GB2222401A - 1,5-Disubstituted imidazole derivatives and process for their preparation - Google Patents

Description

2'IL 2 2 4.0 1 FC 403 1,5-Disubstituted irridazole derivatives and process

for their preparation.

The present invention relates to 1,5-d-Lsubstituted imidazole derivatives, to a process for their preparation, to pharma- ceutical compositions containing them, and to the use-of said compounds for the treatment of estrogen-dependent diseases.

Bic and clinical data indicate that aromatized metabolites as.

of androgens, i.e. the estrogens, are the hormone involved in the pathogenic cellular changes associated with the growth of some hormone-dependent cancers, such as, e.g., breast, endometrial, ovarian and pancreatic carcinomas. Estrogens are 4s o.

also involved in the pathogenes benign prostatic hyperplasia.

-rogens are ultimately formed from either Endogenous est androstened-ione or testosterone as immediate precursors.

The reaction of central importance is the aromatization of the steroidic ring A, which is performed by the enzyme aromatase. As aromatization is a unique reaction and the last in the series of steps in the biosynthesis of estrogens, it has been envisaged that an effective inhibition of aromatase, resulting from compounds able to interact wizn the aromatizing steps, may have useful application for control ling the amount of circulating estrogens, estrogen-dependent processes in reproduction, and estrogen-dependent tumours.

Non-steroidal known substances which have been reported to be endowed with more or less selective aromatase-inhibiting action are, for example, aminoglutethimide [Ann.Surg.187,475 (1978); Lancet 2,646(1978)]; 4-cyclohexylaniline[Endocri nology 114, 2128 (1984)], and 4-pyridyl-3-ethyl-2,6-piperi dinedione[J.Med.Chem.28, 200(1981:))3 - - 2 The present invention provides compounds having the following general formula (I) N 1 1 1 Z N) -a, 1 1.

CH 2 (I) wherein W is a) a 1- or 2- or 9-anthryl or naphthyl radicai wherein each benzene ring is unsubstituted or substituted by a substituent chosen from halogen, C 1- C 4 alkyl, hydroxy, C 1-C4 alkoxy, formyloxy, C 2-C5 alkanoyloxy, aroyloxy, C 2-C5 alkanoyl, carboxy, C 2-C5 alkoxycarbonyl, mono- or di-(C 1-C 4 alkyl)-carbamyl, cyano, nitro, amino, mono- or di-(C 1-C 4 alkyl)- amino, C 2-C5 alkanoylamino and aroylamino; or b) a pyridyl, pyrazinyl, pyrimidinyl or pyridazinyi ring wherein each said ring is unsubstituted or substituted by a substituent defined above; R is C 1-C 4 alkyl, halogen-C I-C 4 alkyl, hydroxy-C I- C 4 alkYl, C 1-C 4 alkoxy-C 1-C 4 alkyl, formyloxy-C I- C 4 alkyl, C 2-C5 alkanoyloxy-C 1- C 4 allkyl or C 2 -C 5 alkanoyl; Z is single, double or triple bond; and the pharmaceutically acceptable salts thereof; and wherein when, at the same time, W is 1-naphthyl substitutea by cyano and Z is a single bond, then R is other than unsubstituted C 1-C 4 alkyl.

i 3.

A halogen is iodine or bromine or fluorine, in particular chlorine. An alkyl group, including the alkyl moiety of the other abovementioned substituents, may be a branched or a straight chain group. A C I-C 4 alkyl group is preferably methyl, ethyl or propyl. The term aryl occurring in the definition of the substituents given above means e.g. phenyl and naphthyl, preferably phenyl. A C I-C 4 alkoxy group is preferably methoxy or ethoxy.

A C 2 -C 5 alkanoyloxy group is preferably acetoxy or propionyloxy, more preferably acetoxy. An aroyloxy group is preferably benzoxy. A C 2- C 5 alkanoyl group is preferably acetyl, propionyl, more preferably acetyl.

C jC, alkoxycarbonyl group is preferablymethoxycarbonyl or ethoxycarbonyl.

mono - or di -(C 1-C 4 alkyl)carbamyl group is preferably methylca.-bamyl or dimethylcarbamyl or diethylca,-bamyl,respectively. A mono - or di -(C 1-C 4 alkyl)amino group is preferably methylamino or dimethylamino or ethylamino or diethylamino, respectively. A C 2-C5 alkanoylamino group is preferably acetylamino. An aroylamino group is preferably benzoylamino. A pyridyl group ise.g. 2- or 3- or 4- pyridyl, in particular 4-pyridyl.

e.g.

A pyrimidinyl group ish- or 4-pyrimidinyl, in particular 2-pyrimidinyl. When W is naphthyl it is e.g. I- or 2-naphthyl, preferably 2-naphthyl.

4.

pyrazinyl group is e.g. a 2-pyrazinyl.

e.g.

pyridazinyl group is/a 3- or 4- pyridazinyl, in particular a 3pyridazinyl. A C 1-C 4 alkoxy -C 1-C 4 alkyl gr oup is preferably methoxymethyl or methoxypropyl.

A C -C alkanoyloxy -C -C alkyl group is preferably acetoxy- 2 5 1 4 methyl or acetoxypropyl. A C 2-C5 alkanoyl group is preferably acetyl or propionyl. In a halogen-C 1-C 4 alkyl group the halogen atom may be linked independently to any one of the carbon atoms of the alkylene chain, preferably the halogen atom is chlorine; examples of such group are chloromethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl and 3chloropropyl. In a hydrcx.v -C I-C 4 alkyl group group the hydroxy group may be linked independently to any one of the carbon atoms of the alkylene chain; examples of such group are hydroxymethyl, 1-hydroxyethyl, 2hydroxyethyl and 1-hydroxypropyl. The formula reported above for the compounds of the invention is meant to comprise all the possible isomers of formula (I) both separately and in mixture, including, e.g. the Z and E isomers of the compounds of formula (I) in which Z is a double bound. Object of the present invention are also the metabolites and the metabolic precursors or bioprecursors of the compounds of formula (I). The invention includes also the pharmaceutically acceptable salts of the compounds of formula (I) either with a pharmaceutically accepta:ble base or acid or in the form of an internal salt. The said salts are preferably the salts of the compounds of formula (I) with pharmaceutically 5.

acceptable acids, both inorganic acids, such as, e.g. hydrochloric and sulfuric, and organic acids such as, e.g., citric, tartaric, maleic, malic,succinic, methanesulfonic and ethanesulfonic. Preferred salts are the hydrochlorides. Preferred compounds of the invention are the compounds of formula (I) wherein W is a 1-anthryl, 2-naphthyl, 4-pyridyl, 2-pyrimidinyl or 2-pyrazinyl radical unsubstituted or substituted by a substituent chosen from halogen, hydroxy and cyano; R is hydroxymethyl, hydroxypropyl, chloromethyl, chloropropyl, acetoxymethyl,acetoxypropyl,methoxymethyl, methoxyp.ropyl, methyl, ethyl, propyl or acetyl; Z is a single, double or triple bond; and the pharmaceutically acceptable salts thereof. As stated above, the present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds (I), i.e. compounds which have a different formula to formula (I) above, but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I). Examples of preferred specific compounds of the invention are the following: 5-(3-hydroxyprop-1-yl)-I-(anthr-1-ylmethyl)-lH-imidazole; 5-(3chloroprop-1-yl)-l-(anthr-1-ylmethyl)-lH-imidazole; 6.

5-(3-acel--oxyprop-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole; 5-(3methoxyprop-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole; 5-(prop-l-en-l-yl)-1(anthr-l-ylmethyl)-1H-imidazole; 5-(but-l-en-l-yl)-1-(anthr-l-ylmethyl)1H-imidazole; 5-(but-l-in-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole; 5(butan-3-on-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole; 5-(5-hydroxypent-lyl)-1-(anthr-l-ylmethyl)-1H-imidazole 5-(5-chloropent-l-yl)-1-(anthr-lylmethyl)-1H-imidazole; 5-(5-acetoxypent-l-yl)-1-(anthr-l-ylmethyl)-1Himidazole; 10 5-(5-methoxypentl-yl)-1-(anthr-l-ylmekllhyl)-1H-imidazole; hr-l-ylmethyl)-1H-imidazole; 5-(n-pent-l-yl)-1-(an41 5-(3-chloroprop-l-yl)-1-(4-chloroanthr-l-ylmethyl)-1H- imidazole; 5-(3-chloroprop-l-yl)-1-(4-cyanoanthr-l-ylmethyl)-1H-imidazol 5-(3-chlo.-oprop-l-yl)-1-(naph41-.h-2-ylmethyl)-1H-imidazole; 5-(prop-l-en-l-yl)-1-(naphth-2-ylmethyl)-1H-imidazole; 5-(butan-3-on-l-yl)-1-(naphth-2-ylmethyl)-1H-imidazole; 5-(5-chloropent-l-yl)-1-(naphth-2-ylmethyl)-IH-imidazole; 5-(3-chlo.-oprop-l-yl)-1-(4-chloronaphth-2-ylmethyl)-1H- imidazole; 5-(prop-l-en-l-yl)-1-(4-chloronaphth-2-ylmethyl)-1H-imidazole 5-(butan-3-on-l-yl)-1-(4-chloronaphth-2-ylmethyl)-1H- imidazole; 5-(5-chloropent-l-yl)-1-(4-chloronaphth-2-ylmethyl)-1H- imidazole; 5-(3-chloroprop-l-yl)-1-(4-cyanonaphth-2-ylmethyl)-1H- imidazole; e; 7.

5-(prop-l-en-l-yl)-1-(4-cyanonaphth-2-ylmethyl)-1H-imidazole; 5-(butan-3-on-l-yl)-1-(4-cyanonaphth-2-ylmethyl)-1H- imidazole; 5-(5-chloropent-l-yl)-1-(4-cyanonaphth-2-ylmethyl)-1H- imidazole; 5-(3-chloroprop-l-yl)-1-(pyrid-4-ylmethyl)-1H-imidazol e; 5-(3-hydroxyprop-l-yl)-1-(pyrid-4-ylmethyl)-1H-imidazole; 5-(prop-l-en-l-yl)-l-(pyrid-4-ylr,lethyl)-1H-imidazole; 5-(5-hydroxypent-l-yl)-14pyrid-4-ylmethyl)-1H-imidazole; 5-(3-hydroxyprop-l-yl)-1-(3-chloropyrid-4-ylmethyl)-1H- imidazole; 5-(3-chloroprop-l-yl)-1-(3-chloropyrid-4-ylmethyl)-1H- imidazole; 5-(butan-3-onl-yl)-1-(3-chloropyrid-4-ylmethyl)-1H- imidazole; 5-(3-hydroxyprop-l-yl-)-1-(pyr-r,,idin-2-ylmethyl)1H-in,idazole; 5-(3-chloroprop-lyl)-1-(pyrimidin-2-ylmethyl)-1H-imidazole; 5-(prop-l-en-l-yl)-1-(pyrim4din-2-ylmethyl)-1H-imidazole; 5-(5hydroxypen'l-l-yl)-1-(pyrimidin-2-ylmethyl)-1H-imidazole; 5-(5-chloropent-l-yl)-1-(pyrimidin-2-ylmethyl)-1H-imidazole; 5-(butan-3-on-l-yl)-1-(pyrimidin-2-ylmethyl)-1H-imidazole; 5-(3-hydroxypropl-yl)-1-(4-chloropyrimidin-2-ylmethyl)-1H- imidazole:

5-(3-chloroprop-l-yl)-1-(4-chloropyrimidin-2-ylmethyl)-1H- imidazole; 5-(3-hydroxyprop-l-yl)-1-(pyrazin-2-ylmethyl)-1H-imidazole; 8.

5-(3-chloroprop-1-yl)-l-(pyrazin-2-ylmethyl)-lH-imidazole; 5-(prop-l-en-1yl)-l-(-pyrazin-2-ylmethyl)-lH-imidazole; 5-(5-hydroxypent-1-yi)-l(pyrazin-2-ylmethyl)-lH-imidazol 5-(5-chloropent-1-yl)-l-(pyrazin-2ylmethyl)-lH-imidazole; 5-(butan-3-on-1-yl)-1-(pyrazin-2-ylmethyl)-lHimidazole; 5-(3-hydroxyprop-1-yl)-l-(5-hydroxypyrazin-2-ylmethyl)lHimidazole; and 5-(3-dhloroprop-1-yl)-I-(5-hydroxypyrazin-2-ylmethyl)lHimidazole; and the pharmaceutically acceptable salts thereof.

e; The compounds of the invention and the salts thereof can be prepared by a process comprising:

(A) reacting a compound of formula (II) z N R' -07 H (ii) wherein R' means R as defined above, excluding halogen -C I-C 4- alkyl, and Z is as defined above, with a compound of formula (III) W - CH 2-X (III) 9.

wherein W is as defined above and X is a leaving group, thus obtaining a compound of formula (I), wherein R is defined above excluding halogen-C lc 4 alkyl; or (B) halogenating a compound of formula (IV) z 1 1 "' N ', J1 W' 0' -- 1 CH 1 2 W (IV) as v-ierein R" is hydroxy-C I- C 4 alkyl and W and Z are as defined above, thus obtainkig a compound of formula (I) wherein R is halogen-C 1- C 4 alkyl; and, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, separating a mixture of isomers of a compound of formula (I) into the single isomers,and/or if desired, salifying 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 intermediate products thereof, groups are present, such as -CHand/or-NH which need to be protected before submitting 2' them to the nerebelow illustrated reactions, they may be protected before the reactions take place and then deprotected, according to well known methods in organic chemistry.

10.

In a compound of fo-rnmila (III) the leaving graup X is preferably an esterified hydroxy group, e.g. acetoxy, mesyloxy or p-toluenesulfonyloxy; or in particular a halogen atom like chlorine or bromine. N-alkylation of a compound of formula (II) with a compound of formula (III) can be performed in the presence of a suitable base, e.g. tertiary amine like triethylamine. But the N-alkylation can also be carried out without the use of any basic agent. It can be carried out in an aprotic organic solvent, e.g. a nitrile, like acetonitrile or an amide, like dimethy1formamide, at temperatures ranging from about 00 to about 1000C. Halogenation of a compound of formula (IV) can be carried out by using conventional halogenation methods, for example by reaction with thionyl chloride, phosphorus trichloride, phosphorus pentachloride,phosphorus oxychloride or thionylbromide. Preferably the chlorination is carried out with thionylchloride in an inert solvent like dichloromethane at temperatures ranging from about 00 to about 800C.

A compound of formula (I) may be converted, as stated above, into another compound of formula (I) by known methods, for example:

(a) A compound of formula (I), wherein R is hydroxy-C I- C 4 alkyl, can be converted into another compound of for- mula (1), wnerein R is formyloxy-C 1-C 4 alkyl or C 2-C5 alkanoyloxy-C 1- C 4 alkyl, by conventional acylation methods. Preferably an acyl halide, like acetyl chloride or an acid anhydride,like acetic anhydride, can be employed, c) in the presence of an organic base, like pyridine. The reaction may be carried out at temperatures ranging from room temperature to about 1000C without or with a suitable solvent like chloroform or benzene.

b) A compound of formula (I), wherein R is hydroxy-C I- C 4 alkyl, can be converted into another compound of formula (I), wherein R is C 1-C 4 alkoxy-C I C 4 alkyl, according to known ways. Preferably the metnod of Williamson JJ. Chem. Soc. 4, 229(1852) is used;accordingro itthealkoxide is prepared first by reaction with e.g. metallic sodium or sodium hydride and then an alkyl halide or alkyl sulfate like methyl iodide -pate is added.

or dimethylsul.

A compound of formula (I), wherein R is halo-C 1- c 4 alkyl in which the halogen atom is linked to the C-1 carbon atom and Z is a single bond, may be dehydrohalogenated to obtain the corresponding compound of formula (I) in which R is C 1- c 4 alkyl and Z is a double bond. The dehydrohalogenation may be carried out by known methods. Preferably a compound with a 1-bromo-C 1- c 4 alkylchain is used. The dehydrohalogenation may be performed in the presence ofa suitable base, e. g. an alkali metal hydroxide, like potassium hydroxide, a bicyclic amidine, like 1,5-diazabicycloC5,4,Olundec-5-ene,orpreferablY a C 1- c 4 alkoxide, like potassium tert-butoxide or an alkali metal hydride, like sodium hydride. Suitable solvents are e.g. ethers like ethyl ether or tetrahydrofuran or amides like dimethylformamide. The temperature range may be from 12.

about -600 to about + 800C. Preferably the bromine compound in tetrahydrofuran solution is treated with potassium tertbutoxide at reflux temperature.

d) A compound of formula (I), wherein R is C 1-C 4 alkyl, C 1-C 4 alkoxyC 1-C 4 alkyl, formyloxy-C 1-C 4 alkyl or C 2- C 5 alkanoyloxy-C 1-C 4 alkyl and Z is a double bond, can be converted into a corresponding compound of formula (I) wherein Z is a triple bond, by a well known dihalogenation/ dehydrohalogenation process. For example the dihalogenation is performed by addition of bromine to the olefin solution in carbon tetrachloride at temperatures ranging from about -500 to about 100C. The dehydrohalogenation of the resulting dibromine compound can be accomplished with the aid of a base e.g. alkali ' hydroxide or alkali alkoxide, preferably with sodium amide in liquid ammonia.

e) A compound of formula (I), wherein R is hydroxy-C 2-C4 alkyl in which the hydroxy group is linked to the C-1 carbon atom, can be oxidized to obtain a corresponding compound of formula (I) in which R is C 2-C4 alkanoyl, by known methods. For example by adding a solution of chromium (III) oxide in diluted sulfuric acid to the substrate solution in acetone, at temperatures below OOC. Alternatively the oxidation may be performed by treatment with dimethyl sulfoxide in the presence of a dehydrating agent, e.g. an acid anhydride like acetic anhydride, an acyl halide like oxalyl chloride, a mineral acid anhydride like phosphorus pentoxide or a carbodiimide like 13.

dicyclohexylcarbodiimide. The ratio dimethyl sulfoxide/ dehydrating agent is about 1: 1. Preferably the oxidation is carried out in the presence of an acidic catalyst like phosphoric acid or pyridinium trifluoroacetate.

f) A compound of formula (I) wherein R is halo-methyl can be converted into a corresponding compound of formula (I) wherein R is hydroxy-propyl or hydroxy-butyl, by methods known per se. That is by converting the starting compound into the corresponding Grignard compound and then reacting with ethylene oxide or trimethylene oxide, respectively. The Grignard reaction can be carried out according to reaction conditions well known in organic chemistry, e.g. as described in "Grignard reactions of non metallic substances" by M. S. Kharasch and O.Reinmuth. Preferably the Grignard reagent is prepared in ethyl ether solution by reaction with magnesium of the compound of formula (I), in which R is halomethyl, e.g. bromomethyl. The ethylene oxide or trimethylene oxide can be introduced under cooling. The reaction temperature ranges from about -ure.

-100C to room tempera+.

g) A compound of formula (I) wherein R is halo-C 1-C 4 alkyl can be converted into a corresponding compound of formula (I) wherein R is C 1-C 4 alkyl by well known reduction procedures. For example when the halogen is bromine or chlorine, the-compound of formula (I) can be reduced by 14.

treatment with a suitable metal hydride, e.g. lithium aluminium hydride, i.n an ether, e.g. tetrahydrofuran or diglyme, at a temperature ranging from room temperature to reflux temperature.

h) A compound of formula (I) wherein R is hydroxymethyl can be converted into another compound of formula (1) whereinR is a -CH(OH) -CIC3 alkyl group by methods known per se For-examplepartial oxidation of the hydroxymethyl compound with dimethyl sulfoxide gives an aldehyde of formula (I) wherein R is formyl.Thereupon the aldehyd is reacted with a Grignard reagent of formula R 3 Mghlg wherein R 3 is a C 1- C 3 alkyl group. The oxidation with dimethyl sulfoxide is carried out in the presence of a dehydrating agent, e.g. an acid anhydride like acetic anhydride, an acyl halide like oxalyl chloride, a mineral acid anhydride like phosphorus pentoxide or a carbodiimide like dicyclohexylcarbodiimide. Preferably the oxidation is carried out in the presence of an acidic catalyst like phosphoric acid or pyridinium trifluoroacetate. The following Grignard reaction can be carried out in analagous fashion to the above described process (f).

i) A compound of formula (I) having a carboxyl substituent can be converted into another compound of formula (I) having a C 1-C 4 alkoxycarbonyl group, by known methods. For example by treatment of tne acid with an excess of the suitable C 1-C 4 alkanol, in the presence of an anhydrous 15.

mineral acid like hydrogen chloride or sulfuric acid, at reflux temperature.

j) A compound of formula (I) wherein the group W is substituted by hydroxy can be converted into another compound of formula (I) wherein the substituent W is substituted by C 1-C 4 alkoxy, according to known methods. For example by following the procedure described above at the optional conversion process (b) or by treating the hydroxy compound first with a suitable base like sodium hydride or sodium amide and then with an alkylating agent like methyl iodide or dimethyl sulfate in a suitable solvent like benzene at temperatures ranging from about 200C to about 1001C.

k) A compound of formula (I), wherein W is an unsubstituted aryl or heteroaryl group as defined in formula (I) under a) and b), can be converted into another compound of formula (I) wherein the substituent W is substituted by cyano according to known methods, e.g. by reaction with cyanogen chloride or bromide or with trichloroacetonitrile.

1) A compound of formula (I), wherein the substituent W is substituted by halogen can be converted into another compound of formula (I), wherein the substituent W is substituted by cyano, by known methods, e.g. by reaction With an inorganic cyanide like sodium cyanide or copper (I) cyanide in a suitable solvent like pyridine, quinoline or dimethylformamide at high temperature, preferably reflux temperature.

16.

m) A compound of formula (I), wherein the substituent, W is substituted by nitro can be reduced into another compound of formula (I), wherein the substituent W is substituted by amino, according to known methods, e.g., by hydrogenation of the nitro compound in the presence of a catalyst like palladium on activated carbon in a suitable solvent like methanol or ethyl acetate. Conventional methods may also be used for salifying a compound of formula (I) and for obtaining a free compound of formula (I) from a salt thereof, and standard procedures, such as, e.g. fractional crystallization and chromatography, may be followed as well for separating a mixture of isomers of a compound of forr,?,ila (I) into the single isomers. The compoundsof formula (II) are known or may be obtained by known methods from known compounds. For example 4-(3-hydroxyprop-1-yl)- IH-imidazole can be prepared according to Gr.A.A. Kivits et al. in J.Het. Chem., 12, 577 (1975). If required the optional conversions from (a) to (h), reported above of a compound of formula (I) into another compound of formula (I), can be performed on the intermediate compounds of formula (II) by following the same procedures. The compounds (III) are known compounds or can be prepared according to well known methods. The compounds of formula (IV) are compounds of formula (I), wherein R is hydroxy-C 1-C 4 alkyl, and can be obtained by process (A), as described above.

17.

The compounds of the present invention are inhibitors of the b-otransformation of androgens into estrogens, -J.e.; they are aromatase inhibitors.

The inhibition of aromatase activity by these compounds was demonstrated by employing the in vivo assay which utilizes the aromatase enzyme system isolated from the microsomal fraction of human placental tissue, according to standard proce dure. The assay of Thompson and Siiteri [F.A.Thompson and P.K.

Siiteri, J.Biol.Chem. 249,5364,(197411 which determines the rate of aromatization as measured by the liberation of 3 H 2 0 from 4-El.B, 2.B- 3 Hlandrostene-3,17-dione was used. All incubations were carried out in a shaking water bath at 370C in air in 10 mM potassium phosphate buffer, pH 7.5, which contained 100 mM KC1, 1 mM EDTA and 1 mM dithiothreitol. The experiments were carried out in 1 ml incubation volume containing 50 nM 4-H]androstenedione, various concentrations of the inhibitors, 100 pM NADPH and 0.05 mg of microsomal proteins. After 15 minutes of incubation the reaction was stopped by the addition of chloroform (5 ml). After centrifugation at 1500 xg for 5 minutes, aliquots (0.5 ml) were removed from the water phase for determination of 3 H 2 0 formed. The concentration of each compound required to reduce control aromatase by 50% (IC 50) was determined by plotting % inhibition versus log of inhibitor concentration.

The new compounds, incubated at various concentrations, showed a relevant aromatase inhibitory activity.

18.

-ase and, consequen- By virtue of their ability to inhibit aromat tly, to reduce estrogen levels, the new compounds are useful in the treatment and prevention of various estrogen dependent in maranals diseases/ i.e., breast, endometrial, ovarian and pancreatic cancers, gynecomastia, benign breast disease, endometriosis, polycystic ovarian disease and precocious puberty. Another application of the compounds of the invention is in the therapeutic and/or prophylactic treatment of prostatic hyperplasia, a disease of the estrogen dependent stromal tissue.

The new compounds can find also use for the treatment of male infertility associated with oligospermia and for female fertility control, by virtue of their ab.ility to inhibit ovulation and egg nidation. In view of their high therapeutic index, the compounds of the invention can be used safely in medicine. For example, the approximate acute toxicity (LD 50) of the compounds of the invention in the mouse, determined by single administration of increasing doses and measured on the seventh day after the treatment was found to be negligible.

The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally, in the form of suppositories; parenterally, e.g. intramuscularly, or by intravenous injection or infusion. The dosage depends on the age, weight, conditions of the patient and administration route; for example the dosage adopted for oral administration to adult humans may range from about 10 to about 150-200 mg pro dose, from 1 to 5 times daily.

i z 19.

The invention includes pharmaceutical compositions com- ion in association with rising a compound of the inventJ a pharmaceutical ly acceptable excipient (which can be a carrier or diluent).

The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For example the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gur,-,s, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e. g. a starch, alginic acid, alginates or sodium, starch glycolate; effervescing mixtures; dyestuffs, sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmaco- logically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g.

syrups, emulsions and suspensions.

20.

The syrups may contain as carrier, for example, saccharose or saccharose with glyc,erine and/or mannitol and/or sorbitol. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethy1cellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. The solutions for intravenous injections or infusions may contain as carrier, for example sterile water or preferably they may bein the form of sterile, aqueous, isotonic saline solutions. The suppositories may contain toghether with the active compound a pharmaceutically acceptable carrier, e.g. cocoabutter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following examples illustrate but do not limit the invention.

21 -L.

Example 1

5-(3-hydroxyprop-1-yl)-I-(anthr-1-ylmethyl)-IH-imid,azole [I, W=anthr-1yl, R=hydroxymethyl, Z=single bond] A mixture of 4-(3-hydroxypropyl)-lH-imidazole (126 mg, 1MMOI) triethylamine (121 mg, 1.2 mmol) and dimethylcarbamyl chloride (118 mg, 1.1 mmol) in dry acetonitrile (2 ml) is refluxed for 24 hours under nitrogen. After cooling to 0-50C triethylamine (121 mg, 1.2 mmol) and trimethylsilyl chloride (130 mg, 1.2 mmol) is added and the reaction mixture stirred for 2 hours at room temperature. After dilution with ethyl ether the insolute is filtered off, the residue washed with ethylkther and the combined ether extracts evaporated under vacuum. The resulting raw 4-(3trimethylsilyloxypropyl)-lH-imidazole-l-dimethylcarboxamide is reacted with anthr-1-ylmethyl bromide (271 mg, 1 mmol) in acetonitrile (2 ml) by heating at reflux for 20 hours. Then gaseous ammonia is introduced for 15 minutes at 0-50C and the mixture concentrated under vacuum. The residue is dissolved in N hydrochloric acid, the resulting acid solution stirred for Y2 hour at room temperature and then washed with ethyl acetate. The pH of the acid solution is brought to 8-9 by addition of potassium

carbonate solution and the raw product is extracted with chloroform. The organic phase is washed with water, dried with sodium sulfate and then evaporated under vacuum. The residue is submitted to column chromatography on silica gel using chloroform/methanol 1% as eluant. Thus 221 mg of title compound is obtained (70% yield).

22.

Elemental analysis found % (calculated %) C 79.65 (79.72), H 6.25 (6.37), N 8.77 (8.85) NMR (CDC1 3' S): 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 (9H, m).

In analogous fashion the following compounds can be prepared:

5-(3-hydroxyprop-l-yl)-1-(pyrid-4-ylmethyl)-1H-imidazole; 5-(3hydroxyprop-l-yl)-1-(3-chloropyrid-4-ylmethyl)-1H-imidazole; 5-(3hydroxyprop-l-yl)-1-(pyrimidin-2-ylmethyl)-1H-imidazole,5-(3-hydroxyprop-l-yl)-1-(4-chloropyrimidin-2-ylmethyl)-1H-imidazole; 5-(3-hydroxyprop-l-yl)-1- (pyrazin-2-ylmethyl)-1H-imidazole, and 5-(3hydroxyprop-l-yl)-1-(5-hydroxypyrazin-2-ylmethyl)-1H-imidazole.

Example 2

5-(3chloroprop-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole is (1, W=anthr-l-yl, R=chloromethyl, Z=single bond) A solution of 5-(3-hydroxyprop-1-yl)-I-(anthr-1-ylmethyl)-lHimidazole (316 mg, 1 mmol) and thionyl chloride (155 mg, 1.3 mmol) in dry dichloromethane (4 ml) is heated to reflux for 2 hours. Then the solution is evaporated under vacuum and the residue taken up with dichloromethane and sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica gel using chloroform/methanol 1% as eluant to give 301 mg of pure title compound (90% yield).

23.

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 (CDC1 3' tb): 2.00 (2H,m), 2.61 (2H, t), 3.49 (2H,t), 5.15 (2H,s), 6.19 (1H,s), 7.60 (1H,s), 7.20-8.20 (9H,m) By proceeding analogously the following compounds can be obtained:

5-(5-chloropent-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole; 5-(3-chloropropl-yl)-1-(4-chloroanthr-l-ylmethyl)-1H-imidazole: 5-(3-chloroprop-l-yl)-1(4-cyanoanthr-l-ylmethyl)-1H-imidazole; 5-(3-chloroprop-l-yl)-1-(naphth-2-ylmethyl)-1H-imidazole; 5-(5-chloropent-l-yl)-1-(naphth-2-ylmethyl)-IH-imidazole; 5-(3-chloropropl-yl)-1-(4-chloronaphth-2-ylmethyl)-1H-imidazole 5-(5-chloropent-l-yl)-1(4-chloronaphth-2-ylmethyl)-1H-imidazole; 5-(3-chloroprop-l-yl)-1-(4eyanonaphth-2-ylmethy-1H-imidazole; 5-(5-chloropent-l-yl)-1-(4-cyanonaphth-2-ylmethyl)-1H-imidazole; 5-(3-chloroprop-l-yl)-1-(pyrid-4-ylmethyl)-1H-imidazole; 5-(3-chloropropl-yl)-1-(3-chloropyrid-4-ylmethyl)-1H-imidazole; 5-(3-chloroprop-l-yl)-1(pyrimidin-2-ylmethyl)-1H-imidazole; 5-(5-chloropent-l-yl)-1-(pyrimidin-2ylmethyl)-1H-imidazole; 5-(3-chloroprop-l-yl)-1-(4-chloropyrimidin-2-ylmethyl)-1H-imidazole; 5-(3chloroprop-l-yl)-1-(pyrazin-2-ylmethyl)-1H-imidazole; 5-(5-chloropent-lyl)-1-(pyrazin-2-ylmethyl)-1H-imidazole,and 5-(3-chloroprop-l-yl)-1-(5hydroxypyrazin-2-ylmethyl)-1H-imidazole.

h 24.

Example 3

5-(3-acetoxyprop-1-yl)-I-(anthr-1-ylmethyl)-lH-imidazole (I, W=anthr-1-yl, R=acetoxymethyl, Z=single bond) To a cooled solution of 5-(3-hydroxyprop-1-yl)-l-(anthr-l- ylmethyl)-lH-imidazole (316 mg, 1 mmol) in dry pyridine (1 mi) acetic anhydride (306 mg, 3 mmol) is added and the mixture kept overnight at room temperature. Then the solvent is removed under vacuum and the residue taken up with dichloromethane and water. The organic phase is separated,washed several times with water, dried over sodium sulfate and evaporated under vacuum.

The residue is chromatographed on silica gel with chloroform/ methanol 1% as eluant to give 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 (CDC1 3' 5): 1.80 (2H, m), 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 (9H, m).

In analogous fashion the following compound can be prepared:

5-(5-acetoxypent-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole.

Example 4

5-(3-methoxyprop-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole (I, W=anthr-l-yl, R=methoxymethyl, Z=single bond) To a cooled solution of 5-(3-hydroxyprop-l-yl)-1-(anthr-l-ylmethyl)-1H- imidazole (316 mg, 1 mmol) in dry tetrahydrofuran (10 ml) sodium hydride (29 mg, 1.2 mmol) is added portionwise 25.

and the mixture stirred for 1 hour. Finally methyl iodide (17 4mg, 1.2 mmol) is added and the mixture heated to reflux for about 2 hours. The solvent is removed by evaporation under vacuum and the residue taken up with ethyl acetate and water. The organic phase is separated, washed with water, dried and evaporated under vacuum. The residue is subjected to column chromatography with silica gel as absorbant and chloroform/ methanol 1% as eluant thus giving pure title compound in 80% yield (264 mg).

lculated Elemental analysis found % (ca C 79.81 (79.97), H 6.65 NMR (CDCI 3' b): 1.85 (2H, 3.42 (2H, 7.63 (1H, (6.71), N 8.35 (8.481' m), 2.51 (2H, t), 3.24 (3H, s), t), 5.22 (2H, s), 6.83 (1H, s), s), 7.158.15 (9H, m).

Example 5

5-(prop-l-en-l-yl)-1-(anthr-l-vlmethyl)-1H-imidazole (I, W=anthr-l-yl, R= methyl; Z = double bond) A solution of 5-(3-hydroxyprop-1-yl)-l-(anthr-1-ylmethyl)-lHimidazole (316 mg, 1 mmol) and thionyl bromide (250 mg, 1.2 mmol) in dry dichloromethane (4 ml) is heated to reflux. for 1 hour. Then the solution is evaporated under vacuum and the residue is taken up with dichloromethane and cold sodium bicarbonate solution. The separated organic phase is washed with water, dried over sodium sulfate and evaporated under vacuum. Thus raw 5-(3-bromoprop-1-yl)-I-(anthr-1- ylmethyl)-lH-imidazole 26.

is obtained (380 mg, 10b% yield). The above obtained raw bromo-compound (380 mg, 1 mmol) is dissolved in dry tetrahydrofuran (3 ml) and the solution cooled to 0-50C. Then potassium tert-butoxide (224 mg, 2 mmol) is added portionwise and the resulting reaction mixture stirred for further 3 hours at reflux temperature under nitrogen. Finally the reaction mixture is concentrated under vacuum, the pH regulated to 8-10 by addition of aqueous acetic acid under cooling and the raw product extracted with chloroform.

The organic layer is separated, dried and evaporated under vacuum. The residue is chromatographed on silica gel using chloroform/methanol,l% as eluant. Thus pure title compound in 70% yield is obtained (208 mg). Elemental analysis found % (calculated %):

C 84.35 (84.53), H 5.95 (6.08), N 9.25 (9.39) NMR (CDC1 3 6): 1.92 (3H, m), 5.20 (2H, s), 6.1 (2H, m) 6.85 (1H, s), 7.60 (1H, s), 7.15-8.15 (9H, m) In analogous fashion the following compounds can be prepared:

5-(but-l-en-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole; 5-(PMP-1-en-l-yl)-1(naphth-2-ylmethyl)-1H-imidazole; 5-(prop-l-en-l-yl)-1-(4-chloronaphth-2ylmethyl)-1H-imidazole; 5-(prop-l-en-l-yl)-1-(4-cyanonaphth-2-ylmethyl)1H-imidazole; 5-(prop-l-en-l-yl)-1-(pyrid-4-ylmethyl)-1H-imidazole; 5(prop- 1-en- l-yl) - 1 - (pyrimi din-2-yIme thyl) - IH-imi dazole, and 5(prcp-l-en-l-yl)-1-(pyrazin-2-ylmethyl)-1H-imidazole.

1 27 Example 6

5-(but-l-in-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole (I, W=anthr-l-yl, R=ethyl,Z =triple bond) To a solution of 5-(but-l-en-l-yl)-1-(anthr-l-ylmethyl)-1H- imidazole (312 mg, 1 mmol),in dry chloroform (5 ml) cooled ' with a freezing mixture of ice and salt,is added dropwise bromine (160 mg, 1 mmol). The mixture is allowed to gradual ly warm up to room temperature and is then evaporated under vacuum. The residue contains raw 5-(1,2-dibromobut-l-yl)-1 (anthr-l-ylmethyl)-1H-imidazole.

To liquid ammonia (about 3 ml) which temperature is maintain ed between -300 and -400C with a dry ice bath and which contains a catalytic amount of ferric nitrate metallic sodium (81 mg, 3.5 mmol) is added portionwise. After about 20 minutes, i.e.

then the colour of the mixture has changed from blue to grey, an ether solution of the above obtained dibromide is added slowly and the mixture kept for another 4 hours at low tempe ratures. Then ammonium chloride is added and the mixture allowed to warm up to room temperature. The residue is taken up with chloroform and water. The organic phase is washed with water, dried and evaporated under vacuum. The residue is chroma tographed on silica gel using chloroform/methanol 1% as eluant.

thus obtaining the pure title compound in 50% yield (155 mg).

Elemental analysis found % (calculated C 85.05 (8513), H 5.75 (5.8.4), N 8.95 (9.02) 2b.

Example 7

5-kbutan-3-on-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole (I, W=anthr-l-yl, R=acetyl, Z=single bond) To a solution of 5-(3-hydroxybut-1-yl)-l-(anthr-1-ylmethyl) 1H-imidazole (330-1mg, 1 mmol) in acetone (5 ml), maintained between -200C and -300C with a dry ice bath, a solution of chromium trioxide (200 mg, 2 mmol) in diluted sulfuric acid (I ml) is added dropwise in about 15 minutes and then the mixture kept for another hour at low temperature. Thereupon the excess of oxidation reagent is destroyed with isopropanol and the mixture concentrated in vacuum. The raw product is f 8-10, the organic extracted with ethyl acetate at a pH o phase washed.with water, dried and evaporated under vacuum.

The residue is subjected to column chromatography on silica gel using chloroform/methanol 2% as eluant. The pure title compound is obtained 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 (CDC1 3' >): 2.10 (3H, s), 2.50 (2H, t), 2.60 (2H, t), 5.25 (2H, s), 6.84 (IH, s), 7.55 (1H, s), 7.15-8.15 (9H, m).

The analogous fashion the following compounds can be prepared:

5-(butan-3-on-l-yl)-1-(naphth-2-ylmethyl)-1H-imidazole; 5-(butan-3-on-lyl)-1-(4-chloronaphth-2-ylmethyl)-1H-imidaz61e; 5-(butan-3-on-l-yl)-1-(4-cyanonaphth-2-ylmethyl)-1H-imidazole; 5-(butan-3-on-l-yl)-1-(3-chloropyrid-4-ylmethyl)-1H-imidazole, 5-(butan-3-on-l-yl)-1-(pyrimidin-2-ylmethyl)-1H-imidazole,and 5-(butan-3-on-l-yl)-1-(pyrazin-2-ylmethyl)-1H-imidazole.

29.

Example 8

5-(5-hydroxypent-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole (I, W=anthr-l-yl, R=3-hydroxyprop-l-yl, Z=single bond) To a vigorously stirred suspension of magnesium turnings (25 mg, 1 mmol) in dry ethyl ether (3 ml) small crystals of iodine are added and then a solution of 5-(3-bromopropl-yl)-1-(anthr-l-ylmethyl)-1H-imidazole (379 mg, 1 mmol) in dry ethyl ether (3 ml) is introduced dropwise at such a rate that the mixture boil s teadily. The mixture is refluxed for another % hour. Then the flask is cooled with a freezing mixture of ice and salt and ethylene oxide gas (66 mg, 1.5 mmol) is introduced gradually. The react"ion mixture is allowed to reach room temperature and then boiled for another hour. Benzene is added and the mixture concentrated by evaporation.

Ice and saturated ammonium chloride solution are added, the raw product extracted with benzene and the organic layer is evaporated under vacuum after having washed and dried it. The residue is chromatographed on silica gel using chloroform/ methanol 2% as eluant thus giving pure title compound in 60% yield (206 mg). Elemental analysis found % (calculated %):

C 80.10 (8.20), H 6.91 (7.02), N 7.95 (8.13) NMR (CDC1 3' h): 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 (9H, m). In analogous fashion the following compounds can be prepared:

30.

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

Example 9

5-(pent-l-yl)-1-(anthr-l-ylmethyl)-IH-imidazole (I, W=anthr-l-yl, R=propl-yl, Z=single bond) To a solution of lithium aluminium hydride (19 mg, 0.5 mmol in diglyme (5 ml) is added gradually a solution of 5-(5-chloropent-l-yl)-1-(anthr-l- ylmethyl)-1H-imidazole (363 mg, 1 mmol) in diglyme (3 ml). The resulting mixture is stirred at 1000C for about 15 hours. Then an aqueous solution of sodium potas sium tartrate is added. The mixture is filtered and concentra ted to a small volume under reduced pressure. The concentrate is taken up in ethyl acetate and washed well with water. The organic layer is dried over sodium sulfate, filtered and the solvent removed under vacuum to yield a residue which is chromato graphed on silica gel using chloroform/methanol 1% as eluant to yield 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-(3-hydroxy-but-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole (I, W=anthr-l-yl, R=l-hydroxy-i-ethyl, Z--single bond) To a solution of dimethyl sulfoxide (156 mg, 2 mmol) in dry dichloromethane (5 ml), which is cooled under nitrogen to 1 al.

-750C, oxalyl chloride (216 mg, 1.7 mmol) is added dropwise. After Y2 hour stirring at -750C a solution of 5-(3-hydroxypropl-yl)-1-(anthr-lylmethyl)-1H-imidazole (316 mg, 1 mmol) in a mixture of dimethyl sulfoxide (0.2 ml) and dichloromethane (1 ml) is added slowly and the mixture stirred for further 3 hours at -750C. Then triethylamine (1 ml) is added and the mixture left to reach room temperature. After dilution with dichloromethane the organic phase is separated, washed with water, dried and evaporated under reduced pressure. The chromatography of the residue on silica gel with chloroform/methanol 1% as eluant yields pure 5(propan-3-on-l-yl)-1-(anthr-l-ylwthyl)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) a small crystall of iodine is added and then a solution of methyl iodide (142 mg, 1 mmol) in dry ethyl ether (2 ml) is introduced dropwise at such a rate that the mixture boils steadily. The mixture is refluxed for another 30 minutes. Now a solution of 5-(propan3on-l-yl)-1-(anthr-lylmethyl)-1H-imidazole (314 mg, 1 mmol) in benzene (5 ml) is introduced dropwise under cooling. Then solvent is removed until the boiling point reaches 770C and heating is continued for further 3 hours. Ice and ammonium chloride solution are added and the raw product is extracted at pH 8-9 with ethyl acetate. The organic layer is washed, dried and evaporated under vacuum. The residue is subjected to column chromatography on silica gel using chloroform/methanol as eluant.

32 Thus'the title compound is obtained in 75% yield (248 mg).

Elemental analysis found % (calculated %):

C 79.85 (79.97), H 6.81 (6.71), N 8.35 (8.48).

Example 11 5-(3-hydroxyprop-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole hydrochloride II, W=anthr-l-yl, R=hydroxymethyl, Z=single bond-7 In order to obtain the hydrochloride salt to a solution of 5-(3-hydroxyprop-l-yl)1-(anth-l-yl-methyl)-1H-imidazole base (316 mg, 1 mmol) in ethyl acetate (4 ml) a stoichiometri amount of hydrochloric acid is added. The precipitated salt is filtered off, washed with solvent and dried. Thus the title compound is obtained in 90% yield (318 mg). Elemental analysis found % (calculated %): C 71.43 (71.48), H 5.85 (6.00), Cl 9.95 (10.05), N 7.85 (7.94).

33.

Example 12

Tablets, each weighing 0.150 g and containing 25 mg of the active substance, can be manufactured as follows:

Composition (for 10,000 tablets) 5-(3-chloroprop-l-yl)-1-(anthr-l-ylmethyl)-IH-imidazole 250 g Lactose 800 g Corn starch Talc powder Magnesium stearate 5-(3-chloroprop-l-yl)-1-(anthr-l-ylmethyl)-1H-imidazole, 1 415 g g 5 g the lactose and half the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml) and the resulting paste is used to granulate the powder.

The granulate is dried, comminuted on a sieve of 1.4 mm mesh size, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets.

Example 13

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

Composition for 500 capsules:

5-(3-chloroprop-1-yl)-l-(pyrid-4-ylmethyl)-lH-imidazole io g 34.

Lactose Corn starch Magnesium stearat g 5 g 5 g This formulation can be encapsulated in two-piece hard gelatin capsules and dosed at 0.200 g for each capsule.

11

Claims (9)

- 35 CLAIMS 1. A compound of formula (I)

1 -N R -Z_. - 1 V," N,-j 1 CH 2 (I) wherein W is a) a 1- or 2- or 9-anthryl or naphthyl radical wherein each benzene ring is unsubstituted or substituted by a substituent chosen from halogen, C 1- C 4 alkyl, hyaroxy, C 1 -C 4 alkoxy, formyloxy, C 2-C5 alkanoyloxy, aroyloxy, C 2-C5 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-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 C 1-C 4 alkyl, halogen-C I-C 4 alkyl, hydroxy-C I-C 4 alkyl, C 1-C 4 alkoxy-C 1-C4 alkyl, formyloxy-C 1-C 4 alkyl, C 2 -C 5 alkanoyloxy-C 1-C 4 alkyl or C 2-C5 alkanoyl; Z is 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 C i-C 4 alkyl.

36.

2) A compound of formula (1), according to claim 1, wherein W is a Ianthryl, 2-naphthyl, 4-pyridyl, 2-pyrimidinyl or 2-pyrazinyl radical unsubstituted or substituted by a substituent chosen from halogen, hydroxy and cyano; R is hydroxymethyl, hydroxypropyl, chloromethyl, chloropropyl, acetoxymethyl,acetoxypropyl,methoxymethyl, methoxypropyl, methyl, ethyl, propyl or acetyl; Z is a single, double or triple bond; and the pharmaceutically acceptable salts thereof. 3) A compound selected from the group consisting of: 5-(3-hydroxyprop-1-yl)-l(anthr-1-ylmethyl)-lH-imidazol 5-(3-chloroprop-1-yl)-l-(anthr-1-ylmethyl)lH-imidazole; 5-(3-acetoxyprop-1-yl)-l-(anthr-1-ylmethyl)-lH-imidazole; 5(3-methoxyprop-1-yl)-l-(anthr-1-ylmethyl)-lH-imidazole; 5-(prop-l-en-1yl)-l-(anthr-1-ylmethyl)-IH-imidazole; 5-(but-l-en-1-yl)-l-(anthr-1ylmethyl)-lH-imidazole; 5-(but-l-in-1-yl)-I-(anthr-1-ylmethyl)-lHimidazole; 5-(butan-3-on-1-yl)-l-(anthr-1-ylmethyl)-lH-imidazole; 5-(5hydroxypent-1-yl)-l-(anthr-1-ylmethyl)-lH-imidazole,; 5-(5-chloropent-1yl)-I-(anthr-1-ylmethyl)-IH-imidazole; 5-(5-acetoxypent-1-yl)-l-(anthr-1ylmethyl)-IH-imidazole; 5-(5-methoxypent-1-yl)-l-(anthr-1-ylmethyl)-lHimidazole; 5-(n-pent-1-yl)-I-(anthr-1-ylmethyl)-lH-imidazole;

5-(3chloroprop-1-yl)-l-(4-chloroanthr-1-ylmethyl)-lHimidazole; 5-(3chloroprop-1-yl)-l-(4-eyanoanthr-1-ylmethyl)-lH-imidazo1 5-(3-chloroprop1-yl)-l-(naphth-2-ylmethyl)-lH-imidazole; 5-(prop-l-en-1-yl)-l-(naphth-2ylmethyl)-lH-imidazole; 5-(butan-3-on-1-yl)-I-(naphth-2-ylmethyl)-lHimidazole; 5-(5-chloropent-1-yl)-l-(naphth-2-ylmethyl)-lH-imidazole; 5-(3- chloroprop-1-yl)-l-(4-chloronaphth-2-ylmethyl)-lHimidazole; e; 37.

5-(prop-l-en-l-yl)-1-(4-chloronaphth-2-ylmethyl)-1H-imidazole; 5-(butan-3-on-l-yl)-1-(4-chloronaphth-2-ylmethyl)-IH- imidazole; 5-(5-chloropent-l-yl)-1-(4-chloronaphth-2-ylmethyl)-1H- imidazole; 5-(3-chloroprop-l-yl)-1-(4-cyanonaphth-2-ylmethyl)-IH- imidazole; 5-(prop-l-en-l-yl)-1-(4-cyanonaphth-2-ylmethyl)-IH-imidazole; 5-(butan-3-on-l-yl)-1-(4-cyanonaphth-2-ylmethyl)-1H- imidazole; 5-(5-chloropent-l-yl)-1-(4-cyanonaphth-2-ylmethyl)-IH- imidazole; 5-(3-chloroprop-l-yl)-1-(pyrid-4-ylmethyl)-IH-imidazole; 5-(3-hydroxyprop-l-yl)-1-(pyrid-4-ylmethyl)-IH-imidazole; 5-(prop-l-en-l-yl)-1-(pyrid-4-ylmethyl)-IH-imidazole; 5-(5-hydroxypent-l-yl)-1pyrid-4-ylmethyl)-IHimidazole; 5-(3-hydroxyprop-l-yl)-1-(3-chloropyrid-4-ylmethyl)-1H- imidazole; 5-(3-chloroprop-l-yl)-1-(3-chloropyrid-4-ylmethyl)-IH- imidazole; 5-(butan-3-on-l-yl)-1-(3-chloropyrid-4-ylmethyl)-1H- imidazole;

5-(3-hydroxyprop-l-yl)-1-(pyrimidin-2-ylmethyl)-IH-imidazole; 5-(3-chloroprop-l-yl)-1-(pyrimidin-2-Ylmethyl)-1H-imidazole; 5-(prop-l-en-l-yl)-1-(pyrimidin-2-ylmethyl)-1H-imidazole; 5-(5-hydroxypent-l-yl)-1-(pyrimidin-2-ylmethyl)-IH-imidazole,5-(5-chloropent-l-yl)-1-(pyrimidin-2-ylmethyl)-IH-imidazole; 5-(butan-3-on-l-yl)-1-(pyrimidin-2-ylmethyl)-IH-imidazole; 5-(3-hydroxyprop-l-yl)-1-(4-chloropyrimidin-2-ylmethyl)-IH- imidazole:

5-(3-chloroprop-l-yl)-1-(4-chloropyrimidin-2-ylmethyl)-1H- imidazole; 5-(3-hydroxyprop-l-yl)-1-(pyrazin-2-ylmethyl)-1H-imidazole; 38.

5-(3-chloroprop-1-yl)-I-(pyrazin-2-ylmethyl)-lH-imidazole; 5-(prop-l-en-1yl)-l-(pyrazin-2-ylmethyl)-lH-imidazole; 5-(5-hydroxypent-1-yl)-l(pyrazin-2-ylmethyl)-lH-imidazole; 5-(5-chloropent-1-yi)-l-(pyrazin-2ylmethyl)-lH-imidazole; 5-(butan-3-on-1-yl)-1-(pyrazin-2-ylmethyl)-lHimidazole; 5-(3-hydroxyprop-1-yl)-l-(5-hydroxypyrazin-2-ylmethyl)lHimidazole; and 5-(3-chloroprop-1-yl)-l-(5-hydroxypyrazin-2-ylmethyl)lHimidazole; and the pharmaceutically acceptable salts thereof.

4) A process for the preparation of a compound of formula (I), -o claim 1, the process and the salts thereof, according 41 comprising (A) reacting a compound of formula (II) N 15 7, N 1 H wherein R' means R as defined in claim 1, excluding halogen -C 1-C 4 alkyl, and Z is as defined in claim 1, with a compound of formula (III) W - CH 2-X (III) 39 wherein W is as defined in claim 1 and X is a leaving group, thus obtaining a compound of formula (I), wherein R is as defined in claim 1, excluding halogen -C 1-C 4 alkyl; or (B) halogenating a compound of formula (IV): N (IV) R" N,00) I CH 1 2 W wherein R" is hydroxy-C 1- C 4 alkyl and W and Z are as defined in claim 1, thus obtaining a compound of formula (I) wherein R is halogen-C 1-C 4 alkyl; and, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, separating a mixture of isomers of a compound of formula (1) into the single isomers, and/or if desired, salifying a compound of formula (I), and/or, if desired, converting a salt into a free compound.

5. A pharmaceutical composition containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

6. A compound of formula (I) as defined in claim i or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.

7. A compound of formula (I) or salt thereof according to claim 6 for useas an aromatase inhibitor.

8. A process for the preparation of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, said process being substantially as hereinbefore described in any one of Example 1 to 11.

9. A pharmaceutical composition substantially as hereinbefore described in Example 12 or 13.

PUed 1990 at The Patent C)tnce, State Kouse.86.7 t Righ Hc)born. London WC1R4TP.Further copies maybe Obtainedtrom The P"=OM".

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