DD296916A5 - NEW AROMATASE INHIBITED 4 (5) SUBSTITUTED IMIDAZOLE DERIVATIVES - Google Patents

Abstract

Novel imidazole derivatives of the formula (Ia) in which R1, R2, R1 and R2, which may be identical or different, are H, CH3, C2H5, C3H7, OCH3, OH, CH2OH, NO2, NH2, CN, CF3, CHF2 , CH 2 F or halogen; R is H or 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 may be the same or different, are a bond, a C1-2 alkyl or the corresponding alkenyl, and z is 0-2, and formula (I b) wherein R1, R2, R1, R2 and R R4 is H or OH and R5 is H or R4 and R5 together form a bond and y is 0-4 and their non-toxic salts show aromatase and desmolase inhibiting properties. Very selective aromatase inhibiting compounds are valuable in the treatment of estrogen-dependent diseases, for example breast cancer. Formulas (I a) and (I b)

Description

The present invention relates to substituted imidazole derivatives and their non-toxic, pharmaceutically acceptable acid addition salts and their presentation, as well as pharmaceutical compositions containing them and their use. The imidazole derivatives of the present invention have the general formulas (Ia) and (Ib):

<^ ^ -CHR ₆ -CHR ₄ - (CH ₂ ) _Z -CHR ₇ -CR ₅ -X

R '

wherein R ₁ , R ₂ R'i and R ' ₂ , which may be the same or different, are H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , OH, CH ₂ OH, NO ₂ , NH ₂ , CN, CF ₃ CHF ₂ , CH ₂ F or halogen; R 'is H

or -CH ₂

R3, where R ₃ is H, CH ₃ or halogen; R ₄ is H, R ₆ is H or OH, R ₆ is H or OH and R ₇ is H or

R ₄ and R ₆ together form a bond or R ₅ and R ₇ together form a bond; X and Y, which may be the same or different, are a bond, a straight CI_ ₂ -alkyl or the corresponding alkenyl, and ζ is 0-2 and

R '

C-CH- (CH ₂ ) _y R ₄ R ₅

wherein R ₁ , R ₂ , R ', and R' _{2 /} which may be the same or different, are H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , OH, CH ₂ OH, NO ₂ , NH ₂ , CN, CF ₃ CHF ₂ , CH ₂ F or halogen, R 'is H

or -CH ₂

R3 / ₃ where H is H, CH ₃ or halogen; R ₄ is H or OH and R ₅ is H or R ₄ and R ₅ form

together a bond and y is 0-4. The non-toxic, pharmaceutically acceptable acid addition salts of this compound are also covered by this invention.

The compounds of formulas (Ia) and (Ib) form acid addition salts with both organic and inorganic salts. They can thus form numerous pharmaceutically acceptable acid addition salts, for example chlorides, bromides, sulfates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

The inventions include pharmaceutical compositions containing at least some of the compounds of formulas (Ia) or (Ib) or a non-toxic pharmaceutically acceptable salt thereof and a suitable pharmaceutically acceptable carrier therefor.

The compounds of the present invention have been found, depending on the substituents R ', R ₁ , R ₂ , H \ and R' ₂ , to varying degrees aromatase and desmolase-inhibiting properties. Among them are very selective enzyme aromatase inhibiting compounds which are valuable in the treatment of estrogen-dependent diseases, for example breast cancer.

The compounds of formula (Ia) can be prepared by the following methods. Compounds of formula (I a) in which the branches

and

may be represented by a consecutive sequence of reactions involving a Grignard reaction of 4 (5) -substituted imidazole derivatives of the formula (Ma)

O Il

CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ C-OR

(Ha)

or its 1-benzyl derivative (III a) with a suitable aryl or arylalkylmagnesium halide (IVa), followed by loss of water and hydrogenation.

.N

O Il

CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ -C-OR

(IIIa)

(CH ₂ ) _n MgHal

(IVa)

In the formulas (Ha) to (IVa), R is alkyl, preferably a lower alkyl, η is 0-2 and Hal is halogen. The first reaction step, the Grignard reaction, leads to the following compounds of formula (Va):

HO-fj-CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ C- (CH ₂ ) _n

(CH ₂ J _n

(Va)

In this reaction, the aryl or arylalkyl magnesium halide derivative can be, for example, an aryl or arylalkyl magnesium derivative represented by the reaction of the corresponding aryl or arylalkylbromide derivative with magnesium. The Grignard reagent (IVa) can not be represented when R ₁ and / or R _{2 are} OH, CH ₂ OH or NH ₂ . Suitable solvents for the reaction include a variety of ethers, preferably tetrahydrofuran.

The aryl or arylalkylmagnesium halide derivative is conventionally prepared by adding the aryl or arylalkyl halide derivative in a suitable solvent, for example, tetrahydrofuran (dropwise) on magnesium turnings covered with tetrahydrofuran, all at the boiling point of the reaction mixture. When the magnesium turnings have reacted, the mixture is gently cooled and the 4 (5) -imidazole derivative (Ha) or its 1-benzyl derivative is added portionwise in solid form or dropwise in tetrahydrofuran. Upon completion of the addition, the reaction mixture is boiled until all of the 4 (5) -substituted imidazole derivative has reacted. The reaction time varies between one and five hours.

According to the aspect of the invention, the compounds of formula (Ia) in which R ₇ and R _{5 are} hydrogen or together form a bond are prepared by dehydrogenation of compounds of formula (I a) where R _{5 is} OH and by catalytic Hydrogen addition in the second stage. Water is eliminated by the usual methods, for example by heating with concentrated hydrochloric acid or by heating with anhydrous potassium hydrogen sulfate. The unsaturated compounds (VIa) (the compounds of formula (Ia) in which R ₇ and R ₆ together form a bond) were isolated and then hydrogenated. Alternatively, they can be hydrogenated directly in an acidic medium without prior isolation. The hydrogenation may conveniently be carried out with good stirring at room temperature in alcohol, for example ethanol, in the presence of a catalyst in a hydrogen atmosphere

 Suitable catalysts are, for example, platinum oxide, palladium on carbon or Raney nickel.

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

"jj CH ₂ CH ₂ (CH ₂ ) ZCH ₂ C- (CH ₂ ) _n

• vT

I R '

wherein R ', Ri, R ₂ , ζ and η are as defined above

(CH ₂ ) n

-H ₂ O

CH ₂ CH ₂ (CH ₂ ) _z CH = C- (CH ₂ ) _n (9 ^H 2) n

N.

N I R '

CH ₂ CH ₂ (CH ₂ ) ZCH ₂ -CH- (CH ₂ ) _n (CH ₂ ) _n

(Vila)

When R 'is a substituted or unsubstituted benzyl, this group can be easily removed by hydrogenation. In this case, the hydrogenation is carried out in an acidic medium such as a hydrochloric acid-ethanol mixture at elevated temperature. The reaction scheme of this hydrogenation, which leads to compounds of formula (Ia) in which R ', R ₇ and R _{5 are} each hydrogen, can be illustrated as follows:

I R '

CH ₂ CH ₂ (CH ₂₎ 2 CH ₂ -CH- (CH _{2) n}

(CH ₂ ) _n

^R 2

(Villa)

CH ₂ CH ₂ (CH ₂ ) ZCH ₂ -CH- (CH ₂ ) _n .

wherein R ₁ , R ₂ Z and η are as defined above.

Another method for removing the benzyl R 'group is a hydrogen transfer reaction in which the starting compound (VII a) with ammonium formate and 10% Pd / C in a suitable lower alcohol such as methanol or

Ethanol is boiled. The compound (Villa) 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 protective benzyl group at the same time. The compounds (VIII a) can also be prepared directly from the compounds (Va) by a hydrogentransfer reaction in which the starting compounds (Va) are boiled with ammonium formate and 10% Pd / C in an acid medium such as acetic acid.

The compounds of formula (VIII a) can also be prepared from the compounds of formula (Va) in which R 'is a substituted or unsubstituted benzyl by removing the benzylic R' by hydrogen exchange reaction as described above to form the compounds of Formula (IXa)

.N,

- [j- CH ₂ CH ₂ (CH ₂ )

(IXa)

wherein Ri, R ₂ , ζ and η are as defined above. The benzylic R 'can also be removed by hydrogenation. The compounds of formula (IXa) are further dehydrogenated by the methods described above and form the compounds of formula (Ia) where R ₅ and R ₇ together form a bond (Xa).

-H- CH ₂ CH ₂ (CH ₂ ) _Z CH = C- (CH ₂ ) _n

(CH ₂ ) n

(Xa)

Ri

The compounds of the formula (Xa) are then hydrogenated by the methods described above and give the compounds of the formula (VIII a).

The compounds of the formula (Ia) in which R 1 and / or R _{2 are} OH, CH ₂ OH or NH ₂ can be prepared by the following reactions. The compounds of formula (Ia) wherein Ri and / or R are OH can be prepared by reacting the 4 (5) -substituted imidazole (IIa) or (IIIa) with a Grignard reagent (IVa) where R ₁ and / or R ₂ 0-CH ₂ -Ph or O-THP (THP = tetrahydropyranyl), and subsequent catalytic hydrogenation by methods already described for the removal of the benzylic R 'group. If R 'is a benzyl protecting group, conveniently it can be simultaneously cleaved off. Another approach is to dealkylate compounds of formula (Ia) where Ri and / or R ₂ is OCH 3, by reacting with BBr 3, for example.

The compounds of formula (Ia) wherein Ri and / or R _{2 are} CH ₂ OH may be prepared from the corresponding compounds in which R ₁ and / or R ₂ are by known methods, for example by hydrolyzing the nitrile Group and subsequent catalytic hydrogenation of the acid group.

The compounds of the formula (Ia) in which R ₁ and / or R _{2 are} NH ₂ can be prepared by hydrogenating the corresponding compounds in which R ₁ and / or R _{2 are} NO ₂ . The protective benzyl group is hydrogenated. The compounds of the formula (Ia) in which R ₁ and / or R _{2 is} CN may be prepared from corresponding compounds in which R ₁ and / or R _{2 is} NH ₂ by diazotization. Compounds of formula (Ia) in which R ₁ and / or R _{2 are} halogen may also optionally be prepared by this method.

Compounds of formula (Ia) in which R 'is a benzyl group can be prepared by benzylating compounds in which R' is hydrogen. The starting compound is first treated with a strong base such as NaOH in water or NaH in a suitable solvent such as dimethylformamide to give the alkali metal salt of imidazole, in the second step benzyl halide is added

 The reaction scheme can be illustrated as follows: • KL

CHR ₆ -CHR ₄ - (CH ₂ ) 2 -CHR ₇ -CR ₅ -X

HR ₆ -CHR ₄ - (CH ₂ ) _Z -CHR ₇ -CR ₅ -X

The free substituents OH, CH ₂ OH and NH ₂ must be protected during the benzylation reaction. Other methods of preparing the compounds of formula (la), in which the branches

and

in the first step comprise a series of two consecutive Grignard reactions starting from the 4 (5) -substituted imidazole derivatives (IIa) or their 1-benzyl derivative (IIIa) as above. Now, however, the amount of Grignard reagent as well as the reaction temperature is reduced to stop the reaction at the ketone stage to obtain the ketone (XI a) which is further reacted with the other Grignard reagent (XII a). whereby the compound of formula (Ia) is obtained with R ₅ = OH

 The reactions are illustrated as follows:

O II

CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ -C-OR

(CH ₂ J _n MgHaI

CH ₂ CH ₂ (CH ₂₎ 2.CH ₂ -C- (CH _{2) n} -

(XIa)

(CH ₂ ) J _n -MgHaI R ' ₂ (XIIa)

HO

CH ₂ CH ₂ (CH ₂₎ 2 CH ₂ -C- (CH ₂ J _n

(9 ^H 2)

(XIIIa)

In the above reaction scheme, m and n, which may be the same or different, are 0-2, ζ is 0-2 and R is an alkyl group, preferably a lower alkyl. The compounds of the formula (XIII a) are further dehydrated and hydrogenated by the methods described above, while compounds of the formula

CH ₂ CH ₂ (CH ₂ ) _z CH ₂ -CH- (CH ₂ ) _n

R '

wherein R ', Ri, R ₂ , FV ₁ , R' ₂ , ζ, η and m are as defined above.

The Grignard compounds (IVa) and (XII a) can not be represented when the substituents are OH, CH ₂ OH or NH ₂ .

When the compounds of formula (Ia) wherein one or more of the substituents R ₁ , R ₂ , R '•, and R' are ₂ OH are desired, they may be represented as follows.

The compounds of formula (Ia) wherein one or more of the substituents R ₁ , R ₂ , R 1 and R ' _{2 are} OH can be prepared by reacting the 4 (5) -imidazole derivative (Ha) or (III a ) first with a Grignard reagent (VIa) and then with the reagent (XII a), wherein the substituent (s) of the compounds (IVa) or (XII a) or both are 0-CH ₂ Ph or OTHP, and catalytic hydrogenation by methods described for the hydrogenation of benzylic R 'groups. The protective benzyl group is split off simultaneously. Another method of dealkylation of the compounds of formula (Ia) where the substituent (s) are OCH ₃ is, for example, in their reaction with BBr ₃ .

The compounds of the formula (Ia) in which one or more of the substituents R ₁ , R ₂ , R 'and R' _{2 is} CH ₂ OH, NH ₂ or CN can be prepared by the methods described above.

For better control of the above reactions, the starting material may be either an amide or a nitrile

j CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ C-NH ₂

CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ CN

I R '

The selection of suitable conditions for the dehydration of the compounds of the formula (Ia) in which R _{5 is} OH leads to the corresponding compounds of the formula (Ia) in which one of the alkyl chains X or Y is converted into the corresponding alkenyl chain

 The starting compounds of the formulas (IIa) and (IIIa) can be prepared, for example, from the 4 (5) -imidazolylalkanoic acid of the formula

-fl CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ COOH

CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ COOH

wherein ζ and R _{3 are} as defined above, are represented by their esterification according to the method described in US Patent No. 3759944.

Another method of preparing the compounds of formula (Ia) is the Wittig reaction where the starting compound is a 4 (5) -imidazole aldehyde (XIVa). In the formula (XIVa), R 'is as defined above.

CHO

(XIVa)

In the Wittig reaction, the first step is to prepare a phosphonium salt (XVa) from the corresponding halogenated hydrocarbon (XVIa) by reacting with triphenylphosphine.

The reaction scheme is illustrated as below.

Hal-CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X-

(XVIa)

ι ι \ j -

R'2-

Ph ₃ P

Ph

Hal® Ph 1 P-CH ₂ - (CH ₂ ) _Z CH ₂ -CH-X Ph Y

(XVa)

Ri. R2, R'i, R'2r X. Y and ζ are as defined above. Shark is halogen.

In the second step of the Wittig reaction, the compound (XVa) is treated with a strong base to obtain a phosphorus ylide which has been further reacted with the 4 (5) -imidazole-carbaldehyde (XIVa) to give the compounds of the Formula (Ia) in which R ₄ and R ₆ together form a bond (XVII a). The strong base may be NaH or BuLi in a suitable solvent such as dimethoxyethane, tetrahydrofuran or DMF. Furthermore, alkali metal alkoxides in the corresponding alcohols can be used as solvent and NaH in DMSO as proton acceptors. The compounds (XVIIa) are isolated and then hydrogenated as described above to give the compounds of formula (Ia) in which R ₄ and R _{6 are} both hydrogen.

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

Ph

Hai ⁰ Ph-P ^ -CH ₂ - (CH ₂ ) _Z CH ₂ -CH-Ph

1) strong base _

(XIVa)

CHO

N I R '

(CH ₂ ) Z-CH ₂ -CH-X Y

R'2

R '

(XVIIa)

R '

CH ₂ -CH ₂ - (CH ₂ ) ₂ -CH ₂ -CH-X-

R '

(XVIIIa)

The Wittig reaction can also be carried out in a different order, for example, a phosphonium salt (XIXa) is prepared from the corresponding halogenated 4 (5) -imidazole derivative (XXa) by reacting with triphenylphosphine. In the second stage, allowing the compound (XIXa) with a strong base and then with a substituted ketone of formula (XXI a) as described above, react to give the compounds of formula (la) in which Rsund R ₇ together form a bond (XXII a)

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

CH ₂ CH ₂ (CH ₂ ) _z CH ₂ Hal (XXa)

Ph ₃ P

-N, -1-CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ P-Ph Hal ©

Ph (XIXa)

strong base

2) O = CX- (C 1 -R ₁

R ' ₂ (XXIa)

-H-CH ₂ CH ₂ (CH ₂ ) _Z CH = CX

R '

(XXIIa) ^

wherein R ', R ₁ , R ₂ , R' _1r R ' ₂ , z, X and Y are as defined above.

The compounds of the formula (Ia) can also be prepared by a modified Wittig reaction, namely by the Horner-Emmons or Wadsworth-Emmons reaction, in which the phosphate (XXIII a) selected from the halogenated

Hydrocarbon (XVIa) and a phosphorous triester (for example, (EtO) ₃ P) was reacted by Arbusow reaction first with a base (for example NaH in DMSO or dimethoxyethane) and then with the aldehyde (XIVa). The

Formed product (XVII a) is a compound of formula (I a) in which R ₄ and R ₆ together form a bond.

The reaction scheme can be illustrated as follows:

Hal-CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X

(RQ) 3 ^P s

(XVIa)

O Il

(RO) ₂ -P-CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X-

R '

1) base

(XXIIIa)

-Η CHO

(XIVa)

CH = CH- (CH ₂ ) 2-

NR ¹

R '

(XVIIa)

In the formula (XXIIIa), R is an alkyl of 1-4 carbon atoms, and Ri, R ₂ , R'i, R'2, X, Y and ζ are as defined above. The unsaturated compounds (XVII a) are then hydrogenated to form the compounds of formula (I a) in which R ₄ and R _{6 are} each hydrogen. The benzylic R 'group and the double bond of the compounds of formula (XVIIa) can be removed simultaneously by the previously described methods.

Another convenient method of preparing compounds of formula (Ia) is the Grignard reaction in which 4 (5) -imidazole-carbaldehyde (XIVa) is reacted with a Grignard compound (XXIVa) and a compound of formula (I a), in which R _{6 is} OH (XXVa). The Grignard compound is prepared by reaction of the corresponding halogenated hydrocarbon with magnesium turnings in the usual manner. The compound (XXVa) is further dehydrated by heating with KHSO _{4 to give} the compounds of the formula (I a) in which R ₄ and R ₆ together form a bond (XVIIa). The unsaturated derivatives were then hydrogenated to the compounds of formula (Ia) in which R ₄ and R _{6 are} each hydrogen. The reaction scheme for these steps can be illustrated as follows:

CHO + HaIMgCH ₂ (CH ₂ ) ZCH ₂ -CH-X

(XIVa)

(XXIVa)

OH

CH-CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X

R ¹

CH = CH- (CH ₂ ) _Z -CH ₂ -CH-X

(XXVa)

(XVIIa)

CH ₂ -CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X

R ¹

R '

(XVIIIa)

In the formulas (XXVa), (XVII a) and (XVIII a), R ', R ,, R ₂ , R', R ' ₂ , X, Y and ζ are as defined above. When R 'is substituted or unsubstituted benzyl, this group can be removed by hydrogenation and hydrogen transfer reaction as described above to give the compounds of formula (XXVI a).

CH ₂ -CH ₂ - (CH ₂ ) 2-

(XXVIa)

The compounds of the formula (XXVIa) can also be prepared directly from the compounds (XVIIa) and (XXVa) by the previously described methods.

The Grignard compound (XXIVa) can not be represented when the substituents are OH, CH ₂ OH or NH ₂ . The compounds of the formula (Ia) in which one or more substituents of Ri, R ₂ , R'i and R ' ₂ and FV _{2 are} OH, CH ₂ OH or NH ₂ can be prepared according to the methods described above.

Another method of preparing the compounds of formula (Ia) in which one or more of the substituents R ₁ , R ₂ , R'i and R 'is ₂ NO ₂ is by nitration of the corresponding compounds in which one or more of the substituents R _1, R _2, R'i and R _'2 are H.

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

Compounds of the formula (I b) can be represented by a sequence of reactions which first comprises a Grignard compound of 4 (5) -imidazolecarbaldehyde (lib) with a suitable arylalkylmagnesium halide (III b), which then gives the compounds (IVb) leads.

CHO

(Mb)

HaIMgCH ₂ (CH ₂ ) _y - / ( A) R _{1 (||| b)}

In the reaction, the arylalkylmagnesium halide derivative may be, for example, an arylalkylmagnesium bromide derivative represented by reaction of the corresponding arylalkylbromide derivative with magnesium.

Suitable solvents for the reaction include a variety of ethers, preferably tetrahydrofuran.

The arylalkylmagnesium halide derivative is conventionally prepared by adding the arylalkyl halide derivative in a suitable solvent, for example, tetrahydrofuran, to magnesium turnings covered with tetrahydrofuran at the boiling point of the reaction mixture. When the magnesium shavings are used up, the mixture is slightly cooled and treated with the 4 (5) -imidazole carbaldehyde (II b) in solid form in small portions or dropwise in tetrahydrofuran. Thereafter, it was refluxed until all of the 4 (5) -imidazole carbaldehyde (II b) had reacted. The reaction time varies between one and five hours.

The compounds (IVb) are then oxidized, for example with manganese dioxide, to give the compounds of the formula (Vb) which are reacted with the further Grignard reagent (VIb) to give the compounds of the formula (I b) in which R ₄ OH is (VIIb). The reaction scheme for these steps can be illustrated as follows.

OH

C-CH ₂ (CH ₂ ) y

(IVb)

O oxidation ν <^ -H- C-CH ₂ (CH ₂ ) _y

(Vb)

MgHaI (VIb)

± \ -HC-CH ₂ (CH ₂₎ N ^ OH

R '(VIIb)

The arylalkylmagnesium halide (VIb) is prepared by reacting the corresponding halogenated aromatic compound with magnesium turnings in the usual manner.

Compounds of the formula (Ib) can also be prepared by reacting a 4 (5) -imidazolecarbaldehyde (Mb) with an arylmagnesium halide (Vlb), which leads to the following compounds (VIIIb)

(VIIIb)

The compounds (VIII b) are then oxidized with, for example, manganese dioxide to the compounds of formula (IXb), which are further reacted with the Grignard reagent (III b) to give the compounds of formula (I b) in which R _{4 is} OH is (VIIb). The reaction scheme for these steps can be illustrated as follows:

OH t vR'i / RO /. RS

Oxidation

HalMgCH ₂ (CH ₂ ) _y (HIb)

C-CH ₂ (CH ₂ ) y OH

(VIIb)

According to the aspect of the invention, the compounds of formula (I b) in which R ₄ and R _{5 are} both hydrogen or together form a bond by dehydration of the compounds of formula (Ib) in which R _{4 is} OH, and catalytic hydrogenation in the second stage. By the usual methods, for example, heating with concentrated hydrochloric acid or heating with anhydrous potassium hydrogen sulfate, water is split off. The unsaturated compounds (Xb) (the compounds of formula (I b) in which R ₄ and R ₆ together form a bond) are isolated and subsequently hydrogenated. Alternatively, they can be hydrogenated directly in an acidic medium without prior isolation. The hydrogenation is usually carried out at room temperature with good stirring in an alcohol, for example ethanol, in the presence of a catalyst in a hydrogen atmosphere. Suitable catalysts are, for example, platinum dioxide, palladium-on-carbon or Raney nickel. The reaction scheme for these steps can be illustrated as follows:

(VIIb).

C-CH ₂ (CH ₂ ) _y OH

wherein R ', R ₁ , R ₂ , R'i, R' ₂ and Y are as defined above

C = CH (CH ₂ Jy

(Xb)

CH-CH ₂ (CH ₂ ) _y

N I R '

(XIb)

wherein R ', R ₁ , R ₂ , R'i, R' ₂ and Y are as defined above.

When R 'is a substituted or unsubstituted benzyl, this group can be cleaved by hydrogenation. In this case, the hydrogenation is carried out in an acidic medium such as a mixture of hydrochloric acid and ethanol at elevated temperature.

The reaction scheme of this hydrogenation leading to compounds of formula (I b) in which R ', R ₄ and R _{5 are} each hydrogen can be illustrated as follows:

CH-CH ₂ (CH ₂ ) _y

(XIb)

H ₂ , H ⁺

CH-CH ₂ (CH ₂ ) _y

(XIIb)

Another method for removing 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 a suitable alcohol such as methanol or ethanol or its aqueous solution , The compounds (XII b) can also be prepared directly from the compounds (Xb) by hydrogen transfer reaction with ammonium formate or by hydrogenating both the double bond and the benzyl protecting group (simultaneously). The compounds (XII b) can also be prepared directly from the compounds (VII b) by hydrogen transfer reaction in which the starting compound (VII b) is refluxed with ammonium formate and 10% Pd / C in an acidic medium such as acetic acid. The compounds of formula (XII b) may also be prepared from the compounds of formula (VII b) wherein R 'is a substituted or unsubstituted benzyl, by first removing the benzylic R' by a hydrogen transfer reaction by the method described above, which comprises Compounds of formula (XIIIb) provides.

CH ₂ (CH ₂ ) _y

(XIIIb)

Wherein R ₁ , R ₂ , R'i, R ' ₂ and y are as defined above. The benzylic R 'can also be removed by hydrogenation. The compounds of formula (XIII b) are further dehydrated by the previously described methods and form the compounds of formula (Ib) where R ₄ and R ₆ together form a bond (XIVb).

(XIVb) C = CH (CH ₂ ) y.

The compounds of formula (XIVb) are further hydrogenated by the previously described methods to form the compounds of formula (XII b). The benzylic R 'can be removed prior to the oxidation reaction by the previously described methods. The reaction scheme for this hydrogenation can be illustrated as follows:

OH -CH ₂ (CH ₂ ) y

(IVb)

OH

C-CH ₂ (CH ₂ ) y

The Grignard compounds (III b) and (Vl b) can not be represented if the substituents are OH, CH ₂ OH or NH ₂ . The compounds of the formula (I b) in which one or more of the substituents R ₁ , R ₂ , R'i and R ' _{2 are} OH, CH ₂ OH or NH ₂ can be prepared by the following methods.

The compounds of the formula (I b) in which one or more of the substituents R ₁ , R ₂ , R ' _n and R' _{2 is} OH can be prepared by reacting the 4 (5) -imidazole derivative (Hb) first with a Grignard compound (IIIb) and then with the reagent (VIb) or where the substituent (s) of compound (IIIb) or (VIb) or both of them OCH ₂ Ph or OTHP (THP = Tetrahydropyranyl) are, by catalytic hydrogenation by means of already described methods for hydrolytic cleavage of the benzylic R 'group. When R 'is a benzyl protecting group, it is simultaneously cleaved off. Another approach is to dealkylate the compounds of formula (I b) where the substituent (s) are OCH ₃ , for example by reaction with BBr ₃ .

The compounds of the formula (I b) in which one or more of the substituents R ₁ , R ₂ , R '• and R' _{2 are} CH ₂ OH can be prepared from the corresponding compounds in which the substituent (s) (EN) CN are, by conventional methods, for example by hydrolyzing the nitrile group and then reducing the acid group. The compounds of the formula (I b) in which one or more of the substituents R ₁ , R ₂ , R'i and R ' _{2 is} NH ₂ can be prepared by hydrogenating the corresponding compounds in which the substituent (s) ( en) is (are). The benzyl protecting group is removed by hydrogenation.

The compounds of formula (I b) in which one or more of the substituents R ₁ , R ₂ , R 'and R' _{2 are} CN may be prepared from the corresponding compounds in which one or more of the substituents are NH ₂ , by diazotizing. Compounds of the formula (I b) in which one or more of the substituents R ₁ , R ₂ , R'-i and R ' _{2 are} halogen can also optionally be prepared by the same method.

Another method for the preparation of compounds of formula (I b) is a McMurry reaction consisting in the reductive coupling of a benzoylimidazole (IXb).

and a suitable aldehyde of the formula (XVb)

(XVb)

in a suitable solvent such as tetrahydrofuran or dimethoxyethane in the presence of a lower-titania compound in an inert atmosphere, for example nitrogen or argon, the compounds of formula (Ib) in which R ₄ and R ₆ together form a bond (Xb) to be obtained.

R'9

C = CH (CH ₂ ) _y

The unsaturated compounds (Xb) are further hydrogenated as described earlier. The aldehyde (XVb) is usually prepared from the corresponding alcohol.

Of the compounds of formula (Xb) in which R ', and / or R' _{2 are} CH ₂ OH, NH ₂ or CN, it is expected that they can be prepared by the methods described earlier.

The compounds of formula (Xb) in which R ', and / or R' _{2 are} OH and Ri and R _{2 are} as defined above can be represented by a McMurry reaction from the compounds of formula (IXb) in which R 'i and / or R' _{2 are} OH, these can be prepared by catalytic hydrogenation of the compounds of formula (IXb) in which RS and / or R ' ₂ OCH ₂ Ph or OTHP, by the methods described earlier. Alternatively, the hydrogenation can be carried out prior to the oxidation reaction. If R 'is a benzyl protecting group, it can conveniently be removed at the same time. Another method consists in the dealkylation of the compounds of the formula (IXb) in which R ', and / or R' _{2 are} OCH ₃ , for example by their reaction with BBr ₃ .

Compounds of the formula (Ib) in which R'i and / or R ' ₂ OH and R ₁ and R _{2 are} as defined above can be represented by a McMurry reaction in which the aldehyde (XVb) is reacted with a ketone ( IXb) in which R ', and / or R' ₂ OCH ₂ Ph or OTHP is reacted, wherein a compound of formula (Xb), in which R ', and / or R' ₂ OCH ₂ Ph or OTHP and R ₁ and R _{2 are} as defined above, which is further hydrogenated to form compounds of the formula (XII b) in which R'i and / or R ' _{2 are} OH.

The compounds of formula (Ib) in which R 'is a benzyl group can be prepared by benzylating the corresponding compound in which R' is hydrogen. The starting compound is first treated with a strong base such as sodium hydroxide in water or sodium hydride in a suitable solvent, for example dimethylformamide, to give the imidazole alkali metal salt, in the second step the benzyl halide is added.

The reaction scheme can be illustrated as follows:

CR ₄ -CHR ₅ - (CH ₂ ) Y

R '

R'2

1) strong base

2) R ₃ -

-CH ₂ Hal

CR ₄ -CHR ₅ (CH ₂ ) _y

The free OH, CH ₂ OH and NH ₂ substituents must be protected during the benzylation reaction. Another method for the preparation of compounds of formula (I b) in which one or more of the substituents R ₁ , R ₂ , R ^f ! and R ' _{2 are} NO ₂ , is the nitration of the corresponding compounds in which one or more of the substituents is H. The compounds of formulas (I a) and (I b), their non-toxic pharmaceutically acceptable salts or mixtures thereof can be administered parenterally, intravenously or orally. Typically, an effective amount of the compound is combined with a suitable pharmaceutical carrier. As used herein, the term "effective amount" includes those

Amounts that give the desired effect without causing adverse side effects. The amount precisely applied in a particular situation depends on numerous factors such as method of administration, animal species, condition for which the derivative is administered, etc. and, of course, the structure of the compound. The pharmaceutical carriers normally used together with the compounds of the present invention may be solid or liquid and will generally be selected in view of the intended route of administration. For example, solid carriers include lactose, sucrose, gelatin, and agar, while the liquid carriers include water, syrup, peanut oil, and olive oil. Other suitable carriers are well known to those skilled in the preparation of pharmaceutical formulations. The combination of compound and carrier can be in many acceptable forms such as tablets, capsules, suppositories, solutions, emulsions and powders.

The compounds of the invention are particularly valuable as aromatase inhibiting agents and therefore particularly useful in the treatment of estrogen-dependent diseases, for example breast cancer.

Estrogens are essential steroids in the physiology and function of normal development of the breast and genitalia of the woman. On the other hand, estrogens are known to stimulate the growth of estrogen-dependent cancers, especially breast and endometrial cancers, and may increase the risk of developing breast cancer when given at pharmacological doses for extended periods of 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 strained by the fact that antiestrogens have become central to the treatment of estrogen receptor rich breast cancer. Antiestrogens act by binding to estrogen receptors and thus by inhibiting the biological effect of the estrogens. The second way to block the estrogen effect is to inhibit estrogen synthesis. Since it was achieved clinically by the nonspecific steroid synthesis inhibitor aminoglutethimide. Estrogen synthesis could be specifically blocked by inhibiting the enzyme aromatase, which is the key enzyme in the biochemical pathway. Aromatase inhibition is important because several breast tumors synthesize estradiol and estrone in situ and therefore show 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 an in vitro assay according to M. Pasanas (Biological Research in Pregnancy, Vol. 6, No. 2, 1985, pp. 94-99). Human aromatase enzyme was used. The enzyme was obtained from human placenta, which is rich in the enzyme. A miomomal fraction (100,000 g precipitate) was prepared by centrifugation. The enzyme representation was used without further purification. The test compounds were added along with 100,000 dpm of 1,2-ditritio-androstene-3,17-dione and NADPH generating system. The concentrations of the test compounds were 0.001.0, 0.01, 1 and 1, OmM. Incubation was at 37 ° C for 40 minutes. The aromatization of the 1,2-ditritio-androstene-3,17-dione led to the generation of ³ H2O. The tritiated water and tritiated substrate are readily separated by a Sep-Pak ^R minicab which absorbs the steroid but allows free water elution. The radioactivity was determined by a liquid scintillation counter. Aromatase inhibition was determined by comparing the ³ H ₂ O radioactivity of treated inhibitor samples with those containing no inhibitor. IC 50 values were calculated as concentrations that inhibited enzyme activity by 50%. These concentrations are presented in Table 2.

The activity (desmolase) of cholesterol side-chain cleavage (CSCC) was measured according to the method of Pasanen and Pelkonen (Steroids 43, 517-527, 1984). The incubations were carried out in 1 liter of Eppendorf plastic tubes and an Eppendorf shaker, centrifuge and incubator were used as a unit. In a 300 μl incubation volume, the substrate (5μΜ) was prepared according to Hanukoglu and Jefcoate (J. Chromatogr, 190, 256-262, 1980), and 10000 dpm of radioactive ³ H-4-cholesterol (the purity of the compound was checked by thin layer chromatography). in 0.5% Tween 20.1mM MgCl ₂ , 5μc cyanogen and 2mM NADPH were added.

Controls contained all of the above, but the enzyme preparation was inactivated prior to incubation by adding 900 μM methanol. The mitochondrial fraction (1 mg protein) from the human placenta or bovine kidney was used as the enzyme source. After 30 minutes incubation at 37 ⁰ C, the reaction was terminated by addition of 900μΙ methanol; 1 500 dpm labeled ^u C-4 pregnenolone was added to each incubate and the tubes shaken vigorously. After equilibration for 10 minutes, the methanol precipitated proteins were separated by centrifugation (8000 xg for 2 minutes), the supernatant solution was aspirated into a 1 ml plastic injection syringe and placed on a pre-equilibrated (75% methanol) mini-column. The column was washed with one ml of 75% methanol and then with 3 ml of 80% methanol. The 80% methanol eluate was collected in a measuring vial and mixed with 10 ml of scintillation fluid. The radioactivity was determined using a double label program on a liquid scintillation counter (LKB RackBeta). Typical activities for placental and bovine kidney enzyme preparations were 0.5-3 and 50 to 100 pmol of pregnenolone formed / mg protein / min.

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

Table 1

Tested connections

No name

1 a. 4- [4- (4-Methyl-phenyl) -4-phenylbutyl] -1H-imidazole

2 a. 1-Benzyl-5- [4- (4-methylphenyl) -4-phenyl-butyl] -1H-imidazole

3 a. 1-Benzyl-5- [4- (3-methyl-phenyl) -4-phenyl-butyl] -1H-imidazole

4 a. 4- [4- (3-Methylphenyl) -4-phenyl-butyl] -1H-imidazole

5 a. 4- [4- (2-methylphenyl) -4-phenyl-butyl] -1H-imidazole

6 a. 1-Benzyl-5-I4- (2-methylphenyl) -4-phenyl-butyl] -1H-imidazole

7 a. 1-Benzyl-5- (4,5-diphenyl-pentyl) -1H-imidazole

8 a. 4- (4,5-diphenyl-pentyl) -1H-imidazole

9 a. 4- (4,4-diphenyl-butyl) -1H-imidazole

10 a. 1-Benzyl-5- (4,4-diphenyl-butyl) -1H-imidazole

11a. 4- [4- (4-Methoxy-phenyl) -4-phenylbutyl] -1H-imidazole

12 a. 4- [4,4-bis (4-methoxy-phenyl) -butyl] -1H-imidazole

13a. 3- [4,4-bis (3-methylphenyl) butyl] -1H-imidazole

14a. 4- [4- (3,5-dimethylphenyl) -4-phenyl-butyl] -1H-imidazole

15a. 4- [4- (3,4-Dimethylphenyl) -4-phenyl-butyl] -1H-imidazole

16a. 4- [4- (3,5-Dimethylphenyl) -4- (3-methyl-phenyl) -butyl] -1H-imidazole

17 a. 4- [4,4-bis (4-methylphenyl) butyl] -1H-imidazole

18 a. 4- (5,5-diphenyl-pentyl) -1H-imidazole

19 a. 4- (6,6-diphenyl-hexyl) -1H-imidazole

20 a. 4- [4- (2-Fluorophenyl) -4-phenyl-butyl] -1H-imidazole

21 a. 4- [4- (4-Fluorophenyl) -4-phenyl-butyl] -1H-imidazole

22 a. 4- (4,4-Diphenyl-but-1-enyl) -1H-imidazole

23 a. 4- [4,4-bis (4-fluoro-phenyl) -butyl] -1H-imidazole

24 a. 4- [4,4-bis (4-nitro-phenyl) -butyl] -1H-imidazole

25 a. 4- [4,4-bis (4-aminophenyl) biityl] -1H-imidazole

26 a. 4- [4- (4-ethyl-phenyl) -4-phenyl-butyl] -1H-imidazole

1 b. 4- [1- (4-fluoro-phenyl) -5-phenyl-pentyl] -1H-imidazole

2 B. 4- [1- (4-fluoro-phenyl) -5- (2-methylphenyl) pentyl] -1H-imidazole

3 b. 4- [1- (4-fluoro-phenyl) -5- (3-methylphenyl) pentyl] -1H-imidazole

4 b. 4- [1- (4-fluoro-phenyl) -5- (4-methylphenyl) pentyl] -1H-imidazole

5 b. 4- [5- (3,5-Dimethyl-phenyl) -1- (4-fluoro-phenyl) -pentyl] -1H-imidazole

6 b. 4- (1,5-diphenyl-pentyl) -1H-imidazole

7 b. 4- (1,3-diphenyl-propyl) -1H-imidazole

8 b. 1-Benzyl-5- (1,3-diphenyl-propyl) -1H-imidazole

9 b. 4- [1- (4-Fluoro-phenyl) -3-phenyl-propyl] -1H-imidazole

10 b. 4- [1- (4-Fluoro-phenyl) -4-phenyl-butyl] -1H-imidazole

11b. 4- [1- (4-fluoro-phenyl) -5- (3-methoxyphenyl) -pentyl] -1H-imidazole

12 b. 4- [1- (4-Fluorophenyl) -5- (4-methoxyphenyl) pentyl] -1H-imidazole

13 b. 4- [1- {4-Fluoro-phenyl) -5- (2,6-dimethylphenyl) -pentyl] -1H-imidazole 14b. 4- [1,3-bis (4-fluorophenyl) propyl] -1H-imidazole

15 b. 4- [1,4-bis (4-fluoro-phenyl) -butyl] -1H-imidazole

Table 2

Inhibition of human aromatase and desmolase (CSCC) by test compounds. IC-50 represents the concentration that inhibits the enzyme by 50%.

connection IC 50 IC-50 CSCC No. μιτιοΙ / Ι pmol / l 1a 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 10a 7 11a 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 19a 14.5 61 20 a 16 38 21a 2.8 80 22 a 8.5 165 23 a 3.3 175 24 a 20 37 25 a 26 210 26 a 8.5 65 1b 2.8 19 2 B 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 10b 0.75 31 11b 2.6 12 12b 3 22.5 13b 7.7 31 14b 2.2 22 15b 0.63 29

The antitumor effect was studied in vivo on DMBA-induced rat mammary adenocarcinomas by the following method. Breast adenocarcinoma was induced with DMBA in 50 + 2 day old female rats. The treatment was started after reaching the palpable tumors with the compounds to be tested. Tumor size in the solvent-treated control group was compared to the test groups. A daily regimen was followed for 5 weeks, then the animals were killed. The change in tumor size was evaluated.

The results were scored as changes in tumor size and divided into three groups, increasing, constant and decreasing tumor size. The antitumor effect of 4- (4,4-diphenyl-butyl) -1H-imidazole (Compound 9a in Table 2) was tested and the results are presented in Table 3.

Table 3

Number of different tumor types in the control and 4- (4,4-diphenyl-butyl) -1 H-imidazole-treated groups of rats with DMBA-induced breast cancer.

Group decreasing steadily increasing

Control 3 21 42

4- (4,4-diphenyl-

butyO-1H-imidazole 3 mg / kg 2 14 37

4- (4,4-diphenyl-

butyl) -1H-imidazole 30 mg / kg 21 3 15

Acute toxicity, LD ₆₀ , was determined in young, adult female mice of the NMRI strain. The administration of the test compounds was oral. The LD ₆₀ values of the test compounds of the formula (I a) were 350 mg / kg or more, of the formula (I b) 400 mg / kg or more.

The daily dose for a patient varied from about 20-200mg, administered orally. The following examples illustrate the invention.

¹ H NMR spectra were determined on a Bruker WP80 DS apparatus. The reference substance was tetramethylsilane.

MS spectra were determined using a Kratos MS80RF Autoconsole apparatus.

example 1

4- (4,4-diphenyl-butyl) -1H-imidazole

a) 1-Benzyl-5- (1-hydroxy-4,4-diphenyl-butyl) -1H-imidazole 2.0 g magnesium turnings are covered with 60 ml of absolute tetrahydrofuran. To the mixture was then added dropwise a solution of 1-bromo-3,3-diphenyl-propane (22.9 g) in 20 ml of absolute tetrahydrofuran at such a rate as to maintain a uniform reaction. After completion of the addition, the reaction mixture was refluxed for an additional hour and then cooled to room temperature. The reaction mixture was then added dropwise to a solution of i-benzylimidazole-5-carbaldehyde (7.35 g) in 80 ml of tetrahydrofuran at 60 ° C. After completion of the addition, the reaction mixture was refluxed for 2 hours, cooled and poured into cold water. The tetrahydrofuran was evaporated and the residue was treated with concentrated hydrochloric acid. The solution was cooled and the precipitate containing the product (as hydrochloride) was filtered off, washed with water and dried.

Yield 14.1 g. F. 160-168 ° C ¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.50-2.30 (m, 4H), 3.82 (t, 1H), 4.65 (t, 1H), 5.43 (s, 2H), 7.05-7.50 ( m, 16H), 8.62 (d, 1H) Using the same method, for example, the following compounds included in the invention were prepared:

1-Benzyl-5- [1-hydroxy-4- (2-methylphenyl) -4-phenyl-butyl] -1H-imidazole ¹ H NMR (as the hydrochloride, MeOH-d "):

1.50-2.40 (m, 4H), 2.21 and 2.15 (2s, 3H), 4.07 (t, 1H), 4.70 (m, 1H), 5.49 and 5.46 (2s, 2H), 6.80-7.50 (m, 15H), 8.88 (s, 1H) 1 -benzyl-5- [1-hydroxy-4- (3-methylphenyl ) -4-phenyl-butyl] -1H-imidazole ¹ H NMR (as hydrochloride, CDCl ₃ ):

1.35-2.35 (m, 4H), 2.26 (s, 3H), 3.73 (t, 1H), 4.62 (m, 1H), 5.38 (s, 2 H), 6.80-7.40 (m, 15H), 8.51 (s, 1H) 1-benzyl-5- [1-hydroxy-4- (4-methylphenyl) -4-phenyl- 'butyl] -1 H -imidazole ¹ H NMR (as hydrochloride, CDCl ₃ ):

1.40-2.40 (m, 4H) 2.23 and 2.24 (2s, 3H), 3.74 (t, 1H), 4.65 (widest, 2H), 5.38 (s, 2H), 6.80-7.40 (m, 15H), 8.55 (s, 1H) 1-benzyl-5- [1-hydroxy-4,4-bis (4-methyl-phenyl) -butyl] -1H-imidazole. Hydrochloride, mp 155-158 ° C.

1-Benzyl-5- (1-hydroxy-4,5-diphenyl-pentyl) -1H-imidazole ¹ H NMR (as hydrogen sulfate, MeOH-d ₄ ):

1.35-1.90 (m, 4H), 2.82 (broad s, 3H), 4.54 (t, 1H), 5.42 (s, 2H), 6.85-7.50 ( m, 16H), 8.80 (s, 1H) 1-benzyl-5- [1-hydroxy-4- (4-methoxyphenyl) -4-phenyl-butyl] -1H-imidazole ¹ H NMR ( as hydrochloride, MeOH-d ₄ ):

1.50-2.30 (m, 4H), 3.70 (s, 3H), 3.79 (t, 1H), 4.69 (t, 1H), 5.46 (s, 2H ), 6.79 (d, 2H), 7.0-7.55 (m, 13H), 8.85 (d, 1H) 1-benzyl-5- [1-hydroxy-4,4-bis ( 4-methoxy-phenyl) -butyl] -1H-imidazole ¹ H NMR (as base, MeOH-d ₄ ):

1.50-2.20 (m, 4H), 3.66 (t, 1H), 3.74 (s, 6H), 4.50 (t, 1H), 5.24 (s, 2H) , 6.70-7.60 (m, 15H) 1-Benzyl-5- [4- (2-fluoro-phenyl) -1-hydroxy-4-phenylbutyl] -1H-imidazole. Hydrochloride, m.p. 160-163 ⁰ C.

¹ H NMR (as hydrochloride, CDCl ₃ ):

1.45-2.45 (m, 4H), 4.17 (t, 1H), 4.67 (t, 1H), 5.43 (s, 2H), 6.80-7.50 (m, 15H), 8.43 (s, 1H) 1-Benzyl-5- [4- (4-fluoro-phenyl) -1-hydroxy-4-phenyl-butyl] -1H-imidazole. Hydrochloride, m.p. 168-171 "C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.50-2.30 (m, 4H), 3.84 (t, 1H), 4.68 (t, 1H), 5.49 (s, 2H), 6.80-7.55 ( m, 15H), 8.87 (d, 1H) 1-Benzyl-5- (1-hydroxy-5,5-diphenyl-pentyl) -1 H -imidazole ¹ H NMR (as base, CDCl ₃ ):

1.2-2.2 (m, 6H), 3.70 (t, 1H), 4.54 (t, 1H), 5.46 (s, 2H), 6.8-7.3 ( m, 16H), 8.58 (s, 1H) 1-benzyl-5- (1-hydroxy-6,6-diphenyl-hexyl) -1H-imidazole. Hydrochloride, m.p. 147-149X.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.6-2.2 (m, 8H), 3.85 (t, 1H), 4.60 (t, 1H), 5.53 (s, 2H), 7.0-7, 4 (m, 15H), 7.47 (s, 1H), 8.90 (s, 1H) 1 -benzyl-5- [4- (4-ethylphenyl) -1-hydroxy-4-phenyl butyl] -1H-imidazole ¹ H NMR (as hydrochloride, MeOH-d _4):

1.71 (t, 3H), 1.50-2.35 (m, 4H), 2.57 (q, 2H), 3.78 (t, 1H), 4.68 (t, 1H) , 5.46 (s, 2H), 6.9-7.5 (m, 15H), 8.82 (d, 1H) 1-benzyl-5- [4,4-bis (4-fluoro-phenyl ) -1-hydroxy-butyl] -1 H -imidazole ¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.50-2.00 (m, 4H), 3.86 (t, 1H), 4.70 (t, 1H), 5.52 (s, 2H), 6.80-7.50 ( m, 14H), 8.89 (d, 1H)

b) 1-Benzyl-5- (4,4-diphenyl-but-1-enyl) -1H-imidazole 1-benzyl-5- (1-hydroxy-4,4-diphenyl-butyl) -1H-imidazole hydrochloride (5.0 g) and 30.0 g of anhydrous potassium hydrogen sulfate were heated at 150 ° C for 4 hours. After cooling the mixture was added with 9OmI ethanol to dissolve the product. The mixture was then filtered and concentrated. After addition of water, the mixture was basified with sodium hydroxide, extracted with methylene chloride, washed with water and evaporated to dryness. The product was then converted to the hydrochloride with anhydrous hydrochloric acid in absolute ethyl acetate. Yield 2.9g.

F. 204-206 ⁰ C.

¹ H NMR (as Hydrochloric !, MeOH-C) ₄ ):

2.88-3.05 (m, 2H), 4.08 {t, 1H), 5.29 {s, 2H), 6.22 €, 32 (m, 2H), 7.00-7 , 50 (m, 16H), 8.87 (d, 1H) Using the same method, for example, the following compounds which fall within the scope of the invention are shown:

1-benzyl-5- [4,4-bis (3-methyl-phenyl) -but-1-enyl] -1H-imidazole. Hydrochloride, mp 152-156 ° C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

2.26 (s, 6H), 2.85-3.05 (m, 2H), 3.99 (t, 1H), 5.27 (s, 2H), 6.21-6.31 (m, 2H ), 6.80-7.50 (m, 14H), 8.86 (d, 1H) 1-benzyl-5- [4- (3,5-dimethylphenyl) -4- (3-methyl) phenyl) -but-1-enyl] -1H-imidazole ¹ H NMR (as hydrochloride, MeOH-d ₄ ):

2.22 (s, 3H), 2.23 (s, 3H), 2.26 (s, 3H), 2.85-3.05 (m, 2H), 3.94 (t, 1H), 5.26 (s, 2H), 6.20-6.30 (m, 2H), 6.75-7.50 (m, 13H), 8.84 (d, 1H ) 1-Benzyl-5- [4- (3,5-dimethyl-phenyl) -4-phenylbut-1-enyl] -1H-imidazole. F. 110-112 ° C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

2.22 (s, 6H), 2.85-3.05 (m, 2H), 3.98 (t, 1H), 5.27 (s, 2H), 6.20-6.30 ( m, 2H), 6.75-7.5 (m, 14H), 8.87 (d, 1 H) 1 -benzyl-5- [4- (2-methylphenyl) -4-phenyl-but- 1-enyl] -1 H-imidazole ^1H NMR (as hydrogen sulphate, MeOH-d _4):

2.19 (s, 3H), 2.80-3.05 (m, 2H), 4.28 (t, 1H), 5.29 (s, 2H), 6.0-6.60 ( m, 2H), 7.0-7.5 (m, 14H), 7.52 (d, 1H), 8.85 (d, 1H), 1-benzyl-5- [4- (3-methyl -phenyl) -4-phenylbut-1-enyl] -1H-imidazole ¹ HNMR (BIsBaSe ₁ CDCl ₃ ):

2.27 (s, 3H), 2.75-3.95 (m, 2H), 3.93 (t, 1H), 4.89 (s, 2H), 5.70-6.10 (m, 2H), 6.80-7.40 (m, 16H) 1-Benzyl-5- [4- (4-methylphenyl) -4-phenylbut-1-enyl] -1 H -imidazole ¹ H NMR (as base, CDCI ₃ ):

2.27 (s, 3H), 2.70-2.95 (m, 2H), 3.93 (t, 1H), 4.89 (s, 2H), 5.60-6, 20 (m, 2H), 6.80-7.50 (m, 16H) 1-benzyl-5- [4,4-bis (4-methyl-phenyl) -but-1-enyl] -1H imidazole. Hydrochloride, mp 128-132 ° C.

1-Benzyl-5- [4- (4-methoxyphenyl) -4-phenylbut-1-enyl] -1H-imidazole ¹ H NMR (as hydrochloride, CDCl ₃ ):

2.70-2.95 (m, 2H), 3.95 (t, 1H), 5.16 (s, 2H), 5.70-6.20 (m, 2H), 6, 70-7.40 (m, 15H), 8.99 (s, 1H) 1-benzyl-5- [4,4-bis (4-methoxy-phenyl) -but-1-enyl] -1 H- imidazole ¹ H NMR (as base, CDCl ₃ ):

2.60-2.90 (m, 2H), 3.74 (s, 6H), 3.78 (t, 1H), 4.92 (s, 2H), 5.80-6.00 ( m, 2 H), 6.65-7.50 (m, 15H) 1-Benzyl-5- (4,5-diphenyl-pent-1-enyl) -1H-imidazole

¹ H NMR (as base, CDCl ₃ ):

2.30-2.55 (m, 2H), 2.88 (m, 3H), 4.93 (s, 2H), 5.5-6.1 (m, 2H), 6.8-7, 5 (m, 17H) 1-Benzyl-5- [4- (2-fluoro-phenyl) -4-phenylbut-1-enyl] -1H-imidazole. Hydrochloride F. 195-201 ⁰ C.

¹ HNMRJaIsBaSe ₁ CDCI ₃ ):

2.75-3.00 (m, 2H), 4.34 (t, 1H), 5.97 (s, 2H), 5.80-6.10 (m, 2H), 6.75-7 , 50 (m, 16H) 1-Benzyl-5- [4- (4-fluorophenyl) -4-phenylbut-1-enyl] -1H-imidazole ¹ HNMRIaIsBaSe ₁ CDCl ₃ ):

2.60-2.95 (m, 2H), 3.96 (t, 1H), 4.93 (s, 2H), 5.80-6.05 (m, 2H), 6.75- 7.50 (m, 16H) 1-Benzyl-5- (6,6-diphenyl-hex-1-enyl) -1H-imidazole. Hydrochloride, mp 184-186 ° C.

1-Benzyl-5- [4- (4-ethylphenyl) -4-phenylbut-1-enyl] -1 H -imidazole ¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.17 (t, 3H), 2.56 (q, 2H), 2.93-2.98 (m, 2H), 4.03 (t, 1H), 5.28 (s, 2H), 6.20-6.34 (m, 2H), 7.08-7.41 (m, 14H), 7.52 (d, 1H), 8.87 (d, 1H) 1 -Benzyl-5- [4,4-bis (4-fluoro-phenyl) -but-1-enyl] -1H-imidazole ¹ H NMR (as hydrochloride, CDCl ₃ ):

2.78-2.94 (m, 2H), 4.01 (t, 1H), 5.27 (s, 2H), 5.82-6.34 (m, 2H), 6.83-7 , 40 (m, 14H), 9.21 (d, 1H)

c) 1-Benzyl-5- (4,4-diphenyl-butyl) -1H-imidazole

1-Benzyl-5- (4,4-diphenyl-but-1-enyl) -1H-imidazole (2.0 g) was dissolved in ethanol and treated with a catalytic amount of Pd / C (10%). The reaction mixture was stirred under a hydrogen atmosphere until the end of hydrogen uptake with vigorous stirring at room temperature. It was then filtered and the filtrate was evaporated to dryness. The residue, which is the product, was purified by flash chromatography eluting with a methylene chloride-methanol mixture.

Yield 1.3g

Hydrochloride, m.p. 200-202 ⁰ C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.30-1.70 (m, 2H), 1.85-2.20 (m, 2H), 2.61 (t, 2H), 3.83 (t, 1H), 5.35 (s, 2H), 7.05-7.50 (m, 16H), 8.89 (d, 1H) Using the same method, for example, the following compounds falling within the scope of the invention were prepared:

1-Benzyl-5- [4- (2-methyl-phenyl) -4-phenyl-butyl] -1H-imidazole. Hydrochloride, m.p. 200-205 ⁰ C.

¹ H NMR (as hydrochloride, CDCl ₃ ):

1.30-1.80 (m, 2H), 1.80-2.15 (m, 2H), 2.22 (s, 3H), 2.48 (t, 2H), 4.02 (t, 1 H), 5.31 (s, 2H), 6.96 (s, 1H), 7.0-7.5 (m, 14H), 9.28 (s, 1H) 1-benzyl 5- [4- (3-methylphenyl) -4-phenyl-butyl] -1H-imidazole. Hydrochloride, mp 148-158 ° C.

¹ H NMR (as hydrochloride, CDCl ₃ ):

1.30-1.80 (m, 2H), 1.80-2.25 (m, 2H), 2.30 (s, 3H), 2.49 (t, 2H), 3.78 (t, 1H), 5.29 (s, 2H), 6.90-7.50 (m, 15H), 9.24 (s, 1H) 1-benzyl-5- [4- ( 4-methylphenyl) -4-phenylbutyl] -1H-imidazole. Hydrochloride, mp 164-170 ° C.

¹ H NMR (as hydrochloride, CDCl ₃ ):

1.25-1.75 (m, 2H), 1.80-2.25 (m, 2H), 2.29 (s, 3H), 2.48 (t, 2H), 3.78 ( t, 1H), 5.31 (s, 2H), 6.80-7.50 (m, 15H), 9.35 (s, 1H) 1-benzyl-5- (4,5-diphenyl pentyl) -1H-imidazole. Hydrochloride, m.p. 166-170 ⁰ C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.1 5-1.90 (m, 4H), 2.49 (t, 2H), 2.81 (m, 3H), 5.30 (s, 2H), 6.90-7 , 50 (m, 16 H), 8.82 (s, 1 H) 1 -benzyl-5- [4- (4-methoxyphenyl) -4-phenyl-butyl] -1H-imidazole. Hydrochloride, m.p. 180-187 ⁰ C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.25-1.70 (m, 2H), 1.85-2.20 (m, 2H), 2.62 (t, 2H), 3.74 (s, 3H), 3.78 (t, 1H), 5.34 (s, 2H), 6.81 (d, 2H), 7.0-7.5 (m, 13H), 8.84 (d, 1H) 1-benzyl 5- [4- (2-fluoro-phenyl) -4-phenylbutyl] -1H-imidazole. Hydrochloride, mp 185-196 ° C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.25-1.75 (m, 2H), 1.80-2.25 (m, 2H), 2.65 (t, 2H), 4.18 (t, 1H), 5.37 (s , 2H), 6.80-7.5 (m, 15H), 8.89 (d, 1H) -benzyl-5- [4- (4-fluoro-phenyl) -4-phenyl-butyl] - 1H-imidazole. Hydrochloride, mp 172-174 ° C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.25-1.70 (m, 2H), 1.80-2.25 (m, 2H), 2.64 (t, 2H), 3.85 (t, 1H), 5.37 (s (2H), 6.80 to 7.50 (m, 15H), 8.90 (d, 1 H) 1-benzyl-5- (5,5-diphenyl-pentyl) -1 H-imidazole ¹ H NMR as base, MeOH-d ₄ ):

1.1-1.6 (m, 4H), 1.8-2.1 (m, 2H), 2.37 (t, 2H), 3.72 (t, 1H), 5.11 (s , 2H), 6.67 (s, 1H), 6.9-7.3 (m, 15H), 7.59 (s, 1H), 1-benzyl-5- (4- (4-ethyl) phenyl) -4-phenyl-butyl] -1H-imidazole ¹ H NMR (as hydrochloride, MeOH-d _4):

1.17 (t, 3H), 1.40-1.70 (m, 2H), 1.90-2.20 (m, 2H), 2.57 (q, 2H), 3.80 (t, 1H), 5.34 (s, 2H), 7.00-7.50 (m, 15H), 8.87 (d, 1H), 1-benzyl-5- [4,4-bis (4- fluorophenyl) butyl] -1H-imidazole ¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.30-1.70 (m, 2H), 1.80-2.25 (m, 2H), 2.64 (t, 2H), 3.87 (t, 1H), 5.40 (s , 2H), 6.80-7.50 (m, 14H), 8.92 (d, 1H)

d) 4- (4,4-diphenyl-butyl) -1H-imidazole 1-Benzyl-5- (4,4-diphenyl-butyl) -1H-imidazole hydrochloride (0.6g) is dissolved in a mixture of 20ml 2n hydrochloric acid and 10 ml of ethanol at 80 ⁰ C of Pd / C (10%) hydrogenated as a catalyst. After completion of the uptake of hydrogen, the reaction mixture was cooled, filtered and evaporated to dryness. After addition of water, it was made alkaline with sodium hydroxide. The product was then extracted with methylene chloride, dried with sodium sulfate and evaporated to dryness.

The residue is the product in the form of the base and is converted to the hydrochloride in ethyl acetate using dry HCl.

Yield 0.2 g.

F. 204-206 ⁰ C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.75 (t, 2H), 3.95 (t, 1H), 7.00-7 , 40 (m, 11H), 8.72 (d, 1H) Using the same method, the following compounds which fall within the scope of the invention are shown:

4- [4,4-bis (3-methylphenyl) butyl] -1H-imidazole. Hydrochloride, m.p. 122-129 ° C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.26 (s, 6H), 2.73 (t, 2H), 3.85 (t, 1H), 6.80-7.25 (m, 9H), 8.73 (d, 1H) 4- [4- (3,5-dimethylphenyl) -4- (3-methyl-phenyl) butyl] -1H-imidazole. Hydrochloride, F.75-82 ⁰ C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

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, 1H), 6.75-7.30 (m, 8H), 8.72 (d, 1H ) 4- [4- (3,5-dimethylphenyl) -4-phenyl-butyl] -1H-imidazole. Hydrochloride, mp 104-106 ° C.

¹ H NMR (hydrochloride, MeOH-d ₄ ):

1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.23 (s, 6H), 2.74 (t, 2H), 3.85 (t , 1H), 6.84 (m, 3H), 7.22 (m, 6H), 8.72 (d, 1H) 4- [4- (3,4-dimethylphenyl) -4-phenyl -butyl] -1H-imidazole. Hydrochloride, m.p. 118-121 ⁰ C.

4- [4- (2-methylphenyl) -4-phenyl-butyl] -1H-imidazole. Hydrochloride, mp 151-154.5 ° C.

¹ H NMR (as hydrochloride, CDCl ₃ ):

1.50-2.20 (m, 4H), 2.22 (s, 3H), 2.71 (t, 2H), 4.09 (t, 1H), 6.81 (s, 1H) , 7.0-7.4 (m, 9H), s, 1H) 5- [4- (3-methylphenyl) -4-phenyl-butyl] -1H-imidazole. Hydrochloride, mp 140-153 ° C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.40-1.85 (m, 2H), 1.85-2.25 (m, 2H), 2.27 (s, 3H), 2.74 (t, 2H), 3.90 (t, 1H), 6.80-7.30 (m, 10H), 8.69 (d, 1H) 4- [4- (4-methylphenyl) -4-phenyl-butyl] -1H-imidazole , Hydrochloride, mp 173-177 ° C.

¹ H NMR (as hydrochloride, CDCl ₃ + 2 drops MeOH-d ₄ ):

1.40-1.80 (m, 2H), 1.80-2.25 (m, 2H), 2.28 (s, 3H), 2.71 (t, 2H), 3.87 (t , 1H), 6.86 (d, 1H), 7.09 (s, 4H), 7.21 (s, 5H), 8.71 (d, 1H) 4- [4- (4- Methoxy-phenyl) -4-phenyl-butyl] -1H-imidazole. Hydrochloride, mp 156-159 ° C.

¹ H NMR (as hydrochloride, CDCl ₃ ):

1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.71 (t, 2H), 3.76 (s, 3H), 3.87 (t , 1H), 6.82 (d, 2H), 6.90 (s, 1H), 7.13 (d, 2H), 7.21 (m, 5H), 8.68

4- [4,4-bis (4-methoxy-phenyl) -butyl] -1H-imidazole. Hydrochloride, mp 138-142 ° C.

¹ H NMR (as hydrochloride, CDCl ₃ ):

1.40-2.25 (m, 4H), 2.71 (t, 2H), 3.75 (s, 6H) of which (t, 1H), 6.78 (d, 4H) , 6.83 (s, 1 H), 7.08 (d, 4 H), 9.02 (s, 1 H) 4- (4,5-diphenyl-pentyl) -1 H-imidazole ¹ H NMR ( as hydrochloride, CDCl ₃ ):

1.20-1.90 (m, 4H), 2.57 (t, 2H), 2.83 (m, 3H), 6.71 (s, 1H), 6.80-7.40 (m , 10H), 8.84 (s, 1H) 4- (5,5-diphenyl-pentyl) -1H-imidazole ¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.3-1.5 (m, 2H), 1.5-1.7 (m, 2H), 1.8-2.3 (m, 2H), 2.656 (t, 2H), 3.746 (t , 1H), 7.06-7.2 (m, 11H), 8.716 (d, 1H) 4- (6,6-diphenyl-hexyl) -1H-imidazole ¹ H NMR (as the base, CDCl ₃ ):

1.1-1.7 (m, 6H), 1.8-2.2 (m, 2H), 2.530 (t, 2H), 3.847 (t, 1H), 6.685 (s, 1H), 7 , 2 (s, 10H), 7.470 (s, 1H), 9.6 (broad s, 1H) 4- [4,4-bis (4-methyl-phenyl) -butyl] -1H-imidazole. Hydrochloride, mp 176-179 ° C.

4- [4- (4-Fluoro-phenyl) -4-phenyl-butyl] -1H-imidazole. Hydrochloride, mp 175-182 ° C.

4- [4- (2-Fluoro-phenyl) -4-phenyl-butyl] -1H-imidazole. Hydrochloride, m.p. 182-190 ⁰ C.

4- [4- {4-ethylphenyl) -4-phenylbutyl] -1H-imidazole

¹ H NMR (as Hydrochloric !, MeOH-d ₄ ):

1.18 (t, 3H), 1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.57 (q, 2H), 2.75 (t, 2H), 3.91 (t, 1H), 6.95-7.30 (m, 10H), 8.73 (d, 1H) 4- [4,4-bis (4-fluoro-phenyl) butyl] -1H-imidazole ¹ H NMR (as hydrochloric MeOH-d ₄ ):

1.40-1.85 (m, 2H), 1.90-2.30 (m, 2H), 2.77 (t, 2H), 3.98 (t, 1H), 6.80-7 , 40 (m, 9H), 8.72 (d, 1H)

Example 2 4- [4- (4-Fluorophenyl) -4-phenyl-butyl] -1H-imidazole A concentrated aqueous solution of ammonium formate (0.98 g, 15.6 mmol) was added dropwise to a boiling mixture of 1 Benzyl 5- [4- (fluoro-phenyl) -4-phenyl-butyl] -1H-imidazole (1.5 g, 3.9 mmol) and 10% Pd / C (0.156 g) in 16 mL of 50% ethanol given. The mixture was refluxed for 2 hours, filtered from the catalyst, then the solvent was evaporated. After adding 2N NaOH, the product was extracted with ethyl acetate. The ethyl acetate phase, upon drying and evaporation to dryness, gave the product. Yield 1.02g. Hydrochloride, m.p. 175-182 ⁰ C. (ethyl acetate) ¹ H NMR (as hydrochloride, MeOH-d _4):

1.40-1.90 (m, 2H), 1.90-2.30 (m, 2H), 2.75 (t, 2H), 3.96 (t, 1H), 6.85-7 , 36 (m, 10H), 8.74 (d, 1H) Following the same method as an example, the following substituted derivatives were prepared:

4- [4- (2-fluoro-phenyl) -4-phenyl-butyl] -1H-imidazole. Hydrochloride, m.p. 182-190 ⁰ C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.45-1.95 (m, 2H), 1.95-2.30 (m, 2H), 2.77 (t, 2H), 4.29 (t, 1H), 6.85-7 , 45 (m, 10H), 8.74 (d, 1H)

Example 3 4- (4,4-diphenyl-butyl) -1H-imidazole

a) 1-Benzyl-5- (4-hydroxy-4,4-diphenyl-butyl) -1H-imidazole

Magnesium shavings (0.49g) were covered with 4ml of absolute tetrahydrofuran. To this mixture, bromobenzene (3.18 g) in 7 ml of absolute tetrahydrofuran was added dropwise so as to keep a quiet reaction going. The reaction mixture was refluxed for an additional hour. Then ethyl 4- (1-benzyl-1H-imidazol-5-yl) butyrate (1.10 g) in 15 ml of absolute tetrahydrofuran was added dropwise and heated at reflux for 2 hours. The cooled reaction mixture was treated with saturated ammonium chloride solution. The tetrahydrofuran was distilled off, the residue collected. Yield 1.41 g. Hydrochloride, m.p. 197-201 ⁰ C. ¹ H NMR (as hydrochloride, MeOH-d _4): 1.35 to 1.80 (m, 2H), 2.20-2.45 (m, 2H), 2 , 61 (t, 2H), 5.33 (s, 2H), 7.0-7.5 (m, 16H), 8.81 (d, 1H)

b) 1-Benzyl-5- (4,4-diphenyl-but-3-enyl) -1H-imidazole

1-Benzyl-5- (4-hydroxy-4,4-diphenyl-butyl) -1H-imidazole (1.3 g) was refluxed in 20 ml of ethanol with 5% by weight of hydrogen chloride for one hour. The solvent was distilled off, the hydrochloride of the product was precipitated with ethyl acetate. Yield 1.1 g. F. 161-168 ° C.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

2.22-2.60 (m, 2H), 2.60-2.90 (m, 2H), 5.29 (s, 2H), 6.06 (t, 1H), 6.90-7 , 60 (m, 16H), 8.88 (d, 1H)

c) 1-Benzyl-5- (4,4-diphenyl-butyl) -1H-imidazole

1-Benzyl-5- (4,4-diphenyl-but-3-enyl) -1H-imidazole hydrochloride was hydrogenated in ethanol as described in Example 1c). Hydrochloride, F.200-202 ⁰ C.

d) 4- (4,4-diphenyl-butyl) -1H-imidazole

The benzyl group of 1-benzyl-5- (4,4-diphenyl-butyl) -1H-imidazole was removed by hydrogenation as in Example 1 (d).

Example 4

4- [4,4-Bis (4-nitro-phenyl) -butyl] -1H-imidazole 1.8g (14.6mmol) urea nitrate was added in small portions to a mixture of 2.0g (7.3mmol) 4- (4 , 4-diphenyl-butyl) -1 H-imidazol added to 6,4ml of concentrated hydrochloric acid below 10 ^0C. The reaction mixture was stirred for 2 hours at room temperature, then basified with 2 M NaOH and extracted with ethyl acetate. The product was purified by flash chromatography using methylene chloride-methanol (95: 5) as eluent.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.4-1.95 (m, 2H), 2.0-2.45 (m, 2H), 2.81 (t, 2H), 4.34 (t, 1H), 7.27 (broad s, 1H), 7.5 (d, 4H), 8.17 (d, 4H), 8.73 (d, 1H)

Example 5 4- [4,4-Bis (4-aminophenyl) butyl] -1H-imidazole 4- [4,4-Bis (4-nitrophenyl) butyl] -1H-imidazole was used in ethanol using hydrogenated from 10% Pd / C as a catalyst.

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.4-2.25 (m, 4H), 2.69 (t, 2H), 3.70 (t, 1H), 6.77 (d, 2H), 6.95 (d, 2H), 7.08 (broad s, 1H), 8.57 (d, 1H)

Example 6

4- (4,4-Diphenyl-but-1-enyl) -1H-imidazole

a) 4- (1-Hydroxy-4,4-di-phenyl-butyl) -1H-imidazole A concentrated aqueous solution of ammonium formate (4.0 g) was added to a boiling mixture of 1-benzyl-5- (1-hydroxy -4,4-diphenyl-butyl) -1H-imidazole (4.5 g) and 10% Pd / C (0.5 g) in 50 ml of 50% ethanol, and the mixture was boiled for 2 hours. The catalyst was filtered off and the solvent was evaporated. After adding 2M NaOH, the product was extracted with ethyl acetate, dried and evaporated to dryness to give the product which was used for the following step b).

b) 4- (4,4-Diphenyl-but-1-enyl) -1H-imidazole

4- (1-hydroxy-4,4-diphenyl-butyl) -1 H-imidazole (3.0 g) and 20 g of anhydrous potassium hydrogen sulfate are heated at 150 ⁰ C for 4 hours. The mixture was cooled and 90 ml of ethanol added to dissolve the product. The mixture was made alkaline with sodium hydroxide. The product was extracted with methylene chloride, washed with water and evaporated to dryness. The product was converted to the hydrochloride with dry hydrogen chloride. F. over 240 ^° C.

¹ H NMR (as hydrochloride, CDCl ₃ ):

2.904-3.068 (m, 2H), 4.116 (t, 1H), 6.05-6.35 (m, 2H), 6.998 (d, 1H), 7.22-7.25 (m, 10H) , 8.719 (d, 1H)

Example 7

4- [1- (4-fluoro-phenyl) -5-phenyl-pentyl] -1H-imidazole

a) 1-Benzyl-5- (1-hydroxy-5-phenylpentyl) -1H-imidazole

2.1 g of magnesium turnings were poured over 60 ml of absolute tetrahydrofuran. A solution of 4-phenylbutyl bromide (18.8 g) in 20 ml of absolute tetrahydrofuran was then added dropwise at such a rate as to maintain a mild reaction; After completion of the addition, the reaction mixture was refluxed for an additional hour and cooled to room temperature. The reaction mixture was then added to a solution of 1-benzyl-imidazol-ö-carbaldehyde (6.5 g) in 80 ml of tetrahydrofuran at 60 ⁰ C. After completion of the addition the reaction mixture for 2 hours was heated under reflux, cooled and poured into cold Poured water. The tetrahydrofuran was evaporated and the residue was treated with concentrated hydrochloric acid. The product, which separated out as an oil, was extracted with methylene chloride, then evaporated to dryness.

b) 4- (1-Hydroxy-5-phenylpentyl) -1H-imidazole

i-benzyl-SD-hydroxy-ö-phenyl-pentyll-IH-imidazole hydrochloride (8.5 g) shown in step a) was dissolved in a mixture of 100 ml of 2N hydrochloric acid and 10 ml of ethanol at 60 ⁰ C in the presence of Pd / C (10%) hydrogenated as a catalyst. After completion of the hydrogen uptake, the reaction mixture was cooled, filtered and evaporated to dryness. Water was added, then made alkaline with sodium hydroxide. The product was then extracted with methylene chloride, washed with water, dried with sodium sulfate and evaporated to dryness. The residue represents the product as a base and is used directly for step c)

¹ H NMR (as base, MeOH-d ₄ + one drop of CDCl ₃ ):

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- (1-Oxo-5-phenyl-pentyl) -1H-imidazole

5.5 g of 4- (1-hydroxy-5-phenylpentyl) -1H-imidazole and 7.0 g of manganese dioxide were refluxed in tetrachlorethylene for four hours. The reaction mixture was filtered, the filtrate evaporated to dryness. After adding water, it was extracted with methylene chloride. The combined extracts were washed with water and evaporated to dryness.

d) 4- [1- (4-Fluoro-phenyl) -1-hydroxy-5-phenylpentyl] -1H-imidazole

0.52g of magnesium shavings were over-poured with 60ml of absolute tetrahydrofuran. Then, a solution of 1-bromo-4-fluorobenzene (3.8 g) in 60 ml of absolute tetrahydrofuran was added dropwise to the solution at such a rate as to keep a weak reaction going. After completion of the addition, the reaction mixture was refluxed for an additional hour and then cooled to room temperature. The reaction mixture was then added dropwise at 60 ° C to a solution of 4- (1-oxo-5-phenyl-pentyl) -1H-imidazole (3.8 g) in 40 ml of tetrahydrofuran. After completion of the addition, the reaction mixture was refluxed for three hours, cooled and poured into cold water. The tetrahydrofuran was evaporated, then concentrated hydrochloric acid was added to the solution. The product was extracted as hydrochloride with methylene chloride. The combined methylene chloride extracts were evaporated to dryness.

e) 4- [1- (4-fluoro-phenyl) -5-phenyl-pent-1-enyl] -1H-imidazole

4- [1- (4-fluoro-phenyl) -1-hydroxy-5-phenyl-pentyl] -1H-imidazole hydrochloride (5.0 g) and 30.0 g of anhydrous potassium hydrogen sulfate are heated for four hours at 150 ⁰ C. , The mixture was cooled, added with 90 ml of ethanol to dissolve the product. The mixture was then filtered and the filtrate was then concentrated. After adding water, the mixture was made alkaline with sodium hydroxide. The product was extracted with methylene chloride, washed with water and evaporated to dryness. With dry hydrogen chloride in absolute ethyl acetate, the product was then converted to the hydrochloride

¹ H NMR (as base, CDCl ₃ ):

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 which fall within the scope of the invention are shown:

4- [1- (4-fluoro-phenyl) -5- (3-methylphenyl) -pent-1-enyl] -1H-imidazole 4- [1- (4-fluoro-phenyl) -5- ( 4-methylphenyl) -pent-1-enyl] -1H-imidazole 4- [1- (4-Fluoro-phenyl) -5- (2-methylphenyl) -pent-1-enyl] -1H imidazole 4- [5- (3,5-dimethyl-phenyl) -1- (4-fluoro-phenyl) -pent-1-enyl] -1H-imidazole 4- [1- (4-fluoro-phenyl) -5- (3-methoxy-phenyl) -pent-1-enyl] -1H-imidazole 4- [5- (3,5-Dimethoxyphenyl) -1- (4-fluoro-phenyl) -pent-1 -enyl] -1H-imidazole

f) 4- [1- (4-fluoro-phenyl) -5-phenyl-pentyl] -1H-imidazole

4- [1- (4-Fluoro-phenyl) -5-phenyl-pent-1-enyl] -1H-imidazole hydrochloride (2.0 g) was dissolved in ethanol and treated with a catalytic amount of 10% Pd / C added. The reaction mixture was stirred vigorously at room temperature in a hydrogen atmosphere until hydrogen uptake ceased. The mixture was filtered, the filtrate evaporated to dryness. The product-forming residue was purified by flash chromatography using a methylene chloride-methanol mixture as eluent. Yield 82%.

¹ H NMR (as base, CDCl ₃ ):

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 falling within the scope of the invention were prepared:

4- [1- (4-Fluoro-phenyl) -5- (3-methylphenyl) pentyl] -1H-imidazole MS: 322 (20, M ⁺ ), 189 (28), 176 (38), 175 (72), 149 (100), 125 (20), 121 (14), 109 (42), 105 (16), 97 (21) ¹ H NMR (as hydrochloride, MeOH-d ₄ ):

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-fluoro-phenyl) -5- (4-methylphenyl) pentyl] -1H-imidazole ¹ H NMR (as the hydrochloride, MeOH-d ₄ ):

1.1-2.7 (m, 8H), 2.26 (s, 3H), 4.05 (t, 1H), 6.8-7.6 (m, 9H), 8.78 (i.e. , 1H) 4- [1- (4-fluoro-phenyl) -5- (2-methylphenyl) pentyl] -1H-imidazole MS: 322 (53, M ⁺ ), 189 (30), 176 (55 175 (100), 148 (18), 121 (12), 105 (42), 101 (11), 79 (12), 77 (13) ¹ H NMR (as the hydrochloride, MeOH-d ₄ ):

1.1-2.7 (m, 8H), 2.24 (s, 3H), 4.11 (t, 1H), 6.9-7.5 (m, 9H), 8.79 (i.e. , 1H) 4- [5- (3,5-dimethyl-phenyl) -1- (4-fluoro-phenyl) -pentyl] -1H-imidazole MS: 336 (47, M ⁺ ), 189 (90), 176 (67), 175 (100), 166 (13), 148 (16), 121 (12), 119 (16), 91 (14) ¹ H NMR (as hydrochloride, MeOH-d ₄ ):

1.1-2.6 (m, 8H), 2.22 (s, 6H), 4.09 (t, 1H), 6.6-7.4 (m, 7H), 7.40 (broad s, 1H), 8.80 (broad s, 1H) 4- [1- (4-fluoro-phenyl) -5- (3-methoxy-phenyl) -pentyl] -1H-imidazole 4- [5- 3,5-dimethoxyphenyl) -1- (4-fluorophenyl) pentyl] -1H-imidazole

Example 8

4- (1,3-diphenyl-propyl) -1H-imidazole

a) 1-Benzyl-5- (1-oxo-3-phenyl-propyl) -1H-imidazole

1-Benzyl-5- (1-hydroxy-3-phenylpropyl) -1H-imidazole was oxidized with manganese dioxide in tetrachlorethylene as described in Example 7c).

¹ H NMR (as base, CDCl ₃ ):

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 belonging to the scope of the invention have been shown:

1-Benzyl-5- [5- (2,6-dimethyl-phenyl) -1-oxo-pentyl] -1H-imidazole. Hydrochloride, m.p. 175-180 ⁰ C.

1-Benzyl-5- (1-oxo-5-phenylpentyl) -1H-imidazole. Hydrochloride, mp 185-189 ° C.

b) 1-Benzyl-5- (1-hydroxy-1,3-diphenyl-propyl) -1H-imidazole

The Grignard reagent was prepared from 5.0 g bromobenzene and 0.76 g magnesium turnings in tetrahydrofuran. This solution was then added to 3.1 g of 1-benzyl-5- (1-oxo-3-phenylpropyl) -1H-imidazole in tetrahydrofuran and the reaction mixture was refluxed for three hours. The mixture was then poured into cold water, tetrahydrofuran was distilled off, the solution acidified with hydrochloric acid. The hydrochloride of the product was filtered off, washed with toluene and dried.

F. 196-198 ° C.

Using the same method, for example, the following compounds which fall within the scope of the invention have been shown:

1-Benzyl-5- (1-hydroxy-1,5-diphenyl-pentyl) -1H-imidazole. Hydrochloride, mp 193-196 ° C.

1-Benzyl-5- [5- (2,6-dimethylphenyl) -1-hydroxy-1-phenylpentyl] -1H-imidazole. Hydrochloride, mp 190-192 ° C.

c) 1-Benzyl-5- (1,3-diphenyl-propyl) -1H-imidazole

1-Benzyl-5- (1-hydroxy-1,3-diphenyl-propyl) -1H-imidazole was heated to 150 ^° C. with anhydrous potassium hydrogensulfate as described in Example 7 e). The double bond of the resulting intermediate, 1-benzyl-5- (1,3-diphenyl-prop-1-enyl) -1H-imidazole, was hydrogenated as described in Example 7f).

Hydrochloride, mp 154-174 ° C (diethyl ether).

¹ H NMR (as hydrochloride, MeOH-d ₄ ):

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:

1-Benzyl-5- (1,5-diphenyl-pentyl) -1H-imidazole ¹ HNMRIaIsBaS ^ CDCl ₃ ):

1.18-2.61 (m, 8H), 3.56 (t, 1H), 4.59 and 4.81 (AB q, 2H), 6.76-7.40 (m, 17H) 1 -Benzyl-5- [5- (2,6-dimethylphenyl) -1-phenylpentyl] -1H-imidazole

d) 4- (1,3-diphenyl-propyl) -1H-imidazole

1-Benzyl-5- (1,3-diphenyl-propyl) -1H-imidazole was hydrogenated in a mixture of 2N hydrochloric acid and ethanol at 60 ° C at 10% Pd / C as a catalyst. The product was isolated as in Example 7b) and purified by flash chromatography using methylene chloride-methanol (9.5: 0.5) as eluent. Yield 73%.

¹ H NMR (as base, CDCl ₃ ):

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, the following compounds were exemplified:

4- (1,5-diphenyl-pentyl) -1 H-imidazole ¹ H NMR (as hydrochloride, MeOH-d _4):

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 9

1-benzyl-4-d, 3-diphenyl-propyl-1H-imidazole 2.0 g benzyl bromide in 5 mL toluene was added to the mixture of 4- (1,3-diphenyl-propyl) -1H-imidazole (2, 6 g), 48% NaOH (10 ml), toluene (20 ml) and tetrabutylammonium bromide (0.2 g) were added dropwise at room temperature. After addition of the reaction mixture was stirred for three hours at room temperature. After addition of water, the toluene layer was separated. The toluene phase was then washed with water and evaporated to dryness. The residue contained the isomers 1-benzyl-4- (1,3-diphenyl-propyl) -1H-imidazole and 1-benzyl-5- (1,3-diphenyl-propyl) -1H-imidazole, of which the the former was separated and purified by flash chromatography (methylene chloride-methanol 9.5: 0.5).

Example 10 4- [1,4-Bis (4-fluoro-phenyl) -butyl] -1H-imidazole

a) 1-Benzyl-5- [1- (4-fluoro-phenyl) -1-hydroxymethyl] -1H-imidazole

The Grignard reaction of 4-bromo-fluorobenzene and 1-benzyl-5-imidazole-5-carbaldehyde is carried out analogously to Example 7 a).

The product is recrystallized from ethyl acetate as the hydrochloride. Yield 94%.

¹ H NMR (as base, CDCl ₃ + MeOH-d ₄ ):

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, M ⁺ ), 265 (5), 191 (18), 91 (100)

b) 1-Benzyl-5- [1- (4-fluoro-phenyl) -1-oxo-methyl] -1H-imidazole

The oxidation of 1-benzyl-5- [1- (4-fluoro-phenyl) -1-hydroxymethyl] -1H-imidazole was carried out analogously to Example 7c). The crude product was recrystallized from methanol as a base. Yield 72%.

¹ H NMR (as base, CDCl ₃ ):

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-fluoro-phenyl) -1-hydroxybutyl] -1H-imidazole

1-Benzyl-5- [1,4-bis (4-fluoro-phenyl) -1-hydroxybutyl] -1H-imidazole was analogous to Example 7a), starting from 3- (4-fluoro-phenyl) -1 bromo-propane and 1-benzyl-5- [1- (4-fluoro-phenyl) -1-oxo-methyl] -1H-imidazole. The product was purified by flash chromatography. ¹ H NMR (as base, CDCl ₃ ):

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 falling within the scope of the invention were shown:

1-Benzyl-5- [1- (4-fluoro-phenyl) -1-hydroxy-3-phenyl-propyl] -1H-imidazole MS: 386 (M ⁺ -, 8), 368 (22), 281 ( 100), 159 (26), 91 (99), 65 (34) 1-Benzyl-5- [1,3-bis (4-fluoro-phenyl) -1-hydroxy-propyl] -1H-imidazole MS: 404 (M ⁺ -, 2), 386 (18), 195 (16), 281 (33), 123 (34), 91 (100), 65 (20) 1-benzyl-5- [1- (4- fluorophenyl) 1-hydroxy-4-phenylbutyl] -1H-imidazole MS: 400 (M ⁺ -, 2), 382 (2), 281 (38), 191 (3), 91 (100) 65 (9) 1-Benzyl-5- [1- (4-fluoro-phenyl) -1-hydroxy-5- (3-methoxyphenyl) pentyl] -1H-imidazole ¹ H NMR (as the hydrochloride, MeOH- d ₄ ):

1.0-1.8 (m, 4H), 2.26 (t, 2H), 2.52 (t, 2H), 4.71 (s, 3H), 5.06 and 5.31 (AB q, 2H), 6.6-7.5 (m, 13H), 7.7 (s, 1H), 8.6 (s, 1H) 1-benzyl-5- [2,6-dimethyl -phenyl) -1- (4-fluorophenyl) -1-hydroxy-pentyl] -1H-imidazole MS: 442 (M ⁺ -, 19), 281 (71), 256 (5), 191 (7) , 119 (21), 91 (100)

d) 4- [1,4-bis (4-fluoro-phenyl) -butyl] -1H-imidazole 1-benzyl-5- [1,4-bis (4-fluoro-phenyl) -1-hydroxy-butyl] -1 H -imidazole (10 g) was dissolved in concentrated acetic acid (100 ml). To this solution was added 0.1 g of palladium / carbon and 0.8 mg of ammonium formate, then refluxed for one hour and cooled to room temperature. The solution was filtered through silica. The acetic acid filtrate was evaporated, the residue was dissolved in methylene chloride and washed once each with 2m aqueous sodium hydroxide solution and water. The methylene chloride solution was dried with sodium sulfate and evaporated in vacuo. The product was then converted to the hydrochloride with dry hydrogen chloride (in diethyl ether). F. 135-137 ° C.

¹ H NMR (as base, CDCl ₃ ):

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 For example, the same method has been shown for the following compounds which fall within the scope of the invention:

4- [1- (4-fluoro-phenyl) -3-phenylpropyl] -1H-imidazole ¹ H NMR (as base, CDCl ₃ ):

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) MS: 280 (4, M ⁺ ), 189 (9), 176 (100), 148 (15), 121 (9), 91 (12) 4- [1.3- Bis (4-fluoro-phenyl) -propyl] -1H-imidazole ¹ H NMR (as base, CDCl ₃ ):

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, M ⁺ ), 189 (8), 176 (100), 122 (22), 109 (42) 4- [1- (4-fluoro-phenyl) -4-phenyl-butyl] -1H-imidazole ¹ HNMR1aBaSe ₁ CDCl ₃ ):

1.3-2.3 (m, 4H), 2.6 (t, 2H), 3.88 (t, 1H), 6.67 (s, 1H), 6.7-7.3 ( m, 9H), 7.39 (s, 1H) MS: 294 (31, M ⁺ ), 189 (24), 175 (100), 91 (31) 4- [1 - (4-fluoro-phenyl) -5- (3-methoxyphenyl) pentyl] -1H-imidazole

¹ H NMR (as base, CDCl ₃ ):

1.1-2.3 (m, 6H), 2.5 (t, 2H), 3.76 (s, 3H), 3.85 (distorted t, 1H), 6.6-7.6 ( m, 1OH) MS: 338 (19, M ⁺ ), 189 (43), 175 (70), 148 (12), 121 (20), 36 (100)

4- [1- (4-Fluorophenyl) -5- (4-methoxyphenyl) pentyl] -1H-imidazole

¹ H NMR (as base, CDCl ₃ ):

1.1-2.3 (m, 6H), 2.49 (t, 2H), 3.75 (s, 3H), 3.8 (distortion test, 1H), 6.6-7.6 (m , 10H) MS: 338 (10, M ⁺ ), 189 (20), 175 (22), 148 (6), 121 (22), 36 (100)

4- [5- (2,6-Dimethyl-phenyl) -1- (4-fluoro-phenyl) -pentyl] -1H-imidazole

¹ H NMR (as base, CDCl ₃ ):

1.25-1.5 (m, 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 (m, 2H), 7.4 (s, 1H)

MS: 336 (50, M ⁺ ), 217 (20), 189 (75), 175 (100), 148 (13), 119 (23)

Example 11

1-Benzyl-5- [1- (4-fluoro-phenyl) -3-phenyl-1-propenyl] -1H-imidazole

To a suspension of zinc powder (0.06 mol) of tetrahydrofuran (30 ml) were added dropwise while stirring at -10 ° C under dry nitrogen, 03 mol of titanium tetrachloride. The mixture was refluxed for one hour. After cooling the solution to 0 ^° C, 1-benzyl-5- [1- (4-fluoro-phenyl) -1-oxo-methyl] -1H-imidazole (0.005 mol) in tetrahydrofuran (10 ml) and phenylacetaldehyde (0.006 mol) in tetrahydrofuran (10 ml). The mixture was refluxed with stirring for one hour, then the dark mixture was poured into water (60 ml). The tetrahydrofuran was evaporated and the mixture extracted with methylene chloride (2 x 100 ml). The methylene chloride solution was washed with 2N sodium hydroxide solution and water, dried with sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography

¹ H NMR (as base, CDCl ₃ ): 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 12 4- [1,3-Bis (4-nitrophenyl) propyl] -1H-imidazole

1.8 g (14.6 mmol) of urea nitrate were added in small portions to a mixture of 2.7 g (7.3 mmol) of 4- (1,3-diphenyl-propyl) -1H-imidazole in 6.4 ml of concentrated sulfuric acid below given by 10 ° C. The reaction mixture was stirred for 2 hours at room temperature, basified (with 2M sodium hydroxide) and purified using methylene chloride-methanol (95: 5) as eluent by flash chromatography.

Claims (35)

claims: or a non-toxic pharmaceutically acceptable acid addition salt thereof, wherein R ₁ , R ₂ , R't and R ' ₂ , which may be the same or different, are H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , NO ₂ , CF ₃ , CHF ₂ , CH ₂ F or halogen; R 'is H or -CH ₂ wherein R _{3 is} H, CH ₃ or halogen; R ₄ is H, R ₅ is H or OH, R ₆ is H or OH and R ₇ is H or R ₄ and R ₆ together form a bond or R ₅ and R ₇ together form a bond; X and Y, which may be the same or different, are a bond, an CT_ ₂ -alkyl or the corresponding alkenyl, and ζ is 0-2 consisting in reacting a 4 (5) -lmidazol derivative of the formula Il N
I
R ' CH ₂ -CH ₂ - (CH ₂ ) _Z -CH ₂ -C-OR wherein R 'and ζ are as defined above, and R is alkyl, with a Grignard reagent of the formula (CH ₂ ) _n MgHal wherein R ₁ and R _{2 are} as defined above, and η is 0-2, to a compound of the formula (la) which is Oh T CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ -C- (CH ₂ ) _n (9 ^H 2) n ι
R 2. A process for the preparation of a compound as defined in claim 1 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the reaction of a 4 (5) -imidazole derivative of the formula - CH ₂ -CH ₂ - (CH ₂ ) _z - (I wherein R 'and ζ are as defined above and R is alkyl, with a Grignard reagent (CH ₂ ) _n MgHal wherein R ₁ and R _{2 are} as defined above and η is 0-2, to a compound of the formula OCH ₂ CH ₂ (CH ₂ J ₂ CH ₂ -C- (CH ₂ ) _n - R ₂ R '
which continues with a second Grignard compound of the formula R '? <JQ V- (CH ₂ ) _m MgHal wherein R'i and R ' _{2 are} as defined above and m is 0-2, to a compound of formula (I a) which appears as follows -N ^ OH CH ₂ CH ₂ (CH ₂ J ₂ CH ₂ -C- (CH ₂ ) _n 3. A process according to claims 1-2 for the preparation of a compound as defined in claim 1 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, wherein an amide of the formula CH ₂ -CH ₂ - (CH ₂ ) _z - ( R ' wherein R 'and ζ are as defined above, is used as the starting material in place of the corresponding ester. 4. A process according to claims 1-2 for the preparation of a compound as defined in claim 1 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, wherein a nitrile of formula _f .N. O-CH ₂ -CH ₂ - (CH ₂ J ₂ -CH ₂ -CN 'N I R' wherein R 'and ζ are as defined above, is used as the starting material in place of the corresponding ester. 5. A process for the preparation of a compound as defined in claim 1 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a 4 (5) -imidazole-carbaldehyde of the formula R ' in which R 'is as defined above, with a Grignard reagent, HaImCHCH ₂ (CH ₂ ) _Z CH ₂ -CH-X R ' in which R ₁ , R ₂ , R'v R'2, X, Y and ζ are as defined above, to give a compound of formula (Ia), $ which is as follows OH CH-CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X R ' 6. A process for the preparation of a substituted imidazole of the formula CHR ₆ -CHR ₄ - (CH ₂ ) _z -CHR ₇ -CR ₅ -X or a non-toxic, pharmaceutically acceptable acid addition salt thereof, wherein Ri, R ₂ , R't and R ' ₂ , which may be the same or different, are H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , OH, CH ₂ OH, NO ₂ , NH ₂ , CN, CF ₃ , CHF ₂ , CH ₂ F or halogen; R 'is H or wherein R _{3 is} H, CH ₃ or halogen; R ₄ is H, R ₅ is H or OH, and R ₆ is H or OH and R ₇ is H or R ₄ and R ₆ together form a bond or R ₅ and R ₇ together form a bond; X and Y, which may be the same or different, are a bond, C | _ ₂ alkyl or the corresponding alkenyl, ζ is 0-2, consisting in reacting a 4 (5) -lmidazol derivative of the formula 0 II CH ₂ -CH ₂ - (CH ₂ ) 2-CH ₂ -C-OR wherein R 'and ζ are as defined above and R is alkyl with a Grignard reagent (CH ₂ J _n MgHaI in which η is 0-2 and Ri and / or R ₂ OCH _{2 are} Ph or OTHP, to a compound of the formula OH CH ₂ CH ₂ (CH ₂ ) ₂ CH ₂ -C- (CH ₂ ) _n ( ^9H 2) n N I R ' wherein R ₁ and / or R _{2 are} OCH ₂ Ph or OTHP, and which is further hydrogenated to a compound of formula (Ia), which appears as follows OH I CH ₂ CH ₂ (CH ₂ J ₂ CH ₂ -C- (CH ₂ ) _n (9 ^Η 2) η wherein ζ and η are as defined above, and R ₁ and / or R ₂ are OH, and where R ₁ or R _{2 is} not OH, they are H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , NO ₂ , CF ₃ , CHF ₂ , CH ₂ F or halogen. 7. A process for the preparation of a compound according to claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the reaction of a 4 (5) -imidazole derivative of the formula if -CH ₂ -CH ₂ - (CH ₂ ) _Z -CH ₂ -C-OR N I R ' wherein R 'and ζ are as defined above and R is an alkyl, with a Grignard reagent wherein η is 0-2, and i) R ₁ and / or R ₂ OCH _{2 are} Ph or OTHP, or ii) neither R ₁ nor R ₂ OCH _{2 are} Ph or OTHP to obtain a compound of the formula below O Il -H-CH ₂ CH ₂ (CH ₂ ) _z CH ₂ -C- (CH ₂ ) _n I R ' which is further reacted with another Grignard compound of the formula _; R ' where m is 0-2, and iii) R't and / or R ' ₂ OCH _{2 are} Ph or OTHP, or iv) neither R'-i nor R ' _{2 are} OCH ₂ Ph or OTHP, provided that ii) and iv) are not simultaneously active to form a compound of formula I oh -Fj- CH ₂ CH ₂ (CH ₂₎ 2 CH ₂ -C- (CH _{2) n} (CH ₂ ) m R ' in which one or more substituents R ₁ , R ₂ , R't and R ' _{2 are} OCH ₂ Ph or OTHP which is then hydrogenated to give a compound of formula (Ia) which appears as follows OH H ₂ CH ₂ (CH ₂ ) _z CH ₂ -C- (CH ₂ ) _n N 'H and in which ζ 0-2, m and n, which may be the same or different, are 0-2 and one or more
several of the substituents R ₁ , R ₂ , R'-i and R ' ₂ are OH, and the substituents which are not OH,
are H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , NO ₂ , CF ₃ , CHF ₂ , CH ₂ F or halogen. A method according to claims 6-7 for the preparation of a compound of formula (I a) as defined in claim 6 or a non-toxic, pharmaceutically acceptable one
Acid addition salt thereof, wherein an amide of the formula 0 W CH ₂ -CH ₂ - (CH ₂ ) _Z -CH ₂ -C-NH ₂ wherein R 'and ζ are as defined above is used as the starting material in place of the corresponding ester. A process according to claims 6-7 for the preparation of a compound of formula (I a) as defined in claim 6 or a non-toxic, pharmaceutically acceptable one
Acid addition salt thereof in which a nitrile of the formula. CH ₂ -CH ₂ - (CH ₂ ) _Z -CH ₂ -CN wherein R 'and ζ are as defined above, is used as the starting material in place of the corresponding ester.
A process for the preparation of a compound as defined in claim 6, or one non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in
Reaction of a 4 (5) -imidazole-carbaldehyde of the formula CHO wherein R 'is as defined above, with a Grignard reagent HaImCHCH ₂ (CH ₂ ) _Z CH ₂ -CH-X wherein X, Y and ζ are as defined above, and one or more of the substituents R ₁ , R ₂ , R'i and R ' _{2 are} OCH ₂ Ph or OTHP to provide a compound of the following formula OH
I CH-CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X wherein one or more of the substituents R ₁ , R ₂ , R't and R ' _{2 is} OCH ₂ Ph or OTHP, which is then hydrogenated to give a compound of formula (I a) which appears as follows OH CH-CH ₂ - (CH ₂ ) ₂ -CH ₂ -CH-X wherein X, Y and ζ are as defined above and one or more of the substituents R ·, R ₂ , R'i and R ' _{2 are} OH, and the non-OH substituents are H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , NO ₂ , CF ₃ , CHF ₂ , CH ₂ F or halogen. 11. A process for the preparation of a compound according to claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the dealkylation of a compound of formula (Ia) CHR ₆ -CHR ₄ - (CH ₂ ) 2 -CHR ₇ -CR ₅ -X R ¹ wherein R ', R ₄ , R ₅ , R ₆ , R ₇ , X, Y and ζ are as defined above and one or more of the substituents R ₁ , R ₂ , R 1 and R' _{2 are} OCH ₃ to form a compound of To give formula (I a) in which one or more of the substituents R ₁ , R ₂ , R ^ and R ' _{2 are} OH. A process for the preparation of a compound according to claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the hydrolysis of a compound of formula (I a), -H-CHR ₆ -CHR ₄ - (CH ₂ ) 2 -CHR ₇ -CR ₅ -X NY R ' wherein R ', R ₄ , R ₅ , Re , R 7, X "Y and ζ are as defined above and one or more of the substituents Ri, R ₂ , R't and R' are ₂ CN, and the subsequent reduction a connection of the formula (I a) wherein one or more of the substituents R ₁ , R ₂ , R'i and R 'is ₂ CH ₂ OH.
A process for the preparation of a compound as defined in claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof consisting in the diazotization of a compound of formula (I a) R ' wherein R ', R ₄ , R ₅ , R ₆ , R ₇ , X, Y and ζ are as defined above and one or more of the substituents R ₁ , R ₂ , R'i and R' _{2 are} NH ₂ to form a Compound of formula (I a) in which one or more of the substituents R ₁ , R ₂ , R't and R ' _{2 are} CN. A process for the preparation of a compound of formula (Ia) as defined in claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof consisting in the hydrogenation of a compound of formula (Ia), CHR ₆ -CHR ₄ - (CH ₂ ) _Z -CHR ₇ -CR ₅ -X N. ι R ' wherein R ', R ₄ , R ₅ , R ₆ , R ₇ , X, Y and ζ are as defined above and one or more of the substituents R ₁ , R ₂ , R' •, and R ' _{2 are} NO ₂ to obtain a compound of the formula (I a) in which R 'is H, R ₄ , R ₅ , R ₆ , R ₇ , X, Y and ζ are as defined above and one or more of the substituents R ₁ , R ₂ , R'i and R ' _{2 is} NH ₂ . A process for the preparation of a compound according to claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the dehydration of a compound of the formula N OH ^v - ^ - CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ -CX- to obtain a compound of formula (I a) which looks like this _} CH ₂ CH ₂ (CH ₂ ) _Z CH = CX Ν 'I R' wherein R ', R _n , R ₂ , R' _1f R ' ₂ and ζ are as defined above. 16. A process for the preparation of a compound according to claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the reaction of a compound of the formula y N OH N, - \ CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ -CX NY in a hydrogen transfer reaction to obtain a compound of the formula (Ia) represented by the following formula _t CH ₂ CH ₂ (CH ₂ ) N H wherein R ₁ , R ₂ , R'i, R'2, X, Y and ζ are as defined above. 17. A process for the preparation of a compound as defined in claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the hydrogenation of a compound of the formula OH I CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ -CX N I R ' R ' wherein R 'is a substituted or unsubstituted benzyl, and R ₁ , R ₂ , R' _v R ' ₂ , X, Y and ζ are as defined above to obtain a compound of formula (I a) represented by the following formula is pictured OH ι N I H CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ -CX R ' A process for the preparation of a compound as defined in claim 6 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a compound of the formula .N N I R ' CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ -CX wherein R 'is substituted or unsubstituted benzyl, and R ₁ , R ₂ , R' _1f R ' ₂ , X, Y and ζ are as defined above, in a hydrogen transfer reaction to obtain a compound of formula (I a) which looks like this OH CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ -CX i
H 19. A process for the preparation of a compound as defined in claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the hydrogenation of a compound of the formula N
-i-CH ₂ CH ₂ (CH ₂ ) _z CH = CX NY I
R ' to obtain a compound of the formula (Ia) represented by the following formula -J] -CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ CH-X R ' wherein R ', R ₁ , R ₂ , R'i, R' ₂ , X, Y and ζ are as defined above. A process for the preparation of a compound as defined in claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof consisting in the hydrogenation of a compound of the formula .KL H ₂ CH ₂ (CH ₂ ) _Z CH = CX N 'Y R '/ ^ N. r ' to obtain a compound of formula (I a) which looks like ₍ wherein R ₁ , R ₂ , R'i, R ' ₂ , X, Y and ζ are as defined above. 21. A process for the preparation of a compound as defined in claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the reaction of a compound of the formula -JJ-CH ₂ CH ₂ (CH _{2) Z} CH = CX NY R ' R ' by a hydrogen transfer reaction to obtain a compound of the formula (Ia) which looks like follows. -CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ CH-X N ι wherein R ₁ , R ₂ , R'i, R'2, X, Y and ζ are as defined above. A process for the preparation of a compound as defined in claim 6 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the dehydration of a compound of the formula .N OH CH-CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X R ' to obtain a compound of formula (Ia) which looks like this R ₁ -f | -CH = CH- (CH ₂ ) _Z -CH ₂ -CH-X wherein R ', Ri, R ₂ , R'i, R' ₂ / X / Y and ζ are as defined above. A process for the preparation of a compound as defined in claim 6 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a compound of the formula OH I CH-CH ₂ - (CH ₂ ) 2- by a hydrogen transfer reaction to obtain a compound of formula (I a) which looks like ₍ , - (CH ₂₎ 2 -CH ₂ -CH-X- "^ Y I f \ J ^ "~ R ' wherein R ₁ , R ₂ , R'i, R'2, X, Y and ζ are as defined above. A process for the preparation of a compound as defined in claim 6 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the hydrogenation of the compound of formula OH CH-CH ₂ - (CH ₂ ) 2- wherein R 'is a substituted or unsubstituted benzyl, and R ₁ , R ₂ , R' _{1 (} R ' ₂ , X, Y and ζ are as defined above to obtain a compound of formula (Ia) having the following appearance. OH is CH-CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X A process for the preparation of a compound as defined in claim 6 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a compound of the formula OH CH-CH ₂ - (CH ₂ ) 2- wherein R 'is a substituted or unsubstituted benzyl, and R ₂ , R' _{1 (} R ' ₂ , X, Y and ζ are as defined above, by a hydrogen transfer reaction to obtain a compound of formula (I a), which is the following Looks like. OH CH-CH ₂ - (CH ₂ ) ₂ -CH ₂ -CH-X R ' 26. A process for the preparation of a compound as defined in claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the hydrogenation of the compound of the formula Ri CH = CH- (CH ₂ ) J ₂ -CH ₂ -CH-X ^R 2 to obtain a compound of the formula (I a) which has the following appearance CH ₂ CH ₂ (CH ₂ ) wherein R ', R ₁ , R ₂ , R' _1f R'2, X, Y and ζ are as defined above. 27. A process for the preparation of a compound as defined in claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the hydrogenation of a compound of formula ₍ CH = CH- (CH ₂ ) ₂ -CH ₂ -CH-X R ' wherein R ', R ₁ , R ₂ , R' _v R ' ₂ , X, Y and ζ are as defined above to give a compound of formula (I a) which appears as follows ^ CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ CH-X NY H ^ \ R A process for the preparation of a compound as defined in claim 6 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a compound of the formula NO' CH = CH- (CH ₂ ) _Z -CH ₂ -CH-X wherein R ', R ₁ , R ₂ , R'i, R'2 / X / Y and ζ are as defined above, by a hydrogen transfer reaction to obtain a compound of formula (I a), which is as follows. -1 + CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ CH-X IT Y H ^ S ^ R'i 29. A process for the preparation of a compound as defined in claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the hydrogenation of a compound of formula _r .N H ₂ CH ₂ (CH ₂ ) _Z CH ₂ CH-X Ϋ R ¹ wherein R ₁ , R ₂ , R ' _1r R' ₂ , X, Y and ζ are as defined above, and R 'is substituted or unsubstituted benzyl to obtain a compound of formula (I a) which appears as follows. CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ CH-X N 'Y H ^ \ R ₁ A process for the preparation of a compound as defined in claim 6 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a compound of the formula CH ₂ CH ₂ (CH ₂ ) ₂ CH ₂ CH-X R ' R ' wherein R ₁ , R ₂ , R'i, R ' ₂ , X, Y and ζ are as defined above, and R' is substituted or unsubstituted benzyl by a hydrogen transfer reaction to obtain a compound of formula (I a) which looks like this. CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ CH-X Y ^R l R2 31. A process for the preparation of a compound as defined in claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the reaction of a compound of the following formula ₍ -H-CHR ₆ -CHR ₄ - (CH ₂ ) _Z -CHR ₇ -CR ₅ -X (Γ ^ / Γ N Y R? I JL in which R ₁ , R ₂ , R '*, R' _{2 /} R ₄ , R ₅ , R ₆ , R ₇ , X, Y and ζ are as defined above, with a strong base and further with a benzyl halide the formula ₍ CH ₂ Hal wherein R _{3 is} as defined above to obtain a compound of formula (Ia) which appears as follows. -H-CHR ₆ -CHR ₄ - (CH ₂ ) 2 -CHR ₇ -CR ₅ -XN γ A method of preparing a compound as defined in claim 6 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the nitration of a compound of formula (Ia), -JJ-CHR ₆ -CHR ₄ - (CH ₂ ) _Z -CHR ₇ -CR ₅ -XN γ R ' wherein R ', R ₄ , R ₅ , R ₆ , R ₇ , X, Y and ζ are as defined above and one or more of the substituents R ₁ , R ₂ , R'-i and R' _{2 are} H to form a Compound of formula (I a) wherein one or more of the substituents R ₁ , R ₂ , R't and R 'are ₂ NO ₂ . 33. A process for the preparation of a compound as defined in claim 6 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a halogenated hydrocarbon of the formula ₍ II) Hal-CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X wherein R ₁ , R ₂ , R'i, R ' ₂ / X / Y and ζ are as defined above, with triphenylphosphine to obtain a phosphonium salt of the following formula ₍ Ph Hai ⁰ Ph-P ^ -CH ₂ (CH ₂ J ₂ CH ₂ CH-X Ph Y R ' which is further reacted with a strong base and then with an imidazole-4 (5) -carbaldehyde of the formula. CHO N 'I R' wherein R 'is as defined above to obtain a compound of formula (I a) which appears as follows. CH = CH- (CH ₂ ) J ₂ -CH ₂ -CH-X R ¹ 34. A process for the preparation of a compound as defined in claim 6 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a halogenated 4 (5) -imidazole derivative of the formula ₍ II) CH ₂ CH ₂ (CH ₂ ) _z CH ₂ Hal NIR ¹ wherein R 'and ζ are as defined above, with triphenylphosphine to a phosphonium salt of the formula CH ₂ CH ₂ (CH ₂ ) _Z CH ₂ -P®-Ph shark © N Ph R 'which is further reacted with a strong base and then with a ketone of the formula R ' wherein R ₁ , R ₂ , R'i, R'2, X and Y are as defined above, to give a compound of formula (Ia) which is as follows. R ' CH ₂ CH ₂ (CH ₂ ) _Z CH = CX Y R ' 35. A process for the preparation of a compound as defined in claim 6 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a halogenated hydrocarbon of formula _f Hal-CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X wherein R ₁ , R ₂ , R'i, R ' ₂ , X, Y and ζ are as defined above, with a phosphonic triester to form a compound of the formula (RO) ₂ -P-CH ₂ - (CH ₂ ) _Z -CH ₂ -CH-X wherein R is alkyl which is further reacted with a base and then with an imidazole-4 (5) -carbaldehyde of the formula -μ- R ' wherein R 'is as defined above to obtain a compound of formula (I a) which appears as follows. -M- CH = CH- (CH ₂ ) _Z -CH ₂ -CH-X NY R ' R ' ^R 2 36. A process for the preparation of a substituted imidazole of the formula R ' R ' (Ib) or a non-toxic, pharmaceutically acceptable acid addition salt thereof, wherein R ₁ , R ₂ , R'i and R ' ₂ , which may be the same or different, are H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , NO ₂ , CF ₃ , CHF ₂ , CH ₂ F or halogen; R 'is H or -CH ₂ R ₃ , where R _{3 is} H, CH ₃ or halogen; R ₄ is H or OH and R ₅ is H or R ₄ and R ₅ together form a bond and y is 0-4, consisting in the reaction of an imidazole-4 (5) -carbaldehyde of the formula CHO where R 'is as defined above, with a suitable arylalkylmagnesium halide of the formula HaImCHCH ₂ (CH ₂ ) y wherein R ₁ , R ₂ and y are as defined above, a compound of the formula which, when R 'is a substituted or unsubstituted benzyl, can be arbitrarily hydrogenated to remove the benzylic R' and which is further oxidized to obtain a compound of the following formula which is further reacted with an aryl magnesium halide of the following formula MgHaI wherein R'i and R ' _{2 are} as defined above and Hai is halogen to obtain a compound of formula (I b) which appears as follows. -U- C-CH ₂ (CH ₂ ) y - OH N \ R ' 37. A process for the preparation of a compound as defined in claim 36 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of an imidazole-4 (5) -carbaldehyde of the formula CHO >> R 'where R' is as defined above, with an arylmagnesium halide of the formula ^R 'l R'2 wherein R'i and R ' _{2 are} as defined above, and Hal is halogen to obtain a compound of the following formula _f N. wherein R ', R'i and R' _{2 are} as defined above which, when R 'is a substituted or unsubstituted benzyl, may be hydrogenated in any manner to remove the benzylic R' and which is oxidized to give a Compound of the formula below which is further reacted with a suitable arylalkyl magnesium halide of the formula. R ₁ HaIMgCH ₂ (CH ₂ ) _y \ ("3ζ wherein R ₁ , R ₂ and y are as defined above to obtain a compound of formula (I b) which appears as follows. C-CH ₂ (CH ₂ ) _y OH 38. A process for the preparation of a substituted imidazole of the formula ^R '2 (Ib) or a non-toxic, pharmaceutically acceptable acid addition salt thereof, wherein R ₁ , R ₂ , R'i and R ' ₂ , which may be the same or different, are H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , OH , CH ₂ OH, NO ₂ , NH ₂ , CN, CF ₃ , CHF ₂ , CH ₂ F or halogen; R 'is H or -CH ₂ R ₃ , where R _{3 is} H, CH ₃ or halogen; R ₄ is H or OH and R ₅ is H or R ₄ and R ₅ together form a bond and y is 0-4, consisting in the reaction of an imidazole-4 (5) -carbaldehyde of the formula -N Ph CHO "KT I R" wherein R 'is as defined above, with an arylalkylmagnesium halide of the formula HaIMGCH ₂ (CH ₂ ) y where y is 0-4, shark is halogen and i) R ₁ and / or R ₂ are OCH ₂ Ph or OTHP or ii) neither R ₁ nor R ₂ are OCH ₂ Ph or OTHP to obtain a compound of the formula: N. N I R ' OH C-CH ₂ (CH ₂ ) _y which is further oxidized to obtain a compound of the following formula R ' I! C-CH ₂ (CH ₂ ) _y which is further reacted with an arylmagnesium halide of the formula r ' R '2 ? Y ^r ^) - MgHaI iii) R't and / or R ' ₂ OCH _{2 are} Ph or OTHP or iv) neither R'i nor R ' ₂ are OCH ₂ Ph or OTHP, provided that ii) and iv) do not apply at the same time in order to obtain a compound of the following formula _f C-CH ₂ (CH ₂ ) _y
OH wherein R 'and y are as defined above and one or more of the substituents R ₁ , R ₂ , R'i and R' _{2 are} OCH ₂ Ph or OTHP which is further hydrogenated to give a compound of formula (I b) which looks like this _f C-CH ₂ (CH ₂ ) _y wherein y is 0-4 and one or more of the substituents R ₁ , R ₂ , R'i and R ' _{2 are} OH, and the non-OH substituents are H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , NO ₂ , CF ₃ , CHF ₂ , CH ₂ F or halogen. 39. A process for the preparation of a compound as defined in claim 38 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of an imidazole-4 (5) -carbaldehyde of the formula .N CHO wherein R 'is as defined above, with an arylmagnesium halide of the formula MgHaI in which shark is halogen and i) R'-, and / or R ' ₂ are OCH ₂ Ph or OTHP or ii) neither R 'nor R' ₂ are OCH ₂ Ph or OTHP to obtain a compound of the following formula which is oxidized to a compound of the formula which is further reacted with an arylalkylmagnesium halide of the formula HaIMGCH ₂ (CH ₂ ) _y S ^ in which y is as defined above and Hal is halogen and iii) R ₁ and / or R ₂ are OCH ₂ Ph or OTHP or iv) neither R ₁ nor R ₂ is OCH ₂ Ph or OTHP, provided that ii) and iv) do not apply simultaneously to a compound of the formula C-CH ₂ (CH ₂ ) _y OH wherein R 'and y are as defined above and one or more of the substituents Ri, R2. R'i and R ' ₂ are OCH ₂ Ph or OTHP which is further hydrogenated to a compound of formula (I b) which looks like ₍ R'i ^ R ' C-CH ₂ (CH ₂ ) _y OH wherein y is O-4 and one or more of the substituents R ₁ , R ₂ , R'i and R ' ₂ are OH and the substituents other than OH are H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , NO ₂ , CF ₃ , CHF ₂ , CH ₂ F or halogen. 40. A process for the preparation of a compound as defined in claim 38 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the dealkylation of a compound of formula (I b), R'i R ' - (CH ₂ ) _y wherein R ', y, R ₄ and R _{5 are} as defined above, and one or more of the substituents R ₁ , R ₂ , R'i and R' _{2 are} OCH ₃ to obtain a compound of the formula (I b) in which one or more of the substituents R ₁ , R ₂ , R'i and R ' _{2 are} OH. 41. A process for the preparation of a compound as defined in claim 38 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the hydrolysis of a compound of formula (Ib), wherein R ', R ₄ , R ₅ and y are as defined above, and one or more of the substituents R ₁ , R ₂ , RS and R' ₂ are CN, and further reduced to a compound of formula (I b), in one or more of the substituents R ₁ , R ₂ , R'i and R 'are ₂ CH ₂ OH. 42. A process for the preparation of a compound as defined in claim 38 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the diazotization of a compound of formula (I b) _f - (CH ₂ ) _y wherein R ', R ₄ , R ₅ and y are as defined above, and one or more of the substituents R ₁ , R ₂ , R'i and R' _{2 are} NH ₂ , to be a compound of the formula (I b) wherein one or more of the substituents R ₁ , R ₂ , R'i and R 'are ₂ CN.
43. A process for the preparation of a compound as defined in claim 38 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the hydrogenation of a compound of formula (I b) ₍ R'i R'o - CH (CH ₂ ) _y wherein R ', R ₄ , R ₅ and y are as defined above and one or more of the substituents R ₁ , R ₂ , R't and R' ₂ NO ₂ to obtain a compound of the formula (1 b), in R 'is H, y is 0-4 and one or more of the substituents R ₁ , R ₂ , R'i and R' ₂ are NH ₂ . A process for the preparation of a compound as defined in claim 38 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the dehydration of a compound of the formula. C-CH ₂ (CH ₂ ) _y
OH to obtain a compound of formula (I b) which looks like R'2 = CH- (CH ₂ ) _y wherein R ', R ₁ , R ₂ , R' _1f R ' ₂ and y are as defined above. 45. A process for the preparation of a compound as defined in claim 38 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a compound of the formula -CH ₂ (CH ₂ ) _y OH by a hydrogen transfer reaction to obtain a compound of the formula (Ib) which looks as follows -CH ₂ (CH ₂ ) _y wherein Ri, R ₂ , R'i, R ' ₂ and y are as defined above. 46. A process for the preparation of a compound as defined in claim 38 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the hydrogenation of a compound of the formula ^R '2 C-CH ₂ (CH ₂ ) _y OH wherein R 'is substituted or unsubstituted benzyl, and R ₁ , R ₂ , RS and R' ₂ are as defined above to obtain a compound of formula (I b) which appears as follows C-CH ₂ (CH ₂ ) _y OH 47. A process for the preparation of a compound as defined in claim 38 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the hydrogenation of a compound of the formula ^R '2 C-CH ₂ (CH ₂ ) y I
OH ^R 2 R ' wherein R 'is substituted or unsubstituted benzyl, and R ₁ , R ₂ , R'i and R' ₂ are as defined above, by a hydrogen transfer reaction to obtain a compound which looks like _r R'2 C-CH ₂ (CH ₂ ) _y
OH wherein R ₁ , R ₂ , R '- \ and R' ₂ and y are as defined above. 48. A process for the preparation of a compound as defined in claims 36 or 38 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the reaction of a benzoylimidazole of the formula wherein R ', RS and R' _{2 are} as defined in claim 36, with an aldehyde of the formula O
HC- (CH ₂ ) _y wherein Ri, R ₂ and y are as defined in claim 38, in the presence of a lower-valent titanium reagent, to obtain a compound of formula (I b) which appears as follows 49. A process for the preparation of a compound as defined in claims 36 or 38 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a benzoylimidazole of the formula wherein R 'is as defined above, and R', and / or R ' ₂ OCH _{2 are} Ph or OTHP, with an aldehyde of the formula HC- (CH ₂ ) _y wherein R ₁ , R ₂ and y are as defined in claim 38 in the presence of a lower titania reagent of a compound of the formula ^R '2 wherein RS and / or R ' _{2 are} OCH ₂ Ph or OTHP, which is further hydrogenated to a compound of formula (I b), which is as follows ^{R /} 2 CHCH ₂ (CH ₂ ) _y wherein R'i and / or R ' _{2 are} OH, the substituents R'i or R' ₂ , which are not OH, H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , OCH ₃ , NO ₂ , CF ₃ , CHF ₂ , CH ₂ F, are halogen, and R ₁ and R ₂ are as defined in claim 38. 50. A process for the preparation of a compound as defined in claim 38 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the hydrogenation of a compound of the formula C = CH (CH ₂ ) _y to a compound of formula (I b), which looks like this CH-CH ₂ (CH ₂ ) _y N
R ' wherein R ', R ₁ , R ₂ , R \, R' ₂ and y are as defined above. 51. A process for the preparation of a compound as defined in claim 38 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the hydrogenation of a compound of the formula C = CH (CH ₂ ) _y to a compound of formula (I b) which looks like ₍ CH-CH ₂ (CH ₂ ) _y - wherein R ₁ , R ₂ , R'i, R'2 and γ are as defined above. 52. A process for the preparation of a compound as defined in claim 38 or a non-toxic, pharmaceutically acceptable acid addition salt consisting in the reaction of a compound of the formula by a hydrogen transfer reaction to a compound of formula (I b), which looks like this. CH-CH ₂ (CH ₂ ) _y wherein R ₁ , R ₂ , R'i, R'2 and y are as defined above. 53. A process for the preparation of a compound as defined in claim 38 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the hydrogenation of a compound of formula _r H-CH ₂ (CH ₂ ) _y wherein R ₁ , R ₂ , R'i, R ' ₂ and y are as defined above, and R' is a substituted or unsubstituted benzyl, to a compound of formula (Ib) which is as follows and wherein R ₁ , R ₂ , R'i »R'2 and y are as defined above. N I H 4J-CH-CH ₂ (CH ₂ ) _y 54. A process for the preparation of a compound as defined in claim 38 or a non-toxic pharmaceutically acceptable acid addition salt thereof consisting in the reaction of a compound of the formula CH-CH ₂ (CH ₂ ) y NI
R ' wherein R ₁ , R ₂ , R'i, R ' ₂ and y are as defined above, and R' is substituted or unsubstituted benzyl, by a hydrogen transfer reaction to a compound of formula (I b), which appears as follows ^R '2 CH-CH ₂ (CH ₂ ) _y 55. A process for the preparation of a compound as defined in claim 38 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the reaction of a compound of formula _f CR ₄ -CHR ₅ - (CH ₂ ) y wherein R ₁ , R ₂ , R'i, R ' ₂ , R ₄ , R ₅ and y are as defined above, with a strong base and further with a benzyl halide of the formula ₍ CH ₂ Hal wherein R _{3 is} as defined above, and Hal is halogen, to a compound of formula (I b) which looks like this R ' CR ₄ -CHR ₅ - (CH ₂ ) _y - 56. A process for the preparation of a compound as defined in claim 38 or a non-toxic, pharmaceutically acceptable acid addition salt thereof, consisting in the nitration of a compound of formula (I b) , C - CH - (CH ₂ J y R ₄ R ₅ wherein R ', R _4, R ₅ and y are as defined above and one or more of the substituents Ri, R _2, R'i and R' ₂ are H, to a compound of formula (I b) wherein one or more the substituents R ₁ , R ₂ , R'i and R 'are ₂ NO ₂ .