DK145645B - ANALOGY PROCEDURE FOR THE PREPARATION OF 1-SULPHONYL-5 (6) -SUBSTITUTED BENZIMIDAZOLES - Google Patents

Description

(19) DENMARK ίΒ \

® (12) PUBLICATION <11) 145645 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 732/77 (51) int.CI.3 C 07 D 2 35/30 (22) Submission day 18 · 1 977 (24) Running day 18 Feb. 1977 (41) Aim. available Jun 16 I978 (44) Submitted 10 Jan. 19¾ (86) International Application No. “(86) International Filing Day ~ (85) Continuation Day ~ (62) Master Application No. -

(30) Priority 15 · Dec. 1976, 750991, US

(71) Applicant ELI LILLY AND COMPANY, Indianapolis, US.

(72) Inventor Charles Johnson Paget, US: James Wesley Chamberlin, US:

James Howard Wikel, US.

(74) Associate Engineer Hofman-Bang & Boutard.

(54) Analogous process for the preparation of 1-sulfonyl-5 (6) -substituted benzimidazoles.

The incidence of disease in the upper part of the respiratory system is immense. It is estimated that approximately 1 billion cases occur annually in the U.S.A. alone. Studies in England (Tyreil and Bynoe, Lancet 1, 76 (1966)) show that 74% of people with a cold were infected with rhinovirus.

Since more than 80 strains of rhinovirus have already been identified, the development of a practical rhinovirus vaccine is not possible and qq chemotherapy seems to be a more suitable treatment.

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The ability of chemical compounds to suppress the growth of virus X) in vitro can be readily demonstrated using a virus stain suppression method analogous to that described by Siminoff in Applied *

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Microbiology / 9 (1), 66 (1961).

From usa. Patent No. 3,853,908 discloses certain antifungal 1-dimethylaminosulfonyl-2-aminobenzimidazole compounds.

From the specification of Danish Patent Application No. 2921/75, benzimidazole derivatives which are closely related to the benzimidazoles prepared according to the invention are known in that they differ in that the substituent R is an esterified carboxyl group instead of the group CgH5 ~ C (OH) -. These known compounds inhibit growth 6

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of certain viruses such as rhinovirus, polio virus, Coxsackie virus, echo virus and Mengo virus, however, they are not as effective as the compounds of the invention.

It is an object of the invention to provide a process for the preparation of novel benzimidazole compounds which inhibit the growth of viruses, especially rhinoviruses, polioviruses, Coxsackie viruses, echoviruses and Mengo viruses.

The compounds of the present invention have the general formula I set out in the preamble of the claim. The process according to the invention is characterized by the characterizing part of the claim.

The term "tautomer benzimidazole" refers to benzimidazole reagents which may be substituted on both nitrogen atoms by a hydrogen atom. The benzimidazole reactant, which is unsubstituted by nitrogen and having a substituent group at the 5-position of the benzene moiety, has a corresponding tautomer The isomeric mixture may be indicated by numbering the alternative positions as 5 (6).

Alkyl of 1-4 carbon atoms refers to straight-chain and branched aliphatic radicals of 1-4 carbon atoms comprising methyl, ethyl, butyl, isobutyl, sec-butyl and tert-butyl. Alkyl of 1-4 carbon atoms also includes alkyl of 1-3 carbon atoms. Alkyl of 1-7 carbon atoms refers to straight and branched chain aliphatic radicals of 1 to 7 carbon atoms comprising methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, 2,4-dimethyl-3-pentyl, t-butyl and neopentyl.

Cycloalkyl of 5-7 carbon atoms refers to saturated alicyclic / rings of 5 to 7 carbon atoms such as cyclopentyl, cyclohexal, 1-, 2-, 3- or 4-methylcyclohexyl and cycloheptyl.

In the process of the invention, an alkyl magnesium halide having 1-7 carbon atoms is a suitable Grinard reagent followed by hydrolysis. The alkyl lithium reagent having 1-7 carbon atoms leads to a product similar to the Grignard reagent. Preferred solvents for the alkylation process are inert organic solvents such as e.g. tetrahydrofuran, aromatics such as benzene or toluene, or ethers such as diethyl ether. The temperature is usually between 25 ° C and the boiling point of the solvent.

The starting materials of formula (II) are prepared as described in Danish Patent Application No. 3860/76.

The reaction product is a 1-sulfonylbenzimidazole compound. This can be isolated by filtration of the reaction mixture and concentration of the filtrate for crystallization. Alternatively, the reaction mixture may be evaporated to dryness and the residue treated with a suitable solvent, such as acetone or methanol, to separate and remove insoluble matter. The solution containing the sulfonylbenzimidazole compound is concentrated to crystallize the product or evaporated to obtain another residue, e.g. dissolved in methanol. The sulfonylbenzimidazole compound is recovered from the methanol by crystallization.

The following examples further illustrate the process for preparing the subject compounds, "m / e" is used to characterize the compounds and refers to the mass-charge ratio of ions found in the mass spectrum of the compounds. In general, the values correspond to the molecular weight of the main fractions.

EXAMPLE 1

To a solution of 600 ml of tetrahydrofuran and 21.7 ml (60 mmol) of methyl magnesium bromide in diethyl ether under nitrogen was added dropwise over 1 hour a solution of 4.1 g (12 mmol) of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole. in 180 ml of tetrahydrofuran. The mixture was refluxed for 5 hours, poured into ice and 1N hydrochloric acid, extracted twice with diethyl ether, washed with saturated sodium chloride, dried and filtered to give 2.9 g of 1-dimethylaminosulfonyl-2-amino-6- ( hydroxy-α-methylbenzyl) -benzimidazole as an amorphous solid. m / e 360.

Analysis: ci7H20N4 ° 3S Molecular 360

Calculated: C 56/67; Η 5> 59; N, 15.54 Found: C, 56.77; H 5> 46; N 15> 27 EXAMPLE 2

The procedure of Example 1 was repeated using 100 ml of tetrahydrofuran, 22.2 ml (60 mmol) of ethylmagnesium bromide (2.7 mmol / ml) in diethyl ether and 4.1 g of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole. to obtain 3.2 g of 1-dimethylamino sulfonyl-2-amino-6- (α-ethyl-α-hydroxybenzyl) benzimidazole in the form of a foam.

Mass spectrum of C 18H22N4 ° 3S Calculated: 374.14123 Found: 374.141 EC8 FMPEL 3

The procedure of Example 1 was repeated using 4.1 g (12 mmol) of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole in 180 ml of tetrahydrofuran, 100 ml of tetrahydrofuran and 28.6 ml (60 mmol) of isopropyl magnesium chloride. 100 ml of tetrahydrofuran to give as a yellow foam 4.0 g of 1-dimethylaminosulfonyl-2-amino-6- (α-isopropyl-α-hydroxybenzyl) -benzimidazole, yield 65%. m / e 388.

Analysis: C-H HN₂S

Calculated: C, 58.74; H, 6.23; N, 14.12

Found: C, 59.00; H, 6.20; N 14.52 EXAMPLE 4

To a solution of 150 ml of tetrahydrofuran and 31 ml (84 mmol) of methyl magnesium bromide in diethyl ether under nitrogen was added dropwise a solution of 5 g (5 mmol) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole in 200 ml of tetrahydrofuran. The mixture was stirred at 25 ° C for 1 hour. It was refluxed for 2 hours and cooled, and the solution was poured into ice and 1N hydrochloric acid, then extracted with diethyl ether.

1500 ml of the solution was concentrated to 800 ml, dried and concentrated under vacuum. The product formed was recrystallized from diethyl ether / hexane by dissolving the product in diethyl ether, adding diethyl ether / hexane and boiling the solution until cloudy. The solution was cooled to 25 ° C, cooled to 10 ° C and filtered to give 2 g of the product. Additional product was recovered by concentrating the filtrate in vacuo, yield 2 grams. The product was 1-isopropylsulfonyl-2-amino-6- (α-hydroxy-α-methylbenzyl) benzimidazole. m / e 360, 344 base.

Analysis: c18H2N3 ° 3S MW 359

Calculated: C, 60.15; Η 5> 89; N, 11.69

Found: (first yield) C 60.37; H, 5.73; N 11.46 (second yield) C 61.30; H, 6.26; N 10.69 EXAMPLE 5

The procedure of Example 4 was repeated using 150 ml of tetrahydrofuran, 31 ml (84 mmol) of n-butylmagnesium bromide and 5.0 g (15 mmol) of 1-isopropylsulfonyl-2-amino-6-benzoyl-benzimidazole. Reflux was boiled for 20 hours to give 5.0 g of 1-isopropylsulfonyl-2-amino-6 - (/ {- hydroxy- / i-n-butylbenzyl) benzimidazole as a light brown foam. m / e 401.

Analysis: C 21 H 27 N 3 ° 3S MV 401

Calculated: C, 62.82; H, 6.78; N, 10.47 Found: C, 63.14; H, 6.57; N 10.17 Example 6

The procedure of Example 4 was repeated using 40 ml (85 mmol) of isopropylmagnesium bromide, 5.0 g (15 mmol) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole and 200 ml of tetrahydrofuran and obtained as a yellow foam 5 µg of 1-isopropylsulfonyl-2-amino-6- (α-hydroxy-α-isopropylbenzyl) benzimidazole.

m / e 387.

Analysis: C ^H ^N ^S MV 387

Calculated: C, 61.99; H, 6.50; N, 10.84. Found: C, 61.74; H, 6.25; N 10.64 W (CH 3 OH): X 213 ¢ 39300, - £ 258 16800 EXAMPLE 7

The procedure of Example 4 was repeated using 31 ml (2.7 mmol in diethyl ether) of ethyl magnesium bromide, 5 g (15 mmol) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole and 150 ml of tetrahydrofuran to give as a beige foam. 4.6 g of 1-isopropylsulfonyl-2-amino-6- (α-hydroxy-cc-ethylbenzyl) -benzimidazole were obtained. m / e 373, 343.

UV (CH 3 OH): 213 633528; Å256 ¢ 14000 EXAMPLE 8

The procedure of Example 1 was repeated using 30 ml (60 mmol) of n-propylmagnesium bromide in 100 ml of tetrahydrofuran and 4.1 g (5 mmol) of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole in 150 ml. tetrahydrofuran to give 3 »5 g of 1-dimethylaminosulfonyl-2-amino-6- (α-hydroxy-an-propylbenzyl) -benzimidazole as a light brown foam. m / e 388.

Analysis: C ^ gi ^ ^N ^O ^S

Calculated: C, 58.74; H, 6.23; N, 14.42 Found: C, 58.49; H, 6.22; N, 14.29 EXAMPLE 9

The procedure of Example 1 was repeated using 80 ml of tetrahydrofuran, 11.1 ml of n-butylmagnesium bromide and 2.05 g of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole in 90 ml of tetrahydrofuran to give 1 as a white foam. 7 g of 1-dimethylaminosulfonyl-2-amino-6- (α-hydroxy-an-butylbenzyl) -benzimidazole. m / e 402.

XX

EXAMPLE 10

To a solution of 5 g (13.1 mmol) of 1-cyclohexylsulfonyl-2-amino-6-benzoylbenzimidazole in 200 ml of tetrahydrofuran under nitrogen was added 84 ml of ethyl lithium rapidly and dropwise. The reaction was carried out in an ice bath. When the reaction was complete, the temperature of the solution was allowed to rise to 25 ° C without removing the ice bath and maintaining this temperature for 2.5 hours. Then the reaction mixture was stirred for 5 hours and diluted with water and then the tetrahydrofuran was distilled off under vacuum. The product was extracted twice with chloroform, washed with a saturated sodium chloride solution, dried over sodium sulfate and filtered. There was thus obtained 4.1 g of 1-cyclohexylsulfonyl-2-amino-6- (α-hydroxy-α-ethylbenzyl) benzimidazole.

Analysis

Calculated: C, 63.90; H, 6.58; N 10.16 Found: C, 64.77; H, 7.09; N 9.38 8 EXAMPLE 11

To a solution of 5 g (13.1 µmol) of 1-cyclohexylsulfonyl-2-amino-6-benzoylbenzimidazole in 200 ml of tetrahydrofuran under nitrogen was added rapidly and dropwise 84 ml of ethyl lithium. The reaction was carried out in an ice bath. After complete reaction, the temperature of the solution was allowed to rise to 25 ° C without removing the ice bath and to remain at 25 ° C for 2 hours and 30 minutes. Then, the reaction mixture was stirred for five hours, then diluted with water and the tetrahydrofuran was distilled off under vacuum. The product was then extracted twice with chloroform, washed with a saturated NaCl solution, dried over Na2SC> 4 and filtered to give 4.1 g of 1-cyclohexylsulfonyl-2-amino-6- (δ (-hydroxy-D (- ethylbenzyl) -benzimidazole.

Analysis: C22H26N3 ° 3S

Calculated: C 63.90, H 6.58, N 10.16

Found: C 64.77, H 7.09, N 9.38.

EXAMPLE 12

By repeating the procedure described in Example 11 using 15 g of 1-cyclohexylsulfonyl-2-amino-6-benzoyl-benzimisaazole, 500 ml of tetrahydrofuran and 78.0 ml of methylnagnesium bromide under reflux, 1-cyclohexylsulfonyl-2-amino was obtained. -6- (oC "hydroxy-d (rmethylbenzyl) -benzimidazole having the following mass spectrum: m / e 381, 315, 235 (base) and 104.

Analysis: c12H25N3 ° 3S (MV 399)

Calculated: C 63.13, H 6.31, N 10.52 Found: C 62.28, H 4.99, N 8.09.

The present compounds of formula (i) exhibit a broad spectrum of antiviral activity. Not only are they particularly effective in inhibiting the growth of echo virus, Mengo, Coxsackie (A9, A21, B5), polio (type I, II, III) or rhinovirus (25 strains), but they inhibit 9

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also various types of influenza virus including influenza strains such as Ann Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a, and Taylor C (type A, B). The ability of the compounds of this invention to suppress the growth of various viruses in vitro can be readily demonstrated by using the spot reduction experiment analogous to that described by Siminoff, Applied Microbiology, 9 (1), 66-72 (1961). The specific experiments are described in detail below. The compounds of this invention were tested by the following methods!

Test methods

Kidney cells from African monkeys (BSC-1) or Hela cells (5-3) were cultured in 25 ml Falcon flasks at 37 ° C in medium 199 with 5 percent inactivated bovine fetal serum (FBS), penicillin (150 units, 1 ml) and Streptomycin (150 µg / ml). When confluent monolayers were formed, the above growth medium was removed and 0.3 ml of a suitable dilution of virus (echo, Mengo, Coxsackie, polio or rhinovirus) was added to each flask. After absorption for 1 hour at room temperature, the cell layer infected with virus was poured with a medium containing 1 part 1 percent ion agar No. 2 and 1 part double strength medium 199 with FBS, penicillin and Streptomycin containing the active compound at concentrations of 100, 50, 25, 12, 6, 3 and 0 µg per day. ml. The flask, which did not contain active compound, served as a control in the experiment. Stock solutions of the sulfonylbenzimidazole compounds were prepared in dimethyl sulfoxide dilution at a concentration of kAA µg / ml. The flasks were incubated for 72 hours at 37 ° C for polio, Coxsackie, echo and Mengo virus, and for 120 hours at 32 ° C for rhinovirus. Stains could be observed in the areas where viruses were infected and reproduced in the cells. A solution of 10% formalin and 2% sodium acetate was added to each flask to inactivate the virus and fix the cell layer to the flask surface. The virus spots, regardless of size, were counted after staining the surrounding cells with crystal violet. The stain number was compared to the control sample at each active compound concentration.

145645 10

The effect of the compound in question was expressed as percent stain reduction or percent inhibition. Alternatively, the concentration that inhibits staining 50 percent can be used as a measure of the effect. 50 percent inhibition is indicated by the symbol χ50 ·

The experiments are expressed as inhibition of Polio virus type I, as this virus is easy to grow and gives consistent results.

The effect of the compounds of this invention was confirmed against other viral cultures such as Coxsackie (A9 »A21, B5), echo virus (strain 1-4), Mengo, rhinovirus (25 strains) and Polio (type I, II, III). Test results for various sulfonylbenzimidazole compounds are given in Table I below, with reference to the above examples in column 1. Column 2 lists the 5 (6) position of the corresponding benzimide sol compound, and columns 3-10 indicate percent inhibition at various dilutions of the active compound.

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In order to demonstrate the useful biological effect of the compounds of the present invention in relation to known benzimidazole compounds, the compound 1-dimethylaminosulfonyl-2-amino-6- (o <'- n-butyl-β-x'-hydroxybenzyl) -benzimidazole, prepared according to the invention, was compared. with the compounds 1-dimethylaminosulfonyl-2-amino-6- (hydrazinocarbonyl) benzimidazole and 1-dimethylaminosulfonyl-2-amino-6- (N-ethylcarboxamido) benzimidazole, both known from Danish Patent Application No. 2921/75. The ability of the compounds to suppress the growth of virus in vitro was determined as described above and the results are shown in Table II. It is clear from this table that the compound of the invention is significantly more effective than the comparative compounds.

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The present sulfonylbenzimidazole compounds of formula (I) were tested as pure compounds and as isomeric mixtures.

Both isomers inhibit virus growth, however, the 6-isomer is generally more active than the 5-isomer.

The present compounds may be administered orally to warm-blooded mammals, including humans, at doses of 1 - 300 mg / kg body weight. The administration may be repeated periodically if necessary.

According to general practice, the antiviral compound can be administered every 4 to 6 hours.