JPS6229429B2 - - Google Patents

Description

[Detailed description of the invention]

The number of viral upper respiratory tract infections is limitless, with approximately 1 billion cases occurring each year in the United States alone. Studies in the UK (Tyrell and Bynoe,
According to Lancet 1 , 76 (1966), 74 patients with common cold
% are infected with rhinovirus (rhinouirus). Since more than 80 strains of rhinovirus have already been identified, it is impossible to develop a practical rhinovirus vaccine, and chemotherapy is a better option. The ability of compounds to inhibit virus growth in in vitro experiments was determined by the viral plaque inhibition test [Siminoff,
Applied Microbiology, 9(1) , 66 (1961)] can be easily tested. Certain antifungal agents 1-dimethylaminosulfonyl-2-aminobenzimidazole are disclosed in US Pat. No. 3,853,908. The aim of the present invention is to obtain new benzimidazole compounds which inhibit the growth of viruses, in particular rhinovirus, poliovirus, Coxsackie virus, echo virus and Mengo virus. The present invention is based on the formula () This invention relates to a pharmacologically useful sulfonylbenzimidazole compound represented by: However, in formula (), R is C ₁ - C ₄ alkyl or -NR ₃ R ₄ (however,
R ₃ and R ₄ independently represent C ₁ -C ₃ alkyl); R ₁ is hydrogen; R ₂ is

[Formula] (wherein R ₅ is phenyl; R ₇ represents C ₁ -C ₇ alkylidene), and R ₂ is located at the 5th or 6th position. formula() (In the formula, R and R ₅ have the same meanings as above)
A tautomeric benzimidazole compound represented by is reacted with a C ₁ -C ₇ alkyl Grignard reagent, and then in formula (), R ₂ is

[Formula] [However, in the formula, R ₆ represents C ₁ to C ₇ alkyl,
R ₅ has the same meaning as above. ] After hydrolysis to a compound that is

[Formula] [However, R ₅ and R ₇ have the same meanings as above. ] A compound represented by the formula () is obtained by subjecting it to a dehydration reaction. Preferred specific examples of the compound represented by formula () include the following: 1-dimethylaminosulfonyl-2-amino-
6-(α-methylenebenzyl)benzimidazole; 1-dimethylaminosulfonyl-2-amino-
6-(α-ethylidenebenzyl)benzimidazole; 1-dimethylaminosulfonyl-2-amino-
6-(α-isopropylidenebenzyl)benzimidazole; 1-isopropylsulfonyl-2-amino-6
-(α-methylenebenzyl)benzimidazole; 1-isopropylsulfonyl-2-amino-6
-(α-n-butylidenebenzyl)benzimidazole; 1-isopropylsulfonyl-2-amino-6
-(α-ethylidenebenzyl)benzimidazole; and 1-dimethylaminosulfonyl-2-amino-
6-(α-n-butylidenebenzyl)benzimidazole. "Tautomeric benzimidazole" means a benzimidazole compound in which any nitrogen atom can be replaced with a hydrogen atom. Benzimidazole having no substituent on the nitrogen atom and having a substituent at the 5-position of the benzene ring has a tautomer having a substituent at the 6-position. Isomer mixtures can be designated by the numbering 5(6). The terms used in this specification are defined below. " _C1 - _C4 alkyl" refers to straight chain and branched aliphatic radicals having 1 to 4 carbon atoms, specifically methyl, ethyl, propyl, isopropyl, butyl,
Refers to isobutyl, sec-butyl and t-butyl, and also includes " _C1 - _C3 alkyl" in this definition. " _C1 - _C7 alkyl" means a straight-chain or branched aliphatic radical 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, t-
Butyl and neopentyl. " _C1 - _C7 alkylidene" means carbon number 1-7
straight-chain or branched radicals, such as methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, 3-methyl-2-butylidene, 2,4-dimethyl-3-
Pentylidene and hexylidene. Suitable dehydrating agents in the reaction step are strong acids such as p-toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, or trifluoromethanesulfonic acid. The _C1 - _C7 alkylmagnesium halide is a suitable Grignard reagent and can be hydrolyzed after the reaction. Preferred solvents for the alkylation reaction are inert organic solvents such as tetrahydrofuran; aromatics such as benzene or toluene; and ethers such as diethyl ether. In addition, preferred solvents in the dehydration reaction are aromatics such as benzene and toluene; alkanes such as hexane;
and halogenated hydrocarbons such as methylene chloride and chloroform; Reaction temperatures commonly used are from about 25°C to the reflux temperature of the solvent. The starting material represented by formula () is prepared according to the method described in pending Japanese Patent Application Laid-Open No. 148074/1983. The reaction product is a 1-sulfonylbenzimidazole compound. The product can be isolated by filtering the mixture and concentrating the lacquer to promote crystallization. Another method is to evaporate the reaction mixture to dryness and treat the residue with a suitable solvent such as acetone or methanol to separate and remove insoluble matter.
The solution containing the sulfonylbenzimidazole compound is either concentrated to crystallize the product or evaporated and the secondary residue is dissolved in, for example, methanol. The sulfonylbenzimidazole compound is recovered from methanol by crystallization. Generally, 5(6)-isomers can be separated by fractional crystallization or column chromatography.
The isomer crystallizes from the mixture first. The following example further details the preparation of the compound represented by formula (). "m/e" used to indicate the characteristics of a product is the ratio of the mass of an ion to the number of charges that appears in the mass spectrum of the product. This value generally corresponds to the molecular weight of the main peak. Example 1 600 ml of tetrahydrofuran and 21.7 ml of diethyl ether solution of methylmagnesium bromide
A solution of 4.1 g (12 mmole) of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole dissolved in 180 ml of tetrahydrofuran was added dropwise to the mixture with (60 mmole) over 1 hour in a nitrogen atmosphere. The mixture was refluxed for 5 hours, poured into ice and 1N hydrochloric acid, extracted twice with diethyl ether, washed with saturated brine, dried,
2.9 g of 1-dimethylaminosulfonyl-2-amino-6-(α-hydroxy-α-methylbenzyl)benzimidazole was obtained as an amorphous solid. m/e=360. Elemental analysis C ₁₇ H ₂₀ N ₄ O ₃ S (molecular weight 360) Calculated value: C, 56.67; H, 5.59; N, 15.54 Experimental value: C, 56.77; H, 5.46; N, 15.27 Example 2 1-dimethylamino Sulfonyl-2-amino-
A solution of 2 g (5.5 mmole) of 6-(α-hydroxy-α-methylbenzyl)benzimidazole dissolved in 130 ml of chloroform was reacted with 1.3 g of p-toluenesulfonic acid. The mixture was stirred and refluxed for 6 hours, washed with saturated sodium carbonate solution, dried,
1.7 g of 1-dimethylaminosulfonyl-2-amino-6-(α-methylenebenzyl)benzimidazole was obtained. mp201~202℃. Elemental analysis C ₁₇ H ₁₈ N ₄ O ₂ S (molecular weight 342) Calculated value: C, 59.63; H, 5.30; N, 16.36 Experimental value: C, 59.67; H, 5.35; N, 16.07 Example 3 Tetrahydrofuran 100 ml, odor Diethyl ether solution of ethylmagnesium chloride (2.7 mmole/
ml) and 4.1 g of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole to obtain 1-dimethylaminosulfonyl-2-amino- 3.2 g of 6-(α-ethyl-α-hydroxybenzyl)benzimidazole were obtained as a foam. Mass spectrum C ₁₈ H ₂₂ N ₄ O ₃ S Calculated value: 374.14123 Experimental value: 374.141 Example 4 1-dimethylaminosulfonyl-2-amino-6-(α-ethyl-α-hydroxybenzyl)
1.2 g (3.21 mmole) of benzimidazole, 750 mg of p-toluenesulfonic acid, and 100 mg of chloroform
When the method described in Example 2 is carried out using ml, 1
-dimethylaminosulfonyl-2-amino-6-
(α-ethylidenebenzyl)benzimidazole
388mg was obtained. mp200~202℃ (decomposition). Mass spectrum C ₁₈ H ₂₀ N ₄ O ₂ S Calculated value: 356.13107 Experimental value: 356.131 Example 5 1-dimethylaminosulfonyl-2-amino-
6-benzoylbenzimidazole 4.1g
(12 mmole) in 180 ml of tetrahydrofuran, 100 ml of tetrahydrofuran, and isopropylmagnesium chloride in tetrahydrofuran.
When the method described in Example 1 is carried out using 28.6 ml (60 mmole) of the solution dissolved in 100 ml, 1-dimethylaminosulfonyl-2-amino-6-(a-
4.0 g (65%) of isopropyl-α-hydroxybenzyl)benzimidazole was obtained as a yellow foam. Example 6 1-dimethylaminosulfonyl-2-amino-
6-(α-isopropyl-α-hydroxybenzyl)benzimidazole 1.2g (3.2mmole), p
- When the reaction described in Example 2 was carried out using 750 mg of toluenesulfonic acid and 100 ml of chloroform, 82 mg of 1-dimethylaminosulfonyl-2-amino-6-(α-isopropylidenebenzyl)benzimidazole was obtained as a grayish brown solid. Obtained. Example 7 150 ml of tetrahydrofuran and 31 ml (84 mmole) of a diethyl ether solution of methylmagnesium bromide
1-isopropylsulfonyl-2-
Amino-6-benzoylbenzimidazole 5.0
A solution prepared by dissolving 100 g (15 mmole) in 200 ml of tetrahydrofuran was added dropwise in a nitrogen atmosphere. 25% of the mixture
The mixture was stirred at ℃ for 1 hour, refluxed for 2 hours, cooled, poured into ice-1N hydrochloric acid, and extracted with diethyl ether. Concentrate the mixed solution (1500ml) to 800ml,
It was dried and concentrated under reduced pressure. The resulting product was dissolved in diethyl ether and diethyl ether/hexane was added, the mixture was boiled until cloudy and recrystallized from diethyl ether/hexane. Mixed liquid at 25℃
The mixture was cooled to 10° C. and then recooled to 10° C. to obtain 2 g of product. The solution was concentrated under reduced pressure to obtain the product, i.e., 1-isopropylsulfonyl-2-amino-
An additional 2 g of 6-(α-hydroxy-α-methylbenzyl)benzimidazole was recovered. m/e=360,344 (standard) Elemental analysis C ₁₈ H ₂₁ N ₃ O ₃ S (molecular weight 359) Calculated value: C, 60.15; H, 5.89; N, 11.69 Experimental value: Primary product C, 60.37 ;H, 5.73;N, 11.46 Secondary product C, 61.30;H, 6.26;N, 10.69 Example 8 1-isopropylsulfonyl-2-amino-6
A solution of 2 g (5.6 mmole) of -(α-hydroxy-α-methylbenzyl)benzimidazole dissolved in 100 ml of chloroform was reacted with 1.3 g of p-toluenesulfonic acid. The mixture was stirred at reflux for 4 hours, cooled to 25°C, washed twice each with saturated potassium carbonate solution and water, and dried over sodium sulfate. The mixture was concentrated under reduced pressure and the residue was recrystallized from diethyl ether/hexane to obtain 1.1 g of 1-isopropylsulfonyl-2-amino-6-(α-methylenebenzyl)benzimidazole as pale orange crystals. mp147-148℃. m/e=341 Elemental analysis C ₁₈ H ₁₉ N ₃ O ₂ S (molecular weight 341) Calculated value: C, 63.32; H, 5.61; N, 12.31 Experimental value: C, 63.58; H, 5.53; N, 12.15 Example 9 The method described in Example 7 was carried out using 150 ml of tetrahydrofuran, 31 ml (84 mmole) of butylmagnesium bromide, and 5.0 g (15 mmole) of 1-isopropylsulfonyl-2-amino-6-benzoylbenzimidazole, and the mixture was Refluxing for 20 hours instead of 2 hours gave 5.0 g of 1-isopropylsulfonyl-2-amino-6-(α-hydroxy-α-butylbenzyl)benzimidazole as a tan foam. Elemental analysis C ₂₁ H ₂₇ N ₃ O ₃ S (molecular weight 401) Calculated value: C, 62.82; H, 6.78; N, 10.47 Experimental value: C, 63.14; H, 6.57; N, 10.17 Example 10 1-isopropylsulfonyl -2-Amino-6
-(α-hydroxy-α-butylbenzyl)benzimidazole 1g (2.5mmole), chloroform
75 ml and 600 mg of p-toluenesulfonic acid and refluxing for 90 minutes instead of 4 hours yields 1-isopropylsulfonyl-2-amino-6-(α-butylidenebenzyl). 790 mg of benzimidazole was obtained. Elemental analysis C ₂₁ H ₂₅ N ₃ O ₂ S (molecular weight 383) Calculated value: C, 65.77; H, 6.57; N, 10.96 Experimental value: C, 65.49; H, 6.31; N, 10.78 Example 11 Isopropyl magnesium bromide 40ml
(85mmole), 1-isopropylsulfonyl-2-
Amino-6-benzoylbenzimidazole 5.0
g (15 mmole), and 200 ml of tetrahydrofuran
When the reaction described in Example 7 is carried out using
Isopropylsulfonyl-2-amino-6-(a
5.0 g of -hydroxy α-isopropylbenzyl)benzimidazole were obtained as a yellow foam. m/e=399 Example 12 1-isopropylsulfonyl-2-amino-6
- When the reaction described in Example 8 is carried out using 890 mg (2.4 mmole) of (α-hydroxy-α-ethylbenzyl)benzimidazole, 50 ml of chloroform, and 600 mg of p-toluenesulfonic acid, 1-isopropylsulfonyl-2-amino -6-(α-
Ethylidenebenzyl)benzimidazole 630mg
was obtained as an amorphous foam. Elemental analysis C ₁₉ H ₂₁ N ₃ O ₂ S (molecular weight 355) Calculated value: C, 64.20; H, 5.96; N, 11.82 Experimental value: C, 63.93; H, 6.04; N, 11.64 Example 13 Tetrahydrofuran 80 ml, odor When the reaction described in Example 1 was carried out using a solution of 11.1 ml of butylmagnesium chloride and 2.05 g of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole dissolved in 90 ml of tetrahydrofuran, 1 was obtained.
-dimethylaminosulfonyl-2-amino-6-
1.7 g of (α-hydroxy-α-butylbenzyl)benzimidazole were obtained as a white foam. m/e=402 Example 14 1-dimethylaminosulfonyl-2-amino-
1-dimethylamino 302 mg of sulfonyl-2-amino-6-(α-butylidenebenzyl)benzimidazole was obtained. m/
e=384 The compound of formula () has a broad spectrum of antiviral action. This compound is associated with echovirus, mengo, coxsatsky (A9,
In addition to inhibiting the growth of various influenza viruses [Ann Arbor, Maryland
land B), Massachusetts
B) Hong Kong A, Pr-8a, and Taylor C
(Taylor C) (type A, B)]. The ability of the compound represented by formula () to inhibit the growth of different types of viruses in in vitro experiments was investigated using a plaque inhibition test [Siminoff,
Applied Microbiology, 9(1) , 66–72 (1961)
[similar to the method described in]]. Details of the test are described below. The compound represented by formula () was tested by the following method. Test method African green monkey kidney cells (BSC-1) or HeLa cells (5-3) were incubated with 5% immobilized fetal bovine serum (5%) at 37°C in a FAlcon flask with a volume of 25 c.c. FBS), penicillin (150 units/ml), and streptomycin (150 mcg/ml) in medium 199. Once a monolayer was formed, the supernatant was removed and 0.3 ml of an appropriately diluted solution of the virus (Echo, Mengo, Coxsatsky, polio, or rhinovirus) was added to each flask. After adsorption for 1 hour at room temperature, the virus-infected cell layers were treated with drug contents of 100, 20, 25, 12, 6, 3, and 3, respectively.
The cells were inoculated into a medium consisting of 1 part of double concentration medium 199 containing 0 mcg/ml of FBS, penicillin, and streptomycin and 1 part of 1% ion agar No. 2. A flask containing no drug was used as a control. A stock solution of the sulfonylbenzimidazole compound was prepared in dimethyl sulfoxide diluent at a concentration of 10 ⁴ mcg/ml. Flasks containing polio, Coxsatsky, echo, or mengo viruses were cultured at 37°C for 72 hours, and flasks containing rhinovirus were cultured at 32°C for 120 hours.
Plaques appeared on cells infected with the virus and where the virus multiplied. A solution consisting of 10% formalin and 2% sodium acetate was added to each flask to adhere the virus-inactivated cell layer to the inner wall of the flask. The surrounding cells were stained with crystal purple and viral plaques, regardless of their size, were counted. Plaque numbers were compared to those of controls at each drug concentration. The activity of the test compound was expressed as plaque reduction rate or inhibition rate (%). Also,
The concentration of drug that inhibits plaque by 50% can be a measure of activity. The 50% inhibition rate was indicated by the symbol _I50 . The test results showed inhibition of poliovirus. Poliovirus was used because this virus grows easily and gives uniform results. However, the activity of the compound represented by formula () is limited to other viruses, namely Coxsatskii (A9, A21, B5), echovirus (strains 1-4),
Mengo, rhinovirus (25 strains), and polio (,, and types) were also confirmed. Test results for various sulfonylbenzimidazole compounds are summarized in a table. In the table, the first
The column shows the example number, the second column shows the bonding position [5(6) position] of the corresponding benzimidazole compound, and the third to tenth columns show the virus plaque reduction rate (%) at a drug concentration of 0.75 to 100 mcg/ml. represent

[Table] The sulfonylbenzimidazole compound of formula () was tested both as a pure compound and as a mixture of isomers. Both isomers inhibit virus growth, but the 6-isomer is generally more active than the 5-isomer. Addition of compounds of formula () to virus culture media inhibits the growth of many viruses. The compounds of formula () can therefore be used in aqueous solution, preferably together with a surfactant. Surfactants are used for polio, Koksatskyi, rhinovirus,
or add to decontaminate surfaces where other viruses are present. Surfaces herein include medical glassware, medical work surfaces and the like in food manufacturing. Furthermore, the compound of formula () can be orally administered to warm-blooded animals, including humans, at a rate of 1 to 300 mg/kg body weight. Moreover, this administration can be repeated at necessary intervals. In practice, antiviral compounds can be administered every 4 to 6 hours. Compounds of the invention may be prepared in a manner suitable for a particular method of administration.
Preferably, it is used in combination with one or more adjuvants. Thus, for oral administration, the compounds may be combined with pharmacological diluents or carriers such as lactose, sucrose, starch, cellulose, talc, magnesium stearate, magnesium oxide, calcium sulfate, acacia powder, gelatin, sodium alginate. , sodium benzoate, stearic acid, and the like. Such compositions can be formulated into tablets or sealed capsules for convenient administration. Additionally, the compounds can also be administered parenterally. The compounds can also be mixed with aqueous solutions and used as nasal drops or nasal sprays.

Claims (1)

[Claims] 1 formula A sulfonylbenzimidazole compound represented by [However, R is C ₁ - C ₄ alkyl or -NR ₃ R ₄
and R ₃ and R ₄ independently represent C ₁ -C ₃ alkyl. R ₁ is hydrogen; R ₂ is (However, R ₅ represents phenyl; R ₇ represents C ₁ to _{C 7} alkylidene); and R ₂ is located at the 5th or 6th position. ] 2. The compound according to claim 1, which is any one of the following compounds. 1-dimethylaminosulfonyl-2-amino-
6-(α-methylenebenzyl)benzimidazole; 1-dimethylaminosulfonyl-2-amino-
6-(α-ethylidenebenzyl)benzimidazole; 1-dimethylaminosulfonyl-2-amino-
6-(α-isopropylidenebenzyl)benzimidazole; 1-isopropylsulfonyl-2-amino-6
-(α-methylenebenzyl)benzimidazole; 1-isopropylsulfonyl-2-amino-6
-(α-n-butylidenebenzyl)benzimidazole; 1-isopropylsulfonyl-2-amino-6
-(α-ethylidenebenzyl)benzimidazole; and 1-dimethylaminosulfonyl-2-amino-
6-(α-n-butylidenebenzyl)benzimidazole. 3 formulas [However, in the formula, R is C ₁ - C ₄ alkyl or -
_NR3R4 , where _R3 and _R4 are independently _{C1 to C3}
Represents alkyl. R ₅ represents phenyl, and [Formula] is located at the 5th or 6th position. ] is reacted with a C ₁ to C ₇ alkyl Grignard reagent, and then R ₂ is [formula] [wherein R ₆ represents C ₁ to C ₇ alkyl and R ₅ has the same meaning as above. has. ] After hydrolysis to a compound of the formula [wherein R ₇ represents C ₁ -C ₇ alkylidene and R ₅ has the same meaning as above. ] is characterized by subjecting it to a dehydration reaction to form a compound. formula [However, R in the formula has the same meaning as above. R ₁ is hydrogen; R ₂ is (However, R ₅ and R ₇ have the same meanings as above.), and R ₂ is located at the 5th or 6th position. ] A method for producing a sulfonylbenzimidazole compound.