JPH02115172A - 1, 5-disubstituted imidazole derivative and production thereof - Google Patents

Abstract

NEW MATERIAL: A compound of formula I [wherein W is 1-, 2- or 9-anthryl, naphthyl (each benzene ring is unsubstituted or substituted with a halogen, a 1-4C alkyl, OH, cyano or the like), pyridyl, pyrazinyl or the like; R is a 1-4C alkyl, a halogen-1-4 C-alkyl, a 2-5C alkanoyl or the like; and Z is a single bond, a double bond or a triple bond] and a salt thereof (except a compound of formula I (wherein R is a 1-4C alkyl when W is cyano-substituted naphthyl, and Z is a single bond).

EXAMPLE: 5-(3-Chloroprop-1-yl)-1-(anthr-1-ylmethyl)-1H-imidazole.

USE: Medicines, aromatase inhibitors, an inhibitor against the in vivo change of androgen into estrogen.

PREPARATION: For example, a compound of formula II (wherein R' is R devoid of a halogen-1-4C alkyl) is reacted with a compound of formula III (wherein X is an eliminate group) to obtain a compound of formula I (wherein R is R').

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to (1), 5-disubstituted imidazole derivatives, processes for their production, pharmaceutical compositions containing them, and the use of said compositions for the treatment of estrogen-dependent diseases. Basic and clinical data indicate that aromatized metabolites of androgens, or estrogens, are hormones involved in pathogenic cellular changes linked to certain hormone-dependent cancers (e.g., breast, endometrial, ovarian, and pancreatic cancers). Show that something is true. Estrogens are also involved in the pathogenesis of benign prostatic hyperplasia.

Endogenous estrogen is ultimately produced from either androstenedione or testosterone as a direct precursor. The central and important reaction is the aromatization of the steroid ring A, which is carried out by the aromatase enzyme. Because aromatization is a unique reaction and the last in a series of steps in estrogen biosynthesis, effective inhibition of aromatase from compounds that can interact with the aromatization step will reduce the amount of circulating estrogen, regenerate It has been anticipated that it may be useful in controlling estrogen-dependent processes in humans and estrogen-dependent tumors. Known nonsteroidal substances that have been reported to have a more or less selective aromatase inhibitory effect include, for example, aminoglutethimide [^nn, Surg, 1H7].
．． 475 (1978); Lancet 2°646
(1978)); 4-cyclohexylaniline (
Endocrinologydan 4.2128 (198
4)) and 4-pyridy-3-ethyl-2,6-piperidinedione (J, Med, Chem, 28.20
0 (1985)).

The present invention provides compounds having the following general 2N) [wherein W
is a) l- or 2- or 9-anthryl or naphthyl group, where each benzene ring is unsubstituted or halogen, C
5-C4 alkyl, hydroxy, C5-C4 alkoxy, formyloxy, 02-C.

Alkanoyloxy, aroyloxy, C2-C.

Alkanoyl, carboxy, 02-C5 alkoxycarbonyl, mono- or di(C+-C4 alkyl)-
or b) pyridyl, pyrazinyl, a pyrimidinyl or pyridazinyl ring, where said ring is substituted or unsubstituted with the above substituents; R is CI-C4 alkyl, halogen-C1-C4 alkyl, hydroxy-01
~C4 alkyl, CI~C4 alkoxy-01~C4 alkyl, formyloxy-01~C, alkyl, 02~
C, alkanoyloxy-CI-C4 alkyl or C2
~C, alkanoyl; Z is a single, double, or triple bond; and pharmaceutically acceptable salts thereof; If is a single bond, then R
is other than unsubstituted 01-c4 alkyl).

Halogen is iodine or bromine or fluorine, especially chlorine.

Alkyl groups (including the alkyl moieties of the other substituents mentioned above) may be branched or straight chain groups. The 01-C4 alkyl group is preferably methyl, ethyl or propyl.

The term aryl in the definition of substituents above means, for example, phenyl and naphthyl, preferably phenyl.

The C2-C4 alkoxy group is preferably methoxy or ethoxy.

The Ct''Cs alkanoyloxy group is preferably acetoxy or propionyloxy, more preferably acetoxy.

Aroyloxy is preferably benzoxy.

The C2-C, alkanoyl group is preferably acetyl, propionyl, more preferably acetyl.

02-C, the alkoxycarbonyl group is preferably methoxycarbonyl or ethoxycarbonyl.

A mono- or di(C+-C,alkyl)carbamyl group is preferably methylcarbamyl or dimethylcarbamyl or diethylcarbamyl, respectively.

A mono- or di(C+-C4 alkyl)amino group is preferably methylamino or dimethylamino or ethylamino or diethylamino, respectively.

The Ct'=Cs alkanoylamino group is preferably acetylamino.

The aroylamino group is preferably benzoylamino.

A pyridyl group is, for example, 2- or 3- or 4-pyridyl, especially 4-pyridyl.

A pyrimidinyl group is, for example, 2- or 4-pyrimidinyl, especially 2-pyrimidinyl.

When W is naphthyl, it is ■- or 2-naphthyl, preferably 2-naphthyl.

Especially 3-pyridazinyl.

C8-C4 alkoxy-01-C4 alkyl is preferably methoxymethyl or methoxypropyl.

The 02-C5 alkanoyloxy-01-C4 alkyl group is preferably acetoxymethyl or acetoxypropyl.

The C2-C, alkanoyl group is preferably acetyl or propionyl.

In the halogen-C2-C4 alkyl group, the halogen atom may be independently bonded to any carbon atom of the alkylene chain, and preferably the halogen atom is chlorine. Examples of such groups are chloromethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl and 3-chloropropyl.

In the hydroxy-01-C4 alkyl group, the hydroxy groups may be independently bonded to any of the carbon atoms in the alkylene region. Examples of such groups are hydroxymethyl, -hydroxyethyl, 2-hydroxyethyl and l
-Hydroxypropyl.

The formulas described above for the compounds of the invention represent the Z of compounds in which Z of 2 (1) is a double bond, both in separated form and in mixtures (e.g. 2N).
, E isomer).

A further object of the invention are metabolites and metabolic or biological precursors of the compounds of formula (1).

The present invention further includes pharmaceutically acceptable salts of the compound of formula (r) either with a pharmaceutically acceptable base or acid or in the form of an internal salt. Said salts preferably contain pharmaceutically acceptable acids, such as inorganic acids such as hydrochloric acid, sulfuric acid, and organic acids such as citric acid, tartaric acid, maleic acid, malic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid. It is a salt of a compound of 2N) having both an acid and an acid. The preferred salt is the hydrochloride.

Preferred compounds of the present invention are compounds represented by (2N) (
where W is 1-anthryl, unsubstituted or substituted with a substituent selected from halogen, hydroxy and cyano;
2-naphthyl, 4-pyridyl, 2-pyrimidinyl or 2
- pyrazinyl group: R is hydroxymethyl, hydroxypropyl, chloromethyl, chloropropyl, acetoxymethyl, acetoxypropyl, methoxymethyl, methoxypropyl, methyl, ethyl, propyl or acetyl; Z is a single bond, a double bond , or triple bond) and pharmaceutically acceptable salts thereof.

As noted above, the present invention further includes within its scope pharmaceutically acceptable biological precursors (otherwise known as blowrags) of compounds of formula (1), i.e. compounds having a include. However, when administered to humans, it is converted directly or indirectly into the compound of formula (1) in υtυ0.

(Left below) Preferred examples of specific compounds of the present invention are as follows: 5-(3-hydroxypro-1-byl)-1(anthr-1-lylmethyl)-1H-imidazole; 5-(3-chloropro- 1-Bill)-1-(Ant-1
-lylmethyl) -1H-imidazole; 5-[3-acetoxybronievil]-1(ant-1-lylmethyl) -1H-imidazole; 5-(3-methoxypro-l-vil)-1-(ant-
1-lylmethyl')-1H-imidazole;5-(pro-1-pen-1-yl)-1-(ant-1-lylmethyl)-1H-imidazole; 5-(but-1-thene-1-
yl)-1-(ant-1-lylmethyl)-1H-imidazole; 5-(but-1-tin-1-yl)-1-(ant-l-solmethyl)-1H-imidazole; 5-(but-3 -Non-1-yl)-1-(ant-1-lylmethyl) -1H-imidazole; 5-(5-hydroxypen-1-thyl)-1(an)・-1-lylmethyl)
-1H-imidazole; 5-(5-chloropen-1-del)-1(ant-1-
5-(5-acetoxypen-I-thyl)-1(ant-1-lylmethyl)-1H-imidazole; 5-(5-methoxypen-1-thyl)-1- (Ant-
1-lylmethyl)-s n-imidazole; 5~(n-
pen-1-thyl)-1-(ant-1-lylmethyl)-
1H-imidazole; 5-(3-chloropro-1-vil)-1-(4-chloroant-1-lylmethyl)-1H
-imidazole; 5-(3-chlorobro-1-vil)-1-(4-cyanoant-1-dylmethyl)-1H-imidazole; 5-[3-chlorobro-1-vil)-1-(nano-2-thylmethyl )-1H-imidazole; 5-(bro-1-pen-1-yl)-1-(nano-2-thylmethyl)-1H-
Imidazole; 5-(but-3-non-1-yl)-1
-(nano 2-thylmethyl)-1H-imidazole; 5-
(5-chloropen-1-thyl)-1-(nara-2-thylmethyl)-1H-imidazole; 5-(3-chlorobro-1-vil)-1-(4chloronaph-2-thylmethyl)-1H-imidazole ; 5-(bro-1-pen-1-yl)-1 chloronara-2
-thylmethyl)-1H-imidazole: 5-(but-3-non-1-yl) -1-(4chloronaph-2-thylmethyl)-1H-imidazole; -(4-Chloronara-2-thylmethyl)-1H-imidazole; 5-(3-chlorobro-1-vil)-1(4cyanonaph-2-thylmethyl)-1H-imidazole; 5-(bro-1-pen-1 -yl) -1-(4cyanonaph-2-thylmethyl)-1H-imidazole; 5-(but-3-non-1-yl)-1-(4cyanonaph-2-thylmethyl)-1H-imidazole; 5- (5-chloropen-1-thyl)-1-(4cyanonaph-2-thylmethyl)-11-I-imidazole; 5-(3-chlorobro-1-vil)-1-(billy4-
dimethyl)-1H-imidazole; 5-(3-hydroxybro-l-bil)-1(bily-4-dylmethyl)
-1H-imidazole; 5- (blow 1-pen-1-
yl)-1-(bily-dylmethyl)-1H-imidazole; 5-(5-hydroxypen-1-thyl)-1(bily-4-dylmethyl)-1H-imidazole;
-Hydroxypro- 1-vil)-1-(3-chlorobily-4-dylmethyl)-1H-imidazole; 5-(3-chloropro-1-vir)-1-(3-chlorobily-4-dylmethyl)-1H -imidazole; 5-(but-3-non-1-yl)-1-(3chlorobily4-dylmethyl)-1H-imidazole; 5-(3-hydroxybro-1-vyl)-1(pyrimidi-2- Nylmethyl)-1H-imidazole; 5-(3-chlorobro-1-vil)-1-(pyrimid-
2-Nylmethyl)-1H-imidazole; 5-(bro-1-pen-1-yl)-1-(pyrimid-2-ylmethyl)-1H-imidazole; 5-(5-hydroxypen-1-thyl)-1 (pyrimidin-2-nylmethyl)-1H
-imidazole; 5-(5-chloropen-1-thyl)-1-(pyrimidi-
2-nylmethyl)-1H-imidazole: 5-(but-3-non-1-yl)-1-(pyrimid-2-ylmethyl)-1H-imidazole; 5-(3-hydroxypro-1-vil)- 1-(4-chloropyrimid-2-ylmethyl)-L H-imidazole; 5-(3-chloropyrimidi-2-ylmethyl)-1H-imidazole; 5-(3-chloropyrimid-2-ylmethyl)-1H-imidazole; 1-Biru)-1(Viraj 2-nylmethyl)-1H-imidazole; 5-(3-chlorobro 1-Biru)-1-(Viraj 2
-Nylmethyl)-1H-imidazole; 5-(Blow 1
-pen-1-yl)-1-(pyrazine-2-ylmethyl)
-11(-imidazole;5-(5-hydroxypen-1-thyl)-1(biradi-2-ylmethyl)-1H
-imidazole; 5-(5-chloropen-1-thyl)-1-(Viraj 2
-nylmethyl)-1H-imidazole; 5-(but-3
-non-1-yl)-1-(pyrazine-2-ylmethyl)
-1H-imidazole; 5-(3-hydroxybro 1
-Biru)-1(5-hydroxypyradi-2-ylmethyl)-1H-imidazole; and 5-(3-chlorobrodi-2-ylmethyl)-1-(5hydroxypyradi-2-ylmethyl)-1H-imidazole; and Pharmaceutically acceptable salts thereof.

The compound of the present invention and its salt can be produced by the following method: (A) Formula (II) (wherein R' means R as defined above, excluding halogen-C1-C4 alkyl), Z is the same as the above definition], a compound of the formula (I[I)W-CHz-X
(I[[) (wherein W is the same as defined above and is a leaving group) to form a compound of formula (1) (where R is the same as defined above, but halogen-
〇 Removal of I-C4 alkyl to obtain (); or (B) formula (■): and/or optionally converting the compound of formula (1) into a salt, and/or optionally converting the salt into the free compound do.

(White space below) [In the formula, R# is hydroxy-C3-C4 alkyl, and W and Z are the same as defined above] is halogenated to form a compound of 2N) (where R is halogen-01-C4).
and optionally converting the compound of formula (1) into another compound of formula (1); and/or optionally separating the isomer mixture of the compound of formula (1) into single isomers. In the compound and in its intermediate products,
If there are groups such as -OH and/or -NH2 that need to be protected before being subjected to the reactions detailed below, these are protected before the reactions are carried out according to methods known in organic chemistry. You can then deprotect it.

In the compounds of formula (III), the leaving group X is preferably an esterified hydroxy group such as acetoxy, mesyloxy or p-)luenesulponyloxy; or a halogen atom, in particular chlorine or bromine. Expression (IT
) may be carried out in the presence of a suitable base, for example a tertiary amine such as triethylamine. However, N-alkylation can be carried out without using a base agent. It may be carried out in the presence of an aprotic organic solvent such as a nitrile such as acetonitrile or an amide such as dimethylformamide at a temperature ranging from about 0°C to about 1H0°C.

Halogenation of compounds of formula (IV) may be carried out using conventional halogenation methods, for example by reaction with thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or thionyl bromide. Preferably, the chlorination is carried out in an inert solvent such as dichloromethane at a temperature ranging from about 0"C to about 1H0C5 thionyl chloride.

The compound of formula (1) may be converted into another compound of formula (1) by a known method as described above.

For example: (a) Compounds of formula ([) where R is hydroxy-〇1-C, alkyl are compound of formula ([) where R is formyloxy-〇l-C4 alkyl or C2-C, alkanoyloxyC1-C4 alkyl. ) can be converted to other compounds by conventional acylation methods.

Preferably, an acyl halide such as acetyl chloride or an acid anhydride such as acetic anhydride may be used in the presence of an organic base such as pyridine. The temperature range for the reaction is room temperature to approximately 1H0°
C, with or without a suitable solvent such as chloroform or benzene.

(b) The compound of Take (1) in which R is hydroxy-01-C4 alkyl, R is C, -C, alkoxy-01-
It may be converted to another compound of formula (1) which is C4 alkyl by known methods.

Preferably, the method of WiIIiaIwson [J,
Ches, Soc.

±L229 (1H52)). Therein, the alkoxide is first prepared, for example by reaction with sodium metal or sodium hydride, and an alkyl halide or alkyl sulfate, such as methyl iodide or dimethyl sulfate, is added.

(C) I? is a halo C1-C4 alkyl (
+) The compound 'PA (where the halogen atom is bonded to the C-1 carbon atom and Z is a single bond) is dehydrohalogenated to form the corresponding compound of formula (1) (where R is 01 to C4 alkyl and Z is a double bond). Dehydrohalogenation can be carried out by known methods. Preferably, compounds having l-bromo-01-C4 alkyl chains are used. Dehydrohalogenation is carried out using a suitable base, for example an alkali metal hydroxide such as potassium hydroxide, 1,5-diazabicyclo[5,/1. It may be carried out in the presence of a bicyclic amidine such as Ol unde-5-cene, or a Cl-C4 alkoxide such as potassium Ler t-butoxide, or an alkali metal hydride such as sodium hydride. Suitable solvents are, for example, ethers such as ethyl ether or tetrahydrofuran, amides such as dimethylformamide. Temperature range is approximately -60℃ to approximately +
80°C is sufficient. Preferably, a solution of the bromine compound in tetrahydrofuran is treated with potassium tert-butoxide at reflux temperature.

(d) R is 01-C, alkyl, C, -C, alkoxy-C, -C, alkyl, formyloxy-C8-C
4 alkyl or 02-C5 alkanoyloxy-C,-
A compound of formula (1) in which C, alkyl and Z is a double bond is converted into a corresponding compound of formula (1) (where Z is a triple bond) by a known dihalogenation/dehydrohalogenation method. Can be converted.

For example, dihalogenation is carried out by adding bromine to a solution of the olefin in carbon tetrachloride at about -50°C to about 1H°C.

Dehydrohalogenation of the dibrominated compound obtained can be completed with the aid of a base such as an alkali hydroxide or alkali alkoxide, preferably sodium amide in liquid ammonia.

(e) Compounds of formula (1) in which R is hydroxy-02-C4 alkyl, where the hydroxy group is attached to the C-1 carbon atom, can be oxidized to the corresponding compound in which R is C2-C4 alkanoyl. Further compounds of 2N) can be obtained by known methods.

For example, a chromium(III) oxide solution in dilute sulfuric acid is added to a substrate solution in acetone at less than 0°C. Alternatively, the oxidation is carried out with dimethyl sulfoxide in the presence of a dehydrogenating agent such as an anhydride such as acetic anhydride, an acyl halide such as oxalyl chloride, an anhydrous mineral acid such as phosphorus pentoxide, or a carbodiimide such as dicyclohexylcarbodiimide. This can be done by processing. The dimethyl sulfoxide/dehydrogenant ratio is about 1:1. Preferably the oxidation is carried out in the presence of an acid catalyst such as phosphoric acid or pyridinium trifluoroacetate.

(“) Compounds of formula (I) in which R is halomethyl,
The corresponding compound of formula (1) (
where R is hydroxy-propyl or hydroxy-butyl). That is, the starting compound is converted into a Grignard compound and then reacted with methylene oxide or trimethylene oxide, respectively. The Grignard reaction uses well-known reaction conditions in organic chemistry (e.g. M, S, Kha
rasch, 0°1? einmuth's "Grign"
ard reaction of nonmetall
Preferably, the Grignard reagent is prepared in ethyl ether solution by reaction of a compound of formula (1) in which R is halomethyl, such as bromomethyl, with magnesium.

Ethylene oxide or trimethylene oxide can be introduced under cooling. The reaction temperature range is about -1H"C to room temperature.

(The compound of formula (1) in which the member R is halo c1-c4 alkyl can be prepared by the corresponding formula (1) by a well-known reduction method.
) compound (where one unit is C, -C, alkyl)
For example when the halogen is bromine or chlorine, the compound of formula (1) can be reduced by treatment with a suitable metal hydride such as lithium aluminum hydride in an ether such as tetrahydrofuran or diglyme at room temperature to reflux temperature. It is possible.

(h) The compound of formula (1) in which R is hydroxymethyl can be converted into another compound of formula (1r) (cocoter? is -CH(OH) -C, ~Cff alkyl) by a method known per se. can be converted. For example, partial oxidation of hydroxymethyl compounds with dimethyl sulfoxide provides aldehydes of formula (1) where R is formyl. The aldehyde is then converted to the formula R'Mg halogen (where R3 is C7-C,
(which is an alkyl group) is reacted with a Grignard reagent.

The oxidation with dimethyl sulfoxide is carried out in the presence of a dehydrogenating agent such as an anhydride such as acetic anhydride, an acyl halide such as oxalyl chloride, an anhydrous mineral acid such as phosphorus pentoxide or a carbodiimide such as dicyclohexylcarbodiimide. Preferably the oxidation is carried out in the presence of an acid catalyst such as pyridinium trifluoroacetate or phosphoric acid. The following Grignard reaction can be carried out in the same manner as in method (f) above.

(i) A compound of formula (+) having a carboxyl substituent may be converted into another compound of formula (1) having a C, -C, alkoxy-carbonyl group by known methods. For example, the acid is treated with an excess of the appropriate C,-C,alkanol in the presence of a mineral acid such as hydrochloric acid or sulfuric acid at reflux temperature.

(j) Formula (1) in which WJJ is substituted with hydroxy
) The substituent W is 01 to C by a known method.

It may be converted to other compounds of formula (1) substituted with alkoxy. For example, by continuing the steps described above in optional conversion method (b), or by first treating the hydroxy compound with a suitable base such as sodium hydride or sodium amide and then converting the hydroxy compound to Treatment with an alkylating agent such as methyl iodide or dimethyl sulfate in a suitable solvent.

(Left space below) (k) Compounds of formula (f) (, = where W is unsubstituted aryl or hetecoaryl as defined in formula (1) of (a) and (b)) can be prepared by known methods, e.g. By reaction with cyanogen chloride or cyanogen bromide or with trichloroacetonitrile, it can be converted into other compounds of formula (D), where W is substituted with cyano.

(1) The compound '#J of (1) (wherein the substituent W is substituted with halogen) can be prepared by a known method, for example in a suitable solvent such as pyridine, quinoline or dimethylformamide.
By reaction with an inorganic cyanide such as sodium cyanide or cyanide w4(1) at elevated temperature preferably at reflux temperature, another compound of formula (1), in which the substituent W is substituted with cyano, is prepared. It is convertible.

(2)) Compounds of formula (1) in which the substituent W is nitro or oxidized by hydrogenation of the nitro compound in the presence of an activated catalyst such as palladium on carbon in a suitable solvent such as ethyl acetate. can be reduced to a compound of formula (1) where the substituent W is substituted with amino.

Conventional methods may be used to salt the compound of formula (1) and from the salt to obtain the free compound of Standard methods such as fractional precipitation and chromatography may follow.

Compounds of formula (II) are known. Alternatively, it may be obtained from known compounds by known methods. For example, 4(3-hydroxypro-1-pyl)-1H-imidazole is Gr, A
, A., KiviLs et al., J., 1l.
etc.

C1+em, 12.577 (1975).

) is substituted with methanol, optionally the conversion of any of (a) to (h) (the above conversions from a compound of formula (1) to another compound of formula (1)) is followed by a similar The process can be carried out with intermediates of formula (II).

Compounds of formula (III) are known. Alternatively, it may be obtained from known compounds by known methods.

The compound of formula (rV) is a compound of (1) in which R is hydroxy-01-C4 alkyl, and is obtained by the above method (A).

The compounds of the invention are inhibitors of the biotransformation of androgens to estrogens. That is, it is an aromatase inhibitor.

Inhibition of aromatase activity by these compounds was demonstrated by an inυtυO assay utilizing the aromatase enzyme system isolated from the microsomal fraction of human placenta &1'N tissue by standard methods. 4-[1β.

2β-zH) Tho determining the degree of aromatization by the release of 'H,O from androstene-3,17-dione
mson and 5iiteri assay CF, A.

Thomson and P.
, J., Biol, Che+s.

249, 5364. (1974)) was used.

All incubations were performed in a shaking water bath at 37° C. in air in 1HmM potassium phosphate buffer (pH 7.5) (1HmM KCI, 1mM EDTA).

(containing 1mM dithiothreitol).

Experiments were performed with 50 nM 4-('H)androstenedione,
Various concentrations of inhibitor, IootlM NAD P
It was carried out with an ld incubation amount containing microsomal protein of HSO, 05. After 15 minutes of incubation, chloroform (5d) was added to stop the reaction. 3H generated after 5 min centrifugation at 1500 x g
(0.5 ml aliquots for identification) were removed from the aqueous phase. The concentration of each compound required to reduce the control aromatase by 50% (IC,.) was calculated as % inhibition versus the log of the inhibitor concentration. Determined by plotting.

The new compounds incubated at various concentrations showed significant aromatase activity.

Because of their ability to inhibit aromatase and not reduce estrogen levels, the new compounds have been shown to be effective against a variety of estrogen-dependent diseases in mammals (i.e. breast, intrauterine, ovarian and pancreatic cancers, gynecomastia, benign breast disease, intrauterine cancers). membranous disease,
It is useful in the treatment and prevention of polycystic ovarian disease (polycystic ovarian disease, precocious puberty). In addition, the compounds of the present invention may be used in the treatment and/or prophylaxis of prostatic hyperplasia, an estrogen-dependent stromal tissue disease.

The new compounds may also find use in the treatment of male infertility due to oligospermia, and in female fertility control due to their ability to inhibit ovulation and egg implantation.

Due to their high therapeutic index, the compounds of the present invention can be safely used in medicine. For example, the proximal acute toxicity (LD, .) in mice determined with single administration of increasing doses of the compounds of the invention and measured on day 7 of treatment was negligible.

The compounds of the invention can be administered in various administration forms, for example orally in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; intramuscular or intravenous injection or It can be administered parenterally, such as by injection.

The dosage depends on the patient's age, weight, condition, and administration route; for example, when administered orally to adults, approximately 1.
The range may be from 150 to 200 times per hour, 1 to 5 times per hour.

The invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient, which may be a carrier or diluent.

Pharmaceutical compositions containing the compounds of the present invention are usually prepared by the following method and administered in a pharmaceutically appropriate form.

For example, solid oral forms contain the active compound together with diluents such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch;
Lubricants such as silica, talc, stearic acid, magnesium stearate or calcium stearate and/or polyethylene gelcol; binders such as starch, acacia, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; decomposition networks such as starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; dyes, sweeteners; humectants such as lecithin, polysorbates, lauryl sulfate; and generally non-toxic and pharmacologically inactive substances used in pharmaceutical compositions). The pharmaceutical preparations may be packaged by known methods such as mixing, granulating, tabletting, dragee coating or film coating methods. Dispersions for oral administration may be syrups, emulsions or suspensions.

The syrup contains a carrier (e.g. saccharose or sucrose together with glycerin and/or mannitol and/or
or sorbitol).

For intramuscular injection, formulations and emulsions may contain as carriers, for example natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. ,Aii
Alternatively, solutions may contain the active compound together with a pharmaceutically acceptable carrier such as sterile water, olive oil, glycols such as ethyl oleate, propylene glycol, and, optionally, a suitable amount of lidocaine hydrochloride.

Solutions for intravenous injection or infusion may contain as a carrier, for example, sterile water (or preferably in the form of a sterile isotonic salt solution).

The active compound may contain a pharmaceutically acceptable carrier such as cocoa butter, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

The invention is explained in more detail in the following non-limiting examples.

(Hereafter, all white) Fruit] u Fresh 1 4-(3-hydroxypropyl)-11(-imidazole (126cm) in dry acetonitrile (2l11).

1111II+01), triethylamine (121■,
1.211111H1) and dimethylcarbamyl chloride (11Hff1g, 1.1mmol) are refluxed under nitrogen for 24 hours. After cooling to 0-5°C, add triethylamine (
121■, 1.2v++ol) and trimethylsilyl chloride (13011g, 1.2+w@ol) were added,
The reaction mixture is stirred for 2 hours at room temperature. After diluting with ethyl ether, insoluble matter is filtered, the residue is washed with ethyl ether, and the ether extracts are combined and evaporated under vacuum. Obtained crude 4-(3-)limethylsilyloxybropyl)
-1) f-imidazole-1-dimethylcarboxamide is heated with ando-1-lylmethyl bromide (271 ml, 1 m+1 ol) in acetonitrile (2-) and reacted under reflux for 20 hours. Then ammonia gas was heated at 0-5°C for 15 minutes.
and concentrate the mixture in vacuo. The residue is dissolved in N-hydrochloric acid and the resulting acid solution is stirred for 1/2 hour at room temperature and then washed with ethyl acetate. The pH of the acid solution was brought to 8-9 by adding potassium carbonate solution and the crude product was extracted with chloroform. The organic phase is washed with water, dried over sodium sulphate and evaporated in vacuo.

The residue was subjected to two cycles of chromatography over silica gel using 1% chloroform/methanol as eluent. Obtain 221 rag of the title compound (70% yield)
).

Elemental analysis measured value % (total 1: value %) C79,65 (79,72), H6,25 (6,37
), N 8.77 (8,85) NMR (cDcIff, δ): 1.81 (2!
l, m), 2.25 (211, t),
3.45 (2H, t), 5.25 (2H,
s), 6.85 (IH, s).

7.60 (1H,sL 7.15-8.15 (
9H, m).

The following compounds can be prepared in the same way: 5-(3-
5-(3-hydroxypro-1-pyl)-1(bily-4-dylmethyl)-1H-imidazole; 5-(3-hydroxypro-1-pyl)-1=(3-chlorobily-4-dylmethyl)-1H-imidazole; (3-Hydroxybro-1-pyru)-1(pyrimid-2-nylmethyl)-1H-imidazole; 5-(3-hydroxybro-1-pyru)-1(4-chloropyrimidin-2-ylmethyl)-1H-imidazole; 5 -(3-hydroxybro-1-pyr)-1=(pyrazi-2-nylmethyl)-1H-imidazole and 5-(3-hydroxybro-1-pyru)-1(5-hydroxypyrazi-2-ylmethyl)-11] -Imidazole.

Example 2 Monymouth LL 5-(3-hydroxybro 1-pill)-1(ant-
1-dylmethyl)-1H-imidazole (316 mg,
lffimol) and thionyl chloride (155u.

A solution of 1.3 afmol) in dry dichloromethane (4 afmol) is heated to reflux for 2 hours. The solution is evaporated under vacuum and the residue is collected in dichloromethane and sodium bicarbonate solution. The organic phase is washed with water and dried over sodium sulfate. Chromatography of the residue on silica gel using 1% chloroform/methanol as eluent affords the purified title compound of 301 (9o% yield).
).

Elemental analysis measured value % (calculated value %) C75,25 (75,33), 85.75 (5,
72), N 8.15 (8,37), CI
1H. 40 (1H,59)NMR (CDCl2.δ)
: 2.00 (2H, m), 2.61 (211,
t), 3.49 (2H, t), 5.15 (21
+, s), 6.19 (Ill, s).

7.60 (ill, s), 7.20-8.20
(9B, m).

The following compounds can be prepared in the same way: 5-(5-
5-(3-chloropro-
5- (3-chlorobro-1-pyr)-1-(nala-2-
5-(5-chloropen-1-thyl)-1-(nano-2-thylmethyl)-1H-imidazole;
1H-imidazole; 5-(3-chlorobro-1-pyl)-1-(4-chloronara-2-thylmethyl)-1H-
Imidazole; 5-(5-chloropen-1-thyl)-1-(4chloronaph-2-thylmethyl)-1H-imidazole; 5-(3-chlorobro-1-pyr)-1-(4cyanonaph-2-thylmethyl )-1H-imidazole: 5-(5-chloropen-1-thyl)-1-(4cyanonaph-2-thylmethyl)-1H-imidazole; 5-(3-chlorobro-1-pyl)-1-(bi-4 -dylmethyl)-1H-imidazole; 5-(3-chlorobro-1-pyl)-1-(3-chlorobily-4-dylmethyl)-1H-imidazole; 5-(3-chlorobro-1-pyl)-1-( Pirimidji
2-Nylmethyl)-1H-imidazole: 5-(5-chloropen-1-thyl)-1-(pyrimid-2-ylmethyl)-1H-imidazole;
-Pyr)-1-(4-chloropyrimidin-2-ylmethyl)-1H-imidazole;
-nylmethyl)-1H-imidazole; 5-(5-chloropen-1-thyl)-1-(biradi-2-nylmethyl)
-1H-imidazole and 5-(3-chlorobro 1-
pill)-1-(5hydroxybiradi-2-nylmethyl)
-1) (-imidazole.

5-(3-Hydroxy blown 1 in dry pyridine (ld)
-Pyr)-1-(ant-1-dylmethyl)11]-imidazole (316 mg, Immol) is added acetic anhydride (306111 g, 3 au+ol) and the mixture is kept at room temperature overnight. The solvent is then removed in vacuo and the residue is taken up with dichloromethane and water. The organic phase is separated, washed several times with water, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed using chloroform/methanol 1% as eluent to give the purified title compound (325■).

yield 90%).

Elemental analysis measured value % (calculated value %) C76,51 (76,69), H6,01 (6,
15), N 7.60 (7,77) NMR (CDCh, δ): 1.80 (211,
m), 2.02 (3H,s), 2.54 (21
+, L), 3. ．． 42 (2H,L), 5.2
0 (2H, s) + 6.81 (III, s), 7.
55 (1)1. s), 7.15-8.15 (9
M, +n) The following compounds can be prepared in a similar manner: 5-(5-acetoxypen-1-thyl)-1(ant-1-dylmethyl)-1H-imidazole.

5-(3hydroxypro-1-byl)-1-(ant-1-lylmethyl)-1H-imidazole (316 tag) in dry tetrahydrofuran (1Hd).

Sodium hydride (29
mg.

1.2 +1 mol) are added gradually and the mixture is stirred for 1 hour. Finally, methyl iodide (174mg, 1.2m
+sol) is added and the mixture is heated and carbonized for about 2 hours. The solvent is removed under vacuum and the residue is taken up with ethyl acetate and water. The organic phase is separated, washed with water, dried in vacuo and dried for 1
make it emit Chloroform/methanol 1% as eluent
The residue was subjected to silica gel column chromatography to obtain the purified title compound in a yield of 80% (264 .mu.m).

Elemental analysis measured value % (calculated value %): C79,81 (79,97), H6,65 (6,7
1), N 8.35 (8,48) NMR (CDC11, δ): 1.85 (2H, at
), 2.51 (211,t), 3.24 (31
(,s), 3.42 (2H,t), 5.22 (
2H,s).

(i, 83 (IH, s), 7.63 (1H, s)
, 7.15-8.15 (9th.

Example 5 - 5-(3-Hydroxypro-1-vil)-1-(ant-1-lylmethyl)-1 in dry dichloromethane (4d)
H-imidazole (316v:, 1mmol) and thionyl bromide (25011g, 1.211+nmol)
) and reflux for 1 hour. The solution is then evaporated in vacuo and the residue taken up in dichloromethane and cold sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulphate and evaporated in vacuo. Crude 5 (3-bromopro-1
-bil)-1-(ant-1-lylmethyl)-1H-
Imidazole is obtained (380 mg, yield 1H0%).

The crude bromo compound obtained above (380×111+l
O1) is dissolved in dry tetrahydrofuran (3d) for 7 hours and the solution is cooled to 0-5°C. Potassium terL butoxide (224111 g, 2++ vol) is added slowly and the resulting reaction mixture is stirred for an additional 3 hours at reflux temperature under nitrogen. Finally, the reaction mixture is concentrated in vacuo, the pH is adjusted to 8-10 by addition of aqueous acetic acid under cooling, and the crude product is extracted with chloroform. The organic layer is separated, dried and evaporated under reduced pressure. The residue is subjected to ram chromatography on silica gel using 1% chloroform/methanol as eluent. The purified title compound is obtained in 70% yield (208■).

Elemental analysis measured value % (calculated value %) C84,35 (84,53), H5,95 (6,0
8), N 9.25 (9,39) N M R (CDC13, δ) = 1.92 (3H,
n+), 5.20 (2H,s), 6.1 (2N
, m), 6.85 (IH,s), 7.60
(III, s) 7.15-8.15 (9H, +i)
.

The following compounds can be prepared in the same way: 5-(bu-
1-ten-1-yl)-1-(ant-1-lylmethyl)
-1H-imidazole; 5-(pro-1-pen-1-yl)-1-(nano-2-thylmethyl)-1H-imidazole; 5-(pro-1-pen-1-yl)-1-(4 -chloronara-2-thylmethyl)-1H-imidazole; 5-(pro-1-pen-1-yl)-1-(4-cyanonaph-2-thylmethyl)-1H-imidazole; 5-(blow 1- Pen-1-yl 11-(pyrimidin-2-ylmethyl)-1H-imidazole; 5-(bro-1-pen-1-yl)-1-(pyrimidin-2-ylmethyl) -
1H-imidazole and 5-(blow 1-pen-1-yl)-1-(pyrazy 2
-nylmethyl)-1H-imidazole.

5-5 in dry chloroform cooled with a frozen mixture of ice and salt.
(But-1-ten-1-yl)-1-(ant-1-dylmethyl)-1H-imidazole (312 mg, lsm
Add bromine (1602 g, lsmol) dropwise to a solution of The mixture is gradually warmed to room temperature and then evaporated in vacuo. The residue contains crude 5-(1,2-dibromobut-1-thyl)-1-(ant-1-dylmethyl)-1H-imidazole.

A catalytic amount of sodium ferric nitrate (81 ml, 3.5 mwol) is added in portions to liquid ammonia (approximately 3 ad) maintained at a temperature of -30°C to -40°C in a dry water bath.

After 20 minutes, when the mixture changes color from blue to gray, the ethereal solution of the dibromide obtained above is slowly added and the mixture is kept at low temperature for an additional 4 hours. Then ammonium chloride is added and the mixture is allowed to warm to room temperature. The residue is collected with chloroform and water. The organic phase was washed with water, dried and evaporated in vacuo. Chloroform/methanol 1% using the residue as eluent
Column chromatography on silica gel using 50% yield of the purified title compound (155■).

Elemental analysis measured value % (calculated value %) C85,05 (85,13), H5,75 (5,84
), N 8.95 (9,02) Compliance Example 1 - 5-(3-Hydroxybu-niethyl) 1- in acetone (5-) maintained at -20°C to -30°C in a red drying water bath. (
anth-1-dylmethyl)-1H-imidazole (33
0■, l m+*ol) solution, add chromium trioxide (
A solution of dilute sulfuric acid (1 dl>200 ml, 2+ws+ol) is added dropwise over about 15 minutes and the mixture is kept cold for an additional hour.The excess oxidant is then destroyed with isopropanol and the mixture is concentrated in vacuo. Crude product to pH 8-1
Extract with H and ethyl acetate, dry and evaporate in vacuo. The residue is subjected to silica gel blade ram chromatography using 2% chloroform/methanol as eluent.

The purified title compound is obtained in 80% yield (262■).

Elemental analysis measured value % (weighing 4fj%): C80,30 (80,,16), H6,00 (13
, 19), N 8.35 (8,53) N M R (CDCl2.δ): 2.1H (3H,
s), 2.50 (2H, t) 2.60 (21+,
L), 5.25 (21(,s), 6.84
(Ill, s).

7.55 (IH,s), 7.15-8.15 (9
)1. m) The following compound can be produced in the same manner =5-(but-3-non-1-yl)-]-(]rough 2
-Tylmethyl-1H-imidazole; 5-(but-3-
5-(but-3-non-1-yl)-1(4cyanonaph-2-thylmethyl)-1H-imidazole 1 5-(but-3-non-1-yl)-1-(3-chlorobily-4-dylmethyl)-1H-imidazole; 5-(but-3-non-1-yl)-1 -(pirimiji-
2-Nylmethyl)-1H-imidazole and 5-(but-3-non-1-yl)-1-(Viraj 2
-nylmethyl)71H-imidazole.

Magnesium turning (tu) in dry ethyl ether (3-)
small crystals of iodine were added to a vigorously stirred dispersion of 5-(3bromopro-1-pyl)-1-(ant-1-dylmethyl)-1H-imidazole (379 mg).

1 snol of dry ether (3d) is introduced dropwise at such a rate that the mixture steadily boils. The mixture is refluxed for an additional 1/2 hour. The flask was then cooled with a frozen mixture of ice and salt and ethylene oxide gas (66 μm).

1.5 snol) gradually. The reaction mixture is allowed to reach room temperature and boiled for an additional hour. Add benzene and evaporate. Ice and saturated ammonium chloride solution are added, the crude product is extracted with benzene, and after washing and drying the organic layer is evaporated under reduced pressure. The residue is subjected to ram chromatography on silica gel using 2% chloroform/methanol as eluent.

The purified title compound is obtained in 60% yield (20611 g).

Elemental analysis measured value % (calculated value %): C80,1H (80,20), 86.91 (7,
02), N 7.95 (8,13) NMR (CDCI: 1.δ): 1.80-2.2
0 (6H, +w), 2.55 (2H, t), 3.
45 (2B, t), 5.20 (2H, s),
6.79(1)1. s), 7.55 (IH,'
s), 7.15-8.15 (9FI, s).

The following compounds can be prepared in the same way: 5-(5-
5-(5-hydroxypen-1-thyl)-1(pyrimidin-2-ylmethyl)-1H
-imidazole and 5-(5-hydroxypen-1-thyl)-1(pyrazi-2-ylmethyl)-1H-imidazole.

Lithium ammonium hydride (19■, '0.5m
Gradually add 5-(5-chloropen-1-tyl)-1-(ant-1-dylmethyl) to the solution of diglyme (5d).
-L H-imidazole (363 mg, I11++
Add a solution of diglyme (3jd. aol). The resulting mixture is stirred at 1H0''C for about 15 hours. An aqueous solution of sodium potassium tartrate is then added. The mixture is filtered and concentrated to a small volume under reduced pressure. Concentrate is collected in ethyl acetate and washed thoroughly with water. The organic layer is dried over sodium sulfate, filtered and the solvent is removed in vacuo to give a residue that is chromatographed on silica gel using chloroform/methanol 1% eluent. The purified title compound was obtained in 80% yield (263■).

Elemental analysis measured value % (calculated value %) C80,15 (80,20), H7,25 (7,3
6), 88.45 (8,53) Oxalyl chloride (2161 g, 1.
7 m5 ol) was added dropwise. 172 hours - 75゛C
5-(3-hydroxypro-1-pyl)-1-(ant-1-lylmethyl)-1 in a mixture of dimethyl sulfoxide <0.2d) and dichloromethane (Ld) after stirring at
A solution of H-imidazole (316 ml, 1 + smol) is slowly added and the mixture is stirred for 3 hours at -75°C. Triethylamine (ld) is then added and the mixture is left to reach room temperature. After dilution with dichloromethane, the organic phase is separated, washed with water, dried and evaporated under reduced pressure. The residue was chromatographed on silica gel using chloroform/methanol 1% as eluent;
Purified 5-(prop-3-non-1-yl)- with 50% yield
Obtain 1-(ant-1-lylmethyl)-1H-imidazole (157■) Adding small crystals of iodine to the solution with vigorous stirring of magnesium turnings (25■ + 1 mmol) in dry ethyl ether (3 relatives) Then a solution of methyl iodide (14211H, 1 mmol) in dry ethyl ether (2-) is introduced dropwise at a rate that brings the mixture to a steady boil. The mixture is refluxed for a further 30 minutes. 5-(
Proper-3-non-1-yl)-1-(ant-1-lylmethyl)-1H-imidazole (31411g, 1
- a solution of benzene (5 mQ) is introduced dropwise while cooling. The solvent is then removed until the boiling point reaches 77°C and heating is continued for a further 3 hours. Ice and ammonium chloride solution are added and the crude product is extracted with ethyl acetate at pH 8-9. The organic layer is washed, dried and evaporated in vacuo. The residue is subjected to silica gel column chromatography using chloroform/methanol as eluent.

The title compound is obtained in 75% yield (248 g).

Elemental analysis measured value % (calculated value %) C79,85 (79,97), 86.81 (6,7
1), N 8.35 (8,48) To obtain Daqi flaming acid 5-3-hydroxypro-1-pyl)-1-(ant-1-lylmethyl)-1H-imidazo hydrochloride, 5- (3-Hydroxypro-1-pyl)-1-(ant-1-lylmethyl)I H-imidazole base (31
6mg, 1mn+ol) of ethyl acetate (4Ili)
? Add a stoichiometric amount of hydrochloric acid to solution g. The precipitated salts are filtered, washed with solvent and dried. The title compound is obtained in 90% yield (31 H mg).

Elemental analysis measured value % (calculated value %) C71,43 (71,48), H5,85 (6,00
), CI 9.95 (1H,05), N 7.
85 (7,94) 1 History Tablets each weighing 0.150 g and containing 25I1 g of active substance can be produced as follows.

Composition (for 1H,000 tablets): 5-(3-chloropro-1-pyl)-1-(antho 1
-lylmethyl)-1H-imidazole.

250g lactose, 80h cornstarch, 415g talcum powder, 30g magnesium stearate, 5g 5-(3-chlorobro-1-pyr)-1,-(ant-1-dylmethyl)-1H-imidazole, lactose, half of the cornstarch mixed together do.

Pass the mixture through a 0.5 wm mesh sieve.

Disperse corn starch (1 Hg) in hot water (90 td) and use the resulting paste to granulate the powder.

The granules are dried and powdered with a 1.4 m mesh sieve, the remaining starch, talc, magnesium stearate are added, mixed carefully and processed into tablets.

Capsules each containing 0.200 g and 20 μ of active substance per serving can be prepared as follows.

Composition (for 500 capsules): 5-(3-chloropro-1-vil)-1(pyrid4-dylmethyl)-1H-imidazole, 1Hg lactose, 8
0g Cornstarch, 5g Magnesium Stearate 5g This composition can be encapsulated in two-piece hard gelatin capsules, each capsule containing 0.200g.

Claims (9)

[Claims] (1) Formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, W is a) 1- or 2- or 9-anthryl or naphthyl group (where each benzene ring is unsubstituted or halogen, C
_1-C_4 alkyl, hydroxy, C_1-C_4 alkoxy, formyloxy, C_2-C_5 alkanoyloxy, aroyloxy, C_2-C_5 alkanoyl, carboxy, C_2-C_5 alkoxycarbonyl, mono- or di-(C_1-C_4 alkyl)-carbamyl, Cyano, nitro, amino, mono or di-
(C_1-C_4 alkyl)-amino, C_2-C_5
or b) a pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl ring, wherein said ring is substituted or unsubstituted with the above-mentioned substituents; , C_1-C_4 alkyl, halogen-C_1-C
_4 alkyl, hydroxy-C_1 to C_4 alkyl,
C_1-C_4 alkoxy-C_1-C_4 alkyl,
Formyloxy-C_1-C_4 alkyl, C_2-C
_5 alkanoyloxy-C_1-C_4 alkyl or C_2-C_5 alkanoyl; Z is a single bond, double bond, or triple bond; and pharmaceutically acceptable salts thereof (provided that
At the same time, if W is 1-naphthyl substituted with cyano and Z is a single bond, R is other than unsubstituted C_1-C_4 alkyl). (2) W is a 1-anthryl, 2-naphthyl, 4-pyridyl, 2-pyrimidinyl or 2-pyrazinyl group, unsubstituted or substituted with a substituent selected from halogen, hydroxy and cyano; R is hydroxymethyl;
Hydroxypropyl, chloromethyl, chloropropyl,
The formula ( I ) and pharmaceutically acceptable salts thereof. (3) A compound selected from the group consisting of: 5-
(3-hydroxypro-1-pyl)-1-(ant-1
-lylmethyl)-1H-imidazole; 5-(3-chloropro-1-pyl)-1-(ant-1
-lylmethyl)-1H-imidazole; 5-(3-acetoxypro-1-pyl)-1-(ant-1-lylmethyl)-1H-imidazole; 5-(3-methoxypro-1-pyl)-1- (Ant-
1-lylmethyl)-1H-imidazole; 5-(pro-
1-pen-1-yl)-1-(ant-1-lylmethyl)-1H-imidazole; 5-(but-1-then-1-yl)-1-(ant-1-lylmethyl)-1H-imidazole ; 5-(but-1-tin-1-yl)-1-(ant-1-lylmethyl)-1H-imidazole; 5-(but-3-non-1-yl)-1-(ant-1- 5-(5-hydroxypen-1-thyl)-1-(ant-1-lylmethyl)-1
H-imidazole; 5-(5-chloropen-1-thyl)-1-(ant-1
-lylmethyl)-1H-imidazole; 5-(5-acetoxypen-1-thyl)-1-(ant-1-lylmethyl)-1H-imidazole; 5-(5-methoxypen-1-thyl)-1- (Ant-
1-lylmethyl)-1H-imidazole; 5-(n-pen-1-thyl)-1-(ant-1-lylmethyl)-1
H-imidazole; 5-(3-chloropro-1-pyl)-1-(4-chloroant-1-lylmethyl)-1H-imidazole; 5-(3-chloropro-1-pyl)-1-(4- cyanoant-1-lylmethyl)-1H-imidazole; 5-(3-chloropro-1-pyl)-1-(naf-2-
5-(pro-1-
pen-1-yl)-1-(naph-2-thylmethyl)-1
H-imidazole; 5-(but-3-non-1-yl)
-1-(naf-2-thylmethyl)-1H-imidazole; 5-(5-chloropen-1-thyl)-1-(naf-2
5-(3-chloropro-1-pyl)-1-(4-chloronaph-2-thylmethyl)-1H-imidazole; 5-(pro-1-pen-1-yl)- 1-(4-chloronaph-2-thylmethyl)-1H-imidazole; 5-(but-3-non-1-yl)-1-(4-chloronaph-2-thylmethyl)-1H-imidazole; 5-(5 5-(3-chloropro-1-pyl)-1-(4-cyanonaph-2-thylmethyl)-1H- Imidazole; 5-(pro-1-pen-1-yl)-1-(4-cyanonaph-2-thylmethyl)-1H-imidazole; 5-(but-3-non-1-yl)-1-(4 -cyanonaph-2-thylmethyl)-1H-imidazole; 5-(5-chloropen-1-thyl)-1-(4-cyanonaph-2-thylmethyl)-1H-imidazole; 5-(3-chloropro-1-pyl )-1-(pyri-4-
5-(3-hydroxypro-1-pyl)-1-(pyry-4-dylmethyl)
-1H-imidazole; 5-(pro-1-pen-1-yl)-1-(pyry-4-zylmethyl)-1H-imidazole; 5-(5-hydroxypen-1-thyl)-1-(
pyry-4-dylmethyl)-1H-imidazole; 5-(
5-(3-chloropro-1-pyl)-1-(3-chloropyry-4-dylmethyl)- 1H-imidazole; 5-(but-3-non-1-yl)-1-(3-chloropyry-4-zylmethyl)-1H-imidazole; 5-(3-hydroxypro-1-pyl)-1-( pyrimid-2-ylmethyl)-1H-imidazole; 5-(3-chloropro-1-pyl)-1-(pyrimid-
2-nylmethyl)-1H-imidazole; 5-(pro-
5-(5-hydroxypen-1-yl)-1-(pyrimid-2-ylmethyl)-1
H-imidazole; 5-(5-chloropen-1-thyl)-1-(pyrimidi-
2-nylmethyl)-1H-imidazole; 5-(but-
5-(3-hydroxypro-1-yl)-1-(4-chloropyrimid-2-ylmethyl)-1H- Imidazole; 5-(3-chloropro-1-pyl)-1-(4-chloropyrimid-2-ylmethyl)-1H-imidazole; 5-(3-hydroxypro-1-pyl)-1-(pyrazi-2- nylmethyl)-1H-imidazole; 5-(3-chloropro-1-pyl)-1-(pyrazi-2
-nylmethyl)-1H-imidazole; 5-(pro-1
-pen-1-yl)-1-(pyrazin-2-ylmethyl)
-1H-imidazole; 5-(5-hydroxypen-1
5-(5-chloropen-1-thyl)-1-(pyraz-2-yl)-1-(pyraz-2-ylmethyl)-1H-imidazole;
-nylmethyl)-1H-imidazole; 5-(but-3
-non-1-yl)-1-(pyrazin-2-ylmethyl)
-1H-imidazole; 5-(3-hydroxypro-1
-pyl)-1-(5-hydroxypyraz-2-nylmethyl)-1H-imidazole; and 5-(3-chloropro-1-pyl)-1-(5-hydroxypyraz-2-nylmethyl)-1H - imidazole; and pharmaceutically acceptable salts thereof. (4) A method for producing a compound of formula (I) and a salt thereof according to claim 1, wherein (A) formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R ' means R as defined in claim 1 (excluding halogen-C_1-C_4 alkyl), Z is the same as defined in claim 1], a compound of formula (III
) W-CH_2-X(III) (wherein W is the same as defined in claim 1 and X is a leaving group) to form a compound of formula (I) (where R is the same as defined in claim 1, except for halogen-C_1 to C_4 alkyl); or (B) Formula (IV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula, R'' is hydroxy-C_1-C_4 alkyl, W and Z are the same as defined in claim 1] to produce a compound of formula (I), where R is halogen-C_1-C_4 alkyl. and optionally converting a compound of formula (I) into another compound of formula (I) and/or optionally separating an isomeric mixture of a compound of formula (I) into single isomers. do, and/
or optionally converting the compound of formula (I) into a salt; and/or
or optionally converting the salt into the free compound. (5) A pharmaceutical composition comprising a suitable carrier and/or diluent and a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. (6) A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for use in a method of therapeutic treatment of the human or animal body. (7) The compound of formula (I) or a salt thereof according to claim 6 for use as an aromatase inhibitor. (8) A method for producing the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, comprising:
12. (9) A pharmaceutical composition substantially as described in Example 12 or 13.