JPH049372A - 4,5,6,7-tetrahydrobenzimidazole derivative - Google Patents

Abstract

NEW MATERIAL:Compounds of formula I (R is alkenyl or alkynyl). EXAMPLE:N-(2-propargyloxyphenyl)-4,5,6,7-tetrahydrobenzimidazole-5- carboxamide-fumaric acid salt. USE:Having 5-HT3 receptor antagonism and useful for prevention and remedy of megrim, complex headache, trigeminal neuralgia, anxiety neurosis, gastrointestinal disorder, peptic ulcer, irritable colon syndrome, etc. PREPARATION:4,5,6,7-Tetrahydrobenzimidazole-5-carboxylic acid of formula II or its reactive derivative is reacted with an amine of formula III in a solvent such as dioxane at a cooled temperature-room temperature-a heated temperature, as necessary, in the presence of a base (e.g. pyridine) to obtain a compound of formula I.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides 4,5,6,7-titrahydrobenzimida (in the formula:
R means an alkenyl group or an alkynyl group. (Solving Means) The inventors of the present invention have conducted intensive research on compounds having an antagonistic effect on 5-HT receptors, and found that the compound represented by the following general formula is a new compound.

They discovered that it has even higher 5-HT3 receptor antagonism and completed the present invention.

In the definition of substituents in this specification, [alkyl group] includes a vinyl group and a 1-propenyl group.

2-Flobenyl group (allyl group), 1-butenyl group, 2-
Butenyl group, 3-butenyl group, 1-methyl-2-7''tenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 2-methyl-1-pentenyl group, 1-hexenyl group, 2- Hexenyl group, 2-methyl-3-hexenyl group, 3-ethyl-4-hexenyl group, etc., and "alkynyl group" includes ethynyl group, 1-propynyl group, 2-ethyl-4-hexenyl group, etc.
-7' Robinyl group (propargyl group), 1-butynyl group, 2-butynyl group, 1-methyl-3-phnyl group, 2-
Methyl-3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pe/tynyl group, 4-pentynyl group, 2-
Examples include methyl-4-hebutynyl group. these"
"Alkenyl group" or "alkynyl group" especially has 2 carbon atoms.
Preferably, the number is 5 to 5.

Furthermore, some of the compounds of the present invention form salts. The present invention also includes salts of the compound of the above general formula (I), and examples of such salts include salts with inorganic bases such as sodium and potassium, ethylamine, propylamine, diethylamine, triethylamine, and morpholine.

Salts with organic bases such as piperidine, N-ethylpiperidine, jetanolamine, and cyclohexylamine, salts with basic amino acids such as lysine and ornithine, ammonium salts, hydrochloric acid, and sulfuric acid.

Mineral acid salts with phosphoric acid, hydrobromic acid, etc., acetic acid, oxalic acid,
Examples include salts with organic acids such as succinic acid, citric acid, maleic acid, linchoic acid, fumaric acid, tartaric acid, and methanesulfonic acid, and salts with acidic amino acids such as glutamic acid and aspartic acid.

Furthermore, in the general formula 2, the compound (I) of the present invention is 9
Although it is expressed as a compound represented by the formula RO-4)JHCOT)C, the compound (I) of the present invention also includes a compound represented by the formula RO(:1rN1(00te)), which is its tautomer. is also included.

Furthermore, the compounds of the present invention have asymmetric carbon atoms in the molecule, and the compounds included in general formula (I) include all isomerisms such as optically active forms, racemates, diastereomers, etc. based on these asymmetric carbon atoms. Includes the body.

(Manufacturing method) A typical manufacturing method of the compound of the present invention will be specifically explained below.

1st M method (m) (U)
(1) The compound (I) of the present invention is an amine represented by the general formula (III), and 4,5,6.
It can be obtained by reacting 7-titrahydropenzimidazole-5-carboxylic acid or a reactive derivative thereof.

The reaction between compound (m) and compound (II) or its reactive derivative is an amide bond-forming reaction, and various conventionally known methods can be applied. There are no particular limitations on the solvent as long as it does not participate in the reaction. Examples include dioxane, diethyl ether, tetrahydrofuran, chloroform, ethyl acetate, dimethylformamide, and the like.

Compound (n) may be subjected to reaction with compound (I[D) as a carboxylic acid, or may be subjected to reaction with compound (I[I) after being made into a reactive derivative of carboxylic acid. Sometimes.

When compound (II) is subjected to the reaction as a carboxylic acid, any conventional condensing agent used in the amide bond forming reaction can be used, and one example is N,N-dicyclohexylcarbodiimide.

When the compound (IF) is a reactive derivative of a carboxylic acid, an example of the reactive derivative is an acid compound.

Examples include acid anhydrides, acid azides, and various active esters used in peptide synthesis reactions.

Depending on the type of reactive derivative of compound (n), it may be preferable to react in the presence of a base. The base in this case is sodium bicarbonate.

Inorganic bases such as potassium hydrogen carbonate, sodium carbonate, and potassium carbonate, and organic bases such as triethylamine, diisopropylethylamine, dimethylaniline, and pyridine are used.

Compound (I[) is usually subjected to the reaction as it is, but if necessary, it can be converted into an alkali metal salt and then
It may also be subjected to a reaction with a reactive derivative of compound (n).

The amount of compound (I[D) to be used is preferably 2 equimole or an excess amount relative to compound (II) or its reactive derivative.

The reaction temperature may be cooled, room temperature, or heated depending on the type of amide bond-forming reaction employed, but it is usually carried out at room temperature or under cooling.

(Method 2 -) The compound of the present invention can also be obtained by alkenylating or alkynylating the phenol compound represented by (TV) in the formula.

Here, the starting compound (IV) can be obtained by the method described in, for example, Japanese Patent Application No. 1-332125, filed by the present applicant.

Alkenylation or alkynylation is hydrochloric acid.

Reaction conditions such as a method in which a lower alkenyl or alkynyl halide such as methanol, ethanol, propatool, etc. is reacted in the presence of a base such as sodium carbonate or potassium carbonate in the presence of a dehydrating agent such as sulfuric acid or aromatic sulfonic acid. It can be adopted as appropriate taking into consideration.

The reaction solvent may be a solvent inert to the reaction such as water, alcohols such as methanol and ethanol, acetone, tetrahydrofuran, ether, dioxane, chloroform, and dichloromethane, or may be used without a solvent.

In addition, in the four reactions, as the compound (■), a free tetrahydrobenzimidazole and a compound in which the nitrogen atom is protected with a protecting group such as a trityl group may be employed. In this case, the protective group can be removed by treatment with hydrochloric acid, acetic acid, or the like.

The compound of the present invention produced in this way remains free,
Alternatively, it is isolated and purified as its salt. Isolation and purification include extraction, crystallization, and recrystallization.

This is carried out by applying ordinary chemical operations such as various chromatography.

In addition, racemic compounds can be obtained by using appropriate raw materials or by a general racemic resolution method, such as a method that leads to a diastereomer salt with a general optically active acid (tartaric acid, etc.) and optically resolves it. It can lead to stereochemically pure isomers.

(Effect of the invention) The compound of the present invention or a salt thereof specifically inhibited serotonin-induced transient bradycardia in anesthetized rats.
It is thought to have an HT3 antagonistic effect. Therefore, the compounds of the present invention suppress vomiting caused by anticancer drugs such as cisplatin and radiation, and are useful for the prevention and treatment of migraines, compound headaches, trigeminal neuralgia, anxiety symptoms, gastrointestinal motility disorders, peptic ulcers, irritable bowel syndrome, etc. It is believed that there is.

Conventionally, 5-HT3 antagonists include azabicyclo compounds described in JP-A-5'J-36675 and JP-A-51-67284, and tetrahydrocarbazole compounds described in JP-A-60-214784.

Azabicyclo compounds described in JP-A No. 61-275276 are known, but the two compounds of the present invention are.

It is a potent 5-HT3 antagonist with a completely different structure from the above compounds.

The pharmacological effects of the compounds of the present invention were confirmed in the following manner.

1) 5-HT3 Receptor Antagonism Nine-week-old Wistar male rats were anesthetized by intraperitoneal administration of urethane Ig/kg, and blood pressure and heart rate under artificial ventilation were measured.

2 is a selective agonist of serotonin or 5-HT3
- A transient decrease in heart rate and blood pressure caused by intravenous administration of methylserotonin was used as an indicator of a response mediated by 5-HT3 receptors (Bezold-Ja
rish reflex; Palintal.

A.S. Pysiol, Rev., 53.159.
(1973)).

The compound of the present invention or a salt thereof is administered intravenously 10 minutes before administration of serotonin and 2-methylserotonin (003-3
μg/kg) or oral administration 60 minutes before (1-30f
tg/kg).

The decrease in heart rate and blood pressure caused by serotonin and 2-methylserotonin was suppressed in a dose-dependent manner.

2) Anticancer drug-induced emesis suppressive effect Dusuplatin 10 mg/kg was administered intraperitoneally or supraperitoneally by subcutaneously or orally administering 0.01 to 0.31 T1 g/kg of the five compounds of the present invention to male phelenots weighing 1 to 1.5 kg. The resulting vomiting was suppressed.

3) Effect of suppressing stress fecal excretion ratio Male Wistar rats withdrew after 9 years of age were housed in restraint stress cages, and the number of feces excreted was measured. The compound of the present invention or a salt thereof can be administered intravenously (from 1 to
(100 μg/kg) inhibited the progression of fecal excretion caused by restraint stress in a dose-dependent manner.

Furthermore, the compounds of the present invention have low toxicity.

Preparations containing one or more of the compounds of the present invention or their salts as active ingredients can be prepared into tablets, powders, fine granules, capsules, etc. using commonly used pharmaceutical carriers, excipients, and other additives. It is prepared into powders, gunpowders, liquids, injections, suppositories, ointments, patches, etc., and is administered orally (including sublingually) or parenterally.

Pharmaceutical carriers and excipients include solid or liquid non-toxic pharmaceutical substances. Examples of these include lactose, manesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, coma oil, cocoa butter, ethylene glycol, and other commonly used substances.

The clinical dosage of the compound of the present invention is appropriately determined taking into consideration the patient's symptoms, body weight, age, gender, etc.9, but is usually 0.1 to iomg per day for adults by intravenous injection, and oral administration. The amount is 0.5 to 501 ng, which is administered at once or divided into several doses.

(Example) EXAMPLES The present invention will be explained in more detail by way of Examples below.

Incidentally, the method for producing the raw material compounds used in the Examples is shown in Reference Examples.

Reference example 1 (2-propargyloxy)ani IJ 7
A solution of 2.7 ml of propargyl bromide in dimethyl sulfoxide (5 tot) is added dropwise to a solution of 483 g of sodium 2-nitropherulide in dimethyl sulfoxide (3 amt) at 5°C or less. The mixture was slowly warmed up to room temperature, and then stirred at room temperature for 2 hours.

The reaction solution was poured into 150 mZ of ice water, and ether (50 ml
×3) After extraction, the combined organic layer was washed with water (50n+t)
do.

After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude crystals were washed with an isopropyl ether-hexane mixture to obtain 3.32 g of (2-furopargyloxy)nitrobenzene. This compound 1.
Dissolve 77 g in 60 m7 of ethanol, add an aqueous solution (50 ml) of 6.28 g of sodium hydrosulfide, and stir under reflux for 3 hours. After cooling, the mixture is made alkaline by adding an aqueous potassium carbonate solution and extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 0.47 g of (2-furopargyloxy)aniline in the form of a perilla oil.

Physical and chemical properties (1) Mass spectrum (EI): m/z 147 (M+
) (11) Nuclear magnetic resonance spectrum (CDC1a) 699
m: 2.45 (t, IH), 3.80 (bs,
2H)! 4.70 (d, 2H), 6.60-7.
10 (m, 4H) Reference example 2. (2-allyloxy)aniline Obtained in the same manner as in Reference Example 1.

Physical and chemical properties (1) Mass spectrum (EI): m/z 149 (M
+) (11) Nuclear magnetic resonance spectrum (cvc 1s)
δppm: 3.90 (bs, 2H), 4.40-
4.60 (m, 2H).

5.1 (1-5, 40 (m, IH), 5.40-5
．． 60 (m, LH').

5.70-6.30 (m, IH), 6.60-7.
10(m, 4H) Example 1 N-(2) 4.5.6.7-titrahydrobenzimidazole-5-carboxylic acid sulfate 083 in 8 ml of propargyl oxy/pheniacetonitrile
Then, 0.46 ml of thionyl chloride was added, and the mixture was stirred at 60°C for 1 hour. After concentration under reduced pressure.

8 ml of acetonitrile and then a solution of 0.45 g of (2-propargyloxy)aniline and 0.49 ml of pyridine in acetonitrile (8 ml) are added under water cooling. After stirring at room temperature for 4 hours, concentrate. Hydrogen carbonate aqueous solution 10nol
was added, extracted with chloroform (10 mt×2), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By adding a calculated amount of fumaric acid to the residue and recrystallizing from methanol-acetonitrile, N-(2-probargyloquinphenyl)-4,5,6,7-titrahydrobenzimidazole-5- 0.42 g of carboxamide fumarate was obtained.

Physical and chemical properties (1) Elemental analysis value (C1?H17N302' C4H
404"HMeOH" as 7H20) C (%) H (%) N (%) Theoretical value 5
9.17 5.54 9.63 Actual value 59.2
1 5.56 9.49 (11) Mass spectrum (
EI): m/z 295 (M'', as free form) (iii) Melting point 123-125°C Actual M Example 2. N -(2-allyloxyphenyl)-
4,56,7-titrahydrobenzimidazole-5-
Carboxamide fumarate N(2-allyloxyphenyl)-4,5,6,7-y-trahydrobenzimidazole-5-carboxamide fumarate was obtained in the same manner as in Example 1.

Physical and chemical properties (1) Elemental analysis value (C,7H+oN30t・C4H,0
,・as 1H20) C (%) H (%)
N (%) Theoretical value 59.71 5.73 9.
95 actual value 59.88 5.59 10.09
(ii) Mass spectrum (EI): m/z 297
(M, as a free integral body) (Face melting point 145-147℃ Patent applicant Yamanouchi Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. 4,5,6,7-tetrahydrobenzimidazole represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R means an alkenyl group or an alkynyl group.) Derivatives or their salts. 2.Claim 1, wherein R is an allyl group or a propargyl group.
The described compound or its salt.