6,7 alpha -DIFLUOROMETHYLENANDROSTA-1,4-DIEN-3-ONE DERIVATIVES AND PROCESS FOR THEIR PREPARATION

Abstract: This invention refers to the use of compounds of formula (I), wherein R is hydrogen or C1-C4 alkyl; and A is a (a), (b) or (c) group, in which R' is an acyl group; in the manufacture of a medicament for use as an aromatase inhibitor; and compounds of formula (I) excluding 17 alpha -acetoxy-6,7 alpha -difluoromethylenandrosta-1,4-dien-3-one.

Description: 6 , 7α-DIFLUOROMETHYLENANDROSTA-l .4-DIEN-3-ONE DERIVATIVES AND PROCESS FOR THEIR PREPARATION The present invention relates to new 6 , 7α-difluoro- methylenandrosta-1 , 4-dien-3-ones , to a process for their preparation, to pharmaceutical compositions containing them, and to their use as therapeutic agents,- in particular in the treatment of hormone-dependent diseases in mammals. Basic and clinical data indicate that aromatized metabolites of androgens, i.e. the estrogens, are the hormones involved in the pathogenic cellular changes associated with the growth of some hormone-dependent cancers, such as breast, endometrial and ovarian carcinomas. Estrogens are aslo involved in the pathogenesis of benign prostatic hyperplasia. Endogenous estrogens are ultimately formed from either androstenedione 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 the aromatase, resulting from compounds able to interact with the aromatizing steps, may have useful application for controlling the amount of circulating estrogens, estrogen-dependent processes in reproduction, and estrogen-dependent tumours. Known steroidal substances which have been reported to be endowed with an aromatase-inhibiting action are, for example, Δ 1 -testololactone (U.S.Pat. 2,744,120), 4- hydroxyandrost-4-ene-3 , 17-dione and esters thereof (see, for example, U.S.Pat. 4,235,893), 10- ( 1 , 2-propadienyl )- estr-4-ene-3,17-dione (U.S.Pat. 4,289,762), 10-(2- propynyl )-estr-4-ene-3 , 17-dione ( J .Amer .Chem. Soc . , 103 , 3221 (1981) and U.S.Pat. 4,322,416), 19-thioandrostene derivatives ( Europ.Pat .Appl . 100,566), androsta-4 , 6- diene-3,17-dione, androsta-l,4,6-triene-3,17-dione (G.B.Pat.Appl . 2,100,601A), androsta-1 , 4-diene-3 , 17- dione (Cancer Res. ( Suppl . ) 4_2, 3327 (1982), 6- alkenylen-androsta-l,4-diene-3,17-diones (U.S.Pat. 4,808,816 and U.S.Pat. 4,904,650) and 6-alkenylen- androsta-1 , 4-dien-l 7-ol-3-one derivatives (U.S.Pat. 4,873,233) . 17α-acetoxy-6, 7α-difluoromethylenandrosta-1,4-dien-3-one is disclosed in US-A-3 , 414 , 592 as an anabolic agent. The present invention provides the use of a compound of formula ( I ) (I where in R is hydrogen or C,-C, alkyl; and A is a ^C=0, ^CH-wOH or ^CH' DR' group, in which R' is an acyl group; in the manufacture of a medicament for use as an aromatase inhibitor. The present invention also provides a compound of formula (I) wherein R is hydrogen or C,-C. alkyl; and A is a group, in which R' is an acyl group; with the exclusion of 17α-acetoxy-6 , 7α-difluoromethylen- androsta-1 ,4-dien-3-one . The present invention additionally provides a compound of formula (I) with the exclusion of 17α-acetoxy-6 , 7α- difluoromethylenandrosta-1 , 4-dien-3-one for use in a method of treatment of the human or animal body by therapy. An agent for use as an aromatase inhibitor comprises a compound of formula (I). The compounds of formula ( I ) may be used in a method of treatment of an estrogen-dependent ;ondition which comprises administering to a subject suffering or liable to suffer therefrom an effective dose of the compound of formula (I). Compounds falling within the scope of formula (I) above are all the possible isomers, stereoisomers and their mixtures, and the metabolites and the metabolic precursors or bio-precursors of the compound of formula (I). In the formulae of specification the heavy solid lines ) indicate that a substituent is in the β- configuration, i.e. above the plane of the ring, whereas a dotted line (mn.) indicates that a substituent is in the α-configuration, i.e. beneath the plane of the ring, and a wavy line (ΛΛV) indicates that a substituent may be either in the α-configuration, i.e. below the plane of the ring, or in the β-configuration or in both, i.e. a mixture thereof. In particular when in the compounds of formula (I) A is -OH<wOH or -CH'v DR j the OH or OR j substituent may be either in the α- or in the β-configuration or in both, i.e. a mixture thereof. Accordingly, object of the present invention are also all the possible isomers, e.g. the single 17α and 17β epimers, as well as the possible mixtures thereof, e.g. 17(α,β). Hence a compound of the invention herein specifically mentioned, without any indication of its stereo¬ chemistry, is intended to represent all the possible single isomers or mixtures thereof. The alkyl radical may be a branched or straight chain. A C.-C. alkyl group is preferably a methyl or ethyl group, more preferably a methyl group. R, as an acyl group may be residue of any physio¬ logically tolerable acid. Preferred examples of said acids are the C,-C, alkanoic ones; in particular acetic, propionic and butyric acids. As stated above, the present invention also includes within its scope pharmaceutically acceptable bio- precursors (otherwise known as pro-drugs) of the compounds of formula (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 ) . Preferred compounds of the invention are the compounds of formula (I) wherein A is a -C=0 or -CH-v OH group or -CH~^OCOCH 3 group; and R is hydrogen. Examples of specific compounds of the invention are the following compounds, which, when appropriate, may be also α,β-mixtures of the 17α-ol and 17β-ol epimers: 6 , 7α-difluoromethylenandrosta-1 ,4-dien-3,l7-dione ; 6 , 7α-difluoromethylenandrosta-1 ,4-dien-17α-ol-3-one; 6 , 7α-difluoromethylenandrosta-1 ,4-dien-17β-ol-3-one; 17 α-acetoxy-6 , 7α-difluoromethylenandrosta-1 ,4-dien-3- one ; and 17β-acetoxy-6 , 7α-difluoromethylenandrosta-1 , 4- dien-3-one. The compounds of the invention can be obtained by a - 6 process comprising: a) reacting a compound of formula (II wherein R and R' are as defined above, with a difluoro- methylene radical generating reagent, so obtaining a compound of formula (I) wherein R is as defined above and A is a -CH-^OR' group wherein R, is as defined above; and, if desired, b) hydrolyzing a compound of formula (III) wherein R and R' are as defined above, thus giving a compound of formula ( I ) , wherein R is as defined above and A is a ^ -CH' OH group; and, if desired, c) oxidizing a compound of formula (IV) (IV wherein R is as defined above, thus obtaining a compound of formula ( I ) , wherein R is as defined above and A is a ^C=0 group; and/or, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, separating a mixture of isomers of compounds of formula (I) into the single isomers. In the reaction of a compound of formula II with a difluoromethylene radical generating reagent, according to the process step a), the difluoromethylene radical generating reagent may be for example sodium chlorodifluoro acetate. This reaction may be carried out e.g. according to J.H. Fried et al . in J.Med.Chem. 11 , 868 (1968). The difluoromethylene radical can be generated from an alkali or alkaline earth metal salt of trifluoroacetic acid or chlorodifluoroacetic acid. The reaction is performed at temperatures above the decomposition temperature as evidenced by CO, evolution. In the case of sodium chlorodifluoroacetate a temperature from about 150° to about 180° is employed. The reaction is preferably effected in an inert non aqueous solvent sufficiently polar to dissolve the salt. Useful solvents are ethylene glycol dimethyl ether, diethyleneglycol dimethylether or triethyleneglycol dimethylether. The hydrolysis of a compound of formula (III), according to the process step b), may be performed by conventional methods, e.g. by treatment with alkali metal hydroxide in anhydrous or aqueous alcoholic solution, preferably with potassium hydroxide in methanol or ethanol at temperatures ranging from about 20°C to reflux temperature. Alternatively the hydrolysis may be carried out with an alkali metal alkoxide in anhydrous alcohol solution, preferably with sodium methoxide in methanol at room temperature. The oxidation of a compound of formula (IV), according to the process step c), can be performed according to known methods, e.g. by treatment with the Jones reagent as described by Fieser and Fieser in Reagents for Organic Synthesis I, 142 (Editor Wiley, 1967). The Jones reagent is a solution of chromic acid and sulfuric acid in water. The oxidation may be carried out by titrating a stirred solution of the alcoholic compound in acetone, at a temperature ranging from about -20 ° C to about 30°C with the Jones reagent. The separation of a mixture of isomers into the single isomers as well as the conversion of a compound of formula (I) into another compound of formula (I) may be carried out according to known methods. For example a 17β-hydroxy derivative of a compound of formula (I) may be converted into the respective 17α-hydroxy derivative - 9 - by basic catalysis, e.g. with 0. IN sodium hydroxide in an aliphatic alcohol, e.g. ethanol . Similarly, processes b) and c) can be regarded as optional conversions of a compound of formula (I) into another compound of formula (I). In fact, a compound of formula (III) is a compound of formula (I) wherein A is and R and R' are as herein defined. A compound of formula (IV) is a compound of formula ( I ) ' wherein A is _CH^--OH and R is as herein defined. A compound of formula (II) wherein R and R' are as defined above may be obtained by dehydrobromination of a compound of formula (V) wherein R and R' are as defined above. This elimination reaction may be carried out in a polar solvent, e.g. acetonitrile , dimethylformamide , dimethylsulfoxide and similar with inorganic or organic basic agent. An inorganic basic agent may be a mixture of an alkali metal halide with alkali metal carbonate. Preferred examples are mixtures of lithium or sodium chloride or bromide with lithium or sodium carbonate. Preferred examples of organic basic agents are diazabicyclo- undecene ( DBU ) , diazabicyclononene ( DBN ) , pyridine, collidine and the like. The reaction may be performed at temperatures ranging from about 25 °C to about 150 ° C, preferably from about 80 ° C to about 120 ° C. A compound of formula (V) wherein R and R' are as defined above may be obtained by allyl bromination of a compound of formula (VI) wherein R and R' are as defined above. The 6β- bromination may be carried out according to known procedures, for example, by reaction with a suitable N- bromoacylamide , e.g. N-bromoacetamide or N-bromo- succinimide, in an inert organic solvent, e.g. carbontetrachloride , at a temperature ranging from about room temperature to reflux temperature. The compounds of formula (VI) are known compounds or may be obtained by known methods from known compounds. When in the new compounds of the present invention and in the intermediate products thereof groups are present, which need to be protected before submitting them to the hereabove illustrated reactions, they may be protected before the reactions take place and then deprotected at the end of the reaction, according to well known methods in organic chemistry. The compounds of the present invention are inhibitors of the biotransformation of androgens into estrogens, i.e. , they are steroidal aromatase inhibitors. The aromatase inhibitory activity of these compounds was demonstrated by employing the in vitro test described by Thompson and Siiteri (E.A. Thompson and P.K. Siiteri, J. Biol. Chem. 249, 5364, 1974) which utilizes the human placental microsomal fraction as enzyme source. In this test the aromatization rate of androstenedione into estrone was evaluated by incubating (lβ-H)andro- stenedione (50 nM ) in the presence of NADPH with the 3 enzyme preparation and by measuring the amount of H0 formed during 20 min incubation at 37°C. The compounds, incubated at various concentrations, showed a relevant aromatase inhibitory activity. By virtue of their ability to inhibit aromatase and, consequently, to reduce estrogen levels, the compounds of the invention are useful in mammals, including humans, in the treatment and prevention of various estrogen-dependent 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 compounds of the invention can find also use for the treatment of male infertility associated with oligo- spermia and for female fertility control, by virtue of their ability to inhibit ovulation and egg nidation. In view of their low toxicity the compounds of the invention can be used safely in medicine. For example, the approximate acute toxicity ( D ) 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. The invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically 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 gums, 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 pharmacologically inactive substances used in pharma¬ ceutical 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. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol . The suspensions and the emulsions may contain as carrier, for example, a natural gum, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, 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 be in the form of sterile, aqueous, isotonic saline solutions. The suppositories may contain togheter with the active compound a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin. The following examples illustrate but do not limit the invention: Example 1 17β-acetoxy-6, 7α-difluoromethylenandrosta-1,4-dien-3-one (I, R=H, A= ^CH-^OCOCH j ) . To a gently refluxing and stirred solution of 17β- acetoxyandrosta-1 ,4 , 6-triene-3-one (3.264 g, 10 mmol ) in diethyleneglycol dimethylether (30 ml) was added over a 3 h period in a dropwise fashion, a solution of sodium chlorodifluoroacetate (15.2 g, 100 mmol) in diethylene¬ glycol dimethyl ether (75 ml ) . The mixture was refluxed until the reation was substantially complete as determined by TLC monitoring (1/4 h). Then the mixture was filtered, the filtrate evaporated to drynesε in vacuo and the residue chromatographed on silica gel using gradient elution with dichloromethane/ethanol 0-4% to obtain pure title compound in 40% yield (1.494 g); mp 157°C. C 22 H, 6 F 2 0 3 Calculated: C 70.19 H 6.96 F 10.09 Found: C 70.15 H 6.93 9.98 MS m/z 376 IR cm "1 (KBr): 1735 (acetate), 1650 ( ketone ) , 1615 (double bonds). According to the above described procedure and starting from the 17α-acetoxy compound of general formula (II), one can prepare the following product: 17α-acetoxy-6 ,7α-difluoromethylenandrosta-1 ,4-dien-3- one . Exampl e 2 6 , 7α-d i f luoromethylenandrosta- 1 , 4 -d i en- 1 7β-ol - 3 -one ( I , R=H , A= ^:CH^i.OH ) . To a solution of 17β-acetoxy-6 , 7α-difluoromethylen- androsta-1 , 4-dien-3-one (3.760 g, 10 mmol) in anhydrous methanol (40 ml) was added portionwise sodium methoxide (1.080 g, 20 mmol) and the resulting solution was stirred at room temperature overnight. After concentration in vacuo the solution was diluted with water and extracted with ethylacetate . The organic phase was washed with sodium bicarbonate solution and water and then evaporated in vacuo to dryness. The residue was crystallized from ethanol/hexane to give pure title compound (2.340 g, 70% yield) ; mp 215°C. C 2() H 2< F 2 0 2 Calculated: C 71.83 H 7.23 F 11.36 Found: C 71.75 H 7.15 F 10.95 MS m/z 334 IR cm "1 (KBr) : 3400(OH), 1735(OAc), 1650(CO), 1615(C=C) According to the above described procedure and starting from the 17α-acetoxy compound of general formula (III) the following compound can be prepared: 6 , 7α-difluoromethylenandrosta-1 ,4-dien-17α-ol-3-one. Example 3 6 , 7α-di f luoromethylenandro sta- 1 , 4 -dien- 3 , 1 7-d ione ( I , R=H , A = ^:C=0 ) . To a solution of 6, 7α-difluoromethylenandrosta-1 ,4-dien- 17β-ol-3-one (3.344 g, 10 mmol) in acetone (100 ml) was added portionwise Jones reagent (10 ml) under cooling at 0-5°C and the stirring was continued for ih at 0-5°C. The isopropanol (10 ml) was added to quench the oxidation and the mixture extracted with ethyl acetate after dilution with water. The organic phase was washed with bicarbonate solution and water, dried and evaporated under vacuum. The residue was submitted to flash chromatography on silica gel using n-hexane/EtOAc 7:3 as eluant to give pure title compound (2.490 g, 75% yield) ; mp 216°C. C 20 H 22 F 2 O 2 Calculated: C 72.26 H 6.67 F 11.43 Found: C 72.15 H 6.67 F 11.59 MS m/z 332 IR cm "1 (KBr): 1725(CO), 1655(CO), 1615, 1600(C=C) Exampl e 4 17β-acetoxyandrosta-l ,4,6-trien-3-one (II, R=H, R'=COCH, ) To a solution of 17β-acetoxy-6-bromoandrosta-l , 4-dien-3- one (4.074 g, 10 mmol) in anhydrous DMF (100 ml) was added lithium carbonate (3.68 g) and lithium chloride (4.22 g). The reaction mixture was stirred and heated at 120°C during 2.5 hours, cooled to room temperature and poured dropwise into a 4-fold volume of water. The resulting precipitate was collected by filtration, washed and dried in vacuo at 90° C. The raw product was purified by column chromatography over silica gel to give pure title compound (2.285 g, 70%); mp 151-3°C. C 2 ,H 2e 0 3 Calculated: C 77.27 H 8.03 Found: C 77.20 H 7.99 MS m/z 326 IR cm "1 (KBr): 1735(CO), 1650(CO), 1620, 1600(C=C). Example 5 17β-acetoxy-6-bromoandrosta-l , 4-dien-3-one (V, R=H, R'=COCH 3 ) A mixture of 17β-acetoxyandrosta-1 , 4-dien-3-one (3.285 g, 10 mmol), N-bromosuccinimide (2.67 g, 15 mmol), benzoylperoxide (0.121 g, 0.5 mmol) and carbon tetrachloride (250 ml) was heated to reflux for 4 hours. After cooling to room temperature the precipitate was filtered off, the residue washed with carbon tetrachloride and the combined filtrates evaporated in vacuo. The residue was chromatographed on silica gel using benzene/ethyl ether as eluant to give pure title compound (2.85 g, 70%); mp 142-4'C. C 2] H 2? Br0 3 Calculated: C 61.92 H 6.68 Br 19.62 Found: C 61.88 H 6.55 Br 19.32 MS m/z 407 Example 6 Tablets each weighing 0.150 g and containing 25 mg of the active substance, were manufactured as follows: Composition (for 10,000 tablets): 6 , 7α-difluoromethylenandrosta- 1 ,4-diene-3,17-dione 250 g Lactose 800 g Corn starch 415 g Talc powder 30 g Magnesium stearate 5 g 6 , 7α-difluoromethylenandrosta-1 ,4-diene-3,l 7-dione , the lactose and half the corn starch were mixed; the mixture was then forced through a sieve of 0.5 mm mesh size. Corn starch (10 g) was suspended in warm water (90 ml) and the resulting paste was used to granulate the powder. The granulate was dried, comminuted on a sieve of 1.4 mm mesh size, then the remaining quantity of starch, talc and magnesium stearate was added, carefully mixed and processed into tablets. Example 7 Capsules, each dosed at 0.200 g and containing 20 mg of the active substance were prepared. Composition for 500 capsules: 6 , 7α-difluoromethylenandrosta-1 , 4- dien-17β-ol-3-one 10 g Lactose 80 g Corn starch 5 g Magnesium stearate 5 g This formulation was encapsulated in two-piece hard gelatin capsules and dosed at 0.200 g for each capsule.

Claims: CLAIMS Use of a compound of formula ( I ) wherein R is hydrogen or C,-C, alkyl; and A is a^IC=0, ^;CH^0H or^TCH-^OR' group, in which R' is an acyl group; in the manufacture of a medicament for use as an aromatase inhibitor. Use of a compound of formula (I) according to claim 1 wherein A is a - group; and R is hydrogen. Use according to claim 1 wherein the compound of formula ( I ) is: 6,7α-difluoromethylenandrosta-l,4-dien-3,17-dione; 6,7α-difluoromethylenandrosta-l,4-dien-17α-ol-3-one; 6, α-difluoromethylenandrosta-l,4-dien-17β-ol-3-one; 17α-acetoxy-6,7α-difluoromethylenandrosta-l,4-dien-3-one; or 17β-acetoxy-6,7α-difluoromethylenandrosta-l,4-dien-3-one. A compound of formula (I) as depicted in claim 1 wherein R is hydrogen or C, -C^ alkyl; and A is a~^C=0, " ^CH-wOH or^CH ^ OR' group, in which R' is an acyl group; with the exclusion of 17α-acetoxy-6 , 7α-difluoro¬ methylenandrosta-l ,4-dien-3-one. 5. A compound of formula (I) according to claim 4 wherein A is a -C=0 or -CH- Λ«0H group and R is hydrogen. A compound selected from the group consisting of: 6, 7α-dif luoromethylenandrosta-l ,4-dien-3 , 17-dione; 6, 7α-dif luoromethylenandrosta-l ,4-dien-17α-ol-3-one; 6, 7α-dif luoromethylenandrosta-l ,4-dien-17β-ol-3-one; and 17β-acetoxy-6 , 7α-di f luoromethylenandrosta-l , 4-dien-3-one . A process for obtaining a compound of formula (I) according to claim 4, the process comprising: a) reacting a compound of formula (II) (II where in R and R' are as defined in claim 4, with a difluoromethylene radical generating reagent, so obtaining a compound of formula (I) wherein R is as defined above and A is a -CH-wv ^ OR' group wherein R' is as defined in claim 4; and, if desired, b) hydrolyzing a compound of formula (III) wherein R and R' are as defined above, thus giving a compound of formula (I), wherein R is as defined in claim 4 and A is a -CH ΛΛ ~OH group; and, if desired, c) oxidizing a compound of formula (IV) wherein R is as defined in claim 4, thus obtaining a compound of formula (I), wherein R is as defined in claim 4 and A is a -C=0 group; and/or, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, separating a mixture of isomers of compounds of formula ( I ) into the single isomers. 8. A pharmaceutical composition comprising . a pharmaceutically acceptable carrier and/or diluent and, as an active principle, a compound of formula (I) according to claim 4. 9. A compound as defined in claim 4 for use as an aromatase inhibitor.

Inventors: BUZZETI FRANCO, DI SALLE ENRICO, LONGO ANTONIO, BUZZETI, FRANCO, DI SALLE, ENRICO, LONGO, ANTONIO
Applicants: ERBA CARLO SPA, FARMITALIA CARLO ERBA S.R.L.
Application year: 1993
Main classification: C07J53
IPC codes: A61K31, A61P5, C07J53