GB2144738A - Imidazolines - Google Patents

Abstract

Imidazoline derivatives of the formula: <IMAGE> (wherein ring A is phenyl, C1-4 alkyl-phenyl, C1-4 alkoxy-phenyl or halophenyl) and their salts are analgesic, anti-inflammatory and/or antipyretic agents.

Description

SPECIFICATION Novel imidazoline derivative and a process for preparing same This invention relates to a novel imidazoline derivative and processes for preparing the same. More particularly, it relates to a compound of the formula:

wherein ring A is phenyl, lower alkyl-phenyl, lower alkoxyphenyl or halogenophenyl, or a pharmaceutically acceptable acid addition salt thereof.

The new imidazoline derivative (I) of the present invention and pharmaceutically acceptable acid addition salts thereof show potent anti-inflammatory, analgesic and anti-pyretic activity against a variety of inflammatory diseases and are useful as anti-inflammatory, analgesic and/or anti-pyretic agent. The imidazoline derivative (I) of the present invention is particularly characterised in that it shows no substantial ulcerogenicity in gastro-intestinal organs, is remarkably low in toxicity and therefore has great safety for use as an anti-inflammatory, analgesic and/or anti-pyretic agent.

Representative examples of the compounds of the present invention are those of the formula (I) in which ring A is phenyl; lower alkyl-phenyl e.g. methylphenyl, ethylphenyl propylphenyl, butylphenyl; lower alkoxy-phenyl e.g. methoxyphenyl, ethoxyphenyl, propoxyphenyl, butoxyphenyl; or halogenophenyl e.g.

fluorophenyl, chlorophenyl, bromophenyl. Among them, a preferred subgenus includes those of the formula (I) in which ring A is phenyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl or bromophenyl.

More preferred subgenus is those of the formula (I) in which ring A is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl or 4-bromophenyl.

As shown in the following formulae, the imidazoline derivative (I) of the present invention has two tautomeric structures which are mutually convertible from one to another. Both of these isomers are included within the scope of the present invention.

Moreover, while the compound (I) of the present invention can exist in the form of two stereoisomers (i.e., cis and trans isomers) or four optical isomers (i.e., (+)-cis, (-)-cis, (+)-trans and (-)-trans isomers) due to the two asymmetric carbon atoms involved therein, all of these stereoisomers, optical isomers or a mixture thereof are included within the scope of the invention.

According to the present invention, the imidazoline derivative (I) may be prepared for example by condensing a diamine compound of the formula:

our a salt thereof with a benzimidic acid compound of the formula:

wherein R is lower alkyl and ring A is the same as defined above, or a salt thereof. Alternatively, the compound (I) is prepared by intra-molecular cyclization of a compound of the formula:

wherein ring A is the same as defined above, or a salt thereof.

In the above-mentioned reactions, examples of the salt of the compounds (11), (III) and (IV) used in the invention are inorganic acid addition salts e.g. hydrochloride, hydrobromide and sulfate; and organic acid addition salts e.g. oxalate, lactate and tartrate.

The condensation reaction of the compound (11) or a salt thereof with the compound (III) or a salt thereof can be readily accomplished. For example, said condensation reaction may be conducted in the presence or absence of a base in a solvent. Suitable examples of the base are alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide), alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkali metal carbonates or bicarbonates (e.g., sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate), tri-lower alkyl amines (e.g., trimethylamine, triethylamine), pyrrolidine and piperazine. Examples of suitable solvents are lower alkanols e.g.

methanol, ethanol or isopropanol, dioxane, tetrahydrofuran, dimethylformamide and deimethylsulfoxide.

It is preferred to carry out the reaction at a temperature of from room temperature to 1 00 C, especially at a temperature of 30"C to 70"C.

The intra-molecular cyclization reaction of the compound (IV) or a salt thereof is preferably conducted in the presence of a dehydrating agent. Examples of the dehydrating agent are calcium oxide; aluminum oxide and silicon dioxide. The reaction may be carried out either in a solvent or without solvent. 1,2,3,4tetrahydronaphthalene is suitable as the solvent. It is preferred to carry out the reaction at a temperature of from 100'Cto 300"C, especiallyatatemperature of 1800Cto 250"C.

As described hereinbefore, the imidazoline derivative (I) of the present invention or a pharmaceutically acceptable acid addition salt thereof is useful as an anti-inflammatory, analgesic and/or anti-pyretic agent having no substantial unfavourable side effects such as ulcerogenicity. Said derivative (I) or an acid addition salt thereof may be used for the therapeutic treatment or alleviation of a variety of inflammatory diseases in skeletal muscles, joints (e.g., knee joint, shoulder joint, elbow joint, ankle joint) and other organs, for example, for the treatment or alleviation of rheumatism, gout and arthritis or of inflammation caused by bone fracture, lesion, trauma and the like. It may also be used for alleviation of pain, pyrexia and other symptoms usually associated with these various inflammatory diseases.

The imidazoline derivative (I) of the present invention can be used for pharmaceutical use either in the free form or in the form of a pharmaceutically acceptable acid addition salt thereof. Pharmaceutically acceptable acid addition salts of the compound (I) are, for example inorganic acid addition salts e.g. hydrochloride, hydrobromide, phosphate and sulfate or organic acid addition salts e.g., oxalate, acetate, lactate, citrate, tartrate, fumarate, maleate, aspartate, methanesulfonate and benzoate. These salts may be prepared, for example, by neutralizing the compound (I) with an acid in a conventional manner.

The imidazoline derivative (I) and an acid addition salt thereof can be administered either orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously). The daily dose of the compound (I) or an acid addition salt thereof may vary over a wide range depending on the age, weight or condition of the patient, and the severity of diseases to be treated. In general, however, a preferred daily dose of said compound (I) or an acid addition salt thereof may be about 0.2 to about 5.0 mg, especially 0.5 to 2.0 mg, per kg of body weight per day. Further, the compound (I) and an acid addition salt thereof may be used in the form of a pharmaceutical preparation containing the same compound in conjunction or admixture with pharmaceutical excipients suitable for oral or parenteral administration. Suitable excipients are, for example, mannitol, lactose, magnesium stearate, starch, talcum, cellulose, sugar, glucose, magnesium carbonate, polypropyleneglycol, water, a saline solution, ethanol, glycerin, sodium acetate, sorbitan monolaurate, triethanol amine oleate and other known medicinal excipients. The pharmaceutical preparations may be in solid form e.g., tablets, coated tablets, pills or capsules; or in liquid form e.g.

solutions, suspensions or emulsions. They may be sterilized and/or may further contain auxiliaries e.g.

stabilizing, wetting or emulsifying agent. Further, when administered parenterally, the pharmaceutical preparation may be used in the form of injection.

The starting compounds (II) and (IV) of the invention are novel compounds and can be prepared, for example, according to the methods shown by the following reaction scheme:

wherein X is halogen, Y is hydrogen or hydroxy and ring A is the same as defined above.

Thus, the compound (II) may be prepared by reacting the compound (V) with 2,2,2-trifluoroethyl halide to give the compound (VI), reacting the compound (VI) with ammonia or hydroxylamine to give the compound (VII), and then subjecting the compound (VII) to catalytic hydrogenation. On the other hand, the compound (IV) may be prepared by reacting the compound (VIII) with 2,2,2-trifluoroethyl halide to give the compound (IX), reacting the compound (IX) with ammonia or hydroxylamine to give the compound (X), and then subjecting the compound (X) to catalytic hydrogenation.

The reaction of the compound (V) or (VIII) with 2,2,2-trifluoroethyl halide is conducted in the presence of an acid acceptor e.g. an alkali metal hydride (e.g., sodium hydride), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide), alkali metal alkoxide (e.g., sodium methoxide, potassium tert.-butoxide), n-butyl lithium or the like in a solvent (e.g., tetrahydrofuran, dimethylformamide, dimethylsulfoxide, ether, methanol, ethanol, propanol). It is preferred to carry out the reaction at a temperature of -78 C to 50"C. The reaction of the compound (VI) or (IX) with ammonia or hydroxylamine is conducted at a temperature of 20"C to 1 00 C in a solvent (e.g., methanol, ethanol, isopropanol, pyridine, chloroform, tetrahydrofuran).The catalytic hydrogenation of the compound (VII) or (X) is carried out in the presence of a catalyst (e.g., palladium-charcoal, palladium black, platinum oxide, nickel) in hydrogen gas atmosphere in a solvent (e.g., methanol, ethanol, formic acid, acetic acid). It is preferred to carry out the reaction at a temperature of 1 0 C to 50"C under one to 50 atmospheres pressure and under shaking. It is also preferred to carry it out in the presence of an acid e.g. hydrochloric acid, hydrobromic acid or sulfuric acid.

While the compound (II) or (IV) thus obtained can exist in the form of two diastereoisomers, i.e., erythroand threoisomers, due to the difference in the steric configuration of the diamino groups substituted at the 3rd- and 4th-positions of the n-butane moiety, both of these diastereoisomers or a mixture thereof are used for the purpose of the present invention.

If required, the compound (II) obtained in the form of erythro- or threo isomer may be further resolved into each optically active enantiomers thereof by using conventional optically active resolving agents. For example, the optical resolution of (+ > -erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane can be accomplished by the steps of reacting said compound with an optically active tartaric acid to form the diastereoisomeric salts thereof, and separating the diastereoisomeric salts into each components thereof by selective crystallization. By said selective crystallization, the less soluble diastereoisomeric salt is obtained as crystals from the solution, and the more soluble one remains dissolved in the solution.To illustate more specifically, (+ )-erythro-4-phenyl-3,4-diamino-1 ,1 ,1 -trifluoro-n-butane forms the less soluble diastereoisomeric salt if d-tartaric acid is used as the resolving agent, and, on the other hand, (-)-erythro-4-phenyl-3,4-diamino-1,1,i4rifluoro-n-butane forms the less soluble diastereoisomeric salt if tartaric acid is used as the resolving agent. Selective crystallization is carried out by recrystallizing the diastereoisomeric salts from a solvent such as for example lower alkanol (e.g., ethanol). After the optical resolution, the optically active compound (II) in free form can be recovered by treating the thus-obtained diastereoisomeric salt with a base (e.g., sodium hydroxide).

Practical and presently-preferred embodiments of the present invention are illustratively shown in the following Examples. Throughout the specification and claims, the term "threo" means that the diamino groups substituted at the 3rd- and 4th-positions of the n-butane moiety have threo-type configuration (i.e., said two groups are placed on opposite side of the central bond in Fisher's projection formula), and the term "erythro" means that said diamino groups have erythro-type configuration (i.e., said two groups are placed on the same side of the central bond). Concomitantly, throughout the specification and claims, the term "lower alkyl" and "lower alkoxy" should be interpreted as referring to alkyl and alkoxy having one to four carbon atoms, respectively.

EXPERIMENT 1 (Anti-inflammatory activity) A test compound dissolved in water was administered orally to Crj:CD male rats (body weight: 160 - 180 g) fasted overnight. One hour after the administration, 0.05 ml of a 1% carrageenin-saline solution was injected into the plantar surface of either one of the hind feet. Then, the volume of both hind feet were measured 4 hours after administration of carrageenin, and the volume of edema was estimated by comparing the volume of both hind feet. The preventive effect (percent) of the test compound against carrageenin-induced edema was determined by comparing the mean edema volume of the medicated group with that of the control group of rats to which water was administered instead of the test compound solution.As a result 30% effective dose (ED30) (i.e., a dose which would produce 30% decrease in carrageenin-induced paw edema) of cis-2-(4-chlorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride of the present invention was 1.3 mg/kg (ED30 of Phenylbutazone (chemical name: 4-butyl-1,2-diphenyl-3,5-pyrazolidinedione) was 80 mg/kg).

EXPERIMENT 2 (Analgesic activity) A test compound dissolved in water was administered orally to Crj:CD male rats (body weight: 70 - 90 g) fasted overnight. Immediately after administration of the test compound, 0.1 ml of 20% dried yeast suspended in a physiological saline solution was injected into the plantar surface of either one of the hind feet. Then, pain threshold of the both hind feet were measured by Analgesy Meter (Ugo Basile CO.,) 2 hours after injection of yeast, and the analgesic activity of the test compound was estimated by comparing the pain threshold of the inflamed foot with that of the control foot. As a result, the effective dose (ED30) [i.e., a dose which would produce 30% reduction in said pain threshold] of cis-2-(4-chlorophenyl)-4-phenyl-5-(2,2,2trifluoroethyl)imidazoline hydrochloride of the invention was 2.5 mg/kg (ED30 of Phenylbutazone was 15 mg/kg).

EXPERIMENT 3 RAnti-pyretic activity) 0.1 ml of a 2% carrageenin-saline solution was injected into the plantar surface of the hind foot of Crj:CD male rats (body weight: 160 - 180 g) fasted overnight. Three hours after the injection, a test compound dissolved in water was administered orally to said rats. The temperature of the rectum of the rats were measured by Thermister Thermometer before injection of carrageenin and two hours after administration of the test compound, and the anti-pyretic activity of the test compound was estimated therefrom. As a result, the effective dose (ED50) [i.e., a dose which would produce 50% reduction in carrageenin-induced hyperthermia] of cis-2-(4-chlorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride of the invention was 1.0 mg/kg (ED50 of Phenylbutazone was 11 mg/kg).

EXPERIMENT 4 {Ulcerogenicity) Atest compound suspended in a 0.25% carboxymethylcellulose solution was administered orally to ddY male mice (body weight: 22 - 25 g) fasted overnight. Immediately after administration of the test compoud, the mice were placed in a stress cage and immersed to the level of cervix in water bath (24 0.5 C). The mice were taken out from the cage 15 minutes after the immersion, and were allowed to stand at 22i 1 0C in the animal room. Then, the mice were sacrificed two hours after administration of the test compound, and the stomach was removed. The stomach was then incised along the greater curvature, and the number of ulcerations was examined. As a result, cis-2-(4-chlorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride at the dose of 100 mg/kg was found to show no substantial ulcerogenicity, whereas Phenylbutazone was found to show ulcerogenicity at the dose of 100 mg/kg.

EXPERIMENT 5 (Acute toxity) cis-2-(4-chlorophenyl )-4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride (dose: 1000 mg/kg) sus pended in a 0.25% carboxymethylcellu lose solution was administered orally to ddY male mice (body weight: 18 - 22 g), and the mortality of the mice were observed for 14 days. No mice died during the experiments.

EXPERIMENT 6 (Preliminary subacute toxicity test) cis-2-(4-chlorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride dissolved in water was administered orally to Crj:CD male rats (body weight: 160 - 180 g) at a dose of 10 mg/kg once a day for 4 consecutive days. As a result, no changes in body weight gain and in relative organ weights were observed during the experiments.

Example 1 514 mg of sodium ethoxide are dissolved in 20 ml of ethanol, and the solution is heated at 80 C. 1.1 g of erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane dihydrochloride are added to said solution, and the mixture is stirred at the same temperature for 5 minutes. 702 mg of ethyl benzimidate hydrochloride are added to the mixture, and the mixture is refluxed for one hour. After cooling, insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. 20 ml of 1 N sodium hydroxide are added to the residue, and the mixture is extracted with chloroform. The extract is washed with water, dried and then concentrated under reduced pressure to remove solvent.The residue is treated with 10% hydrogen chloride-ethanol. 930 mg of cis-2,4-diphenyl-5-(2,2,2-trifluoroethyl )imidazoline hydrochloride are obtained.

Yield: 72% M.p.199-201 C IR#maxnujol (cm-') :1620, 1600,700 NMR (DMSO-d6)8 : 1.8-2.3 (m, 1 H), 2.6-3.3 (m, 1 H), 4.8-5.2 (m, 1 H), 5.6 (d, 1 H, J 12 Hz), 7.2-8.55 (m, 10H), 11.8 (brs, 2H) Example 2 1.1 g of erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane dihydrochloride and 0.83 g of ethyl 3-chlorobenzimidate hydrochloride are treated in the same manner as described in Example 1. 1.22 g of cis-2-(3-chlorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride are obtained.

Yield: 86% M.p. > 250 C IRvnuuoI (cm-1) :1630, 1580 NMR (DMSO-d6)8 : 1.8-2.3 (m, 1 H), 2.6-3.0 (m, 1 H) 4.9-5.25 (m, 1 H), 5.88 (d, 1 H, J = 12Hz), 7.5(s, 5H), 7.6-8.6 (m, 4H) 11.90 (br, 2H) Example 3 1.1 g of erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane dihydrochloride and 0.83 g of ethyl 4-chlorobenzimidate hydrochloride are treated in the same manner as described in Example 1. 1.25 g of cis-2-(4-chlorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride are obtained.

Yield: 88% M.p. > 250 C IRvnuuol (cm-5) : 1615,840 NMR (DMSO-d6)8 .1.8-2.3 (m, 1 H), 2.6-3.1 (m, 1 H), 4.8-5.2 (m, 1 H), 5.67 (d, 1 H, J = 12Hz),7.1-8.6 (m, 9H), 11.8 (brs, 2H) Example 4 1.1 g of erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane dihydrochloride and 0.77 g of ethyl 4-fluorobenzimidate hydrochloride are treated in the same manner as described in Example 1. 1.25 g of cis-2-(4-fluorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride are obtained.

Yield: 92% M.p.246-247tC IRvnuuol (cm-1) : 1610,850 NMR (DMSO-d6)8 : 1.8-2.3 (m, 1H), 2.65-3.3 (m, 1H), 4.7-5.1 (m, 1 H), 5.6 (d, 1 H, J = 12Hz), 7.1-8.8 (m, 9H), 11.8 (br, 2H) Example 5 1.1 g of erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane dihydrochloride and 1.0 g of ethyl 4bromobenzimidate hydrochloride are treated in the same manner as described in Example 1. 1.32 g of cis-2-(4-bromophenyl)-4-phenyl-5-(2,2,2-trifluoro-ethyl)imidazoline hydrochloride are obtained.

Yield: 83% M.p. > 250 C IRvmuuxl (cm ) :1625, 1590 NMR (DMSO-d6)8 : 1.8-2.3 (m, lH), 2.5-3.0 (m, 1H), 4.9-5.2 (m, H), 5.85 (d, 1 H, J = 12Hz), 7.5 (5, 5K), 8.3 and 7.95 (A2B2 q, 4K, J = 9Hz), 11.80 (br, 2H) Example 6 1.1g of erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane dihydrochloride and 0.75 g of ethyl 4methylbenzimidate hydrochloride are treated in the same manner as described in Example 1. 1.18 g of cis-2-(4-methylphenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride are obtained.

Yield: 88% M.p.248-249 C IR#maxnujol (cm-1) :1620, 1595 NMR (DMSO-d6)8 : 2.5 (s, 3H), 1.8-2.3 (m, 1 H), 2.6 - 3.0 (m, 1K), 4.9-5.25 (m, 1K), 5.85 (d, H, J = 12Hz), 7.5 (s, 5K), 8.28 and 7.58 (A2B2 q, 4K, J = 9Hz), 11.65(br,2H) Example 7 1.1 g of erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane dihydrochloride and 0.75 g of ethyl 4-methoxybenzimidate hydrochloride are treated in the same manner as described in Example 1. 1.2 g of cis-2-(4-methoxyphenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride are obtained.

Yield: 86% M.p. > 250 C IRvmugxl (cm-1) :1610, 1595 NMR (DMSO-d6)S : 1.8-2.4 (m, 1H), 2.5-3.0 (m, 1K), 3.95 (s, 3H), 4.9-5.2 (m, 1K), 5.82 (d, H, J = 12Hz), 7.5 (s,5H), 8.42 and 7.29 (A2B2 q, 4H, J = 9Hz), 11.60 (br s,2H) Example 8 A mixture of 524 mg of(+)-erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane, 547 mg of ethyl 4-chlorobenzimidate hydrochloride and 25 ml of ethanol is refluxed for one hour. After cooling, the mixture is treated in the same manner as described in Example 1. 786 mg of (+ )-cis-2-(4-chlorophenyl)4-phenyl-5 (2,2,2-trifluoroethyl)imidazoline hydrochloride are obtained.

Yield: 87% M.p. > 250 C [a185 + 15.0 (C = 0.49, ethanol) The IR and NMR spectra of this compound are identical with those of the sample obtained in Example 3.

Example 9 A mixture of 750 mg of (-)-erythro-4-phenyl-3,4-diamino-1 1,1 4rifluoro-n-butane, 786 mg of ethyl 4-chlorobenzimidate hydrochloride and 30 ml of ethanol is refluxed for one hour. After cooling, the mixture is treated in the same manner as described in Example 1. 879 mg of (-)-cis-2-(4-chlorophenyl)-4-phenyl-5- (2,2,2-trifluoroethyl)imidazoline hydrochloride are obtained.

Yield 68% M.p. > 250 C [&alpha;]D25- 15.0 (C = 0.50, ethanol) The IR and NMR spectra of this compound are identical with those of the sample obtained in Example 3.

Example 10 A mixture of 1.0 g of erythro-4-phenyl-4-amino-3-(4-chlorobenzoylamino)-1,1,1-trifluoro-n-butane and 1.5 g of calcium oxide is heated in nitrogen gas atmosphere at 230 C to 240 C for 3 hours. After the reaction, 30 ml of chloroform are added to the mixture and insoluble materials are filtered off. The filtrate is extracted with 20 ml of 10% hydrochloric acid. The acidic layer separated is neutralized with potassium carbonate and extracted with ethyl acetate. The extract is washed with water, and 5 ml of methanol containing 10% hydrochloric acid are added thereto. The mixture is concentrated under reduced pressure to remove solvent.

Crystalline residue is washed with ether, whereby 0.23 g of cis-2-(4-chlorophenyl)-4-phenyl-5-(2,2,2trifluoroethyl)imidazoline hydrochloride is obtained. Yield: 24.% The physico-chemical properties of this compound are identical with those of the sample obtained in Example 3.

PREPARATION OF STARTING COMPOUNDS Preparation ofcompound (11) (1) 50 g of 2-oxo-2-phenylethylamine hydrochloride are suspended in a mixture of 500 ml of water and 500 ml of ethyl acetate, and 61 g of sodium bicarbonate are added thereto at 50C. 50 g of benzyloxycarbonyl chloride are added dropwise to the mixture at the same temperature, and the mixture is stirred at room temperature for 2 hours. After the reaction, the ethyl acetate layer is collected from the mixture, washed twice with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively. The ethyl acetate solution is dried and concentrated under reduced pressure to remove solvent. Crystalline precipitates are washed with diisopropyl ether, whereby 73.1 g of N benzyloxycarbonyl-2-oxo-2-phenylethylamine are obtained.

Yield: 93.1% M.p.65-66 C IRvnu l (cm-1) : 3320,1715,1680 (2) 6.1 g of sodium hydride (61.4% oil dispersion) are suspended in 100 ml of dimethylformamide, and a solution of 35 g of N-benzyloxycarbonyl-2-oxo-2-phenylethylamine and 30 g of 2,2,2-trifluoroethyl iodide in 130 ml of dimethylformamide is added dropwise thereto at -20 to -30"C. After the addition, the mixture is gradually raised to room temperature and further stirred at room temperature for one hour. After the reaction, the mixture is neutralized with acetic acid, and 800 ml of water are added thereto. The mixture is extracted with ether, and the extract is washed with a saturated aqueous sodium bicarbonate solution and water, successively. The ether extract is dried and concentrated under reduced pressure to remove solvent.

Crystalline residue is washed with n-hexane, whereby 40 g of 4-phenyl-4-oxo-3-benzyloxycarbonylamino1,1,1 -trifluoro-n-butane are obtained.

M.p.99.5-100.5 C IRvnuJxl (cm-1) : 3270, 695 (3) 10 g of 4-phenyl-4-oxo-3-benzyloxycarbonylamino-1,1,1-trifluoro-n-butane are dissolved in 200 ml of methanol, and 3.95 g of hydroxylamine hydrochloride and 8.1 g of pyridine are added thereto. The mixture is refluxed for 4 hours under heating. After the reaction, the mixture is concentrated under reduced pressure to remove solvent. Ethyl acetate and water are added to the residue, and the ethyl acetate layer is collected therefrom. The ethyl acetate solution is washed with 2% hydrochloric acid and water, successively. The ethyl acetate solution is then dried and concentrated under reduced pressure to remove solvent.Crystalline precipitates are washed with diisopropyl ether, whereby 5.6 g of 4-phenyl-4-hydroxyimino-3 benzyloxycarbonylamino-1 ,1 ,1 -trifluoro-n-butane are obtained.

Yield: 53.6% M.p.143-144 C IRvnul l (cm ) :3350,1690,700 (4) 5.0 g of 4-phenyl-4-hydroxyimino-3-benzyloxycarbonylamino-1 ,1,1 -trifluoro-n-butane are dissolved in 300 ml of ethanol, and 2.8 ml of conc.hydrochloric acid and 1.0 g of 10% palladium-charcoal are added thereto. The mixture is shaken at room temperature in hydrogen gas atmosphere for 4 hour under increased pressure (4 kg/cm2). After the reaction, insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. The residue is recystallized from a mixture of methanol and ether, whereby 3.71 g of erythro-4-phenyl-3,4-diamino-1 ,1 ,1 -trifluoro-n-butane dihydrochloride are obtained.

Yield: 93.4% M.p. > 250 C IRVUaB' (cm-l) :1600,700 NMR (DMSO-d6)8 : 2.55-3.1 (m, 2K), 4.1-4.4 (m, 1K), 5.04 (br s, 1K), 7.3-7.9 (m, 5H), 8.2-10.0 (br s,6 H).

erythro-4-phenyl-3,4-diamino-1 1,1 -trifluoro-n-butane dihydrochloride thus obtained is treated with 2N sodium hydroxide solution, whereby erythro-4-phenyl-3,4-diamino-1 ,1 ,1 -trifluoro-n-butane is obtained.

B.p. 120-130"C (2 mmHg) IRvfimamx(cm 3370,3300,1600 NMR (CDCI3)8 :1.55(s,4H), 1.7-2.65 (m, 2H), 3.2-3.5 (m, 1K), 3.86 (d, H, J = 7Hz), 7.35 (s,5H) (5) 2.03 g of erythro-4-phenyl-3,4diamino-1,1,1-trifluoro-n-butane are dissolved in 40 ml of ethanol and 1.4 g of d-tartaric acid are added thereto. The mixture is heated gradually at 80"C to dissolve said tartaric acid therein and allowed to stand at room temperature overnight Crystalline precipitates are collected by filtration.The crystals are dissolved in 20 ml of water, and the solution is neutralized with 2N sodium hydroxide solution under cooling. The mixture is extracted with chloroform, and the extract is concentrated under reduced pressure. 0.59 g of (+)-erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane is obtained as an oil.

[(X]25 +8.1 (C = 1.21, ethanol) On the other hand, the filtrate is concentrated under reduced pressure to remove solvent. After the residue is dissolved in water, the solution is treated in the same manner as described above. 0.88 g of (-)-erythro-4-phenyl-3,4-diamino-1 1,1 -trifluoro-n-butane is obtained as an oil.

[aj25 -7.08 (C = 0.37, ethanol) Preparation ofcompound fIV) (1) 50 g of 2-oxo-2-phenylethylamine hydrochloride are suspended in a mixture of 500 ml of water and 500 ml of ethyl acetate, and 61 g of sodium bicarbonate are added thereto at 5"C. 56 g of 4-chlorobenzoyl chloride are added dropwise to the mixture at the same temperature, and the mixture is stirred at room temperature for 2 hours. After the reaction, the ethyl acetate layer is collected from the mixture, washed twice with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively. The ethyl acetate solution is dried and concentrated under reduced pressure to remove solvent.Crystalline precipitates are washed with diisopropyl ether, whereby 76.6 g of N-(4 chlorobenzoyl)-2-oxo-2-phenyl-ethylamine are obtained.

Yield: 96% M.p.155-156 C IRvnmugXl (cm~1) : 3360, 1690,1645, 1595 (2) 2.1 g of sodium hydride (61.4% oil dispersion) are suspended in 40 ml of dimethylformamide, and a solution of 11.5 g of N-(4-chlorobenzoyl)-2-oxo-2-phenylethylamine and 9.8 g of 2,2,2-trifluoroethyl iodide in 50 ml of dimethylformamide is added dropwise thereto at -20 to -30 C. After the addition, the mixture is gradually raised to room temperature and further stirred at room temperature for one hour. After the reaction, the mixture is neutralized with acetic acid, and 400 ml of water are added thereto. The mixture is extracted with ethyl acetate, and the extract is washed with a saturated aqueous sodium bicarbonate solution and water, successively.The ethyl acetate solution is dried and concentrated under reduced pressure to remove solvent. Crystalline residue is washed with diisopropyl ether, whereby 12.7 g of 4-phenyl-4-oxo-3-(4-chlorobenzoylamino)-1 ,1 ,1 -trifluoro-n-butane are obtained.

M.p.138-139 C IRvmuåx l (cm~1) : 3240,3080,1690, 1640, 1600 (3) 12.6 g of 4-phenyl-4-oxo-3-(4-chlorobenzoylamino)-1,1,1-trifluoro-n-butane are dissolved in 300 ml of methanol, and 4.9 g of hydroxylamine hydrochloride and 11.1 g of pyridine are added thereto. The mixture is refluxed for4 hours under heating. After the reaction, the mixture is concentrated under reduced pressure to remove solvent. Ethyl acetate and water are added to the residue, and the ethyl acetate layer is collected therefrom. The ethyl acetate solution is washed with 2% hydrochloric acid and water, successively. The ethyl acetate solution is then dried and concentrated under reduced pressure to remove solvent. Crystalline precipitates are washed with diisopropyl ether, whereby 6.3 g of 4-phenyl-4-hydroxyimino-3-(4 chlorobenzoylamino)-1 ,1 ,1 -trifluoro-n-butane are obtained.

Yield: 48% M.p. 172-173"C IRvmuåxl (cm-1) : 3280,3090, 1639,1660 (4) 4.5 g of 4-phenyl-4-hydroxyimino-3-(4-chlorobenzoylamino)-1 ,1 ,1 -trifluoro-n-butane are dissolved in 60 ml of methanol, and 1.2 ml of conc.-hydrochloric acid and 0.5 g of 10% palladium-charcoal are added thereto. The mixture is shaken at room temperature in hydrogen gas atmosphere for 4 hours under increased pressure (4 kg/cm2). After the reaction, insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. The residue is crystallized with methanol, whereby 1.9 g of erythro-4-phenyl-4-amino-3-(4-chlorobenzoylamino)-1 1,1 -trifluoro-n-butane hydrochloride are obtained.

Yield: 40% M.p. > 250 C IRvnuaoxl (cm~1) : 3300, 1640, 1600 1.5 g of erythro-4-phenyl-4-amino-3-(4-chlorobenzoyl)-1 ,1 ,1 -trifluoro-n-butane hydrochloride are dis solved in 30 ml of methanol and 0.31 g of sodium ethoxide is added thereto. The mixture is stirred at room temperature for 30 minutes and concentrated under reduced pressure to remove methanol. 30 ml of water are added to the residue, and insoluble precipitates are collected therefrom. The precipitates are washed with ether, whereby 1.0 g of erythro-4-phenyl-4-amino-3-(4-chlorobenzoylamino)-n-butane is obtained.

M.p.176-178 C IRvjnnucgoxl (cm-1) : 3250,3150, 1640,1610, 1600

Claims (12)

1. An imidazoline derivative oftheformula:

wherein ring A is phenyl, lower alkyl-phenyl, lower alkoxy-phenyl or halogenophenyl, or a pharmaceutically acceptable acid addition salt thereof.

2. A compound as claimed in claim 1, in which ring A is phenyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl or bromophenyl.

3. A compound as claimed in claim 1, in which ring A is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 3-chlorophenyl, 4-ch lo rophenyl or4-bromophenyl.

4. A compound as claimed in claim 1, 2 or 3, which is cis-2-(4-chlorophenyl)-4-phenyl-5-(2,2,2trifluoroethyl)imidazoline or a pharmaceutically acceptable acid addition salt thereof.

5. An imidazoline derivative of the formula given in claim 1, substantially as herein described with reference to and as illustrated in any of the Examples.

6. A process for preparing an imidazoline derivative of the formula given in claim 1 or a pharmaceutically acceptable acid addition salt thereof, which comprises the steps of condensing a diamine compound of the formula:

or a salt thereof with a benzimidic acid compound of the formula:

wherein R is lower alkyl and ring A has the meaning given in claim 1, or a salt thereof, and if required, further converting the product into a pharmaceutically acceptable acid addition salt thereof.

7. A process for preparing an imidazoline derivative of the formula given in claim 1, or a pharmaceutically acceptable acid addition salt thereof, which comprises cyclizing a compound of the formula:

wherein ring A has the meaning given in claim 1, or a salt thereof, and if required, further converting the product into a pharmaceutically acceptable acid addition salt thereof.

8. A process for preparing an imidazoline derivative of the formula given in claim 1, or a pharmaceutically acceptable acid addition salt thereof, substantially as herein described with reference to and as illustrated in any of the Examples.

9. A pharmaceutical composition which comprises a pharmaceutically effective amount of an imidazoline derivative as claimed in any of claims 1 to 5, or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier therefor.

10. An imidazoline derivative as claimed in any of claims 1 to 5, or a pharmaceutically acceptable acid addition salt thereof, for use as an analgesic, anti-inflammatory and/or anti-pyretic agent.

11. Adiaminecompound oftheformula:

12. Acompound oftheformula:

wherein ring A has the meaning given in claim 1.