Representatives of this connection type are:

[iS, 2Rj-1- (5-methoxy-2-benzimidazolyl) -2- (6-methoxy-2-benzothiazolyl) -1,2-ethanediol;

[iS, 2R] -1- (5-methoxy-2-benzimidazolyl) -2- (6-methoxy-2-7f benzothiazolyl) -1,2-ethanediol;

1- (5,6 ~ dimethoxy-2-benzimidazolyl) -2- (6-methoxy-2-benzoxazolyl) ethanol;

1- (5 ~ methoxy-1-methyl-2-benzimidazolyl) -2- (6-methoxy-2 ~ benzoxazolyl) ethane;

1- (5,6-methylenedioxy-2-benzimidazolyl) -2- (5-methoxy-2-indolyl) ethanol;

1- (5-trifluoromethoxy-2-benzimidazolyl) -2- (5-methoxy-2-indolyl) ethanediol;

1- (5-methoxy-2-benzimiaazolyl) -2- (5-methoxy-2-indolyl) -1,2-ethanediol;

1- (5-Ethoxy-1-ethyl-2-benzimidazolyl) -2- (5-ethoxy-2-indolyl) -1,2-ethanediol.

14108

2219

A second aspect of the preferred Ausfükcungsform the ύοτ- lying floor invention can be represented by the following structural formulaί

in which each radical R ! "is lower alkoxy ₉ halo-lower alkoxy or. lower alkyl, or in which _s when m stands for 2 _? the R groups can together form a methylenedioisocyanate? in which R" is hydrogen or lower alkyl and each radical Rp is hydrogen or hydroxyl Represented representatives of this connection type are.

1- (5-Metho.xy-2-benzimidazolyl) -2- [2-4 (3H) -cliinazolinonyl] -1,2-ethanediol-dihydrate ο chloride?

1 - (5-lthoxy-2-benzimidazolyl) -2- [2-4 (3H) -cMnaaolinonyl] -1,2-ethanediol-dihydrochloride j

1- (5-Methoxy-6-methyl-2-benzimidazolyl) -2- [2-4 (3H) -quinazolinonyl] -1,2-ethanediol dihydrochloride j

1- (5-Trifluoromethoxy-2-ben3imidazolyl) -2- [2-4 (3H) -7-methoxyquinazolinonylj-ethanediol-dihydroculorido . ■ '

The compounds of the present invention are prepared by combining an o-phenylenediamine or a substituted derivative thereof with a titanium carboxylic acid or a derivative thereof brings into contact and thus produces a benzimidazolylcarboxylic acid derivative »This compound is then treated with a phenolic

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derivative or an analogous fhioverfeigung converted to form the second heterocyclic ring. On the other hand, the dicarboxylic acid can first with the phenol derivative or the analogous thio compound and then with the o-pheny-. Lenediamine or a derivative thereof are reacted, the order of the reaction is irrelevant «In the present case, the carboxylic acid derivatives should include the aldehydes, the Shiff bases derived therefrom and the nitriles, as well as the more common carboxylic acid derivatives such as esters, amides and the like» The butanedisarboxylic acid or its derivative includes as an integral part of the atoms constituting the aentrale linking group piping linking group may also be substituted, as defined above * BrLe hydroxyl group may jedosh vorliegenj in gescMiater form S ₆ B. as acyl derivative, -when such to Ease of implementation is more useful »Implementation can best be described with the help of the following reaction clause:

- 6 209B44M25Ö

tS!

CX]

ErJ-O - »J

OJ

O - tu I

IS]

- tr;

Nl

CVJ

209844/1750

14108

In the reaction scheme, R _f, R ₁ , R ^, X, A, m and η have the meanings already defined and Z in each case represents a carboxylic acid derivative radical, as defined above. The specific identity of Z depends on the specific group with which it reacts on the benzene ring and on the heterocyclic group whose formation is desired. If Z represents a nitrile group, the group -X-AH of the structural formula VII must be -COOH -Group and if Z is not a nitrile group, the -X-AH group becomes an -X-NH _Q group.

C.

When R _{2 is} a hydroxyl group it is often advantageous, but not always necessary, to protect it from attack by the reagents or reactants used in the reaction. The most convenient way to protect the hydroxyl group is to prepare the ester derivative. The ester derivative is prepared by methods known to those skilled in the art, it is relatively insensitive to attack by the reagents used in the present invention. However, as soon as the hydroxyl group is no longer attacked, the ester group can be removed by methods known to the person skilled in the art, which give the hydroxyl group.

The above sequence of reactions is general and provides the possibility of making a large number of variations. The specific associated with this sequence of reactions Reaction conditions and techniques can best be seen from an analysis of the preparation of the preferred See embodiments of the present invention. One should be aware, however, that minor Variations in the methods described below result in compounds other than the preferred embodiments.

The benzimidazole heterocyclic ring preferred in all

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Embodiments of the present invention is present, can be made by having an o-phenylenediamine. a carboxylic acid, a salt of a carboxylic acid such as an alkali metal salt, a carboximidate hydrohalogenide and the like. Is in the 1-position of the benzimidazole nucleus if a substituent is desired, the o-phenylenediamine starting material will usually be chosen so that the desired substituent is already attached to it. In some cases, the substituent can then be inserted into the Molecule are introduced, but the preferred route is to choose a previously substituted starting material. Man found that the alternative route offers too great an opportunity for competitive reactions, which is the case with the preferred route is not the case. The implementation is through hydrolytic Coupling of the two reactants with removal of water caused by the use of dicyclohexylcarbondiimide, or> where the reaction is easier, by union the reactant and heating in a solvent inert to the reaction at a temperature of Room temperature to the reflux temperature of the solvent used. Typical solvents that prove to be usable are lower alkanols such as methanol, ethanol, propanol and the like; or other polar solvents, such as dimethylformamide, tetrahydrofuran, dioxane and dimethyl sulfoxide. The reaction mixture is heated for 5 minutes to 5 hours depending on the reactivity of the particular Reactants and the temperature at which the reaction is carried out. The implementation can be carried out in one step are, wherein the reactants are coupled to each other and dehydrated at the same time or the Steps can be performed separately, with or without isolation and purification of the intermediate. The implementation can be carried out in a reaction medium of acidic, basic or neutral pH. The special choice of pH depends on the solubility and stability of the

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AO

Respondents. It has been shown that the reaction proceeds equally well at any pH value from 3 to 9 if the Reactants are soluble in the reaction medium at the specially chosen pH.

The heterocyclic benzothiazolyl ring is synthesized by adding a carboxylic acid or a derivative thereof, an aldehyde or a derivative thereof or a nitrile on the one hand as a reactant and an o-aminothiophenol, optionally substituted, as the other reactant chooses. The reaction is achieved in that both reactants are inert for the reaction in one Solvent dissolves and the mixture to a temperature from room temperature to the reflux temperature of the solvent Heated for half an hour to 10 hours. Suitable solvents have been aromatic hydrocarbons, such as Benzene or toluene; Lower alkanols such as methanol, ethanol, propanol and the like proved. After the heating time has ended the reaction mixture is worked up and the product is isolated in a manner known to the person skilled in the art Reaction is often exothermic and a temperature rise is noted when the two reactants are in one be combined with a single solvent. If the solvent allows, the reaction can proceed azeotropic removal of the water that is released in the course of the reaction can be followed. The theoretically released amount of water can be calculated and if this Amount of the reaction mixture was withdrawn, the reaction is complete. Particularly suitable for this purpose Solvents are water immiscible solvents such as benzene and toluene. Alternatively, an agent for reaction mixing which is able to absorb the released water. However, the means must not disrupt the implementation or react with any of the reactants. Anhydrous are suitable for this purpose

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inorganic salts and molecular sieves which have a strong affinity for water or for crystallization. Particularly suitable are anhydrous potassium carbonate, anhydrous magnesium carbonate, anhydrous calcium sulfate, anhydrous
Sodium carbonate and the like.

The heterocyclic benzoxazolyl ring is prepared analogously to the heterocyclic benzthiazolyl ring. The benzene reactant is an o-aminophenol, which can optionally be substituted. The reaction conditions for the o-aminophenol and the o-aminothiophenol reactions are the same. There is no significant difference in the observed reactivity between the phenol and the thiophenol conversion. The reaction temperatures,
Reaction times and reaction solvents are therefore interchangeable.

The preparation of the indolyl compound differs somewhat from that of the benzthiazolyl or benzoxazolyl derivative. The compound IV is brought into contact with a 3- (2-indolyl) propionic acid derivative instead of the compound V.
The preparation of the 3- (2-indolyl) propionic acid derivative is known to the person skilled in the art. The implementation is best
represent by the following reaction scheme:

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lii 108

X H

OJ

κ -ο- cn;

O O O

- 12 -

In this reaction scheme, each of the radicals R, R ₁ , R ₂ and m has the meaning defined earlier. The reaction conditions of this reaction are the same as the reaction conditions for the coupling and ring closure of the benzimidazole ring discussed in connection with the earlier benzimidazole synthesis and which can be used for the preparation of the compound X.

The quinazolinonyl heterocyclic ring is prepared by reacting a carboxylic acid derivative with anthranilic acid or an anthranilamide, which may optionally be substituted, in contact. If the non-benzene If the reactant is a nitrile, the benzene reactant is anthranilic acid. The nitrogen of the The nitrile group forms the ring nitrogen, a nitrogen atom on the carbonyl group of the benzene reactant is therefore not required. When the benzene reactant Is anthranilamide or a derivative thereof, the reaction is carried out in an inert solvent. Aromatic hydrocarbons such as benzene or toluene; a lower alkanol such as methanol, ethanol, propanol and the same; or other organic solvents such as tetrahydrofuran or dimethylformamide have been found to be useful proven. The reaction is carried out at a temperature from room temperature to the reflux temperature of the used Solvent carried out for 1/2 to 10 hours, the time being inversely proportional to the temperature at which the reaction is carried out is. The reaction mixture is worked up and the product is known to those skilled in the art known way isolated. The water released during the reaction can be azeotroped from the reaction medium using Distillation methods or by absorbing the water with an absorbent, v / ie already discussed above, removed.

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When the non-benzene reactant is a nitrile and the benzene reactant is an anthranilic acid or a substituted derivative thereof, the reaction is somewhat different. The two reactants are combined without the use of a solvent and the mixture is heated to a temperature of 100 ^° C. or to a temperature sufficient to melt both reactants, up to 200 ^° C. or to a temperature below which no excessive decomposition takes place, heated. The removal of the water released during the reaction has not proven to be necessary since it does not interfere with the reaction. However, the water can easily be removed by simple distillation. A solvent has generally not been found to be necessary in this reaction. However, in certain cases where either reactant or the product is susceptible to decomposition at the temperature at which the reaction is carried out, a solvent can be used. Higher-boiling inert organic solvents such as benzene, toluene, xylene, dimethylformamide and the like have proven to be suitable solvents. The reaction time of the reaction without a solvent is 5 minutes to 1 hour, with most reactions being completed in 10 to 20 minutes. Where a solvent must be used, the reaction time is longer, up to 10 hours. The reaction mixture is worked up and the products are isolated in a manner known to the person skilled in the art.

The non-benzene reactant as mentioned above can be a carboxylic acid, a derivative thereof Be aldehyde, a derivative thereof or a nitrile. The respondent is chosen to be both another provides reactive group for the second heterocyclic ring closure as well as for the correct substituents at the centrally arranged linking group. as

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appropriate reactants for the preferred embodiments the present invention have tartaric anhydride, rather in the protected form of diacetyltartaric anhydride is used, 3-cyanopropyl.carboximidate hydrochloride and the like proved. Dicarboxylic acids with only one carboxy group can be used is implemented at a time.

As mentioned above, the products of the present Invention generally isolated in salt form. Acid addition salts have been found to be useful, with the hydrohalide derivatives are preferred. The salt is made by putting the free base in an inert solvent dissolves in which it is readily soluble and in which the salt has limited solubility. Non-polar solvents have been found to be most useful, but polar solvents are also useful. Ether, chloroform, Benzene and the like have been found to be useful, with the lower alkanols such as methanol, ethanol and propanol are also useful if the salt is not appreciably soluble therein. The salt is made by adding one molar equivalent or a slight excess of anhydrous acid to the solution of the free base. if the solvent is miscible with water, a concentrated aqueous solution of the acid can be used «, Das Salt generally precipitates spontaneously and is isolated and purified in a manner known to the person skilled in the art.

The following examples are intended to explain the invention further. but without restricting them.

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14-108
example 1

[2R, 3R] -2,3-diacetoxy-3- (6-methoxy-2-benztMazolyl) propionic acid 7 Sodium salt

5172 g (0.0369 mol) of 2-amino-5-methoxythiophenol are dissolved in 100 ml of benzene and added to a suspension of 7.98 g (0.0369 mol) of L-diacetyltartaric anhydride dissolved in 100 ml of benzene. A little warmth is formed when they join. The mixture is refluxed for 1 hour, during which time a solid material precipitates. It is cooled, the insoluble material is filtered off and washed with benzene. Then 429 ml of hexane are added to the mixture. The precipitated pest substance is filtered off, washed with hexane and dried in vacuo at room temperature. The dry crude product is suspended in 45 ml of benzene and extracted with aqueous ammonium bicarbonate. The benzene layer is then washed with 10 ml of water. The combined aqueous layers are washed twice with 10 ml portions of benzene and lyophilized. The crude ammonium salt is further dried by washing it with methanol and then with hexane. The residue is dissolved in 33 ml of methanol and treated with 3.3 g of sodium methylate. The reaction mixture warms up spontaneously to 47 ° C., the product crystallizing. The reaction mixture is cooled to 3O ⁰ C and held for 1 hour at this temperature, during which time the crystallization is terminated. The product is filtered, washed three times with 10 ml portions of methanol, dried in vacuo at 50 ^° C. and the sodium salt of [2R, 3R] -2,3-dihydroxy-3- (6-methoxy-2-benzthiazolyl) - propionic acid, Pp = 233 to 235 ⁰ C.

The above sodium salt (6.5 g, 0.022 mol) is added to a solution of 2.1 ml of pyridine and 65 ml of acetic anhydride under a nitrogen atmosphere The reaction mixture is _β 90 minutes

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stirred long at 25 ⁰ C rind added to 1500 ml of ether. The precipitated Pestsubstanz is filtered, dried, washed with ether, in vacuo at 5O ⁰ C and yields the sodium salt of [2R, 3R] -2,3-diacetoxy-3- (6 ~ methoxy-2-benzothiazolyl) propionic acid ~, - - - Pp = 210 to 211 ⁰ C (with decomposition). · - ·

If 2-amino-5-methylthiophenol, 2-amino-5-chlorothiophenol or 2-amino-5-ethoxy-thiophenol is used instead of 2-amino-5-methoxythiophenol in the above process, [2R, 3Rj-2 , 3-Diacetoxy-3- (6-methyl-2-benzothiazolyl) -propionic acid, sodium salt, [2R ₁ 3R] -2,3-diacetoxy-3- (6-chloro-2-benzothiazolyl) -propionic acid, sodium salt or - [2R, 3R] -2,3-diacetoxy-3- (6-ethoxy-2-benzthiazolyl) propionic acid, sodium salt.

Example 2

[2R, 3RJ-2,3-diacetoxy-3 ~ (6-methoxy-2-benzthiazolyl) propion ~ [2-ainino-4 (5) methoxy] anilide \

0.647 g (0.0047 mol) of 4-methoxy-o-phenylenediamine are in 15 ml of dimethylformamide dissolved. To the solution obtained is added 0.405 ml (0.0047 mol) of concentrated hydrochloric acid. The sodium salt of [2R, 3R] -2,3-diacetoxy-3- (6-methoxy-2-benzthiazolyl) propionic acid is then added to the acidified solution. The reaction mixture is stirred for 5 minutes and 0.947 g (0.0047 mol) of dicyclohexylcarbodiimide become added at room temperature. The reaction mixture obtained is stirred for 3 1/2 hours at room temperature, a solid substance precipitates during this time. The reaction mixture is filtered to separate the dicyclohexylurea, the piltrate is added to 100 ml of cold (5 ° C.) water.

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λ Q

100 ml of methylene chloride are added to the aqueous phase and the pH of the aqueous phase is adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate. The layers are separated and the aqueous layer is washed four times with 25 ml portions of methyl chloride. The combined organic layers are washed five times with 15 ml of cold water, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue is purified by chromatography on silica gel, eluting with benzene: acetone (8: 2), whereby [2R, 3R] -2,3-diacetoxy-3- (6-ynethoxy-2-benzthiazolyl) propion- [2- amino-4 (5) -methoxyJ-anilide obtained, mp = 175 to 179 ⁰ C - ·. '■ ·

In the above procedure, [2R ₁ 3R] -2,3-diacetoxy-3- (6-methyl-2-benzthiazolyl) propionic acid, sodium salt, [2R, 3R] -2,3-diacetoxy-3- (6-chloro -2-benzthiazolyl) propionic acid sodium salt or [2R ₁ 3R] -2,3 ~ diacetoxy-3- (6-ethoxy-2-benzthiazolyl) propionic acid sodium salt instead of [2R, 3R] ~ 2,3 ~ diacetoxy -3 ~ (6-methoxy-2-benzthiazolyl) propionic acid sodium salt is used, one obtains [2R, 3R] -2,3-diacetoxy-3- (6-methyl-2-benzthiazolyl) propion ~ [2- amino-4 (5) -methoxy] -anilide, [2R, 3R] -2,3-diacetoxy-3- (6chlor-2-benzthiazolyl) -propion- [2-amino-4 (5) -methoxy] -anilide and [2R, 3R] -2,3-diacetoxy-3 ~ (6-ethoxy-2-benzthiazole) propion [2-amino-4 (5) methoxy] anilide.

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8-JUM250

B e is ρ ie 1

[2R, 3Rj-2,3-Mhydroxy-3- (6-methoxy-2-benzthiazolyl) propion- [2-amino-4 (5) -roethoxy] anilide

0.442 g of [2R, 3RJ-2,3-Macetoxy-3- (6-methoxy-2-benzthiazolyl) -propion- [2-amino-4 (5) -methoxy] -anilide (0.0094 mol) are added in 13 ml of methanol "suspended under a nitrogen atmosphere. 0.001 g of sodium methylate is added to the resulting solution, whereupon spontaneous crystallization takes place. The suspension is stirred for 2 1/2 hours at room temperature and then filtered. The solid material is washed with cold methanol and hexane, dried at 5O ⁰ C in vacuum, and [2R, 3R ^ -2,3-dihydroxy-3- (6-methoxy-2-benzthiazolyl) -propionic [2-amino-4 (5) methoxy] -anilide , Pp = 232 to 233 ^° C. (the dihydrochloride melts at 217 to 218 ^° C. with decomposition).

If in the above process [2R, 3R] -2,3-Macetoxy-3- (6-methyl-2-benzthiazolyl) -propion- [2-amino-4 (5) -methoxy] -anilide, [2R, 3RJ-2,3-Macetoxy-3- (6-chloro-2- benzthiazolyl) -propion- [2-ainino-4 (5) -methoxy] -anilide or [2R, 3R] -2,3-diacetoxy-3- (6-ethoxy-2-benzthiazolyl) propion [2-amino-4 (5) methoxy] anilide instead of [2R, 3R] -2,3-diacetoxy-3- (6-methoxy-2-benzthiazolyl) -propion- [2-amino-4 (5) -methoxy] -anilide used, one obtains [2R, 3R] -2,3-Mhydroxy-3- (6-methyl-2-benzthiazolyl) -propion- [2-amino-4 (5) -methoxy] -anilide, [2R, 3R] -2,3 ~ dihydroxy-3- (6-chloro-2-benzthiazolyl) propion [2-amino-4 (5) methoxy] anilide and [2R, 3R] -2,3-dihydroxy-3- (6-ethoxy-2-benzthiazolyl) propion [2-amino-4 (5) methoxy] anilide, respectively.

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Example 4

[iS_, 2R] -1- (5-methoxy-2-beri2imidazole) -2- (6-ynethoxy-2-benzthiazolyl) -1,2-ethanediol

0.300 g of [2R, 3R] -2,3-dihydroxy-3- (6-methoxy-2-benzthiazolyl) -propion- [2-amino-4 (5) -methoxy] -anilide (0.00077 mol) are in 6 ml of glacial acetic acid suspended under nitrogen. The reaction mixture is ^{stirred for 45 minutes at 98 °} C., during which time complete solution is achieved. The reaction mixture is cooled and lyophilized and the residue is washed with aqueous sodium bicarbonate and then with water. The solid material is air-dried. The crude product is suspended in methanol at room temperature, stirred for 5 minutes and then filtered off. The solid material is dried in vacuo and [1S., 2R] -1- (5-methoxy-2-benzimidazolyl) -2- (6-methoxy-2-benzthiazolyl) -1,2-ethanediol, Ip = 229 - 231.5 ⁰ C. the free base is suspended in a solution of hydrogen chloride and methanol to afford the dihydrochloride, Pp = 182-184 ⁰ C.

If in the above process [2R, 3R] -2,3-dihydroxy-3- (6-methyl-2-benzthiazolyl) -propion- [2-amino-4 (5) -methoxy] -anilide, [2R, 3R] -2,3-dihydroxy-3- (6-chloro-2-benzthiazolyl) propion- [2-amino-4 (5) methoxyanilide or [2R, 3R] -2,3-dihydroxy ~ 3- (6-ethoxy-2-benzthiazolyl) propion [2-amino-4 (5) methoxy] - anilide instead of [2R, 3R] -2,3-dihydroxy-3- (6-methoxy-2-benzthiazolyl) propion- [2-amino-4 (5) methoxy] anilide used, one obtains [1E ^, 2R] -1- (5-methoxy-2-benzimidazole) -2- (6-methyl-2-benzthiazolyl) -1,2-ethanediol, [i £, 2R] -1- (5-methoxy-2-benzimidazole) -2- (6-chloro-2-benzthiazolyl) -1,2-ethanediol or [iS_, 2R] -1- (5-methoxy-2-benzimidazole) -2- (6-ethoxy-2-benzthiazolyl) -1,2-ethanediol.

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Example 5

5-methoxy-2- (ß-cyanoethyl) benzimidazole - ■

43.8 g (0.296 mol) of methyl-S-cyanopropylcarboximidat-hydro-, chloride are dissolved in 180 ml of absolute ethanol and the solution is cooled to 5 ⁰ C. The above cooled ethanol. solution is added to a precooled solution (5 ^° C.) of 40.8 g (0.296 mol) of 4-methoxy-o-phenylenediamine in 162 ml of absolute ethanol in the course of 30 minutes. The reaction mixture is then refluxed for 40 minutes, cooled to room temperature and then filtered. The combined filtrates are concentrated in vacuo. 410 ml of water are added to the residue and the crystalline soluble material is filtered off, washed with water and dried at 40 ^° C. in a vacuum. TJmkristallisation from chloroform gives 5-methoxy-2- (ß ~ cyanoethyl) -benzimidazole, Pp = 139 to 141.5 ⁰ C.

If 4-methyl ~ o ~ phenylenediamine is used in the above process, 4-chloro-o-phenylenediamine, 4-methoxy-o-phenylenediamine, 4,5-methylenedioxy-o-phenylenediamine, 4,5 ~ dimethoxy-o-phenylenediamine, 4-methylthio-o-phenylenediamine or 4-trifluoromethoxyo-phenylenediamine instead of 4-methoxy-o-phenylenediamine, 5-methyl-2- (ß-cyanoethyl) benzimidazole, 5-chloro-2- (ß-cyanoethyl) benzimidazole are obtained 5-ethoxy-2- (ß-cyanoethyl) benzimidazole, 5-methylthio-2- (ß-cyanoethyl) benzimidazole 5,6-methylenedioxy-2- (ß-cyanoethyl) -benzimidazole 5,6-dimethoxy-2- (ß-cyanoethyl) -benzimidazole or »5-trifluoromethoxy-2- (ß-cyanoethyl) benzimidazole.

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Example 6

2- [2- (5-methoxy-2-benzimidazolyl) ethyl] -4 (3H) quinazolinone

0.500 g (0.0025 mole) of 5-methoxy-2- (ß ~ cyanoethyl) benzimidazole and 0.342 g (0.0025 mol) of anthranilic acid are combined and immersed in a preheated oil bath at 150 ⁰ C. The reaction mixture melts and after 15 minutes it solidifies again. Removing the oil bath, and the solid material slurried with hot methanol, cooled, filtered, washed with methanol and hexane, and dried at 5O ⁰ C in vacuo. The 2 ~ [2- (5-methoxy-2-benzimidazolyl) ethyl] -4 (3H) -quinazolinone ~ melts are converted at 274-275 ⁰ C with decomposition and may be in the hydrochloride salt obtained, which at 231-232 ⁰ C. melts with decomposition by dissolving the free base in methanol and treating the solution with anhydrous hydrogen chloride.

If 5-methyl-2- (ß-cyanoethyl) -benzimidazole, 5-chloro-2- (ß-cyanoethyl) -benzimidazole, 5-ethoxy-2- (ß-eyanoethyl) -benzimidazole, 5-ethylthio are used in the above process -2- (ß-cyanoethyl) -benzimidazole, 5,6-methylenedioxy- (2-ß-cyanoäthy!) - benzimidazole _f 5,6-dimethoxy-2- (ß-cyanoethyl) -benzimidazole and 5 ~ trifluoriiiethoxy-2- (ß-cyanaoethyl) benzimidazole instead of 5-methoxy-2- (ß-cyanoethyl) benzimidazole gives 2- [2- (5-methyl-2-benzimidazolyl) ethyl] -4 (3H) -quinazolinone , 2- [2 -. (5-chloro-2-benzimidazolyl) ethyl] -4 (3H) quinazolinone _s 2 ~ [2- (5-ethoxy ~ 2 ~ benzimidazolyl) ethyl] -4 (3H) - quinazolinone ^ 2- [2- (5-methylthio-2 ~ benzimidazolyl) ethyl] -4 (3H) -quinazolinonj 2 ~ [2- (5,6-methylenedioxy-2-benzimidazolyl) ethyl] -4 (3H) -quinazolinone, 2- [2- (5,6-dimethoxy-2-benzimidazolyl) -ethyl] -4 (3H) -quinasolinone or 2- [2- (5-trifluoromethoxy-2-benzimidazolyl) -ethyl] -4 (3H) -quinazolinone.

- 22 209844/1250

14108 2219A08

Example "7

Ethyl 3- (5-methoxy-2-benzimidazolyl) propionimidate dihydrochloride

4.0 g (0.020 mole) of 2- (ß-Cyanoäthyi) -5-methoxybenzimidazole and 1.28 ml (1.01 g, 0.022 mole) of ethanol were combined in 20 ml of chloroform and the resulting solution is cooled to 5 ⁰ C . The temperature being maintained at 5 ⁰ C in the reaction mixture is allowed to anhydrous hydrogen chloride bubbled into it, have been added to a total of 2.4 g (0.066 mol) of hydrogen chloride. The reaction mixture is stirred ^{at 5 ° C. overnight.} 70 ml of ether are added to the reaction mixture, whereupon the product precipitates. The reaction mixture is warmed to room temperature and then filtered. The solid material is washed with ether and dried in vacuo at 25 ⁰ C, there is obtained ethyl 3- (5-methoxy-2-benzimidazolyl) -propionimidat dihydrochloride, Pp = 232-234 ⁰ C.

If 2- (ß-cyanoethyl) -4,5-dimethoxybenzimidazole is used in the above process or 2- (ß-cyanoethyl) -4,5-dimethylbenzimidazole instead of 2 - * (ß-cyanoethyl) -5-methoxybenzimidazole, this gives ethyl 3- (4,5-dimethoxy-2-benzimidazolyl) propionimidate dihydrochloride and ethyl 3- (4,5-dimethyl-2-benzimidazolyl) propionimidate dihydrochloride.

Example 8

6-methoxy-2- [2- (5-methoxy-2-benzimidazolyl) ethyl] benzoxazole dihydrochloride

0.875 g (0.00274 mol) of ethyl 3- (5-methoxy-2-benzimidazolyl) propionimidate dihydrochloride are added to a mixture

- 23 - '

209844/1250

of 0.500 g (0.00285 mol) of 2-amino-5-methoxyphenol hydrochloride and 1.2 g (0.0087 mol) of anhydrous potassium carbonate in 10 ml of absolute ethanol. The reaction mixture is stirred At room temperature for 30 minutes and then refluxed for 90 minutes. The reaction mixture is cooled, the insoluble material is filtered off and the piltrate is concentrated in vacuo to a small volume (2 ml). to 10 ml of water are added to this residue, and the precipitated product is filtered off, washed with water and in vacuo dried. The residue is dissolved in methylene chloride, into which anhydrous hydrogen chloride is bubbled, thereby 6-Methoxy-2- [2- (5-methoxy-2-benzimidazolyl) ethyl] -benzoxazole dihydrochloride precipitates spontaneously off, Pp = 230 to 23l.5 ° E (with decomposition). .

If ethyl 3- (4,5-dimethoxy-2-benzimidazolyl) propionimidate dihydrochloride is used in the above process or ethyl 3- (4,5-dimethyl-2-benzimidazolyl) propionimidate dihydrochloride instead of ethyl 3- (5-methoxy-2-benzimidazolyl) propionimidate dihydrochloride, 6-methoxy-2- [2- (4,5-dimethoxy-2- benzimidazolyl) ethyl] benzoxazole dihydrochloride is obtained in this way and 6-methoxy-2- [2- (4,5-dimethyl-2-benzimidazolyl) ethyl] benzoxazole dihydrochloride.

Example 9

[aR, ßR] -diacetyltartaric acid-1-carbamoyl-anilide

5.5 g (0.0407 mol) of antheranilamide and 8.8 g (0.0407 mol) Ir-diacetyltartaric anhydride are dissolved in 100 ml of tetrahydrofuran combined and refluxed for 1 hour. The reaction mixture is cooled and concentrated in vacuo. The residue is redissolved in 45 ml of tetrahydrofuran

- 24 209844/1250

^: ~ 2s ^: ~ Ί

and filtered. The piltrate is treated with 400 ml of methylene chloride, a solid precipitate is obtained. The mixture is allowed to stand at room temperature for 30 minutes to complete the precipitation. The product is filtered, air-dried, one obtains [aR, ßR] -diacetyltartaric acid- (1-carbamoyl) -anilide, Pp = 186 to · 188 ⁰ C with decomposition, ■ ··

If 5-methyl-anthranilamide is used in the above process, 5-chloroanthranilamide, 5-ethoxyanthranilamide or 5-methyl ~ thioanthranilamide instead of ■ anthranilamide, one obtains [cxR, ßR] -diacetyltartaric acid-2-carbamoyl-5-methylanilide, ': [a R, ßR] -diacetyltartaric acid ~ 2-carbamoyl-5-chloroanilide, [cxR, βR] ~ Dia ce ty! tartaric acid - 2-carbamoyl-5-methoxyanilide or [ocR, βR] -diacetyltartaric acid-2-carbamoyl-5-methylthioanilide.

Example 10

[2R, 3S_] - 2,3-dihydroxy-3- [2-4 (3H) -quinazolinonyl! -Propionic acid . .

6> 0 g (0.017 mol) of [aR, βR] -diacetyltartaric acid-2-carbamoylanilide are dissolved in 75 ml of 3% aqueous sodium hydroxide (0.055 mol) and heated on the steam bath for 1 hour. The reaction mixture is cooled and concentrated in vacuo to a moist powdery substance. The residue is suspended in 20 ml of 4N hydrochloric acid and filtered. The solid material is washed twice with 5 ml portions of v / water and then air dried. The drying is completed under vacuum at 5O ⁰ C, thereby to obtain [2R, 3S _1] -2,3-dihydroxy-3- [2-4 (3 H) -chinazolinonyl! -Propionic acid, Pp = 197 bit 199 ⁰ C under Decomposition.

- 25 209844/1250

If [aR, ßR] -diacetyltartaric acid-2-oarbamoyl-5-methylanilide is used in the above process, [tfR, ßR] -diacetyltartaric acid ~ 2-carbamoyl-5-chloroanilide, [o-R, βR] -diacetyltartaric acid-2-carbamoyl-5-methoxyanilide or [aR, βR] -diacetyltartaric acid-2-carbamoyl-5-methylthioanilide instead of [a.R, ßR] -diacetyl- · tartaric acid-1-carbamoylanilide, one obtains [2R, 3 £ [] - 2,3-dihydroxy-3- [7-methyl-2- (3H) -ehinazolinonyl-propionic acid, [2R, 3S _] - 2,3-dihydroxy-3- [7-chloro-2-4 (3H) -cMnazolinonyl] propionic acid, [2R, 3SJ-2,3-dihydroxy-2- [7-methoxy-2-4 (3H) -quinazolinonylj-propionic acid and [2R, 3Sj-2,3-dihydroxy-3- [7-methylthio-2-4 (3H) -quinazolinonyl] propionic acid, respectively.

Example 11

[2R, 3S _i ] -2,3-dihydroxy-3- ^; [2-4 (3H) -quinazolinonyl] propion- [2-amino-4 (5) -inethoxy] anilide

1 | 94 g (0.0141 mol) 4-methoxy-o-phenylenediamine and 3.0 g (0.0128 mol) [2R, 3S] -2.3 ~ Mhydroxy-3- [2-4 (3H) - chinazolinonyl] -propionic acid were combined in 35 ml of dimethylformamide under a nitrogen atmosphere and treated with 2.98 g (0.141 mol) Mcyclohexylcarbodiimid at 25 ⁰ C. The reaction mixture is stirred for 5 hours at room temperature and the precipitated dicyclohexyl urea is filtered off. The Piltrat is concentrated under vacuum at 55 ⁰ C, there is obtained a dark resin. This material is dissolved in 40 ml of chloroform, which causes the immediate precipitation of a plague substance. The suspension is stirred overnight at room temperature and then filtered. The solid material is washed four times with 40 ml portions of chloroform and once with a 40 ml portion of ether. The solid material is dried in vacuo and [2R, 3S _i ] -2,3-dihydroxy-3- [2-4 (3H) -

- 26 -

209844/1250

chinazolinonyl! -propionic [2-amino-4 (5) ~ methoxy! anilide, = 206 to 208 ⁰ C.

Using [2E., 3S _i ] -2,3-dihydroxy-3- [7-methyl-2-4 (3H) -quinazolinonyl! -Propionic acid, [2R, 3Sj-2,3-dihydroxy-3 - [7-chloro-2-4 (3H) -quinazolinonyl! -Propionic acid, [2R ₁ 3S,! ~ 2,3-dihydroxy-3 ~ [7-methoxy-2-4 (3H) -quinazolinonyl! -Propionic acid or [2R, 3SJ-2,3-dihydroxy-3- [7-methylthio-2-4 (3H) -quinazolinonyl] propionic acid part of [2R13 ^ 3-2,3-dihydroxy-3- [2-4 (3H ) -quinazolinonyl! -propionic acid, this gives [2R, 3Sj-2,3-dihydroxy-3- [7-methyl-2-4 (3H) -quinazolinonyl! -propion- [2-amino-4 (5) - methoxy! anilide, [2R »3S! -2,3-dihydroxy-3- [7-chloro-2-4 (3H) -quinazolinonyl] -propion- [2-amino-4 (5) -methoxy! -anilide , [2R, 3SJ-2,3-dihydroxy 3- [7-methoxy-2-4 (3H) -quinazolinonyl! -Propion- [2-amino-4 (5) -methoxy! -Anilide or [2R, 3S _p ] -2,3-dihydroxy-3- [7-methylthio-2-4 (3H) -quinazolinonyl! -Propion- [2-amino-4 (5) -methoxy! -Anilide. ■ · ·

Example 12

1_ (5-Methoxy-2-benzimidazolyl) -2- [2-4 (3H) -quinazolinonyl! -1,2-ethanediol dihydrochloride

0.750 g (0.002 moles) [2R, 3S_] - 2,3-dihydroxy-3- [2-4 (3H) -quinazolinonyl! -Propion- [2-amino-4 (5) -methoxy! -Anilide are suspended in 100 ml of acetic acid and stirred for 90 hours at room temperature under a nitrogen atmosphere. the At this time, the reaction mixture is a clear solution which is lyophilized, the residue is washed with ether. That Product is dissolved in isopropanol and treated with anhydrous hydrogen chloride in methanol to give 1- (5-methoxy-2-benzimidazolyl) -2- [2-4 (3H) -quinazolinonyl! -1,2-

- 27 -

209844/1250

Ethandiol dihydrochloride, Pp = 268 to 27O ⁰ C with decomposition,

If [2R, 3S _< ] -2,3-dihydroxy-3- [7-methy1-2-4 (3H) -quinazolinonylJ-propion- [2-amino-4 (5) methoxy] anilide is used in the above process, [2R, 3S] -2,3-Mhydroxy-3- [7-chloro-2-4 (3H) -quinazolinonyl] -propion- [2-amino-4 (5) -methoxyJ-anilide, [2R, 3S_] -2,3-Dinydroxy-3- [7-methoxy-2-4 (3H) -quinazolinonyl J-propion- [2-amino-4 (5) -methoxy] -anilide or [2R, 3S, J-2 , 3-Dihydroxy-3- [7-methylthio-2-4 (3H) -quinazolinonyl] -propion- [2-amino-4 (5) -methoxyJ-anilide instead of [2R, 3S_J-2,3-dihydroxy -3- [2-4 (3H) -quinazolinonyl] - propion- [2-amino-4 (5) methoxyJ-anilide so one obtains 1- (5-methoxy-2-benzimidazolyl) -2- [7- methyl-2 (3H) -quinazolinonylJ-1,2-ethanediol dihydrochloride, 1- (5-methoxy-2-benzimidazolyl) -2- [7-chloro-2-4 (3H) -quinazolinonylJ-1,2- ethanediol dihydrochloride, 1- (5-methoxy-2-benzimidazolyl) -2- [7-methoxy-2-4 (3H) -quinazolinonylJ-1,2-ethanediol dihydrochloride or 1- (5-methoxy-2- benzimidazolyl) -2- [7-methylthio-2-4 (3H) -quinazolinonylI-1,2-ethanediol dihydrochloride.

Example 13

6-methoxy-2- [2- (5-methoxy-2-benzimidazolyl) ethyl] -benz thiazole dihydrochloride

0.500 g (0.00156 mol) of ethyl 3 ~ (5-methoxy-2-benzimidazolyl) propionimidate dihydrochloride are added to a mixture of 0.315 g (0.00285 mol) of 2-amino-5-methoxythiophenol hydrochloride and 0 , 69 g (0.005 mol) of anhydrous potassium carbonate dissolved in 5 ml of absolute methanol. The reaction mixture is stirred at room temperature for 45 minutes and then refluxed for 90 minutes. The reaction mixture is cooled and the insoluble material is filtered off.

709844/1 250

3L9

14108 '

The filtrate is concentrated in vacuo. 10 ml of water are added to the residue and the precipitated product is filtered off, washed with water and dried. The residue is dissolved in methanol and combined with a solution of anhydrous hydrogen chloride in methanol, giving 6-methoxy-2- [2- (5-methoxy-2-benzimidazolyl) ethyl] benzothiazole dihydrochloride, mp = 223 bis 223.5 ⁰ C with decomposition.

If 2-amino-5-methylthiophenol hydrochloride, 2-amino-5-chlorothiophenol hydrochloride and 2-amino-5-ethoxythiophenol hydrochloride are used in the above process instead of 2-amino-5-methoxythiophenol hydrochloride, 6-methyl 2- [2- (5-methoxy-2-benzimidazolyl) ethyl] benzthiazole dihydrochloride, 6-chloro-2- [2- (5-methoxy-2-benzimidazolyl) ethyl] benzothiazole dihydrochloride or 6-Ethoxy-2- [2- (5-methoxy-2-benzimidazolyl) ethyl] benzthiazole dihydrochloride _e

Example H

2- [2- (5-Methoxy-3-indolyl) ethyl] -5-methoxybenzimidazole dihydric chloride

0.50 g (2.28 mmol) of 4-methoxy-o-phenylenediamine and 0.477 g (2.28 mmol) NjN'-dicyclohexylcarbodiimide v / earth in 5 ml N, W-dimethylformamide combined and for 24 hours at room temperature touched. The reaction mixture is filtered and the anilidine oil intermediate is isolated by addition of water / water (10 ml) to the ΪΙ, Ν-dimethylformamide solution. The crude anilide is dissolved in ethyl acetate, dried over sodium sulfate and then filtered. The Piltrat is concentrated in vacuo, the anilide is purified by column chromatography on silica gel, using an ethyl

- 29 -

20984 k / 12 5 0 ORJQINAtINSPECTED

? 219 .- ■. : ia

acetate / bensol mixture (90:10) eluted. The intermediate indole anilide (0.127 g) is cyclized to the product by combining it with 12 ml of xylene and 1 ml of glacial acetic acid and refluxing the mixture for 90 minutes. The reaction mixture is concentrated to an oil in vacuo. The 2- [2- (5-methoxy-3-indolyl) ethyl] -5-methoxybenziinidazolol dihydrochloride is isolated by treating the oil with chloroform which has previously been saturated with anhydrous hydrogen chloride. This gives 0.111 g of melting point 217.5 to 219.5 ⁰ C.

If 5-methylindolyl-3-propionic acid is used in the above process, 5-chloroindolyl-3-propionic acid, 5-ethoxyindolyl-3-propionic acid or 5-methylthioindolyl-3-propionic acid instead of 5-methoxyindolyl-3-propionic acid, this gives 2- [2- (5-methyl-3-indolyl) ethyl] -5-methoxybenzimidazole hydrochloride, 2- [2- (6-chloro-3-indolyl) ~ ethyl] -5-methoxybenzimidazole hydrochloride, 2- [2- (5-ethoxy-3- indolyl) ethyl] -5-methoxy- benzimidazole hydrochloride or 2- [2- (5-methyithio-3-indolyl] -5-methoxybenzimidazole hydrochloride.

Example 15

2_ [2 -. (5-Methoxy-1-methyl-2-benzimidazolyl) ethyl] -4 (3H) · quinazolinone

4.5 g of methyl 3-cyanopropyl carboximidate hydrochloride are added to 18 ml of absolute ethanol are dissolved and the resulting solution is cooled to 5 ° C. This solution is given in the course of 30 minutes to a pre-cooled (5 ° C) solution of 4.2 g of 4-methoxy-N-methyl-o-phenylenediamine and 16 ml of absolute Methanol. The reaction mixture is heated for 1 hour

- 30 209fU4M? S0

ORIGINAL INSPECTED

22 19 /. 08

Reflux, cool to room temperature and filter. The solid material is washed with absolute ethanol and the combined piles are concentrated in vacuo. 75 ml of water are added to the residue and the crystalline solid material is filtered off, washed with water and dried. The 5-methoxy-1-methyl-2- (ß-cyanoethyl) benzimidazole intermediate is used in the next step without further purification. This intermediate product is combined with 0.3 g of anthranilic acid, dipped in a pre-chilled oil bath and heated to 150 ⁰ C. The . The reaction mixture is kept at this temperature for 15 minutes. Remove the oil bath, slurry the solid material with hot methanol, cool, filter, and wash with methanol and hexane. The 2- [2- (5-methoxy-1-methyl-2-benzimidazolyl) -ethyl] -4 (3H) -quinazolinone obtained is converted into the hydrochloride salt and purified by recrystallization from ethanol.

Example 16

6-Methoxy-2- [2- (5-methoxy-1-methyl-2-benzimidazolyl) ethyl] benzoxazole dihydrochloride

4.1 g of 2-ß-cyanoethyl-5-methoxy-1-methylbenzimidazole and 1.28 ml of ethanol are combined in 20 ml of chloroform and the resulting solution is cooled ^{to 5 ° C.} Anhydrous hydrochloric acid is bubbled into the reaction mixture and held at 5 ° C. until a total of 2.4 g of hydrogen chloride have been added. The reaction mixture is stirred at 5 ° C. overnight. 70 ml of ether are added to the reaction mixture, causing immediate precipitation of the hydrochloride salt. The suspension is warmed to room temperature and filtered. The solid material is washed with ether, dried, recrystallized from ethanol and 6-methoxy-

- 31 -

14108 · · '■■' ^ύ

2- [2- (5-methoxy-1-methyl-2-benzimidazolyl) ethyl] benzoxazole dihydrochloride.

Example 17

2- [2- (5 ~ methoxy-3-indole) ethyl] -4,5-dimethoxybenzimidazole dihydrochloride

5 g of 4,5-dimethoxy-o-phenylenediamine and 4.7 g of NjN'-dicyclohexylcarbodiimide are combined in 50 ml! ", !! - dimethylformamide and stirred overnight at room temperature. The reaction mixture is filtered and the anilidindole intermediate is precipitated by adding 100 ml of water. The solid material is filtered off, dissolved in ethyl acetate and the resulting solution is dried over sodium sulfate. The dried solution is concentrated in vacuo, the anilide purified by column chromatography, eluting through a silica gel column with ethyl acetate / benzene (85:15) The purified anilide is suspended in 100 ml of xylene and 10 ml of glacial acetic acid and the resulting solution is 2 hours heated under reflux for a long time. The reaction mixture is cooled and concentrated in vacuo. The residue is treated with a solution of hydrogen chloride in chloroform, the solid substance obtained is recrystallized from ethanol, thereby 2- [2- (5-methoxy-3-ynol) ethyl] -4,5-dimethoxybenzimidazole dihydrochloride is obtained.

- 32 -

209844/1?

:? 19 4.18 Hioo

Example 18

1- (2-Benzimidazolyl) -2- [2- |. (3H) -chiiiazolinonyl] -1 _l 2-ät] mndio! -Dihydro chloric!

0.750 g [2R,: - 5S _i ] -2,3-dihydcoxy-3- [2-4 (3II) -quinazolino.nyl] -propion- (2-amino) -anilide, prepared according to the method of Example 1i, are suspended in 100 ml of glacial acetic acid and stirred for 24 hours at room temperature door under a nitrogen atmosphere. The resulting clear solution is lyophilized and the residue is washed with ether. The solid material is dissolved in isopropanol and treated with anhydrous hydrogen chloride until an acidic reaction occurs. The solution is cooled and filtered. The solid material obtained is crystallized from ethanol, giving 1 ~ (2-benzimidazolyl) -2- [2-4 (3H) ~ quinazolinonyl] -1,2-ethanediol dihydrochloride.

In view of the fact that the benzimidazoles of the present Invention useful inhibitors of the viruses described, they can be in pharmaceutical compositions, used for oral use, for injections, topical applications as an ointment or as an oral or nasal spray are suitable.

For example, a water-soluble acid addition salt of the benzimidazoles can be used in finely ground form in a Propellant composition dispersed. A very small amount of a suspending agent can be used as a coating the finely crushed ar; jrieimit telparticles are present. The propellant chosen can be any of the many useful known, non-toxic, volatile, liquid propellants. These materials are generally fluorinated or fluorochlorinated low saturated aliphntisnhe Hydrocarbons.

INSPECTED

: ° 2 1 9 ':.' 8

These aerosol compositions are produced by intimately mixing, for example, 2 parts by weight [1S_, 2E.] - 1- (5-methoxy-2-benzimidazolyl) -2- (6-ynethoxy-2-benzthiazolyl) -1, 2-ethandiol with 3 parts by weight of oleyl or myristyl alcohol (up to 2 parts by weight mg to 1 part suspending agent can be used). The resulting mixture can be sent through a colloid mill. This mixture then becomes the formulation of a self-propelling composition ends by mixing with a suitable, non-toxic, volatile propellant, about 100 to 5OC mg of the colloidal drug with 10 to 20 g of propellant.

The compounds of the present invention can be used in one solid or liquid inert pharmaceutically acceptable carriers for oral administration. the active compound is present in the composition in amounts of 1 mg to 1 g before, depending on the nature of the virus, its severity the infection and the stage of infection at which the treatment is started. The carrier can be one or more of the inert, pharmaceutically acceptable, solid or liquid carriers known to the pharmacist, such as lactose, sucrose, calcium phosphate, Water, alcohol or a vegetable oil such as corn oil, peanut oil and the like. The compositions can also contain other ingredients, such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, flavorings and the like included.

- 34 209844/125 (J.

| _NS pECTED

Claims (19)

.CASE: 14108 MERCK & CO. IHC. PATENT CLAIMS Compounds of the formula: in which each radical R is lower alkoxy, lower alkyl, cyclone lower alkoxy, halo lower alkoxy, lower alkenyl, lower alkylthio or halogen; R ^ represents hydrogen or lower alkyl, each radical R _{2 represents} hydrogen or hydroxyl; "A represents oxygen, sulfur, nitrogen or carbon; X represents a carbonyl group; η represents zero or 1; m represents zero, 1 or 2 and in which the dotted line indicates that a double bond can be in either of the two positions available between A and N. - 35 - ORIGINAL INSPEC7H) 14108 2. Compounds of the formula: in which each radical.E denotes lower alkoxy, halo-lower alkoxy or lower alkyl or in which, when m is 2, the R groups together can form a methylenedioxy group; R ₁ denotes hydrogen or lower alkyl, each radical R ₂ denotes hydrogen or hydroxyl, A ₁ denotes carbon, oxygen or sulfur, m denotes Hull, 1 or 2, and their acid addition salts. 3. A compound according to claim 2, in which A _{1 is} oxygen and m is the number 1. 4. A compound according to claim 3> in which R is methoxy. 5. 1- (5-Methoxy-2-benzimidazolyl) -2- (6-methoxy-2-benzoxazolyl) ethane. 6. [iS_, 2R] -1- (5-methoxy-2-benzimidazolyl) -2- (6-methoxy-2-benzthiazolyl) -1,2-ethanediol. 7. A compound according to claim 2, in which A _{1 is} sulfur. 8. A compound according to claim 7 »in which R is methoxy. - 36 - 2 219 U) 8 U108 9. 6-Methoxy-2- [2- (5-methoxy-2-benzimidazolyl) ethyl] benzthiazole dihydrochloride. 10. A compound according to claim 2, in which A _{1 is} carbon. - 11. A compound according to claim 10, in which R is methoxy. 12. Compounds of the formula s • H nh h- nt in which each radical R "denotes hydrogen or lower alkoxy, halo-lower alkoxy or lower alkyl or in which, when m is 2, the RG groups together can form a methylenedioxy group; R ₁ denotes hydrogen or lower alkyl; each radical R _{2 represents} hydrogen or hydroxyl; m stands for Bull, 1 or 2, as well as their acid addition salts. 13. A compound according to claim 12, in which R is methoxy. 14. 1- (5-Methoxy-2-benzimidazolyl) -2 ~ [2-4 (3H) -quinazolinonyl] -1,2-ethanediol. 15. Means for combating a caused by rhino viruses Infection, characterized by an effective amount - 37 -2 09 8.44 / 1 ^ SO Η108 22194Ü8 of a substituted benzimidazole of the formula: in which each radical R is hydrogen, lower alkoxy, lower alkyl, cyclonic lower alkoxy, halo lower alkoxy, lower alkenyl,
Is lower alkylthio or halogen; R _{1 is} hydrogen or
Represents lower alkyl; each R _{2 is} hydrogen or
Means hydroxyl; A oxygen, sulfur, or nitrogen
Represents carbon; X represents a carbonyl group;
η for UuIl or 1 and in for zero, 1 or 2, and in
which the dotted line indicates that a double bond
are available in each of the two between A and N.
standing positions. 16. Composition according to claim 15, characterized by a content of substituted benzimidazole, wherein A is oxygen
and η mean the number zero. 17. Means according to claim 15, characterized by a Substituted benzimidazole content, where A is sulfur and m mean the number zero. 18. Composition according to claim 15, characterized by a content of substituted benzimidazole, wherein A is carbon
and m mean the number zero » 19. Composition according to claim 15, characterized by a content of substituted benzimidazole, wherein A is nitrogen and η mean the number 1. - 38? 09fU4 / 1? 5O 22Ί9408 Formula: Process for the preparation of compounds of in which each radical R is hydrogen, lower alkoxy, lower alkyl, cyclone lower alkoxy, halo lower alkoxy, lower alkenyl, lower alkylthio or halogen; R _{1 is} hydrogen or lower alkyl; each R _{2 is} hydrogen or hydroxyl; A is oxygen, sulfur, nitrogen or carbon, X is a carbonyl group; η denotes the number Hull or 1 and m denotes the number zero, 1 or 2 and in which the dotted line indicates that a double bond can be in either of the two positions available between A and N, characterized in that a phenylenediamine derivative of formula in which R, R and m have the meanings given above, with a compound of the formula: Z - H H t I CCZ
ι ι - 39 209844/1750 «W 14108 is implemented, in which E _{2 has the} meanings given above and Z is a carboxylic acid group, an aldehyde group or a Shiff base derivative thereof, a nitrile, carboxylic acid ester or carboxamide group and Z ^ has the meaning of Z or the group: means in the R, X, A, m and η and the dotted line have the meanings given above, so that when Z- has the meaning of Z, the intermediate product thus formed with a compound of the formula: is implemented, .in the R, X, A and m those mentioned earlier Have meanings. - 40 - 209844/1250