KR810000232B1 - Process for preparing 1-thiazoli-nyl-5(6)-substituted-benzimidazoles - Google Patents

Abstract

Anti-viral title compds.[I; R = H, C1-4 acyl; R1 = (R2) R3C(OH)-(where, R2 is C1-3 cycloalkyl, C3-6 cyclo alkyl methyl, C3-6 cycloalkyl ethyl, (R2)R4:C- (where, R4 is C1-7 alkylydene were prepd. II was reacted with C1-7 alkyl magnesium halide or C1-7 alkyllithium and hydrolysed to give Ia(R1 = (R2)R3COH-; R = H). Ia was dehydrated to give Ib(R1 = (R2)R4: C-; R = H) and acylation of Ib gave I.

Description

Method for preparing 1-thiazolinyl-5 (6) -substituted-benzimidazole derivatives

The present invention relates to a method for preparing a pharmaceutically useful 1-thiazolinyl-5 (6) -substituted-benzimidazole derivative, the following structural formula (I) which inhibits the growth of the following virus.

In the above structural formula

R is hydrogen or C ₁ -C ₄ acyl

또는

이고 5번 또는 6번 위치에 있으며R ₁ is

or

At position 5 or 6

R ₂ is C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, (C ₃ -C ₆ cycloalkyl) methyl, (C ₃ -C ₆ cycloalkyl) ethyl, thienyl or phenyl

R ₃ is C ₁ -C ₇ alkyl

R ₄ is C ₁ -C ₇ alkylidene.

There are a lot of upper respiratory diseases caused by viruses. Almost one billion cases occur each year in the United States alone.

A study in the UK (Tyrell and Bymoe, 1966) found that 74% of people with a cold were infected with nasal cold virus. Since more than 80 species of nasal cold virus are already identified, the development of actual nasal cold virus wax is impossible. Thus, chemotherapy has become more desirable.

The efficacy of compounds that inhibit the growth of viruses by in vivo testing is readily demonstrated by a virus spot inhibition test similar to that described below.

(1), 66(1961)][See: Siminoff, Applied Microbiology,

(1), 66 (1961)]

Thiazolinyl benzimidazole compounds are described in the following references.

Reference: 1. US Pat. No. 3,749,717: 1-thiazolinyl-2-aminobenzimidazole effective as an antiparasitic and anti-inflammatory agent

2. US Pat. No. 3,825,537: 2-thiazolinyl-2-aminobenzimidazole effective as an antiparasitic and anti-inflammatory agent

3. US Pat. No. 3,833,574: Preparation of 1-thiazolinyl benzimidazolin-2-silver effective as an anti-inflammatory agent

4. Derwent No. 26199W / 16: 1-thiazolinyl-2-phenylbenzimidazole effective as an antiparasitic agent

Previously, thiazolinyl benzimidazole has not been described as an antiviral agent.

The present invention relates to the preparation of compounds which inhibit the growth of influenza of viruses, especially nasal cold virus, polio virus, Coxackie virus, echo virus, and Mengo virus. The novel thiazolinyl benzimidazole compounds are useful for inhibiting the growth of these viruses.

인 구조식(Ⅰ)화합물을 제조하고 임의로 탈수시켜 R₁이

인 구조식(Ⅰ) 화합물을 제조하거나 및/또는 아실화시켜 R이 C₁-C₄아실인 구조식(Ⅰ)화합물을 얻음을 특징으로 하는 구조식(Ⅰ)인 약학적으로 유용한 벤즈이미다졸 화합물의 제조방법에 관한 것이다.The present invention reacts the benzimidazole compound, a tautomer of formula (II), with C ₁ -C ₇ alkyl magnesium halide or C ₁ -C ₇ alkyllithium and hydrolyzes to give R ₁

Phosphorus (I) compound was prepared and optionally dehydrated so that R ₁

Preparation of a pharmaceutically useful benzimidazole compound of formula (I) wherein the compound is prepared and / or acylated to obtain a compound of formula (I) wherein R is C ₁ -C ₄ acyl. It is about a method.

In the above structural formula

R ₂ is as described above.

An ideal compound is a compound of formula (I) wherein R is hydrogen and R ₂ is phenyl.

Examples of preferred thiazolinyl benzoimidazole compounds in the structural formula (I) category are as follows.

1- (thiazolin-2-yl) -2-amino-5 (6)-(α-hydroxy-α-methylbenzyl) benzimidazole,

1- (thiazolin-2-yl) -2-amino-5 (6)-(α-methylenebenzyl) benzimidazole,

1- (thiazolin-2-yl) -2-amino-5 (6)-(α-ethylidenebenzyl) benzimidazole,

1- (thiazolin-2-yl) -2-amino-5 (6)-(α-hydroxy-α-n-hexylbenzyl) benzimidazole,

1- (thiazolin-2-yl) -2-amino-5 (6)-(α-η-hexylidenebenzyl) benzimidazole,

1- (thiazolin-2-yl) -2-amino-5 (6)-[α-hydroxy-α- (2,4-dimethyl-3-pentyl) benzyl] benzimidazole,

1- (thiazolin-2-yl) -2-amino-5 (6)-[α- (2,4-dimethyl-3-pentylidene) benzyl] benzimidazole,

Benzimidazole ＂a tautomer relates to a benzimidazole reactant capable of substituting hydrogen for nitrogen atoms.

Benzimidazole reactants that contain a substituent at position 5 of the benzene moiety without substitution at nitrogen are optionally of the corresponding tautomeric form parallel to the substituent at position 6.

Mixtures of isomers may be numbered with the optional positional relationship 5 (6).

The following is the definition of the various terms used herein.

“C ₁ -C ₃ alkyl” is a straight or branched aliphatic group having 1-3 carbon atoms, methyl ethyl, propyl and isopropyl.

C ₁ -C ₃ alkyl also contains C ₁ -C ₂ alkyl.

＂C ₁ -C ₇ alkyl＂ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, 2,4-dimethyl-3 Linear or branched aliphatic groups such as -pentyl, tert-butyl and -neopentyl.

The "thienyl" is a thiophene group attached to the 2 or 3 position.

＂C ₁ -C ₄ acyl is an aliphatic acyl group having 1 to 4 carbon atoms, such as formyl, acetyl, propionyl, butyryl and methylpropionyl.

1C ₁ -C ₇ Alkalidene ＂is methylene, ethylidene, propylidene, isopropylidene, butylidene, isobutylidene, 3-methyl-2-butylidene, 2,4-dimethyl-3-pentyl Linear or branched groups such as den and? -Hexylidene.

“C ₃ -C ₆ cycloalkyl” is a saturated alicyclic ring having 3 to 6 carbon atoms such as cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. ＂(C ₃ -C ₆ cycloalkyl) methyl 메틸 is a methyl group substituted with a saturated alicyclic ring having 3 to 6 carbon atoms as exemplified in the above C ₃ -C ₆ cycloalkyl＂.

＂1- (C ₃ -C ₆ cycloalkyl) ethyl＂ is ethyl substituted at position 1 with a saturated substituted group ring having 3 to 6 carbon atoms as described above.

Suitable dehydrating agents in the preparation include strong acids such as P-toluenesulfonic acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid or trifluoromethanesulfonic acid. C ₁ -C ₇ alkylmagnesium halides are suitable Grignard reagents and are hydrolyzed.

C ₁ -C ₇ alkyl lithium is like a Grignard reagent. Ideal solvents for the alkyl reaction are aromatic solvents such as tetrahydrofuran, benzene or toluene, or inert organic solvents such as diethyl ethyl. Ideal solvents for dehydration include alkynes such as hexane, aromatic solvents such as benzene or toluene, chlorinated alkanes such as methylene chloride or chloroform.

The reaction temperature usually ranges from 25 ° C. to the reflux temperature of the solvent.

Starting materials of formula (II) are prepared as described in what we are pending.

The thiazolyl benzimidazole product is separated by conventional methods such as filtration and the filtrate is concentrated to crystallize.

The reaction mixture can optionally be evaporated to dryness and the residue is treated with a suitable solvent such as acetone or methanol and separated to remove all insoluble matters. The solution containing the product is concentrated to crystallize or evaporate the product to obtain a second residue which is recrystallized from methanol. Benzimidazole compounds are recovered by filtration or centrifugation.

5 (6) -isomers can be separated by fractional crystallization or column chromatography. Usually the 6-isomer is first crystallized in the mixed solution.

The thiazolinyl benzimidazole compound wherein R is C ₁ -C ₄ acyl is prepared by using 1-thiazolinyl-2-amino-5 (6) -substituted-benzimidazole prepared as described above with acetic anhydride, propionic anhydride or butyl Or a mixed anhydride of formic acid and acetic acid.

1-thiazolinyl benzimidazole compounds are tested as both pure compounds and isomer mixtures. Both isomers inhibit viral growth and the 6-isomer generally acts stronger than the 5-isomer. Compounds belonging to the structural formula (I) category can inhibit various viruses when the medium in which the virus is growing is added. Therefore, the compound of formula (I) can be used as an aqueous solution, preferably as a surfactant solution, which can be used for polio, coxsacks, nasal contusions with nasal colds and influenza viruses, and similar areas used for the manufacture of food and working surfaces of hospitals. Used to prevent contamination of the same surface.

In addition, the compound can be administered orally 1-300mg / kg to warm-blooded animals and human body. Administration can be repeated periodically as needed. Typically, antiviral compounds can be administered every 4-6 hours.

Ideally, the compound of formula (I) is used in admixture with one or more additives suitable for the particular administration method. Thus, in the case of oral administration, the compound may contain pharmaceuticals such as lactose, sucrose starch powder, cerose, talc, magnesium, stearate, magnesium oxide, calcium sulfate, acacia powder, gelatin, sodium alginate, sodium benzoate and stearic acid. It is made into a composition together with a diluent and a carrier. Such compositions may be formulated into capsules filled in tablets or capsules for ease of administration. In addition, the compound may be administered parenterally.

The compounds may also be administered as liquid drops or nasal sprays, mixed with liquids.

The following example describes in more detail the preparation of the compound of formula (I) and the 'n / e' used to characterize the product is the ratio of mass to drop of ions appearing in the mass spectrometry of the product. In general, the numerical value corresponds to the molecular weight of the mother bus.

Example 1

4 g (12.4 mmol) of 1- (thiazolin-2-yl) -2-amino-6-benzoylbenz imidazole are added to 1,000 ml of tetrahydrofuran at −10 ° C. under nitrogen gas. To the solution was added 50 ml (1.6 M) of η-butyl lithium in hexane dropwise under nitrogen gas. The temperature is raised to -5 ° C. The temperature of the solution is kept at -5 ° C to -10 ° C for 1 hour. Warm the solution to 25 ° C. and hold at this temperature for 3 hours. The solution was added to 1 L of water, evaporated, washed with tetrahydrofuran and filtered to give the white solid 1- (thiazolin-2-yl) -2-amino-6- (α-hydroxy-α-butyl) benzylbenz 4.56 g of imidazole is obtained. Melting Point 206-209 ℃

Example 2

2 g (5.26 mmol) of 1- (thiazolin-2-yl) -2-amino-6- (α-hydroxy-α-η-butylbenzyl) benzimidazole are dissolved in 250 ml of chloroform. To the solution is added 1.3 g of P-toluene sulfonic acid. The mixture was cooled to 25 ° C., washed twice with saturated aqueous sodium carbonate solution, dehydrated and evaporated to 900 mg of 1- (thiazolin-2-yl) -2-amino-6- (α-η-butylidenebenzyl) Obtain benzimidazole. Melting point 177-179 ℃

Example 3

Example 1 was prepared using 5.0 g (15.5 mmol) of 1- (thiazolin-2-yl) -2-amino-6-benzoylbenzimidazole, 500 ml of tetrahydrofuran, 50 ml of isopropyl magnesium bromide ( Repeating with 2.1 M in diethyl ether) yields 1.24 g of 1- (thiazolin-2-yl) -2-amino-6- (α-hydroxy-α-isopropylbenzyl) benzimidazole . Melting Point 212-215 ℃

Example 4

Example 2 was prepared with 1.2 g of 1- (thiazolin-2-yl) -2-amino-6- (α-hydroxy-α-isopropylbenzyl) benzamidazole, 250 ml of chloroform and 1.3 g of Repeat with P-toluenesulfonic acid to obtain 280 mg of 1- (thiazolin-2-yl) -2-amino-6 (α-isopropylidenebenzyl) benzimidazole. Melting Point 242-245 ° C (Decomposition)

Example 5

Example 1 was prepared with 2.0 g (6.22 mmol) of 1- (thiazolin-2-yl) -2-amino-6-benzoyl-benzimidazole 23 ml ethyllithium (1.25 M in benzene) and 500 ml Repeated use with tetrahydrofuran yields 2.5 g of 1- (thiazolin-2-yl) -2-amino-6- (α-hydroxy-α-ethylbenzyl) benzimidazole.

Melting Point 206-208 ° C m / e 352

Example 6

The preparation of Example 2 was prepared using 1 g of 1- (thiazolin-2-yl) -2-amino-6- (α-hydroxy-α-ethylbenzyl) benzimidazole, 0.7 g of P-toluenesulfonic acid, 100 Repeat with mL of chloroform to afford 700 mg of crude product. The crude product is recrystallized from ethyl acetate to give 300 mg of 1- (thiazolin-2-yl) -2-amino-6- (α-ethylidenebenzyl) benzimidazole. Melting point 186-187 ℃

Melting point after recrystallization 211 ° C., m / e 352

[Test Methods]

Fetal bovine serum (FBS), penicillin (150 units per ml) and streptomycin (150 mcg / kg) in the fetus with 5% inactivation of African green monkey kidney cells (BSC-1) or Hela cells (5-3) Ml) was grown in 37 cc Falcon flasks on medium 199 at 37 ° C. Once the fused monolayer is formed, the supernatant growth medium is removed and 0.3 ml of appropriate virus (eco, mengo, coxsackie, polio or nasal cold) diluent is added to each flask.

After 1 hour of absorption at room temperature, the virus-infected cell surface was partially diluted with 1% ionagar No 2 and partly doubled in medium 199 containing FBS, penicillin and streptomycin and 100, 50 ml / drug. Cover with medium containing 25, 12, 6, 3 and 0mcg. Flasks containing no (mcg / ml) drug are used as a control for testing.

The stock solution of the thiazolinyl or thiazinyl benz imidazole compound of formula (I) was prepared by treatment with dimethyl sulfoxide at a concentration of 104 mcg / ml. The flasks are incubated for 72 hours at 37 ° C. for polio, coxsackie, Echo and Mengo virus, and 120 hours at 32 ° C. for nasal cold virus. Influenza virus, Ann Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8a and Taylor C (Type A, Type B) are 37 ° C. Incubate for 72 hours using MDCK cells (Madin Darby dog kidney cells).

A 10% formalin and 2% sodium acetate solution is added to each flask to inactivate the virus and fix the cell surface to the flask surface. Stain the virus spots of any size after staining the cells with crystal violet. The score for each drug concentration is compared to the control score. The action of the test compound is expressed as a spot reduction percentage or an inhibition percentage. A drug concentration, I ₅₀ , which selectively inhibits speckle formation by 50%, can be used as a measure of action.

The test results are expressed as inhibition against poliovirus type I because poliovirus type I is easy to culture and robust test results can be obtained. However, the structural formula (I) compounds include coxsackies (A9, A21 and B5), echoviruses (1-4 species), mengo, nasal cold (25 species), polio (types I, II, and III) and an arbo, MD B It also works on other viruses, such as influenza viruses such as Massachusetts B, Hong Kong A, PI-8A and Taylor C (types A and B). The test results of the various thiazolinyl or thiazinyl benzimidazole compounds are summarized in the following table (I), where column 1 is the example number for the preceding compound and column 2 is the isomer of position 5 (6). Means 3-10 are percentages of viral spot reduction for 0.75-100 mcg of drug dilution solution per ml.

Table 1. Polio of 1- (thiazolin-2-yl) -2-amino-5 (6) -substituted-benzimidazole]

[Virus Type I Spot Reduction]

Drug concentration (micrograms per milliliter)

** 5 or 6 represents each isomer.

Claims (1)

The following compound of formula (II) is reacted with C ₁ -C ₇ alkyl magnesium halide or C ₁ -C ₇ alkyllithium and hydrolyzed to give R ₁

Phosphorus (I) compounds are prepared or the product is dehydrated to give R ₁

A process for preparing a compound of formula (I), characterized in that a compound wherein R is C ₁ -C ₄ acyl is prepared by preparing or acylating a compound of formula (I)

In the above structural formula R is hydrogen or C ₁ -C ₄ acyl R ₁ is

or

At position 5 or 6 R ₂ is CC ₃ alkyl, C ₃ -C ₆ cycloalkyl, (C ₃ -C ₆ cycloalkyl) methyl, (C ₃ -C ₆ cycloalkyl) ethyl, thienyl or phenyl R ₃ is C ₁ -C ₇ alkyl R ₄ is C ₁ -C ₇ alkylidene.