IL107260A - Aromatase inhibiting diphenylalkyl 4(5)-imidazoles and pharmaceutical compositions containing them - Google Patents

Description

αηικ t nn ο>>ηο·ηη η>νκ>3ηι AROMATASE INffl ITING DIPHENYLALKYL 4(5)-IMIDAZOLES AND PHARMACEUTICAL CCSVIPOSITIONS CONTAINING THEM AROMATASE INHIBITING DIPHENYIALKYL 4 f51 -IMIDAZOLES AND PHARMACEUTICAL COMPOSTTTONS CONTAINING THEM This application is a divisional application from Israel Patent Application No. 93940, filed March 29, 1990.

The invention relates to substituted imidazole derivatives and their non-toxic, pharmaceutically acceptable acid addition salts, and their preparation, to pharmaceutical compositions containing the same and their use.

The imidazole derivatives of the invention have the general formula (I) : wherein Rlf R2, R'x and R'2, which can be the same or different, are H, CH3 C2H5 C3H7 OCH3 OH, CH2OH, .90 m2, NH2, CN, CF3, CHF2, CH2F or halogen; R' is H or where R3 is H, CH3 or halogen; R4 is H or R4 and R5 together form a bond and y io 0 to .

The non-toxic pharmaceutically acceptable acid additjon salts of these compounds are also within the scope of the invention.

The compounds of the formula (I) form acid addition salts with both organic and inorganic acids. They can thus form many pharmaceutically usable acid addition salts, as, for instance, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

The invention includes within its scope pharmaceutical compositions comprising at least one of the compounds of formula (I) or a non-toxic, pharmaceutically acceptable salt thereof, and a compatible pharmaceutically acceptable carrier therefor.

The compounds of the invention have been found, depending on the substituents R' , R1# R^ R'n and R'2, to possess varying degrees of aromatase and desmolase inhibiting properties . Among them there are very selective enzyme aromatase inhibiting compounds which are valuable in the treatment of estrogen dependent diseases, e.g. breast cancer.

Compounds of formula ( I ) can be prepared by the following methods .

Compounds of formula (I >) can be prepared by a successive sequence of reactions comprising firstly a Grignard reaction of ( 5 ) -imidazole aldehyde (II ) R' (II ) with an appropriate arylalkylmagnesiumhalide (III. ) which leads to following compounds (IV ) R' (IV ) In the reaction the arylalkylmagnesium halide derivative can be, for example, an arylalkylmagnesiumbromide derivative, which is prepared by reacting the corresponding ar lalkylbromide derivative with magnesium. Suitable solvents for the reaction include a variety of ethers, preferably tetrahydrofuran .

The arylalkylmagnesiumhalide derivative is prepared in the usual way by adding the arylalkylhalide derivative in a suitable solvent, e.g. tetrahydrofuran, dropwise onto magnesium turnings covered by tetrahydrofuran, at the boiling point of the reaction mixture. When the magnesium turnings have reacted, the mixture is cooled slightly and the 4(5)-imidazole aldehyde (II ) is added in solid form in small portions or dropwise in tetrahydrofuran. After the addition, the reaction mixture is refluxed until all of the 4 ( 5 ) -imidazole aldehyde (II: ) has reacted. The reaction time varies between one and five hours.

The compounds (IV ) are further oxidized for example with manganese dioxide to achieve compounds of formula (V ) which are allowed to react with another Grignard reagent (VI ) to give the compounds of formula (I ) where R4 is OH (VII ) . The reaction scheme for these steps can be illustrated as follows: The arylmagnesium halide (VI ) is prepared by reacting the corresponding halogenated aromatic compound with magnesium turnings in the usual way.

Compounds of formula (I. ) can also be prepared by reacting an 4(5 ) -imidazole aldehyde (II ) with an arylmagnesiumhalide (VI ) which leads to following compounds (VIII ) The compounds (VIII ) are further oxidized for example with manganese dioxide to achieve the compounds of formula (IX ) which are further allowed to react with the Grignard reagent (III ) to give the compounds of formula (I. ) where R4 is OH (VII ). The reaction scheme for these steps can be illustrated as follows : According to the feature of the invention, the compounds of formula ( I. ) , wherein R4 and R5 both are hydrogen or together form a bond, are prepared by dehydration of the compounds of formula (I ), where R is OH, and by catalytic addition of hydrogen in the second step.

Water is eliminated by usual methods, i.e. by heating with concentrated hydrochloric acid or by heating with dry potassium hydrogen sulfate. The unsaturated compounds (X ) (the compounds of formula (I ) wherein R4 and R5 together form a bond) are isolated and after that hydrogenated . Alternatively they can be hydrogenated directly in an acidic medium without previous isolation. The hydrogenation is conveniently carried out at room temperature with good stirring in alcohol, e.g. ethanol in the presence of a catalyst in a hydrogen atmosphere. Suitable catalysts are for example platinium oxide, palladium-on-carbon or Raney-nickel .

The reaction scheme for these steps can be illustrated as follows: 3 wherein R',.Rl R2, R'l* R'2 and Y are as defined before wherein R' , R±, R2/ R'l^ R'2 and Y are as defined before.

If R' is a substituted or unsubstituted benzyl, this group may be removed by hydrogenation as well . In this case the hydrogenation is performed in an acidic medium such as hydrochloric acid-ethanol mixture at elevated temperature .

The reaction scheme of this hydrogenation which leads to compounds of formula (I ) wherein R' , R4 and R each are hydrogen can be illustrated as follows: H (XII ) Another method to remove the benzylic R' group is a hydrogen transfer reaction in which the starting compound (XI ) is refluxed with ammonium formate and 10 % Pd/C in an appropriate alcohol, such as methanol or ethanol, or its aqueous solution. The compounds (XII ) can also be prepared directly from the compounds (X ) by hydrogen transfer reaction with ammonium formate or by hydrogenating both the double bond and the protecting benzyl group at the same time. The compounds (XII. ) can also be prepared directly from the compounds (VII ) by hydrogen transfer reaction in which the starting compound (VII ) is refluxed with ammonium formate and 10 % Pd/C in an acidic medium such as acetic acid.

The compounds of formula (XII ) can also be prepared from the compounds of formula (VII ) wherein R' is a substituted or unsubstituted benzyl by removing first the benzylic R' by a hydrogen transfer reaction by the method described before to give the compounds of formula (XIII ) ιρ. wherein Rl R2, R'l R'2 anc v are as defined before. The benzylic R' can be removed by hydrogenation as well. The compounds of formula (XIII ) are further dehydrated by the methods described before to form the compounds of formula (I ) where R4 and R5 together form a bond (XIV ) .

The compounds of formula (XIV ) are further hydrogenated by the methods described before to give the compounds of formula (XII ) .

The benzylic R' can be removed already before the oxidizing reaction by the methods described before. The reaction scheme for this hydrogenation can be illustrated as follows: R' (IV ) The Grignard reagents (III ) and (VI ) cannot be prepared when the substituents are OH, CH2OH or NH2. The compounds of formula (I ) wherein one or more of the substituents Rlf R2, R'i and R'2 are OH, CH2OH or NH2 can be prepared by the following methods.

The compounds of formula (I ) wherein one or more of the substituents R^, R2, R'i and R'2 are OH can be prepared by reacting the 4 (5 ) -imidazole derivative (II ) first with a Grignard reagent (III ) and then with reagent (VI ) or revise order where the substituent/substituents of either compound (III ) or (VI ) or both of them are OCH2Ph or OTHP (THP = tetrahydropyranyl) and then hydrogenating catalytically by the methods described to hydrogenate the benzylic R' group. If R' is a protecting benzyl group it will be removed conveniently at the same time. Another method is to dealkylate the compounds of formula (I ) where the substituent/substituents are OCH3 by allowing them to react with BBr3 , for example .

The compounds of formula (I ) wherein one or more of the substituents R^, R2, R' ± and R'2 are CH2OH may be prepared from the corresponding compounds where the substituent/substituents are CN by conventional methods, i.e. by hydrolyzing the nitrile group and then reducing the acid group.

The compounds of formula (I ) wherein one or more of the substituents Rl7 R2, R'i and R'2 are NH2 can be prepared by hydrogenating the corresponding compounds where the substituent/substituents are Ο2· The protecting benzyl group will be hydrogenated as well.

The compounds of formula (I ) wherein one or more of the substituents R^, R'i and R'2 are CN can be prepared from the corresponding compounds where one or more of the substituents are NH2 by diazotization.

Compounds of formula (I ) wherein one or more of the substituents R^, R2/ R'i and R'2 are halogen may also optionally be prepared by the same method.

Another method of preparing compounds of formula (I ) is a McMurry reaction which comprises a reductive coupling of a benzoylimidazole (IX ) and an appropriate aldehyde of the formula (XV ) in an appropriate solvent, such as tetrahydrof ran or dimethoxyethane , in the presence of a low valent titanium reagent in an inert atmosphere, e.g. in nitrogen or argon, to give the compounds of formula (I ) where R4 and R5 together form a bond (X ) The unsaturated compounds (X ) are further hydrogenated as described before. The aldehyde (XV ) is prepared from the corresponding alcohol in the usual way.

When the compounds of formula (X ) where R'^ and/or R'2 are C^OH, NH2 or CN are wanted they can be prepared by the methods described before.

The compounds of formula (X ) where R'^ and/or R'2 are OH and R^ and R2 are as defined before can be prepared by a McMurry reaction from the compounds of formula (IX ) where R'i and/or R'2 are OH which can be prepared by hydrogenating catalytically the compounds of formula (IX ) wherein R'i and/or R'2 are OOH^Ph or OTHP by the methods described before. Alternatively the hydrogenation can be done before the oxidizing reaction. If R' is a protecting benzyl group it will be removed conveniently at the same time. Another method is to dealkylate the compounds of formula (IX. ) where R'^ and/or R'2 are OCH3 by allowing them to react with BBr3, for example.

Compounds of formula (I ) wherein R'i and/or R'2 are OH and R^ and R2 are as defined before can be prepared by a McMurry reaction in which the aldehyde (XV ) is allowed to react with a ketone (IX ) wherein R'^ and/or R'2 are 0CH2P or OTHP to give a compound of formula (X ) where R' 1 and/or R'2 are OC^Ph or OTHP and R± and R2 are as defined before which is further hydrogenated to give compounds of formula (XII ) where R'^ and/or R'2 are 0Η· Compounds of formula (I. ) where R' is a benzyl can be prepared by benzylating the corresponding compounds where R' is hydrogen. The starting compound is first treated with a strong base such as sodium hydroxide in water or sodium hydride in an appropriate solvent, e.g. dimethyl formamide, to give the alkali metal salt of the imidazole and then in the second step adding to this benzyl halide . The reaction scheme can be illustrated as follows: The free OH, CH2OH and H2 substituents must be protected during the benzylation reaction.

Further method to prepare the compounds of formula (I ) wherein one or more of the substituents R^, R2/ 'i and R'2 are NO2 is nitration of the corresponding compounds where one or more of the substituents are H.

The compounds of formula (I ), their non-toxic, pharmaceutically acceptable acid salts or mixtures thereof may be administered parenterally, intravenously or orally. Typically, an effective amount of the 13- compound is combined with a suitable pharmaceutical carrier. As used herein, the term "effective amount" encompasses those amounts which yield the desired activity without causing adverse side-effects. The precise amount employed in a particular situation is dependent upon numerous factors such as method of administration, type of mammal, condition for which the derivative is administered, etc., and of course the structure of the compound.

The pharmaceutical carriers which are typically employed with the compounds of the - invention may be solid or liquid and are generally selected with the planned manner of administration in mind. Thus, for example, solid carriers include lactose, sucrose, gelatin and agar, while liquid carriers include water, syrup, peanut oil and olive oil. Other suitable carriers are well-known to those skilled in the art of pharmaceutical formulations. The combination of the compound and the carrier may be fashioned into numerous acceptable forms, such as tablets, capsules, suppositories, solutions, emulsions and powders.

The compounds of the invention are especially valuable as aromatase inhibiting agents and are therefore useful in the treatment of estrogen dependent diseases, e.g. breast cancer.

Estrogens are essential steroids in the physiology and function of normal development of breast and sex organs in women. On the other hand estrogens are known to stimulate the growth of estrogen dependent cancers , especially breast and endometrial cancers, and they may increase the risk of development of breast cancer if given at pharmacological doses for a long time. Excessive production of estradiol may also cause other, benign disorders in hormone dependent organs . The importance of estrogens as cancer growth stimulators and/or regulators is clearly stressed by the fact that anti-estrogens have reached a central position in the treatment of estrogen receptor rich breast cancers .

Antiestrogens act by binding to estrogen receptors and thereby inhibiting the biological effects of estrogens. Another approach for blocking estrogen effect is to inhibit the synthesis of estrogens . This has been achieved clinically by the unspecific steroid synthesis inhibitor aminoglutethimide . The estrogen synthesis could be blocked specifically by inhibiting the enzyme aromatase, which is the key enzyme in biochemical estrogen synthesis pathway. Aromatase inhibition is important because several breast tumors synthesize estradiol and estrone in situ and exhibit therefore continuous growth stimulation (Alan Lipton et al., Cancer 59:779-782, 1987).

The ability of the compounds of the invention to inhibit the enzyme aromatase has been tested by in vitro assay according to M. Pasanen (Biological Research in Pregnancy, vol. 6, No. 2, 1985, pp. 94-99). Human aromatase enzyme was used. The enzyme was prepared from human placenta, which is rich of the enzyme. Microsomal fraction (100000 x g precipitate) was prepared by centrifugation. The enzyme preparation was used without further purification. Test compounds were added together with 100000 dpm of l,2[3H]-androstene-3,17-dione and NADPH generating system. The concentrations of the test compounds were 0,001; 0,01; 0,1 and 1,0 mM. The incubation was carried out at 37 °C for 40 min.

Aromatization of l,2[½]-androstene-3, 17-dione results in the production of ½2°· Tne tritiated water and the tritiated substrate are easily separated by a Sep-Pak^ minicolumn, which absorbs the steroid but allows free water elution. Radioactivity was counted by a liquid scintillation counter. Aromatase inhibition was evaluated by comparing the ^l^O-radioactivity Df inhibitor treated samples to controls containing no inhibitor. IC-50 values were calculated as concentrations which inhibited the enzyme activity 50 %. These concentrations are presented in Table 2.

Cholesterol side chain cleavage (CSCC) activity (desmolase) was measured according to the method of Pasanen and Pelkonen (Steroids 43:517-527, 1984).

Incubations were carried out in 1,5 ml Eppendorf plastic tubes, and an Eppendorf shaker, centrifuge and incubator were used as a unit. In a 300 μΐ incubation volume, the substrate (5 μΜ) was prepared according to Hanukoglu and Jefcoate (J. Chromatogr. 190:256-262, 1980), and 100000 dpm of radioactive ¾-4-cholesterol (the purity of the compound was checked by TLC) in 0,5 % Tween 20, 10 mM MgCl2 5 μΜ cyanoketone and 2 mM NADPH was added. Controls contained all the above substances but the enzyme preparation was inactivated prior to the incubation by the addition of 900 μΐ of methanol. The mitochondrial fraction (1 mg protein) from human placenta or bovine adrenals was used as a source of enzyme.

After 30 min incubation at 37 °C, the reaction was terminated by the addition of 900 μΐ of methanol; 1500 dpm of marker -^C-4-pregnenolone was added to each incubate and the tubes were vigorously shaken.

After 10 min equilibration, the methanol-precipitated proteins were separated by centrifugation (8000 x g for 2 min) and the supernatant was sucked into 1 ml plastic injection syringe and loaded onto the pre-equilibrated (75 % methanol) minicolumn. The column was washed with one ml of 75 % methanol and then with 3 ml of 80 % methanol. The 80 % methanol eluate was run into the counting vial and 10 ml of scintillation liquid was added. Radioactivity was counted using a double-label program on a liquid scintillation counter (LKB RacJcBeta). Typical activities for placental and bovine adrenal enzyme preparation were 0,5-3 and 50-100 pmol pregnenolone formed/mg protein/min, respectively.

In inhibition experiments, the substance (final concentration range from 1 to 1000 μΜ) was added into incubation mixture in a volume of 10-20 μΐ', usually as methanol or ethanol solution. The same volume of the solute was added into control incubation vial. The IC-50 values (concentration causing a 50 % inhibition) were determined graphically and are presented in Table 2.

Table 1: Compounds tested No. Name 1 . 4-[l-( 4-fluorophenyl) -5-phenylpentyl ]-lH-imidazole 2 . 4-[l-(4-fluorophenyl)-5-(2-methylphenyl)pentyl]-lH- imidazole 3 - 4-[l-(4-fluorophenyl)-5-(3-methylphenyl)pentyl]-lH- imidazole 4 . 4-[ l-(4-fluorophenyl) -5- ( 4-me hylphenyl ) pentyl ]-1Η- imidazole 5... 4-[5-(3,5-dimethylphenyl)-l-(4-fluorophenyl ) - pentyl ] -IH-imidazole 6 . 4-(l,5-diphenylpentyl)-lH-imidazole 7 . 4-( 1, 3-diphenylpropyl)-lH-imidazole 8 . l-benzyl-5- ( 1 , 3-diphenylpropyl ) -lH-imidazole 9 . 4-[ l-(4-fluorophenyl )-3-phenylpropyl]-lH-imidazole 10 . 4-[l-(4-fluorophenyl)-4-phenylbutyl]-lH-imidazole 11 . 4-[l-(4-fluorophenyl)-5-(3-methoxyphenyl)pentyl]- lH-imidazole 12 . 4-[ l-( 4-fluorophenyl) -5- ( -methoxyphenyl )pentyl ] - lH-imidazole 13 . 4- [l-( -fluorophenyl) -5- (2, 6-dimethylphenyl ) - pentyl ] -lH-imidazole 4-[l,3-bis(4-fluorophenyl) ropyl ]-lH-imidazole 4- [1, 4-bis (4-fluorophenyl )butyl]-lH-imidazole Inhibition of human aromatase and desmolase (CSCC) by test compounds. IC-50 represents the concentration which inhibits the enzyme 50 %.

IC-50 IC-50 CSCC umol/l umol/l 2,8 19 3,5 16 3,8 57 8,5 170 7,5 80 25 4,5 7,5 30 0,72 22 0,75 31 2,6 12 3 22,5 7,7 31 2,2 22 0,63 29 Acute toxicity, LD50/ was determined by using young adult female mice of N RI-Strain. The administration of the test compounds was oral. The LD 0 values of the test compounds of formula Γ were 400 rag/kg or more.

The daily dose for a patient varies from about 20 to 200 mg administered orally.

The following examples illustrate the invention. 1H NMR spectra were determined with a Bruker WP 80 DS apparatus (80 MHz). The reference substance was tetra-methylsilane . MS spectra were determined with Kratos MS80RF Autoconsole apparatus.

Example 4-[l-(4-fluorophenyl ) -5-phenylpenty1 ] -1H-imidazole ) l-benzyl-5- ( l-hydroxy-5-phenylpentyl ) -lH-imidazole 2,1 g of magnesium turnings are covered with 60 ml of dry tetrahydrofura . A solution of 4-phenylbutylbromide (18,8 g) in 20 ml of dry tetrahydrofuran is then added dropwise to the mixture at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of l-benzyl-5-imidazolecarbaldehyde (6,5 g) in 80 ml of tetrahydrofuran at 60°C. After the addition is complete, the reaction mixture is refluxed for 2 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and cone, hydrochloric acid is added to the solution. The product which is separated as an oil, is extracted with methylene chloride and evaporated to dryness. b ) 4- ( 1-hydroxy-5-phenylpenty1 ) -lH-imidazole l-benzyl-5- ( 1-hydroxy-5-phenylpenty1 ) -lH-imidazole hydrochloride (8,5 g), prepared in the Step a, is hydrogenated in the mixture of 100 ml of 2 N hydrochloric acid and 10 ml of ethanol at 60 °C Pd/C (10 %) as catalyst. When the uptake of the hydrogen ceases, the reaction mixture is cooled, filtered and evaporated to dryness. Water is added and the mixture is made alkaline with sodium hydroxide. The product is then extracted to methylene chloride which is washed with water, dried with sodium sulphate and evaporated to dryness. The residue is the product as base, and it is used as such in Step c .

XH MR (as base, MeOH-d4 + a drop of CDCI3): 1.2-2.0 (m, 6H), 2.61 (distorted t, 2H), 4.65 (t, 1H) , 6.91 (dd, 1H), 7.0-7.3 (m, 5H), 7.56 (d, 1H) c) 4-(l-oxo-5-phenylpentyl)-lH-imidazole 5,5 g of 4-(l-hydroxy-5-phenylpentyl)-lH-imidazole and 7,0 g of manganese dioxide are refluxed stirring in tetrachloroethylene for four hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. Water is added and the product is extracted into methylene chloride. The combined extracts are washed with water and evaporated to dryness. d ) 4- [ 1- ( 4-fluorophenyl ) -l-hydroxy-5-phenylpentyl ] -1H- imidazole 0,52 g of magnesium turnings are covered with 60 ml of dry tetrahydrofuran. Then a solution of l-bromo-4-fluorobenzene (3,8 g) in 60 ml of dry tetrahydrofuran is added dropwise to the mixture at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of 4-( l-oxo-5-phenylpentyl )-lH-imidazole (3,8 g) in 40 ml of tetrahydrofuran at 60°C. After the addition is complete, the reaction mixture is refluxed for 3 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and cone, hydrochloric acid is added to the solution. The product is extracted as hydrochloric salt into methylene chloride. Combined methylene chloride extracts are then evaporated to dryness. e ) 4- [ 1- ( 4-fluorophenyl ) -5-phenyl-l-pentenyl ] -1H- imidazole 4- [ 1- ( 4-fluorophenyl ) -1-hydroxy-5-phenylpentyl ] -1H-imidazole hydrochloride (5,0 g) and 30,0 g of anhydrous potassium hydrogen sulphate are heated at 150°C for 4 hours. The mixture is cooled and 90 ml of ethanol is added to dissolve the product. The mixture is then filtered and the filtrate is evaporated to minor volume. Water is added and the mixture is made alkaline with sodium hydroxide. The product is extracted into methylene chloride, washed with water and evaporated to dryness. The product is then made to hydrochloride salt with dry hydrogen chloride in dry ethylacetate .

MR (as base, CDCI3): 1.5-2.7 (m, 6H), 4.8 (broad s, 1H) , 6.34 (t, 1H), 6.48 (broad s, 1H) , 6.9-7.4 (m, 9H), 7.52 (broad s, 1H) Using the same method for example the following compounds included in the invention were prepared: 4- [ 1- ( 4-fluorophenyl ) -5- ( 3-methylphenyl ) -1-pentenyl ] -lH-imidazole 4-[l-(4-fluoropheny1 ) -5- ( 4-methylphen 1 ) -1-penteny1 ] -lH-imidazole 4- [ 1- ( 4-fluorophenyl ) -5- ( 2-methylpheny1 ) -1-pentenyl ] -lH-imidazole 4- [ 5- ( 3 , 5-dimethylpheny1 ) -1- ( 4-fluoropheny1 ) -1-pentenyl ] -lH-imidazole 4- [ 1- ( 4-fluorophenyl ) -5- ( 3-methoxyphenyl ) -1-pentenyl ] -lH-imidazole 4-[ 5- ( 3 , 5-diitiethoxyphenyl ) -1- ( 4-fluorophenyl ) -1-pentenyl ] -lH-imidazole f ) 4-[ 1- ( 4-fluorophenyl ) -5-phenylpentyl ] -lH-imidazole 4- [ 1- ( 4-fluorophenyl ) -5-phenyl-l-pentenyl ] -lH-imidazole hydrochloride (2,0 g) is dissolved in ethanol and a catalytic amount 10 % Pd/C is added. The reaction mixture is agitated vigorously at room temperature in a hydrogen atmosphere until the uptake of hydrogen ceases. The mixture is filtered and the filtrate is evaporated to dryness. The residue which is the product is purified by flash chromatography eluting with methylene chloride- ethanol mixture. Yield 82 %.

NMR (as base, CDC13): 1.1-2.7 (m, 8H), 3.84 (t, 1H), 6.71 (broad s, 1H), 6.80-7.38 (m, 9H), 7.47 (broad s, 1H), 9.22 (broad s, 1H) Using the same method for example the following compounds included in the invention were prepared: 4- [ 1- ( 4-fluorophenyl ) -5- ( 3-methylphenyl )pentyl ] -1H-imidazole MS: 322 (20, Μ+·), 189 (28), 176 (38), 175 (72), 149 (100), 125 (20), 121 (14), 109 (42), 105 (16), 97 (21) NMR (as HCl-salt, MeOH-d4 ) : 1.1-2.7 (m, 8H), 2.27 (s, 3H), 4.06 (t,. 1H), 6.7-7.5 (m, 8H), 7.37 (d, 1H) , 8.77 (d, 1H) 4- [ 1- ( 4-fluorophenyl ) -5- ( 4-methylphenyl ) enty1 ] -1H-imidazole 1H NMR (as HCl-salt, MeOH-d4 ) : 1.1-2.7 (m, 8H), 2.26 (s, 3H), 4.05 (t, IH) , 6.8-7.6 (m, 9H), 8.78 (d, IH) 4_ 1_ ( 4-fluorophenyl ) -5- ( 2-methylpheny1 )pentyl ] -lH-imidazole MS: 322 (53, Μ+·), 189 (30), 176 (55), 175 (100), 148 (18), 121 (12), 105 (42), 101 (11), 79 (12), 77 (13) NMR (as HCl-salt, MeOH-d4 ) : 1.1-2.7 (m, 8H), 2.24 (s, 3H), 4.11 (t, IH) , 6.9-7.5 (m, 9H), 8.79 (d, IH) 4-[ 5- ( 3 , 5-dimethylpheny1 ) -1- ( 4-fluorophenyl ) pentyl ] -1H-imidazole MS: 336 (47, M+ · ) , 189 (90), 176 (67), 175 (100), 166 (13), 148 (16), 121 (12), 119 (16), 91 (14) NMR (as HCl-salt, MeOH-d4 ) : 1.1-2.6 (m, 8H), 2.22 (s, 6H) , 4.09 (t, IH) , 6.6-7.4 (m, 7H), 7.40 (broad s, IH), 8.80 (broad s, IH) 4- [ 1- ( 4-fluorophenyl ) -5- ( 3-methoxyphenyl )pentyl ] -1H-imidazole 4- [ 5- ( 3 , 5-dime hoxypheny1 ) -1- ( 4-fluorophenyl )pentyl ] -1H-imidazole Example 2 4- ( 1 , 3-diphenylpropyl ) -lH-imidazole a ) l-benzyl-5- ( l-oxo-3-phenylpropyl ) -lH-imidazole l-benzyl-5- ( 1-hydroxy-3-phenylpropyl ) -IH-imidazole is oxidized with manganese dioxide in tetrachloroethylene, as it is described in Example 1 c).

½ NMR (as base, CDC13): 3.03 (m, 4H), 5.53 (s, 2H) , 7.07-7.4 (m, 10H), 7.60 (s, 1H), 7.77 (s, 1H) Using the same method for example the following compounds included in the invention were prepared: l-benzyl-5- [ 5- ( 2 , 6—dimethyl henyl ) -1-oxopentyl ] -1H-imidazole. M.p. of hydrochloride 175-180°C. l-benzyl-5- ( l-oxo-5-phenylpentyl ) -IH-imidazole . M.p. of hydrochloride 185-189°C. b) l-benzyl-5- ( 1-hydroxy-l , 3-diphenylpropyl ) -IH-imidazole Grignard reagent is prepared from 5,0 g of bromobenzene and 0,76 g of Mg turnings in tetrahydrofuran . This solution is then added to 3,1 g of l-benzyl-5- ( l-oxo-3-phenylpropyl)-lH-imidazole in tetrahydrofuran and the reaction mixture is refluxed for 3 hours. The mixture is then poured into cold water, tetrahydrofuran is evaporated and the solution is made acidic with hydrochloric acid. The hydrochloride of the product is filtered, washed with toluene and dried. M.p. 196-198°C.

Using the same method for example the following compounds included in the invention were prepared: l-benzyl-5- ( 1-hydroxy-l , 5-diphenylpentyl ) -IH-imidazole . M.p. of hydrochloride 193-196°C. l-benzyl-5-[ 5- ( 2 , 6-diraethylphenyl ) -1-hydroxy-1-phenylpentyl]-lH-imidazole. M.p. of hydrochloride 190-192°C. c) l-benzyl-5-(lf3-diphenylpropyl)-lH-imidazole l-benzyl-5-( 1-hydroxy-l , 3-diphenylpropyl ) -lH-imidazole is treated with anhydrous potassium hydrogen sulphate at 150°C as described in Example 1 e). The double bond of the obtained intermediate, l-benzyl-5-(l,3-diphenyl-l-propenyl)-lH-imidazole, is hydrogenated as described in Example I f). M.p. of the hydrochloride salt is 154-174°C (from diethylether) . 1H NMR (as HCl-salt, MeOH-d4 ) : 2.2-2.7 (m, 4H), 3.90 (t, 1H) , 5.12 (AB q, the middle of the quartet, 2H) , 6.90-7.37 (m, 15H) , 7.70 (broad s, 1H), 8.88 (d, 1H) Using the same method for example the following compounds were prepared: l-benzyl-5- ( 1 , 5-diphenylpentyl ) -lH-imidazole NMR (as base, CDC13): 1.18-2.61 (m, 8H) , 3.56 (t, 1H) , 4.59 and 4.81 (AB q, 2H), 6.76-7.40 (m, 17H) l-benzyl-5- [ 5- ( 2 , 6-dimethylphenyl ) -1-phenylpentyl ] -1H-imidazole d ) 4- ( 1 , 3-diphenylpropyl ) -lH-imidazole l-benzyl-5- ( 1 , 3-diphenylpropyl ) -lH-imidazole is hydrogenated in the mixture of 2N hydrochloric acid and ethanol at 60 °C 10 % Pd/C as catalyst. The product is isolated as in Example 1 b) and is purified by flash chromatography methylene chloride-methanol (9,5:0,5) as eluent. Yield 73 %.

½ NMR (as base, CDC13): 2.1-2.7 (m, 4H), 3.88 (t, 1H) , 6.71 (broad s, 1H), 7.01-7.26 (m, 10H) , 7.30 (d, 1H), 10.5 (broad s, 1H) Using the same method for example the following compound was prepared: 4- ( 1 , 5-diphenylpentyl ) -1H-imidazole ½ NMR (as HCl-salt, MeOH-d4 ) : 1.2-2.3 (m, 6H), 2.57 (distorted t, 2H) , 4.05 (t, 1H), 7.05-7.40 (m, 11H) , 8.73 (d, 1H) Example 3 1-benzy1-4- (1,3-diphenylpropy1 ) -1H-imidazole 2,0 g of benzylbromide in 5 ml of toluene is added dropwise to the mixture of 4-(l,3-diphenylpropyl)-lH-imidazole (2,6 g), 48 % NaOH (10 ml), toluene (20 ml) and tetrabutylammoniumbromide (0,2 g ) at room temperature. After addition the reaction mixture is stirred at room temperature for 3 hours . Water is added and the toluene layer is separated. The toluene phase is then washed with water and evaporated to dryness .

The residue contains the isomers l-benzyl-4-(l,3-diphenylpropyl)-lH-imidazole and l-benzyl-5- ( 1 , 3-diphenylpropyl ) -lH-imidazole and the former is separated and purified by flash chromatography (methylene chloride-methanol 9,5:0,5).

Example ^ 4-[ 1 , 4-bis { 4-fluorophenyl )butyl ]-lH-imidazole a) l-benzyl-5-[l-( 4-fluorophenyl )-l-hydroxymethyl]-lH- Imidazole Grignard reaction of 4-bromofluorobenzene and 1-benzyl- 5-imidazolecarbaldehyde is performed analogously to Example 1 a). The product is crystallized as hydrochloride salt from ethylacetate . Yield 94 %.

NMR (as base, CDCI3 + MeOH-d4 ) : 5.05 and 5.21 (AB q, 2H), 5.64 (s, 1H) , 6.61 (s, 1H), 6.97-7.1 (m, 4H) , 7.26-7.33 (m, 5H) , 7.41 (s, 1H) MS: 282 (22, Μ+·), 265 (5), 191 (18), 91 (100) b ) l-benzyl-5- [ 1- ( 4-fluorophenyl ) -1-oxomethyl ] -1H- imidazole Oxidation of l-benzyl-5- [ l-( 4-fluorophenyl ) -1-hydroxymethyl]-lH-imidazole is performed analogously to Example 1 c). The crude product is recrystallized as a base from methanol. Yield 72 %.

NMR (as base, CDCI3): 5.62 (s, 2H), 7.1-7.4 (m, 7H) , 7.5-8.0 (m, 4H) MS: 280 (46, Μ+·), 123 (13), 107 (4), 95 (19), 91 (100) c ) 1-benzyl-5-[l,4-bis(4-fluorophenyl ) -1-hydroxybutyl ] - lH-imidazole l-benzyl-5- [ 1 , 4-bis ( 4-fluorophenyl ) -1-hydroxybutyl ] -1H-imidazole is prepared analogously to Example 1 a) starting from 3-(4-fluorophenyl)-l-bromopropane and 1-benzyl-5-[ 1- ( 4-fluorophenyl ) -1-oxomethyl ] -lH-imidazole . The product is purified by flash chromatography.

NMR (as base, CDC13): 1.2-1.4 (m, 1H), 1.65-1.85 (m, 1H), 2.1-2.25 (m, 2H), 2.52 (t, 2H), 4.73 and 4.81 (AB q, 2H), 6.75-7.3 (m, 15H) Using the same method for example the following compounds included in the invention were prepared: l-benzyl-5-[ 1- ( 4-fluorophenyl ) -1-hydroxy-3-phenylpropyl ] -1H-imidazole MS: 386 (Μ+·, 8), 368 (22), 281 (100), 159 (26), 91 (99), 65 (34) l-benzyl-5-[ 1 , 3-bis ( 4-fluorophenyl ) -1-hydroxypropyl ] -lH-imidazole MS: 404 (Μ+·, 2), 386 (18), 195 (16), 281 (33), 123 (34), 91 (100), 65 (20) l-benzyl-5-[l-( 4-fluorophenyl) -1-hydroxy-4-phenylbutyl -lH-imidazole MS: 400 (Μ+·, 2), 382 (2), 281 (38), 191 (3), 91 (100), 65 (9) l-benzyl-5-[ 1- ( 4-fluorophenyl ) -l-hydroxy-5- ( 3-methoxyphenyl )pentyl ] -lH-imidazole 1H NMR (as HCl-salt, MeOH-d4 ) : 1.0-1.8 (m, 4H), 2.26 (t, 2H) , 2.52 (t, 2H) , 4.71 (s, 3H), 5.06 and 5.31 (ABq, 2H) , 6.6-7.5 (m, 13H) , 7.7 (s, 1H), 8.6 (s, 1H) 1-benzyl-5- [ 5- ( 2 , 6-dimethylphenyl ) -1- ( 4-fluorophenyl ) -1-hydroxypentyl ] -lH-imidazole MS: 442 (Μ+·, 19), 281 (71), 256 (5), 191 (7), 119 (21), 91 (100) d) 4-[ l,4-bis(4-fluorophenyl)butyl ]-lH-imidazole l-benzyl-5- [ 1 , 4-bis ( 4-fluorophenyl ) -1-hydroxybutyl] -1H-imidazole (10 g) is dissolved in cone, acetic acid (100 ml ) . Into the solution is added 0,1 g of palladium on carbon and 0,8 g of ammoniumformate . The mixture is refluxed for an hour and cooled to room temperature.

The solution is filtered through silicous earth. The acetic acid filtrate is evaporated, the residue is dissolved in methylene chloride and washed once with 2 M aqueous sodium hydroxide solution and once with water. The methylene chloride solution is dried with sodium sulphate and evaporated under reduced pressure. The product is then made to hydrochloride salt with dry hydrogen chloride in diethylether . M.p. 135-137 °C.

^■H NMR (as base, CDCl3): 1.4-1.65 (m, 2H), 1.8-1.95 (m, 1H), 2.05-2.2 (m, 1H) , 2.5-2.65 (m, 2H), 3.87 (t, 1H) , 6.7 (s, 1H) , 6.8-7.2 (m, 8H), 7.5 (s, 1H) Using the same method for example the following compounds included in the invention were prepared: 4- [ 1- ( 4-fluorophenyl ) -3-phenylpropyl ] -lH-imidazole 1H NMR (as base, CDCI3): 2.0-2.7 (m, 4H), 3.7-4.0 (m, 1H), 6.7 (s, 1H) , 6.75- 7.45 (m, 9H), 7.57 (s, 1H) S: 280 (4, Μ+·), 189 (9), 176 (100), 148 (15), 121 (9), 91 (12) 4- [ 1 , 3-bis ( 4-fluoropheny1 ) ropyl ] -lH-imidazole NMR (as base, CDC13): 2.1-2.25 (m, 1H) , 2.3-2.6 (m, 3H), 3.88 (t, 1H), 6.76 (s, 1H), 6.9-7.2 (m, 8H) , 7.63 (s, 1H) MS: 298 (5, Μ+·), 189 (8), 176 (100), 122 (22), 109 (42) 4- [ 1- ( 4-fluoropheny1 ) -4-phenylbutyl ] -IH-imidazole ½ NMR (as base, CDCI3): 1.3-2.3 (m, 4H), 2.6 (t, 2H) , 3.88 (t, IH), 6.67 (s, IH), 6.7-7.3 (m, 9H) , 7.39 (s, IH) MS: 294 (31, Μ+·), 189 (24), 175 (100), 91 (31) 4- [ 1- ( 4-fluoropheny1 ) -5- ( 3-methoxypheny1 )pent 1 ] -1H-imidazole 1H NMR (as base, CDCI3): 1.1-2.3 (m, 6H), 2.5 (t, 2H), 3.76 (s, 3H), 3.85 (distorted t, IH) , 6.6-7.6 (m, 10H) MS: 338 (19, Μ+·), 189 (43), 175 (70), 148 (12), 121 (20), 36 (100) 4-[l-(4-fluoropheny1 ) -5- ( 4-methoxypheny1 ) penty1 ] -1H-imidazole NMR (as base, CDCI3): 1.1-2.3 (m, 6H), 2.49 (t, 2H) , 3.75 (s, 3H) , 3.8 (distorted t, IH), 6.6-7.6 (m, 10H) S: 338 (10, Μ+·), 189 (20), 175 (22), 148 (6), 121 (22), 36 (100) 4-[ 5- ( 2 , 6-dimethylphenyl ) -1- ( 4-fluorophenyl )pentyl ] -1H-imidazole ½ NMR (as base, CDC13): 1.25-1.5 (πι, 4H), 1.8-1.95 (m, 1H) , 2.05-2.2 (m, 1H) , 2.25 (s, 6H), 2.52 (t, 2H), 3.86 (t, 1H), 6.71 (s, 1H) , 6.9-7.0 (m, 5H), 7.1-7.2 (ro, 2H) , 7.4 (s, 1H) MS: 336 (50, Μ+·), 217 (20), 189 (75), 175 (100), 148 (13), 119 (23) Example 5 l-benzyl-5- [ 1- ( 4-fluorophenyl ) -3-phenyl-1-propenyl ] -lH-imidazole Titanium tetrachloride (0,03 mol) is added dropwise to a stirred suspension of zink powder (0,06 mol) in tetrahydrofuran (30 ml) at -10 °C under dry nitrogen. The mixture is heated to reflux and refluxing is continued for 1 hour. The solution is cooled to 0 °C and l-benzyl-5- [l-(4-fluorophenyl) -1-oxomethyl]-lH-imidazole (0,005 mol) in tetrahydrofuran (10 ml) and phenylacetaldehyde (0,006 mol) in tetrahydrofuran (10 ml) are added into the mixture, respectively. The mixture is refluxed with stirring for 1 hour. The dark mixture is poured into water (60 ml), tetrahydrofuran is evaporated and the mixture is extracted with methylene chloride (2 x 100 ml). The methylene chloride solution is washed with 2 N sodium hydroxide and water, dried with sodium sulphate and evaporated to dryness. The residue is purified by flash chromatography.

½ NMR (as base, CDCl3): 3.35 and 3.45 (2d, 2H), 4.62 and 4.65 (2s, 2H) , 6.03 and 6.20 (2t, 1H) , 6,8-7.3 (m, 15H) , 7.50 and 7.64 (2s, 1H) .

Example 6 4-[l,3-bis (4-nitrophenyl)propyl] -IH-imidazole 1,8 g (14,6 mmol) of urea nitrate is added in small portions to a mixture of 2,7 g (7,3 mmol) of 4- (1 , 3-diphenylpropyl) -IH-imidazole in 6,4 ml of concentrated sulphuric acid under 10°C. The reaction mixture is stirred for 2 hours at room temperature. The mixture is made alkaline with 2 M sodium hydroxide and the product is purified by flash chromatography using methylene chlo ide-methanol (95:5) as eluent.

In formula I , preferably R4, R¾ and R 1 are each H. If one phenyl group in formula I is mono-substituted then preferably R^, 2 and R'2 are each H and R' 1 is not hydrogen and is in the para position of the phenyl group. Preferably If both phenyl groups in formula I are mono-substituted, preferably R2 and R'2 are both H, R^ and R 1 ^ are both not H, R^ is in the ortho, meta or para position of the phenyl group and R'-^ is the para position of the phenyl group. Preferably R^ is in the para position.

Preferred substituents are CH^ and F, in particular it is prferred that ^ and R'-^ are both F or 1 is CH3 and R'^ is F.

If one phenyl group is di-substituted and the other is mono-substituted, preferably R'2 is H, R^, 2 and R'-^ are each not H and R'^ is the para position of the phenyl group and R^ and R2 are in the 3 and 5 or 2 and 6 positions of the phenyl group. 107260/2 37

Claims (27)

1. A substituted imidazole of the formula or a non-toxic pharmaceutically acceptable acid addition salt thereof wherein Rx , R2 , R'x and R'2 # which can be the same or different, are H, CH3 , C2 H5 , C, H, , OCH3 ,. 0Ht CH2OH, N02 , NH2 , CN, CF3 , CHF2 , CH2 F or halogen; R ' is H or -CH2 —— R3 where 3 is H, CH3 or halogen; 4 is H or OH and Rs is H or R4 and R5 together form a bond and y is 0 to 4.

2. A substituted imidazole according to claim 1 wherein R4, R5 and R' each are H.

3. A substituted imidazole according to claim 1 or 2 wherein Ru Rg and R'2 each are H and R', which is as defined in claim 1, is in the para position of the phenyl group.

4. A substituted imidazole according to claim 3 wherein R', is F.

5. A substituted imidazole according to claim 1 or 2 wherein R2 and R'2 each are H and R1# which is as defined in claim 1, is in the ortho, meta or para position of the phenyl group and R'1f which is as defined in claim 1, is in the para position of the phenyl group.

6. A substituted imidazole according to claim 5 wherein R2 and R'2 both are H and Rx and which are as defined in claim 1, both are in the para position of the phenyl group.

7. A substituted imidazole according to claim 6 wherein Rx and R'x both are F.

8. A substituted imidazole according to claim .6 wherein Rx is CH3 and R'x is F.

9. A substituted imidazole according to claim 1 or 2 wherein R'2 is H, R^, which is as defined in claim 1, is in the para position of the phenyl group and x and R2 , which are defined as in claim 1, are in the 3 and 5 positions of the phenyl group.

10. /. A substituted imidazole according to claim 1 or >2 wherein R'2 is H, R' , which is as defined in claim 1, is in the para position of the phenyl group and R1 and R2 , which are as defined in claim 1, are in the 2 and 6 positions of the phenyl group.

11. A compound according to claim 1, which is 4-[ l-( 4-fluorophenyl ) -5-phenylpentyl ]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof .

12. A compound according to claim 1, which is 4-[ l-( 4-fluorophenyl ) -5- ( 2-methylphenyl )pentyl ]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof .

13. A compound according to claim 1, which is 4-[ l-( 4-fluorophenyl )-5-( 3-me hylphenyl )pentyl ] -1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

14. A compound according to claim 1, which is 4-[ l-( 4-fluorophenyl )-5-( 4-methylphenyl )pentyl ]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

15. A compound according to claim 1, which is 4-[ 5-( 3 , 5-dimethylphenyl )-l-( 4-fluorophenyl )pentyl ]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

16. A compound according to claim 1, which is 4-( 1 , 5-diphenylpentyl ) -lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

17. A compound according to claim 1, which is 4-( 1 , 3-diphenylpropyl )-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

18. A compound according to claim 1, which is l-benzyl-5- ( 1 , 3-diphenylpropyl ) -lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

19. A compound according to claim 1, which is 4-t l-( -fluorophenyl )-3-phenylpropyl ]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

20. A compound according to claim 1, which is 4-[ l-( -fluorophenyl )-4-phenylbutyl ]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

21. A compound according to claim .1, which is 4-[ l-( -fluorophenyl )-5-( 3-methoxyphenyl )pentyl ] -lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

22. A compound according to claim 1, which is 4-[ l-( 4-fluorophenyl )-5-( 4-methoxyphenyl )pentyl ]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof .

23. A compound according to claim 1, which is 4-[ l-( 4-fluorophenyl ) -5- ( 2 , 6-dimethy1phenyl ) pentyl ] -lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

24. A compound according to claim 1, which is 4- [ 1 , 3-bis ( 4-fluorophenyl ) propyl ] -lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

25. A compound according to claim 1, which is 4-[ 1 , -bis ( 4-fluorophenyl )butyl ] -lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

26. A pharmaceutical composition comprising a substituted imidazole as claimed in any one of claims 1 to 65 and a pharmaceutically acceptable carrier.

27. An imidazole derivative as claimed in any one of claims 1 to 26 or a non-toxic acid addition salt for use in therapy as an aromatse inhibiting agent. ADVOCATE. PATENT ATTORNEY P.O.B.23008. TEL-AVIV.61 230. ISRAEL