JP3388301B2 - Benzimidazole derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel benzimidazole derivative useful as a pharmaceutical having an anti-inflammatory action, an analgesic action and an inhibitory action on platelet aggregation.

[0002]

2. Description of the Related Art A benzimidazole derivative according to the present invention is disclosed in Japanese Unexamined Patent Publication (Kokai) No. 64-56665.
[4- (4-Acetyl-3-hydroxy-2-propylphenoxy) butylthio] benzimidazole-5-carboxylic acid and the like, JP-A-61-186368 and JP-B-6-1986.
2- [3- (4-acetyl-) described in 3-35626
3-Hydroxy-2-propylphenoxy) propylthio] benzimidazole has an antiallergic effect, as described in Japanese Patent Application Laid-Open No. 63-179840, ethyl 6- {p- [5-
(2-Benzimidazolylthio) pentyloxy] phenoxy} -2,2-dimethylhexanoate has an antitumor effect, as described in 4,63-dihydro-6- {4- [3] described in JP-A-63-145269. It has been reported that-(2-benzimidazolylthio) propyloxy] phenyl} -3 (2H) -pyridazinone has a platelet aggregation inhibitory action. EP 407 217 also discloses 2-
[6- (2-chloro-4-methoxyphenoxy) -1-
[Hexylthio] benzimidazole has been reported to have an antiviral effect, an anti-inflammatory effect, and a platelet aggregation inhibitory effect. Furthermore, the compounds described in EP520552 have been reported to have an antihyperlipidemic effect. However, there is no disclosure of a benzimidazole derivative having an alkanoic acid on a benzene ring as in the present invention, and no description suggesting this. Furthermore, it is of course not known that it has an anti-inflammatory action, an analgesic action and a platelet aggregation inhibitory action.

[0004]

At present, many non-steroidal anti-inflammatory drugs have been put on the market, but they have relatively strong effects, but also have remarkable side effects such as gastrointestinal tract disorders, or have side effects. The effect of an anti-inflammatory agent with a small amount is not necessarily sufficient. Therefore, a drug having better anti-inflammatory and analgesic effects and less side effects such as gastrointestinal tract disorders is desired.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies with the aim of obtaining a drug having excellent anti-inflammatory action, analgesic action and platelet aggregation inhibitory action, and having few side effects. The present inventors have found that a benzimidazole derivative achieves an intended purpose and completed the present invention. The benzimidazole derivative of the present invention has the following general formula (I)

Embedded image Wherein Q and m are integers of 1 to 3, and R ¹ and R ² are a hydrogen atom, a halogen atom, a trihalomethyl group, an alkyl group, a hydroxyl group, an alkoxy group, a mercapto group, an alkylthio group, an amino group, and a nitro group. are shown, may be the same or different, the R ³ is a hydrogen atom or an alkyl group, R ⁴
Is a hydroxyl group, an alkoxy group, or an amino group, and X and n are 1 to
Which means an integer of 10].

The general formula (I) will be described more specifically. In the above general formula, a halogen atom is fluorine, chlorine, bromine, iodine, a trihalomethyl group is a trifluoromethyl group or the like, and an alkyl group is methyl, ethyl, n
-Propyl, iso-propyl, n-butyl, iso-
And a lower alkyl group having 1 to 6 carbon atoms such as butyl and tert-butyl. The alkoxy group is a lower alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy group, and the alkiothio group is methylthio, ethylthio. , N-propylthio, iso-propylthio, n-butylthio, iso-
1-6 carbon atoms such as butylthio and tert-butylthio groups
Lower alkylthio groups respectively.

In the above formula, the amino groups of R ¹ and R ² are unsubstituted amino groups and monoalkylamino groups such as methylamino, ethylamino and propylamino groups, dimethylamino, diethylamino and dipropylamino groups. Indicates a dialkylamino group. Further, the amino group of R ⁴ is an unsubstituted amino group and a monoalkylamino group such as methylamino, ethylamino, propylamino group, dimethylamino, diethylamino, dialkylamino group such as dipropylamino group, cyclobutylamino, cyclopentylamino, cyclic alkylamino group such as a cyclohexylamino _{group, -NH- (CH 2) Y -R} 5 ( wherein, Y is an integer of 0 to 6, R ⁵ is a hydroxyl group, an alkoxy group, a monoalkylamino group, a dialkylamino Amino group, piperidino, pyrrolidino,
A substituted phenylamino group in which a cyclic amino group such as morpholino, piperazino, and pipecolino, a phenyl group or a halogen atom, an alkyl group, an alkoxy group, a nitro group, a hydroxyl group, a trihalomethyl group, or the like is substituted at any position) A heterocyclic amino group such as a group, pyridylamino, thienylamino, furylamino, pyrrolylamino, oxazolylamino, thiazolylamino, imidazolylamino group, and a cyclic amino group such as morpholino, piperidino, pyrrolidino, piperazino, and pipecolino.

The compound of the present invention having the above general formula (I) can take the form of a pharmaceutically acceptable drug in combination with a conventional excipient. For example, it can be used as an oral drug such as tablets, granules, syrups and capsules, or a parenteral drug such as injections, suppositories, ointments, gels, creams, lotions and patches. In addition,
The compound of the present invention may contain, if necessary, an inorganic salt (sodium salt, potassium salt, calcium salt, aluminum salt, hydrochloride, etc.) or an organic salt (fumarate, maleate, succinate, triethylamine salt, ethanolamine). Salts, triethanolamine salts and the like).

Further, since the compound of the present invention has an asymmetric carbon atom, the structural formula represented by the above general formula (I) includes those optical isomers and a mixture of optical isomers. When the compound having the general formula (I) is a racemic compound, it can be optically resolved by a known method to obtain each of the isomer of d-form or l-isomer.

Next, a method for producing the compound according to the present invention will be described. The compound of the present invention can be obtained in good yield according to the following production methods, but can also be produced by other methods chemically similar to these production methods or completely different from the above. Manufacturing method 1

Embedded image [However, in the above production method, Z represents a halogen atom such as chlorine, bromine or iodine, an alkanesulfonyloxy group such as methanesulfonyloxy, A represents CN or COR ⁴ , and Q, m, n, X, R ¹ , R ² , R ³ and R ⁴ have the same meanings as defined above.] Compound (II) and compound (III) are converted to a base (for example, potassium carbonate, sodium hydroxide, sodium hydride, sodium ethoxide). , 1,8-diazabicyclo [5,
4,0] undec-7-ene in an inert solvent (eg, ethanol, benzene, acetone, tetrahydrofuran, dimethylformamide, etc.) in the presence of 0-150.
C. for 0.5 to 24 hours to give Compound (I)
V) can be obtained. Manufacturing method 2

Embedded image [However, in the above production method, Q, m, n, X, R ¹ , R ² ,
R ³ , Z, and A have the same meanings as defined above.] Compound (V) and compound (VI) are reacted in the presence of a base (eg, potassium carbonate, sodium hydroxide, etc.) in an inert solvent (eg, acetone, tetrahydrofuran, Compound (IV) can be obtained by reacting at 0 to 150 ° C. for 1 to 24 hours in dimethylformamide, benzene and the like.

Manufacturing method 3

Embedded image [However, in the above production method, Q, m, n, x, R ¹ , R ² ,
R ³ , R ⁴ , and A have the same meanings as defined above.] Compound (IV) is an inorganic base (eg, sodium hydroxide, potassium hydroxide, potassium carbonate, etc.) or an inorganic acid (eg, hydrochloric acid, sulfuric acid, etc.). Hydrolysis at 20-120 ° C. for 0.5-10 hours in the presence gives the compound of formula (I) (R ⁴ ＯＨOH). Further, the compound of the formula (I) (R ⁴ ＯＨOH) can be converted into various amides and esters according to known methods.

[0013]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which, of course, are not intended to limit the scope of the present invention.

Example 1 15 g of 2-mercaptobenzimidazole and 30 g of ethyl 4- (3-bromopropoxy) phenylacetate were mixed with 3 g of ethyl acetate.
After dissolving in 00 ml of ethanol, 21 g of potassium carbonate was added, and the mixture was refluxed for 2 hours with stirring. After completion of the reaction, insolubles were filtered off, and the filtrate was subjected to solvent removal under reduced pressure. Then, 200 ml of chloroform was added to the residue, washed with water, dried, and after removing the solvent under reduced pressure, recrystallized from isopropyl ether to give 4- [3- (2-benzimidazolylthio).
32.6 g of ethyl propoxy] phenylacetate (yield 8
8.1%). The melting points and instrumental analysis values of the obtained compound are shown below. Melting point 69-71 ° C IR spectrum 1731cm ^-1 (-COO-) Mass spectrum (m / e) 370 (M ⁺ ) Elemental analysis C ₂₀ H ₂₂ N ₂ O ₃ S Found C: 64.90 H: 6.01 N: 7.50 Calculated The value C: 64.84 H: 5.99 N: 7.56 1 HNMR spectrum _{(CDCl 3, δ) 1.25 (} 3H, t, J = 6.96Hz, -CH 2 - CH 3), 2.19 ~2.29 (2H, m, -CH 2
-CH ₂ -CH _2- ), 3.46 (2H, t, J = 6.59 Hz, -S-CH _2- ), 3.55 (2H, s
-CH ₂ COO-), 4.04 (2H, t, J = 5.86Hz, -O-CH _2- ), 4.15 (2H, q, J
= 6.96Hz, -CH ₂ CH ₃ ), 7.80 (2H, d, J = 8.43Hz, Ar-H), 7.14〜
7.75 (6H, m, Ar-H), 9.93 (1H, br, NH)

Example 2 80 ml of aqueous ethanol containing 2.8 g of potassium hydroxide was added to 8 g of ethyl 4- [3- (2-benzimidazolylthio) propoxy] phenylacetate, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the solvent was concentrated under reduced pressure, 50 ml of water was added, and the mixture was washed with 50 ml of ethyl acetate. The aqueous layer was neutralized with dilute hydrochloric acid. Then, the mixture was extracted with 80 ml of ethyl acetate, washed with water, dried and the solvent was removed. The residue was recrystallized from a mixture of methanol and ether to obtain 6.9 g (yield 93.3%) of 4- [3- (2-benzimidazolylthio) propoxy] phenylacetic acid. The melting points and instrumental analysis values of the obtained compound are shown below. Melting point 129.5-130.5 ° C IR spectrum 1678cm ^-1 (-COOH) Mass spectrum (m / e) 342 (M ⁺ ) Elemental analysis C ₁₈ H ₁₈ N ₂ O ₃ S Observed value C: 63.09 H: 5.25 N: 8.20 Calculated value C: 63.14 H: 5.30 N: 8.18 1 HNMR spectrum _{(DMSO-d 6, δ)} 2.12~2.22 (2H, m, -CH 2 - CH 2 - CH 2 -), 3.41 (2H, t, J = 6.96H
z, -S-CH _2- ), 3.46 (2H, s-CH ₂ COOH), 4.09 (2H, t, J = 6.23Hz,-
O-CH _2- ), 6.87 (2H, d, J = 8.61Hz, Ar-H), 7.07 ~ 7.12 (2H, m,
Ar-H), 7.15 (2H, d, J = 8.61 Hz, Ar-H), 7.36 to 7.47 (2H, m, Ar
-H), 12.39 (1H, br, -COOH)

Example 3 10 g of 2-mercaptobenzimidazole and 20 g of ethyl 2- (3-bromopropoxy) phenylacetate were added to 1
After dissolving in 50 ml of ethanol, 5 g of sodium ethoxide was added, and the mixture was refluxed for 1 hour with stirring. After the completion of the reaction, the reaction solution was poured into water and extracted twice with 100 ml of ethyl acetate. The extract was washed with water, dried and the solvent was removed. The residue was recrystallized from a mixture of acetone and isopropyl ether to give 21.6 g of ethyl 2- [3- (2-benzimidazolylthio) propoxy] phenylacetate (yield 87.
6%). The melting points and instrumental analysis values of the obtained compound are shown below. Melting point 97.5-98.5 ° C IR spectrum 1738cm ^-1 (-COO-) Mass spectrum (m / e) 370 (M ⁺ ) Elemental analysis C ₂₀ H ₂₂ N ₂ O ₃ S Found C: 64.93 H: 5.95 N: 7.48 Calculated Value C: 64.84 H: 5.99 N: 7.56 ¹ H NMR spectrum (CDCl ₃ , δ) 1.25 (3H, t, J = 6.96 Hz, -CH ₂ -CH ₃ ), 2.20 to 2.30 (2H, m, -CH ₂
-CH ₂ -CH _2- ), 3.40 (2H, t, J = 6.96Hz, -S-CH _2- ), 3.69 (2H,
s, -CH ₂ -COO-), 4.04. (2H, t, J = 5.50Hz, -O-CH _2- ), 4.18 (2
H, q, J = 6.96Hz, - CH 2 - CH 3), 6.68 ~6.71 (1H, m, Ar-H), 6.87
~ 6.93 (1H, m, Ar-H), 7.10 ~ 7.75 (6H, m, Ar-H), 10.24 (1H, b
r, NH)

Example 4 To 13 g of ethyl 2- [3- (2-benzimidazolthio) propoxy] phenylacetate was added 100 ml of aqueous ethanol containing 4.1 g of potassium hydroxide.
Heated for a minute. After completion of the reaction, the solvent was concentrated under reduced pressure, and water 100
After adding thereto ml and washing with 100 ml of ethyl acetate, the aqueous layer was weakly acidified with dilute hydrochloric acid. Next, the precipitated crystals are filtered, washed with water, dried, and then recrystallized from a mixture of methanol and hexane to give 2- [3- (2-benzimidazolthio).
Propoxy] phenylacetic acid 10.1 g (84.1 yield)
%). The melting points and instrumental analysis values of the obtained compound are shown below. Melting point 194-197 ° C IR spectrum 1676cm ^-1 (-COOH) Mass spectrum (m / e) 342 (M ⁺ ) Elemental analysis C ₁₈ H ₁₈ N ₂ O ₃ S Observed value C: 63.19 H: 5.30 N: 8.21 Calculated value C: 63.14 H: 5.30 N: 8.18 1 HNMR spectrum _{(DMSO-d 6, δ)} 2.13~2.22 (2H, m, -CH 2 - CH 2 - CH 2 -), 3.43 (2H, t, J = 6.96H
z, -S-CH _2- ), 3.54 (2H, s, -CH ₂ -COOH), 4.10 (2H, t, J = 6.23 H
z, -O-CH _2- ), 6.85-6.97 (2H, m, Ar-H), 7.09-7.24 (4H,
m, Ar-H), 7.41 ~ 7.47 (2H, m, Ar-H), 11.80 (1H, br, -COOH)

Example 5 10 g of 2-mercaptobenzimidazole and 23.3
g of 4- (4-bromobutoxy) -3-chlorophenylacetate in 200 ml of ethanol,
3.8 g of potassium carbonate was added, and the mixture was refluxed for 2 hours with stirring. After completion of the reaction, insolubles were filtered off, and the filtrate was subjected to solvent removal under reduced pressure. Then, 150 ml of chloroform was added to the residue, washed with water, dried, and the solvent was removed under reduced pressure. The residue was recrystallized from a mixed solution of isopropyl ether and petroleum ether.
-[4- (2-benzimidazolthio) butoxy] -3
-Ethyl chlorophenylacetate 25.1 g (yield 90%)
Got. The melting points and instrumental analysis values of the obtained compound are shown below. Melting point 78-81 ° C IR spectrum 1734cm ^-1 (-COO-) Mass spectrum (m / e) 418 (M ⁺ ) Elemental analysis C ₂₁ H ₂₃ ClN ₂ O ₃ S Observed value C: 60.32 H: 5.60 N: 6.62 Calculated Value C: 60.21 H: 5.53 N: 6.69 ¹ H NMR spectrum (CDCl ₃ , δ) 1.26 (3H, t, J = 6.96 Hz, -CH ₂ -CH ₃ ), 1.96 to 2.03 (4H, m, -CH ₂
-CH ₂ -CH ₂ -CH _2- ), 3.41 (2H, t, J = 6.78Hz, -S-CH _2- ), 3.52 (2
H, s, -CH ₂ COO-), 4.04 (2H, t, J = 5.68Hz, -O-CH _2- ), 4.16 (2H,
q, J = 6.96 Hz, - CH 2 - CH 3), 6.82 (1H, d, J = 8.42Hz, Ar-H),
7.07 〜7.75 (6H, m, Ar-H), 9.29 (1H, br, NH)

Example 6 To 10 g of ethyl 4- [4- (2-benzimidazolylthio) butoxy] -3-chlorophenylacetate was added 150 ml of aqueous ethanol containing 6.6 g of potassium carbonate.
Heated to reflux for an hour. After completion of the reaction, the solvent was concentrated under reduced pressure, 50 ml of water was added, and the mixture was washed with 100 ml of ethyl acetate. The aqueous layer was weakly acidified with dilute hydrochloric acid. Then, the mixture was extracted with 200 ml of ethyl acetate, washed with water, dried and the solvent was removed. The residue was recrystallized from a mixture of acetone and petroleum ether to give 4- [4
7.7 g (yield 82.5%) of-(2-benzimidazolylthio) butoxy] -3-chlorophenylacetic acid was obtained.
The melting points and instrumental analysis values of the obtained compound are shown below. Melting point 159-161 ° C IR spectrum 1696 cm ^-1 (-COOH) Mass spectrum (m / e) 390 (M ⁺ ) Elemental analysis C ₁₉ H ₁₉ ClN ₂ O ₃ S Observed value C: 58.41 H: 4.93 N: 7.06 Calculated value C: 58.38 H: 4.90 N: 7.17 1 HNMR spectrum _{(DMSO-d 6, δ)} 1.88~1.93 (4H, m, -CH 2 - CH 2 -CH 2 - CH 2 -) 3.36 (2H, t, J = 6.9
6 Hz, -S-CH _2- ), 3.50 (2H, s, -CH ₂ COOH), 4.08 (2H, t, J = 6.0
4 Hz, -O-CH _2- ), 7.04 to 7.17 (4H, m, Ar-H), 7.29 (1H, d, J = 2.
19 Hz, Ar-H), 7.39 to 7.45 (2H, m, Ar-H), 12.18 (1H, br, -COO
H)

Examples 7 to 26 The compounds shown in Tables 1 and 2 were synthesized according to the methods of Examples 1 to 6.

[Table 1]

[Table 2]

[0021]

Next, pharmacological experiments and pharmacological data of the compound of the present invention will be described. Pharmacological experiment 1 (carrageenan footpad edema experiment in rats) One rat was injected into the footpad of a Wistar male rat weighing around 150 g.
The reaction was initiated by subcutaneous injection of 0.1 ml of% lambda carrageenin. Thereafter, the footpad volume was measured over time. In addition, the test compounds shown in the following Table 3 obtained in the Examples 6
Oral administration at 0 minutes. In addition, the results were shown as the inhibition rate with respect to the control group at 3 hours after the induction of the reaction. Table 3 below shows the experimental results.

[Table 3] From the above results, it was found that the compound of the present invention had a clear inhibitory action on carrageenan footpad edema.

Pharmacological experiment 2 (acetic acid writhing experiment in mice) Intraperitoneal injection of ddy male mice weighing 20 to 24 g.
0.1 ml / 10 g of 6% acetic acid was intraperitoneally administered, and the number of writhing that occurred in 5 minutes to 10 minutes was counted. The test compounds shown in Table 4 below were orally administered 30 minutes before administration of acetic acid. In addition, the results are shown by the inhibition rate with respect to the control group. Table 4 below shows the experimental results.

[Table 4] From the above results, it was found that the compound of the present invention had a clear inhibitory action on acetic acid rising.

Pharmacological experiment 3 (Experiment of gastric mucosal damage in rats) Eight male Wistar rats weighing around 160 g were used in each group. After fasting the rats for 18 hours, the test compounds shown in the following Table 5 obtained in Examples were orally administered, and after 3.5 hours, the stomach was excised, the stomach was fixed, and after dissection along the greater curvature, The presence or absence of ulcer formation was visually observed. Table 5 below shows the experimental results.

[Table 5] From the above results, it was found that the compound of the present invention has almost no gastric mucosal damage effect as a side effect.

[0024]

As is clear from the above pharmacological experiments, the compounds of the present invention have excellent anti-inflammatory activity, analgesic activity and platelet aggregation inhibitory activity, and have very few side effects such as gastrointestinal tract disorders and anti-inflammatory drugs and analgesics. It is very useful in the pharmaceutical industry as a drug or a platelet aggregation inhibitor.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 235/28 A61K 31/415 CAOLD (STN) CAPLUS (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (I) Wherein Q and m are integers of 1 to 3, and R ¹ and R ² are a hydrogen atom, a halogen atom, a trihalomethyl group, an alkyl group, a hydroxyl group, an alkoxy group, a mercapto group, an alkylthio group, an amino group, and a nitro group. are shown, may be the same or different, the R ³ is a hydrogen atom or an alkyl group, R ⁴
Is a hydroxyl group, an alkoxy group, an amino group, X and n are 1 to 1
A benzimidazole derivative represented by the formula: