PH26820A - Substituted tetrahydro-benzimidazole derivatives - Google Patents

Description

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Specificatton 1. Title of the Invention

Substituted Tetrahydrobenzimidaznle Derivative 2. Detailed Description of the Invention (Field of the invention)

This invention relates to the N-(2-methoxyphenyl})~-4,5,6,7- tetrahydrobenzimidazole-5-carboxamide shown by the formula (I) or salts thereof.

CO

OCH3 N Clo

The compound (1) may form inorganic acid addition salts with conventional acids such as hydrochloric acid, hydrobromic acid, boric acid, phosphoric acid, and sulfuric acid and organic acid addition salts, for example, acetic acid, tartaric acid, dibenzoyltartaric acid, maleic acid, fumaric acid, citric acid, succinic acid, benzoic acid, and p-toluenesul fonic acid.

Furthermore, the compound (J) includes all sorts of isomers such as optical isomers and racemic compound due to asymmetric carbon atom, tautomers due to an imidazole ring in the molecule. (Method of production)

The compound (1) can be prepared by various routes and typical examples are illustrated below.

CU

) Method 1

OCHz * o ~~

C1 cll NHCO N

CX CI, )

Cer 7 OCH; H ) Method 2

OH ~N (IV)

Method 1 (Amidation?

The compound (1) is obtained by the reaction of an 0- anisidine shown by the formula (II) and a ‘tetrahydrobenz- imidazole compound shown by formula (II) or their reactive derivatives.

The reaction of compounds (II) and (Hl) or their reactive derivatives are generally carried out in a suitable solvent at room or elevated temperatures. Any solvents can be used and are selected from inert solvents which does not interfere the reaction, for example acetone, dioxane, ether, tetrahydrofuran, methylethylketone, chloroform, dichlorao- ethane, dichloromethane, ethyl acetate, ethyl formate, dimethyl formamide, and dimethylsulfoxide. These solvents can be used singly or in a suitable combination.

Compound (Il) can be used in the form of free carboxylic acid or a reactive derivative. The reactive derivatives include active esters such as l-hydroxybenzotriazole ester,

mixed acid anhydrides, acid halides, active amides, an acid’ anhydride and an acid azide. If the compound (II) is used in the free carboxylic acid form, then the reaction is preferably carried out in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide, N,N'-diethylcarbo- diimide.

Some reactive derivatives of the carboxylic acid require the presence of a base for a smooth proceeding of the reaction and the bases include inorganic bases such as sadium hydrogen carbanate, potassium hydrogen carbonate, sodium carbonate and potassium carbonate, and organic bases for example trimethvlamine, triethylamine, dimethylaniline and pyridine.

Method 2 (Alkylation)

The compound (1) can be obtained by an alkylation of a phenol derivative shown by the formula (IV). ‘The alkylation includes various method such as the reaction with a lower alcohol, e.g. methanol, ethanol or propanol in the presence of a dehydrating agent such as hydrochloric acid, sulfuric acid, or aromatic sulfonic acids, the reaction with a lower alkyl halide e.g. methyl iodide, ethyl iodide, propyl bromide in the presence of a base such as sodium carbonate or potassium carbonate, or by the reaction with an alkyl sulfate such as dimethyl sulfate or diethyl sulfate and the method is properly selected in consideration of the preferred reaction condition.

Various inert reaction solvents such as water, alcohols, e.g. methanol or ethannl, acetone, tetrahydrofuran, ether, dioxane, chloroform or dichloromethane can be used, and a salventless reaction may alsn be performed.

The obtained compound (J ) is isolated and purified as it is or in the form of a salt by known procedures such as extraction, crystallization, re-crystallization, or various chrematographic methods.

A racemic compound can be divided to the respective pure stereoisomers using suitable raw materials or by conventional optical resolution, for example stepwise preparation of diastereomer salts with optically active acid, e.g. tartaric acid or dibenzoyltartaric acid and an optical resolution of the obtained salts. (The effect of the invention)

The compound (1?) and the salts thereof in the present invention are expected to exhibit 5HT 5 antagonistic activity because of the inhibition of transient bradycardia caused by serotonin. Therefore, the compound (1) will exhibits an inhibitory effect on vomiting due to cytotoxic or anticancer agents such as cisplatin or irradiation therapy and will be useful for the treatment and prevention of migraine, cluster headaches, trigeminal neuralgia, anxiety, disorder of gastric motility, peptic ulcer, irritable bowel syndrome, etc. The pharmacological activities of the compound «1»

ee ———————————————————— eee er ete were confirmed by the following experiments. 1) 9HTq receptor antagonistic activity

Male Wistar rats of nine weeks old were anesthetized with intraperitoneal administration of 1 g/kg of urethane and the blood pressure and heart rate were determined undev artificial respiration. Transient decreasesof heart rate and blood pressure due to serotonin or 2-methylserotonin, a 5HT 4 selective agonist, were used as indexes of the responses mediated by 5HTq receptor.

The compound and its salts of the present invention inhibited dose-dependently the decrease of heart rate and blood pressure due to 2-methylserotonin by the intravenous administration (0.1-3 JL g/Kg) 10 minutes or oral administration (1-30 IL g/kg) 60 minutes before the administration of serotonin or 2-methylserotonin.

The inhibitory activity against Bezold-Jarisch (BJ) reflex in rats by the compound (1) of the present invention is shown below.

No. (EDg qs IL g/kg)

LTE

0.32 5.9 2) Inhibitory activity against vomiting induced by an anticancer agent.

Male ferrets weighing 1 to 1.5 kg, were subcutaneously or orally administered 0.01-0.3 mg/kg of the compound ¢ 1) and vomiting caused by an intraperitoneal administration of 10 mg/kg of cisplatin was inhibiled.

The compound of the present invention has low toxicity.

Pharmaceutical compositions containing one ov more of the compound of the present invention or the salts thereof may be prepared in the forms of tablets, powders, fine particles, capsules, pills, emulsions, syrups, elixirs, injections, suppositories, ointments, cataplasms, etc. and an administered orally, including sublingually, or parenterally.

Carriers and additives for pharmaceutical preparations include conventional solid or liquid non-toxic materials for medical preparations such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame 0il, cacao butter, ethylene glycol, etc.

Clinical doses of the compound of the present invention may properly determined in consideration of the symptom, body weight, age and sex of the patients. General daily dose for adults are 0.1-10 mg intravenously or 0.5-50 mg orally, and are administered in one time or dividedly in several portions. (Example)

The present invention is explained in detail by the following examples. Preparation of the raw materials used for the examples are described also as reference examples.

Example 1

In 5 ml of thionyl chloride, 0.60 g (2.95 mmol) of 4,5,6,7- tetrahydrobenzimidazole-5-carboxylic acid mono hydrochloride was added and heated at 90 (C for 2.5 hrs. The reaction mixture was condensed under reduced pressure and excess thionyl «chloride was removed and 10 ml! of dichloromethane, 0.4 ml (3.57 mmol) of n-anisidine, and 1.0 ml (7.22 mmol) of triethylamine were added and stirred for 18 hrs. at room temperature. The reaction mixture was washed with 5% aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and the solvent was distilled off. The oily residue was purified by silica gel column chromatography (elution solvent, dichloromethane : methanol = 10 : 1) and the obtained foamy product, 0.22 g, was mixed with 0.10 g of fumaric acid to give fumarate. The fumarate was re-crystallized from a mixture of ethyl acetate-methanol (10 : 1) to give crystals of N-(2-methoxyphenyl})-4,5,6,7- tetrahydrobenzimidazole-5-carboxamide fumarate 0.8 hydrate.

Physicochemical properties:

Melting point ; 168-1707

Elemental analysis (as CygHyN30g-0.8 Hy0)

C(x) H(%) N(%)

Calculated 56.79 5.67 10.46

Found 56.91 5.62 10. 42 'H-NMR (CDC14) 6 ppm 7

A

2.20 (2H, br, CHqy d, 2.90 (5H, m, CH, Xx 2, CH», 3.81 3H, s, OCHg», 6.90 (3H, m, H in aromatic ving, 7.50 (IH, br, 2-CHY, 7.96(1H, s, CONH), 8.35C1H, dd, 9Hz, 1Hz, H in aromatic ring:

Mass spectrum (El): m/z 271 (MY)

Reference example 1 (a) H n — (1 i N COOCH 3 "H,S04 +H 504

In an 1 liter autoclave, J0.0 g of methyl benzimidazole- b-carboxylate sulfate was dissolved in 600 ml of acetic acid and hydrogenated at 60 atm and 80 ( for five hrs. in the presence of 11 g of 10% palladium carbon catalyst. The reaction mixture was filtered to separate the catalyst, the obtained filtrate was condensed under reduced pressure to give 11.0 g of oily methyl 4,5,6,7-tetrahydrobenzimidazole- 5-carbaxylate sulfate (yield 101%). (b) _ 0 JI

SN C 00CH3 N COOH + Hy$04 + H2504

In a mixture of 350 ml of water and 340 ml of concentrated hydrochloric acid was dissolved 41.0 g of the above oily ester sulfate and stirred at 100°C for three hrs. The reaction mixture was condensed and the resultant crystals were washed with acetone to give 29.6 g of 4,5,6,7-

tetrahydrobenzimidazole-5-carboxylic acid sulfate (yield of 76.8% from the benzimidazole ester).

Melting point : 145-1187.

NMR spectrum ¢ in dg-DMSO) : o 1.60-3.00 (7H, m) 8.84 (1H, s)

Mass spectrum (EI) : m/z 166 (M*, as a {free base) (CI) : m/z 167 (M'+1, as a free base)

Example 2 ~NH2

N SoC] f CL NHCO ~~ N

GIL GI J, UL

COOH N coc] OCH *H2S0,4 -HpS504

In a mixture of 50 ml of 1,2-dichloroethane and 3 ml of thionyl! chloride, 5.42 g of 4,5,6,7~-tetrahydrobenzimidazole- 5-carboxylic acid was added and stirred at 55-60°C for one hr. The reaction mixture was condensed under reduced pressure and the residue was re-evaporated with 50 ml of l1,2-dichloroethane. The residue was dissolved in 50 ml of 1,2-dichloroethane and 6.25 g of o0-anisidine was added dropwise below 30°C with stirring. The resultant reaction mixture was stirred for two hrs. at room temperature. The reaction mixture was added in a mixture of 60 ml of water and 30 ml of methanol and adjusted pH around 4.8 with 10% sodium hydroxide. The organic layer was separated and the obtained aqueous layer was gradually basified to pH 11.0 with 10% sodium hydroxide. The precipitated crystals were eet rete 1 TTT filtered and washed with a chilled mixture of water-methanol = 3:1 tn give 5.62 g of N-(2-methoxyphenyl)-4,5,6,7- tetrahydrobenzimidazole-5-carboxamide (yield >100%).

Melting point : 100-101.5C

NMR spectrum (CDCI 5-DMSO-dg): & 1.80-2.40 (m, 2H), 2.52-3.04 (m, 5D 3.90 (s, 3H) 6.80-7.12 (m, 3H 7.40 (5s, 1H), 8.12-8.28 (dd, LH», 8.30 (bs, br, 1H)

Mass spectrum (El): m/z 271 (M*, as a free base)

Example 3 } 5.07 g of N-(2-methoxyphenyl)-4,5,6,7-tetrahydrobenz- imidazole-5-carboxamide obtained by example 2 was treated with ethanolic hydrogen chloride to give 5.66 g of N-(2- methoxyphenyl)-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide hydrochloride (yield 98.4%).

Melting point : >250°C

Elemental analysis (as Cyg5Hyp7Ng0Oy- HCI)

C(x) H(%) N(%) Cl (x)

Calculated 58.54 5.89 13.65 11.52

Found 58.24 5.98 13.48 11.68

Mass spectrum (EI) : m/z 271 Mh, as a free base)

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Example 4

CYT

>

OCH3 N + HCY (S)-(~)-N-(2-methoxyphenyl)-1,5,6,7-telrahydro= benzimidazole-5-carboxamide hydrochloride (a) In 70 ml of methanol, 5.0 g of (Xx )-N-(2-methoxy- phenyl)-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide obtained by example 2 was dissolved and 3.47 g of (-)- dibenzoyltartaric acid in methanol (300 ml) was added, the precipitated crystals were filtered and re-crystallized twice from a mixture of dimethyl formamide, and water to give 1.89 g of (S)-(-)-N-(2-methoxyphenyl)-4,5,6,7-tetrahydro- benzimidazole-5-carboxamide (-)-dibenzoyltartaric acid salt.

La13® = -55.9° (c= 1.02, DMF).

Melting point : 142.0-143.57C

Elemental analysis (as C 5H 7Ng09 CygHy 40g 1.2Hy0)

C(%) H (2%) N(%)

Calculated 60.86 5.17 6.45

Found 60.86 5.17 6.61

Mass spectrum (EI) : m/z 271 (M¥, as a free base) (b) In 2N hydrochloric acid, 1.70 g of the above mentioned salt was added, washed with ethyl acetate and adjusted to pH =9 with sodium carbonate. The aqueous layer was extracted with a mixture of chloroform-methanol (4:1), dried over anhydrous magnesium sulfate and distilled off the snlvent. The obtained foamy product, v.15 g, was re- crystallized from aqueous ethanol to give 0.1 g of (S)- (-)-N-(2-methoxyphenyl}-4,5,6,7-tetrahydrobenzimidazole-5- carboxamide. [a 130= -27.0° (c=1.08. MeOID).

Melting point ; 99.5-100.5C

Elemental analysis (as Cj gH;;Ng0,:H,0) cox) Hx) N22)

Calculated 62.27 6.62 14.52

Found 62.33 6.67 14.565

Mass spectrum (El) ; m/z 271 (Mt, as a free base) (c) The resultant above compound was dissolved in an ethanol-ethyl acetate mixture and treated with hydrogen chloride in ethyl acetate to give 0.49 g of (S)-{(-)-N-(2- methoxyphenyl)-4,5,6,7-tetrahydrobenzimidazole-56-carboxamide hydrochloride. [e180 -12.2° (c=1.08, MeOH).

Melting point : 215-222°C (decomp.)

Elemental analysis (as Cy gH) 7N50, HCL. 0.5H,0)

C(x) H{%) N(%)

Calculated 56.87 6.05 13.26

Found 56.77 6.01 13.24

Mass spectrum (EI) ; m/z 271 (MY, as a free base)

Example 5 (R)

CIC

OCH3 R « HCI (R)-(+)-N-(2-methoxyphenyl)=4,5,6,7-tetrahydrobenzimidazole -5-carboxamide hydrochloride (al (+)-Dibenzoyl tartaric acid was used similarly to example 4 (a) and crystals of (RY-(+)-N-(2-methoxyphenyl)- 1,5,6,7-tetrahydrobenzimidazole-5-carboxamide (+)-dibenzovl- tartaric acid salt was obtained.

Ca 130 486.1 (c=1.03, DMI

Melting point ; 139.0-141.0C

Elemental analysis (as CygHy7N309 CygHy 40g 1. 1H0)

C(2%) H (2%? N(%)

Calculated ) 61.03 5.156 6.47

Found 60.99 5.11 6.57

Mass spectrum (EI) ; m/z 271 M*, as a free base) (by The salt obtained by example 5 (a) was treated similarly to example 4 (b) and nbtained crystals of (R)-(+)-

N-(2-methoxyphenyl)-4,5,6,7-tetrahydrobenzimidazole-5- carboxamide [a 130 +27.4° (c=1.04, MeOH)

Melting point ; 100.0-101.00C

Elemental analysis (as CygHy7Ng09- Hy OD

C(%) H(%) N(%)

Calculated 62.27 6.62 14.52

Found 62.07 6.65 14.51

Mass spectrum (Ely: m/z 271 MY, as a free base) (¢c) The compound obtained by example 5 (bh) was treated similarly to example 1 (c¢) and crystals of (R)-(+)Y-N-(2~ methoxyphenyl)-4,5,6,7-tetrahydrobenzimidazole-5-carboxamide hydrochloride was obtained. [13% 12.3" (c=1.09, MeOl)

Melting point ; 217-223 C

Elemental analysis (as Cygl 7NgO,- HCI)

C(%) H(%) N (2%)

Calculated 58.54 6.01 13.24

Found 58.51 5.93 13.59

Mass spectrum ; (El) m/z 271 (MY, as a free base)

Claims (7)

T CX ! AMENDED CLAINS:

1. 2 compound tf MN (Remethoxyphnyl) ~a4,5 6,7 tetrahydrobenzimidarole-S-carboramide, or, tautomers «

. £& 3 or pharmaceutically acceptable salts thereof. --

< . Pe ”y . . . . . & C.: .

2. A pharmaceutical composition comprising Lofpound = ofp N-(Z-methoxyphenyl) 4,546, T-tetrahydroblenzimi dS ol e- vl : : S-carboramide or tautomers or phapmaceut deal ly

RO . =~ acceptable salts thereof and pharmaceutically acceptable carriers.

3. A JHTx antagonistic pharmaceutical composition according to claim 3. C

4, A pharmaceutical composition according to claim 3 for the treatment and prevention of disorder of gastric motility, peptic weer, and irritable bowel syndrome.

5. A pharmaceutical composition according to claim 4 for the treatment and prevention of irritable bowel syndrome.

b. A pharmaceutical composition according to claim 3 tor the treatment or inhibition of nausea and/or vomiting induced by cytotoxic or anticancer agents or irradiation therapy.

7. A pharmaceutical composition according to claim 3 for the treatment of migraine, cluster headaches, and trigeminal neuralgia.

a. A pharmaceutical composition according to claim 3 for the treatment and prevention of anxiety, migraine, cluster headaches, ancl trigeminal neuralgia. / BAD ORIGINAL 4

S .