JPH0542432B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a novel imidazoline derivative useful as a pharmaceutical compound and a method for producing the same. (Objective of the Invention) The present invention exhibits excellent anti-inflammatory, analgesic and antipyretic effects on various inflammatory diseases, is free from undesirable side effects such as ulcer formation, has low toxicity and is highly safe. An object of the present invention is to provide an imidazoline derivative having the following properties. (Structure and Effects of the Invention) The novel imidazoline derivative of the present invention is represented by the following general formula (). (However, ring A represents a phenyl group, a lower alkyl-substituted phenyl group, a lower alkoxy-substituted phenyl group, or a halogen-substituted phenyl group.) Examples of the compounds of the present invention include, in general formula (), when ring A is a phenyl group; methyl phenyl lower alkyl-substituted phenyl groups such as ethyl phenyl, propylphenyl and butylphenyl groups; lower alkoxy-substituted phenyl groups such as methoxyphenyl, ethoxyphenyl, propoxyphenyl and butoxyphenyl groups; or fluorophenyl groups Examples include compounds which are halogen-substituted phenyl groups such as , chlorophenyl group, and bromophenyl group. Among these, preferred compounds include those in which ring A is a phenyl group, methylphenyl group, methoxyphenyl group, fluorophenyl group, chlorophenyl group, or bromophenyl group. More preferred compounds include compounds in which ring A is a phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-fluorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group or 4-bromophenyl group. It will be done. The imidazoline derivative of the present invention has two tautomeric structures as shown by the following formula, and both of these isomers are included within the scope of the present invention. (However, Ring A has the same meaning as above.) Furthermore, since the compound () of the present invention contains two asymmetric carbon atoms in the molecule, it has two stereoisomers (i.e., cis and trans isomers). ) or four optical isomers (i.e. (+)-cis, (-)-cis,
(+)-trans and (-)-trans isomers), and the present invention includes any of these stereoisomers, optical isomers, or mixtures thereof. According to the invention, imidazoline derivatives ()
is the expression The compound shown by () or its salt and the general formula (However, R represents a lower alkyl group, and ring A has the same meaning as above.) By subjecting the compound represented by () or a salt thereof to a condensation reaction, or by subjecting the compound represented by the general formula (However, ring A has the same meaning as above.) It can be obtained by subjecting the compound represented by () or a salt thereof to an intramolecular ring-closing reaction. In the above reaction, the compound of the present invention (),
Examples of salts of () and () include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, etc. and organic acid addition salts such as oxalate, lactate, tartrate, etc. can also be used. Compound () or its salt and compound ()
or a condensation reaction with a salt thereof is easily carried out. For example, the condensation reaction proceeds in a solvent in the presence or absence of a base. Examples of the base include alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, etc.);
Alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate or alkali metal hydrogencarbonate (e.g., sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, etc.), or tertiary lower Preferred examples include alkylamides (eg, trimethylamine, triethylamine), and the like. Preferred examples of the solvent include lower alkanols (eg, methanol, ethanol, isopropanol, etc.), dioxane, tetrahydrofuran, dimethylformamide, and dimethyl sulfoxide. This reaction is preferably carried out at room temperature to 100°C, particularly at 30 to 70°C. The intramolecular ring closure reaction of the compound () or a salt thereof is preferably carried out in the presence of a dehydrating agent. Examples of the dehydrating agent include calcium oxide, aluminum oxide, and silicon dioxide. This reaction can be carried out in the presence or absence of a solvent, and a suitable example of the solvent is 1,2,3,4-tetrahydronaphthalene. This reaction is 100
Preferably it is carried out at ~300°C, especially 180-250°C. As mentioned above, the imidazoline derivative () or its pharmacologically acceptable acid addition salt of the present invention is useful as an anti-inflammatory, analgesic, and/or antipyretic agent without undesirable side effects such as peptic ulcer formation. It is. For example, the compound of the present invention () or its acid addition salt can be used to treat various inflammatory diseases in skeletal muscles, joints (e.g., knee joints, shoulder joints, elbow joints, ankle joints, etc.) and other organs (e.g., rheumatism, gout, arthritis). Or fracture, lesion,
It can be used to treat or alleviate inflammation (inflammation caused by injury, etc.), and can also be used to alleviate other symptoms associated with various inflammatory diseases, such as pain and fever. When the imidazoline derivative () of the present invention is used as a medicine, it can be used in a free form or as a pharmacologically acceptable acid addition salt. Examples of pharmacologically acceptable acid addition salts include hydrochloride,
Inorganic acid addition salts such as hydrobromide, phosphate and sulfate or oxalate, acetate, lactate, citrate, tartrate, fumarate, maleate, aspartate, methane Included are organic acid addition salts such as sulfonic acids and benzoates. These salts can be produced, for example, by neutralizing compound () with an acid in a conventional manner. The imidazoline derivative () and its acid addition salt can be administered either orally or parenterally (eg, intravenous injection, intramuscular injection, subcutaneous injection, etc.). The pharmaceutical dosage of Compound () or its acid addition salt varies depending on the patient's age, weight, condition, and severity of the disease to be treated, but the daily dosage is usually
0.2 to 5.0 mg/Kg, especially 0.5 to 2.0 mg/Kg are preferred. Furthermore, the compound (2) and its acid addition salts can be used in combination with pharmacologically acceptable excipients suitable for oral or parenteral administration. Excipients include, for example, mannitol, lactose, magnesium stearate, starch, talc, cellulose, sucrose, glucose, magnesium carbonate, polypropylene glycol, water, saline, ethanol, glycerin, sodium acetate, sorbitan monolaurate, Ethanolamine oleate and the like are preferably used. The dosage form may be a solid dosage form such as a tablet, coated tablet, pill, or capsule, or a liquid dosage form such as a solution, suspension, or emulsion. They may be sterilized and may contain adjuvants such as stabilizers, wetting agents and emulsifiers. Furthermore, the dosage form for parenteral administration is an injection. The raw material compounds () and () of the present invention are novel compounds, and can be produced, for example, by the method shown in the following reaction formula. (However, X represents a halogen atom, Y represents a hydrogen atom or a hydroxyl group, and Ring A has the same meaning as above.) In other words, the compound () or () is a compound () or () that is 2,2 , 2-trifluoroethyl halide to produce the compound () or (), and then the compound () or ()
It can be produced by reacting with ammonia or hydroxylamine and catalytically reducing the obtained compound () or (). The reaction between compound () or () and 2,2,2-trifluoroethyl halide is carried out using a deoxidizer (e.g., alkali metal hydride, alkali metal hydroxide, alkali metal alkoxide, n-butyllithium, etc.) in a suitable solvent. ) at -78 to 50°C. The reaction between compound () or compound () and ammonia or hydroxylamine is carried out in a solvent for 20~
It can be carried out at 100°C. Further, the catalytic ring reaction of compound () or () can be carried out in a solvent in a hydrogen gas atmosphere in the presence of a catalyst (eg, palladium on charcoal, palladium on black, platinum oxide, Raney nickel, etc.). This reaction can be suitably carried out in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or the like. The compound () or compound () obtained in this way has two diastereomers (for example, erythro form and threo form) due to the difference in the configuration of the diamino groups substituted at the 3- and 4-positions of the n-butane moiety. However, in the present invention, both of these diastereomers or a mixture thereof can be used. Furthermore, erythro or threo type compounds ()
If desired, can be resolved into each optically active substance using a conventional optical resolution reagent. for example,
The optical resolution of (±)-erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane involves reacting the compound with optically active tartaric acid and then selecting its diastereomers. This can be done by directly crystallizing it. More specifically, when d-tartaric acid is used as a resolving reagent, (+)-erythro-4-phenyl-3,4-
Diamino-1,1,1-trifluoro-n-butane forms poorly soluble diastereomeric salts, while l
- When tartaric acid is used as the resolving reagent, (-)-erythro-4-phenyl-3,4-diamino-1,
1,1-trifluoro-n-butane forms sparingly soluble diastereomeric salts. Selective crystallization can be carried out, for example, by recrystallizing from a solution of lower alkanol (eg, ethanol, etc.). Hereinafter, the present invention will be explained in detail with reference to Examples and Reference Examples.
It means that the two amino groups substituted at the 3- and 4-positions of the n-butane moiety have a threo configuration (the two groups are located on opposite sides of each other in the Fischer projection system), "Erythro" means that the amino group has an erythro configuration (the two groups are located on the same side). In addition, in this specification, a lower alkyl group and a lower alkoxy group each have 1 carbon number.
-4 represents an alkyl group and an alkoxy group. Experimental Example 1 (Anti-inflammatory effect) A sample dissolved in water was orally administered to male Crj:CD rats (body weight: 160-180 g) that had been fasted overnight. One hour after administration, 0.05 ml of a 1% carrageenan saline solution was administered to one side of the rat. It was injected subcutaneously into the hind footpad. Four hours after administration of carrageenan, the volume of both hind paws of the rat was measured, and the edema volume was determined from the difference in volume between both hind paws.This was compared with the edema volume of a control group in which water was administered instead of the sample to determine whether inflammation had subsided. The effect was measured. The anti-inflammatory activity of the specimens was expressed in terms of the 30% effective dose (ED ₃₀ ), ie the dose required to suppress the inflammation caused by carrageenan by 30%.

[Table] Experimental Example 2 (Analgesic effect) After the sample dissolved in water was orally administered to male Crj:CD rats (body weight: 70-90 g) that had been fasted overnight, 20% dry yeast was immediately suspended in physiological saline. 0.1ml
was injected subcutaneously into the sole of one of the hind legs of the rat.
Two hours after dry yeast administration, the pain thresholds of both hind paws were measured, and the difference between the pain thresholds of the inflamed paw and the other paw was calculated, and this was compared to the pain threshold of the control group in which water was administered instead of the specimen. The analgesic effect of the specimen was evaluated by comparing with The analgesic effect of the test compound was expressed in terms of the 30% effective dose (ED ₃₀ ), ie, the dose required to reduce the difference in pain thresholds by 30%. The results are shown in Table 2 below.

[Table] Example 3 (Antipyretic effect) Crj:CD male rats fasted overnight (body weight: 160
-180 mg/Kg) 0.1 ml of 2% carrageenan saline solution was subcutaneously injected into the hind footpad. Three hours after the administration of carrageenan, the sample dissolved in water was orally administered to the rats. Two hours after administration of the sample, the rectal body temperature of the rats was measured with a thermistor thermometer, and the difference between the rectal body temperature before carrageenan administration was determined, and this was compared with that of a control group in which water was administered instead of the sample. The antipyretic effect of the test compound was expressed in terms of the 50% effective dose, ie the dose required to reduce the fever caused by carrageenan by 50%. The results are shown in Table 3 below.

[Table] Experimental example 4 (Peptic ulcer formation effect) ddY male mice fasted overnight (body weight: 22-25
g) A sample suspended in a 0.25% carboxymethyl cellulose solution was orally administered. Immediately after administering the sample, the mouse was placed in a restraint cage and immersed up to the neck in a water bath at 24±0.5°C. After 15 minutes, the mice were removed from the cage, placed in a breeding cage, and returned to the animal room at 22±1°C. Two hours after administration of the sample, the mouse was sacrificed, the stomach was removed, and the presence or absence of ulcer formation was examined under a stereomicroscope. The results are shown in Table 4 below.

[Table] Experimental example 5 (acute toxicity) ddY male mice fasted overnight (body weight: 18-22
g) cis-2-(4-chlorophenyl)-4 suspended in 0.25% carboxymethylcellulose solution
-Phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride (dose: 1000mg/
Kg) was orally administered and kept for 14 days to observe mortality. No mouse deaths were observed during the experimental period. Experimental Example 6 (Toxicity due to continuous administration) Crj:CD male rats fasted overnight (body weight: 160
cis-2-(4-chlorophenyl)-4-phenyl-5-(2,2,2-
Trifluoroethyl) imidazoline hydrochloride 10
mg/Kg was orally administered once a day for 4 consecutive days and compared with the control group. No effects on body weight gain or related organ weights were observed during the experiment. Example 1 514mg of sodium ethylate in 20ml of ethanol
After heating to 80℃, add 1.1g of erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane dihydrochloride, and stir at the same temperature for 5 minutes. do. 702 mg of benziminoethyl ether hydrochloride was added to the reaction solution, and the mixture was refluxed for 1 hour.
After cooling, insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove the solvent. Add 1N sodium hydroxide to the residue 20
ml and extracted with chloroform. The extract is washed with water, dried, and concentrated under reduced pressure to remove the solvent. Cis-2,4-diphenyl-5-(2,2,
2-trifluoroethyl)imidazoline hydrochloride
Get 930mg. Yield: 72% Mp199-201℃ IRν ^nujol _nax (cm ^-1 ): 1620, 1600, 700 NMR (DMSO-d ₆ ) δ: 1.8-2.3 (m, 1H), 2.6
-3.3 (m, 1H), 4.8-5.2 (m, 1H), 5.6 (d,
1H, J=12Hz), 7.2-8.55 (m, 1OH), 11.8
(brs, 2H) Examples 2 to 7 The following compounds were obtained from the corresponding raw material compounds in the same manner as in Example 1. (In the above formula, R=ethyl group)

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[Table] Example 8 (+)-erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane
A mixture of 524 mg of 4-chlorobenziminoether ether hydrochloride and 25 ml of ethanol was refluxed for 1 hour, and after cooling, the reaction solution was treated in the same manner as in Example 1 to obtain (+)-cis-2-(4- chlorophenyl)-4-phenyl-5-(2,2,2-
Trifluoroethyl) imidazoline hydrochloride 786
Get mg. Yield: 87% Mp>250°C [α] ²⁵ _D +15.0° (C=0.49, ethanol) The IR and NMR spectra of this product match those of the specimen obtained in Example 3. Example 9 (-)-Erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane
750mg, 4-chlorobenziminoether ether
By treating 786 mg and 30 ml of ethanol in the same manner as in Example 8, (-)-cis-2-(4-chlorophenyl)-4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride 879mg
get. Yield: 68% Mp>250°C [α] ²⁵ _D −15.0° (C=0.50, ethanol) The IR and NMR spectra of this product match those of the standard sample obtained in Example 3. Example 10 Erythro-4-phenyl-4-amino-3-
(4-chlorobenzoylamino)-1,1,1-trifluoro-n-butane 1.0g and calcium oxide
1.5 g of the mixture is heated at 230-240° C. for 3 hours in a nitrogen gas atmosphere. Add 30 ml of chloroform to the reaction solution and filter off insoluble matter. After extracting the filtrate with 20 ml of 10% hydrochloric acid, the acidic layer is neutralized with potassium carbonate and extracted with ethyl acetate. After washing the extract with water, add 5 ml of a 10% hydrochloric acid-methanol mixture. The mixture was concentrated under reduced pressure to remove the solvent, and the crystalline residue was washed with ether to give cis-2-(4-chlorophenyl).
0.23 g of -4-phenyl-5-(2,2,2-trifluoroethyl)imidazoline hydrochloride is obtained. The physicochemical properties of this product are consistent with the sample of Example 3. (Preparation of raw material compound) Reference example 1 (1) Suspend 50 g of 2-oxo-2-phenylethylamine hydrochloride in a mixture of 500 ml of water and 500 ml of ethyl acetate, and add 61 ml of sodium bicarbonate at 5°C.
Add g. 50 g of benzyloxycarbonyl chloride was added dropwise to the mixture at 5° C., and the mixture was stirred at room temperature for 2 hours. After the reaction, the ethyl acetate layer is separated and washed twice each with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The ethyl acetate solution was dried and concentrated under reduced pressure to remove the solvent.
By washing the crystalline residue with diisopropyl ether, N-benzyloxycarbonyl-
2-oxo-2-phenylethylamine 73.1g
get. Yield: 93.1% Mp65-66℃ IRν ^nujol _nax (cm ^-1 ): 3320, 1715, 1680 (2) Sodium hydride (61.4% oily dispersion) 6.1
Suspend g in 100ml of dimethylformamide,
N-benzyloxycarbonyl-
A solution of 35 g of 2-oxo-2-phenylethylamine and 35 g of 2,2,2-trifluethyl iodide in dimethylformamide (130 ml) is added dropwise at -20 to -30°C. The mixture was gradually warmed up to room temperature and stirred for an additional hour at room temperature. Neutralize the reaction solution with acetic acid,
Add 800ml of water and extract with ether. The extract was washed with saturated sodium bicarbonate solution and water, dried and concentrated under reduced pressure to remove the solvent, and the crystalline residue was washed with n-hexane to give 4-phenyl-4-oxo-3- 40 g of benzyloxycarbonylamino-1,1,1-trifluoro-n-butane are obtained. Yield: 87.6
% Mp99.5−100.5℃ IRν ^nujol _nax (cm ^-1 ): 3270, 1690, 695 (3) 4-phenyl-4-oxo-3-benzyloxycarbonylamino-1,1,1-trifluoro-n- Dissolve 10 g of butane in 200 ml of methanol, then hydroxylamine hydrochloride 3.95
g and 8.1 g of pyridine were added, and the mixture was heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and the solvent was distilled off. Ethyl acetate and water are added to the residue, and the ethyl acetate layer is separated, washed with 2% hydrochloric acid and water, dried, and concentrated under reduced pressure to remove the solvent. By washing the precipitated crystals with diisopropyl ether, 4-phenyl-4-hydroxyimino-3-benzyloxycarbonylamino-
1,1,1-trifluoro-n-butane 5.6g
get. Yield: 53.6% Mp143−144℃ IRν ^nujol _nax (cm ^-1 ): 3350, 1690, 700 (4) 4-Phenyl-4-hydroxyimino-3-
Benzyloxycarbonylamino-1,1,1
-Dissolve 5.0 g of trifluoro-n-butane in 300 ml of ethanol, add 2.8 ml of concentrated hydrochloric acid and 1.0 g of 10% palladium on charcoal, and shake for 4 hours at room temperature in a hydrogen gas atmosphere (hydrogen pressure: 4 Kg/cm ² ). I'll do it.
After the reaction, insoluble materials are filtered off, the filtrate is concentrated under reduced pressure, and the solvent is distilled off. By recrystallizing the residue from a methanol/ether mixture, erythro-4-
3.71 g of phenyl-3,4-diamino-1,1,1-trifluoro-n-butane dihydrochloride are obtained. Yield: 93.4% Mp＞250℃ IRν ^nujol _nax (cm ^-1 ): 1600, 1700 NMR (DMSO-d ₆ ): 2.55-3.1 (m, 2H), 4.1
−4.4 (m, 1H), 5.04 (brs, 1H), 7.3−7.9
(m, 5H), 8.2−10.0 (brs, 6H) Erythro-4-phenyl- obtained above
Erythro-4-
Phenyl-3,4-diamino-1,1,1-trifluoro-n-butane is obtained. Bp120-130℃ (2mmHg) IRν ^film _nax (cm ^-1 ): 3370, 3300, 1600 NMR (CDCl ₃ ) δ: 1.55 (s, 4H), 1.7-2.65
(m, 2H) 3.2−3.5 (m, 1H), 3.86 (d, 1H,
J=7Hz), 7.35 (s, 5H) (5) Erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane 2.03
Dissolve g in 40 ml of ethanol and add d-tartaric acid.
Add 1.4g. The mixture is heated to 80° C. to dissolve the tartaric acid and left overnight at room temperature. Collect the precipitated crystals by filtration, dissolve in 20ml of water, and add 2N under cooling.
- Neutralize with aqueous sodium hydroxide solution and extract with chloroform. By concentrating the extract under reduced pressure, (+)-erythro-4-phenyl-3,
4-diamino-1,1,1-trifluoro-n
-0.59 g of butane are obtained as an oil. [α] ²⁵ _D +8.1° (C = 1.21, ethanol) On the other hand, the filtrate was concentrated under reduced pressure to remove the solvent,
After dissolving the residue in water, the solution was treated in the same manner as above to obtain 0.88 g of (-)-erythro-4-phenyl-3,4-diamino-1,1,1-trifluoro-n-butane in the form of an oil. Obtain it as a thing. [α] ²⁵ _D −7.08° (C=0.37, ethanol) Reference Example 2 The following compound was obtained in the same manner as in Reference Example 1-(1) to (4).

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Claims (1)

[Claims] 1. General formula (However, Ring A represents a phenyl group, a lower alkyl-substituted phenyl group, a lower alkoxy-substituted phenyl group, or a halogen-substituted phenyl group.) An imidazoline derivative or a pharmacologically acceptable acid addition salt thereof. 2 formulas The diamine derivative or its salt represented by and the general formula (However, R represents a lower alkyl group, and ring A represents a phenyl group, a lower alkyl-substituted phenyl group, a lower alkoxy-substituted phenyl group, or a halogen-substituted phenyl group.) A compound represented by or a salt thereof is subjected to a condensation reaction. , optionally converting the product into its pharmacologically acceptable acid addition salt. (However, Ring A has the same meaning as above.) A method for producing an imidazoline derivative or a pharmacologically acceptable acid addition salt thereof. 3 General formula (However, Ring A represents a phenyl group, a lower alkyl-substituted phenyl group, a lower alkoxy-substituted phenyl group, or a halogen-substituted phenyl group.) The general formula is characterized in that it is an acid addition salt that is acceptable to the general public. (However, Ring A has the same meaning as above.) A method for producing an imidazoline derivative or a pharmacologically acceptable acid addition salt thereof.