JPH0115506B2 - - Google Patents

Description

20 is the formula The compound according to claim 19, having the following. 21 2-[4-(3-tertiary butylamino-2-
hydroxypropoxy)-phenyl]4-trifluoromethylimidazole and its pharmaceutically acceptable salts; (S)-2-[4-(3-tertiary butylamino-
2-[4-(3-tertiary-butylamino-2-hydroxypropoxy)phenyl]-4-methylimidazole and a pharmaceutically acceptable salt thereof; 2-[4-(3-cyclopropylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole and a pharmaceutically acceptable salt thereof; S-2- [4-(3-tertiary butylamino-2-
2-[4-(3-tertiary-butylamino-2-hydroxypropoxy)phenyl]-4- Cyanoimidazole and its pharmaceutically acceptable salts, and S-2-[4-(3-tertiary butylamino-2-
2. A compound according to claim 1 selected from hydroxypropoxy)phenyl]-4-(2-thienyl)imidazole and its pharmaceutically acceptable salts. 22 formula reaction of an epoxide having the formula HNR ₅ R ₆ with an amine having the formula HNR 5 R 6 (wherein R and R ₁ are each selected from hydrogen, unsubstituted or halogen-substituted lower alkyl, unsubstituted or halogen- or lower alkoxy-substituted phenyl, furyl, thienyl, pyridyl, cyano, carboxy and carboxy derivatives;
R ₂ is selected from hydrogen and lower alkyl; R ₃ is selected from unsubstituted or halogen substituted pyridylene, unsubstituted or halogen or lower alkyl substituted phenylene, naphthylene and tetrahydronaphthylene; R ₄ is hydroxyl; R ₅ and R ₆ are hydrogen, respectively;
selected from lower alkyl, lower cycloalkyl and lower alkyl substituted with unsubstituted phenyl or lower alkoxy substituted phenyl. )
A method for producing imidazole having 23 formula A compound with the formula A formula characterized by reacting with a compound having in the presence of NH ₃ (wherein R and R ₁ are each selected from hydrogen, unsubstituted or halogen-substituted lower alkyl, unsubstituted or halogen- or lower alkoxy-substituted phenyl, furyl, thienyl, pyridyl, cyano, carboxy and carboxy derivatives;
R ₂ is selected from hydrogen and lower alkyl; R ₃ is selected from unsubstituted or halogen substituted pyridylene, unsubstituted or halogen or lower alkyl substituted phenylene, naphthylene and tetrahydronaphthylene; R ₄ is hydroxyl; R ₅ and R ₆ are hydrogen, respectively;
selected from lower alkyl, lower cycloalkyl and lower alkyl substituted with unsubstituted phenyl or lower alkoxy substituted phenyl. )
A method for producing imidazole having

[Detailed description of the invention]

The present invention relates to novel substituted imidazoles, their preparation and uses. More specifically, the present invention relates to novel imidazoles having antihypertensive activity and β-adrenergic neuroleptic activity. A variety of chemicals can be used to treat hypertension in humans and animals. It is known that certain trifluoromethylimidazoles have substantial antihypertensive activity. These imidazoles are described in US Pat. No. 3,786,061. Other classes of chemicals known as beta-adrenergic neuroleptics can also be used. These β-blockers affect cardiac, vascular and pulmonary artery function and may be mild antihypertensive agents. In particular, these chemicals have the ability to reduce heart rate, counteract vasomotor depression, and inhibit bronchodilation. β-adrenergic neuroleptics, their chemical structure and activity are described in Clinical Pharmacology and Therapeutics, Vol. 10, pp. 292-306 (1969). In addition, various β-adrenergic neuroleptics are disclosed in U.S. Pat.
No. 3655663, No. 3794650, No. 3832470, No.
No. 3836666, No. 3850945, No. 3850946, No.
3850947, 3852291 and UK Patent No. 1194548
It is explained in the issue. If an antihypertensive agent operates primarily via vasodilation, it produces undesirable side effects such as substantially increased heart rate. Novel imidazoles have been discovered that are characterized by having amino-substituted propoxyaryl substitutions. These imidazoles have surprising antihypertensive and β-adrenergic neuroleptic activity. Compounds of the invention have the formula and its pharmacologically usable acid addition salts and quaternary ammonium salts. In the above formula, R and R ₁ are each hydrogen, unsubstituted or halogen-substituted lower alkyl, unsubstituted or halogen- or lower alkoxy-substituted phenyl,
selected from furyl, thienyl, pyridyl, cyano, carboxy and carboxy derivatives; R ₂ is selected from hydrogen and lower alkyl; R ₃ is unsubstituted or halogen substituted pyridylene, unsubstituted or halogen or selected from lower alkyl substituted phenylene, naphthylene and tetrahydronaphthylene; R ₄
is hydroxyl; R ₅ and R ₆ are each selected from hydrogen, lower alkyl, lower cycloalkyl and lower alkyl substituted with unsubstituted phenyl or lower alkoxy substituted phenyl. A compound of particular interest has the formula: It is preferred that at least one of R and R ₁ is hydrogen. one of R ₅ and R ₆ is hydrogen and the other is C _1
-C6 alkyl is preferably _C3 - _C4 branched hydrocarbon alkyl. Compounds of formula () that are suitable are represented by the formula: A compound in which R is hydrogen. Another series of suitable compounds are those in which R and R ₂ are each hydrogen. These compounds have the formula: When R ₂ is hydrogen, the 4 and 5 positions of the imidazole are substantially equivalent. Another more preferred family of compounds is one having the formula: where R ₁ is selected from -CH ₃ , H, phenyl, pentafluorophenyl, P-chlorophenyl, P-fluorophenyl, P-methoxyphenyl, 2-thienyl, -CF ₃ and pyridyl; be. x is 0, 1 or 2. R _c is halogen, preferably chlorine, C ₁ -C ₃ alkyl, preferably −
_CH3 . A particularly preferred system of compounds is one in which R ₁ is _-CF3 ;
R ₄ is -OH and one of R ₅ and R ₆ is hydrogen and the other is C ₁ -C ₆ alkyl, preferably C ₃ -
C ₄ cyclic or branched hydrocarbon alkyl, especially tertiary butyl, having the formula (). The compounds of the present invention encompass all optically isomeric forms. In other words, compounds include mixtures containing optical isomers, such as racemic mixtures, as well as individual optical isomers. The compounds of the invention also include non-toxic pharmacologically usable acid addition salts and quaternary ammonium salts of the imidazoles of the invention. Acid addition salts are prepared by treating imidazole with a suitable amount of a suitable organic or inorganic acid. Examples of useful organic acids are maleic acid, tartaric acid, acetic acid, pamoic acid, oxalic acid, propionic acid, salicylic acid, succinic acid, malic acid, malic acid, isethionic acid, and the like. Useful inorganic acids include hydrohalic acids such as HCl, HBr and HI, sulfuric acid, _{H3PO4 ,} and the like. Quaternary salt is a group (wherein R ₅ and R ₆ are C ₁ -C ₆ alkyl, R _d
is C _1-6 alkyl and L is a non-toxic anion, preferably a halide such as iodide. ) is characterized by These salts are
e.g. methanol, by any suitable method.
Tertiary amino groups in a suitable solvent such as ethanol or dimethylformamide (DMF)

It is prepared by reacting the imidazoles of the invention having the formula with an alkyl halide, preferably an iodide such as ethyl iodide or methyl iodide. The reaction is generally carried out at room temperature. Quaternary salts are obtained directly by removing the solvent. Compounds of the invention may be prepared by conventional methods. One method of making compounds of the invention (Method A) is the formula By amination of a compound with . where X is halogen, preferably B _r , I or Cl. _NH3
When is an aminating agent, X is replaced by _-NH2 . On the other hand, if a primary or secondary, acyclic or cycloaliphatic amine is used, X is substituted by _the corresponding _-NR5R6 group. usually,
Amination involves halo compounds () and amines such as t
- by heating the mixture of butylamine for a sufficient period of time and then isolating the amination product. US Pat. No. 3,337,628 describes such a method. A particularly useful method of preparing the imidazoles of this invention in which R ₄ is -OH is by reaction of an epoxy compound with ammonia or a suitable amine reagent as shown by the following general formula. Method B The reaction is generally carried out in solution with an excess of amine reactant serving as a solvent. However, other solvents such as triethylamine, pyridine, tetrahydrofuran, etc. may be used. The reaction is advantageously carried out at reflux temperature. However, the reaction temperature can vary from room temperature to above reflux temperature. The reaction may be carried out at atmospheric pressure, or, if necessary, at subatmospheric pressure. R and R ₂ are H, R ₁ is trihaloalkyl, and is at the 2-position of the imidazole ring.
3-dihaloacetone, aryl aldehyde and
Consists of a reaction of _NH3 . Depending on the type of aryl aldehyde used, different reaction sequences are used. These are explained by the following equation. In these formulas, X and X ¹ are halogens selected from F, B _r and Cl. X is F and
Preferably, X ¹ is B _r . The intermediate in the above formula is glyoxal

[Formula] or hydrated glyoxal

It is believed that [formula]. This intermediate is generally prepared as an aqueous mixture by treating halogenated acetone with a weakly basic solution such as sodium acetate trihydrate.
The solution is heated for a time and at a temperature sufficient to form the intermediate. Once cooled, the intermediate-containing solution is added to a solution of the appropriate aryl aldehyde and aqueous ammonia. Any suitable water-miscible solvent may be used. Methanol is advantageously used. Reactions to obtain substituted imidazoles are generally carried out at room temperature. Elevated temperatures may also be used. The solvent is then removed and the product imidazole is collected. The imidazole intermediate

[Formula] When the intermediate has a substituent, KOH, potassium butoxide,
Epoxy resin is prepared by treating with a suitable strong base such as NaOH in a solvent such as methanol.

[Formula] Performs conversion to a group. This epoxy derivative is then converted to the desired amine end product as previously described. R ₂ is H and

Another method for preparing compounds of formula (2) in which formula (2) is in the 2-position of imidazole is by reaction of an aryl aldehyde with glyoxal or its acetal and _NH3 . When using acetals, first e.g. aqueous
It must be hydrolyzed by treatment with a strong acid solution such as H ₂ SO ₄ . This reaction is explained by the following equation. If in method D, the aryl aldehyde used has the formula,

If the imidazole product has the formula:
Requires dehydrochlorination and amine treatment as shown in (4). The method of Method D is generally carried out in solution and at temperatures ranging from about room temperature to 100°C. No pressure is necessary. The solvent used will vary depending on the type of reactant used. Generally, this reaction is carried out in an aqueous solution such as H ₂ O or H ₂ O/miscible alkanol. Another method of preparing compounds of formula () in which R ₂ is other than H is to treat the corresponding compound in which R ₂ is H with a suitable reagent using well-known techniques. When the R ₂ group is alkyl, _the corresponding compound of formula () where R ₂ is H can be _converted into diazomethane, _{alkyl halides} e.g.
Alkylation using a suitable reagent such as butyl or dialkyl sulfate. formula The aryl aldehyde intermediate having (hal is Cl or Br) is advantageously prepared by reacting the corresponding hydroxyaryl aldehyde with epihalohydrin as shown by the following reaction scheme: . Formula O=CH-R ₃ -O-CH ₂ -CHOH-CH ₂ -NR ₅ R ₆
The aryl aldehyde intermediate having () is advantageously prepared by reacting the corresponding hydroxyaryl aldehyde with an epihalohydrin as shown in the following formula. Reaction conditions are similar to those used to prepare compound (). Arylaldehydes () can also be prepared by reacting arylaldehydes with oxazolidines as shown by the following formula. where R ₈ is the residue of an aldehyde as explained below. R ₇ is an alkyl or arylsulfonyl group such as benzenesulfonyl, toluenesulfonyl, methanesulfonyl and the like. The coupling reaction between oxazolidine () and aryl aldehyde is generally carried out in a suitable solvent such as dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), hexamethylene fluoramide (HMPP), alkanols such as methanol, ethanol, etc. It will be carried out inside. The reaction can be carried out at temperatures ranging from 0 to 200°C, but it is advantageously carried out at the reflux temperature of the solution. To carry out the hydrolysis, conventional techniques and reagents are used, such as H 2 _Cl , H ₂ SO ₄ . Oxazolidines () are obtained by reacting aldehydes with 1-amino-2,3-dihydroxypropane followed by treatment with a suitable alkyl or arylsulfonyl halide. This reaction is shown by the following equation. Any method that does not adversely affect oxazolidine production

[Formula] Aldehydes may also be used. Examples of suitable aldehydes are aryl aldehydes such as benzaldehyde, substituted benzaldehydes, naphthyl aldehyde etc. and alkanals such as acetaldehyde, formaldehyde, butyraldehyde etc. Commercially available aldehydes are also advantageously used. Methods for making oxazolidines are described in U.S. Pat. R ₄ is an ester group

Imidazoles of the formula are advantageously prepared by treating the corresponding imidazoles in which R ₄ is OH with the desired organic acid anhydride or halide, preferably a chloride. The reaction is carried out at ambient temperature or at elevated temperatures up to about 100°C. If R ₂ of the starting imidazole is hydrogen, then 1 of the imidazole
-The reaction is carried out under acidic conditions to avoid acylation of nitrogen. The general reaction is described by the following equation. The imidazoles of the present invention encompass all optically isomeric forms, which are mixtures of isomers, such as racemates as well as individual optical isomers. These individual isomers are commonly designated by the optical rotations they exhibit by 1 and +, L and D, or combinations of these symbols. These isomers are designated by the symbol S for sinister and R for rectus due to their absolutely unique configuration. Usually, the imidazole of the present invention is obtained as a racemate. These racemates can be separated into individual optical isomers using techniques used in the art. These methods are
It is usually tedious, time consuming and does not always provide complete separation of the isomers. This separation of isomers can be bypassed and the optical isomers of one or the other of the present invention can be isolated by utilizing a single optical enantiomer of the oxazolidine () of the aryl aldehyde intermediate (). It can be produced directly by producing one optical isomer. By using this single isomeric intermediate it is possible to obtain the desired imidazole final product in the form of a single optical isomer. A single optical isomer of oxazolidine () is advantageously obtained by using a single optical isomer of the 1-amino 2,3-dihydroxypropane reactant in the oxazolidine preparation described above. A compound of formula () in which NR ₅ R ₆ is at the 4-position of the imidazole ring can be produced by the method shown by the following formula. Method E consists of reacting an alkoxyaryl acetal with an aldehyde in the presence of ammonia. This ammonia may be liquid ammonia. In this case, the reaction temperature is in the range of about -33°C to 70°C and the reaction is carried out under pressure. Ammonia can also be provided as an aqueous solution, ie ammonia hydroxide. In this case, from about the freezing point of the reaction mixture to about 100°C
reaction temperatures can be used. When using aqueous ammonia systems, room temperature is advantageously used. If necessary lower alkanol e.g.
Other water-miscible aqueous solvents such as CH ₃ OH or DMF may also be used. Ether cleavage step (2) is aqueous
This can be accomplished using any suitable reagents and methods such as HI or aqueous HBr or AlCl ₃ in a hydrocarbon solvent (hexane, benzene, etc.). Method A of Method E allows the production of a single optical isomer, whereas Method B of Method E yields a racemate. The compounds of the present invention are: (1) active as antihypertensive agents, ie, these compounds have a blood pressure lowering effect in hypertensive animals; The compounds of the invention also include:
(2) It is active as a β-adrenergic neuroleptic. Many of the imidazoles of this invention are also active vasodilators. Antihypertensive effects are determined by administering the compounds of the invention (orally or intraperitoneally) to spontaneously hypertensive (SH) mice and measuring the effect on blood pressure. Typical imidazoles, generally administered as salts such as hydrochloride, have been found to lower blood pressure in SH mice. The β-adrenergic neuroleptic activity (β-blockade) of the compounds of the present invention demonstrates the ability of representative compounds to block isoproterenol-induced tachycardia, vasomotor depression, and bronchial dilatation in animals. Determined by measuring. Intravenous administration of imidazole (generally as an acid addition salt) was used for this evaluation. Typical imidazoles exhibit the ability to exhibit β-blockade in addition to having the above-mentioned antihypertensive effects. In evaluating the β-blocking effects of the compounds of the present invention, many of the compounds showed some evidence that the compounds were more effective at reducing the heart rate effects of isoproterenol than at blocking isoproterenol's effects on the bronchi. It was found that it exhibits cardioselectivity.
In other words, less compound is required to block the isoproterenol-induced rise in heart rate than is required to block isoproterenol-induced relaxation of the bronchi. This cardioselectivity factor can be expressed as the ratio of _ED50 to cardiac effect ( _β1 ) to pulmonary effect ( _β2 ): _ED50 .
When the β ₂ :β ₁ ratio is 1 or more, the compound can be considered to have cardioselective activity. 1 above
Test compounds ˜11 are examples of compounds with a β ₂ :β ₁ ratio greater than 1. The ability of the compounds of the present invention to reduce blood pressure in SH mice indicates that the compounds and their salts are useful in treating hypertension in humans. The β-adrenergic neuroleptic effect of the compounds of the invention may also be associated with angina pectoris or certain arrhythmias, which the compounds of the invention are known to be able to treat by treatment with β-adrenergic neuroleptics. Shows its usefulness in the treatment of humans suffering from undesirable diseases such as. Furthermore, the cardioselectivity of certain compounds of the invention provides the advantage of limiting blockade to only β ₁ -receptors and thus modulation of heart rate. For use as antihypertensive agents and/or beta-adrenergic neuroleptics, the compounds of the invention may be administered orally or parenterally, i.e. intravenously, intraperitoneally, and any appropriate use. It can be administered in any form. (a) For oral administration, the compounds may be formulated into tablets with other commonly used ingredients such as talc, vegetable oils, polyols, benzyl alcohol, gums, gelatin, starch and other carriers. (b) for parenteral administration, dissolved or dispersed or emulsified in a suitable liquid carrier; (b) for parenteral administration, dissolved or dispersed or emulsified in a suitable liquid carrier; It may be provided in emulsified form or (c) in a form such as an aerosol. The ratio of active compound to formulation ingredients, carrier, diluent, etc., will vary depending on the desired form of use. Whichever form of use is used, the amount of a compound of the invention administered may be sufficient to (a) reduce blood pressure in a patient suffering from hypertension and/or
(b) an amount sufficient to effect the patient's desired degree of β-blockade; Generally, 1 kg of body weight per day
A dosage of about 0.01 to 50 mg, preferably about 0.1 to 10 mg, of a compound of the invention may be used. The dosage may be single or multiple depending on the total daily amount required. The following are examples illustrating representative pharmaceutical formulations containing imidazoles of the present invention. Conventional techniques are used to manufacture these formulations. Tablet formulation Ingredient Amount (mg) (S)-2-[4-(3tert-butylamino-2-
Hydroxypropoxy)phenyl]-4-methylimidazole 5.0 Calcium phosphate 120.0 Lactose 50.0 Starch 23.5 Magnesium stearate 1.5 Tablet formulation Ingredients Amount (mg) 2-[4-(3-Cyclopropylamino-2-hydroxypropoxy)phenyl ]-4-Trifluoromethylimidazole 500.0 Starch Paste-12 1/2%, 100 c.c. Aron 12.5 512.5 Starch USP Onion 25.0 Magnesium Stearate 5.5 Capsule Formula Ingredients Amount (mg) (S)-2-[4- (3-tertiary butylamino-2
-hydroxypropoxy)phenyl]-4-P-
Methoxyphenylimidazole dihydrochloride dihydrate
250 Lactose USP 93 Talc 7 Injectable solution ingredients Amount (mg) 2-[4-(3-isopropylamino-2-hydroxypropoxy)phenyl]-4-cyanoimidazole hydrochloride 1 Sodium chloride 9 Dilute to 1.0 ml with distilled water Sufficient amount Liquid suspension component Amount (g/) (S)-2-[4-(3-Methylamino-2-hydroxypropoxy)phenyl]-4-(4-pyridyl)imidazole 5.0 Veegum HV 3.0 Methyl parable 1.0 Kaolin 10.0 Glycerin 250.0 Sufficient to 1 part water The following example illustrates the preparation of a typical imidazole of the present invention. All parts and percentages are by weight unless otherwise specified. Example 1 A 3-(3chloro-2-hydroxypropoxy)
Production of benzaldehyde m-hydroxybenzaldehyde (24.4g),
A mixture of epichlorohydrin (55.2 g) and pyridine (0.4 ml) is heated at 100° C. for 5 hours, then concentrated on steam under reduced pressure (20 mm Hg). The residual oil is taken up in chloroform (200 ml), concentrated hydrochloric acid (50 ml) is added and the mixture is stirred at room temperature for 0.5 hour. Separate the chloroform layer, wash with water and then vacuum the chloroform over steam (20 mmHg).
Remove. Distill the residual oil to a boiling point of 166℃/0.25
28.9 g of 3-(3-chloro-2-hydroxypropoxy)benzaldehyde are obtained as a yellow to brown oil at mmHg. B Preparation of 2-[3-(3chloro-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole To a solution of sodium acetate trihydrate (11.6 g) in water (40 ml) was added trifluorodibromoacetone ( 11.6g) and then the resulting solution
Heat at 100°C for 0.5 hour. After cooling to room temperature, it was dissolved in 3-(3-chloro-
Add to a solution of 2-hydroxypropoxy)benzaldehyde (9.45 g). The resulting thick solution is allowed to stand at room temperature for 5 hours and then the methanol is removed under reduced pressure (20 mm Hg) over steam. The oil separates and crystallizes. The supernatant was decanted and the residue was triturated with benzene and isolated by filtration to yield 6.97 g of solid. After recrystallization from toluene, the solid is suspended in hot water and then dissolved by adding acetonitrile. Upon cooling, 2-[3-(3-
Chloro-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained. Preparation of C 2-[3-(2,3-epoxypropoxy)phenyl]-4-trifluoromethylimidazole 2-[3-(3-chloro-2-hydroxypropoxy)phenyl] in methanol (150 ml)
-4-trifluoromethylimidazole (3.8
Powdered potassium hydroxide (3 g) is added to the solution of g) and the mixture is stirred at room temperature for 4 hours. Glacial acetic acid (2.75 ml) is added and the mixture is concentrated on steam under reduced pressure (20 mm Hg). The residue obtained is stirred with water, filtered and recrystallized from xylene to give 2-[3-(2,3-epoxypropoxy)phenyl]-4-trifluoromethylimidazole 2.5 m.p. 145-146.5°C. get g. D Preparation of 2-[3-(3-isopropylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole 2-[3-(2,3-epoxypropoxy)phenyl] in isopropylamine (10 ml) A solution of -4-trifluoromethylimidazole (0.9 g) is heated to reflux for 6 hours. Excess isopropylamine is removed by distillation over steam under atmospheric pressure. The residue was triturated with nitromethane (5 ml) and the remaining solids were removed by filtration. Melting point 162.5 ~ after recrystallization from nitromethane
2-[3-(3-isopropylamino-2-hydroxypropoxy)phenyl]-4 at 163.5℃
-0.65 g of trifluoromethylimidazole are obtained. Example 2 Preparation of 2-[4-(3-isopropylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole 2-[4-
(2,3-epoxypropoxy)phenyl]-4-
A solution of trifluoromethylimidazole (1 g) is heated to reflux for 7 hours and then left at room temperature for 16 hours.
Excess isopropylamine is removed by distillation under atmospheric pressure and the residue is triturated with nitromethane to give a solid. After filtration and recrystallization from acetonitrile, 2-
0.6 g of [4-(3-isopropylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained. Example 3 A Preparation of 2-methyl-4-(2,3-epoxypropoxy)benzaldehyde Epichlorohydrin (20 g,
0.216 mol) is added dropwise with a solution of 2-methyl-4-hydroxybenzaldehyde (9.0 g, 0.066 mol) in 2,5N sodium hydroxide solution (40 ml). After the addition, the solution is stirred for a further 3 hours at 55°C and then overnight at room temperature. The oil was distilled to give 2-methyl-4-(2,3-
8.3g of epoxypropoxy)benzaldehyde
get. B Preparation of 2-methyl-4-(3-tertiary-butylamino-2-hydroxypropoxy)benzaldehyde 2-Methyl-4-(2,3-epoxypropoxy)benzaldehyde (8.3 g, 0.043 mol)
, tertiary butylamine (10 g, 0.137 mol)
is added and the resulting solution is refluxed for 2 hours and then left overnight at room temperature. Excess tertiary butylamine is removed under reduced pressure (20 mm Hg) and the residue is heated on a steam bath with 6N hydrochloric acid (50 ml) for 5 hours and then basified hot with solid sodium hydroxide. The mixture is cooled to room temperature, extracted with chloroform (3 x 50 ml), dried over sodium sulfate, filtered and concentrated to dryness. The residual oil was crystallized from hexane to give 8.75 g of 2-methyl-4-(3-tert-butylamino-2-hydroxypropoxy)benzaldehyde, melting point 82-84°C.
get. C 2-[2-methyl-4-(3-tertiary-butylamino-2-hydroxypropoxy)phenyl]
- Preparation of 4-trifluoromethylimidazole To sodium acetate trihydrate (6.26 g, 0.046 mol) in water (26 ml) is added dibromotrifluoroacetone (6.26 g, 0.23 mol). The solution was heated on a steam bath for 45 minutes, cooled, then treated with methanol (60 ml) and concentrated aqueous ammonia (20 ml).
of 2-methyl-4-(3-tert-butylamino-2-hydroxypropoxy)benzaldehyde (3.05 g, 0.0115 mol) in the solution.
The solution is left at room temperature for 5 hours. The methanol is removed under reduced pressure (20 mmHg) over steam and the residue is then treated with chloroform (3 x 50 ml) and saturated sodium carbonate (50 ml). The organic phase was concentrated to dryness and the residue was crystallized from acetonitrile to give 2-[2-methyl-4-
1.2 g of (3-tert-butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole are obtained. Example 4 Production of 2-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-4-phenylimidazole 4-(3-tert-butylamino-2-hydroxypropyl)benzaldehyde (5.0 g, 0.02 mol), phenylglyoxal hydrate (6.04 g,
0.04 mol), concentrated aqueous ammonia (50 ml), water (50
ml) and methanol (200 ml) at room temperature.
Leave it for a while. Vacuum the solution over steam (20 mmHg)
Concentrate to obtain a residual oil, then saturated sodium carbonate (50
ml) and chloroform (3 x 50 ml). The organic phase is concentrated to dryness and then chromatographed on neutral alumina (500 g) using a gradient elution technique starting with chloroform. The product is eluted with 10% methanol-90% chloroform. Final purification is achieved by passage through a column of silica gel (150 g) followed by elution with 20% methanol-80% chloroform. The solvent was removed under steam vacuum (20 mm Hs) and the residue was crystallized from acetonitrile to give a melting point of 176
2-[4-(3-tertiary butylamino-
0.7 g of 2-hydroxypropoxy)-phenyl]-4-phenylimidazole is obtained. Example 5 A Preparation of S-4-(3-tert-butylamino-2-hydroxypropoxy)benzaldehyde S-2-phenyl-3 in pyridine (75 ml)
- To a solution of tertiary-butyl-5-hydroxymethyloxazolidine (47 g, 0.2 mol) is added P-toluenesulfonyl chloride in small portions while maintaining the internal temperature between 25 and 30°C. After the addition, the mixture is extracted with chloroform (3 x 100 ml) while maintaining the temperature at 25-30°C. The organic extract was dried over sodium sulfate and then reduced to a temperature of 50°C.
Concentrate first at 20 mmHg and then at 1 mmHg while maintaining the temperature below °C. The residual oil was dissolved in N,N-dimethylformamide (150ml) and then dissolved in N,N-dimethylformamide (150ml).
P in N-dimethylformamide (200ml)
- Add dropwise the sodium salt of hydroxybenzaldehyde (0.2 mol) to a refluxing solution. After refluxing for 10 hours, the reaction mixture was first heated 20 mm above steam.
Hg and then concentrate to 1 mmHg. 5 residues
% sodium hydroxide solution and then extracted with chloroform (3 x 100 ml). The organic extract is dried over sodium sulfate and the residue is chromatographed on alumina (500 g, active grade). Concentrate the chromatographic fraction and then incubate the residue at 240℃ and 0.3℃.
Distill at mmHg. The distillate (21 g) is treated with 1N hydrochloric acid (75 ml), heated over steam for 1/2 hour, cooled and extracted with ether. The aqueous phase was made basic to pH 10 by the addition of 2% sodium hydroxide solution and then chloroform (3 x 100 ml).
Extract with The organic extract is dried over sodium sulfate and concentrated to give an oil. After crystallization from hexane, 14 g of S-4-(3-tert-butylamino-2-hydroxypropoxy)benzaldehyde with a melting point of 60 DEG-62 DEG C. are obtained. B S-2-[4-(3-tertiary butylamino-2
Preparation of -hydroxypropoxy)phenyl]-4-trifluoromethylimidazole To sodium acetate trihydrate (20.2 g, 0.15 mol) in water (100 ml) is added dibromotrifluoroacetone (20.2 g, 0.075 mol).
The solution was heated over steam for 45 minutes, cooled and then dissolved in methanol (200ml) and concentrated aqueous ammonia (75ml).
S-P-(3-tertiary butylamino-2-
Hydroxypropoxy)benzaldehyde (12.5 g, 0.05 mol) is added to the solution. The solution is allowed to stand at room temperature for 5 hours. The methanol is removed by distillation over steam under reduced pressure (20 mm Hg). The mixture is made basic with saturated aqueous sodium carbonate solution. None then extracted with ethyl acetate (3 x 100 ml). The organic extract is dried over sodium sulfate and then concentrated over steam under 20 mm Hg. The resulting residue is recrystallized from acetonitrile, mp 181-182.
S-2-[4-(3-tertiary butylamino-
2-hydroxypropoxy)phenyl]-4-
7.6 g of trifluoromethylimidazole are obtained. Other imidazoles of formula (1) prepared using methods substantially as described in Examples 1-5 are shown in the following table.
It should be understood that similar reagents are used to obtain specific imidazole products.

【table】 Listed 〓

Claims (1)

[Claims] 1 Formula: (wherein R and R ₁ are each selected from hydrogen, unsubstituted or halogen-substituted lower alkyl, unsubstituted or halogen- or lower alkoxy-substituted phenyl, furyl, thienyl, pyridyl, cyano, carboxy and carboxy derivatives;
R ₂ is selected from hydrogen and lower alkyl; R ₃ is selected from unsubstituted or halogen substituted pyridylene, unsubstituted or halogen or lower alkyl substituted phenylene, naphthylene and tetrahydronaphthylene; R ₄ is hydroxyl; R ₅ and R ₆ are hydrogen, respectively;
selected from lower alkyl, lower cycloalkyl and lower alkyl substituted with unsubstituted phenyl or lower alkoxy substituted phenyl. )
and pharmaceutically acceptable salts thereof. 2 formula: A compound according to claim 1. 3 R ₃ is pyridylene, halopyridylene, naphthylene, tetrahydronaphthylene and the formula: The compound according to claim 2, wherein Rc is selected from halogen and lower alkyl, and x is 0, 1 or 2. . 4 R ₃ is The compound according to claim 3, which is 5. The compound of claim 3, wherein R ₁ is selected from hydrogen, halogen-substituted lower alkyl, lower alkyl, furyl, thienyl, pyridyl, phenyl, halogen-substituted phenyl, and lower alkyl ester. 6. A compound according to claim 5, wherein R ₁ is selected from trifluoromethyl, phenyl, pyridyl, thienyl, furyl, lower alkyl, cyano, lower alkoxyphenyl and halophenyl. 7. A compound according to claim 6, wherein R ₅ is H and R ₆ is lower alkyl. 8. The compound according to claim 7, wherein _R6 is _C3 - _C4 alkyl. 9. The compound according to claim 8, wherein R ₆ is tertiary butyl. 9. A compound according to claim 8, wherein 10 R ₁ is trifluoromethyl. 11. The compound according to claim 2, wherein R is H, R ₂ is H, R ₅ is H, and R ₆ is lower alkyl. 12. The compound according to claim 11, wherein _R1 is _-CF3 . 13 R ₃ is pyridylene, naphthylene, tetrahydronaphthylene and the formula The compound according to claim 11, wherein Rc is selected from halogen and lower alkyl, and x is 0, 1 or 2. . 14 R ₃ is The compound according to claim 13, which is 15. The compound according to claim 14, wherein 15 x is 1. 15. The compound according to claim 14, wherein 16 x is 0. 17 formula The compound according to claim 1, which is a compound of 18. The compound according to claim 17, wherein 18R is hydrogen. 19. The compound according to claim 1, wherein R ₃ is halopyridylene.