Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
  • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
  • C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
  • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
  • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom

Definitions

• the present invention relates to 4-aza- ⁇ -androstan-3-one and androst-1 , 4-dien-3-one derivatives with a fluorinated acylureidic type side chain, to a process for their preparation, to pharmaceutical compositions containing them, and to the use of said compounds as inhibitors of androgen action, by means of testosterone ⁇ -reductase inhibition.
• testosterone ⁇ -reductase inhibition.
• DHT dihydrotestosterone
• the conversion of testosterone to dihydrotestosterone is catalyzed by the enzyme ⁇ -reductase and if ⁇ -reductase is inhibited, the formation of dihydrotestosterone is reduced and its specific androgenic effect is attenuated or prevented.
• the ⁇ -reductase inhibitors may find medical application for the treatment of hyperandrogenic conditions, e.g. certain prostatic diseases, such as benign prostatic hyperplasia and prostatic cancer, and certain skin-hair conditions, such as acne, seborrhoea, female hirsutism and male pattern baldness (Siiteri P.K. , Wilson J.D. , J. Clin. Invest. 49 , 1737, 1970; Price V.H. , Arch. Dermatol . Ill, 1496, 197 ⁇ ; Sandberg A.A. , Urology i_7_, 34, 1981).
• certain prostatic diseases such as benign prostatic hyperplasia and prostatic cancer
• skin-hair conditions such as acne, seborrhoea, female hirsutism and male pattern baldness
• breast cancer treatment can take advantage from use of ⁇ -reductase inhibitors as the said tumor is known to ⁇ be aggravated by presence of androgens.
• Androst-4-en-3- one-17 ⁇ -carboxylic acid and its methyl ester are among the first steroidic compounds described as ⁇ -reductase inhibitors.
• the present invention provides compounds of the following formula I :
• A is a CH group or an N-R group wherein R is a hydrogen atom or a C* -C, alkyl group provided that, when A is a CH group, (Y) is a double bond, and when A is an N-R group (Y) is a single bond and in position ⁇ there is a hydrogen atom with ⁇ -configuration;
• B is an oxygen atom or a sulphur atom; each of R, , R, , R, independently is a hydrogen atom or a
• the invention includes also all the possible isomers of formula (I) and their mixtures. .
• metabolites and the metabolic precursors of the l ⁇ compounds of formula (I) are within the scope of the present invention.
• alkyl groups may be straight or branched chain.
• a C j -C, alkyl group may be, for example, methyl, ethyl, 20 n-propyl , isopropyl, tert-butyl;
• a C.-C R alkyl group may be, for example, a C.-C r alkyl group or a C.-C ⁇ alkyl group, such as e.g. -CH, , -C,H r ,
• the C.-C» alkyl group may be unsubstituted or substituted 2 ⁇ by one or more, preferably one to nine or one to three, fluorine atoms, for example: -CH,F, -CHF,, CF , CH,CF,, -CHICH, )CF., -CH(CF.),, -C(CH,F),, -C(CHF, ),, -C(CF, ),, -CH,CH,CH,CF. )
• An aryl group may be, for example, phenyl or phenyl (C,-C, ⁇ alkyl), in particular tolyl , preferably o- , m- or p- tolyl .
• the aryl group may be unsubstituted or substituted by one or more, preferably one, two or three, fluorine atoms, for example o-fluorophenyl , m-fluorophenyl , p- fluorophenyl , o-trifluoromethylphenyl , m-trifluoro-
• a preferred class of compounds according to ⁇ he invention are the compounds of formula (I) wherein: the symbol is a single or a double bond;
• A is a CH group or an N-R group wherein R is a hydrogen l ⁇ atom or a methyl group provided that when A is a CH group (Y) is a double bond, and when A is an N-R group (Y) is a single bond and in position ⁇ there is a hydrogen atom with ⁇ con iguration;
• B is an oxygen atom or a sulphur atom;
• each of R,i , R, c-. and RRONv independently is H, CH * , C,-H t *. ,
• R. substituted by a fluorine atom.
• the compounds of formula (I) may be obtained by a process comprising: a) reacting a compound of formula (II)
• R, and R are as defined above and R, is hydrogen; or b) reacting a compound of formula (IV)
• each of R, and Rr independently is a C. -C. alkyl group or an aryl group wherein, optionally, one or more hydrogen atoms are substituted by one or more fluorine atoms, so obtaining a compound of formula (I) wherein the symbol , A and B are as defined above, each of R. and
• R is independently a C,-Cg alkyl group or an aryl group wherein, optionally, one or more hydrogen atoms are substituted by one or more fluorine atoms and R, is hydrogen, provided that at least one hydrogen atom in R. or R, is substituted by a fluorine atom; or c) reacting a compound of formula (VI)
• R, R j , R j , R3 and B are as defined above and reducing a compound of formula (XI) as defined above, so obtaining a compound of formula (I) wherein the (X) bond and the (Y) bond are single bonds
• A is an N-R group wherein R is as defined above and R j , R, , R, and B are as defined above and/or, if desired, f) dehydrogenating a compound of formula (I) wherein A, B, R j , R, RJ are as defined above, the (X) bond is a single bond and (Y) is a single or a double bond, so obtaining a compound of formula (I) wherein A, B, R. , R, , R, are as defined above and the (X) bond is a double bond and the (Y) bond is a single or double bond and, if desired, separating a mixture of isomers into the single i somers .
• the reaction between a compound of formula (II) and a compound of formula (III), according to the process variant a), may be carried out, e.g. , refluxing the compound of formula (II) with a large excess of the compound of formula (III) in an organic solvent such as, for example, dioxane, toluene or xylene, or in pyridine in the presence of sodium, for a time varying from about 1 hour to about 48 hours, under inert atmosphere, of, e.g. , nitrogen at a temperature varying from room temperature to about the refluxing temperature of the reaction mixture.
• an organic solvent such as, for example, dioxane, toluene or xylene, or in pyridine in the presence of sodium
• reaction may be carried out by methods analogous to those described in Eur. J. Med. Chem. ⁇ , 421-26 (1989).
• the reaction between a compound of formula (IV) and a compound of formula (V), according to the process variant b), may be carried out, e.g. , stirring the mixture of the two compounds in a suitable anhydrous solvent such as, for example, diethyl ether, benzene, dioxane, methylene chloride, dimethylformamide , tetrahydrofuran, ethyl acetate or a mixture of them, optionally in the presence of an organic base such as, for example, pyridine or triethylamine at a temperatue ranging from about 0 "' C to the reflux temperature of the reaction mixture, for a time ranging from about 2 hours to about 48 hours.
• the reaction may be carried out by gradual addition of a compound of formula (IV) to a compound of formula (V) in hot pyridine.
• reaction between a compound of formula (VI) and a ⁇ compound of formula ( YI I > according to the process variant c), may be carried out, e.g. , by adding a solution of freshly prepared acyl chloride of formula (VI) dissolved in a solvent such as, for example, tetrahydrofuran , dimethyl formamide , dimethoxyethane ,
• the oxidation of a compound of formula (I) according to the process variant e) may be carried out, for example, in the presence of an oxidizing agent such as sodium 5 metaperiodate and potassium permanganate and a base such as aqueous potassium carbonate in an organic solvent. It is suitably performed at a temperature of from room temperature to about 60°C, typically for a period of from about one hour to about five hours.
• the organic solvent is methanol, ethanol, acetone, tetrahydrofuran, dioxane, isopropanol , tert- butanol or a mixture of any of these.
• the reaction is suitably performed by adding a solution of the oxidizing agent, for example sodium metaperiodate ⁇ and potassium permanganate, and the base such as potassium carbonate, in water to a solution of a compound of formula (I) in an organic solvent, or by adding simultaneously an aqueous solution of .sodium meta ⁇ periodate and an aqueous solution of potassium 0 permanganate to a solution of a compound of formula (I) in an organic solvent and aqueous potassium carbonate.
• the oxidation of a compound of formula (I) may be carried out with ozone in an organic solvent.
• the reaction is typically continued until all the ⁇ " starting material is consumed.
• the temperature of the reaction is suitably from about -78°C to room temperature.
• an oxidizing agent is then added to the reaction mixture to destroy the resulting ozonide.
• the solvent is methylene chloride, ethylacetate, methanol or a mixture of any of these.
• the oxidizing agent is preferably hydrogen peroxide.
• reaction between a compound of formula (IX) and a compound of formula (X) is preferably carried out in an anhydrous organic solvent at a temperature from about 60°C to the reflux temperature of the solvent. It is suitably continued for a period of from about 30 minutes to about four hours.
• the solvent is ethylene glycol, dimethyl- formamide , dimethylsulphoxide , ethanol, methanol, dioxane, ethylacetate or a mixture of any of these.
• oxidation of a compound of formula (I) is carried out with ozone, it is possible to perform the cyclization reaction by treating directly the ozonide containing reaction mixture with the amine o formula (X), typically in excess, thereby directly obtaining a compound of formula (XI) .
• the reduction of a compound of formula (XI) is preferably carried out in an organic solvent under hydrogen pressure varying from about 1 atm to about 10 atm, in the presence of hydrogenation catalyst.
• the temperature is typically from room temperature to about 60 ° C.
• the reduction time typically varies from about 30 minutes to about five hours .
• the solvent is ethanol, acetic acid or a mixture of any of these and the hydrogenation catalyst is platinum oxide (Adam's Catalyst), ⁇ % or 10 % palladium ⁇ on charcoal or palladium hydroxide.
• platinum oxide Adam's Catalyst
• ⁇ % or 10 % palladium ⁇ on charcoal or palladium hydroxide platinum oxide
• the dehydrogenation of a compound of formula (I) according to the abov p process variant f), which is preferably performed on a compound of formula (I) wherein R. is hydrogen, may be carried out by treatment with a 0 suitable dehydrogenating agent such as, e.g. , chloranil, benzeneseleninic anhydride or dichlorodicyanobenzoquinone (DDQ), operating in an anhydrous solvent, such as, for example, chlorobenzene , dioxane., xylene, toluene or benzene, and, optionally, in the presence of BSTFA [bis- ⁇ ( trimethylsilyl )trifluoroacetamide] .
• the reaction temperature may range from the room temperature to the reflux temperature of the solvent and the reaction time may vary approximately from about 2 hours to about 24 hours.
• the reaction is carried out under inert 0 atmosphere, e.g. , nitrogen atmosphere.
• the compounds of formula (II) wherein (X), (Y), A and R, are as defined above, are known compounds or they can be prepared by the methods usually used in the synthesis of amides (J.WU . 29, 2298-231 ⁇ , 1986) excluding the ⁇ compounds of formula (II) wherein A is an N-R group wherein R is as defined above, (Y) is a single bond, (X) is a single or double bond and R, is a C-C R alkyl group wherein one or more hydrogen atoms are substituted by one or more fluorine atoms.
• a solvent such as, for example, methylene chloride, ethyl acetate, tetra ⁇ hydrofuran, dimethylforma ide, benzene or toluene at a temperature ranging from about O'C to about 100°C, for a time varying from about 1 hour to about 48 hours.
• a stoichiometric amount of an organic base such as, for example, pyridine, or a tri-C,-Cg-alkylamine , preferably triethylamine has to be added to the reaction mixture.
• 20 A is an -N-R group wherein R is as defined above according to the process variant B), which is preferably performed on a compound of formula (II) wherein R is hydrogen, may be carried out by treatment with a suitable dehydrogenating agent such as, e.g., chloranil , benzene-
• reaction temperature may range from the room temperature to the reflux temperature ⁇ of the solvent and the reaction time may vary approximately from about 2 hours to about 24 hours.
• reaction is carried out under inert atmosphere, e.g. , nitrogen atmosphere.
• the compounds of formula (IV) are known compounds or can
• each of R, and R independently is a hydrogen atom a C.-C p alkyl group or an aryl group are known compounds.
• l The compounds of formula (V), wherein each of R, and R, is independently a C,-C alkyl group or an aryl group, wherein one or more hydrogen atoms are substituted by one or more fluorine atoms, are known compounds (see, for example: Izv. Akad. Nauk. SSSR, Ser. Khim. 1967 (9),
• the fluorinated ureas of formula (VII) are known compounds (see, for example, J. Med. Chem. 9 . , 892-911 (1966)) or they can be prepared by known methods for the synthesis of ureas (see, for example, J.O.C. 4J5, 886 (1980) or J. Chem. Soc. 1936, 1273).
• the compounds of the present invention inhibit specifically the testosterone ⁇ -reductase enzyme and, therefore, are potent antiandrogens .
• the inhibitory effect of the compounds of the invention on ⁇ -reductase was determined in vitro-, according to the procedure reported herebelo .
• Inhibition of ⁇ -reductase was evaluated using the 5 particulate fraction from homogenates of hyperplastic human prostates as the enzyme source.
• the particulate fraction was prepared centrifuging prostate homogenate at 140,000 x g.
• the resulting pellet washed several times, was resuspended in buffer and stored at -80'C in aliquots 0 containing ⁇ 10 mg protein/ml.
• the assay for ⁇ -reductase was done in a final volume of O. ⁇ ml, in 40 mM TRIS-HC1 buffer pH 5.5, containing 1 mM dithiothreitol, 5 mM NADPH , 1 ⁇ M [ C] testosterone, an aliquot of the enzyme preparation and various ⁇ concentrations of the inhibitors. After 30 min incubation at 37°C the reaction was terminated by addition of 2 ml cold diethyl ether and the organic phase was separated, evaporated under N, and resuspended in ethyl acetate. Testosterone metabolites in this extract were separated ⁇ in T C on silica gel F 2 ⁇ 4 plates (Merck) using chloroform, acetone and n-hexane (2:1:2) as developing solvent system.
• Radioactivity on the plate was scanned and analyzed from quantitative plots printed by a TLC-analyzer (Berthold).
• the fractional ⁇ -reduction of testosterone was calculated by relating the HC-radioactivity in the ⁇ - reduced metabolites ( ⁇ -dihydrotestosterone , 3 ⁇ - and 3 ⁇ - androstanediols ) regions to the total radioactivity in the testosterone and ⁇ -reduced metabolites regions.
• l ⁇ The concentration of each compound required to reduce control ⁇ -reductase activity by ⁇ 0% ( ICr n ) was determined.
• a mammal e.g. a human or animal, may thus be treated by a method which comprises administering thereto a pharmaceutically effective amount of a compound of formula (I) as defined above.
• the toxicity of the compounds of the invention is quite negligible so that they can be safely used in therapy, ⁇
• 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 0 intravenous injection or infusion; topically, e.g. in the form of creams.
• 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 1 to 200 mg pro dose, from 1 to 3 times daily.
• the invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be carrier or diluent).
• a pharmaceutically acceptable excipient which can be 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.
• 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.
• binding agents e.g. starches, arabic gums, gelatin, methylcellulose , carboxymethylcellulose or ⁇ polyvinyl pyrrolidone
• dis-aggregating agents e.g. a starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners
• compositions 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.
• the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular a syrup to be administered
• 20 to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, for example sorbitol.
• the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate,
• the suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharma ⁇ ceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycol, e.g. propylene glycol and if ⁇ desired, a suitable amount of lidocaine hydrochloride .
• a pharma ⁇ ceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycol, 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 together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
• a pharmaceutically acceptable carrier e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
• Conventional carriers may be used for topical l ⁇ formulations.
• reaction mixture was then heated to reflux for 80 minutes, cooled to room temperature and treated dropwise 0 with a solution of 4-methyl-3-oxo-4-aza- ⁇ -androstane- 17 ⁇ -carbonyl chloride (l ⁇ O mg ) in tetrahydrofuran (3 ml). After stirring at room temperature for 36 hours the mixture was cooled with an ice-bath, acidified with IN hydrochloric acid and extracted thoroughly with ethyl ⁇ acetate .
• Aqueous 2% potassium permanganate solution (0.441 ml) and sodium metaperiodate (1.05 g in 6.53 ml of water) are added dropwise simultaneously to the mixture over a period of 30 minutes.
• a suspension of seco-ketoacid (300 mg ) in dioxane (10 ml) ⁇ is treated with an excess of liquid methylamine and heated to about 80 * C for 1 hour into an autoclave. After removing the excess of methylamine by a nitrogen flow, the solution is concentrated, poured into water and extracted with ethyl acetate; the organic extracts are 0 washed with IN hydrochloric acid, with brine, anhydrified over sodium-sulphate and the solvent is removed under vacuum.
• the brown crude oil is purified by flash chromatography (eluant: methylene chloride/acetone 9:1), so obtaining 5 130 mg of 1-(4-methyl-3-oxo-4-aza- ⁇ -androst-5-ene-17 ⁇ - carbonyl )-l,3-di-(2,2, 2-trifluoroethyl)urea.
• the ⁇ 5'6-unsaturated-4-aza-steroid (130 m ) is dissolved in absolute ethanol and hydrogenated over platinum oxide
• Scored tablets for oral use each containing 2 ⁇ 0 mg of the active substance, were manufactured as follows. Composition (for 10,000 tablets) 1-(4-methyl-3-oxo-4-aza- ⁇ -androstane-17 ⁇ - carbonyl)-l , 3-di-( 2,2,2-trifluoroethyl )urea 2 ⁇ 00 g Corn starch 280 g
• Calcium stearate 40 g The active substance was granulated with a 4% w/v aqueous solution of methyl cellulose. To the dried granules a mixture of the remainder of the ingredients_is added and the final mixture compressed into tablets of proper weight.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Steroid Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=10719595

Family Applications (1)

Country Status (4)

Families Citing this family (8)

Family Cites Families (2)

• 1992
  • 1992-07-31 GB GB929216280A patent/GB9216280D0/en active Pending
• 1993
  • 1993-07-29 EP EP93917703A patent/EP0610472A1/de not_active Withdrawn
  • 1993-07-29 WO PCT/EP1993/002035 patent/WO1994003474A1/en not_active Ceased
  • 1993-07-29 JP JP6504992A patent/JPH06511496A/ja active Pending

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events