IE43397B1 - Novel substituted imidazoles, their preparation and use - Google Patents

Description

Various chemical agents are available for treating hypertension in man and animals. Certain trifluoromethyl imidazoles are known to have substantial antihypertensive activity. These imidazoles are disclosed in U.S. 3,786,061.

Another class of agents known as β-adrenergic blocking agents, are also available. These β-blocking agents affect cardiac vascular and pulmonary functions and can be mild antihypertensives. Specifically, these agents have the capability of reducing heart rate, counteracting vasodepression and supressing bronchodilation. β-adrenergic blocking agents, their chemical structure and activity, are disclosed in Clinical Pharmacology and Therapeutics 10, 292-306 (1969). Various β-adrenergic blocking agents are also described in the following patents: U.S. 3,048,387; U.S. 3,337,628; U.S. 3,655,663; U.S.3,794,650; U.S.3,832,470; U.S. 3,836,666; U.S. 3,850,945; U.S. 3,850,946; U.S. 3,850,947; U.S. 3,852,291 and Irish 31963.

Where an antihypertensive agent acts principally via vasodilat ion,it may cause undesirable side effects such as substantially increased heart rate (tachycardia).

The present invention provides novel imidazoles having the formula: ,R,-O-CIL-CH-CH,-N 2 2 x in which each of R and R^, which are similar or dissimilar, is hydrogen, alkyl, substituted c1_^0 alkyl having 1-3 substituents, cyeloalkyl, aryl, substituted aryl having 1-5 substituents, a heterocyclic group having 5-6 ring atoms, halogen, cyano, carboxy, carboxy derivatives, or -C-R„ 43337 where R^ is H or C^_g alkyl? is hydrogen, C^_^Q alkyl, hydroxy ci_i0 alkyl or Cg_g alkenyl; R^ is a bivalent aromatic group having 6 ring atoms of which 0-2 are other than carbon, a substituted bivalent aromatic group having 1-4 substituents,fused-ring bivalent aromatic group having 9-10 ring atoms of which 0-2 are other than carbon, or substituted fused-ring bivalent aromatic group having 1-4 substituents? R^ is hydroxy or -O-C-R, where R^ is C1-g alkyl, and each of Rg and Rg, which are similar or dissimilar, is hydrogen, C^_g alkyl, eycloalkyl or substituted C^_g alkyl or Rg and Rg are joined to form a 5-6 membered N-alicyclic ring; and pharmacologically acceptable salts thereof. Compounds of this present invention have unexpected antihypertensive activity and ¢3-adrenergicblocking activity. The salts may be acid-addition or quaternary ammonium salts.

Compounds of particular interest have the formulae: R, '2 R '4 R, '5 R, '6 IB Useful R and R^ alkyl groups include unsubstituted as wclL as substituted alkyl, cyeloalkyl as well as branched and linear alkyl groups. These alkyl groups may contain up Lo 10 alkyl carbons, preferably up to 8 alkyl carbon atoms and particularly from 1 to 6 alkyl carbons. Examples of suitable R and Rg unsubstituted alkyl groups are methyl, isopropyl, cyclopropyl, cyclopentyl, 2-methyl-n-butyl, decyl and 2-ethyln-hexyl; suitable R and Rg substituted alkyl groups have 1-3 substituents such as halo (Cl, Br, I, F), hydroxy, phenyl, Cg_^ alkoxy, exemplified by -CClg, bromohexyl, CHg-O-CHg-CHg-, hydroxypropyl, diiodethyl, trifluoromethyl, benzyl and chlorodecyl.

Useful R and Rg aryl groups include aryl groups having up to 10 ring carbon atoms. These aryl groups include single-ring and fused-ring aryls, either unsubstituted or having from 1 to 5 substituents. These substituents include alkyl, preferably cg_g alkyl, especially methyl, alkoxy, preferably Cg_g alkoxy, cyano, halo, (Cl, I, Br and F), -CO.NYZ where each of Y and Z is hydrogen or Cg__6 alkyl, nitro, amino, carboxy, hydroxy, carbonyl, -SH, sulfamoyl, thioalkyl and phenyl. Examples of suitable aryl R and Rg groups are phenyl, chlorophenyl, dibromophenyl, fluorophenyl, toluyl, xylyl, hexylphenyl, dodecylpheny1, tert-butylpheny!, methoxyphenyl, CgHig-O-phenyl, ΗΟ-CgHj-, carboxyphenyl, II sulfamoylphenyl, Ν,Ν-dimethylsulfamoylphenyl, napthyl, indanyl, chloronaphthyl, trichlorophenyl, HO-CHg-CgH^-, pentafluorophenyl, the tetralin group (tetrahydronaphthyl), cyanophenyl, chlorohydroxyphenyl,(Cg_g alkyl)-S-CgH4~, and SH Useful R and Rg heterocyclic groups are those having 5-6 ring atoms of which 1-3 and preferably 1-2 are hetero atoms, and the quinolyl group. Substituted as well as unsubstituted heterocyclic groups are included. The hetero atoms are 0, S and N. Examples of suitable R and R^ heterocyclic groups are pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, substituted pyridyl such as dimethylpyridyl, methylpyridyl, chloropyridyl, dichloropyridyl, diethylpyridyl, trimethylpyridyl, methylethylpyridyl, ethylpyridyl, bromopyridyl, and analogous substituted pyrazinyl, pyrimidinyl and pyridazinyl groups; pyridyl-N-oxide, methylpyridyl-N-oxide,furyl and thienyl.

Other useful R and R^ groups are cyano, carboxy, carboxy derivatives such as (C^_g alkoxy) carbonyl, carbamoyl, N-mono-fC^g alkyl) carbamoyl and N,N-di-(C1_g alkyl) carbamoyl; halogen, preferably Br, Cl and F; and -CO-r 3. where Ra is hydrogen or C^_g alkyl.

It is preferred that at least one of R and R^ be hydrogen.

Useful R2 alkyl groups have up to 10 carbons, are unsubstituted or mono-hydroxysubstituted and include cycloalkyl as well as branched and straight-chain alkyl. R2 alkyl groups having 1-6 carbons and especially 1-4 carbon atoms are preferred. Examples of suitable R2 alkyl groups are methyl, ethyl, decyl, tert-butyl, isopropyl, 2,2,4-trimethyl-nbutyl, cyclohexyl, 2-hydroxyethyl, 3-hydroxypropyl and 2-hydroxybutyl. Useful R2 alkenyl groups have 3-6 carbon atoms and are exemplified by allyl and -CH2-CH2-CH2-CH£CH=CH2· Preferred compounds are those where R2 is H.

R3 is a bivalent aromatic group. It may be single-ring (6 ring atoms) or fused-ring, (9-10 ring atoms); it has 0, 1 or 2 nitrogen ring atoms, and it may be substituted or unsubstituted. Examples of useful heterocyclic groups are pyridinediyls, (1,2-pyridinediyl, 1,3-pyridinediyl and 1,4-pyridinediyl), halopyridinediyl, alkylpyridinediyls, especially C^-Cg alkylpyridinediyls, pyridinediyl-N-oxides, cyanopyridinediyl, pyrazinediyl, pyridazinediyl, pyrimidinediyl and quinolinediyl, preferably pyridinediyl and substituted pyridinediyl, e.g. chloropyridinediyl, methylethylpyridinediyl, methylpyridinediyl, 2-chloro-4-methylpyridinediyl, bromopyridinediyl, 2,4,6trimethyIpyridinediyl, dimethylpyridinediyl, and the N-oxides, e.g. pyridinediyl-N-oxide and methyIpyridinediyl-N-oxide.

Useful Rg carbocyclic aromatic groups include phenylene groups and fused ring groups such as napthalenediyl, hydrogenated naphthalenediyls such as tetrahydronaphthalenediyl, and indanediyl.

Preferred Rg carbocyclic aromatic groups are those having the formula where x is 0, 1,2,3, or 4. and Rc is an alkyl group, linear or branched, and preferably containing from one to four carbon atoms, a Cg_g cycloalkyl groups, halogen such as Cl, I, Br or F, alkoxy, preferably alkoxy, hydroxy, nitro, cyano, phenyl, carbamoyl, N-(C-^_g alkyl) carbamoyl and N,N-di-(C^_g alkyl)carbamoyl. Examples of suitable preferred carbocyclic aromatic groups of Formula II are phenylene, tetrahydronaphthalenediyl, fluorophenylene, dibromophenylene, trichlorophenylene, iodophenylene, hydroxyphenylene, methylphenylene, methyl-hydroxy-phenylene, nitrophenylene, carboxyhenylene, methoxyphenylene, eyelohexylphenylene, aminophenylene, dimethyIchlorophenylene, butoxyphenylene, dichlorophenyl ene, cyanophenylene, tetramethylphenylene, dimethylphenylene, carbamoylphenylene and N,N-dimethylcarbamoylphenylene.

An .especially preferred Rg group is the carbocyclic group having the formula particularly when x is 0, 1 or 2 and especially 0.

Rj includes the hydroxy group and the ester group II Rb-C-O5 where R^ is C^-Cg alkyl such as methyl, isopropyl, tert-butyl, hexyl or ethyl. Compounds where R^ is hydroxy are preferred The Rg and Rg groups are hydrogen or alkyl groups. The alkyl groups preferably have from 1-6 alkyl carbon atoms and may be branched, linear, or cyclic; substituted or unsubstituted, Examples of suitable alkyl and substituted alkyl groups are methyl, n-hexyl, isopropyl, 2,2,4-trimethyl-n-butyl, cyclopropyl, cyclohexyl, chlorobutyl, tert-butyl, benzyl, 3,4-dimethoxyphenethyl and 6-phenylhexyl.

The Rg and Rg groups may also be joined to form a 5-6 membered N-alicyclic ring such as where Z is H or c]_“CbQ alkyl.

It is preferred that one of Rg and Rg be hydrogen while the other is Cg-Cg alkyl, preferably Cg-C^ branched alkyl and preferred by the particularly t-butyl. Compounds of formula I Which are are those in which R is hydrogen, which are represented formula N, R, Rg-O-CHg-CH-CHg-N / III Another series of preferred compounds is that in which R 25 and Rg are both hydrogen. These compounds have the formula - 7 4 339 7 When R2 is hydrogen, the 4 and 5 positions in the imidazole are substantially equivalent.

In the compounds of Formula IV, it is preferred that R^ be hydrogen, trihaloalkyl (preferably-CF^), cyano,-CH-j, phenyl, substituted phenyl having 1-5 substituents (preferably Cl, Br or F), or a heterocyclic group such as thienyl, furyl, methylpyridyl pyridyl or pyrlclyl-N-oxide.

Another preferred series of compounds is that having the formula XR5 where is -CH3, H, phenyl, pentafluorophenyl, p-chlorophenyl, ρ-fluorophenyl, p-methoxyphenyl, 2-thienyl, -CFj- or pyridyl; x is 0, 1, 2 or 3 and Rc is halo (preferably chloro), C^_3 alkyl (preferably -011^) , or cyano.

Another series of preferred compounds are those having the formula V where R^ is -OH.

In a particularly preferred series of compounds having formula V, R^ is OH and only one of and Rg is C^_g alkyl, preferably cyclic, cyclic-substituted or branched c3_4 alkyl such as tert-butyl, cyclopropyl, l-methyl-3-phenyIpropyl or 1-methyl-2-pheny lethyl. - 8 An especially preferred series of compounds is one having formula V where is ~cp3, is OH and one of Rg and Rg is hydrogen while the other is C^_g alkyl, preferably cyclic or branched hydrocarbon alkyl, especially tert-butyl.

The compounds of the present invention include all the optical isomer forms. In other words, the compounds may be mixtures containing the optical isomers such as racemic mixtures, as well as the individual optical isomers.

The compounds of the present invention also include 10 the non-toxic pharmacologically acceptable acid addition and quaternary ammonium salts of the present imidazoles. The aeid addition salts are prepared by treating the imidazole with an appropriate amount of a suitable organic or inorganic acid. Examples of useful organic acids are carboxylic acids such as maleic acid, tartaric acid, acetic acid, pamoic acid, oxalic acid, propionic acid, salicylic acid, succinic acid, citric acid, malic acid and isethionic acid; useful inorganic acids are hydrohalo acids such as HCl, HBr and Hl, sulfuric acid and H3PO420 The quaternary salts are characterized by the group -NI Rc {+) Rd where Rg anion of iodide. and Rg are a non-toxic These salts alkyl, Rfl is C1_g alkyl and L is the acid, preferably a halide such as the are prepared by any suitable method - for example, by reacting any imidazole of the present invention having the tertiary amine group -N with an alkyl halide, preferably the iodide such as ethyl iodide or methyl iodide·, in a suitable solvent such as methanol, ethanol or dimethylformamide (DMF). The reaction is generally carried out at room temperature. The quaternary salt is obtained directly on removing the solvent.

Compounds of the present invention may be prepared by any convenient method.

One method (Method A) of preparing the present compounds is by amination of a compound having the formula VI where X is a halogen, preferably Br, X or Cl. When NHg is the aminating agent, X is replaced by -NH2 while when a primary or secondary, acyclic or alicyclic amine is used, X is replaced by the corresponding -NRgRg group. Typically, the amination can be carried out by heating a mixture of the halo compound VI and the amine e.g. t-butylamine for a sufficient period Of time and then isolating the aminated product. O.S. 3,337,628 discloses such procedures.

An especially useful method of preparing imidazoles of the present invention where is -OH is by reaction of ammonia or a suitable amine reactant with an epoxy compound as illustrated by the following general reaction equation: - -10 43397 METHOD Β \n/ I R„ R 1-$ Ri Ο R3-O-CH2-H^_CH2 + RgRgNH Η^Τ R3°' OH R I /R5 -o-ch,-ch-ch_-n 2 2 χκ6 The reaction is generally carried out in solution with excess amine reactant serving as the solvent. However, other solvents may be used such as triethyiamine, pyridine ail'd-tetrahydrofuran- The reaction is conveniently conducted at reflux temperature. However, the reaction temperature can be varied from room temperature to temperatures above reflux. The reaction may be carried out at atmospheric pressure but it can be carried out at pressures above atmospheric, if desired.

A method of preparing compounds of formula I whereR and R2 are H, R^ is trihaloalkyl and zS4 -R,-O-CH--CH - CH„-N is in the 2 position in the imidazole ring involves the reaction of 1,1,1 trihalo-3, 3-dihaloacetone, aryl aldehyde and NHg. Depending on the type of arylaldehyde used, different sequences of reactions are utilized,and these are illustrated by the following sets of equations. In these equations X and X^ are F, Br or Cl- and it is preferred that X is F and X1 is Br.

METHOD C SEQUENCE 1 (1) X 0 Xx X-C-C-|-H X X1 WEAK BASE (INTERMEDIATE] (2) [INTERMEDIATE] + H-C-R^O-CHg-CH-CHg-NRgRg + NHg X I x-c I X CH_-CH-CH_-NR_R, 2 2 5 6 SEQUENCE 2 (1) X 0 X1 I I X-C-C-C-H WEAK BASE 1 'l X x1 [INTERMEDIATE] OH Cl (2) [INTERMEDIATE] + H-C-Rg-O-CHg-CH-CHg + NH^ C3) I tr—Ϊ1 X-C OH Cl C —Η- I I I i \n/-V°-CH2-CH-CI I H 3-O-CH2-C^-CH, x « --N X-C I X CH_ STRONG BASE (4) HNR-R, NRgRg The intermediate in the above equations is believed to be a glyoxal (X-^-^-2-H) or a hydrated X 0 OH ' II I glyoxal (X-C-C-C-H). This intermediate is generally X ok prepared as an aqueous mixture by treating the halogenated acetone with a aqueous solution of a weak base such as sodium acetate trihydrate. This solution is heated for a period of time and at a temperature sufficient to form the intermediate. On cooling, the intermediate containing solution is added to a solution of the appropriate arylaldehyde and aqueous ammonia. Any suitable water miscible solvent may be used. Methanol is conveniently used. The reaotion to yield the substituted imidazole is generally conducted at room temperature, although elevated temperatures may ba used. The solvent is then stripped and the product imidazole is recovered.

Where the imidazole intermediate has the -Rg-O-CHg-^H-^Hg substituent, this intermediate is treated with a suitable strong base such as KOH, potassium butoxide, NaOH,in a solvent such as methanol, to effect conversion to the epoxy (Rg-O-CHg-C^-^Hg) group. This epoxy derivative is then converted to the desired amine final product as illustrated above.

Still another method for preparing compounds of formula X where Rg is H and -Rg-O-CH^-CH-CHg-N^ is in the Rg position in the imidazole is by the reaction of aryl - 13.aldehyde with a glyoxal or acetal thereof and. NH^. When the acetal ia used, it must first be hydrolyzed e.g. by treatment with a strong acid solution such as aqueous This reaction scheme is illustrated by the following equations: METHOD D 0 II II r-C-C-R .0 H R« ZR— I4 / 5 R,-O-CH,-CH-CH,-N ο * z R6 the aryl aldehyde used has the formula If, in Method D, OH Cl ιι I ' C-R3-O-CH2-CH“CH2 H , the imidazole product would require dehydrochlorination and treatment with amine, as shown in Method C sequence 2, steps (3) and (4), to afford the imidazole of the present invention.

The process of Method D is generally carried out in solution and at temperatures ranging from about room temperature to about 100“C. Pressure is not required. Solvents used will vary depending on the type of reactants used. Generally, this reaction is carried out in an aqueous solution e.g, H^O or H^O/miscible alkanol.

Another method for preparing Formula I compounds where R2 is other than H is by treating the corresponding compound where R2 is H with a suitable reagent using a recognized technique.

Where the R2 group ia to be an alkyl group, the corresponding Formula I compound where R2 is H is alkylated - -14 43397 using a suitable reagent such as diazomethane, an alkyl halide e.g. C^-Br, CgH^-I or n-butylchloride, or a dialkylsulfate.

Where the R2 group is to be an alkenyl group, recognized alkenylating reagents and techniques are used.

Illustrative of these techniques is the reaction of the imidazole in which lb, is hydrogen with NaH followed by treatment with an alkenyl halide e.g. allylbromide to produce the corresponding imidazole in which R2 is alkenyl.

Where the R2 group is to be hydroxyalkyl, the imidazole in which R2 is H is reacted with an epoxy compound e.g. 1,2-epoxyethane, 1,2-epoxypropane, or 1-,2-epoxyhexane to produce the corresponding imidazole where R2 is monohydroxyalkyl. Conditions (temperature, catalysts, solvents etc.) for this type of reaction are disclosed in U.S. 3,786,061 and to the extent necessary the disclosure is incorporated herein by reference.

The aryl aldehyde intermediates having the formula 0 0H hal tl ι > H-C-R3-O-CH2-CH-CH2 VII where hal is Cl or Br, are conveniently prepared by reacting the corresponding hydroxyaryl aldehyde with epihalohydrin as illustrated by the following reaction equation: °d /°\ H-C-R3“OH + CH2— CH-CH2-C1 J, NaOH/H2O j hc1/h2o Φ qi H-C-R3-O-CH2-CH-CH2 The aryl aldehyde intermediates having formula - 15 43337 O=CH-R3-O-CH2-CHOH-CH2-NR5-Rg (VIII) are conveniently prepared by reacting the corresponding hydroxyarylaldehyde with an epihalohydrin as the following equations illustrate: 0 A II / \ H-C-R -OH + Br-CH„-CH-CH„ KOH/H-O h-c-r3-o-ch2-ch —>h2 HNRgRg NR=R, OH II 5 6 | H-C-R,-O-CH_-CS-CH_-NR_R, 2 2 5 6 HCl OH H-C-R3-O-CH2-CH-CH2-NR5Rg Reaction conditions are similar to those used to prepare the VII compound.

The aryl aldehydes VIII can also be prepared by reacting an aryl aldehyde with an oxazolidine as illustrated by the following equations: h-c-r3-oh R?O-CH2ΙΊ ,N-R_ X. 5 H Ro ft h-c-r3-o-ch2 IX π ,N-E /Z HYDROLYSIS h-c-r3-o-ch2-ch-ch2-nhr5 VII A Ro is the residue of an aldehyde as will be described below, o R? is an alkyl or aryl sulfonyl group e.g. benzene sulfonyl, toluene sulfonyl, or methane sulfonyl. This coupling reaction of the oxazolidine IX and the aryl aldehyde is generally carried out in suitable solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylenephosphoramide (HMPP) or alkanols such as methanol or ethanol. While the reaction cart be carried out at temperatures ranging from 0°C. to 200°C., it is conveniently carried out at the reflux temperature of the solution. Conventional techniques and reagents e.g. HCl, H2SO4, are used to effect the hydrolysis.

The oxazolidine IX is obtained from the reaction of an aldehyde with a l-amino-2,3-dihydroxypropane followed by treatment with an appropriate alkyl or aryl sulfonyl halide. This reaction is illustrated by the following equations: (1) Rq-c-4 HO-CH,-.-r 2 2 5 / 2~I| -N-Rr XX (2) HO-CH2 Any RgC aldehyde may be used provided that it does not adversely affect the oxazolidine preparation. Examples of suitable aldehydes are aryl aldehydes such as benzaldehyde, substituted benzaldehydes and napthylaldehyde, and alkanals such as acetaldehyde, formaldehyde, and 2£> butyraldehyde. Commercially available aldehydes are most '7---7 7 .N-R, X 5 H 8. ru x, 4333 7 conveniently used. Processes for preparing oxazolidines are disclosed in U.S. 3,718,647 and U.S. 3,657,237 The imidazoles of the present invention wherein is the ester group R^-^-O- are conveniently prepared by treating the corresponding imidazole where- R^ is OH with the desired organic acid anhydride or halide, preferably the chloride. This reaction oan be carried out at ambient temperature or at elevated temperature up to about 100°c.

When Rg in the starting imidazole is hydrogen, then in order to avoid acylating the 1-nitrogen in the imidazole the reaction is carried out under acidic conditions. The general reaction is illustrated by the following equation: The present imidazoles encompass all optical isomer forms that is mixtures of isomers e.g. racemates as well as the individual optical isomers. These individual isomers are commonly designated, according to the optical rotation they effect, by (-) and (+), (L) and (D) or a ί combination of these signs and letters. These optical ί isomers may also be designated according to their absolute ’ - 18 43397 spatial configuration, by the symbols (S) for sinister and (R) for rectus.

Ordinarily, the imidazoles of the present invention are obtained as racemates. These racemates can be separated into the individual optical isomers using techniques available in the art. These methods are normally tedious, time consuming and rarely effect a complete separation of isomers. This separation of isomers can be circumvented and one or the other optical isomer of the present imidazoles can be directly prepared by utilizing a single enantiomer of the oxazolidine IX.to prepare a single optical isomer of the aryl aldehyde intermediate VIII. By using this single isomer intermediate, a single optical isomer form of the desired imidazole final product can be obtained. The single optical isomer of the oxazolidine IX is conveniently obtained by using a single optical isomer of the l-amino-2,3-dihydroxypropane reactant in the oxazolidine preparation disclosed above. 0H Compounds of formula I in which the -Rg-O-CH2-CHCHj-N-Rg-Rg is in the 4-position in the imidazole ring can be prepared according to the method illustrated by the following equations: METHOD E 8 •C-C + R-C-H + NH. \h (1) '3 H HI - 19 i ι 43337 Method E, as the equation illustrates·, involves the reaction of alkoxyarylacetal with an aldehyde in the presence of ammonia. This ammonia may be liquid ammonia in which the reaction temperature would range from about -33°C up to about 70®C, the reaction being carried out under pressure where the temperature requires. The ammonia may also be provided as aqueous solution i.e. ammonium hydroxide, in which case reaction temperatures of from about the freezing point of the reaction mixture to about 100°C can be used. With the aqueous ammonia system, room temperature is conveniently, used. Other water-miscible aqueous solvents such as a C^g alkanol e.g. CHgOH, or DMF may also be - 20 43397 used as necessary. The ether cleavage, 3tep (2), may be accomplished using any suitable reagents and procedure such as aqueous HI or aqueous HBrjor AlCl^ in a hydrocarbon solvent (hexane, benzene etc.). The Method E route A of course permits preparation of a single optical isomer while the route B results in a racemate.

Compounds of the present invention have been found to be active (1) as antihypertensives, i.e. they have an immediate blood pressure lowering effect in hypertensive animals and (2) as β-adrenergic blocking agents. Many of the present imidazoles also are active vasodilators.

The antihypertensive effect was determined by administering (orally or intraperitoneally) the present compounds to spontaneously hypertensive (SH) rats and measuring the effect on the blood pressure. Representative imidazoles, generally administered as salts e.g. the hydrochloride, were found to lower the SH rat's blood pressure.

The β-adrenergic blocking activity (β-blockade) of the present compounds was determined by measuring the ability of representative compounds to block isoproterenol induced tachycardia, vasodepression and bronchodilatation in animals. Intravenous administration of the imidazole, (generally as an acid addition salt) was used for this evaluation. Representative imidazoles showed ability to effect β-blockade in addition to having the aforesaid antihypertensive effect of immediate onset.

Representative compounds which were tested and found to have antihypertensive and β-adrenergic blocking activity are listed below. The compounds were racemates 3Q except where otherwise indicated. 13337 ϊ COMPOUND NO. 43337 2-(4-(3-tert.-butyl-2-hydroxypropoxy)phenyl]4- (3-pyridyl)imidazole l-methyl-2- (4- (3-tert.-butyl-2-hydroxypropoxy) phenyl]4(and 5)-trifluoromethylimidazole 3 3 9 7 In evaluating the β-blocking effectiveness of the present compounds, it was noted that many of the compounds exhibit some cardioselectivity that is the compound is more effective in reducing the heart rate effects of isoproterenol than it is in blocking the isoproterenol effects on the bronchi. Expressed in different terms, a smaller amount of the compound is required to block isoproterenol-induced elevation in heart rate than is required to block the isoproterenol-induced ) relaxation of the bronchi. This cardioselectivity factor can be expressed as the ratio of Εϋ^θ for pulmonary effect (P2)sfib50 for cardiac effect (βχ). Where the β2:βχ ratio is over 1, then the compound would be considered to have cardioselective activity. The tested compounds numbered 1-11 above are examples of compounds having β2ι β^ ratios greater than 1.

The ability of the compounds of the present invention to reduce blood pressure in the SH rat indicates that the compounds and their salts may be useful to treat essential hypertension in humans.

The β-adrenergic blocking effectiveness of the compounds of the present invention indicates that they are also useful to treat humans suffering from undesirable conditions such as angina pectoris or certain arrhythmias which are known to be amenable to treatment with β-adrenergic blocking agents. Furthermore, the cardioselective nature of some of the present compounds offers the advantage of limiting blockade to only the β^ receptors, i.e. those which control heart rate.

For use as antihypertensives and/or β-adrenergic blocking agents, the present compounds can be administered - 24 43397 orally or parenterally i.e. intravenously, interperitoneally, etc. and in any suitable dosage form. The compounds may be offered in a form (a) for oral administration e.g. as tablets in combination with other compounding ingredients customarily used such as talc, vegetable oils, polyols, benzyl alcohols, gums, gelatine, starches and other carriers; dissolved or dispersed or emulsified in a suitable liquid carrier; in capsules or encapsulated in a suitable encapsulating material or (b) for parenteral administration e.g. dissolved or dispersed in a suitable liquid carrier or emulsified or (c) as an aerosol. The ratio of active compound to compounding ingredients i.e. carrier, diluent etc. will vary as the dosage form requires. Whatever dosage form is used, the amount of compound of the present invention administered should be sufficient to effect (a) a reduction in blood pressure of the patient suffering from hypertension and/or (b) desirable level of β-blockade in the patient. Generally, doses of the present compounds of from about 0.01 to about 50 mg/kg and preferably from about 0.1 to about 10 mg/kg of body weight per day may be used. Dosage may be single or multiple depending on the daily total required and the unit dosage.

Following are examples illustrating representative pharmaceutical formulations containing imidazoles of the present invention. Conventional techniques are used to prepare these formulations TABLET FORMULATION I INGREDIENT (S)-2[4-(3-tert-butyIamino-2hydroxypropoxy)phenyl]-4methylimidazole calcium phosphate AMOUNT (Mg.) .0 120.0 3 3 97 TABLET FORMULATIONKcont.) INGREDIENT lactose starch magnesium stearate AMOUNT (Mg.) 50.0 23.5 1.5 TABLET FORMULATION II INGREDIENT 2- (4-(3-cyclopropylamino-2-hydroxy-propoxy)phenyl]-4-trifluoromethylimidazole Starch paste -12 1/2%, 100 cc allon.

AMOUNT (Mg.) 500.0 12.5 Starch, U.S.P. corn 25.0 Magnesium stearate 5.5 CAPSULE FORMULATION HI INGREDIENT (S) -2 [4- (3-tert-bu.tylamino- 2-hydroxypropoxy)phenyl]-z-p-methoxyphenylimidazole dihydrochloride dihydrate lactose, U.S.P.

AMOUNT (Mg.) 250 talc INJECTABLE SOLUTION FORMULATION IV INGREDIENT 2-[4-(3-isopropylamino-2“hydroxypropoxy)phenyl]-4-cyanoimidazole hydrochloride sodium chloride distilled water, q.s. 1.0 ml.

AMOUNT (Mg.) LIQUID SUSPENSION FORMULATION V INGREDIENT AMOUNT (g/1) (S)-2-[4-(3-methylamino-2-hydroxy- 5.0 propoxy)phenyl]-4-(4-pyridyl) imidazole Veegum H.v. 3.0 methyl paraben 1.0 kaolin 10.0 glycerin 250.0 water, q.s. -> 1 liter ('Veegum' is a trade mark) The following examples illustrate preparation of representative imidazoles of the present invention. All parts and percentages are by weight unless otherwise indicated. 4 3 3 3 7 EXAMPLE 1 A. Preparation of 3- (3-Chloro-2-hydroxypropoxy)Benzaldehyde A mixture of m-hydroxybenzaldehyde (24,4 g.) , epichlorohydrin (55.2 g.), and pyridine (0.4 ml.) is heated for hours at 100°C. and then concentrated under reduced pressure (20 mm. Hg.) over steam. The residual oil is taken up in chloroform (200 ml.), concentrated hydrochloric acid (50 ml.) is added, and the mixture is stirred for. 0.5 hours at room temperature. The chloroform layer is separated, and I washed with water, and the chloroform removed under reduced pressure (20 mm. Hg.) over steam. Distillation of the residual oil yields 28.9 g. of 3-(3-chloro-2-hydroxypropoxy)benzaldehyde as a yellow-brown oil, b.p. 166eC./0.25 mm. Hg.

B. Preparation of 2-(3-(3-Chloro-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole To a solution of sodium acetate trihydrate (11.6 g.) in water (40 ml.) is added trifluorodibromoacetone (11.6 g.) and the resulting solution is heated for 0.5 hours at 100°C. After cooling to room temperature, it is added in one portion to a solution of 3-(3-chloro-2-hydroxypropoxy)benzaldehyde (9.45 g.) in methanol (100 ml.) and aqueous ammonia 50 ml.). The resulting cloudy solution is allowed to stand for 5 hours at room temperature and the methanol is removed under reduced pressure (20 mm Hg.) over steam. An oil separates and crystallizes. The supernatant liquid is decanted and the residue is triturated with benzene and isolated by filtration to yield 6.97 g. of solid. After recrystallization from toluene, the solid is suspended in warm water and acetonitrile added tc cause solution. Upon - 28 43397 cooling, 2-[3-(3-chloro-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained as a white solid, m.p. 181-183’C.

C. Preparation of 2-[3-(2,3-Epoxypropoxy)phenyl]-4trifluoromethylimidazole To a solution of 2-[3-(3-chloro-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole (3.8 g.) in methanol (150 ml.) is added powdered potassium hydroxide (3.g.) and the mixture is stirred for 4 hours at room temperature.

Glacial acetic acid (2.75 ml.) is added and the mixture concentrated under reduced pressure (20 mm. Hg., over steam.

The resulting residue is stirred with water, filtered and recrystallized from xylene to yield 2.5 g. of 2— [3-(2,3epoxypropoxy)phenyl]-4-trifluoromethylimidazole, m.p. 145-146.5°C.

D. Preparation of 2-[3-(3-Isopropylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole A solution of 2-[3-(2,3-epoxypropoxy)phenyl]-4trifluoromethylimidazole (0.9 g.) in isopropylamine (10 ml.) is heated for 6 hours at reflux. The excess of isopropylamine is removed by distillation at atmospheric pressure over steam.

The residue is triturated with nitromethane (5 ml.) and the resulting solid removed by filtration. After recrystallization from nitromethane 0.65 g. of 2-[3-(3-isopropylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 162.5-163.5’C. 43307 EXAMPLE 2 Preparation of 2-[4-(3-isopropylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimldazole A solution of 2-[4-(2.3-epoxypropoxy)phenyl]-4trifluoromethylimidazole (1 g) in isopropylamine (10 ml.) is heated for 7 hours at reflux ana then allowed to stand for 16 hours at room temperature. The excess of isopropylamine is removed by distillation at atmospheric pressure and the residue is triturated with nitromethane to yield a solid.

After filtration and recrystallization from acetonitrile, 0.6 g. of 2-[4-(3-isopropylamino-2-hydroxypropoxy)phenyl]4-trifluoxomethylimidazole is obtained, m.p. 173°-173.5°C.

EXAMPLE 3 A. preparation of 2-methyl-4-(2,3-epoxypropoxy)benzaldehyde...........

To epichlorohydrin (20 g., 0.216 mole) heated at 55°C. is added dropwise a solution of 2-methyl-4hydroxybenzaldehyde (9.0 g.,0.066 mole) in 2.5 N sodium hydroxide solution (40 ml.). After the addition, the solution is stirred for an additional 3 hours at 55°C. and then at room temperature overnight. The oil is distilled to give 8.3 g. of 2-methyl-4-(2,3-epoxypropyl)benzaldehyde, m.p. 160-170°C. at 1 mm. Hg.

B. Preparation of 2-methyl-4- (3-tert,-butylamino-2hydroxypropoxy)benzaldehyde To 2-methyl-4-(2,3-epoxypropoxy)benzaldehyde (8.3 g., .043 mole) is added tert-butylamine (10 g., 0.137 mole) and the resulting solution refluxed for 2 hours and allowed to stand overnight at room temperature. The excess of tert butylamine is removed, under - 30 43337 reduced pressure (20 mm. Hg.), the residue is heated on a steam bath with 6 N hydrochloric acid (50 ml.) for 5 hours, and then basified while hot with solid sodium hydroxide. The mixture is cooled to room temperature, extracted with chloroform (3x50 ml.), dried over sodium sulfate, filtered and concentrated to dryness. The residual oil is crystallized from hexane to give 8.75 g. of 2-methy1-4-(3-tertrbutylamino-2-hydroxypropoxy)benzaldehyde, m.p. 82-84°C.

C. Preparation of 2-[2-methyl-4-(3-tertrbutylamino-2hydroxypropoxy)phenyl]-4-trifluoromethylimidazole To Sodium acetate trihydrate (6.26 g., .046 mole) in water (26 ml.) is added dibromotrifluoroaoetone (6.26 g., .023 mole). The solution -is heated for 45 minutes on a steam bath, cooled, and added to a solution of 2-methy 1-4- (3-tert.-butylamino-2-hydroxypropoxy) benzaldehyde (3.05 g., .0115 mole) in methanol (60 ml.) and concentrated aqueous ammonia (20 ml.). The solution is allowed to stand for 5 hours at room temperature. The methanol is removed under reduced pressure (20 mm. Hg.) over steam and the residue treated with chloroform (3 x 50 ml.) and saturated sodium carbonate (50 ml.). The organic layer is concentrated to dryness and the residue crystallized from acetonitrile to give 1.2 g. of 2-[225 methy 1-4-( 3- tertrbutylamino-2-hydroxypropoxy) phenyl] 4-trifluoromethylimidazole, m.p. 162-164’C. 3 3 9 7 Example 4 Preparation of 2-[4-(3-tert, butylamino-2-hydroxypropoxy) phenyl]-4-phenyiimidazole_ A solution of p-(3-tert. butylamino-2-hydroxypropoxy.)benzaldehyde (5.0 g·., 0.02 mole], phenylglyoxal monohydrate (6.04 g., 0.04 mole), concentrated aqueous ammonia (50 ml.), water (50 ml.) and methanol (200 ml.) is allowed to stand at room temperature for 5 hours.

The solution is concentrated to a residual oil under reduced pressure (20 mm.,Hg.) over steam and treated with saturated sodium carbonate (50 ml.) and chloroform (3 x 50 ml.). The organic layer is concentrated to dryness and 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 accomplished by passing through a column of silica gel (150 g.) and eluted with 20% methanol-80% chloroform. The solvent is removed under reduced pressure (20 mm. Hg.) over steam and the residue crystallized from acetonitrile to give 0.7 g. of 2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-phenylimidazole, m.p. 176-178°C.

Example 5 A. Preparation of S-4-(3-tert. butylamino-2-hydroxypropoxy) benzaldehyde - To a solution of S-2-phenyl-3-tert. butyl-5hydroxymethyloxazolidine (47 g., 0.2 mole) in pyridine (75 ml.) is added portionwise p-toluenesulfonyl chloride keeping the internal temperature between 25 and 3O’C.

The mixture is stirred, for 2 hours after addition is complete keeping the temperature between 25 and 30°C. Ice water (150 ml.) and potassium carbonate (27.5 g.) are added and the mixture is extracted with chloroform (3 x 100 ml.).

The organic extract is dried over sodium sulfate and concentrated first at 20 mm. Hg. and then at 1 mm. Hg. keeping the temperature below 50°C. The residual oil is dissolved in N,N-dimethylformamide (150 ml.) and added dropwise to a refluxing solution of the sodium salt of phydroxybenzaldehyde (0.2 mole) in N,N-dimethylformamide (200 ml.). After refluxing for 10 hours, the reaction mixture is concentrated first at 20 mm. Hg. and then at 1 mm. Hg. over steam. The residue is treated with 5% sodium hydroxide solution and extracted with chloroform (3 x 100 ml.). The organic extract is dried over sodium sulfate and the residue chromatographed on alumina (500 g. activity grade II). The chromatographic fractions are concentrated and the residue distilled at 240°C. at 0.3 mm. Hg. The distillate (21 g.) is treated with 1 N hydrochloric acid (75 ml.), heated for 1/2 hour over steam, cooled and extracted with ether. The aqueous layer is made basic to pH 10 by the addition of 2% sodiim hydroxide solution and extracted with chloroform (3 x 100 ml.). The organic extract is dried over sodium sulfate and concentrated to an oil which after crystallization from hexane yields 14.5 g. of S-4-(3tert. butylamino-2-hydroxypropoxy)benzaldehyde, m.p. 60-62°C. 3 34)7 B. Preparation of S-2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole To sodium acetate trihydrate (20.2 g.z 0.15 mole) in water (100 ml.) is added dibromotrifluoroacetone (20.2 g., 0.075 mole). The solution is heated for 45 minutes on a steam bath, cooled and added to a solution of S-p-(3-tert. butylamino-2-hydroxypropoxy)benzaldehyde (12.5 g., 0.05 mole) in methanol (200 ml.) and concentrated aqueous ammonia (75 ml.). The solution is allowed to stand for 5 hours at room temperature. The methanol is removed by distillation under reduced pressure (20 mm. Hg.) over steam. The mixture is made basic with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (3 x 100 ml.). The organic extract is dried over sodium sulfate and conj centrated at 20 mm. Hg. over steam. The resulting residue is recrystallized from acetonitrile to yield 7.6 g. of S-2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]4-trifluoromethylimidazole, m.p. 181-182°C.

Other Formula I imidazoles prepared using the procedures substantially as described in Examples 1-5 are listed in the following table. It is to be understood that analogous reactants are used to obtain the particular imidazole products.

— TABLE 1 PREPARED IMIDAZOLES OF FORMULA R—--11 OH H I , R3-O-CH2-CH-CH2-N-Rg ΐ H Using Procedure „ of , Example)_1 Imidazole Substituents -R, H -CF, H -CF, M.P.

(°C) _/ t-butyl 207°-210’ t-butyl 139--141° H -CF3 _^F^_\:h-CH2-CH2-^> 159 H -CF, H -CF, H -CF, CH propyl —-ch-ch2ch2 iHs __/ A— oyclo\=/ propyl CH, CH, H -CF3 —/ J- t-butyl ,CH3 η -cf3 -v/- t-kuty1 H -CF, t-butyl 0¾ H “CF, // isopropyl ’-170° 153--155° -o 120--133 163.5--165° 187--190° 183--185· 159°162s 210--213° 3 3 9 7 3 Η Η 181°-182° 167°-171° 2072.210° 174°-177° HQ 'Q- HQb- t-butyl O” t-butyl 180--181° t-butyl 162°-164° © 193.5°-195° 4 t-butyl H t-butyl 186°-188° 167°-169° 179°-181° - 36 4339? 4 Hci-b· Zz t-butyl 189°-190e 26 4 H & -o t-butyl 101’-105° 27 4 H -O- t-butyl 158°-162° 23 4 H 0- t-butyl 172e-173° 29 4 H F F t-butyl 178°-180° 30 4 H -Cl· F F t-butyl 168’-170’ 31 5 HCP3 t-butyl 178O-179.5° 32 5 H ch3^ -cf3 -iCC/iS) t-butyl © 141e-143° 33 5 H -3 -O t-butyl 110e-120e The glyoxal reagent used was CC HCl Salt © R-isomeg „ S-isomer © © O-CH2-CH2-CH£NR| Monohydrate i S- g attached Isomer at this position - 37 43397 Additional Examples illustrating preparation of other imidazoles of the present invention follow. All parts and percentages are by weight unless otherwise indicated.

EXAMPLE 34 A. Preparation of 2-[4-(3-Chloro-2-hydroxypropoxy)phenyl]-4-trifluoromethyllmlda2ole To sodium acetate trihydrate (5.8 g.) in water (20 ml.) is added trifluorodibromoacetone (5.8 g.); the result) ing mixture is heated for 0.5 hour on a steam bath. After cooling, the solution is added to p-(3-chloro-2-hydroxypropoxy)benzaldehyde (4.2 g.) in methanol (100 ml.) and concentrated aqueous ammonia (25 ml.). After standing for 4.5 hours at room temperature, the methanol is removed by distillation at 20 mm. Hg. over steam; a solid separates and is filtered. After recrystallization from nitromethane, 1.65 g. of 2-[4-(3-chloto-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 181-183°C.

B. Preparation of 2-(4-(2,3-Epoxypropoxy)phenyl]-4trifluoromethyiimidazoie To a solution of 2-[p-(3-chloro-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole (1.92 g.) in methanol (100 ml.) is added crushed potassium hydroxide (1.5 g.). The mixture is stirred for 3 hours at room temperature, neutralized with acetic acid ahd concentrated under reduced pressure (20 mm. Hg.) over steam. The residue is triturated with water (25 ml.), filtered and recrystallized by dissolving in benzene and adding hexane until turbid.

A yield of 1.2 g. of 2-[4-(2,3-epoxypropoxy)phenyl]-4trifluoromethylimidazole is obtained, m.p. 152-153.5°C.

C. Preparation of 2- [4- (3-tert. Butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole A solution of 2-[4-(2,3-epoxypropoxy)phenyl]trifluoromethylimidazole (2.5 g.) in tert, butylamine (20 ml.) Is heated 6 hours at reflux. The excess of tert, butylamine is removed by distillation at atmospheric pressure over steam. The residue is triturated with nitromethane (5 ml.) and the resulting solid removed by filtration. After recrystallization from acetonitrile, (1.2 g.) of 2-[4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole is obtained, m.p. 185.5-186.5°C.

EXAMPLE 35 A. Preparation of 4-(3-tert. Butylamino-2-hydroxypropoxy)benzaldehyde To 4-(2,3-epoxypropoxy)benzaldehyde (20 g.) is added tert, butylamine (50 ml.) and the resulting solution is refluxed for 17 hours. The excess of tert, butylamine is removed by heating at atmospheric pressure to yield a solid residue. To this residue is added 6 N hydrochloric acid (20o ml.) and the resulting mixture is heated for 5 hours on a steam bath. The solution is cooled and concentrated to 100 ml. on a steam bath under reduced pressure (20 mm.

Hg.). The concentrated solution is made basic to pH 10 with saturated aqueous sodium carbonate and extracted with chloroform. The chloroform extract is concentrated - 39 4 339 7 to a solid which after recrystallization from acetonitrile yields 18 g. of 4-(3-tert.butylamino-2-hydroxypropoxy)benzaldehyde, m.p. 123-125.5°C.

B. Preparation of 2-[4-(3-tert.Butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole To sodium acetate trihydrate (11.8 g., 0.088 moles) in water (40 ml.) is added dibromotrifluoroaoetone (11.8 g., 0.044 moles). The solution is heated for 45 minutes on a steam bath, cooled and added to a solution of 4-(3-tert. butylamino-2-hydroxypropoxy)benazldehyde (5 g., 0.02 mole ) in methanol (200 ml.) and concentrated aqueous ammonia (25 ml.). The solution is allowed to stand for 5 hours at room temperature. The methanol is removed under reduced pressure (20 mm. Hg.) over steam and chloroform (50 ml.) and saturated aqueous sodium carbonate (25 ml.) are added to the residue. After stirring a solid separates is filtered and washed with water.

After recrystallization from acetonitrile, 3 g. of 2-[4-(3-tert.butylamino-2-hydroxypropoxy)phenyl]-4trifluoromethylimidazole is obtained, m.p. 189-191eC. - 40 43397 EXAMPLE 36 A. Preparation of Salicylaldehyde Diethyl acetal A mixture of salicylaldehyde (80 g., 0.0655 mole), triethylorthoformate (110 g., 0.765 mole), absolute ethanol (40 ml.) and concentrated sulfuric acid (3 drops) is heated to reflux overnight. The volatiles are removed under reduced pressure (20 mm. Hg.) over steam to give diethyl acetal of salicylaldehyde which is used without further purification.

B. Preparation of 2-(2,3-Epoxypropoxy)benzaldehyde Diethyl acetal To epichlorohydrin (37 g., 0.4 molel heated at 50°c. is added dropwise a solution of salicylaldehyde diethyl acetal (25 g., 0.13 mole, in 2 H sodium hydroxide solution (200 ml.) and the mixtureis stirred overnight at 50°C. The reaction mixture is extracted with chloroform (3 x 100 ml.), dried over potassium carbonate, and concentrated to dryness to give 34,3 g. of 2-(2,320 epoxypropoxy)benzaldehyde diethyl acetal.

C. Preparation of 2-(3-tert. butylamino-2-hydroxypropoxy) benzaldehyde A solution of 2-(2,3-epoxypropoxy)benzal25 dehyde diethyl acetal (53 g., 2.1 mole) and tert, butylamine (100 ml.) is heated to reflux for 2 hours and allowed to stand at room temperature overnight. The excess of tert, butylamine is removed under reduced pressure (20 mm. Hg.) and the residue heated on a steam bath with 43337 N hydrochloric acid (300 ml.). After cooling, the solution is neutralized with solid sodium bicarbonate, extracted with chloroform (3 x 100 ml.), dried over sodium sulfate, filtered and concentrated to dryness.

The residue is chromatographed on silica gel (500 ml.) using gradient elution techniques starting with chloroform and the product is obtained with 10% methanol 90% chloroform. After removal of the solvent under reduced pressure (20 mm. Hg.), the residue is crystallized from acetonitrile to give 13.8 g. of 2-(3-tert. butylamino2-hydroxypropoxy)benzaldehyde, m.p. 156-160°C.

D. Preparation of 2-[2-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethyiimidazole To sodium acetate trihydrate (5.4 g., 0.0396 mole) in water (20 ml.) is added dibromotrifluoroacetone (5,4 g., 0.02 mole). The solution is heated for 45 minutes on a steam bath, cooled and added to a solution Of 2-(3-tert. butylamino-2-hydroxypropoxy)benzaldehyde (3.6 g., 0.0143 mole) in methanol (100 ml.) and concentrated aqueous ammonia (25 ml.). The solution is allowed to stand overnight at room temperature. The methanol is removed by distillation under reduced pressure (20 mm. Hg.) and the residue treated with saturated sodium carbonate (50 ml.), extracted with chloroform (3 x 50 ml.) and separated. The organic layer is dried over sodium sulfate, filtered and concentrated to dryness. The residue is chromatographed on silica gel (400 ml.) and the product eluted with 20% methanol-80% chloroform. Recrystallization of the product from nitro--42 43397 methane gives 700 mg. of 2- [2-(3-tert. butylamino-2hydroxypropoxy)phenyl]-4-trifluoromethylimidazole, m.p. 105-107°C.

EXAMPLE 37 2- [4-(-3-tert. butylamino-2-hydroxypropoxy)pheny1]-4methylimldazole......

To a mixture of cupric acetate (5.0 g., .025 mole), acetoxyacetone (1.5 g., .013 mole), concentrated aqueous ammonia (25 ml.) is added a solution of p-(310 tert. butylamino-2-hydroxypropoxy)benzaldehyde (3.2 g., .0127 mole) in methanol (25 ml.). After the addition, the mixture is heated at reflux overnight. The methanol is removed by distillation under reduced pressure (20 mm. Hg.) over steam and water (200 ml.) is added to the residue. The resulting solution is treated with hydrogen sulfide, filtered through a filter aid, treated with solid potassium carbonate until basic and extracted with chloroform (3 x 50 ml.). The chloroform is concentrated to dryness and the residue chromatographed on neutral alumina (170 g.) using a gradient elution technique starting with chloroform. The material is eluted iff the column using 5% methanol-95% chloroform. The organic solvent is removed by distillation under reduced pressure (20 mm. Hg.) and the residue crystal25 lized from acetonitrile to give 0.79 g. of 2- [4-(3tert. butylamino-2-hydroxypropoxy)phenyl]-4-methylimidazole, m.p. 202-203’C. - 43 43337 EXAMPLE 38 A. β-Pyridylglyoxal-dimethylacetal To a solution of butyl lithium (129 ml., 193N, 0.25 m.) in ether (3.00 ml.) cooled below -50’C. is added 3-bromopyridine (33.02, 0.209 m.) in ether (60 ml.). The yellow suspension which results is stirred fox an additional 1/2 hour at -50°C. and dimethoxyacetic acid piperidide (33.6 g., 0.179 m.) in ether (90 ml.) is added over 1 hour at -50°C. After complete addition, ) the reaction mixture is allowed to warm to room temperature and heated to reflux for 1/2 hour. After cooling, a solution of ammonium chloride (500 ml.) is added and separated and the aqueous layer extracted with 2x100 ml. ether. The ethereal layer is washed with 3N H^SO^ till acid; the aqueous layer is neutralized with KOH, and extracted with 3x100 ml. CH2C12(dried over Na2SO4, filtered and concentrated to dryness. The remainder is distilled at 95-100/0.4 mm. to give 13.8 g. of β-pyridylglyoxaldimethylacetal.

B. 4-(3-Pyridyl)-2-(4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-imidazole To concentrated sulfuric acid (15 g.) cooled to 0-4’ is added β-pyridylglyoxal-dimethylacetal (5.4 g., 0.03 m) and the solution allowed to stand at room temperature. After 3 days, the mixture is cooled and neutralized With NaHCO (26 g., 0.30m).

To this solution is added water (25 ml.), 37% aqueous ammonia (75 ml.), methanol (25 ml.) and a solution of p-(3-tert-butylamino-2-hydroxypropoxy)benzal- 44 4&aAj7, dehyde (5.1 g., 0.02 m) in methanol (200 ml.). After standing at room temperature for 3 days, the methanol is removed under reduced pressure (20 mm) over steam and the residue is covered with saturated Na2C03 (100 ml.), extracted with CHC13 (3x150 ml.), dried over Na2SO4, filtered and concentrated to dryness. The residue is chromatographed on silica gel (600 ml.) and the product eluted with 50% CHCl3/MeOH. The crude product is further purified by chromatography on No. 2 neutral alumina (90 g.) and eluted with 2% MeOH/CHCl3 . Recrystallization from acetonitrile/chloroform gave 125 mg. of 4-(3-pyridyl)[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-imidazole.

EXAMPLE 39 (S) Methyl-2-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl] imidazole-4-carboxylate To IN sodium hydroxide solution (20 ml.) is added (S) -2- t'i- (3-tert-butylamino-2-hydroxypropoxy) phenyl] 4-trifluoromethylimidazole (1 g.) and the mixture is heated for 0,5 hour over steam. The resulting solution is neutralized to pH 7 with concentrated hydrochloric acid and concentrated on a stt am bath over a stream of nitrogen. The resulting solid crude S-2- [4-(3-tert.-butylamino-2-hydroxypropoxy) phenyl]-4-carboxy-imidazole is suspended in methanol (25 ml.) saturated with hydrogen chloride. The mixture is refluxed for three hours, with hydrogen chloride being added after the first and second hours. After being concentrated under reduced pressure (20 mm.) over steam, saturated aqueous sodium carbonate solution is added (25 ml.) and the mixture is extracted with ethyl acetate. The organic extract is concentrated to a gum which on trituration with aqueous sodium carbonate - 45 solidifies and is filtered. After recrystallization from acetonitrile 200 mg. of (S)-methyl 2-[4-(3-tert. butylamino2-hydroxypropoxy)phenyl]imidazole-4-carboxylate melting at 159-161°C. is obtained.

EXAMPLE 40 A. S-2-Phenyl-3-Tert. butyl-5-(3-cyano-6-pyridyloxymethyDoxazolidine To a solution of S-2-phenyl-3-tert. butyl-5hydroxymethyloxazolidine (12.35 g., 0.0526 mole) in dimethyl-formamide (65 ml.) is added sodium hydride (2.22 g., 0.0526 mole of 57%. After heating for 25 minutes on a steam bath, the mixture is stirred and cooled to room temperature in 30 minutes and added to a solution of δ-chloronicotinonitrile (7.28 g., 0.0526 mole) in dimethylformamide (35 ml.). The reaction mixture is stirred at room temperature for 4¾ hours and is then concentrated under reduced pressure. The fluid residue is taken up in ether and washed with water. The ethereal solution is dried and concentrated Under reduced pressure to yield 18.5 g.

Of S-2-phenyl-3-tert. butyl-5-(3-cyano-6-pyridyl-oxymethyl) oxazolidine as an Oil.

B· S- 6- (3-Tert. butylamino-2-hydroxypropoxy) nicotlnoni.tr ile A suspension of S-2-phenyl-3-tert. butyl-5(3-cyano-6-pyridyloxymethyl) oxazolidine (18.5 g.) in IN hydrochloric acid (60 ml.) is heated for 5 minutes on_a-steam bath and then stirred at room temperature for 1/2 hour.

The mixture is extracted with chloroform and the aqueous layer is made basic with 40% sodium hydroxide solution.

The basic solution is extracted with ethyl acetate and the extract is dried and concentrated under reduced pressure.

The residual white solid is recrystallized from hexane-n- 46 4 3 39 7 butyl chloride to yield 5.14 g. of S-6-(3-tert. butylamino2-hydroxypropoxy) nicotinonitrile, m.p. 103-105°C.

C. S-6-(3-Tert. butylamino-2-hydroxypropoxy) nicotinaldehyde .

A suspension of S-6-(3-tert. butylamino-25 hydroxypropoxy) nicotinonitrile (5.14 g. 0.0204 mole) in toluene (128 ml.) in a flamed flask is heated with stirring until a solution is obtained. The toluene is allowed to distil off until a total of 21 ml. is collected. Heating is discontinued and the reaction solution is cooled in a dry ice- acetone bath causing the starting material to reprecipitate. To the cold reaction mixture is added diisobutylaluminum hydride in toluene (62.6 ml. 0.075 mole of 0.17 g./ml.) dropwise under nitrogen with stirring. The yellow reaction mixture is stirred cold for 1 hour, and then IS the acetone bath is removed as methanol (22 drops) is added followed by the addition of water (22 drops). Chloroform is added to the mixture and then water (43 ml.), and after good stirring the mixture is filtered. The filtrate is shaken in a separatory funnel and the organic layer is sep20 arated, dried, and concentrated under reduced pressure. To the residual oil is added 1% hydrochloric acid (43 ml.) and the mixture is heated on a steam bath for 1/2 hour. At this point the pH is basic. Concentrated hydrochloric acid is added until the pH is acid and heating is continued for 15 minutes. The mixture is cooled and made basic with 40% sodium hydroxide solution and then extracted with chloroform. The extract is dried and concentrated under reduced pressure to yield 5.1 g. of S-6-(3-tert. butylamino-2-hydroxypropoxy) nicotinaldehyde as an oil which solidifies. - 47 539 Ί D. S-2- [2- (3-t£ri.-Bu.tylamino-2-hydroxypropoxy) -5-pyridyl] 4-trifluoromethylimidazole To sodium acetate trihydrate (2.16 g., 0.016 moles) in H20 (15 ml.) is added dibromotrifluoroacetone (2.16 g., 0.008 moles) and the mixture is heated for 1/2 hour on a steam bath. After cooling the solution is added to 6-(3-tert.butylamino-2-hydroxypropoxy) nicotinaldehyde (1 g.) in methanol (SO ml.) and concentrated aqueous ammonium hydroxide (15 ml.). After standing for 20 hours at room temperature, the methanol is removed under reduced pressure (20 mm.) over steam. Concentrated aqueous sodium carbonate (10 ml.) and ethyl acetate (50 ml.) are added to the concentrated solution. After extracting the organic layer is separated dried over sodium sulfate and concentrated to a gum which is chromatographed on activity grade IX alumina with chloroform methanol using a gradient elution technique. The fractions containing product are combined and concentrated to a gum which is dissolved in ethyl acetate. The ethyl acetate solution is washed with saturated sodium carbonate solution, dried and concentrated to yield 2(2-(3-tert.-butylamino-2-hydroxypropoxy)-5-pyridyl]-4trifluoromethylimidazole as a non-crystalline solid (650 mg).

This non-crystalline solid was covered with hexane and allowed to stand at about 0°C. for 7 days. The hexane was then decanted and the residue triturated with ether to yield a solid. The ethereal filtrate also yielded solid on standing at room temperature. These solids were combined and dissolved in benzene. Hexane was added to the point of turbidity, which on cooling yielded a solid. The solid was dried at 66e-73°C. and 0.2 mm for about 48 hours.

The dried solid was S-2-[2-(3-tert. butylamino-2-hydroxypropoxy)-5-pyridyl]-4-trifluoromethylimidazole monohydrate (NMR • 48 43307 A and Mass Spectroscopic analysis), melting at 110°-120°C.

EXAMPLE 41 A. 4-(p-methoxyphenyl)-2-(3-pyridyl)imidazole A solution of sodium acetate trihydrate (5.8 g, 0.04 m) , 3-pyridinecarboxaldehyde (2.3 g., 0.02 m), p5 methoxyphenylglyoxal monohydrate (3.92 g., 0.02 m), water (20 ml.), concentrated aqueous ammonia (25 ml.), and methanol (75 ml.) is allowed to stand at room temperature overnight. The solution is concentrated to dryness under reduced pressure (20 mm) over steam, treated with saturated Na2co3 (100 ml.) and extracted with chloroform ι (3 x 100 ml.). The organic layer is dried over NagSO^, filtered and concentrated to dryness. The residue is chromatographed on silica gel (300 ml.) and the product eluted with 3-5% MeOH/CHClg. The material is crystallized from acetonitrile to give 2.3 g. of 4-(p-methoxyphenyl)2-(3-pyridyl)imidazole of m.p. 184-186.

B. 2-(3-pyridyl)-4-(4-hydroxyphenyl)imidazole A mixture of 4-(p-methoxyphenyl)-2-(3-pyridyl)imidazole (2.0 g.) and 48% HBr (100 ml.) is heated to reflux for 20 hrs. After cooling, the precipitate is filtered off and crystallized from isopropanol-methanol to give 2.05 g. of 2-(3-pyridyl)-4-(4-hydroxyphenyl)imidazo .e of m.p. 315-318°C.

C. 4- [4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-2(3-pyridyl)imidazole A solution of 2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine (2.4 g., 0.01 m) in pyridine (3 ml.) is cooled to 0-4°C. and treated portionwise with p-toluenesulfonylchloride (2.0 g., 0.01 m). The cooled solution is slowly warmed to room temperature while not allowing the temperat 3 3 9? ure of the reaction mixture to exceed 30°C. After 2.5 hrs., the mixture is treated with a solution of K^CO^ (1.4 g.) in water (20 ml.) and extracted with chloroform (3 x 50 ml.).

The organic layer is dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure (20 mm) over steam and finally at 60’C. and 1 mm. The residual oil is dissolved in dry N,N dimethylformamide (DMF) (20 ml.) and added dropwise to a mixture of 2-(3-pyridyl)-4-(4hydroxyphenyl)imidazole:2HBr:H2O (4.0 g., .0095 m) in DMF (20 ml.) and sodium hydride (57% oil suspension, 1.3 g., .031 m). After refluxing for 11 hours, the mixture is concentrated to dryness under reduced pressure (1-2 mm Hg.) over steam. The residue is treated with IN HCl (100 ml.), heated for 1/2 hr. on a steam bath, cooled, ahd extracted with ether. The aqueous layer is neutralized with 10N NaOH (12 ml.), extracted with CHCl^ (3 x 50 ml.), dried over Na2SO^, filtered and concentrated to dryness.

The residue is chromatographed on No. 2 neutral alumina (200 g.) and eluted with 4% MeOH/CHCl^. The crude product is further purified by chromatography on silica gel (200 ml.) and eluted with 40-50% MeOH/CHClj. The material is crystallized from acetonitrile to give 0.425 g. of4-[4-(3-tert-butylamlno“2-hydroxypropoxy)phenyl]-2-(3pyridyl)imidazole of m.p. 163-165°C.

EXAMPLE! 42 Methyl 2-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]imidazole-4-carboxylate A solution of 30 g. of crude 2- [4-(3-tert-butylamino-2hydroxypropoxylphenyl]-4-carboxyimidazole,prepared from the corresponding 4-trifluoromethvlimidazole by the product of Example_39, So 43397 methanol (600 ral.) ia heated to reflux, and then heating is discontinued as hydrogen chloride is bubbled rapidly through the solution with stirring for a half hour, followed by two and a half hours at reflux. Bubbling of hydrogen chloride is continued for another two hours followed by another hour at reflux and then the reaction mixture is stirred at room temperature overnight. The mixture is filtered and the filtrate is then concentrated to dryness under-reduced pressure. The residue is dissolved in water (150 ml.) and the pH is adjusted to 8 with saturated sodium carbonate solution. The basic mixture is extracted with ethyl acetate and the extracts are dried, filtered, and concentrated under reduced pressure to yield a solid which is recrystallized from acetonitrile to yield the methyl 2-[4-(3-tert.butylamino2-hydroxypropoxy)phenyl]-imidazole-4-carboxylate as a cream-colored solid, m.p. 168-172°C.

EXAMPLE 43 A. 2-[4-(3-Tert. butylamino-2-hydroxypropoxy)phenyl]-4carbamoylimidazole A solution of methyl 2-[4-(3-tert. butylamino2-hydroxypropoxy)phenyl]imidazole-4-carboxylate (10 g.) in methanol (100 ml.) is reacted in a bomb with ammonia (44 g.) at 100eC. for 24 hours. The reaction mixture is concentrated under reduced pressure and the residue is chromatographed on silica gel. The product is eluted with chloroform that is washed with concentrated aqueous ammonia (90%) and methanol (10%) and is recrystallized from acetonitrile to yield the 2- [4-(3-tert. butylamino-2-hydroxypropoxy)phenyl]-4carbamoyiimidazole as a white solid, m.p. 149-154ec. 15524 ΙΑ 339 7 Β. 2- [4-(3-tert.-butylamino-2-hydroxypropoxy)phenyl]-4cyanoimidazole To a solution of 2- [4-(3-tert.-butylamino-2hydroxypropoxy)phenyl]-4-carbamoylimidazole (0.5 g.) in dry pyridine (10 ml.) is added trifluoroacetic anhydride (1.26 g.) portionwise with stirring. The reaction solution is refluxed with stirring for four hours and then concentrated under reduced pressure. The residual gum is taken up in ethanol and saturated sodium carbohate solution (15 ml.) and stirred at room temperature for 20 hours. The ethanol is removed under reduced pressure and the remaining aqueous mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residual glass is converted to its hydrochloride salt With ethanolic HCl and is recrystallized from ethanolether. The resulting tan solid is converted back to its free base by trituration with saturated sodium carbonate solution. The free base is extracted into ethyl acetate and the extract is dried over sodium sulfate, filtered and concentrated under reduced pressure. The residual gum is recrystallized from acetonitrile to yield 40 mg. of 2- [4-(3-tert.-butylamino-2-hydroxypropoxy)phenyl]-4cyanoimidazole, m.p. 174-177°C. - 52 4339? EXAMPLE 44 A. 4-Hydroxy-5,6,7,8-tetrahydronapthaldehyde Step A: Dry hydrogen chloride gas is bubbled into a suspension of 5.0 gms. of 5,6,7,8-tetrahydronaphthol and 6.0 gm. zinc cyanide in 60 ml. of dry ethyl ether for two hours. To the mixture is added cautiously 50 ml. of water and 10 ml. 95% ethanol, and the resulting mixture is refluxed for 1/2 hour. After cooling, the mixture is extracted with ethyl ether. The ethereal layer is washed with water and dried over anhydrous sodium sulfate. The ether ia filtered and concentrated to an oil. The oil is dissolved in benzene, and 4-hydroxy-5,6,7,8-tetrahydronapththaldehyde crystallizes and i3 filtered.

S. 4- (2,3-Epoxypropoxy)-5,6,7,8-tetrahydronapthaldehyde Step B: To a solution of 4-hydroxy-5,6,7,8-tetrahydronapthaldehyde (20 gms., 0.012 m) in 1.5N sodium hydroxide (20 ml.) at 50’C. is added epichlorohydrin (3.3 gms., 0.036 m) dropwise. After 3 hours at 50°C., the solution is cooled and extracted with chloroform. The chloroform is dried over anhydrous sodium sulfate, filtered and concentrated to an oil. The oil is purified by column chromatography to give 2.4 gm. of 4-(2,3-epoxypropoxy)5,6,7,8-tetrahydronapthaldehyde.

C. 4 (3-tert.-Butylamino-2-hydroxypropoxy) -5,6,7,8tetrahydronapthaldehyde Step C; To 4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydronapthaldehyde (2.4 gms) is added tert.-butylamine (15 ml.). The resulting solution is heated at 45°C. for 15 hours. The excess of tert.-butylamine is removed at reduced pressure (20 mm). To the residue is added 30 ml. 6N hydrochloric acid, and the resulting mixture is refluxed for three hours. The acidic mixture is poured into a saturated solution of sodium carbonate which is heated on a steam bath with nitrogen bubbling through it. The basic mixture is extracted with chloroform, which is dried over anhydrous sodium sulfate, filtered and concentrated to give 2.3 g of 4-(3-tert.butylamino-2-hydroxypropoxy)-5,6,7,85 tetrahydronapthaldehyde as an oil.

D. 2-[(-3-tert.-Butylamine-2-hydroxypropoxy)-5,6,7,8tetrahydronapthyll-4-trifluoromethylimidazole Step D; To sodium acetate trihydrate (2.07 gm., 0.015 m) I in water (20 ml.) is added dibromotrifluoroacetone (2.07 g., 0.0075 m). The solution is heated far 40 minutes on a steam bath, cooled and added to a solution of 4-(3-tert -butylamino-2-hydroxypropoxy)-5,6,7,8-tetrahydronapth- 54 43397 aldehyde (2.3 mgs., 0.0075 m) in methanol (100 ml.) with concentrated aqueous ammonium hydroxide (15 ml.). The solution is allowed to stand at room temperature for 17 hours. The methanol is removed under reduced pressure (20 mm) over steam,and ethyl acetate (100 ml.) and saturated aqueous sodium carbonate are added to the residue. The ethyl acetate is separated, dried over anhydrous sodium sulfate, filtered and concentrated. The oil is crystallized from acetonitrile to give 500 mg. of 2-((3-tert-butylamino- 2 -hydr oxypropoxy) -5,6,7,8-tetrahydronaphthyl]-4trifluoromethyl-imidazole. Melting point 203e-205’C.

EXAMPLE 45 A. 4-(3-n-Butylamino-2-hydroxypropoxy)benzaldehyde Step A; To 4-(2,3-epoxypropoxy)benzaldehyde (8.9 gms., 0.05 m) is added n-butylamine (30 ml.) and the resulting solution is refluxed fdr 17 hours. The excess of n-butylamine is removed under reduced pressure (20 mm). The oil is dissolved in 6N hydrochloric acid (30 ml.) and the solution is heated on a steam bath for 40 minutes. The hot acidic solution is poured into a hot saturated aqueous sodium carbonate solution with nitrogen bubbling through it. The basic solution is extracted with chloroform.

The chloroform is dried over sodium sulfate and concentrated t.o yield 4-(3-n-butylamino-2-hydroxypropoxy) benzaldehyde, as an oil. Β. 2-[4-(3-n-Butylamino-2-hydroxypropoxy) phenyl]-4trifluoromethylimidazole Step Bi To a solution of sodium acetate trihydrate (5.0 g.) in water (20 ml.) is added dibromotrifluoro5 acetone (5.0 g.). The solution is heated on a steam bath for 30 minutes. After cooling to room temperature, this solution is added to the methanolic solution of 4- (3-n-butylamino-2-hydroxypropoxy)-benzaldehyde and concentrated aqueous ammonium hydroxide (25 ml.).

After standing at room temperature for 48 hours, the methanol it removed under reduced pressure (20 mm), The residue is dissolved in ethyl acetate and saturated aqueous sodium carbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oil is placed in acetonitrile to yield 800 mg. of 2-[4-(3-nbutylamino-2-hydroxypropoxy) phenyl]-4-trIfluoromethylimidazole, melting at 151-154’C.

EXAMPLE 46 - 4-(4-methoxyphenyl)-2-[4-(3-tert-butylamino-2-hydroxypropoxy)-phenyl]-imidazole dihydrophloride dihydrate A heterogeneous solution of p-methoxyphenylglyoxal monohydrate (3.19 g. 0.018 m) sodium acetate (2.90 g., 0.036 m), water (23 ml), 37% aqueous ammonia (23 ml) and (S)-p-(3-tert-butylamina-2-hydroxypropoxy)- . benzaldehyde (2.90 g., 0.012 m) in methanol (75 ml) is - stirred at 25°C. for 72 hours. The reaction mixture is concentrated to dryness under reduced pressure (15 mm) at 80°C. The residual solid is treated with saturated aqueous Na2CO3 (7Ξ ml), extracted with chloroform (4x75 ml), - 56 43307 dried over anhydrous MgSO^, filtered and concentrated to dryness. The residue is dissolved in chloroform (50 ml) and absorbed on an alumina pad (200 g). The pad is eluted with chloroform (2 1), 5% methanol/chloroform (1 liter), % methanol/chloroform (1), 20% methanol/chloroform (1), 40% methanol/chloroform (1 1) and methanol (1 liter). Concentration of the 20% methanol/chloroform, 40% methanol/ chloroform and methanol solutions gives 1.5 g of crude (S)-4-(4-methoxyphenyl)-2-[4-(3-tert-butylamino-2-hydroxy10 propoxy)-phenyl]-imidazole. This treatment of this crude product with 8N ethanolic hydrogen chloride (1 ml) yields the hydrochloride salt which is purified by three precipitations from isopropyl alcohol/ethyl acetate to give 810 mg of (S)-4-(4-methoxyphenyl)-2-[4-(3-tert-butylamino-215 hydroxypropoxy)-phenyl]-imidazole dihydrochloride dihydrate; m.p. 132.0-135.0°C.

EXAMPLE 47 A. 2,6-Dichloro-4-hydroxybenzaldehyde To a stirred suspension of calcium hydroxide (61 gm), sodium carbonate (69.7 gm), and 3,5 diehlorophenol (20.97 gm) in water (436 ml)at 74°C is added chloroform (45.3 gm) over 90 minutes. The solution is refluxed for 3-¾ hours. After the slow addition of concentrated hydro25 chloric acid (170 ml), the acidic solution is steam distilled the aqueous residue is cooled and the solid which separates is filtered. Recrystallization from toluene gives 1.1 gm of 2,6-dichloro-4-hydroxybenzaldehyde. 43 39 7 Β. 2,6-Dichloro-4-(2,3 epoxypropoxy)benzaldehyde To a stirred solution of 2,6-dichloro-4-hydroxy benzaldehyde (3.0 gm 0.0167 m) in 1.5 N sodium hydroxide (25 m) at 50° is added epichlorohydrin (4.4 gm, 0.048 m).

After stirring at 50° for 3 hours, the solution is cooled and extracted with chloroform. The chloroform is dried over anhydrous sodium sulfate, filtered and concentrated to 2,6-dichloro-4-(2,3-epoxypropoxy)-benzaldehyde (3 g) which is used without further purification. c. 2,6-Dichloro-4-(3-tert-butylamino-2-hydroxypropoxy)benzaldehyde .

A mixture of 2,6-dichloro-4-(2,3-epoxypropoxy)benzaldehyde.(3 gm) and tert-butylamine (20 ml) is heated at 45° for 17 hours. The excess oftert.-butylamine is removed under reduced pressure (20 mm). The oil is dissolved in 6 N hydrochloric acid (25 ml) and heated for 1 hour. The acid solution is added to boiling Saturated aqueous sodium carbonate with nitrogen ebullition. The basic solution is extracted with chloroform. The chloroform ι is dried over anhydrous sodiuin sulfate, filtered and concentrated to 2,6-dichloro-4-(3-tert-butylamino-2hydroxypropoxy)benzaldehyde which is used without further purification.

D. 2-(2,6-Dichloro-4-(tert-butylamino-2-hydroxypropoxy) phenyl]-4-trifluoromethyl imidazole A solution of sodium acetate trihydrate (2.7 gm 0.02 m) and dibromotrifluoroacetone (276 gm (0.01 m) in water (20 ml) is refluxed for 45 minutes. Xt is cooled and added to a solution of 2,6-dichloro-4-(3-tert-butylamino - 58 43397 2-hydroxypropoxy)benzaldehyde (3.0 gm, 0.009 m) in methanol (200 ml) and saturated aqueous ammonia (30 ml). After standing at room temperature for 17 hours, the solution is concentrated to an oil. The oil is dissolved in ethylacetate and washed with saturated aqueous sodium carbonate. The ethylacetate is dried over anhydrous sodium sulfate, filtered and concentrated. The gum is purified by chromatograph on silica gel with chloroforme washed with ammonium hydroxide and methanol as solvents. After purification 90 mg of 2-[2,6-dichloro-4(3-tert-butylamino-2-hydroxypropoxy)-phenyl]-4-trifluoromethy1 imidazole is obtained.

EXAMPLE 48 1-Methy1-2-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]4 (and 5)-trifluoromethyl imidazole An ethereal solution of diazomethane (1.5 gm) is added to a solution of 2-[4-(3-tert-butylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole in ether (100 ml) and methanol (50 ml). The solution is allowed to stand at room temperature until the yellow color has disappeared.

The solvents are removed under reduced pressure. The resulting gum is chromatographed on silica gel with chloroform treated with aqueous ammonium hydroxide and methanol to yield l-methyl-2-[4-(tert-butylamino-2-hydroxypropoxy)phenyl]-4-(and 5)-trifluoromethyl imidazole, which is a 50-50 mixture of the two N-methyl isomers.

ANALYSIS: NMR (d DMSO) N-CH3 doublet. 3.72 3.74 (CH)-tert-butyl 1.04 Mass spec 371 m peak 356 m - 15 *(1.7 gm) - 59 43337 EXAMPLE 4 9 2- [4-(3~dimethylamino-2-hydroxypropoxy)phenyl]-4-trifluoromethylimidazole A solution of 2-(4-(2,3-epoxypropoxy)pheny1-4trifluoromethylimidazole in triethylamine (15 ml) is added 1.1 equivalents of a dimethylamine. This solution is refluxed until reaction is complete as indicated by TLC. The solvent is removed under reduced pressure and the residue recrystallized to yield 2-[4-(3-dimethylamino-2hydroxypropoxy)phenyl]-4-trifluoromethylimidazole.

The methods illustrated in the examples 1-49 above are readily utilized to prepare other analogous imidazoles which are encompassed by the present invention.

EXAMPLE 50 S-2-[2-(3-tert. butylamino-2-hydroxypropoxy)-3-chloro-5pyridyl]-4-trifluoromethylimidazole hydrogen maleate A. A mixture of 57% sodium hydride in mineral oil (0.53 g., equivalent to 0.30 g., 0.0126 m, of active sodium hydride) is added over a period of ten minutes to a stirred solution of S-2-phenyl-3-tert. butyl-5-hydroxymethyloxazolidine (2.97g, 0.0126 m) in 25 ml of anhydrous toluene under nitrogen. The reaction mixture is stirred at 25’C for 15 minutes, 100eC for 15 minutes and finally at 25°C for 30 minutes. The homogeneous solution obtained is added dropwise over a period of 60 minutes to a rapidly stirred solution of 2,3-dichloro-5-oyanopyridine (2.0 g, 0.0126 m) in 20 ml of anhydrous toluene at 0°c under nitrogen. The heterogenous reaction mixture is stirred rapidly at 0-5aC for 60 minutes and at 25°C for 16 hours. This reaction mixture is then poured into 50 ml of water and the toluene layer separated. The aqueous phase is extracted with additional toluene 3x25 ml). The toluene extracts are combined, washed with saturated aqueous sodium chloride (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure i (25 mm). The residue is diluted with 60 ml of IN aqueous hydrochloric acid and stirred on a steam bath for 5 minutes and at 25eC for 30 minutes. The acidic reaction mixture is extracted with diethylether (5x50 ml) and chilled in an ice bath. 10 M aqueous sodium hydroxide is added dropwise until the pH is approximately 12-14. The basic reaction mixture is extracted with chloroform (4x50ml). - 61 337 The chloroform extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure (25 mm). The remaining oil is dissolved in refluxing petroleum ether (400 ml), and on cooling to 25°C., 1.38 g of S-2-(tert. butylamino-2-hydroxypropoxy)-3-chloro5-cyanopyridine is isolated melting at 62.0-63.0eC.

B. A solution of S-2-(3-tert. butylamino-2-hydroxypropoxy)-3-chloro-5-cyanopyridine (11.19 g, 0.0394 m) in anhydrous toluene (100 ml) is stirred rapidly at -73° C. under nitrogen. A solution of diisobutylaluminum hydride in toluene (66.3 ml, (0.0394 m) of a 9.37 M solution) is added dropwise over a ten minute period. The heterogeneous reaction mixture is stirred at -73 aC for 6 hours and then allowed to stand at 0°C. for 16 hours. The reaction L5 mixture is stirred at 0°C. and treated dropwise with methanol (50 ml) followed by water (200 ml). The turbid solution is extracted with chloroform (3x200 ml). Chloroform extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (25 mm). The residual oil (11.4g) is diluted with 60 ml of 6N aqueous hydrochloric acid and stirred at 100°C for 30 minutes. The homogeneous acid solution is cooled to 0-59C. and treated with 10 M aqueous sodium hydroxide until the pH is approximately 12-14. The basic solution is saturated with sodium chloride and extracted with chloroform (3x150 ml).

The chloroform extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure (25 mm) to yield 11.66 g cf S-2-(3-tert. butylamino-2-hydroxy propoxy)-3-chloronicotinaldehyde as a light brown oil. - 62 43307 C. Sodium acetate (8.66 g., 0.0636m) is treated with 60 ml of water and the homogeneous solution stirred rapidly at 25°C. Trifluorodibromoacetone (8.58g, 0.0318m) is added in one portion and the mixture heated at l00eC for 40 minutes and cooled to 25eC. This solution is immediately added to a homogeneous mixture of'S-2-(3-tert. butylamino-2-hydroxypropoxy)-3-chloronicotinaldehyde (6.09g, 0.0212m), methanol (150 ml) and concentrated aqueous ammonium hydroxide (60 ml). The reaction mixture is allowed to stir at 25’C for 16 hrs., and concentrated at reduced pressure (25 mm) to remove the methanol. The aqueous solution is extracted with 3% methanol/chloroform (2x100 ml) and 5% methanol/chloroform (2x100 ml). All extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure (25 mm) to yield 6.98g of glassy foam. This foam is dissolved in absolute ethanol and the solution filtered through a 150g silica pad. The filtrate is concentrated to a small volume, treated with a 10% excess of maleic acid and chilled. Upon dilution with diethyl ether, 1.82 g of S-2-[2-(3-tert. butylamino-2-hydroxypropoxy)-3-chloro-5-pyridyl]-4-trifluoromethylimidazole hydrogen maleate was isolated melting at 80.0-85’C.

The free base may be obtained by conventional neutralization of the hydrogen maleate salt.

Claims (46)

1. CLAIMS:1. A compound having the formula: in which each of R and R^, which are similar or dissimilar, is hydrogen, Cj_jq alkyl, substituted C 1 _ 1Q alkyl having 1-3 substituents, cycloalkyl, aryl, substituted aryl having 1-5 substituents, a heterocyclic group having 5-6 ring atoms, halogen cyano, carboxy, carboxy- derivatives, or II -C-R a , where R a is H or C 1 _ g alkyl; R 2 is hydrogen, Cq-io hydroxy-C 1 _^ c3 alkyl or C 2 _ g alkenyl; R^ is a bivalent aromatic group having 6 ring atoms of which 0-2 are other than carbon, a substituted bivalent aromatic group having 1-4 substituents, fused-ring bivalent aromatic group having 9-10 ring atoms of which 0-2 arc other than carbon, or substituted fused-ring bivalent aromatic group having 1-4 substituents; R^ is hydroxy or II -0-C-R b where R^ is C^g alkyl,-and each of R g and R g , which are similar or dissimilar, is hydrogen, C^_ g alkyl, cycloalkyl or substituted C^_ g alkyl or R g and R g are joined to form a 5-6 membered N-alicyclic ring; and pharmacologically acceptable salts thereof. <3337

2. A compound of the formula: 1 -R--O-CH--CH-CH--N 3. 2 2 \ in which R, RjyRgrRgfR^rRg and R g are as defined in claim 1.

3. A compound as claimed in claim 2 in 'which Rg is a pyridinediyl, alkylpyridinediyl, halopyridinediyl, naphthalenediyl, or hydrogenated naphthalenediyl radical.

4. A compound as claimed in claim 2 in which Rg is phenylene having the formula: 10 where x is 0, 1, 2, 3 or 4 and each R o , which may be the same as or different from any other R c , is halogen, alkoxy, hydroxy, cyano, phenyl or C^_ 4 alkyl.

5. A compound as claimed in claim 4 where each R c is, independently of any other R c , halogen or c i_4 alkyl. 15

6. A compound as claimed in claim 3 in which R^ is hydrogen, haloalkyl, Cg_ g alkyl, heterocyclic, phenyl, substituted phenyl having 1-5 substituents independently selected from halogen, C^_ g alkyl, cyano, /° -C NYZ 2o where each of Y and Z is hydrogen or Cj_ g alkyl; or a ^11-6 alkox y> carbonyl.

7. A compound as claimed in claim 3 in which R^ is trifluoromethyl, phenyl, pyridyl, thienyl, furyl, C^_ g alkyl, cyano, (Cg„_ g alkoxy)phenyl, halophenyl or methylphenyl. 25

8. A compound as claimed in claim 7 in which R g is H and R g is C.j_g alkyl.

9. , A conpound as claimed in claim 8 in which R g is Cg-C^ branched alkyl. - 65

10. A compound as claimed in claim 9 in which R g is tert-butyl.

11. A compound as claimed in claim 9 in which R^ is trifluoromethyl .

12. A compound as claimed in claim 2 in which R is H, R 2 is H, R g is II, R g Is alkyl and R^ is hydroxy.

13. A compound as claimed in claim 12 in which R^ is -CFj.

14. A compound as claimed in claim 12 in which Rj iS as. defined in claim 3.

15. A compound as claimed in claim 12 in which Rj is as defined in claim 4.

16. A compound as claimed in claim 15 in which R c in the formula of R 3 is as defined in claim 5.

17. A compound as claimed in claim 15 in which x iii the formula of Rj is 1.

18. A compound as claimed in claim 15 in which x is C L

19. A compound of the formula: in which R, Rp R 2 , Rj, R^, Rg and R g are as defined in claim 1.

20. A compound as claimed in claim 19 in which R is hydrogen.

21. A compound as claimed in claim 1 in which Rj is cyanopyridined iyl.

22. A compound as inediyl.

23. A oompound as claimed claimed -r 3 -o-gh in claim 20 in which R, is halopyridin claim 22 in which the 2 -CU“CH 2 -N group has the formula: - 66 43337

24. 2-|,4-(3-tert-butylamino-2-hydroxypropoxy)-phenyl|-4-trifluoro methylimld izole and pharmacologically acceptable salts thereof.

25. (S)-2- |,4-(3-tert-butylamino-2-hydroxypropoxy)-phenyl]-45 trifluoromethylimidazole and pharmacologically acceptable salts thereof.

26. (S) 2- [4-(3-tert-butylamino-2-hydroxypropoxy)-phenyl]-4methylimidazole and pharmacologically acceptable salts thereof.

27. 2- [4-(3-cyclopropylamino-2-hydroxypropoxy)-phenyl]-4“ 10. Trifluoromothylimidazole and pharmacologically acceptable salts thereof.

28. (S)(3-tert-butylamino-2-hydroxypropoxy)-phenyl]-4(4-methoxyphenyl)imidazole and pharmacologically acceptable salts thereof.

11. 15 29. 2-C4-(3-tert-butylamino-2-hydroxypropoxy)-phenylJ-4-cyanoimidazole and pharmacologically acceptable salts thereof.

30. (S)-2-t4-(3-tert-butylamino-2-hydroxypropoxy)-phenyl]-4(2-thienyl)imidazole and pharmacologically acceptable salts thereof.

12. 20 31. A compound having the formula and pharmacologically acceptable salts thereof.

32. A compound as claimed in Claim 31 having the S-isomer configuration.

13. 25 33. S-2-12-(3-tert.butylamlno-2-hydroxypropoxy)-3-chloro-5pyrldyl ]-4- trifIuoromethylimidazole. - 67 4-3 3 3 7

34. S-2-C2-(3-tert.butylamino-2-hydroxypropoxy)-3-chloro-5pyridyl]-4-trifluoromethylimidazole hydrogen maleate.

35. Λ method of preparing an imidazole as claimed in claim 1 in which R^ is hydroxy, that comprises the reaction of an epoxide having the formula: R Z°s -O-CH 2 -CH-CH 2 R with an amine having the formula: HNRgRg where R, Rg, R 2 , Rg, Rg and Rg are as defined in claim 1.

36. A method of preparing an imidazole as claimed in claim 1 in which R 2 is hydrogen, that comprises reacting a compound having with a the formula: // E lC -C x compound having the formula \ / 5 C-R-,-O-CH„-CH-CHtN z \ - H - \ R 6 in the presence of ammonia. Where R, Rj, Rg, R^, Rg and Rg are as defined in claim 1.

37. A method of preparing a compound as claimed in claim 1, substantially as hereinbefore described in any one of examples 1-50.

38. A compound as claimed in claim 1 when prepared by a method as claimed in any one of claims 35 to 37.

39. A pharmaceutical composition comprising a compound as claimed in claim 1 and a pharmacologically acceptable compounding agent. -68 43397

40. of a

41. sule. Λ composition as tablet. Λ composition as claimed claimed in in claim 39, in in the form claim 39, the form 5

42. Λ composition as claimed in claim 39, in the form of an injectable solution.

43. Λ composition as claimed in claim 39, in the form of a liquid suspension.

44. A composition as claimed in claim 39, in the form 10 of a solution, dispersion, emulsion or aerosol.

45. a composition as claimed in any one of claims 39 to 44, in which the said compound is a compound as claimed in any one of claims 1 to 34 and 38.

46. λ composition as claimed in claim 39 substantially as 15 hereinbefore described in any one of Formulations I to V.