CH632756A5 - Process for preparing 1-thiazolinyl-5(6)-substituted benzimidazoles - Google Patents

Abstract

1-Thiazolinyl-5(6)-substituted benzimidazoles of the formula <IMAGE> are prepared in which R2 represents C1-C3-alkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)methyl, (C3-C6-cycloalkyl)ethyl, thienyl or phenyl, and R4 represents C1-C7-alkylidene, and the radical <IMAGE> is located in the 5 or 6 position. These compounds are obtained by dehydrating a corresponding tautomeric benzimidazole compound which has, in the 5 or 6 position, a substituent of the formula <IMAGE> in which R3 is C1-C7-alkyl. Compounds of the formula I are converted by acylation of the amino group into corresponding C1-C4-acyl derivatives. The compounds which are obtained can be used for suppressing and controlling the growth of viruses.

Description

The invention relates to a process for the preparation of pharmacologically useful benzimidazole compounds of the formula

632756

R,

Aa

4 v / y

A

y- nh2

(i)

10th

where R2 is Ci-C3-alkyl, C3-C6-cycloalkyl, (Cî-Cé-cyclo-15 alkyl) -methyl, (C3-C6-cycloalkyl) ethyl, thienyl or phenyl and R4 is Ci-C7-alkylidene and the group of the formula

R.2-C- 20

II

R4

is in the 5 or 6 position.

The process according to the invention is characterized in that a tautomeric benzimidazole compound of the formula

30th

® —N'H

(II) 35

40

o o in which R2 has the meaning given above and R3 is Ci-C7-alkyl, dehydrated.

Compounds of the formula I obtained are converted into compounds of the formula by acylation

R_ — C 2 II

A \

50

v / v

NHR

(IA)

55

/ \

60

transferred, wherein R2 and R4 are defined above and R is Ci-C4-acyl.

A preferred group of compounds are compounds of the formula (I) in which R 2 is phenyl. 65

Examples of preferred thiazolinyl-benzimidazole compounds which come under the general formula (I) are e.g. the following connections:

1- (thiazolin-2-yl) -2-amino-5 (6) - (a-methylenebenzyl) benz imidazole,

1- (thiazolin-2-yl) -2-amino-5 (6) - (a-ethylidene-benzyl) -benz-imidazole,

l- (Thiazolin-2-yl) -2-amino-5 (6) - (an-hexylidenbenzyl) benzimidazole, and l- (thiazolin-2-yl) -2-amino-5 (6) - [ a- (2,4-dimethyl-3-pentyl-idene) benzyl] benzimidazole.

The term “tautomeric benzimidazole” means a benzimidazole reagent that can be substituted with a hydrogen atom on each nitrogen atom. The benzimidazole reagent, which is unsubstituted on nitrogen and contains a substituent group in the 5-position of the benzene moiety, has a corresponding tautomeric form which is in equilibrium with its form in which the substituent is alternatively in the 6-position. The mixture of isomers can be designated by designating the possible mutual positions as 5 (6).

The following definitions refer to the various terms used here. The term “Ci-C3-alkyl” means straight-chain or branched alkyl having 1 to 3 carbon atoms, namely methyl, ethyl, propyl and isopropyl. The term “Ci-C3-alkyl” also includes the term “C1-C2-alkyl” in its definition. The term “Ci-C7-alkyl” means straight-chain or branched-chain alkyl having 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl , 2,4-dimethyl-3-pentyl, tert-butyl and neopentyl; for technical reasons, tertiary alkyl, which cannot be converted into alkylidene, is excluded.

The term “thienyl” means the thiophene group attached to the 2- or 3-position.

The term “Ci-C4-acyl” means straight-chain or branched-chain acyl groups with 1 to 4 carbon atoms, namely formyl, acetyl, propionyl, butyryl and 2-methyl-propionyl.

The term "Ci-C7-alkylidene" means straight-chain or branched-chain groups with 1 to 7 carbon atoms such as methylene, ethylene, propylidene, isopropylidene, butylidene, isobutylidene, 3-methyl-2-butylidene, 2,4-dimethyl-3-pentylidene and n-hexylidene.

The term “C3-C6-cycloalkyl” means cycloalkyl having 3 to 6 carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The expression “(C3-C6-cycloalkyl) methyl” means a methyl group substituted by the above cycloalkyl radicals. The expression “(C3-C6-cycloalkyl) ethyl” means ethyl groups which are substituted in particular on the carbon atom in the 1-position with one of the above cycloalkyl radicals.

In the process according to the invention, suitable dehydrating agents are e.g. strong acids such as p-toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid. The preferred solvents for the dehydration process are alkanes such as hexane; aromatic compounds such as benzene or toluene; chlorinated alkanes such as methylene chloride or chloroform. The temperature range generally used for the reaction is in the range from about 25 ° C. to the reflux temperature of the solvent.

The starting materials of formula (II) can advantageously be produced according to a separate proposal (CH-PS 629 202).

According to this preferred process, which was found and protected by the patentee, a tautomeric benzimidazole of the formula is used

632756

/ 'V \

v-î-lr I> -

0 v / Y

1

/ \

wherein R2 has the meaning given above, with a Ci-C7 alkyl magnesium halide or a C1-C7 alkyl lithium and then hydrolyzes to the tertiary alcohol.

The thiazolinyl-benzimidazole products can be isolated by methods known per se, such as by filtration and concentration of the filtrate to induce crystallization. Alternatively, the reaction mixture can be evaporated to dryness and the residue treated with a suitable solvent such as acetone or methanol to separate and remove insoluble materials. The solution containing the product can be concentrated to crystallize the product or evaporated to form a second residue. This residue can then e.g. be recrystallized from methanol. The benzimidazole compound is isolated by filtration or centrifugation.

The 5 (6) isomers can be separated by fractional crystallization or by column chromatography. The 6-isomer normally crystallizes out of the solution of the mixture first.

The thiazolinyl-benzimidazole compounds of the formula IA, in which R is Ci-C4-acyl, are prepared by reacting l-thiazolinyl-2-amino-5 (6) -subst. -Benzimidazoles as described above. Anhydrides of acetic acid, propionic acid or butyric acid or the mixed anhydride of formic acid and acetic acid, propionic acid or butyric acid are preferably used. If R is formyl, the compounds of the formula IA can be obtained by reacting the mixed anhydride of formic acid and acetic acid.

The following examples illustrate the preparation of the compounds of formula (I). The term “m / e” used in the characterization of the products means the mass-to-charge ratio of the ions that appear in the mass spectrum of the products. In general, the values correspond to the molecular weights of the main peaks.

EXAMPLE 1 2 g (5.26 mmol) of l- (thiazolin-2yl) -2-amino-6- (a-hydroxy-a-n-butylbenzyl) benzimidazole are dissolved in 250 ml of chloroform. 1.3 g of p-toluenesulfonic acid are added to the solution. The mixture is heated under reflux for 1.5 h. The mixture is cooled to 25 ° C., washed twice with saturated aqueous sodium carbonate, dried and evaporated; 900 mg of l- (thiazolin-2-yl) -2-amino-6- (a-n-butylidene-benzyl) -benzimidazole are obtained, mp. 177 to 179 ° C.

EXAMPLE 2 The procedure is as described in Example 1, except that 1.2 g of l- (thiazoline-2-yl) -2-amino-6- (a-hydroxy-a-iso-propylbenzyl) benzimidazole, 250 ml of chloroform and 1.3 g p-toluenesulfonic acid; 280 mg of l- (thiazolin-2-yl) -2-amino-6- (a-isopropylidene-benzyl) -benzimidazole are obtained, mp. 242 to 245 ° C. (dec.).

Embodiment 3

The procedure is as described in Example 1, but 1 g of l- (thiazolin-2-yl) -2-amino-6- (a-hydroxy-a-ethyl-benzyl) benzimidazole, 0.7 g of p-toluenesulfonic acid and 100 ml chloroform; 700 mg of crude product are obtained. The crude product is recrystallized from ethyl acetate; 300 mg of l- (thiazolin-2-yl) -2-amino-6- (a-ethylidenbenzyl) benzimide-azole are obtained, mp. 186 to 187 ° C .; then reconsolidation and melting at 211 ° C, m / e 352.

Examination methods

Kidney cells (BSC-1) or hela cells (5-3) of African green vervet monkeys are grown at a temperature of 37 ° C in 25 cm3 falcon flasks in medium 199, which contains 5% inactivated fetal bovine serum (FBS), penicillin (150 units / 1 ml) and streptomycin (150 [ig / ml) contains. As soon as coherent monolayers are formed, the supernatant growth medium is removed and 0.3 ml of a suitable virus dilution (echovirus, mengovirus, coxsackie virus, poliovirus and rhinovirus) is added to each flask. After absorption for one hour at room temperature, the cell layer infected with the viruses is covered with a medium comprising a part of 1% ion agar No. 2 and a part of double-strength medium 199 with FBS, penicillin and streptomycin, the drug in concentrations of 100.50.25 , 12,6,3 and 0 jig / ml. The flask containing no active ingredient serves as a control for the examination. Corresponding stock solutions of the thiazolinyl-benzimidazole compounds of the formula (I) are prepared in dimethyl sulfoxide at a concentration of 10 "[ig / ml. The flasks are 72 hours at a temperature of 37 ° C with polio, coxsackie, echo and Mengoviruses and incubated with rhinovirus for 120 h at 32 ° C. The influenza viruses Ann Carbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a and Taylor C (species A, B) are incubated for 72 h at 37 ° C using MDCK- Cells (Madin-Darby dog kidney cells) are incubated at the sites where the virus has infected and reproduced the cells. To inactivate the virus and to fix the cell layer on the surface of the flask, one is added to each flask Solution of 10% formalin and 2% sodium acetate. The virus platelets are counted with crystal violet regardless of their size after staining the surrounding cell areas. The platelet count is compared for each active ingredient concentrate ion with the control count. The activity of the respective active ingredient is expressed in the form of the percentage reduction in platelets or the percentage inhibition. The active substance concentration indicated by the symbol Iso, which inhibits the formation of platelets by 50%, can optionally also be used as a measure of the activity.

The results obtained in the above experiments are expressed in terms of the inhibition of type I poliovirus, since this virus grows easily and gives consistent results. The activity of the compounds of formula (I) is compared to other virus cultures such as coxsackie (A9, A21, B5), echovirus (strains 1-4), mengo, rhinovirus (25 strains), polio (type I, II, III) and influenza viruses as determined by Ann Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8A and Taylor C (types A, B). The test results for various thiazolinyl-benzimide-azole compounds are summarized in Table I below. In the table in column 1 is the example number

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5 632 756

of the various chemical examples listed; in the platelet reduction for active ingredient dilutions of 0.75 column 2, the isomer is given in the 5 (6) position, and is listed in up to 100 ng / ml.

columns 3 to 10 is the percentage virus

Table

Polio I platelet reduction by l- (thiazolin-2-yl) -2-amino-5 (6) -subst.-benzimidazole

Example isomer <2) active substance concentration (ng / ml) <"

No.

100 50 25 12 6 3 1.5 0.75

% Platelet reduction

2 6 toxic toxic moderate moderate 100 100 78 22

toxic toxic

16 33 0 0 0 0000

(1) Active ingredient concentration in micrograms / milliliter m the number 5 or 6 means the corresponding isomer

The thiazolinyl benzimidazole compounds will be. In general, the antiviral compound becomes every 4

administered both as pure compounds and as isomeric to 6 hours.

mix checked. Both isomers inhibit the virus “, ^

Growth; the 6-isomer is generally more active than the preferred compounds of formula (I)

5-isomer 25 together with one or more, for the special kind

The compounds of the formula (I) suppress suitable adjuvants used in general administration. I'm referring to the growth of various viruses when they connect to the case of oral "administration

Medium is added in which the virus is grown. pharmaceutical diluents or carriers such as

The compounds of formula (I) can therefore in aqueous lactose, sucrose, starch powder, cellulose, talc, magnesia

Solutions, preferably with a surface-active agent, 30 "mstearate magnesium oxide calcium sulfate, acacia powder,

used for decontamination of surfaces, GelJa "ne 'Natnumalgmat, Natnumbenzoat and Steannsaure on which Polio, Coxsackie, Rhino and Influenza viruses are modified. Preparations of this kind can be used for

are present, e.g. Hospital glassware, miserable administration purposes as tablets or

housework surfaces and similar surfaces that formulate locks in capsules for the production. In addition, food can be used. 35 also the connections produced according to the invention

The compounds obtained according to the invention can be administered parenterally.

Warm-blooded animals and humans in a dose of 1 to The compounds can also be taken with a liquid

300 mg / kg of animal body weight are administered orally. The mixed and administered in the form of nose drops

Administration can be repeated periodically as needed or used as an intranasal spray.

B

Claims (5)

632756 2. The method according to claim 1 for the preparation of l- (thiazolin-2-yl) -2-amino-6- (an-butylidenbenzyl) -benz-imidazole, characterized in that l- (thiazolin-2-yl) - 2-amino-6- (a-hydroxy-an-butylbenzyl) benzimidazole treated with p-toluenesulfonic acid. ™ 2 (I) 10th / 5 \ A. n-E- i) v / v I. A _ NHR (IA) / \ Ì 15 wherein R is Ci-C4-acyl, R2 for Ci-C3-alkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl) methyl, (C3-C6-cycloalkyl) ethyl, thienyl or phenyl and R4 for Ci -C7-alkylidene and the rest where R2 is Ci-C3-alkyl, C3-C6-cycloalkyl, (C3-C6-cyclo-20 alkyl) -methyl, (C3-C6-cycloalkyl) -ethyl, thienyl or R2 -C- Phenyl and R4 stands for Ci-C7-alkylidene and the rest || R4 R2-C- II R4 is in the 5- or 6-position, characterized in that a tautomeric benzimidazole compound of the formula 25 is in the 5- or 6-position, characterized in that a compound of the formula I is prepared by the process according to claim 1 and this is then acylated accordingly. 30th OH // *> - NH (II) o o in which R2 has the meaning given above and R3 is correspondingly Ci-C7-alkyl, dehydrated. 2nd PATENT CLAIMS 1. Process for the preparation of a compound of the formula R, Aa Ro 5 2 <v / v 3. The method according to claim 1 for the preparation of l- (thiazolin-2-yl) -2-amino-6- (a-isopropylidenbenzyl) -benz-imidazole, characterized in that l- (thiazolin-2-yl) - 2-amino-6- (a-hydroxy-a-isopropylbenzyl) benzimidazole treated with p-toluenesulfonic acid. 4. The method according to claim 1 for the preparation of l- (thiazolin-2-yl) -2-amino-6- (a-ethylidenbenzyl) benzimide-azole, characterized in that l- (thiazolin-l-yl) - 2-amino-6- (a-hydroxy-a-ethylbenzyl) benzimidazole treated with p-toluenesulfonic acid. 5. Process for the preparation of compounds of the formula The occurrence of viral diseases in the upper respiratory tract is immense. It is estimated that nearly 1 billion cases occur annually in the United States alone. Studies carried out in England (Tyrell and Bynoe, Lancet 16, 1966) show that 74% of people with colds are infected with rhinoviruses. More than 80 strains of rhinoviruses have been identified, and 40 development of a simple rhinovirus vaccine is therefore not possible. Chemotherapy appears to be a better remedy. The ability of chemical compounds to suppress virus growth in vitro can easily be demonstrated using a virus platelet suppression test similar to that described by Siminoff in Applied Microbiology, 9 (1), 66 (1961). Certain thiazolinyl-benzimidazole compounds are described in the following references: From 50 of US Pat. No. 3,749,717, l-thiazolinyl-2- (heterocyclic) benzimidazoles are known which can be used as anthelmintics and anti-inflammatory agents. From US Pat. No. 3,825,537, l-thiazolinyl-2-amino-benzimidazoles are known which can be used as anthelmintics and anti-inflammatory agents. US Pat. No. 3,833,574 describes a process for the preparation of l-thiazolinylbenzimidazolin-2-ones which can be used as anti-inflammatory agents. DE-OS 2 446 266 discloses l-thiazolinyl-2-phenyl-60 benzimidazoles which are suitable as anthelmintics. The aim of the invention is to provide a method for producing compounds with which the growth of viruses, in particular rhinoviruses, polioviruses, coxackie viruses, echoviruses, mengoviruses and influenza viruses, can be suppressed or combated.