CA2013395A1

CA2013395A1 - Aromatase inhibiting 4(5)-imidazoles

Info

Publication number: CA2013395A1
Application number: CA002013395A
Authority: CA
Inventors: Arto Johannes Karjalainen; Reino Olavi Pelkonen; Marja-Liisa Sodervall; Matti Antero Lahde; Risto Arvo Sakari Lammintausta; Arja Leena Karjalainen; Arja Marketta Kalapudas
Original assignee: Farmos Yhtyma Oy
Current assignee: Farmos Yhtyma Oy
Priority date: 1989-03-30
Filing date: 1990-03-29
Publication date: 1991-09-29
Also published as: DD296916A5; ZA902479B; LTIP847A; LT3657B; GB8907218D0; PL162554B1; UA19310A1; GB2229719B; RU2021263C1; PL288962A1; FI901316A0; RU1836355C; GB2229719A

Abstract

Abstract Novel imidazole derivatives of the formula (Ia) wherein R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2, NH2, CN, CF3, CHF2, CH2F or halogen; R' is H or where R3 is H, CH3 or halogen; R4 is H, R5 is H or OH, R6 is H or OH and R7 is H or R4 and R6 together form a bond or R5 and R7 together form a bond;
X and Y, which can be the same or different, are a bond, a straight C1-2-alkyl or the corresponding alkenyl and z is 0 to 2 and (Ib) wherein R1, R2, R'1, R'2 and R' are as defined before, R4 is H or OH and R5 is H or R4 and R5 together form a bond and y is 0 to 4, and their non-toxic salts exhibit aromatase and desmolase inhibiting properties. Very selective aromatase inhibiting compounds are valuable in the treatment of estrogen dependent diseases, e.g.
breast cancer.

Description

~ 3 -Novel aromatase inhibiting 4(5)~imidazoles The present 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 present invention have the general formulae (Ia) and (Ib):
~ 3 CHR6-CHR4-(CH2, z-CHR7-CR5 x~RR2 R~ R'2 ~ (Ia~

wherein R1, R2, R'l and R'2, which can be the same or different, are H, CH3, C2H5, C3H7~ OCH3, OH~ CH20H, N02, NH2, CN, CF3, CHF2, CH2F or halogen; R' is H or -CH2 ~ R3 where R3 is H, CH3 or halogen; R4 is H, R5 is H or OH, R6 is H or OH and R7 is H or R4 and R6 together form a bond or R5 and R7 toyether form a bond;
X and Y, which can be the same or different, are a bond, a straight Cl_2-alkyl or the corresponding alkenyl and z is O to 2 and ~iJ )~J~3 ~

R'l R'2 3c CH - (CH2)y ~ R12 N R4 R5 (Ib) R' wherein Rl, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2Hs, C3H7, OCH3, OH, CH20H, NO2, NH2, CN, CF3, CHF2, C~2F or halogen; R' is H or -CH2 ~ R3 where R3 is H, C~3 or halogen; R4 is H or OH and R5 is H or R4 and R5 together form a bond and y is 0 to 4.

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

The compounds of the formulae (Ia) and (Ib) 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 (Ia) or (Ib) or a non-~oxic, pharmaceutically acceptable salt thereof, and a compatible pharmaceutically acceptable carrier therefor.

The compounds of the present invention have been found, depending on the substituents R', Rl, R2, R'l and R'2, to possess varying degrees of aromatase and desmolase t ~ ~
_f .J ~J ,J

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 (Ia) can be prepared by the following methods. Compounds of formula (Ia) wherein the branches -X ~ Rl and ~Y ~ RR'2 are identical, can be prepared by a successive sequence of reactions comprising a Grignard reaction of 4(5)-imidazole derivative of the formula (IIa) o N CH2CH2 ( CH2 ) ZCH2C-OR

N
H (IIa) or its 1-benzyl derivative (IIIa) with an appropriate aryl- or arylalkylmagnesium halide (IVa) following the loss of water and hydrogenation.

N O
3 CH2CH2 ( CH2, zcH2 c o~
N (IIIa) CH2 ~ - R3 Rl ~ (CH2)nMgHal (IVa) In the formulae (IIa) to (IVa) R is alkyl, preferably lower alkyl, n is O to 2 and Hal is halogen. The first reaction step, the Grignard reaction, leads to the following compounds of formula (Ia):

~ rs ~ s~ r~ r~

</ ~ CH2CH2(CH2)zcH2c~(cH2)n < ~ ~ R2 N (CH2)n R' R2 ~ (Va) In this reaction the aryl- or arylalkylmagnesium halide derivative can be, for example, an aryl- or arylalkyl-magnesiun~romide derivative, which is prepared by reacting the corresponding aryl- or arylal~ylbromide derivative with magnesium~ The Grignard reagent (IVa) cannot be prepared if Rl and/or R2 are OH, CH20H or NH2.
Suitable solvents for the reaction include a variety of ethers, preferably tetrahydrofuran.

The aryl- or arylalkylmagnesiumhalide derivative is prepared in the usual way by adding the aryl~ or arylalkylhalide derivative in a suitable solvent, e.g.
tetrahydxofuran, 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 4t5)-imidazole derivative (IIa) or its l-benzylsubstituted derivative (IIIa) 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 derivative has reacted. The reaction time varies between one and five hours.

According to the feature of the invention, the compounds of formula (Ia), wherein R7 and Rs both are hydrogen or together form a bond, are prepared by dehydration of the compounds of formula (Ia), where R5 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 j v s dry potassium hydrogen sulfate. The unsaturated compounds (VIa) (the compounds of formula (Ia) wherein R7 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 fox example platinium oxide, palladium-on-carbon or Raney-nickel.

The reaction scheme for these steps can be illustrated as follows:

CH2CH2(CH2)zcH2c~(cH2)n ~ RR2 R' R2 ~ (Ya) wherein R', Rl, R2, z and n are as defined before N ~ 2 2(CH2)zcH-c-(cH2) ~ RR2 R' R2 ~ (VIa) </ ~ CH2CH2(C~2)zcH2~lcH~(cH2)n ~ RR2 N (CH2)n R' R2 ~ (VIIa 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 (Ia) wherein R', R7 and R5 each are hydrogen can be illustrated as follows:

<, 3 CH2cH2(cH2)zcH~-cH-(cH2)n ~ R

R~ R2 ~ R1 ~H2 < ~ CH2CH2(CH2)zcH2~cH~(cH2)n - ~ R

R2 ~ R1 (VIIIa) wherein R1, R2, z and n are as defined before.

Another method to remove the benzylic R' group is a hydrogen kransfer reaction in which the starting compound (VIIa) is refluxed with ammonium formate and 10 ~ Pd/C
in an appropriate lower alcohol, such as methanol or ethanol, or its aqueous solution. The compounds (VIIIa) can also be prepared directly from the compounds (VIa) 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 (VIIIa) can also be prepared directly from the compounds (Va) by hydrogen transfer reaction in which the starting compound 7 ~ ~ ?, "~, j (Va) is refluxed with ammonium formate and 10 ~ Pd/C in an acidic medium such as acetic acid.

The compounds of formula (VIIIa) can also be prepared from ~he compounds of formula (Va) wherein R' is a substituted or unsubstituted benzyl by removing first the benzylic R' by a hydrogen transfer reaction as described before to give the compounds of formula (IXa) CH2CH2~CH~)zcH2c~(cH2)n { ~ RR2 R2 ~ Rl (IXa) wherein Rl, R2, z and n are as defined before.

The benzylic R' can be removed by hydrogenation as well. The compounds of formula (IXa) are further dehydrated by the methods described before to form the compounds of formula (Ia) where R5 and R7 together form a bond (Xa).

</ ~ CH2CH2(CH2)zCH-C-(cH2)n ~ ~ ~ R2 R2 - ~ (Xa) The compounds of formula (Xa) are further hydrogenated by the methods described before to give the compounds of formula (VIIIa).

When the compounds of formula (Ia3 wherein R1 andtor R2 are OH, CH20H or NH2 are wanted, they can be prepared by the following reactions.

8 ~' '1 ~ ~, ~,~ ~, ~ J., The compounds of formula (Ia) wherein R1 andJor R2 are OH can be prepared by reacting the 4(5)-imidazole derivative (IIa) or (IIIa) with a Grignard reagent (IVa) where R1 and/or R2 are OCH2Ph or OTHP (THP = tetrahydro-pyranyl) and then hydrogenating catalytically by ~he 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 (Ia) where R1 and/or R2 are OCH3 by allowing them to react with BBr3, for example.

The compounds o~ formula ~Ia) wherein Rl and/or R2 are CH20H may be prepared ~rom the corresponding compounds where Rl and/or R2 are CN by conventional methods, i.e.
by hydrolyzing the nitrile group and then catalytical reduction of the acid group.

The compounds of formula (Ia) wherein R1 and/or R2 are NH2 can be prepared by hydrogenating the corresponding compounds where R1 and/or R2 are NO2. The protecting benzyl group will be hydrogenated as well.

The compounds of formula (Ia) wherein R1 and/or R2 are CN can be prepared from the corresponding compounds where R1 and/or R2 are NH2 by diazotiæation. Compounds of formula (Ia) wherein Rl and/or R2 are halogen may also optionally be prepared by the same method.

Compounds o~ formula ~Ia) where R' is a benzyl group 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 9 ?J',fJ~

adding to this benzyl halide~ The reaction scheme c~n be illustrated as follows:
~ 3 CHR6-cHR4-(cH2)z-cHR7-cR5-x ~ R

R'2 ~R'l 1)strong base > /N ~__~R

2) ~ CH2Hal ~ 3 CHR6-cHR4-(cH2)z-cHR7-cR5-x ~

CH2 ~ R3 R~2 ~ R~1 The free OH, CH20H and NH2 substituenks must be protected during the benzylation reaction.

Another process for the preparations of compounds of formula (Ia) wherein the branches -X ~ R1 and -Y - ~ R 1 are different, comprises in the first stage a series of two successive Grignard reactions starting from 4(5)-imidazole derivative (IIa) or its 1-benzyl substituted derivative (IlIa) as previously. Now/ however, the amount of the Grignard reagent is reduced as well as the reac-tion temperature, to stop the reaction at the ketone stage to give the ketone (XIa), which further is reacted with another Grignard reagent (XIIa) to give a compound of formula (Ia) where R5 is OH. The reactions are illustrated as follows:

~.J J ~. -J ~) 3., N O R2 ~ (CH2)nMgHal 3 CH2cH2(cH2)zcH2-c-oR (IVa~>
N

R' ( CH2 )m-MgHal N\O ~-~R1 R'2 (XIIa) CH2CH2(CH2)zcH2~c~(cH2)n ~

R'(XIa) ~ 3 CH2CH2(CH2,~CH2 c (CH2)n < ~ lR2 R' R~2 ~ R'l (XIIIa) In the reaction scheme above m and n, which can be the same or different, are 0 to 2, z is 0 to 2 and R is an alkyl group, preferably a lower alkyl. The compounds of formula (XIIIa) are fuxther dehydrated and hydrogenated by the methods described before to give the compounds of formula < ~ CH2CH2(CH2)zcH2-cH~(c~2)n ~ R

R' R'2 ~

wherein R', Rl, R2, R'1, R'2, z, n and m are as defined before.

The Grignard reagents ~IVa) and (XIIa)cannot be prepared when the substituents are OH, CH20H or NH2. When the compounds of formula (Ia), wherein one or more of the S~s ~

suhstituents Rl, R2, R~1 and R~2 are OH are wanted they can be prepared by the following method.

The compounds of formula (Ia) wherein one or more of the substituents R1, R2, R'l and R'2 are OH can be prepared by reacting the 4(53-imidazole derivative (IIa) or (IIIa) first with a Grignard reagent (IVa) and then with reagent (XIIa) where the substituent/substituents of either compound (IYa) or (XIIa) or both of them are OCH2Ph or OTHP and hydrogenating catalytically by the methods described to hydrogenate the benzylic R' group.
The protecting benzyl group will be remov~d conveniently at the same time. Another method is to dealkylate the compounds of formula (Ia) where the substituent/
substituents are OCH3 by allowing them to react with BBr3, for example.

The compounds of formula (Ia) wherein one or more of the substituents Rl, R2~ R'1 and R'2 are CH20H, NH2 or CN can be prepared by the methods described before.

In order to achieve a better control of the reactions above, the starting material may be an amide N O
3 CH2CH2 ( CH2, zCH2C-NH2 N
R' or a nitrile N ~
CH2cH2(cH2)zC~CN
N

R' as well.

Choosing appropriate conditions for the dehydration of the compounds of formula (Ia) where R5 is OH results in 12 ~ J~ ? ~

the corresponding compounds of formula (Ia) where one of the alkyl chains X or Y is transformed to the corre-sponding alkenyl chain.

The starting compounds of the formulae (IIa) and (IIIa) may be prepared for example from 4(5)-imidazole alkyl acid of the formula N ~ CH2cH2(cH2)zcH2cooH
H
and its 1-benzyl derivative of the formula N

<~ ~ CH2CH2(CH2)ZCH2COOH
N

CH~ ~ R3 wherein z and R3 are as defined before, by esterifying them according to the method described in US patent No.
3759944.

A further method of preparing the compounds of formula (Ia) is the Wittig reaction where the starting compound is an 4(5~-imidazole aldehyde (XIVa). In the formula (XIVa) R' is as defined before.
N

CHO
N
R' (XIVa) In the Wittig reaction the first step is to prepare a phosphonium salt (XVa) from the corresponding halogenated hydrocarbon ~XVIa) by reacting it with triphenyl-phosphine. The reaction scheme can be illustrated asfollows:

Hal-CH2-(CH2)Z-cH2-cH-x ~ RR2 ~ R'l R 2 ~ (XVIa) > Hal~ Ph P~_CH2_(CH2)ZCH2_CH_X ~ R

R'2 ~ (XVa) in which Rl, R2, R'l, R'2, X, Y and z are as defined before and Hal is halogen.

In the second step of the Wittig reaction the compound (XVa) is treated with a strong base to form a phosphorus ylide which is further allowed to react with the 4(5)-imidazole aldehyde (XIVa) to achieve the compounds of formula (Ia) wherein R4 and R6 together form a bond (XVIIa). The strong base can be NaH or BuLi in a proper solvent such as dimethoxyethane, tetrahydrofuran or DMF. Further alkali metal alkoxides the corresponding alcohols as solvent and NaH in DMSO can be used as proton acceptors. The compounds (XVIIa) are isolated and after that hydrogenated as has been described befoxe to achieve the compounds of formula (Ia) wherein R4 and R6 both are hydrogen. The reaction scheme for these stsps can be illustrated as follows:

3~

Hal~ Ph-P~-CH2-[CH2)zCH2~CH~X ~ l? strong base >
Ph y R2 2) ,N

< IN ~ CHO
R' (XIVa) </ ~ CH=CH-(CH2)z~CH2~CH~X ~ Rl H2 R' ~ R'1 R'2 ~ (XYIIa) - 3 CH2-CH2-(CH2)z~CH2-CH-X ~ 2 R' R'2 ~ (XVIIIa) The Wittig reaction can be performed in another order i.e. a phosphonium salt (XIXa) is prepared from the corresponding halogenated 4(5)-imidazole derivative (XXa) by reacting it with triphenylphosphine. In the second step the compound (XIXa)is allowed to react with a strong base and then with a substituted ketone of the formula (XXIa) as described before to give the compounds of formula (Ia) wherein R5 and R7 together form a bond (XXIIa). The reaction scheme for these steps can be illustrated ~s follows~
N

CH2cH2(cH2)zcH2Hal Ph3P
N (XXa) R~

~ J.~

N Ph ~ ~ CH2cH2(cH2)zcH2p~-ph Hal~ 1) strong base - N Ph 2) O=C-X ~ Rl R' (XIXa) Y ~ R2 [~ R 1 3 CH2CH2(CH2)zCH=C-x ~ R12 R' R'2 ~ R'l (XXIIa) wherein R', Rl, R2, R'1, R'2, z, X and Y are as defined before.

The compounds of formula (Ia) can also be prepared by a modified Wittig reaction, namely the Horner-Emmons or Wadsworth-Emmons reaction where ~he phosphonate (XXIIIa) which is prepared from the halogenated hydrocarbon (XVIa) and a triester of phosphonic acid (e.g. (EtO)3P) by the Arbuzow reaction reacts firstly with a base (e.g. NaH
in DMSO or in dimethoxyethane) and then with the aldehyde (XlVa). The product (XVIIa) formed is a compound of formula (Ia) where R4 and R6 together form a bond. The reaction scheme can be illustrated as follows:

Hal CH2-(CH2)2-CH2-~H-x ~ R1 (RO)3P

R 2 ~ R~ l (XvIa) ~ff ," ~ , f ~6 Rl (Ro)2-p-cH2-(cH2)z~cH2-cH-x ~ R2 1) base - Y 2) N
R'2- ~ R'l < N 3 (XXIIIa) R' (XIVa) =CH-(CH2)Z-CH2-CH-X ~ ~2 R' R~2 ~ (XVIIa) In the formula ~XXIIIa) R is alkyl with 1-4 carbon atoms and R1, R2, R'l, R'2, X, Y and z are as defined before.
The unsaturated compounds (XVIIa) are further hydrogenated to form the compounds of formula (Ia) wherein R4 and R6 both are hydrogen. The benzylic R' group and the double bond of the compounds of formula ~XVIIa) can be removed at the same time by the methods described before.

Another useful method to prepare compounds of forrnula (Ia) is the Grignard reaction in which the 4(5)-imidazole aldehyde (XIVa) is allowed to react with a Grignard reagent (XXIVa) to give a compound of forrnula (Ia) where R6 is OH (XXVa). The Grignard reagent is prepared by reacting the corresponding halogenated hydrocarbon with magnesium turnings in the usual way. The compound (XXVa) is further dehydrated by heating ~ith KHS04 to achieve the compounds of formula (Ia) where R4 and R6 together form a bond (XVIIa).

The unsaturated derivatives are then hydrogenated to forrn the compounds of formula (Ia) wherein R4 and R6 17 ~ 3 ~,J ~

both are hydrogen. The reaction scheme for these steps can be illustrated as follows-<, 3 CHO + HalNgcH2(cH2)zcH2-cH-x ~ RR2 R(XIVa) R'2 ~ (X~IVa 3--CH-CH2-(CH2~z-CH2-CH-X ~ = RR2 R~ R'2 ~ (XXVa) H20~ ~ ~ CH=CH-(CH2)z-CH2-CH-X ~ R

R' R'2 ~ (XVIIa ~, // ~ CH2-cH2-(cH2)z-cH2-c~-x~RR2 R' R'2 ~ (XVIIIa) In the formulae (XXVa), (~VIIa) and (XVIIIa) R', Rl, R2, R'l, R'2, X, Y and z are as defined before.

If R' is substituted or unsubstituted benzyl, this group may be removed by hydrogenation and hydrogen transfer reaction as described before to give the compounds of formula ~XXVIa).

18 )~ ?_S ' ~, ~, 3 CH2-CH2- ( CH2 ~ Z-CH2-CH-x C~RR2 H R~2 ~ (XXVIa) The compounds of formula (XXVIa) can also be prepared directly from the compounds (XVIIa) and (XXVa) by the methods described before.

The Grignard reagent (XXIVa) cannot be prepared when the substituents are OH, CH20H or NH2. The compounds of formula (la) wherein one or more of the substituents R1, R2, R'l and R'2 are OH, CH20H or NH2 can be prepared according to the methods described before.

Further method to prepare the compounds of formula (Ia) wherein one or more of the substituents Rl, R2, R' and R'2 are NO2 is nitration of the corresponding compounds wherein one or more of the substituen~s R1, R2, R'l and R'2 are H.

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

Compounds of formula ~Ib) can be prepared by a successive se~uence of reactions comprising firstly a Grignard reaction of 4(5)-imidazole aldehyde (IIb) N
R' (~Ib) with an appropriate arylalkylmagnesiumhalide (IIIb) ~ " ~ s-3 ~; ~f, HalMgCH2~CH2)Y ~ R21 whicn leads to following compounds (IVb) ~ 3--C-C~(CH2)Y ~ lR2 R' (IVb~

In the reaction the arylalkylmagnesium halide derivative can be, for example, an arylalkylmagnesiumbromide derivative, which i5 prepared by reacting the corre-sponding arylalkylbromide 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 coolsd slightly and the 4(5)-imidazole aldehyde (IIb) is added in solid form in small portions or dropwise in tetra-hydrofuran. After the addition, ~he reaction mixture is refluxed until all of the 4(5)-imidazole aldehyde (IIb) has reacted. The reaction time varies between one and five hours.

The com~ounds (IVb) are further oxidized for example with manganese dioxide to achieve compounds of formula (Vb) which are allowed to react with another Grignard reagent (VIb) to give the compounds of formula (Ib) where R4 is OH (VIIb). The reaction scheme for these steps can be illustrated as follows:

ZO ~ t,j '3f3~

<N3 OH ~ 12 R~ (IVb) oxidation~ ~ 3 C-CH2(CH2)y ~ R12 R' (Vb) R'l R'2 R'1 MgHal ~ R1 (VIb) > ~ C-OE12(CH2)y - ~ R2 R~ (VIIb) The arylmagnesium halide (VIb) is prepared by reacting the corresponding halogenated aromatic compound with magnesium turnings in the usual way.

Compounds of formula (Ib) can also be prepared by reacting an 4(5)-imidazole aldehyde (IIb) with an arylmagnesiumhalide (VIb) which leads to following compounds (VIIIb) N~ ~EI 2 R' (VIIIb) The compounds (VIIIb) are further oxidized for example with manganese dioxide to achieve the compounds of formula (IXb) which are further allowed to react with the Grignard reagent (IIIb~ to give the compounds of 2 ~ J ~I SJ /~ ~j "~) formula (Ib) where R4 is OH (VIIb). The reaction scheme for these steps can ~e illustrated as follows:

N 3 ~ oxidatio ~ </ 3 C ~ R' R' (VIIIb) R' (IXb) R ~ R~2 HalMgCH2(C~2)Y ~ R2 N
~IIIb) ~ < 3 c CH2 ( CH2 j Y~RR2 R' (VIIb) According to the feature of the in~ention, the compounds of formula (Ib), wherein R4 and R5 both are hydrogen or together form a bond, are prepared by dehydration of the compounds of formula (Ib), where R4 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 (Xb) (the compounds of formula lIb) 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 conveniantly 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:

~2 <~1 H~2 ( CH2 )y ~ Rl R' (VIIb) wherein R', Rl, R2, R'l, R'2 and y are as defined before -~2 > ~ ~ R'2 RR21 R' (Xb) < ~2(CH2)y <(~R2 R' (XIb) wherein R , Rl, R2, R~l, R'2 and y are as defined bafore.

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 (Ib) wherein R', R4 and R5 each are hydrogen can be illustrated as follows:

~JJ r~

~ } ~ (CH2)y ~ R1 (XIb) R' ¦H2~ H+
\/

~z(CH2 )y ~=Rl H (XIIb) Another method to remove the benzylic R' group is a hydrogen transfer reaction in which the starting compound (XIb) is refluxed with ammonium formate and 10 % Pd/C in an appropriate alcohol, such as methanol or ethanol, or its aqueous solution. The compounds (XIIb) can also be prepar~d directly from the compounds (Xb) 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 (XIIb) can also be prepared directly from the compounds (VIIb) by hydrogen transfer reaction in which the starting compound (VlIb) is refluxed with ammonium formate and 10 % Pd/C
in an acidic medium such as acetic acid.

The compounds of formula (XIIb) can also be prepared from the compounds of formula (VIIb) wherein R' is a substituted or unsubstitu~ed benzyl by removing first the benzylic R~ by a hydrogen transfer reaction by the method described before to give the compounds of formula (XIIIb) 2 ~ ~ t3 ~

< I CH2 ( CH2 ) Y--~ Rl H (XIIIb) wherein R1, R2, R'l, R'2 and y are as defined before.
The benzylic R' can be removed by hydrogenation as well. The compounds of formula (XIIIb~ are further dehydrated by the methods described before to form the compounds of formula (Ib) where R4 and R5 together form a bond (XIVb).

R ~ R 2 < ~ ~ C=CH(CH2)y ~ R

~ (XIVb) The compounds of formula (XIVb) are further hydrogenated by the methods described before to give the compounds of formula (XIIb).

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:

N 3 OH ~ RRl R' (IVb) ~ r~, J i S~,i i'~ J

H2, H ~ </ 3 C-CH2(CH2)y ~ ~ = R2 The Grignard reagents (IIIb) and (VIb) cannotbe prepared when the substituents are OH, CH20H or NH2. '~he compounds of formula (Ib) wherein one or more of the substituents Rl, R2, R~1 and R'2 are OH, CH20H or NH2 can be prepared by the following methods.

The compounds of formula (Ib) wherein one or more of the substituents Rl, R2, R'l and R'2 are OH can be prepared by reacting the 4(5)-imidazole derivative (IIb) first with a Grignard reagent (IIIb) and then with reagent (VIb) or revise order where the substituent/substituents of either compound (IIIb3 or (VIb) 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 (Ib) where the substituent/substituents are OCH3 by allowing them to react with BBr3, for example.

The compounds of formula (Ib) wherein one or more of the substituents R1, R2, R'l and R'2 are CH20H may be prepared from the corresponding compounds where the substituent/substituents are CN by conventional me~hods, i.e. by hydrolyzing the nitrile group and then reducing the acid group.

The compounds of formula (Ib) wherein one or more of the substituents R1, R2~ R~1 and R~2 are NH2 can be prepared by hydrogenating the corresponding compounds '~; d~

where the substituent/substituents are N02. The protecting benzyl group will be hydrogenated as well.

The compounds of formula (Ib) wherein one or more of the substituents Rl, R2, R'l 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 (Ib) wherein one or more of the substituents Rl, R2, R'1 and R'2 are halogen may also optionally be prepared by the s~me method.

Another method of preparing compounds of formula (Ib) is a McMurry reaction which comprises a reducti~e coupling of a benzoylimidazole (IXb) ~R ~ 2 R' (IXb~

and an appropriate aldehyde of the formula (XVb) ~I R
HC--( CH2 )y ~
R2 (XVb) in an appropriate solvent, such as tetrahydrofuran 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 foxmula (Ib) where R4 and R~ together form a bond (Xb) ~J ~ J~

< ~ ~ R2 (Xb) The unsaturated compounds (Xb) are further hydrogenated as described before. The aldehyde (XVb) is prepared from the corresponding alcohol in the usual way.

When the compounds of formula (Xb) where R'1 andtor R'2 are CH20H, NH2 or CN are wanted they can be prepared by the methods described before.

The compounds of formula (Xb) where R'1 and/or R'2 are OH and R1 and R2 are as defined before can be prepared by a McMurry reaction from the compounds of formula (IXb) where R'1 and/or R'2 are OH which can be prepared by hydrogenating catalytically the compounds of formula (IXb) wherein R'1 and/or R'2 are OCH2Ph 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 (IXb) where R'1 and/or R'2 are OCH3 by allowing them to react with BBr3, for ~xample.

Compounds of formula (Ib) wherein R'l and/or R'2 are OH
and Rl and R2 are as defined before can be prepared by a McMurry reaction in which the aldehyde (XVb) is allowed to react with a ketone (IXb) wherein R'1 and/or R'2 are OCH2Ph or OTHP to give a compound of formula (Xb~ where R'1 and/or R'2 are OCH2Ph or OTHP and R1 and R2 are as defined before which is further hydrogenated to give compounds of formula (XIIb) where R'l and/or R'2 are OH.

2~3 c~ ~ "' s, r~ r ~

Compounds of formula (Ib3 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 ben~yl halide.
The reaction scheme can be illustrated as follows:

~CNR5-(CH2)Y~RR2 R'l R'2 l~stronq base > N ~ Rl 2)R3 ~ CH2Hal </ ~ CR4-CHRs(CH23y ~ R2 CH2 ~ R3 The free OH, CH20H and NH2 substituents must be protected during the benzylation reaction.

Further method to prepare the compounds of formula (Ib) wherein one or more of the substituents R1, R2, R' and R~2 are NO2 is nitration of the corxesponding compounds where one or more of the substituents are H.

The compounds of formula (Ia) and (Ib), their non-toxic, pharmaceutically acceptable acid salts or mixtures thereof may be administered parenterally, intravenously or orally. Typically, an effective amount of the 2 9 ~ r; ~ s compound is combined with a suitable pharmaceutical carrier. As used herein, the term "effective amount' encompasses those amounts ~hich 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 o 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 present 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 3 0 ~ rj ~ ~

disorders in hormone dependent organs. The importance of estrogens as cancer growth stimulators and/o,r regulators is clearly stressed by the fact that anti-estrogens have reached a central position in the treatment of estrogen receptor rich ~reast cancers.
Ar.tiestrogens 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 estro~ens. ThiS has been achieved clinically by the unspecific steroid synthesis inhibitor aminoglutethimide. The estro~en synthesis could be blocked specifically by inhibiting the en~yme 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, 19~5, pp. 94-99). Human aromatase enzyme was used. The enzyme was prepared from human placenta, which is rich of ~he 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 1,2[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 37C for 40 min.
Aromatization of 1,2[3H3-androstene-3,17-dione results in the production of 3H20. The tritiated water and the tritiated substrate are easily separated by a Sep-PakR
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 3H20-radioactivity of 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 E~pendorf plastic tubes, and an Eppendorf shaker, centrifuge and incubator ~ere used as a unit. In a 300 ~1 incubation volume, the substrate (5 ~M) was prepared according to Hanukoglu and Jefcoate (J. Chromatogr. 190:256-262, 1980), and 100000 dpm of radioactive 3H-4-cholesterol ~the purity of the compound was checked by TLC) in 0,5 % ~een 20, 10 mM MgC12, 5 ~M 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 ~l 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 37C, the reaction was terminated by the addition of 900 ~l of methanol; 1500 dpm of marker 14C-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 th~ supernatant was sucked into 1 ml plastic inj~ction syringe and loaded onto the pre-equili~rated (7~ % 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 RackBeta).
Typical activi~ies for placental and bovine adrenal enæyme preparation were 0,5-3 and 50-100 pmol pregnenolone formed/mg protein/min, respectively.

In inhibition experiments, the substance (final concen-tration range from 1 to 1000 ~M) was added into incuba-tion mixture in a volume of 10-20 ~1, 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 la. 4-[4-(4-methylphenyl)-4-phenylbutyl]-lH-imidazole 2a. 1-benzyl-5-[4-(4-methylphenyl)-4-phenylbutyl]-lH-imidazole 3a. 1-benzyl-5-~4-(3-methylphenyl)-4-phenylbutyl]-lH-imidazole 4a. 4-~4-(3-methylphenyl)-4-phenylbutyl]-lH-imidazole 5a. 4-[4-(2-methylphenyl)-4-phenylbutyl]-lH-imidazole 6a. 1-benzyl-S-[4-(2-methylphenyl)-4-phenylbutyl]-lH-imidazole 7a. 1-benzyl-5-(4,5-diphenylpentyl)-lH-imidazole ~ i ~ s l ~ s~s ~

8a. 4-(4,5-diphenylpentyl)-lH-imidazole 9a. 4-(4,4-diphenylbutyl)-lH-imidazole lOa. l-benzyl-5-(4,4-diphenylbutyl)-lH-imidazole lla. 4-[4-(4-methoxyphenyl)-4-phenylbutyl]~lH-imidazole 12a. 4-[4,4-bis(4-methoxyphenyl)butyl]-lH-imidazole 13a. 4-[4,4-bis(3-methylphenyl)butyl]-lH-imidazole 14a. 4-[4-(3,5-dimethylphenyl)-4-phenylbutyl]-lH-imidazole 15a. 4-[4-(3,4-dimethylphenyl)-4-phenylbutyl]-lH-imidazole 16a. 4-[4-(3,5-dimethylphenyl)-4-(3-methylphenyl)butyl]-lH-imidazole 17a. 4-[4,4-bis(4-methylphenyl)butyl]-lH-imidazole 18a. 4-~5,5-diphenylpentyl)-lH-imidazole l9a. 4-(6,6-diphenylhexyl)-lH-imidazole 20a. 4-[4-(2-fluorophenyl)-4-phenylbutyl]-lH-imidazole 21a. 4-[4-(4-~luorophenyl)-4-phenylbutyl]-lH-imidazole 22a. 4-(4,4-diphenyl-1-butenyl)-lH-imidazole 23a. 4-[4,4-bis(4-fluorophenyl~butyl]-lH-imidazole 24a. 4-[4,4-bis(4-nitrophenyl)butyl]-lH-imidazole 25a. 4-[4,4-bis~4-aminophenyl)butyl]-lH-imidazole 26a. 4-[4-(4-ethylphenyl) 4-phenylbutyl]-lH-imidazole lb. 4-[1-(4-fluorophenyl)-5-phenylpentyl]-lH-imidazole 2b. 4-[1-(4-fluorophenyl)-5-(2-methylphenyl)pentyl]-lH-imidazole 3b. 4-[1-(4-fluorophenyl)-5-(3-methylphenyl)pentyl]-lH-imidazole 4b. 4-[1-(4-fluorophenyl)-5-(4-methylphenyl)pentyl]-lH-imidazole 5b. 4 [5-(3,5-dimethylphenyl)-1-(4-fluorophenyl)-pentyl]-lH-imidazole 6b. 4-(1,5-diphenylpentyl)-lH-imidazole 7b. 4-(1,3-diphenylpropyl)-lH-imidazole 8b. 1-benzyl-5-(1,3-diphenylpropyl)-lH-imidazole 9b. 4-[1-(4-fluorophenyl)-3-phenylpropyl~-lH-imidazole lOb. 4-[1-(4-fluorophenyl)-4-phenylbutyl]-lH-imidazole llb. 4-[1-(4-fluorophenyl3-5-(3-methoxyphenyl)pentyl]-lH-imidazole 12b. 4-[1-(4-fluorophenyl)-5-(4-methoxyphenyl)pentyl]-lH-imidazole 13b. 4-[1-(4-fluorophenyl)-5-(2,6-dimethylphenyl)-pentyl]-lH-imidazole ~ ,J

14b. 4-[1,3-bis(4-fluorophenyl)propyl]-lH-imidazole 15b. 4-tl,4-bis(4-fluorophenyl)butyl]~lH-imidazole Table 2: Inhibition of human aromatase and desmolase (CSCC) by test compounds. IC-50 represents the concentration which inhibits the enzyme 50 %.

Compound IC-50IC-50 CSCC
No. ~mol/l~mol/l la 2,9 96 2a 19 50 3a 13 38 4a 2,5 7,5 5a 3,4 29 6a 8,5 32 7a 15 8a 4,7 27 9a 2 320 lOa 7 lla 3,5 190 12a 10 46 13a 28 48 14a 7,5 65 15a 5,0 39 16a 125 95 17a 3,5 110 18a 1,7 68 l9a 14,5 61 20a 16 38 21a 2,8 80 22a 8,5 165 23a 3,3 175 24~ 20 37 36 ~ J ~~ J ~ rJ ~J

25a 26 210 26a 8,5 65 lb 2,8 19 2b 3,5 16 3b 3,8 57 4b 8,5 170 5b 7,5 80 6b 25 7b 4,5 7,5 8b 30 9b 0,72 22 lOb 0,75 31 llb 2,6 12 12b 3 22,5 13b 7,7 31 14b 2,2 22 15b 0,63 29 The anti-tumour effect was investigated in vivo against DMBA-induced rat mammary adenocarcinomas by the following method. Mammary adenocarcinoma was induced with DMBA in 50+2 days old female rats. Treatment with the compound under test was started after palpable tumours had appeared. Tumour size and amount of tumours were evaluated once a week. Tumour sizes in the control group, treated with solvent, were compared with the test groups. Daily administration schedule was employed for five weeks and animals were sacrificied. The change in tumour sizes was evaluated.

Results were evaluated as changes in the sizes of tumours and divided into three groups, namely increasing, stable and decreasing sizes of tumours. The anti-tumour effect of 4-(4,4-diphenylbutyl)-lH-imidazole (compound 9a in ~ J ~ ,~ ~3 ,J ~

Table 2) was tested and the results are presented in Table 3.

Table 3: Number of different tumour types in control and 4-(4,4-diphenylbutyl)-lH-imidazole treated groups of DMBA-induced mammary tumour rats.

qroup decreasing stable increasin~

control 3 21 42 4-(4,4-diphenyl- 2 14 37 butyl)-lH-imidazole 3 mg/kg 4-(4,4-diphenyl- 21 3 15 butyl)-lH-imidazole 30 mg/kg Acute toxicity, LD50, was determined by using young adult female mice of NMRI-Strain. The administration of the test compounds was oral. The LD50 values of the test compounds of formula (Ia) were 350 mg/kg or more and of formula (Ib) 400 mg/kg or more.

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

The following examples illustrate the invention.

lH 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.

38 ~ i L~'J'.f'~

Example 1 4-(4,4-diphenylbutyl)-lH-imidazole a) l-benzyl-5-(1-hydroxy-4,4-diphenylbutyl)-lH-imidazole 2,0 g of magnesium turnings are covered with 60 ml of dry tetrahydrofuran. To the mixture is then added dropwise a solution of 1-bromo~3,3-diphenylpropane (22,9 g) in 20 ml of dry tetrahydrofuran at such a rate that a smooth reaction is maintained. After the ~ddition is complete, the reaction mixture is refluxed ~or one additional ho~r and cooled to room temperature. The reaction mixture is then added dropwise to a solution of l-benzyl-5-imidazolecarbaldehyde (7,35 g) in 80 ml of tetrahydrofuran at 60C. After the addition is complete, the reaction mixture is refluxed for 2 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and to the solution is added conc. hydro-chloric acid. The solution is cooled and the precipitate which contains the product as hydrochloride salt is removed by filtration, washed with water and dried.
Yield 14,1 g. M.p. 160-168C.

1H NMR (as HCl-salt, MeOH-d4):
1.50-2.30 (m, 4H), 3.82 (t, lH), 4.65 (t, lH), 5.43 (s, 2H), 7.05-7.50 (m, 16H), 8.62 (d, lH) Using the same method ~or example the following compounds included in the invention were pr~pared:

l-benzyl-5-[1-hydroxy-4-(2-methylphenyl)-4-phenylbutyl]-lH-imidazole ~J .J ~ ~3 ~ ~;, 1H NMR (as HCl-salt, MeOH-d4):
1.50-2.40 (m, 4H), 2.21 and 2.15 (2s, 3H), 4.07 lt, lH), 4.70 (m, lH), 5.49 and 5.46 (2s, 2H), 6.80-7.50 (m, l5H), 8-88 (s, lH) l-benzyl-5-[1-hydroxy-4-(3-methylphenyl)-4-phenylbutyl]-lH-imidazole lH NNR (as HCl-salt, CDC13):
1.35-2.35 (m, 4H), 2.26 (s, 3H), 3.73 (t, lH), 4.62 (m, lH), 5.38 (s, 2H), 6.80-7.40 (m, 15H), 8.51 (s, lH) l-benzyl-5-[1-hydroxy-4-(4-methylphenyl)-4-phenylbutyl]-lH-imidazole lH NMR (as HC1-salt, CDC13~:
1.40-2.40 ~m, 4H), 2.23 and 2.24 (2s, 3H), 3.74 (t, lH), 4.65 (broad t, 2H), 5.38 (s, 2H), 6.80-7.40 (m, 15H), 8.55 (s, lH) l-benzyl-S-[l-hydroxy-4,4-bis(4-methylphenyl)butyl]-lH-imidazole. M.p. of hydrochloride 155-158C.

l-benzyl-5-(1-hydroxy-4,5-diphenylpentyl)-lH-imidazole H NMR (as hydrogen sulphate salt, MeOH-d4):
1.35-1.90 (m, 4H), 2.82 (broad s, 3H), 4.54 (t, lH), 5.42 (s, 2H), 6.85-7.50 (m, 16H), 8.80 (s, lH) l-benzyl-5-[1-hydroxy-4-(4-methoxyphenyl)-4-phenylbutyl]-lH-imidazole lH NMR (as HCl-salt, MeOH-d4):
1.50-2.30 (m, 4H), 3.70 (s, 3H), 3.79 (t, lH), 4.69 (t, lH), 5.46 (s, 2H), 6.79 (d, 2H), 7.0-7.55 (m, 13H), 8.85 (d, lH) 2 ~

l-benzyl-5-[1-hydroxy-4,4-bis(4-methoxyphenyl)butyl]-lH-imidazole lH NMR (as base, MeOH-d4):
1.50-2.20 (m, 4H), 3.66 (t, lH), 3.74 (s, 6H), 4.50 (t, lH), 5.24 (s, 2H), 6.70-7.60 (m, 15H) 1-benzyl-5-[4-(2-fluorophenyl)-1-hydroxy-4-phenylbutyl]-lH-imidazole. M.p. of hydrochloride 160-163C.

1H NMR (as HCl-salt, CDC13):
1.45-2.45 (m, 4H), 4.17 (t, lH), 4.67 (t, lH), 5.43 (s, 2H), 6.80-7.50 (m, 15H), 8.43 (s, lH) 1-benzyl-5-[4-(4-fluorophenyl)-1-hydroxy-4-phenylbutyl]-lH-imidazole. M.p. of hydrochloride 168-171C.

lH NMR (as HCl-salt, MeOH-d4):
1.50-2.30 (m, 4H), 3.84 (t, lH), 4.68 (t, lH), 5.49 (s, 2H), 6.80-7.55 (m, 15H), 8.87 (d, lH) l-benzyl-5-(1-hydroxy-5,5-diphenylpentyl)-lH-imidazole 1H NMR (as base, CDC13):
1.2-2.2 (m, 6H), 3.70 (t, lH), 4.54 (t, lH), 5.46 (s, 2H), 6.8-7.3 (m, 16H), 8.58 (s, lH) 1-benzyl-5-(1-hydroxy-6,6-diphenylhexyl)-lH-imidazole.
M.p. of hydrochloride 147-149C.

H NMR (as HCl-salt, MeOH-d4):
1.6-2.2 (m, 8H), 3.85 (t, lH), 4.60 (t, lH), 5.53 (s, 2H), 7.0-7.4 (m, 15H), 7.47 (s, lH), 8.90 (s, lH) l-benzyl-5-[4-(4-ethylphenyl)-1-hydroxy-4-phenylbutyl~-lH-imidazole lH NMR (as HCl-salt, MeOH-d4):
1.71 (t, 3H), 1.50-2.35 (m, 4H), 2.57 (q, 2H), 3.78 (t, lH), 4.68 (t, lH), 5.46 ts, 2H), 6.9-7.5 (m, 15H), 8.82 (d, lH) l-benzyl-5-[4,4-bis(4-fluorophenyl)-1-hydroxybu~yl]-lH-imidazole lH NMR (as HCl-salt, MeOH-d4):
1.50-2.00 (m, 4H), 3.86 (t, lH), 4.70 (t, lH), 5.52 (s, 2H), 6.80-7.50 ~m, 14 H), 8.89 (d, lH) b) 1-benzyl-5-(4,4-diphenyl-1-butenyl)-lH-imidazole 1-benzyl-5-(1-hydroxy-4,4-diphenylbutyl)-lH-imidazole hydrochloride (5,0 g) and 30,0 g of anhydrous potassium hydrogen sulphate are heated at 150C for 4 hours. The mixture is cooled, 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 in methylene chloride, washed with water and evaporated to dryness. The product is then made to hydrochloride salt with dry hydrochloric acid in dry ethylacetate. Yield is 2,9 g. M.p. 204-206C.

lH NMR (as HCl-salt, MeOH-d4):
2.88-3.05 (m, 2H), 4.08 (t, lH), 5.29 (s, 2H3, 6.22-6.32 (m, 2H), 7.00-7.50 (m, 16H), 8.87 (d, lH) Using the same method for example the following compounds included in the invention were prepared:

1-benzyl-5-[4,4-bis(3-methylphenyl~-1-butenyl]-lH-imidazole. M.p. of hydrochloride 152-156C.

~,2 7~ J J .~

H NMR (as HCl-salt, MeOH-d4):
2.26 (s, 6H), 2.85-3.05 (m, 2H), 3.99 (t, lH), 5.27 (s, 2H), 6.21-6.31 (m, 2H), 6.80-7.50 (m, 14H), 8.86 ~d, lH) 1-benzyl-5-[4-(3,5-dimethylphenyl)-4-(3-methylphenyl)-l-butenyl]-lH-imidazole H NMR (as HCl-salt, MeOH-d4):
2.22 (s, 3H), 2.23 (s, 3H), 2.26 (s, 3H), 2.85-3.05 (m, 2H), 3.94 (t, lH), 5.26 (s, 2H), 6.20-6.30 (m, 2H), 6.75-7.50 (m, 13H), 8.84 (d, lH) 1-benzyl-5-[4-(3,5-dimethylphenyl)-4-phenyl-1-butenyl]-lH-imidazole. M.p. 110-112C.

H NMR (as HCl-salt, MeOH-d4):
2.22 (s, 6~), 2.85-3.05 (m, 2H), 3.98 (t, lH), 5.27 (s, 2H), 6.20-6.30 (m, 2H), 6.75-7.5 (m, 14H), 8.87 (d, lH) 1-benzyl-5-[4-(2-methylpheny~)-4-phenyl-1-butenyl]-lH-imidazole 1H NMR (as hydrogen sulphate, MeOH-d4):
2.19 (s, 3H), 2.80-3.05 (m, 2H), 4.28 (~, lH), 5.29 (s, 2H), 6.0-6.60 (m, 2H), 7.0-7.5 (m, 14H), 7.52 (d, lH), 8.85 (d, lH) l-benzyl-5-[4-(3-methylphenyl)-4-phenyl-1-butenyl]-lH-imidazole 1H NMR (as base, C~Cl3):
2.27 (s, 3H), 2.75-3.95 (m, 2H~, 3.93 (t, lH), 4.89 (s, 2H), 5.70-6.10 (m, 2H), 6.80-7.40 (m, 16H) 1-benzyl-5-[4-(4-methylphenyl)-4-phanyl-1-butenyl]-lH-imidazole 43 ~ ~ r~

lH NMR (as base, CDC13):
2.27 (s, 3H), 2.70~2.95 (m, 2H), 3.93 (t, lH), 4.89 (s, 2H), 5.60-6.20 (m, 2H), 6.80-7.50 (m, 16H) l-benzyl-5-[4,4-bis(4-methylphenyl)-1-butenyl]-lH-imidazole. M.p. of hydrochloride 128-132C.

l-benzyl-5-[4-(4-methoxyphenyl)-4-phenyl-1-butenyl]-lH-imidazole lH NMR (as HCl-salt, CDC13):
2.70-2.95 ~m, 2H), 3.95 (t, lH~, 5.16 (s, 2H), 5.70-6.20 (m, 2H), 6.70-7.40 (m, 15H), 8.99 (s, lH) l-benzyl-5-[4,4-bis(4-methoxyphenyl)-1-butenyl]-lH-imidazole lH NMR (as base, CDC13):
2.60-2.90 (m, 2H), 3.74 (s, 6H), 3.78 (t, lH), 4.92 (s, 2H), 5.80-6.00 (m, 2H), 6.65-7.50 (m, 15H) l-benzyl-5-(4,5-diphenyl-1-pentenyl)-lH-imidazole H NMR (as base, CDC13):
2.30-2.55 (m, 2H), 2.88 (m, 3H), 4.93 (s, 2H), 5.5-6.1 (m, 2H), 6.8-7.5 tm, 17H) l-benzyl-5-[4-(2-fluorophenyl)-4-phenyl-1-butenyl]-lH-imidazole. M.p. of hydrochloride 195-201C.

lH NMR tas base, CDC13):
2.75-3.00 (m, 2H), 4.34 (t, lH), 5.97 (s, 2H), 5.80-6.10 (m, 2H), 6O75-7.50 (m, 16H) l-benzyl-5-[4-(4-fluorophenyl)-4-phenyl-1-butenyl]-lH-imidazole ~-v ~'~ J~J

lH NMR (as base, CDCl3):
2.60-2.95 (m, 2H), 3.96 (t, lH), 4.93 (s, 2H), 5.80-6.05 (m, 2H), 6.75-7.50 tm, 16H) 1-benzyl-5-(6,6-diphenyl-1-hexenyl)-lH-imidazole. M.p.
of hydrochloride 184-186C.

1-benzyl-5-[4-(4-ethylphenyl)-4-phenyl-1-butenyl]-lH-imidazole 1H NMR (as HCl-salt, MeOH-d4):
1.17 (t, 3H), 2.56 (q, 2H), 2.93-2.98 (m, 2H), 4.03 (t, lH), 5.28 (s, 2H), 6.20-6.34 (m, 2H), 7.08-7.41 (m, 14H), 7-52 (d, lH), 8.87 (d, lH) 1-benzyl-5-[~,4-bis(4-fluorophenyl)-1-butenyl]-lH-imidazole HNMR (as HCl-salt, CDC13):
2.78-2.94 (m, 2H), 4.01 (t, lH), 5.27 (s, 2H), 5.82-6.34 (m, 2H), 6.83-7.40 (m, 14H), 9.21 (d, lH) c) 1-benzyl-5-(4,4-diphenylbutyl)-lH-imidazole 1-benzyl-5-(4,4-diphenyl-l-butenyl)-lH-imidazole hydrochloride (2,0 g) is dissolved in ethanol and a catalytic amount of Pd/C (10 ~) is added. The reaction mixture is a~itated 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-methanol mixture. Yield 1,3 g. M.p. of the hydrochloride salt is 200-202C.

4 5 ~ ~ ~ c r~

1H NMR (as HCl-salt, MeOH-d4):
1.30-1.70 (m, 2H), 1.85-2.20 (m, 2H), 2.61 (t, 2H), 3.83 (t, lH), 5.35 (s, 2H), 7.05-7.50 (m, 16H), 8.89 (d, lH) Using the same method for example the following compounds included in the invention were prepared:
.

1-benzyl-5-[4-(2-methylphenyl)-4-phenylbutyl]-lH-imidazole. Mp. of hydrochloride 200-205C.

1H NMR (as HCl-salt, CDCl3):
1.30-1.80 (m, 2H), 1.80-2.15 (m, 2H), 2.22 (s, 3H), 2.48 (t, 2H), 4.02 (t, lH), 5.31 (s, 2H), 6.96 (s, lH), 7.0~7.5 (m, 14H), 9.28 (s, lH) 1-benzyl-5-[4-(3-methylphenyl)-4-phenylbutyl]-lH-imidazole. M.p. of hydrochloride 148-158C.

H NMR (as HCl-salt, CDCl3):
1.30-1.80 (m, 2H), l.B0-2.25 (m, 2H), 2.30 (s, 3H), 2.49 (t, 2H), 3.78 (t, lH), 5.29 (s, 2~), 6.90-7.50 (m, 15H), 9.24 (s, lH) l-benzyl-5-[4-(4-methylphenyl)-4-phenylbutyl]-lH-imidazole. M.p. of hydrochloride 164-170C.

H NMR (as HCl~salt, CDCl3):
1.25-1.75 (m, 2H), 1.80-2.25 (m, 2H), 2.29 (s, 3H;, 2.48 (t, 2H), 3.78 (t, lH), 5.31 (s, 2H), 6.80-7.50 ~m, 15H~, 9.35 (s, lH) 1-benzyl-5-(4,5-diphenylpentyl)-lH-imidazole. M.p. of hydrochloride 166-170C.

lH NMR ~as HCl-salt, MeOH-d4):
1.15-1.90 (m, 4H), 2.~9 (t, 2H), 2.81 (m, 3H), 5.30 (s, 2H), 6.90-7.50 (m, 16H), 8.82 (s, lH) l-benzyl-5-[4-(4-methoxyphenyl)-4-phenylbutyl]-lH-imidazole. M.p. of hydrochloride 180-187C.

lH NMR (as HCl-salt, MeOH-d4):
1.25-1.70 (m, 2H), 1.85-2.20 (m, 2H), 2.62 (t, 2H), 3.74 (s, 3H), 3.78 (t, lH), 5.34 (s, 2H), 6.81 (d, 2H), 7.0-7.5 (m, 13H), 8.84 (d, lH) 1-benzyl-5-[4-(2-fluorophenyl)-4-phenylbutyl]-lH-imidazole. M.p. of hydrochloride 185-196C.

lH NMR (as HCl-salt, MeOH-d4):
1.25-1.75 (m, 2H), 1.80-2.25 (m, 2H), 2.65 (t, 2H), 4.18 (t, lH), 5.37 (s, 2H), 6.80-7.5 (m, l5H), 8.89 (d, lH) l-benzyl-5-[4-(4-fluorophenyl)-4-phenylbutyl]-lH-imidazole. M.p. of hydrochloride 172-174C.

H NMR (as HCl-salt, MeOH-d4):
1.25-1.70 (m, 2H), 1.80-2.25 (m, 2H), 2.64 (t, 2H), 3.85 (t, lH), 5.37 (s, 2H), 6.80-7.50 (m, 15H), 8.90 (d, lH3 l-benzyl-5-(5,5-diphenylpentyl)-lH-imidazole lH NMR (as base, MeOH-d~):
1.1-1.6 (m, 4H), 1.8-2.1 (m, 2H), 2.37 (t, 2H~, 3.72 (t, lH), 5.11 (s, 2H), 6.67 (s, lH), 6.9-7.3 (m, 15H), 7.59 (s, lH) ~ ~3 ~ .~

l-benzyl-5-[4-(4-ethylphenyl)-4-phenylbutyl]-lH-imidazole H NMR (as HCl-salt, MeOH-d4):
1.17 (t, 3H), 1.40-1.70 (m, 2H), 1.90-2.20 (m, 2H), 2.57 (q, 2H), 3.80 (t, lH), 5.34 (s, 2H), 7.00-7.50 (m, 15 H), 8-87 (d, lH) 1-benzyl-5-[4,4-bis(4-fluorophenyl)butyl]-lH-imidazole 1H NMR (as HCl-salt, MeOH-d4):
1.30-1.70 (m, 2H), 1.80-2.25 (m, 2H), 2.64 (t, 2H), 3.87 (t, lH), 5.40 (s, 2H), 6.80-7.50 (m, 14 H), 8.92 (d, lH~

d) 4-(4,4-diphenylbutyl)-lH-imidazole l-benzyl-5-(4,4-diphenylbutyl)~lH-imidazole hydrochloride (0,6 g) is hydrogenated in the mixture of 20 ml of 2 N
hydrochloric acid and 10 ml of ethanol at 80C 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 i5 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 made to its hydrochloride in ethyl acetate using dry hydrochloric acid. Yield 0,2 g. M.p. 204-206C.

1H NMR !as HCl-salt, MeOH-d4):
1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.75 ~t, 2H), 3.95 (t, lH), 7.00-7.40 tm, llH), 8.72 (d, lH) Using the same method for example the following compounds included in the invention were prepared:

4-[4,4-bis(3-methylphenyl)butyl]-lH-imidazole. M.p. ~f hydrochloride 122-129C.

H NMR (as HCl-salt, MeOH-d4):
1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.26 (s, 6H), 2.73 (t, 2H), 3.85 (t, lH), 6.80-7.25 (m, 9H), 8.73 (d, lH) 4-~4-(3,5-dimethylphenyl)-4-(3-methylphenyl)butyl]-lH-imidazole. M.p. of hydrochloride 75-82C.

lH NMR (as HCl-salt, MeOH-d4):
1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.22 (s, 3H), 2.23 (s, 3H), 2.27 (s, 3H), 2.74 (t, 2H), 3.81 (t, lH), 6.75-7.30 (m, 8H), 8.72 (d, lH) 4-[4-(3,5-dimethylphenyl)-4-phenylbutyl]-lH-imidazole.
M.p. of hydrochloride 104-106C.

lH NMR (HCl-salt, MeOH-d4):
1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.23 (s, 6H), 2.74 (t, 2H), 3.85 (t, lH), 6.84 (m, 3H), 7.22 (m, 6H), 8.72 (d, lH) 4-[4-(3,4-dimethylphenyl)-4-phenylbutyl]-lH-imidazole.
M.p. of hydrochloride 118-121 C.

4-[4-(2-methylphenyl)-4-phenylbutyl]-lH-imidazole. M.p.
of hydrochloride 151-154,5C.

lH ~R (as HC1-salt, CDC13):
1.50-2.20 (m, 4H), 2.22 (s, 3H), 2.71 (t, 2H), 4.09 (t, lH), 6.81 (s, lH), 7.0-7.4 (m, 9H), 9.04 (s, lH) 5-[4-(3-methylphenyl)-4-phenylbutyl]-lH-imidazole. M.p.
of hydrochloride 140-153C.

lH NM~ (as HCl-salt~ MeOH-d4):
1.40-1.85 (m, 2H), 1.85-2.25 (m, 2H), 2.27 (s, 3H), 2.74 (t, 2H), 3.90 (t, lH), 6.80-7.30 (m, lOH), 8.69 (d, lH) 4-[4-(4 methylphenyl)-4-phenylbutyl]-lH-imidazole. M.p.
of hydrochloride 173-177C.

lH NMR ~as HCl-salt, CDC13 + 2 drops of MeOH-d4):
1.40-1.80 (m, 2H), 1.80-2.25 (m, 2H), 2.28 (s, 3H), 2.71 (t, 2H), 3.87 (t, lH), 5.86 (d, lH), 7.09 (s, 4H), 7.21 (s, 5H), 8.71 (d, lH) 4-[4-(4-methoxyphenyl)-4-phenylbutyl]-lH-imidazole.
M.p. of hydrochloride 156-159C.

lH NMR (as HCl-salt, CDC13):
1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.71 (t, 2H), 3.76 (s, 3H), 3.87 (t, lH), 6.82 (d, 2H), 6.90 (s, lH), 7.13 (d, 2H), 7.21 (m, 5H), 8.68 (s, lH) 4-[4,4-bis(4-methoxyphenyl)butyl]-lH-imidazole. M.p. of hydrochloride 138-142C.

H NMR (as HCl-salt, CDC13):
1.40-2.25 (m, 4H), 2.71 (t, 2H), 3.75 (s, 6H) under which there is (t, lH), 6.78 (d, 4H), 6.83 (s, lH), 7.08 (d, 4H), 9.02 (s, lH) 4-(4,5-diphenylpentyl)-lH-imidazole lH NMR ( as HCl-salt, CDC13):
1.20-1.90 (m, 4H), 2.57 (t, 2H), 2.83 (m, 3H), 6.71 (s, lH), 6.80-7.40 (m, lOH), 8.84 (s, lH) 4-(5,5-diphenylpentyl)-lH-imidazole 1H NMR (as HCl-salt, MeOH-d4):
1.3-1.5 (m, 2H), 1.5-1.7 tm, 2H), 1.8-2.3 (m, 2H), 2.656 (t, 2H), 3.746 (t, lH), 7.06-7.2 (m, llH), 8.716 (d, lH) 4-(6,6-diphenylhexyl)-lH-imidazole lH NMR (as base, CDCl3):
1.1-1.7 (m, 6H), 1.8-2.2 (m, 2H), 2.530 (t, 2H), 3.847 (t, lH), 6.685 (s, lH), 7.2 (s, lOH), 7.470 (s, lH), 9.6 (broad s, lH) 4-[4,4-bis(4-methylphenyl)butyl]-lH-imidazole. M.p. of hydrochloride 176-179C.

4-[4-(4-fluorophenyl)-4-phenylbutyl]-lH-imidazole. M.p.
of hydrochloride 175-182C.

4-[4-(2-fluorophenyl)-4-phenylbutyl]-lH-imidazole. M.p.
of hydrochlo~ide 182-190C.

4-[4-(4-ethylphenyl)-4-phenylbutyl]-lH-imidazole 1H NMR (as HCl-salt, MeOH-d4):
1.18 (t, 3H), 1.40-1.90 (m, ~H), 1.90-2.30 (m, 2H), 2.57 (q, 2H~, 2.75 (t, 2H), 3.91 (t, lH), 6.95-7.30 (m, lOH), 8.73 (d, lH) 4-[4,4-bis(4-fluorophenyl)butyl]-lH-imidazole lH NMR (as HCl-salt, MeOH-d4):
1.40-1.85 (m, 2H), 1.90-2.30 (m, 2H), 2.77 (t, 2H), 3.98 (t, lH), 6.80-7.40 (m, 9H), 8.72 (d, lH) 5~ ;J~

Example 2 4-[4-(4-fluorophenyl)-4-phenylbutyl]-lH-imidazole A concentrated water solution of ammon~umformate (0,98 g, 15,6 mmol) is added dropwise to the boiling mixture of l-benzyl-5-[4-(4-fluorophenyl)-4-phenylbutyl]-lH-imidazole (1,5 g, 3,9 mmol) and 10 % Pd/C (0,156 g) in 16 ml of 50 % ethanol. The mixture is refluxed for 2 hours. The catalyst is filtrated off and the solvent is evaporated. 2 M NaOH is added and the product is ext~acted into ethyl acetate. The ethyl acetate phase is dried and evaporated to dryness to give the produc~.
Yield 1,02 g. Nelting point of the hydrochloride salt (from ethyl acetate) is 175-182C.

lH NMR (as HCl-salt, MeOH-d4):
1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.75 (t, 2H), 3.96 (t, lH), 6.85-7.36 (m, 10H), 8.74 (d, lH) According to the same procedure as the example the following substituted dexivative was prepared:

4-[4-(2-fluorophenyl)-4-phenylbutyl]-lH-imidazole. M.p.
of hydrochloride 182-190C.

H NMR (as HCl-salt, MeOH-d4):
1.45-1.95 (m, 2H), 1.95-2.30 (m, 2H), 2.77 (t, 2H), 4.29 (t, lH), 6.85-7.45 ~m, 10H), 8.74 (d, lH) Example 3 4-(4,4-diphenylbutyl3-lH-imidaz~le a) 1-benzyl-5-(4-hydroxy-4,4-diphenylbutyl)-lH-imidazole 2 ~

~agnesium turnings (0,49 g) are covered with 4 ml of dry tetrahydrofuran. Brombenzene (3,18 g) i~ 7 ml o~
dry tetrahydrofuran is added dropwise to the mixture at such a rate that a smooth reaction is maintained. The reaction mixture is refluxed for an additional hour.
Ethyl 4-(1-benzyl-lH-imidazol-5-yl)butyrate (1,10 g) in 15 ml of dry tetrahydrofuran is then added dropwise to the Grignard reagent and the reaction mixture is refluxed for 2 hours. Saturated ammonium chloride is added to the cooled reaction mixture. Tetrahydrofuran is evaporated and the precipitated product is collected.
Yield 1,41 g. Melting point of the hydrochloride salt is 197-201C.

lH MMR (as HCl-salt, MeOH-d4):
1.35-1.80 (m, 2H), 2.20-2.45 (m, 2H), 2.61 (t, 2H), 5.33 (s, 2H), 7.0-7.5 (m, 16~), 8.81 (d, lH) b) l-benzyl-5-(4,4-diphenyl-3-butenyl)-lH-imidazole 1-benzyl-5-(4-hydroxy-4,4-diphenylbutyl)-lH-imidazole (1,3 g) is refluxed in 20 ml of ethanol containing 5 %
(W/w) hydrogen chloride for 1 hour. The solvent is evaporated and the HCl-salt of the product is precipitated with ethyl acetate. Yield 1,1 g, m.p. 161-168C.

lH NMR (as HCl-salt, MeOH-d4):
2.22-2.60 (m, 2H), 2.60-2.90 (m, 2H), 5.29 (s, 2H), 6.06 (t, lH), 6.90-7.60 (m, 16H~, 8.88 (d, lH) c) 1-benzyl-5-(4,4-diphenylbutyl)-lH-imidazole 1-benzyl-5-(4,4-diphenyl-3-butenyl)-lH-imidazole hydrochloride salt is hydrogenated in ethanol as ~ J~

described in Example 1 c). M.p. of the product as hydrochloride is 200-202C.

d) 4-(4,4-diphenylbutyl)-lH-imidazole The benzyl group of l-benzyl-5-(4,4-diphenylbutyl)-lH-imidazole is hydrogenated as is described in Example 1 d).

Example 4 4-[4,4-bis(4-nitrophenyl)butyl]-lH-imidazole 1,8 g (14,6 mmol) of urea nitrate is added in small portions to a mixture of 2,0 g (7,3 mmol) of 4-(4,4-diphenylbutyl)-lH-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 alkalin~ with 2 M sodium hydroxide and the product is extracted into ethyl acetate. The product is purified by flash chromatography using methylene chloride-methanol (95:5) as eluent.

H NMR (as HCl-salt, MeOH-d4):
1.4-1.95 (m, 2H), 2.0-2.45 (m, 2H), 2.81 (t, 2H), 4.34 (t, lH~, 7.27 (broad s, 1~), 7.5 (d, 4H), B.17 (d, 4H), 8.73 (d, lH) Example 5 4-t4,4-bis(4-aminophenyl)butyl]-lH-imidazole 4-[4,4-bis(4-nitrophenyl)butyl]-lH-imidazole is hydrogenated in ethanol using 10 ~ palladium on carbon (Pd/C) as a catalyst.

1H NMR (as HCl-salt, MeOH-d4):
1.4-2.25 (m, 4H), 2.69 (t, 2H), 3.70 (t, lH), 6.77 ~d, 4H), 6-95 (d, 4H)t 7.08 (broad s, lH), 8.57 (d, lH) Example 6 4-(4,4-diphenyl-1-butenyl)-lH-imidazole a) 4-(1-hydroxy-4,4-diphenylbutyl)-lH-imidazole A concentrated water solution of ammonium formate (4,0 g) is added dropwise to the boiling mixture of l-benzyl-5-(1-hydroxy-4,4-diphenylbutyl)-lH-imidazole (4,5 g) and 10 % Pd/C (0,5 g) in 50 ml of 50 % ~thanol. The mixture is refluxed for 2 hours. The catalyst is filtrated and the solvent is evaporated. 2 M NaOH is added and the product is extracted into ethyl acetate.
The ethyl acetate phase is dried and evaporated to dryness to give the product which is used in the following step b).
b) 4-(4,4-diphenyl-1-butenyl)-lH-imidazole 4-(1-hydroxy-4,4 diphenylbutyl)-lH-imidazole (3,0 g) and 20 g of anhydrous potassium hydrogen sulfate are heated at 150 C for 4 hours. The mixture is cooled and 90 ml ethanol is added to dissolve the product. 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 ~o hydrochloride salt with dry hydrogen chloride in ethyl acetate. M.p. above 240 C.

lH NMR (as HCl-salt, CDC13):
2.904-3.068 (m, 2H), 4.116 (t, lH), 6.05-6.35 (mr 2H), 6.g98 (d, lH), 7.22-7.25 (m, 10H3, 8.719 (d, lH) ~ ~J ~

Exam~le 7 4-[1-(4~fluorophenyl)-5-phenylpentyl]-lH-imidazole a) 1-benzyl-5-(1-hydroxy-5-phenylpentyl)-lH-imidazole 2,1 g of magnesium turnings are covered with 60 ml of dry tetrahydrofuran. A solution of 4-phenylbutylbromide (18,8 g) in 20 ml of dry tetrah~drofuran is then added dropwise to the mixture at such a rate that a smooth reaction is maintained. After the addition is complete, ~he 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 ~0 ml of tetrahydrofuran at 60C. After the addition is complete, the reaction mixture is refluxed for 2 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and conc.
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~ hydroxy-5-phenylpentyl)-lH-imidazole 1-benzyl-~ hydroxy-5-phenylpentyl)-lH-imidazole hydrochloride (8,5 g), prepared in the Step a, i5 hydrogenated in the mixture of 100 ml of 2 N hydrochloric acid and 10 ml of ethanol at 60C 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 i8 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.

lH NMR (as base, MeOH-d4 + a drop of CDCl3):
1.2-2.0 ~m, 6H), 2.61 (distorted t, 2~), 4.65 (t, lH), 6.91 (dd, lH), 7.0-7.3 (m, 5H), 7.56 (d, lH) c) 4-(1-oxo-5-phenylpentyl)-lH-imidazole 5,5 g of 4-~1-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 com~ined extracts are washed with water and evaporated to dr~ness.

d) 4-[1-(4-fluorophenyl)-l-hydroxy-5-phenylpentyl]-lH-imidazole 0,52 g of magnesiurn turnings are covered with 60 ml of dry tetrahydrofuran. Then a solution of l-~romo-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. ~fter 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-(1-oxo-5-phenylpentyl)-lH-imidazole t3,8 g) in 40 ml of tetrahydrofuran at ~0C. After the addition is complete, the reaction mixture is refluxed for 3 hours, cooled and poured into cold water. Tetrahydrofuran is evaporat~d and conc. hydrochloric acid is added to the sol~tion. The product is extracted as hydrochloric salt into methylene chloride. Combined methylene chloride extracts are then evaporated to dryness.

~ J3 e) 4-[1-(4-fluorophenyl)-5-phenyl-1-pentenyl]-lH-imidazole 4-[1-(4-fluorophenyl)-l-hydroxy-5-phenylpentyl]-lH-imidazole hydrochloride (5,0 g) and 30,0 g of anhydrous potassium hydrogen sulphate are heated at 150C 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 ethylaceta~e.

lH NMR (as base, CDCl3):
1.5-2.7 (m, 6H), 4.8 (broad s, lH), 6.34 (t, lH), 6.48 (broad s, lH), 6.9-7.4 (m, 9H), 7.52 (broad s, lH) Using the same method for example the following compounds included in the invention were prepared:

4-[1-(4-fluorophenyl)-5-(3-methylphenyl)-l-pentenyl]-lH-imidazole 4-[l-(4-fluorophenyl)-5-(4-methylphenyl)-1-pentenyl]-lH-imidazole 4-[1-(4-fluorophenyl)-5-(2-methylphenyl)-1-pentenyl]-lH-imidazole 4-[5-(3,5-dimethylphenyl)-1-(4-~luorophenyl)-l-pentenyl]-lH-imidazole 4-[1-(4-fluorophenyl)-5-(3-methoxyphenyl)-l-pentenyl]-lH-imidazole ?, ~

4-[5-(3/5-dimetho~ypheny~ (4-fluorophen pentenyl]-lH-imidazole f) 4-[1-(4-fluorophenyl)-5-phenylpentyl]-lH-imidazole 4-[1-(4-fluorophenyl)-5~phenyl-1-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-methanol mixture. Yield 82 ~.

1H NMR (as base, CDCl3):
1.1-2.7 (m, 8H), 3.84 (t, lH), 6.71 (broad s, lH), 6.80-7.38 (m, 9H), 7.47 (broad s, lH), 9.22 (broad s, lH) Using the same method for example the following compounds included in the invention were prepared:

4-[1-(4-~luorophenyl)-5-(3-methylphenyl)pentyl]-lH-imidazole MS: 322 (20, M+-), 189 (28), 176 (38), 175 (72), 149 (100), 125 (20), 121 (14), 109 (42), 105 (16), 97 (21) 1H NMR (as HCl-salt, MeOH-d~):
1.1-2.7 (m, 8H), 2.27 (s, 3H), 4.06 (t, lH), 6.7-7.5 (m, 8H), 7.37 (d, lH), 8.77 (d, lH) 4-tl-(4-fluorophen~1)-5-(4-methylphenyl)pentyl]-lH-imidazole 59 ~ J~

H NMR (as H~l-salt, MeOH-d4):
1.1-2.7 (m, 8H), 2.26 (s, 3H), 4.05 (t, lH), 6 8-7.6 (m, 9H), 8-78 (d, lH) 4-[1-(4-fluorophenyl)-5-(2-methylphenyl)pentyl]-lH-imidazole MS: 322 (53, M~-), 189 (30), 176 (55), 175 (100), 148 (18), 121 (12), 105 (42), 101 (11), 79 (12), 77 (13) lH NMR (as HCl-salt, MeOH-d4):
1.1-2.7 (m, 8H), 2.24 (s, 3H), 4.11 (t, lH), 6.9-7.5 (m, 9H), 8.79 (d, lH) 4-t5-(3,5-dimethylphenyl)-1-(4-fluorophenyl~pentyl]-lH-imidazole MS: 336 (47, M+-), 189 (90), 176 (67), 175 (100), 166 (13), 148 (16), 121 (12), 119 (16), 91 (14) H NMR (~s HCl-salt, MeOH-d4):
1.1-2.6 (m, 8H), 2.22 (s, 6H), 4~09 (t, lH), 6.6-7.4 (m, 7H), 7.40 (broad s, lH), 8.80 (broad s, lH) 4-[1-(4-fluorophenyl)-5-(3-methoxyphenyl)pentyl~-lH-imidazole 4-[5-(3,5-dimethoxyphenyl)-1-(4-fluorophenyl)pentyl]-lH-imidazole Example 8 4-(1,3-diphenylpropyl)-lH-imidazole a) l-benzyl-5-(1-oxo-3-phenylpropyl)-lH-imidazole 7i ~ ~J

l-benzyl-5-(l-hydroxy-3-phenylpropyl)-lH-imidazole is oxidized with manganese dioxide in tetrachloroethylene, as it is described in Example 7 c).

lH NMR (as base, CDCl3):
3.03 (m, 4H), 5.53 (s, 2H), 7.07-7.4 (m, lOH), 7.60 (s, lH), 7.77 (s, lH) Using the same method for example the following compounds included in the invention were prepared:

l-benzyl-5-[5-(2,6-dimethylphenyl)-1-oxopentyl]-lH-imidazole. M.p. of hydrochloride 175-180C.

1-benzyl-5-(l-oxo-5-phenylpentyl)-lH-imidazole. M.p. of hydrochloride 185-189C.
b) l-benzyl-5-(1-hydroxy-1,3-diphenylpropyl)-lH-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 1-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:

1-benzyl-5-(1-hydroxy-1,5-diphenylpentyl)-lH-imidazole.
M p. of hydrochloride 193-196~C.

?3 7) ,3 l-benzyl-5-[5-(2,6-dimethylphenyl)-1-hydroxy-1-phenylpentyl]-lH-imidazole. M.p. of hydrochloride 190-192C.
c) l-benzyl-5-tl,3-diphenylpropyl)-lH-imidazole 1-benzyl-5-(1-hydroxy-1,3-diphenylpropyl)-lH-imidazole is treated with anhydrous potassium hydrogen sulphate at 150C as described in Example 7 e). The double bond of the obtained intermPdiate, l-benzyl-5-(1,3-diphenyl-1-propenyl)-lH-imidazole, is hydrogenated as described in Example 7 f). M.p. of the hydrochloride salt is 154-174C (from diethylether).

1H NMR (as HCl-salt, MeOH-d4):
2.2-2.7 (m, 4H), 3.90 (t, lH), 5.12 (AB q, the middle of the quartet, 2H), 6.90-7.37 (m, 15H), 7.70 (broad s, lH), 8.88 (d, lH) Using the same method for example the following compounds were prepared:
l-benzyl-5-(1,5-diphenylpentyl)-lH-imidazole lH NMR (as base, CDCl3~:
1.18-2.61 (m, 8H), 3.56 (t, lH), 4.59 and 4.81 (AB q, 2H), 6.76-7.40 (m, 17H) 1-benzyl-5-[5-(2,6-dimethylphenyl) l-phenylpentyl]-lH-imidazole d) 4-(1,3 diphenylpropyl)-lH-imidazole 1-benzyl-5-(1,3-diphenylpropyl)-lH-imidazole is hydrogenated in the mixture o~ 2N hydrochloric acid and ethanol at 60C 10 % Pd/C as catalyst. The product is ~2 isolated as in Example 7 b) and is purified by flash chromatography methylene chloride-methanol (9,5:0,5) as eluent. Yield 73 %.

1H NMR (as base, CDC13):
2.1-2.7 (m, 4H), 3.88 (t, lH), 6.71 (broad s, lH), 7.01-7.26 (m, 10H), 7.30 (d, lH), 10.5 (broad s, lH) Using the same method for example the following compound was prepared:

4-~1,5-diphenylpentyl)-lH-imidazole lH NMR (as HCl-salt, MeOH-d4):
1.2-2.3 (m, 6H), 2.57 (distorted t, 2H), 4.05 (t, lH), 7.05-7.40 (m, llH), 8.73 (d, lH) Example 9 l-benzyl-4-(1,3-diphenylpropyl)-lH-imidazole 2,0 g of benzylbromide in 5 ml of toluene is added dropwise to the mixture of 4-(1,3-diphenylpropyl)-lH-imidazole (2,6 g), 48 % NaOH (10 ml), toluene (20 ml) and tetrabutylammoniumbromide (O,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-(1,3-diphenylpropyl)-lH-imidazole and 1-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 10 4-[1,4-bist4-fluorophenyl)butyl]-lH-imidazole a) l-benzyl-5-[1-(4-fluorophenyl)-l-hydroxymethyl]-lH-imidazole Grignard reaction of 4-bromofluorobenzene and l-benzyl-5-imidazolecarbaldehyde is performed analogously to Example 7 a). The product is crystallized as hydrochloride salt from ethylacetate. Yield 94 %.

lH NMR (as base, CDC13 + MeOH-d4):
5.05 and 5.21 (AB q, 2H), 5.64 (s, lH), 6.61 (5, lH), 6.97-7.1 (m, 4H), 7.26-7.33 (m, 5H), 7.41 (s, lH) MS: 282 (22, M+-), 265 (5), 191 (18), 91 (100) b) l-benzyl-5-[1-(4-fluorophenyl)-1-oxomethyl]-lH-imidazole Oxidation of l-benzyl-5-[1-(4-fluorophenyl)-1-hydroxymethyl]-lH-imidazole is performed analogously to Example 7 c). The crude product is recrystallized as a base from methanol. Yield 72 %.

lH NMR (as base, CDCl3):
5.62 (s, 2H), 7.1-7.4 (m, 7H), 7.5-8.0 (m, 4H) MS: 280 (46, M+-), 123 (13), 107 (4), 95 (19), 91 (100) c) 1-benzyl-5-[1,4-bis(4-fluorophenyl)-1-hydroxybutyl]-lH-imidazole l-benzyl-5- L 1, 4-bis(4-fluorophenyl)-1-hydroxybutyl]-lH-imidazole is prepared analogously to Example 7 a) ~ S~3 1 ,~

starting from 3-(4-fluorophenyl)-1-bromopropane and 1-benzyl-5-[1-(4-fluorophenyl)-1-oxomethyl]-lH-imidazole.
The product is p~rified by flash chromatography.

lH NMR (as base, CDCl3):
1.2-1.4 (m, lH), 1.65-1.85 (m, lH), 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]-lH-imidazole MS: 386 (M+-, 8), 368 (22), 281 (lO0), 159 (26), 91 (99), 65 (34) l-benzyl-5-[1,3-bis(4-fluorophenyl)-1-hydroxypropyl]-lH-imidazole MS: 404 (M+ , 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 (M+ , 2), 382 (2), 281 (38), l91 (3), 91 (100), 65 (9) l-benzyl-5-[1-(4-fluorophenyl)-1-hydroxy-5-(3-methoxyphenyl)pentyl]-lH-imidazole lH 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, lH), 8.6 (s, lH) ~ 3 l-benzyl-5-[5-(2,6-dimethylphenyl)-1-(4-fluorophenyl~-l-hydroxypentyl]-lH-imidazole MS: 442 (M+ , 19), 281 (71), 256 (5), 191 (7), 119 (21), 91 (100) d) 4-[1,4-bis(4-fluorophenyl)butyl]-lH-imidazole 1-benzyl-5-[1,4-bis(4-fluorophenyl)-1-hydroxybutyl]-lH-imidazole (10 g) is dissolved in conc. 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 raduced pressure. The product is then made to hydrochloride salt with dry hydrogen chloride in diethylether. M.p. ~35-137 C.

lH NMR (as base, CDCl3):
1.4-1.65 (m, 2H), 1.8-1.95 (m, lH), 2.05-2.2 (m, lH), 2.5-2.65 (m, 2H)~ 3.87 (t, lH), 6.7 (s, lH~, 6.8-7.2 (m, 8H), 7.5 (s, lH) Using the same method for example the following compounds included in the invention were prepared:

4-tl-(4-fluorophenyl)-3-phenylpropyl]-lH-imidazole 1H NMR (as base, CDCl3):
2.0-2.7 (m, 4H), 3.7-4.0 (m, lH), 6.7 (s, lH), 6.75-7.45 (m, 9H), 7.57 (s, lH) 66 2 Jf~v ~J

MS: 280 (4, M~-), 189 (9), 176 (100), 148 (15), 121 (9), 91 (12) 4-[1,3-bis(4-fluorophenyl)propyl]-lH-imidazole lH NMR (as base, CDC13):
2.1-2.25 (m, lH), 2.3-2.6 (m, 3H), 3.88 (t, lH), 6.76 (s, lH), 6.9-7.2 (m, 8H~, 7.63 (s, lH) MS: 298 (5, M+-), 189 (8), 176 (100), 122 (22), 109 (42) 4-[1-(4-fluorophenyl)-4-phenylbutyl3-lH-imidazole lH NMR (as base, CDC13):
1.3-2.3 (m, 4H), 2.6 (t, 2H), 3.88 (t, lH), 6.67 (s, lH), 6.7-7.3 (m, 9H), 7.39 (s, lH) MS: 294 (31, M+ ), 189 (24), 175 (100), 91 (31) 4-[1-(4-fluorophenyl)-5-(3-methoxyphenyl)pentyl]-lH-imidazole H NMR (as base, CDC13):
1.1-2.3 (m, 6H), 2.5 (t, 2H), 3.76 (s, 3H), 3.85 (distorted t, lH), 6.6-7.6 (m, lOH) MS: 338 (19, M+ ), 189 (43), 175 (70), 148 (12), 121 (20), 36 (100) 4-[1-(4-fluorophenyl)-5-(4-methoxyphenyl)pentyl]-lH-imidazole lH NMR (as base, CDC13):
1.1-2.3 (m, 6H), 2.49 (~, 2H), 3.75 (s, 3H), 3.8 (distorted t, lH), 6.6-7.6 (m, lOH) 67 ~3 ~3. ~ ~ r~ ~-t '' MS: 338 (10, M+ ), 189 ~20), 175 (22), 148 (6), 121 (22), 36 (100) 4-[5-(2,6-dimethylphenyl)-1-(4-fluorophenyl)pentyl]-lH-imidazole lH NMR (as base, CDC13):
1.25-1.5 (m, 4H), 1.8-1.95 (m, lH), 2.05-2.2 (m, lH), 2.25 (s, 6H), 2.52 (t, 2H), 3.86 (t, lH~, 6.71 (s, lH), 6.9-7.0 (m, 5H), 7.1-7 2 (m, 2H), 7.4 (s, lH) MS: 336 (50, M+-), 217 (20), 189 (75), 175 (100), 148 (13), 119 (23) Example 11 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 1-benzyl-5-[1-(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 hydroxîde and water, dried with sodium sulphate and evaporated to dryness. The residue is purified by flash chromatography.

- 6~ -H NMR (as base, C~C13):
3.35 and 3.45 (2d, 2H), 4.62 and 4.65 (2s, 2H), 6.03 and 6.2 (2t, lH), 6,8-7.3 (m, 15H), 7.50 and 7.64 (2s, lH).
Example 12 4-[1,3-bis(4-nitrophenyl)propyl]-lH-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)-lH-imidazole in 6,4 ml of concentrated sulphuric acid under 10C. 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 chloride-methanol (95:5) as eluent.
In formula Ia, preferably Rl, R2, R'l and R'2 are each H and R4, R5, R6 and R7 are each H. If one phenyl group in formula Ia is mono-substituted then preferably Rl, R'2 and R2 are each H and Rl is not hydrogen and is in the ortho, meta or para position of the phenyl group, preferably the para position. When one phenyl group is mono-substituted in the para position and the other group is unsubstituted, preferably the substituent is OCH3.
If both phenyl groups in formula Ia are mono-substituted, preferably R2 and R'2 are both H, Rl and R'l are both not H and are each in the para position on the respective phenyl groups. Rl and R'l are preferably both F.
If a phenyl group is di-substituted, preferably R'l and R'2 are both H, Rl and R2 are both not H and are in the 3 and 5 or 3 and 4 positions on the phenyl group.

,- " s~ f~ ~ ~

Preferred compounds of formula Ia also include those in which R4 and R6 together form a bond, and those in which R' is H.
In formula Ib, preferably R4, R5 and R' are each H.
If one phenyl group in formula Ib is mono-substituted then preferably Rl, R2 and R'2 are each H and R'l is not hydrogen and is in the para position of the phenyl group. Preferably R'l is F.
If both phenyl groups in formula Ib are mono-substituted, preferably R2 and R'2 are both H, Rl and R'l are both not H, Rl is in the ortho, meta or para position of the phenyl group and R'l is the para position of the phenyl group. Preferably Rl is in the para position.
Preferred substituents are CH3 and F, in particular it is prferred that Rl and R'l are both F or Rl is CH3 and R'l is F.
If one phenyl group is di-substituted and the other is mono-substituted, preferably R'2 is H, Rl, R2 and R'l are each not H and R'l is the para position of the phenyl group and Rl and R2 are in the 3 and 5 or 2 and 6 positions of the phenyl group.

Claims

WE CLAIM:

1. A substituted imidazole of the formula (Ia) or a non-toxic pharmaceutically acceptable acid addition salt thereof wherein R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2, NH2, CN, CF3, CHF2, CH2F or halogen; R' is H or where R3 is H, CH3 or halogen; R4 is H, R5 is H or OH, R6 is H or OH and R7 is H or R4 and R6 together form a bond or R5 and R7 together form a bond; X and Y, which can be the same or different, are a bond, a straight C1-2-alkyl or the corresponding alkenyl and z is 0 to 2.

2. A substituted imidazole according to claim 1 wherein R4, R5, R6 and R7 are H.

3. A substituted imidazole according to claim 2 wherein R1, R2, R'1 and R 2 each are

4. A substituted imidazole according to claim 2 wherein R'1 R'2 and R2 each are H and R1 is CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2, NH2, CN, CF3, CHF2, CH2F or halogen, and is in the ortho, meta or para position of ths phenyl group.

5. A substituted imidazole according to claim 4 wherein R1, which is as defined in claim 1, is in the position of the phenyl group.

6. A substituted imidazole according to claim 5 wherein R1 is OCH3.

7. A substituted imidazole according to claim 2 wherein R2 and R'2 both are H and R1 and R'1 which are each CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2, NH2, CN, CF3, CHF3, CH2F or halogen, are each in the para position of the phenyl group .

8. A substituted imidazole according to claim 7 wherein R1 and R'1 both are F.

9. A substituted imidazole according to claim 2 wherein R'1 and R'2 both are H and R1 and R2, which are each CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2, NH2, CN, CF3, CHF2, CH2F or halogen, are in the 3 and 5 positions of the phenyl group.

10. A substituted imidazole according to claim 2 wherein R'1 and R'2 are H and R1 and R2, which are each CH3, C2H5, C3H7, OCH3, OH CH2OH, NO2, NH2, CN, CF3, CHF2, CH2F or halogen, are in the 3 and 4 positions of the phenyl group.

11. A substituted imidazole according to claim 1 wherein R4 and R6 together form a bond.

12. A substituted imidazole according to claim 1 wherein R' is H.

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

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

15. A compound according to claim 1, which is 1-benzyl-5-[4-(3-methylphenyl)-4-phenylbutyl]-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

16. A compound according to claim 1, which is 4-[4-(3-methylphenyl)-4-phenylbutyl]-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

17. A compound according to claim 1, which is 4-[4-(2-methylphenyl)-4-phenylbutyl]-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

18. A compound according to claim 1, which is 1-benzyl-5-[4-(2-methylphenyl)-4-phenylbutyl]-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

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

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

21. A compound according to claim 1, which is 4-(4,4-diphenylbutyl)-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

22. A compound according to claim 1, which is 1-benzyl-5-(4,4-diphenylbutyl)-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

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

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

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

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

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

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

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

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

31. A compound according to claim 1, which is 4-(6,6-diphenylhexyl)-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

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

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

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

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

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

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

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

39. A pharmaceutical composition comprising a substituted imidazole of the formula (Ia) or a non-toxic pharmaceutically acceptable acid addition salt thereof wherein R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2, CN, CF3, CHF2, CH2F or halogen; R' is H or where R3 is H, CH3 or halogen; R4 is H, R5 is H or OH, R6 is H or OH and R7 is H or R4 and R6 together form a bond or R5 and R7 together form a bond; X and Y, which can be the same or different, are a bond, a straight C1-2-alkyl or the corresponding alkenyl and z is 0 to 2 and a pharmaceutically acceptable carrier.

40. A composition according to claim 39 wherein in the compound of formula Ia, R4, R5, R6 and R7 are H.

41. A substituted imidazole of the formula (Ib) or a non-toxic pharmaceutically acceptable acid addition salt thereof wherein R1, R2, R'1 and R'2, which can be the same or different, are H, CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2, NH2, CN, CF3, CHF2, CH2F or halogen; R' is H or where R3 is H, CH3 or halogen; R4 is H or OH and R5 is H or R4 and R5 together form a bond and y is 0 to 4.

42. A substituted imidazole according to claim 41 wherein R4, R5 and R' each are H.

43. A substituted imidazole according to claim 42 wherein R1, R2 and R'2 each are H and R'1 which is CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2 NH2, CN, CF3, CHF2, CH2F or halogen, is in the para position of the phenyl group.

44. A substituted imidazole according to claim 43 wherein R'1 is F.

45. A substituted imidazole according to claim 42 wherein R2 and R'2 each are H and R1, which is CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2 NH2, CN, CF3, CHF2, CH2F or halogen, is in the ortho, meta or para position of the phenyl group and R'1, which is CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2 NH2, CN, CF3, CHF2, CH2F or halogen, is in the para position of the phenyl group.

46. A substituted imidazole according to claim 45 wherein R2 and R'2 both are H and R1 and R'1, which are each CH3, C2H5, C3H7, OCH3, OH , CH2OH, NO2 NH2, CN, CF3, CHF2, CH2F or halogen, both are in the para position of the phenyl group.

47. A substituted imidazole according to claim 46 wherein R1 and R'1 both are F.

48. A substituted imidazole according to claim 46 wherein R1 is CH3 and R'1 is F.

49. A substituted imidazole according to claim 42 wherein R'2 is H, R'1, which is CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2 NH2, CN, CF3, CHF2, CH2F or halogen, is in the para position of the phenyl group and R1 and R2, which are each CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2 NH2, CN, CF3, CHF2, CH2F or halogen, are in the 3 and 5 positions of the phenyl group.

50. A substituted imidazole according to claim 42 wherein R'2 is H, R'1, which is CH3, C2H5, C3H,, OCH3, OH, CH2OH, NO2 NH2, CN, CF3, CHF2, CH2F or halogen, is in the para position of the phenyl group and R1 and R2, which are each CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2 NH2, CN, CF3, CHF2, CH2F or halogen, are in the 2 and 6 positions of the phenyl group.

51. A compound according to claim 41, which is 4-[1-(4-fluorophenyl)-5-phenylpentyl]-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

52. A compound according to claim 41, which is 4-[1-(4-fluorophenyl)-5-(2-methylphenyl)pentyl]-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

53. A compound according to claim 41, which is 4-[1-(4-fluorophenyl)-5-(3-methylphenyl)pentyl]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

54. A compound according to claim 41, which is 4-[1-(4-fluorophenyl)-5-(4-methylphenyl)pentyl]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

55. A compound according to claim 41, which is 4-[5-(3,5-dimethylphenyl)-1-(4-fluorophenyl)pentyl]-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

56. A compound according to claim 41, which is 4-(1,5-diphenylpentyl)-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

57. A compound according to claim 41, which is 4-(1,3-diphenylpropyl)-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

58. A compound according to claim 41, which is 1-benzyl-5-(1,3-diphenylpropyl)-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

59. A compound according to claim 41, which is 4-[1-(4-fluorophenyl)-3-phenylpropyl]-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

60. A compound according to claim 41, which is 4-[1-(4-fluorophenyl)-4-phenylbutyl]-1H-imidazo1e or a non-toxic pharmaceutically acceptable acid addition salt thereof.

61. A compound according to claim 41, which is 4-[1-(4-fluorsphenyl)-5-(3-methoxyphenyl)pentyl]-1H-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

62. A compound according to claim 41, which is 4-[1-(4-fluorophenyl)-5-(4-methoxyphenyl)pentyl]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

63. A compound according to claim 41, which is 4-[1-(4-fluorophenyl)-5-(2,6-dimethylphenyl)pentyl]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

64. A compound according to claim 41, which is 4-[1,3-bis(4-fluorophenyl)propyl]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

65. A compound according to claim 41, which is 4-[1,4-bis(4-fluorophenyl)butyl]-lH-imidazole or a non-toxic pharmaceutically acceptable acid addition salt thereof.

66. A pharmaceutical composition comprising a substituted imidazole of the formula (Ib) or a non-toxic pharmaceutically acceptable acid addition salt thereof wherein R1, R2, R'1 and R'2, which can be the same or diferent, are H, CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2, NH2, CN, CF3, CHF2, CH2F or haloqen; R' is H or where R3 is H, CH3 or halogen; R4 is H or OH and R5 is H or R4 and R5 together form a bond and y is 0 to 4, and a pharmaceutically acceptable carrier.