DE3928764A1 - 1,5-DISUBSTITUTED IMIDAZOLE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF - Google Patents

Abstract

A compound of formula (I> <IMAGE> wherein W is a) a 1- or 2- or 9-anthryl of naphthyl radical wherein each benzene ring is unsubstituted or substituted by a substituent chosen form halogen, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, formyloxy, C2-C5 alkanoyloxy, aroyloxy, C2-C5 alkanoyl, carboxy, C2-C5 alkoxycarbonyl, mono- or di-(C1-C4 alkyl)-carbamyl, cyano, nitro, amino, mono- or di-(C1-C4 alkyl)-amino, C2-C5 alkanoylamino and aroylamino; or b) a pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl ring wherein each said ring is unsubstituted or substituted by a substituent defined above; R is C1-C4 alkyl, halogen-C1-C4-alkyl, hydroxy-C1-C4 alkyl, C1-C4 alkoxy-C1-C4 alkyl, formyloxy-C1-C4 alkyl, C2-C5 alkanoyloxy-C1-C4 alkyl or C2-C5 alkanoyl; Z is a single, double or triple bond; and the pharmaceutically acceptable salts thereof; and wherein when, at the same time, W is 1-naphthyl substituted by cyano and Z is a single bond, then R is other than unsubstituted C1-C4 alkyl; are aromatase inhibitors. The compounds may be used in the treatment of oestrogen-dependent diseases.

Description

The present invention relates to 1,5-disubstituted Imidazole derivatives, a process for their preparation, they containing pharmaceutical compositions and the Use of the compounds in the treatment of estrogen-dependent diseases. Basic and clinical Data indicate that aromatic metabolites of Androgens, d. h., Estrogens, which are hormones present in the pathogenic cell changes associated with the growth of some hormone-dependent cancers, such as Breast cancer, Uterine cancer, ovarian cancer and pancreatic cancer, are included. Estrogens are too in the pathogenesis of benign prostatic hyperplasia locked in.

Endogenous estrogens ultimately become either Androstenedione or testosterone as direct precursors educated. The reaction of central importance is the Aromatization of the steroid ring A, by the enzyme Aromatase is performed. Since the aromatization a only reaction is and the last in a series of Steps in the biosynthesis of estrogens has been ins It is envisaged that effective inhibition of aromatase, that comes from connections that are capable of having  to interact with the aromatization steps, perhaps a useful application in controlling the amount circulating estrogens, the estrogen-dependent Procedures in reproduction and estrogen-dependent Could have tumors. Known, non-steroidal substances, one of which is more or less selective Aromatase inhibition has been reported, z. B. Aminoglutethimide (Ann Surg 187, 475 (1978); Lancet 2, 646 (1978)); 4-cyclohexylaniline (Endocrinology 114, 2128 (1984)), and 4-pyridyl-3-ethyl-2,6-piperidinedione (J. Med. Chem. 28, 200 (1985)).

The present invention provides compounds which the have the following general formula (I):

where W

• a) a 1- or 2- or 9-anthryl or naphthyl radical wherein each benzene ring is unsubstituted or substituted a substituent is substituted from halogen, C₁-C₄alkyl, hydroxy, C₁-C₄alkoxy, formyloxy, C₂-C₅ alkanoyloxy, aroyloxy, C₂-C₅ alkanoyl, Carboxy, C₂-C₅ alkoxycarbonyl, mono- or di- (C₁-C₄alkyl) carbamyl, cyano, nitro, amino, Mono- or di- (C₁-C₄-alkyl) amino, C₂-C₅ alkanoylamino and aroylamino is selected; or
• b) a pyridyl, pyrazinyl, pyrimidinyl or Pyridazinylring is where each ring is unsubstituted or by one of the substituents defined above  is substituted;

R is C₁-C₄alkyl, halo-C₁-C₄alkyl, hydroxy-C₁-C₄alkyl, C₁-C₄alkoxy-C₁-C₄alkyl, formyloxy-C₁-C₄alkyl, C₂-C₅-alkanoyloxy C₁-C₄ alkyl or C₂-C₅ alkanoyl;
Z is a single, double or triple bond;
and the pharmaceutically acceptable salts thereof; and wherein, when at the same time W is 1-naphthyl substituted by cyano and Z is a single bond, R is not unsubstituted C₁-C₄ alkyl.

A halogen is iodine or bromine or fluorine, in particular Chlorine.

An alkyl group, including the alkyl portion of the others above substituents, may be a branched or be a straight-chain group. A C₁-C₄ alkyl group is preferably methyl, ethyl or propyl.

The term aryl, in definition of the above Substituent occurs, means z. Phenyl and naphthyl, preferably phenyl.

A C₁-C₄ alkoxy group is preferably methoxy or Ethoxy.

A C₂-C₅ alkanoyloxy group is preferably acetoxy or propionyloxy, with acetoxy being particularly preferred is.

An aroyloxy group is preferably benzoxy.  

A C₂-C₅ alkanoyl group is preferably acetyl, Propionyl, with acetyl being particularly preferred.

A C₂-C₅ alkoxycarbonyl group is preferred Methoxycarbonyl or ethoxycarbonyl.

A mono- or di- (C₁-C₄alkyl) carbamyl group preferably methylcarbamyl or dimethylcarbamyl or Diethylcarbamyl.

A mono- or di (C₁-C₄ alkyl) amino group preferably methylamino or dimethylamino or Ethylamino or diethylamino.

A C₂-C₅ alkanoylamino group is preferably Acetylamino.

An aroylamino group is preferably benzoylamino.

A pyridyl group is z. 2- or 3- or 4-pyridyl, in particular 4-pyridyl.

A pyrimidinyl group is z. B. 2- or 4-pyrimidinyl, in particular 2-pyrimidinyl.

If W is naphthyl, then it is z. B. 1- or 2-naphthyl, preferably 2-naphthyl.

A pyrazinyl group is z. B. 2-pyrazinyl.

A pyridazinyl group is z. A 3- or 4-pyridazinyl, in particular a 3-pyridazinyl.  

A C₁-C₄-alkoxy-C₁-C₄-alkyl group is preferably methoxymethyl or methoxypropyl.

A C₂-C₅-alkanoyloxy-C₁-C₄-alkyl group is preferably acetoxymethyl or acetoxypropyl.

A C₂-C₅ alkanoyl group is preferably acetyl or Propionyl.

In a halo-C₁-C₄-alkyl group, the Halogen atom independently on one of the carbon atoms of Be bonded alkylene chain, wherein the halogen is preferably Chlorine is; Examples of such a group are Chloromethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl and 3-chloropropyl.

In a hydroxy-C₁-C₄-alkyl group, the Hydroxy group independently at one of the carbon atoms of Be bound alkylene chain; Examples of such a group are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-hydroxypropyl.

The above formulas for the compounds of Invention are all possible isomers of the formula (I), both separately and in mixture include, wherein z. B. the Z and E isomers of the compounds of the formula (I) are included, in which Z is a double bond.

The objects of the present invention are also Metabolites and metabolite precursors and bioprecursors of Compounds of the formula (I).

The invention also includes the pharmaceutical Compatible salts of the compounds of the formula (I)  either with a pharmaceutically acceptable base or Acid or in the form of an internal salt. The salts are preferably salts of the compounds of the formula (I) pharmaceutically acceptable acids, both inorganic Acids, such as. As hydrochloric acid and sulfuric acid, as well organic acids, such as. Citric acid, tartaric acid, Maleic acid, malic acid, succinic acid, methanesulfonic acid and ethanesulfonic acid. Preferred salts are hydrochlorides. Preferred compounds of the invention are the Compounds of formula (I) wherein W is 1-anthryl, 2-naphthyl, 4-pyridyl, 2-pyrimidinyl or 2-pyrazinyl radical is unsubstituted or by a substituent selected from halogen, hydroxy and Cyano, is substituted; where R is hydroxymethyl, Hydroxypropyl, chloromethyl, chloropropyl, acetoxymethyl, Acetoxypropyl, methoxymethyl, methoxypropyl, methyl, Ethyl, propyl or acetyl; where Z is a single, Double or triple bond; and the pharmaceutical acceptable salts thereof.

As noted above, the present invention includes in its scope also pharmaceutically acceptable Bioprecursor (otherwise known as Pro-Drug) the compounds (I), d. h., compounds that have a different formula compared to the above formula (I) which, however, when administered to a human directly or indirectly in vivo into a compound of the formula (I) to be converted.

Examples of preferred specific compounds of Invention are the following:

5- (3-hydroxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (3-acetoxy-prop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (3-methoxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (but-1-en-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (but-1-in-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (5-hydroxypent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (5-acetoxypent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (5-methoxypent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (n-pent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-chloroanthr-1-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-cyanoanthr-1-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (5-hydroxypent-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (3-chloropyrid-4-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (3-chloropyrid-4-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (3-chloropyrid-4-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (5-hydroxypent-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (4-chloropyrimidine-2-ylmethyl) -1H-imidazole; -
5- (3-chloroprop-1-yl) -1- (4-chloropyrimidine-2-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (5-hydroxypent-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (5-hydroxypyrazine-2-ylmethyl) -1H-imidazole; and
5- (3-chloroprop-1-yl) -1- (5-hydroxypyrazine-2-ylmethyl) -1H-imidazole

and the pharmaceutically acceptable salts thereof.  

The compounds of the invention and the salts thereof can be be prepared by a process that

• (A) the reaction of a compound of formula (II) wherein R 'has the meaning of R as above, except halo-C₁-C₄-alkyl, and wherein Z is as defined above, with a compound of formula (III) W-CH₂-X (III) wherein W is as defined above and X is a leaving group to obtain a compound of formula (I) wherein R is as defined above except for halo-C₁-C₄ alkyl; or
• (B) the halogenation of a compound of the formula (IV) wherein R "is hydroxy-C₁-C₄ alkyl and W and Z are as defined above to obtain a compound of formula (I) wherein R is halo-C₁-C₄ alkyl; and, if desired, the conversion of a compound of formula (I) to another compound of formula (I) and / or, if desired, the separation of a mixture of isomers of a compound of formula (I) into the individual isomers, and / or, if desired, salting a compound of formula (I), and / or if desired, converting a salt into a free compound.

When in the compounds of the present invention and in the intermediates thereof groups, such as -OH and / or -NH₂, are present, which must be protected before they undergo the reactions shown below then they can before the expiration of the reactions be protected and then again unprotected be made according to known methods in the organic chemistry.

In a compound of the formula (III), the leaving group is X is preferably an esterified hydroxy group, e.g. B. Acetoxy, mesyloxy or para-toluenesulfonyloxy; or in particular a halogen atom, such as chlorine or bromine. The N-alkylation of a compound of formula (II) with a Compound of formula (III) can in the presence of a suitable base, for. B. a tertiary amine, such as Triethylamine. The N-alkylation can even without using a basic agent become. It can be in an aprotic organic Solvent, e.g. As a nitrile, such as acetonitrile or an amide, such as dimethylformamide, at temperatures in the Range from about 0 ° to about 100 ° C become.

The halogenation of a compound of formula (IV) can be carried out by ordinary Halogenation method used, for. B. by reaction with Thionyl chloride, phosphorus trichloride, phosphorus pentachloride, Phosphorus oxychloride or thionyl bromide. Preferably  the chlorination with thionyl chloride in an inert Solvents, such as dichloromethane, at temperatures in the Range from about 0 ° to about 80 ° C.

A compound of formula (III) may be as above found in another compound of formula (I) be converted by known methods, for. B .:

• (a) A compound of formula (I) wherein R is hydroxy C₁ C₄ alkyl may be converted to another compound of formula I wherein R is formyloxy C₁ C₄ alkyl or C₂ C₅ -Alkanoyloxy-C₁-C₄-alkyl, by conventional acylation.
  Preferably, an acyl halide such as acetyl chloride or an acid anhydride such as acetic anhydride can be used in the presence of an organic base such as pyridine. The reaction may be conducted at temperatures ranging from room temperature to about 100 ° C with or without a suitable solvent such as chloroform or benzene.
• (b) A compound of formula (I) wherein R is hydroxy-C₁-C₄ alkyl may be converted into another compound of formula (I) wherein R is C₁-C₄ alkoxy-C₁-C₄ alkyl, be converted according to known methods.
  Preferably, the method of Williamson (J. Chem., Seoc., 4, 229 (1952)) will be used; Accordingly, first the alkoxide is reacted by reaction with z. Metallic sodium or sodium hydride, and then an alkyl halide or alkyl sulfate such as methyl iodide or dimethyl sulfate is added.
• (c) A compound of the formula (I) in which R Halo-C₁-C₄-alkyl, wherein the halogen atom to the C-1 carbon atom is bonded, and Z is a Represents single bond, can be dehydrohalogenated be the appropriate compound of the formula (I) to obtain, in which R is C₁-C₄-alkyl and Z represents a double bond. The Dehydrohalogenation may be by known methods be performed. Preferably, a Compound with a 1-bromo-C₁-C₄-alkyl chain used. Dehydrohalogenation may occur in Presence of a suitable base, e.g. B. one Alkali metal hydroxide, such as potassium hydroxide, a bicyclic amidine, such as 1,5-diaza-bicyclo (5,4,0) undec-5-ene, or preferably a C₁-C₄ alkoxide, such as Potassium tertiary butoxide, or a Alkali metal hydride, such as sodium hydride become. Suitable solvents are, for. Ethers, such as ethyl ether or tetrahydrofuran, or amides, like dimethylformamide. The temperature range can at about -60 ° C to about + 80 ° C. Preferably, the bromine compound is in a Tetrahydrofuran solution with Kaliumtertiärbutoxid at Reflux temperature treated.
• (d) A compound of formula (I) wherein R is C₁-C₄ alkyl, C₁-C₄ alkoxy C₁-C₄ alkyl, formyloxy C₁-C₄ alkyl or C₂-C₅ alkanoyloxy C₁-C₄ alkyl and Z is a double bond can be converted to a corresponding compound of formula (I) wherein Z is a triple bond via a known dihalogenation / dehydrohalogenation process.
  For example, dihalogenation is performed by adding bromine to the olefin solution in carbon tetrachloride at temperatures ranging from about -50 ° C to about + 10 ° C.
  The dehydrohalogenation of the resulting dibromo compound can be carried out with the aid of a base, for. For example, alkali metal hydroxide or Alkalialkoxid, preferably with sodium amide, can be achieved in liquid ammonia.
• (e) A compound of the formula (I) in which R Hydroxy-C₂-C₄-alkyl, wherein the hydroxy group is attached to the C-1 carbon atom be oxidized to a corresponding compound of the formula (I) in which R is C₂-C₄alkanoyl is, via known methods; for example by adding a solution of chromium (III) oxide in dilute sulfuric acid to the substrate solution in Acetone, at temperatures below 0 ° C. Alternatively, the oxidation may be by treatment with dimethyl sulfoxide in the presence of a Dehydrating agent, for. B. one Acid anhydride, such as acetic anhydride, a Acid halide, such as oxalyl chloride, one Mineral acid anhydride, such as phosphorus pentoxide, or a carbodiimide such as dicyclohexylcarbodiimide, be performed. The relationship Dimethyl sulfoxide / dehydrating agent about 1: 1. Preferably, the oxidation is in  Presence of an acid catalyst, such as Phosphoric acid or pyridinium trifluoroacetate, carried out.
• (f) A compound of formula (I) wherein R is halo-methyl may be converted to a corresponding compound of formula (I) by known methods wherein R is hydroxy-propyl or hydroxy-butyl. This is accomplished by converting the starting compound to the corresponding Grignard compound and then reacting with ethylene oxide or trimethylene oxide. The Grignard reaction can be carried out according to the reaction conditions known in organic chemistry, e.g. B. in "Grignard reactions of non metallic substances" by MS Kharasch and O. Reinmuth are described. Preferably, the Grignard reagent is dissolved in an ethyl ether solution by reaction of the compound of formula (I) wherein R is halomethyl, e.g. As bromoethyl, prepared with magnesium.
  The ethylene oxide or trimethylene oxide may be supplied under cooling. The reaction temperature ranges from about -10 ° C to room temperature.
• (g) A compound of the formula (I) in which R Halo-C₁-C₄-alkyl, may be in a corresponding compound of the formula (I) in which R C₁-C₄alkyl is, by known Reduction process to be converted. To the Example, if the halogen is bromine or chlorine, For example, the compound of formula (I) may be treated by treatment with a suitable metal hydride, e.g. B.  Lithium aluminum hydride, in an ether, e.g. B. Tetrahydrofuran or diglyme, at a temperature ranging from room temperature to Reflux temperature can be reduced.
• (h) A compound of the formula (I) in which R Hydroxymethyl may be in another compound of formula (1) wherein R is a -CH (OH) -C₁-C₃ alkyl group is, by methods known per se being transformed. For example, the partial oxidation of the hydroxymethyl compound with Dimethylsulfoxide an aldehyde of the formula (I), wherein R is formyl. Subsequently, the aldehyde with a Grignard reagent of the formula R³Mghlg implemented, wherein R³ is a C₁-C₃ alkyl group is. The oxidation with dimethyl sulfoxide is in Presence of a dehydrating agent, e.g. B. an acid anhydride such as acetic anhydride Acyl halide, such as oxylyl chloride, a Mineral acid anhydride, such as phosphorus pentoxide, or a carbodiimide such as dicyclohexylcarbodiimide, carried out. Preferably, the oxidation is in Presence of an acid catalyst, such as Phosphoric acid or pyridinium trifluoroacetate, carried out. The following Grignard reaction can in a manner analogous to that described above Method (f) are performed.
• (i) a compound of formula (I) having a Carboxyl substituent can be in another A compound of the formula (I) which is a C₁-C₄ alkoxy carbonyl group carries, over known ones Process to be converted; for example through Treat the acid with an excess of  suitable C₁-C₄-alkanol in the presence of a anhydrous mineral acid, such as hydrochloric acid or Sulfuric acid, at reflux temperature.
• (j) A compound of the formula (I) in which the group W substituted by hydroxy, may be in another Compound of the formula (I) in which the substituent W is substituted by C₁-C₄-alkoxy, according to converted to known methods; to the Example according to the method described above as possible conversion process (b) is described, or by treating the hydroxy compound first with a suitable base, such as sodium hydride or Sodium amide, and then with an alkylating agent, such as methyl iodide or dimethyl sulfate, in one suitable solvents, such as benzene Temperatures in the range of about 20 ° C to about 100 ° C.
• (k) A compound of formula (I) wherein W is a unsubstituted aryl or heteroaryl group, as in formula (I) under (a) and (b) can be defined in another connection of the Formula (I) in which the substituent W is cyano is substituted, according to known methods be converted, for. B. by reaction with Cyanogen chloride or bromide or with Trichloroacetonitril.
• (I) A compound of the formula (I) in which Substituent W is substituted by halogen into another compound of the formula (I) in which the substituent W is substituted by cyano, be converted by known methods, for. B.  by selection with an inorganic cyanide, such as Sodium cyanide or copper (I) cyanide, in one suitable solvents, such as pyridine, quinoline or dimethylformamide, at high temperature, preferably reflux temperature.
• (m) A compound of the formula (I) in which the substituent W is substituted by nitro can be reduced to another compound of the formula (I) in which the substituent W is substituted by amino, according to known methods, e.g. By hydrogenating the nitro compound in the presence of a catalyst such as palladium or charcoal in a suitable solvent such as methanol or ethyl acetate.
  Ordinary processes may also be used for salt formation of a compound of formula (I) and for obtaining a free compound of formula (I) from a salt thereof, and standard techniques such as fractional crystallization and chromatography may be used for the separation of a mixture of isomers a compound of formula (I) into the individual isomers.

The compounds of the formula (II) are known or they can be prepared by known methods from known compounds to be obtained. For example, can 4- (3-hydroxyprop-1-yl) -1H-imidazole according to Gr. A. A. Kivits et al. in J. Het. Chem., 12, 577 (1975).

If desired, the possible transformations of (a) bis (h), which for a compound of formula (I) in a  other compounds of formula (I) have been described above, with regard to the intermediate compounds of the formula (II) carried out in accordance with the same procedures.

The compounds (III) are known compounds or they can be prepared according to known methods.

The compounds of formula (IV) are compounds of Formula (I) wherein R is hydroxy-C₁-C₄ alkyl, and can by the method (A), as described above, to be obtained.

The compounds of the present invention are Inhibitors of biotransformation of androgens in Estrogens, d. they are aromatase inhibitors.

The inhibition of aromatase activity by these compounds has been demonstrated using an in vivo assay employing the aromatase enzyme system isolated from the microsomal fraction of human placental tissue, according to the standard procedure. The assay of Thompson and Siiteri (FA Thompson and Siiteri PK, J. Biol. Chem. 249, 5364, (1974)), which, β the aromatization by measuring the release of ³H₂O of 4- (1, 2- b -³H ) androsten-3,17-dione was used.

All incubations were done in a shaken water bath at 37 ° C air temperature in a 10 mM Potassium phosphate buffer, pH 7.5, containing 100 mM KCl, 1 mM EDTA and 1 mM dithiothreitol.

The experiments were carried out with a 1 ml incubation volume containing 50 nM 4- (3 H) androstenedione, various concentrations of the inhibitors, 100 μM NADPH and 0.05 mg of the microsomal proteins. After 15 minutes of incubation, the reaction was stopped by adding chloroform (5 ml). After centrifuging at 1500 g for 5 minutes, portions (0.5 ml) were removed from the water phase to determine the ³H₂O formed. The concentration of each compound required to reduce the control aromatase to 50% (IC₅₀) was determined by plotting the degree of inhibition (%) against the logarithm of the inhibiting concentrations.

The new compounds, incubated at different Concentrations showed a remarkable Aromataseinhibierungswirkung.

Because of their ability to inhibit aromatase, and Accordingly, to reduce the estrogen level, are the new compounds in the treatment and prevention various estrogen-dependent diseases in Mammals, e.g. Breast, uterine, ovarian and Pancreatic cancer, Gynecomastia, benign breast disease, endometriosis, polycystic Ovarian disease and early puberty, suitable. Another application of the compounds of the invention exists in the therapeutic and / or prophylactic Treatment of prostatic hyperplasia, a disease of the estrogen-dependent stromal tissue.

The new connections can also be applied to the Treatment of male infertility associated with Oligospermia, and female fertility control, because of their property, ovulation and the To inhibit egg output to be used.  

In view of their high therapeutic index, the Compounds of the invention safely in the field of medicine be used. For example, the approximate was acute Toxicity (LD₅₀) of the compounds of the invention in the Mouse, determined by single administration of ascending Doses and measured on the 7th day after treatment, as found negligible.

The compounds of the invention can be used in a variety of ways of dosage forms, e.g. B. orally in the form of tablets, capsules, sugar- or film-coated Tablets, liquid solutions or suspensions; rectally in Form of suppositories; parenterally, for example intramuscularly, or by intravenous injection or infusion.

The dosage depends on age, weight, condition of the patient and the mode of administration; for example may be a dosage suitable for oral administration on adult humans in the range of about 10 to about 150-200 mg per dose, from 1 to 5 times daily rich.

The invention includes pharmaceutical preparations, a compound of the invention together with a pharmaceutically acceptable excipient (the Carrier or diluent).

The pharmaceutical preparations containing the compounds of the present invention are commonly used produced by the following conventional methods and are administered in pharmaceutically suitable form.

For example, the solid oral forms can be combined with the active compound extender, z. Lactose, dextrose,  Sucrose, cellulose, corn starch or potato starch; Lubricants, such as silica, talc, stearic acid, magnesium or calcium stearate and / or polyethylene glycol, Binders, e.g. Starches, gum arabic, gelatin, Methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; Antiagglomarate agents, e.g. B. starch, Alginic acid, alginates or sodium starch glycolate; Aufschäummischungen; Dyes, sweeteners; Wetting agents, such as lecithin, polysorbate, lauryl sulfates; and, completely general, non-toxic and pharmacologically inactive Substances used in pharmaceutical preparations can be used. The pharmaceutical Preparations may be prepared in known manner, e.g. B. by Mixing, granulating, tableting, sugar coating or be prepared by film coating process. The liquid dispersions for oral administration z. As syrups, emulsions and suspensions.

The syrups can be used as a carrier z. B. sucrose or Sucrose with glycerine and / or mannitol and / or sorbitol contain. The suspensions and the emulsions can be used as Carrier z. A natural gum, agar, sodium alginate, Pectin, methylcellulose, carboxymethylcellulose or Polyvinyl alcohol included.

The suspensions or solutions for the intramuscular Injections, together with the active component one pharmaceutically acceptable carriers, e.g. Sterile water, Olive oil, ethylolate, glycols, e.g. For example, propylene glycol, and, if desired, an appropriate amount Lidocaine hydrochloride included.

The solutions for intravenous injections or Infusions may be used as carriers e.g. B. sterile water  contain, or they are preferably in the form of sterile, aqueous, isotonic saline solutions.

The suppositories can together with the active component one pharmaceutically acceptable carriers, e.g. Cocoa butter, Polyethylene glycol, a Polyoxyethylene sorbitan fatty acid ester surfactant or Containing lecithin.

The following examples illustrate the invention, But do not limit it.

Example 1 5- (3-hydroxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (I, W = anthr-1-yl, R = hydroxymethyl, Z = single bond)

A mixture of 4- (3-hydroxypropyl) -1H-imidazole (126 mg, 1 mmol), triethylamine (121 mg, 1.2 mmol) and Dimethylcarbamyl chloride (118 mg, 1.1 mmol) in dry Acetonitrile (2 ml) is kept under nitrogen for 24 hours refluxed. After cooling to 0 to 5 ° C is Triethylamine (121 mg, 1.2 mmol) and trimethylsilyl chloride (130 mg, 1.2 mmol) and the reaction mixture is stirred for two hours at room temperature. To Dilution with ethyl ether becomes insoluble Particles filtered off, the residue is with Washed ethyl ether, and the combined ether extracts evaporated under vacuum. The obtained raw 4- (3-trimethylsilyloxypropyl) -1H-imidazol-1-dimethylcarboxamide is treated with anthr-1-ylmethylbromide (271 mg, 1 mmol) in Acetonitrile (2 ml), refluxing for 20 hours heated for a long time.  

Then, gaseous ammonia is added for 15 minutes 0 to 5 ° C introduced, and the mixture is under vacuum concentrated. The residue is dissolved in N hydrochloric acid, the acidic solution obtained for half an hour at room temperature stirred and then washed with ethyl acetate. The pH value the acidic solution is added to 8 to 9 by adding Potassium carbonate solution adjusted, and the crude product is extracted with chloroform. The organic phase is with Washed with water, dried with sodium sulfate and then in Vacuum evaporated.

The residue is column chromatographed on silica gel, with chloroform / methanol 1% as eluent used. This gives 221 mg of the title compound obtained (70% yield).

Elemental analysis:
found,% C 79.65 (79.72); H 6.25 (6.37); N 8,77 (8,85).

NMR (CDCl₃, δ) :
1.81 (2H, m); 2.55 (2H, t); 3.45 (2H, t); 5.25 (2H, s); 6.85 (1H, s); 7.60 (1H, s); 7: 15-8: 15 (9 H, m).

In an analogous way, the following compounds getting produced:

5- (3-hydroxyprop-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (3-chloropyrid-4-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (4-chloropyrimidine-2-ylmethyl) -1H-imidazole; -
5- (3-hydroxyprop-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (5-hydroxypyrazine-2-ylmethyl) -1H-imidazole.

example 2 5- (3-chloroprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (I, W = anthr-1-yl, R = chloromethyl, Z = single bond)

A solution from 5- (3-hydroxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (316 mg, 1 mmol) and thionyl chloride (155 mg, 1.3 mmol) in dry dichloromethane (4 ml) is refluxed two Heated for hours. Then the solution is in a vacuum evaporated, and the residue is washed with dichloromethane and Sodium bicarbonate solution added. The organic phase is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is on Silica gel chromatographed, taking chloroform / methanol 1% used as the eluent, and 301 mg of the pure Title compound (90% yield).

Elemental analysis:
found,% (calculated,%): C 75.25 (75.33); H 5.75 (5.72); N 8.15 (8.37) Cl 10.40 (10.59).

NMR (CDCl₃, δ) :
2.00 (2H, t); 3.49 (2H, t); 3.49 (2H, t); 5.15 (2H, s); 6.19 (1 H, s); 7.60 (1H, s); 7,20-8,20 (9 H, m).

In an analogous manner, the following compounds can be prepared:
5- (3-chloropent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-chloroanthr-1-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-cyanoanthr-1-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (3-chloropyrid-4-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-chloropyrimidine-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (pyrazine-2-ylmethyl) -1H-imidazole, and
5- (3-chloroprop-1-yl) -1- (5-hydroxypyrazine-2-ylmethyl) -1H-imidazole.

example 3 5- (3-acetoxy-prop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (I, W = anthr-1-yl, R = acetoxymethyl, Z = single bond)

To a cooled solution of 5- (3-hydroxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (316 mg, 1 mmol) in dry pyridine (1 ml) is added acetic anhydride (306 mg, 3 mmol), and the mixture is added overnight Kept at room temperature. Then the solvent is in Vacuum removed, and the residue is dichloromethane and water added. The organic phase becomes separated, washed several times with water, over Dried sodium sulfate and evaporated in vacuo. The Residue is on silica gel with chloroform / methanol 1% chromatographed as eluent, where the pure Title compound (325 mg, 90% yield).

Elemental analysis:
found,% (calculated,%): C 76.51 (76.69); H 6.01 (6.15); N 7.60 (7.77).

NMR (CDCl₃, δ) :
2.02 (3H, s); 2.02 (3H, s); 2.54 (2H, t); 3.42 (2H, t);
5.20 (2H, s); 6.81 (1H, s); 7.55 (1H, s); 7: 15-8: 15 (9 H, m).

In an analogous manner, the following compound can be prepared:
5- (5-acetoxypent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole.

example 4 5- (3-methoxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (I, W = anthr-1-yl, R = methoxymethyl, Z = single bond)

To a cooled solution of 5- (3-hydroxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (316 mg, 1 mmol) in dry tetrahydrofuran (10 ml) Sodium hydride (29 mg, 1.2 mmol) in portions added, and the mixture will last for an hour touched. Finally, methyl iodide (174 mg, 1.2 mmol) added, and the mixture is refluxed for heated for about 2 hours. The solvent is through Evaporate in vacuo and remove the residue Ethyl acetate and water. The organic phase is separated, washed with water, dried and im Vacuum evaporated. The residue is treated with silica gel Absorbent and chloroform / methanol 1% as eluent säulenchromatographiert, where the pure Title compound in 80% yield (264 mg).

Elemental analysis:
found,% (calculated,%): C, 79.81 (79.97); H, 6.65 (6.71); N 8,35 (8,48).

NMR (CDCl₃, δ) :
1.85 (2H, m); 2.51 (2H, t); 3.24 (3H, s); 3.42 (2H, t);
5.22 (2H, s); 6.83 (1H, s); 7.63 (1H, s); 7: 15-8: 15 (9 H, m).

example 5 5- (prop-1-en-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (I, W = anthr-1-yl, R = methyl, Z = double bond)

A solution from 5- (3-hydroxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (316 mg, 1 mmol) and thionyl bromide (250 mg, 1.2 mmol) in dry dichloromethane (4 ml) is refluxed Heated for an hour. The solution is then in a vacuum evaporated, and the residue is washed with dichloromethane and cold sodium bicarbonate solution. The separated organic phase is washed with water, dried over sodium sulfate and evaporated in vacuo. This gives you raw 5- (3-bromoprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (380 mg, 100% yield).

The crude bromine compound obtained above (380 mg, 1 mmol)  is dissolved in dry tetrahydrofuran (3 ml), and the Solution is cooled to 0 to 5 ° C. Than it will be Potassium tertiarybutoxide (224 mg, 2 mmol) in portions is added, and the resulting reaction mixture is for another three hours at reflux temperature below Nitrogen stirred. Finally, the reaction mixture concentrated in vacuo, the pH is at 8 to 10 by adding aqueous acetic acid with cooling adjusted, and the crude product is chloroform extracted. The organic layer is separated dried and evaporated in vacuo. The residue will be on silica gel using chloroform / methanol 1% chromatographed as eluent. This will be the pure Title Compound obtained in 70% yield (208 mg).

Elemental analysis:
found,% (calculated,%): C 84.35 (84.53); H 5.96 (6.08); N 9,25 (9,39).

NMR (CDCl₃, δ) :
1.92 (3H, m); 5.20 (2H, s); 6.1 (2H, m);
6.85 (1H, s); 7.60 (1H, s); 7: 15-8: 15 (9 H, m).

In an analogous manner, the following compounds can be prepared:
5- (but-1-en-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole.

example 6 5- (but-1-in-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (I, W = anthr-1-yl, R = ethyl, Z = triple bond)

To a solution of 5- (but-1-en-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (312 mg, 1 mmol) in dry chloroform (5 ml), those with a frozen mixture of ice and salt Is cooled, is dropwise bromine (160 mg, 1 mmol) added. The mixture is allowed to rise gradually Room temperature rise, and then it is in a vacuum evaporated. The residue contains tube 5- (1,2-dibromobut-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole.

To liquid ammonia (about 3 ml), its temperature kept between -30 ° C and -40 ° C with a dry ice bath and a catalytic amount of iron nitrate contains metallic sodium (81 mg, 3.5 mmol) added in portions. After about 20 minutes, d. h. when the color of the mixture turns from blue to gray is changed, an ether solution of the above obtained Dibromids are slowly added, and the mixture is used for kept at low temperatures for a further 4 hours. Subsequently, ammonium chloride is added, and the Mixture is allowed to rise to room temperature. The Residue is taken up with chloroform and water. The organic phase is washed with water, dried and evaporated in vacuo. The residue is on silica gel  chromatographed, with chloroform / methanol 1% as Eluent used and the pure title compound in 50% yield obtained (155 mg).

Elemental analysis:
found,% (calculated,%): C 85.05 (85.13); H 5.75 (5.84); N 8.95 (9.02).

example 7 5- (butan-3-on-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (I, W = anthr-1-yl, R = acetyl, Z = single bond)

To a solution of 5- (3-hydroxybut-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (330mg, 1mmol) in acetone (5ml), maintained between -20 ° C and -30 ° C with a dry ice bath, a solution of Chromium (III) oxide (200 mg, 2 mmol) in dilute Sulfuric acid (1 ml) dropwise in about 15 minutes added, and then the mixture for another Hour at low temperature. Thereupon becomes the excess of oxidizing agent with isopropanol destroyed and the mixture concentrated in vacuo. The Crude product is treated with ethyl acetate at pH 8 Extracted to 10, the organic phase is washed with water washed, dried and evaporated in vacuo. The Residue is applied to silica gel using Chloroform / methanol 2% as eluent columned. The pure title connection will be in 80% yield (262 mg).

Elemental analysis:
found,% (calculated,%): C 80.30 (80.46); H 6,00 (6,19); N 8.35 (8.53).

NMR (CDCl₃, δ) :
2.10 (3H, s); 2.50 (2H, t); 2.60 (2H, t); 5.25 (2H, s);
6.84 (1H, s); 7.55 (1H, s); 7: 15-8: 15 (9 H, m).

In an analogous way, the following compounds getting produced:

5- (butan-3-on-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (3-chloropyrid-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole.

example 8 5- (5-hydroxypent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (I, W = anthr-1-yl, R = hydroxyprop-1-yl, Z = single bond)

To a vigorously stirred suspension of magnesium turnings (25mg, 1mmol) in dry ethyl ether (3ml)  small crystals of iodine are added, and then one becomes Solution of 5- (3-bromoprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (379 mg, 1 mmol) in dry ethyl ether (3 ml) dropwise introduced at such a speed that the Mixture is constantly boiling. The mixture is for a continue to reflux for half an hour. Then the piston is with a frozen mixture of ice and salt cooled, and Ethylene oxide gas (66 mg, 1.5 mmol) gradually becomes introduced. The reaction mixture is allowed to Room temperature rise, and she will then for another Hour brought to a boil. Benzene is added, and the mixture is concentrated by evaporation. Ice cream and Saturated ammonium chloride solution is added, the Crude product is extracted with benzene, and the organic Layer is evaporated under vacuum after being was washed and dried. The residue is on Silica gel using chloroform / methanol 2% as Eluiermittel chromatographed, where a pure Title compound in 60% yield (206 mg).

Elemental analysis:
found,% (calculated,%): C, 80.10 (80.20); H, 6.91 (7.02); N 7,95 (8,13).

NMR (CDCl₃, δ) :
1.80-2.20 (6H, m); 2.55 (2H, t); 3.45 (2H, t); 5.20 (2H, s);
6.79 (1H, s); 7.55 (1H, s); 7: 15-8: 15 (9 H, m).

In an analogous way, the following compounds getting produced:

5- (5-hydroxypent-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (5-hydroxypent-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (5-hydroxypent-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole.

example 9 5- (pent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (I, W = anthr-1-yl, R = prop-1-yl, Z = single bond)

To a solution of lithium aluminum hydride (19 mg, 0.5 mmol) in Diglyme (5 ml) is gradually a solution of 5- (5-chloropent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (363 mg, 1 mmol) in diglyme (3 ml). The obtained Mixture is stirred at 100 ° C for about 15 hours. Then an aqueous solution of sodium / potassium tartrate added. The mixture is filtered and placed on small volume concentrated under reduced pressure. The Concentrate is taken up in ethyl acetate and washed well with Washed water. The organic layer is over Dried sodium sulfate, filtered, and the solvent is removed under vacuum, leaving a residue obtained, which is chromatographed on silica gel, wherein Chloroform / methanol 1% used as eluent, and to the pure title compound in 80% yield (263 mg).

Elemental analysis:
found,% (calculated,%): C 80.15 (80.20); H 7,25 (7,36); N 8.45 (8.53).

example 10 5- (pent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (I, W = anthr-1-yl, R = prop-1-yl, Z = single bond)

To a solution of dimethyl sulfoxide (156 mg, 2 mmol) in dry dichloromethane (5 ml) which was added under nitrogen Cooled to -75 ° C, oxalyl chloride (216 mg, 1.7 mmol) is added dropwise. After half an hour of stirring at -75 ° C, a solution of 5- (3-hydroxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (316 mg, 1 mmol) in one Mixture of dimethyl sulfoxide (0.2 ml) and dichloromethane (1 ml) is added slowly, and the mixture is poured for stirred at -75 ° C for a further three hours. Than it will be Triethylamine (1 ml) was added, and allowed to Increase the mixture to room temperature. After dilution with dichloromethane the organic phase is separated, washed with water, dried and reduced Evaporated pressure. Chromatography of the residue on Silica gel with chloroform / methanol 1% as eluent gives pure 5- (propan-3-one-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole in 50% yield (157 mg).

To a vigorously stirred suspension of magnesium turnings (25 mg, 1 mmol) in dry ethyl ether (3 mL) becomes small iodine crystal is added, and then one becomes Solution of methyl iodide (142 mg, 1 mmol) in dry Ethyl ether (2 ml) dropwise in such a Speed added that the mixture constantly boils. The mixture is left for another 30 minutes refluxed. Subsequently, a solution of 5- (propan-3-one-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole (314 mg, 1 mmol) in benzene (5 ml) dropwise with cooling introduced. The solvent is then removed until the  Boiling point reaches 77 ° C, and heating is used for continued for another 3 hours. Ice cream and Ammonium chloride solution is added, and the Crude product is at a pH of 8 to 9 with Extracted ethyl acetate. The organic layer becomes washed, dried and evaporated in vacuo. The Residue is applied to silica gel using Chloroform / methanol as eluent columned.

This yields the title compound in 75% yield (248 mg). receive.

Elemental analysis:
found,% (calculated,%): C, 79.85 (79.97); H, 6.81 (6.71); N 8,35 (8,48).

example 11 5- (3-hydroxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole hydrochloride (I, W = anthr-1-yl, R = hydroxymethyl, Z = single bond)

To obtain the hydrochloride salt, it becomes a solution of 5- (3-hydroxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H- imidazole base (316 mg, 1 mmol) in ethyl acetate (4 ml) stoichiometric amount of hydrochloric acid added. The precipitated salt is filtered off, with solvent washed and dried. This will be the title link in 90% yield (318 mg).

Elemental analysis:
found,% (calculated,%): C 71.43 (71.48); H 5.85 (6.00); N, 7.85 (7.94); Cl 9.95 (10.05).

example 12

Tablets each weighing 0.150 g and 25 mg of the Active substance can be prepared as follows become:

Composition for 10 000 tablets 5- (3-chloroprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole | 250 g lactose 800 g corn starch 415 g talcum powder 30 g magnesium stearate 5 g

5- (3-chloroprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole, the lactose and half of the corn starch are mixed, and the mixture is then passed through a sieve with a Mesh width of 0.5 mm driven.

Cornstarch (10 g) is poured into warm water (90 ml) suspended, and the resulting paste is used to to granulate the powder.

The granules are dried on a sieve with a Mesh size of 1.4 mm crushed, and then the remaining portion of starch, talc and magnesium stearate added, mixed carefully and into tablets processed.  

example 13

Capsules dosed at 0.200 g each and 20 mg of the active substance can be prepared as follows become:

Composition for 500 capsules 5- (3-chloroprop-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole | 10 g lactose 80 g corn starch 5 g magnesium stearate 5 g

This formulation can be in two-part, hard Encapsulated gelatin capsules and 0.200 g for each Capsule be dosed.

Claims (10)

1. Compound Formula (I) where W

• a) is a 1- or 2- or 9-anthryl or Naphthylradikal, each benzene ring is unsubstituted or substituted by a substituent selected from halogen, C₁-C₄-alkyl, hydroxy, C₁-C₄-alkoxy, formyloxy, C₂-C₅ Alkanoyloxy, aroyloxy, C₂-C₅ alkanoyl, carboxy, C₂-C₅ alkoxycarbonyl, mono- or di- (C₁-C₄-alkyl) carbamyl, cyano, nitro, amino, mono- or di- (C₁-C₄-) Alkyl) -amino, C₂-C₅ alkanoylamino and aroylamino; or
• b) a pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl ring, each ring being unsubstituted or substituted by one of the substituents defined above;

R is C₁-C₄alkyl, halo-C₁-C₄alkyl, hydroxy-C₁-C₄alkyl, C₁-C₄alkoxy-C₁-C₄alkyl, formyloxy-C₁-C₄alkyl, C₂-C₅-alkanoyloxy C₁-C₄ alkyl or C₂-C₅ alkanoyl;
Z is a single, double or triple bond;
and the pharmaceutically acceptable salts thereof; and wherein when at the same time W is 1-naphthyl substituted by cyano, and Z represents a single bond, R is not unsubstituted C₁-C₄ alkyl. 2. A compound of formula (I) according to claim 1, where W is a 1-anthryl, 2-naphthyl, 4-pyridyl, 2-pyrimidinyl or 2-pyrazinyl radical, the unsubstituted or substituted by one Substituents selected from halogen, hydroxy and Cyano, is; where R is hydroxymethyl, hydroxypropyl, Chloromethyl, chloropropyl, acetoxymethyl, Acetoxypropyl, methoxymethyl, methoxypropyl, methyl, Ethyl, propyl or acetyl; where Z is a single, Double or triple bond; and the pharmaceutically acceptable salts thereof. 3. Compound selected from the series: 5- (3-hydroxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (3-acetoxy-prop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (3-methoxyprop-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (but-1-en-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (but-1-in-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (5-hydroxypent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (5-acetoxypent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (5-methoxypent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (n-pent-1-yl) -1- (anthr-1-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-chloroanthr-1-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-cyanoanthr-1-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (naphth-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (butan-1-on-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (4-chloronaphth-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (butan-1-on-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (4-cyanonaphth-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (5-hydroxypent-1-yl) -1- (pyrid-4-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (3-chloropyrid-4-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (3-chloropyrid-4-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (3-chloropyrid-4-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (5-hydroxypent-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (pyrimidin-2-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (4-chloropyrimidine-2-ylmethyl) -1H-imidazole; -
5- (3-chloroprop-1-yl) -1- (4-chloropyrimidine-2-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (3-chloroprop-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (prop-1-en-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (5-hydroxypent-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (5-chloropent-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (butan-3-on-1-yl) -1- (pyrazin-2-ylmethyl) -1H-imidazole;
5- (3-hydroxyprop-1-yl) -1- (5-hydroxypyrazine-2-ylmethyl) -1H-imidazole; and
5- (3-chloroprop-1-yl) -1- (5-hydroxypyrazino-2-ylmethyl) -1H-imidazole and the pharmaceutically acceptable salts thereof. 4. A process for the preparation of a compound of formula (I) and the salts thereof according to claim 1, wherein the process

• (A) the reaction of a compound of formula (II) wherein R 'R, as defined in claim 1, means, with the exception of halo-C₁-C₄-alkyl, and wherein Z is as defined in claim 1, with a compound of formula (III) W-CH₂- X (III) wherein W is as defined in the claim and X represents a leaving group to obtain a compound of the formula (I) wherein R is as defined in claim 1 except for halo-C₁-C₄ alkyl; or
• (B) the halogenation of a compound of the formula (IV) wherein R "is hydroxy-C₁-C₄ alkyl and W and Z are as defined in claim 1, to give the compound of formula I wherein R is halo-C₁-C₄ alkyl;
  and, if desired, the conversion of a compound of the formula (I) into another compound of the formula I, and / or, if desired, the separation of a mixture of isomers of a compound of the formula (I) into the individual isomers, and / or if desired, the salt formation comprises a compound of formula (I) and / or, if desired, the conversion of a salt into a free compound.

5. Pharmaceutical preparation containing a suitable Carrier and / or extender and as active compound a compound of formula (I) according to claim 1 or contains a pharmaceutical salt thereof.   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. A compound of the formula (I) or a salt thereof Claim 6 for use as an aromatase inhibitor. 8. A process for the preparation of a compound of the formula (I) according to claim 1 or a pharmaceutical acceptable salt thereof, the process being in essentially that in any of Examples 1 to 11 described method. 9. Pharmaceutical preparation which essentially like in Example 12 or 13 is described.