DK143757B - ANALOGY PROCEDURE FOR THE PREPARATION OF 16,16-DISUBSTITUTED 3-OXOANDROSTEN - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF 16,16-DISUBSTITUTED 3-OXOANDROSTEN Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
- C07J1/0037—Androstane derivatives substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being a saturated hydrocarbon group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
- C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/005—Ketals
- C07J21/006—Ketals at position 3
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Description
(19) DANMARK (^)(19) DENMARK (^)
|j| 02) FREMLÆGGELSESSKRIFT ου 143757 B| J | 02) PRESENTATION WRITING ου 143757 B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM
(21) Ansøgning nr. 1234/76 (51) (^.α.3 C 07 J 1/00 (22) Indleveringsdag ^ 9 · ♦ 1 97 6 (24) Løbedag 19* ®ar. 1976 (41) Aim. tilgængelig 22. s ep. 1976 (44) Fremlagt 5· okt. 1981 (86) International ansøgning nr.(21) Application No. 1234/76 (51) (^ .α.3 C 07 J 1/00 (22) Filing Day ^ 9 · ♦ 1 97 6 (24) Race Day 19 * ®ar. 1976 (41) Aim. available 22 p. 1976 (44) Submitted 5 · Oct. 1981 (86) International Application no.
(86) International indleveringsdag (85) Videreførelsesdag “ (62) Stamansøgning nr. ~(86) International Filing Day (85) Continuation Day “(62) Application No. ~
(30) Prioritet 21. mar. 1975, 1l8l9/75, GB(30) Priority Mar 21 1975, 1986/75, GB
(71) Ansøger BEECHAM GROUP LIMITED, Brentford, GB.(71) Applicant BEECHAM GROUP LIMITED, Brentford, GB.
(72) Opfinder Frederick £asfsidy, GB.(72) Inventor Frederick £ asfsidy, GB.
(74) Fuldmægtig Plougmann & Vingtoft Patent tur eau.(74) Plougmann & Vingtoft Patent Tur eau.
(54) Analogifremgangemåde til frem» stilling af 1 6,1 6-disubstituerede 3-oxoandrostener.(54) Analogous procedure for the preparation of 1 6.1 6-disubstituted 3-oxoandrostens.
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte forbindelser med farmaceutisk virkning, nemlig 16,16-disubstituerede 3-oxoandrostener, som kan anvendes til behandling af androgenafhængige hudlidelser.The present invention relates to an analogous process for the preparation of novel compounds having a pharmaceutical effect, namely 16,16-disubstituted 3-oxoandrostenes, which can be used to treat androgen-dependent skin disorders.
Mange hudlidelser, f.eks. acne og seborrhoea, antages at opstå på grund af usædvanlig stor talgsekretion fra talgkirtlerneMany skin disorders, e.g. acne and seborrhoea, are believed to occur due to unusually large sebum secretion from the sebaceous glands
Mk U under androgenisk stimulering. Det antages nu, at testosteron, D den overordnede cirkulerende androgen, omdannes til 5a-dihydrotesto- ^ steron (DHT) på androgen-receptorceller, og at DHT derfor er den bio- ;f logisk aktive androgen, der forårsager denne stimulering. Det enzym, ιέ 2 2 t43757 4 der fremkalder denne omdannelse, er Δ -3-ketosteroid-5a-reductase.Mk U under androgenic stimulation. It is now believed that testosterone, D the major circulating androgen, is converted to 5α-dihydrotestosterone (DHT) on androgen receptor cells, and that DHT is therefore the biologically active androgen causing this stimulation. The enzyme ιέ 2 2 t43757 4 that induces this conversion is Δ -3-ketosteroid-5α reductase.
Det er derfor klart, at en forbindelse, som kan inhibere dette enzyms virkning på det cirkulerende testosteron, eller som har anti--androgenisk virkning i kraft af sin evne til at konkurrere med DHT om receptorpositionerne, kan anvendes til behandling af de ovennævnte hudlidelser.Therefore, it is clear that a compound which can inhibit the action of this enzyme on circulating testosterone, or which has anti-androgenic effect by virtue of its ability to compete with DHT for the receptor positions, can be used to treat the aforementioned skin disorders.
Det har nu vist sig, at visse hidtil ukendte androstener, som er beslægtet med testosteron, men di-substitueret i 16-stillingen med bestemte carbonhydridgrupper, har 5a-reductase-inhiberende virkning, og at de tilsvarende androstaner er svage anti-androgener i kraft af deres evne til at konkurrere med DHT om receptorpositionerne. Disse androstener har også en meget svag anti-androgenisk virkning af denne konkurrerende art. Disse steroider kan derfor anvendes til behandling af de ovenfor anførte hudlidelser, f.eks. acne og seborrhoea. Det antages, at behandling af andre androgenafhængige lidelser, som er knyttet til huden og hårfolliklerne, f.eks. hirsutisme hos kvinder, androgenisk alopecia og maskulint skaldethedsmønster hos kvinder, også er mulig med disse steroider.It has now been found that certain novel androstens which are related to testosterone but di-substituted at the 16-position with certain hydrocarbon groups have 5α-reductase inhibitory effect and that the corresponding androstanes are weak anti-androgens in effect. of their ability to compete with DHT for the receptor positions. These androstenes also have a very weak anti-androgenic effect of this competing species. These steroids can therefore be used to treat the above-mentioned skin disorders, e.g. acne and seborrhoea. It is believed that treatment for other androgen-dependent disorders associated with the skin and hair follicles, e.g. hirsutism in women, androgenic alopecia and masculine baldness pattern in women are also possible with these steroids.
Det er kendt (W. Voigt og S.L. Hsia, Endrocrinology, 1973, 92_, 1216 -1222), at 4-androsten-3-on-17β-carboxylsyre med den nedenfor anførte formel A og dens methylester har 5a-reductase-inhiberende virkningIt is known (W. Voigt and S.L. Hsia, Endrocrinology, 1973, 92, 1216 -1222) that 4-androsten-3-one-17β-carboxylic acid of formula A and its methyl ester listed below has 5α-reductase inhibitory effect.
^^COOH^^ COOH
Disse to forbindelser er imidlertid strukturelt mindre nært beslægtede med androstenerne, som fremstilles ved fremgangsmåden ifølge den foreliggende opfindelse, end testosteron, som anvendes som standardreference-androgen.However, these two compounds are structurally less closely related to the androstens produced by the process of the present invention than testosterone used as the standard reference androgen.
Det er også kendt fra USA patentskrift nr. 3.853.926, at 173-hydroxy--16,16-dimethyl-estr-4-en-3-on med formlen BIt is also known from United States Patent No. 3,853,926 that 173-hydroxy-16,16-dimethyl-estr-4-en-3-one of formula B
3 1437673 143767
OHOH
er en anti-androgen og kan undertrykke talgsekretionen hos rotter.is an anti-androgen and can suppress sebum secretion in rats.
Steroidet B er en estren, medens de umættede steroider, som fremstilles ved fremgangsmåden ifølge opfindelsen, er androstener. Det faktum at 19-nor-testosteron, en estren, og de fleste derivater deraf er gestagener, og at testosteron, en androsteron, er en androgen, viser klart, at der ikke med sikkerhed kan forudsiges noget om farmaceutisk virkning fra den ene til den anden klasse af steroider.The steroid B is an ester, while the unsaturated steroids produced by the method of the invention are androstenes. The fact that 19-nor-testosterone, an ester, and most of its derivatives are progestogens, and that testosterone, an androsterone, is an androgen, clearly shows that there is no certainty of predictable pharmacological action from one to the other. second class of steroids.
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af forbindelser med den almene formel IThe present invention relates to an analogous process for the preparation of compounds of general formula I
r4 r5 o 3 hvor R betegner alkyl med 1-5 carbonatomer, alkenyl med 3-6 carbonatomer eller phenylalkyl, hvor alkyldelen indeholder 1-3 carbonatomer, og phenyIdelen eventuelt er substitueret med alkyl 4 med 1-4 carbonatomer, halogen eller nitro; R betegner hydroxy 6 6 eller en gruppe OR , hvor R betegner acyl med 2-7 carbonatomer, alkyl med 1-4 carbonatomer eller eventuelt i phenylkernen med alkyl med 1-4 carbonatomer, halogen eller nitro substitueret 5 benzyl; R betegner hydrogen eller alkyl med 1-5 carbonatomer; 4 5 eller R og R sammen med det carbonatom, til hvilket de er knyttet, danner en carbonylgruppe.wherein R is alkyl having 1-5 carbon atoms, alkenyl having 3-6 carbon atoms or phenylalkyl, wherein the alkyl moiety contains 1-3 carbon atoms and the phenyl moiety is optionally substituted with alkyl 4 having 1-4 carbon atoms, halogen or nitro; R represents hydroxy 6 or a group OR, wherein R represents acyl of 2-7 carbon atoms, alkyl of 1-4 carbon atoms or optionally in the phenyl nucleus of alkyl of 1-4 carbon atoms, halogen or nitro substituted benzyl; R represents hydrogen or alkyl of 1 to 5 carbon atoms; Or R and R together with the carbon atom to which they are attached form a carbonyl group.
* 3 4 143757 I formlen I vil R ofte være en alkylgruppe med 1-5 carbonatomer eller en phenylalkylgruppe, hvor alkyldelen indeholder 1-3 carbonatomer, og phenylgruppen eventuelt er substitueret.In formula I, R will often be an alkyl group having 1 to 5 carbon atoms or a phenylalkyl group wherein the alkyl moiety contains 1-3 carbon atoms and the phenyl group is optionally substituted.
33
Egnede eksempler på R er følgende grupper: methyl, ethyl, propyl, benzyl og phenylethyl. Phenyldelene i benzyl- og phenylethyl- grupperne kan være substitueret med en alkylgruppe med 1-4 carbonatomer, halogen eller en nitrogruppe. R kan også hensigts- -¾ mæssigt være en allyl- eller butenylgruppe. R- er fortrinsvis en methyl-, ethyl- eller n- eller isopropylgruppe, navnlig en methylgruppe.Suitable examples of R are the following groups: methyl, ethyl, propyl, benzyl and phenylethyl. The phenyl moieties of the benzyl and phenylethyl groups may be substituted by an alkyl group of 1-4 carbon atoms, halogen or a nitro group. R can also conveniently be an allyl or butenyl group. Preferably, R- is a methyl, ethyl or n or isopropyl group, especially a methyl group.
4 o 44 o 4
Det er særlig hensigtsmæssigt, at R er en hydroxygruppe. Nar R imid- 6 6 lertid er en gruppe OR , er egnede eksempler på R følgende grupper: acetyl, n- og isopropionyl, n-, sek.- og tert.butyryl, caproyl, hepta-noyl, methyl, ethyl, n- og isopropyl og n-, sek.- og tert.butyl samt benzyl. PhenyIdelen i benzylgruppen kan være substitueret med alkyl med 1-4 carbonatomer, halogen eller nitro.It is particularly convenient that R is a hydroxy group. When R imide is a group OR, suitable examples of R are the following groups: acetyl, n- and isopropionyl, n-, sec- and tert-butyl, caproyl, heptanoyl, methyl, ethyl, n- and isopropyl and n-, sec- and t-butyl and benzyl. The phenyl moiety of the benzyl group may be substituted by alkyl of 1-4 carbon atoms, halogen or nitro.
Egnede eksempler på r~* er hydrogen, methyl, ethyl, n- og isopropyl og n-butyl. R5 er fortrinsvis hydrogen eller methyl, navnlig hydrogen.Suitable examples of r ~ * are hydrogen, methyl, ethyl, n- and isopropyl and n-butyl. Preferably, R 5 is hydrogen or methyl, especially hydrogen.
Inden for forbindelserne med formlen I er en særlig foretrukken klasse forbindelser sådanne, som har den almene formel IIIWithin the compounds of formula I, a particularly preferred class of compounds are those having the general formula III
*lc 11 L ~ - -r11 \ ch. in o hvor R10 betegner hydroxy, som eventuelt er acyleret med acyl med 2 -7 carbonatomer, R^"*· betegner hydrogen eller methyl, eller R10 og R^ sammen med det carbonatom, til hvilket de er bundet, danner en carbo-nylgruppe.* lc 11 L ~ - -r11 \ ch. wherein R 10 represents hydroxy optionally acylated with acyl of 2 to 7 carbon atoms, R 2 represents hydrogen or methyl, or R 10 and R 2 together with the carbon atom to which they are attached form a carbonyl group .
R"^ kan f.eks. være hydroxy, acetoxy, n- eller isopropionyloxy, ca-proyloxy og heptanoyloxy.R "may be, for example, hydroxy, acetoxy, n- or isopropionyloxy, ca-proyloxy and heptanoyloxy.
«· ^ 5 143757 R·*·^ er fortrinsvis en hydroxygruppe.Preferably, R 5 is a hydroxy group.
R11 er fortrinsvis hydrogen eller methyl, eller R^ og R^ danner sammen med det carbonatom, til hvilket de er bundet, en carbonyl-gruppe. R^·*" er især et hydrogenatom.Preferably, R 11 is hydrogen or methyl, or R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group. R 2 is a hydrogen atom in particular.
På grund af den særlig gode virkning, som sådanne forbindelser udviser, går en foretrukken udførelsesform for fremgangsmåden ifølge opfindelsen ud på, at der fremstilles en forbindelse med den almene formel III, hvor R10 betegner hydroxy eller caproyloxy, og R·^ betegner hydrogen.Due to the particularly good action exhibited by such compounds, a preferred embodiment of the process of the invention is to prepare a compound of general formula III wherein R 10 represents hydroxy or caproyloxy and R 5 represents hydrogen.
En forbindelse, som har den almene formel III, og som er særlig nyttig i kraft af sin 5-a-reductase-inhiberende virkning, er androst-4-en--16,16-dimethyl-173-ol-3-on.A compound which has the general formula III and which is particularly useful by virtue of its 5-α-reductase inhibitory effect is androst-4-ene-16,16-dimethyl-173-ol-3-one.
Fremgangsmåden ifølge opfindelsen til fremstilling af forbindelser med den almene formel I er ejendommelig ved, at 1 en forbindelse med den almene formel IV 4The process of the invention for the preparation of compounds of general formula I is characterized in that 1 is a compound of general formula IV 4
IVIV
3 4 5 hvor X betegner beskyttet carbonyl, og R , R og R har den i forbindelse med formlen I anførte betydning, fjernes beskyttelsesgruppen til dannelse af en ubeskyttet carbonylgruppe i 3-stillingenf 4 hvorefter, om ønsket, en hydroxygruppe R omdannes til en gruppe OR6 ved acylering eller forethring på i og for sig kendt måde.Where X represents protected carbonyl and R, R and R have the meaning set forth in formula I, the protecting group is removed to form an unprotected carbonyl group at the 3-position f 4 and then, if desired, a hydroxy group R is converted to a group OR6 by acylation or etherification in a manner known per se.
Bindingen i formlen IV omlejres under reaktionen til fjernelse af beskyttelsen, hvorved der fås den ønskede 4,5-binding i produktet.The bond of formula IV is rearranged during the reaction to remove the protection to give the desired 4.5 bond in the product.
143757 6143757 6
Fremgangsmåden ifølge opfindelsen er en sædvanlig fjernelse af beskyttelsen fra en beskyttet carbonylgruppe. Gruppen X kan således være en ketaliseret carbonylgruppe, f.eks. ^^0 (CH0) C, hvor n er 2 n / 2 eller 3, eller R'X^ C, hvor R'X er en alkohol- eller thiolrest (X er henholdsvis oxygen eller svovl), i hvilket tilfælde fjernelsen af beskyttelsen hensigtsmæssigt udføres ved syrehydrolyse; eller den kan være en thioketaliseret carbonylgruppe, f.eks.The method of the invention is a conventional removal of the protection from a protected carbonyl group. The group X may thus be a ketalized carbonyl group, e.g. O (CHO) C, where n is 2 n / 2 or 3, or R'X ^ C, where R'X is an alcohol or thiol residue (X is oxygen or sulfur, respectively), in which case the removal of the protection conveniently carried out by acid hydrolysis; or it may be a thioketalized carbonyl group, e.g.
/°\ (CH-),; C eller (CH0) x C, hvor n er 2 eller 3, i hvilket til- 2 n\ X 2 X / s xs fælde fjernelsen af beskyttelsen hensigtsmæssigt kan udføres under anvendelse af mercurisalte eller ved syrehydrolyse./ ° \ (CH-),; C or (CHO) x C, where n is 2 or 3, in which case the 2 n \ X 2 X / s xs trap removal of the protection can conveniently be performed using mercuric salts or by acid hydrolysis.
Efter fjernelse af beskyttelsen kan nedenstående fakultative trin udføres: o 4 5 4 Når R og R ikke danner en carbonylgruppe, kan gruppen R varieres på sædvanlig måde. F.eks. kan forbindelser med formlen I, hvor 4 R er en acyleret eller forethret hydroxygruppe, fremstilles ved sædvanlig acylering eller forethring af forbindelser med formlen 4 I, hvor R er en hydroxygruppe. Sådanne reaktioner omfatter omsætning af hydroxygruppen med acylchlorider eller acylanhydrider såsom acetylchlorid eller eddikesyreanhydrid under vandfrie betingelser til dannelse af acylderivater, og omsætning af et natriumsalt af hydroxygruppen med et alkylhalogenid til dannelse af et forethret derivat.After removing the protection, the following optional steps can be performed: o 4 5 4 When R and R do not form a carbonyl group, the group R can be varied in the usual manner. Eg. For example, compounds of formula I wherein 4 R is an acylated or etherified hydroxy group may be prepared by conventional acylation or etherification of compounds of formula 4 I wherein R is a hydroxy group. Such reactions include reacting the hydroxy group with acyl chlorides or acyl anhydrides such as acetyl chloride or acetic anhydride under anhydrous conditions to form acyl derivatives, and reacting a sodium salt of the hydroxy group with an alkyl halide to form an etherified derivative.
Forbindelserne med formlen IV er hidtil ukendte og kan anvendes som mellemprodukter til dannelse af de farmaceutisk aktive forbindelser med formlen I.The compounds of formula IV are novel and can be used as intermediates to form the pharmaceutically active compounds of formula I.
7 1437577 143757
Forbindelserne med formlen IV kan på deres side fremstilles ved en fremgangsmåde, som består i, at der i 16-stillingen i en forbindelse med den almene formel VThe compounds of formula IV, in turn, can be prepared by a process consisting of the fact that in the 16-position of a compound of the general formula V
3 substitueres med de ønskede grupper R , hvorefter, om ønsket, 17- 4 5 -carbonylgruppen omdannes til andre grupper R og R på sædvanlig .45 made. R og R har den i forbindelse med formlen IV anførte betydning. Mindre foretrukket kan de 16-monosubstituerede mellemprodukter først isoleres og derefter yderligere substitueres i 16- stillingen.3 is substituted with the desired groups R and then, if desired, the 17-4 carbonyl group is converted to other groups R and R in the usual .45 way. R and R have the meaning given in formula IV. Less preferably, the 16-mono-substituted intermediates can first be isolated and then further substituted at the 16-position.
Substitutionsreaktionen kan hensigtsmæssigt udføres ved at omsætte 3 den valgte forbindelse med formlen V med en forbindelse R Y i nærværelse af en stærk base, der er kun lidt nucleofil. Det er hensigtsmæssigt, at Y er et halogenid, tosylat, mesylat eller azid,at basen er et hydrid såsom natriumhydrid, og at reaktionen udføres under vandfri betingelser.The substitution reaction may conveniently be carried out by reacting 3 the selected compound of formula V with a compound R Y in the presence of a strong base which is only slightly nucleophilic. It is convenient that Y is a halide, tosylate, mesylate or azide, that the base is a hydride such as sodium hydride and that the reaction is carried out under anhydrous conditions.
Den fakultative omdannelse af 17-carbonylgruppen til andre grupper 4 5 R og R kan udføres under anvendelse af sædvanlige metoder. F.eks.The optional conversion of the 17-carbonyl group to other groups 45 R and R can be carried out using conventional methods. Eg.
4 5 kan forbindelser, hvor R er hydroxy, og R er enten hydrogen eller alkyl med 1-5 carbonatomer, fremstilles ud fra den tilsvarende 17- carbonylforbindelse enten ved reduktion eller ved omsætning med et C^_g-alkyl-Grignatd-reagens eller et C^_,--alkyl-metalcomplex (hensigtsmæssigt et C1_5-alkyllithiumcomplex). Reduktionen kan hensigtsmæssigt udføres under anvendelse af lithiumaluminiumhydrid. Der- 4 efter kan den således dannede R “hydroxygruppe, om ønsket, selv acy- 4 leres eller forethres til dannelse af en anden gruppe R som ovenfor beskrevet.45, compounds wherein R is hydroxy and R is either hydrogen or alkyl of 1 to 5 carbon atoms can be prepared from the corresponding 17-carbonyl compound either by reduction or by reaction with a C 1-6 alkyl-Grignatd reagent or a C ^, alkyl alkyl-metal complex (conveniently a C15 alk alkyl lithium complex). The reduction may conveniently be carried out using lithium aluminum hydride. Subsequently, the R hydro hydroxy group thus formed can, if desired, be itself acylated or etherified to form another group R as described above.
143757 8143757 8
Forbindelserne med formlen V kan fremstilles ved oxidation af de tilsvarende 17-hydroxyforbindelser med den almene formel VIThe compounds of formula V can be prepared by oxidation of the corresponding 17-hydroxy compounds of general formula VI
OHOH
c£> vi hvor X har den i forbindelse med formlen V anførte betydning, under neutrale eller basiske betingelser.where X has the meaning given in the formula V, under neutral or basic conditions.
Denne omsætning udføres bekvemt under anvendelse af enten sølvcarbo-nat på et inert bærestof såsom kiselgur eller ved anvendelse af Collins-reagens, som er en blanding af chromtrioxid og pyridin i methylendichlorid.This reaction is conveniently carried out using either silver carbonate on an inert carrier such as diatomaceous earth or using Collins reagent, which is a mixture of chromium trioxide and pyridine in methylene dichloride.
Forbindelserne med formlen VI kan fremstilles ved at beskytte car-bonylgruppen i den tilsvarende forbindelse med formlen VIIThe compounds of formula VI can be prepared by protecting the carbonyl group of the corresponding compound of formula VII
VI1VI1
Denne omsætning udføres under sædvanlige betingelser til dannelse af den ønskede beskyttede carbonylgruppe X. Når der f.eks. skal fremstilles en ketaliseret carbonylgruppe, omsættes forbindelsen med formlen VII med en egnet alkohol eller thiol i nærværelse af syre. På denne måde fører anvendelse af f.eks. ethylenglycol til en 3,3-ethylendioxy--carbonylbeskyttende gruppe.This reaction is carried out under usual conditions to form the desired protected carbonyl group X. If a ketalized carbonyl group is to be prepared, the compound of formula VII is reacted with a suitable alcohol or thiol in the presence of acid. In this way, use of e.g. ethylene glycol to a 3,3-ethylenedioxy carbonyl protecting group.
9 143757 4.5- Bindingen omlejres under reaktionen til dannelse af en 5.6- binding.4.5- The bond is rearranged during the reaction to form a 5.6 bond.
Det fremgår af det ovenstående, at en særlig velegnet præparativ vej til forbindelser med formlen I er som vist på nedenstående diagram:It can be seen from the above that a particularly suitable preparative route for compounds of formula I is as shown in the diagram below:
OHOH
VI1 beskyttelse . vVI1 protection. v
OHOH
^ VI^ VI
oxidationoxidation
16,16-disub-stitution 'V16,16 disubstitution 'V
10 14375710 143757
Fortsat R4 3 3 fakultativ s carbonylomdannelse fjernelse af beskyttelsenContinued R4 3 3 optional carbonyl conversion removing protection
Den således fremstillede forbindelse med formlen I kan derefter, om ønsket, omdannes til en anden forbindelse med formlen I som ovenfor beskrevet.The compound of formula I thus prepared can then, if desired, be converted to another compound of formula I as described above.
Med de ved fremgangsmåden ifølge den foreliggende opfindelse fremstillede forbindelser kan der fremstilles et farmaceutisk præparat, som indeholder en forbindelse med formlen I sammen med et farmaceutisk tolerabelt bærestof.With the compounds of the process of the present invention, a pharmaceutical composition can be prepared which contains a compound of formula I together with a pharmaceutically tolerable carrier.
De omhandlede forbindelser vil normalt blive formuleret til en creme eller salve til topisk administration på huden. Et foretrukket præparat er derfor et farmaceutisk præparat til topisk 11 143757 administration på huden, hvilket præparat indeholder en forbindelse med formlen I, som er blevet formuleret til en creme eller salve.The present compounds will usually be formulated into a cream or ointment for topical administration to the skin. Therefore, a preferred composition is a pharmaceutical composition for topical administration to the skin which contains a compound of formula I which has been formulated into a cream or ointment.
Creme- eller salvepræparater, som kan anvendes til forbindelser med formlen I, er sædvanlige præparater, som er kendt på området, f.eks. præparater, som er beskrevet i standardværker angående farmaceutika og kosmetika, f.eks. Harry's Cosmeticology, udgivet af Leonard Hiil Books, og British Pharmacopoeia. Simple eksempler på velegnede formuleringer er sådanne, som indeholder en emulgerende standardsalve-basis eller en vandfri polyethylenglycol.Cream or ointment preparations which can be used for compounds of formula I are conventional compositions known in the art, e.g. preparations described in standard pharmaceutical and cosmetic works, e.g. Harry's Cosmeticology, published by Leonard Hiil Books, and British Pharmacopoeia. Simple examples of suitable formulations are those containing a standard emulsifying base ointment or anhydrous polyethylene glycol.
Det antages, at visse af forbindelserne med formlen I er aktive, når de indtages ad oral vej. Sådanne forbindelser kan derfor formuleres sammen med inerte bærestoffer til præparater, som er sædvanlige til administration på denne måde, f.eks. tabletter, kapsler og sirupper .It is believed that some of the compounds of formula I are active when taken orally. Such compounds can therefore be formulated together with inert carriers for preparations which are usual for administration in this manner, e.g. tablets, capsules and syrups.
Ved administration af en effektiv mængde af en forbindelse med formlen I kan androgenafhængige hudlidelser behandles.By administering an effective amount of a compound of formula I, androgen-dependent skin disorders can be treated.
Forbindelserne med formlen I er særlig værdifulde til behandling af acne og seborrhoea.The compounds of formula I are particularly valuable for the treatment of acne and seborrhoea.
Forbindelserne med formlen I administreres fortrinsvis topisk på den angrebne hud.Preferably, the compounds of formula I are topically administered to the affected skin.
Forbindelserne med formlen I har den fordel, at de giver effektiv lindring ved behandlingen af androgenafhængige hudlidelser, samtidig med at de tilsyneladende ikke har skadelige hormonale bivirkninger.The compounds of formula I have the advantage of providing effective relief in the treatment of androgen-dependent skin disorders, while apparently not having harmful hormonal side effects.
Det er klart, at ét eller flere af de antibakterielle midler, som almindeligvis anvendes ved behandlingen af acne og seborrhoea-infek-tioner, kan inkorporeres i de omhandlede præparater, når disse præparater skal anvendes til en sådan behandling.It is to be understood that one or more of the antibacterial agents commonly used in the treatment of acne and seborrhoea infections may be incorporated into the present compositions when these preparations are to be used for such treatment.
Fremgangsmåden ifølge opfindelsen til fremstilling af forbindelserne med formlen I og fremstillingen af mellemprodukter deraf til anvendelse dertil samt farmakologiske forsøg illustreres nærmere i det følgende:The process of the invention for the preparation of the compounds of formula I and the preparation of their intermediates for use therewith as well as pharmacological tests are further illustrated below:
Eksempel 1.Example 1.
143757 12143757 12
OHOH
Androstan-5-en-3,3-ethylendioxy-173_ol fremstilles ud fra androst--4-en-173~ol-3-on og fås i form af fine hvide nåle med smeltepunkt 185 - 186°C (af methanol/vand) under anvendelse af den af J.A. Campbell, J.C. Babcock og J.A. Hogg i J. Am. Chem. Soc., 1958, 80, 4717 - 4721 angivne metode.Androstan-5-ene-3,3-ethylenedioxy-173-ol is prepared from androst-4-ene-173 ~ ol-3-one and is obtained in the form of fine white needles, melting point 185 - 186 ° C (of methanol / water ) using that of YES Campbell, J.C. Babcock and J.A. Hogg in J. Am. Chem. Soc., 1958, 80, 4717 - 4721 disclosed method.
Eksempel 2.Example 2.
OISLAND
20 g sølvcarbonat på kiselgur tørres ved azeotrop afdestillation af eventuelt tilstedeværende fugtighed ved hjælp af benzen. Oxidationsmidlet suspenderes i 200 ml tørt benzen, og der tilsættes 1 g androst-5-en-3,3-ethylendioxy-173”Ol i 50 ml benzen, og blandingen koges under tilbagesvaling i 4 timer. Der opnås fuldstændig oxidation. Reaktionsblandingen filtreres, og filtratet inddampes, hvorved der fås 0,95 g androst-5-en-3,3-ethylendioxy-17-on i form af fine hvide nåle, som efter krystallisation af methanol smelter ved 189 - 190°C.20 g of silver carbonate on diatomaceous earth is dried by azeotropic distillation of any moisture present by means of benzene. The oxidizing agent is suspended in 200 ml of dry benzene and 1 g of androst-5-ene-3,3-ethylenedioxy-173 ° Ol is added to 50 ml of benzene and the mixture is refluxed for 4 hours. Complete oxidation is obtained. The reaction mixture is filtered and the filtrate is evaporated to give 0.95 g of androst-5-ene-3,3-ethylenedioxy-17-one in the form of fine white needles which after crystallization of methanol melt at 189 - 190 ° C.
13 14375713 143757
Der kan også fås fuldstændig oxidation ved anvendelse af chromtrio-xid og pyridin i raethylenchlorid.Complete oxidation can also be obtained using chromium trioxide and pyridine in ethylene chloride.
Eksempel 3.Example 3
0 'CH3 0^ 2,92 g androst-5-en-3,3-ethylendioxy-17-on opløses i 60 ml tørt tetrahydrofuran. 2,92 g natriumhydrid tilsættes efterfulgt af 5 ml methyliodid, og reaktionsblandingen koges under tilbagesvaling i 4 timer. Tetrahydrofuranet afdampes under reduceret tryk, og remanensen fordeles mellem ethylacetat og vand. Ethylacetatfasen vaskes atter med vand, tørres over vandfrit magnesiumsulfat og inddampes til tørhed, hvorved der fås 3,21 g fast stof. Dette faste stof om-krystalliseres af methanol/vand, hvorved der fås 2,4 g androst-5--en-3,3-ethylendioxy-16,16-dimethyl-17-on i form af farveløse krystaller med smeltepunkt 138 - 142°C.2.92 g of androst-5-ene-3,3-ethylenedioxy-17-one is dissolved in 60 ml of dry tetrahydrofuran. 2.92 g of sodium hydride is added followed by 5 ml of methyl iodide and the reaction mixture is refluxed for 4 hours. The tetrahydrofuran is evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The ethyl acetate phase is washed again with water, dried over anhydrous magnesium sulfate and evaporated to dryness to give 3.21 g of solid. This solid is recrystallized from methanol / water to give 2.4 g of androst-5-en-3,3-ethylenedioxy-16,16-dimethyl-17-one in the form of colorless crystals, mp 138 - 142 ° C.
På lignende måde fremstilles de nedenfor anføtte forbindelser:Similarly, the following compounds are prepared:
Eksempel 3a.Example 3a.
Androst-5-en-3,3-ethylendioxy-16,16-diallyl-17-on, smeltepunkt 100 - 101°C (af methanol).Androst-5-ene-3,3-ethylenedioxy-16,16-diallyl-17-one, m.p. 100-101 ° C (of methanol).
Eksempel 3b.Example 3b.
Androst-5-en-3,3-ethylendioxy-16,16-dibenzyl-17-on, i form af et hvidt skum (infrarød carbonylabsorption ved 1725 cm ^).Androst-5-ene-3,3-ethylenedioxy-16,16-dibenzyl-17-one, in the form of a white foam (infrared carbonyl absorption at 1725 cm 2).
Eksempel 3c.Example 3c.
143757 14143757 14
Androst-5-en-3,3-ethylendioxy-16,16-di-n-butyl-17-on, smeltepunkt 165 - 167°C (af methanol).Androst-5-ene-3,3-ethylenedioxy-16,16-di-n-butyl-17-one, mp 165 - 167 ° C (of methanol).
Eksempel 3d.Example 3d.
Androst-5-en-3,3-ethylendioxy-16,16-diethyl-17-on, smeltepunkt 146 -148°C (af methanol).Androst-5-ene-3,3-ethylenedioxy-16,16-diethyl-17-one, mp 146 -148 ° C (of methanol).
Eksempel 4.Example 4
OHOH
'CH3 1,5 g androst-5-en-3-ethylendioxy-16,16-dimethyl-17-on opløses i 100 ml tørt ether, og der tilsættes 0,1 g lithiumaluminiumhydrid. Reaktionsblandingen omrøres ved stuetemperatur i 30 minutter, hvorefter den overskydende mængde hydrid sønderdeles ved tilsætning af et overskud af ethylacetat. Blandingen rystes derpå med en opløsning af kalium-natriumtartrat, og den organiske fase fraskilles og vaskes med vand, før den tørres over vandfrit magnesiumsulfat. Ved filtrering og inddampning af filtratet til tørhed fås 1,47 g androst-5-en-3,3--ethylendioxy-16,16-dimethyl-173-ol i form af et hvidt pulver, som efter krystallisation af ethylacetat smelter ved 178 - 179°C.CH3 1.5 g of androst-5-ene-3-ethylenedioxy-16,16-dimethyl-17-one is dissolved in 100 ml of dry ether and 0.1 g of lithium aluminum hydride is added. The reaction mixture is stirred at room temperature for 30 minutes, after which the excess amount of hydride is decomposed by adding an excess of ethyl acetate. The mixture is then shaken with a solution of potassium sodium tartrate and the organic phase is separated and washed with water before being dried over anhydrous magnesium sulfate. Filtration and evaporation of the filtrate to dryness afforded 1.47 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-173-ol in the form of a white powder which after crystallization of ethyl acetate melts at 178 - 179 ° C.
På lignende måde fremstilles de nedenfor anførte forbindelser:Similarly, the compounds listed below are prepared:
Eksempel 4a.Example 4a.
Androst-5-en-3,3-ethylendioxy-16,16-diallyl-178-ol, smeltepunkt 149 -151°C.Androst-5-ene-3,3-ethylenedioxy-16,16-diallyl-178-ol, m.p. 149 -151 ° C.
Eksempel 5.Example 5
143757 15 θΗ 1 g androst-5-en-3,3-ethylendioxy-16,16-dimethyl-17i3-ol opløses i 30 ml methanol, og der tilsættes 5 ml 2,5N saltsyreopløsning. Blandingen koges under tilbagesvaling i 1 time for at opnå fuldstændig hydrolyse af ketalen. Reaktionsblandingen optages i et overskud af ethylacetat og vaskes med vand til neutral reaktion. Den organiske fase tørres over magnesiumsulfat og filtreres, og filtratet inddampes til tørhed, hvorved der fås 0,88 g af et hvidt fast stof. Ved omkrystallisation af petroleumsether (kogeinterval 60 -80°C)/ethylacetat fås 0,76 g androst-4-en-16,16-dimethyl-17|3-ol--3-on i form af hvide nåle med smeltepunkt 170 - 172°C.Dissolve 1 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-17i3-ol in 30 ml of methanol and add 5 ml of 2.5N hydrochloric acid solution. The mixture is refluxed for 1 hour to achieve complete hydrolysis of the ketal. The reaction mixture is taken up in excess ethyl acetate and washed with water for neutral reaction. The organic phase is dried over magnesium sulfate and filtered, and the filtrate is evaporated to dryness to give 0.88 g of a white solid. Recrystallization of petroleum ether (boiling range 60 -80 ° C) / ethyl acetate gives 0.76 g of androst-4-ene-16,16-dimethyl-17 | 3-ol-3-one in the form of white needles, melting point 170 - 172 ° C.
På lignende måde fremstilles følgende forbindelse:Similarly, the following compound is prepared:
Eksempel 5a.Example 5a.
Androst-4-en-16,16-diallyl-17|3-ol-3-on, som er en tyk olie med infrarød carbonylabsorption ved 1680 cm”1.Androst-4-ene-16,16-diallyl-17 | 3-ol-3-one, which is a thick oil with infrared carbonyl absorption at 1680 cm ”1.
Eksempel 6.Example 6
OISLAND
ch3 16 1*3?” 0,25 g androst-5-en-3,3-ethylendioxy-16,16-dimethyl-17-on opløses i 7,5 ml methanol, og der tilsættes 1,5 ml 2,5N saltsyreopløsning. Opløsningen koges under tilbagesvaling i 30 minutter, og efter afkøling tilsættes et overskud af ethylacetat. Den organiske fase vaskes med vand til neutral reaktion, tørres over vandfrit magnesiumsulfat og inddampes til tørhed, hvorved der fås 0,2 g af et hvidt fast stof, som omkrystalliseres af petroleumsether (kogeinterval 60 - 80°C), hvorved der fås 0,16 g androst-4-en-16,16-dimethyl--3,17-dion i form af hvide nåle med smeltepunkt 164 - 165°C.ch3 16 1 * 3? " Dissolve 0.25 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-17-one in 7.5 ml of methanol and add 1.5 ml of 2.5N hydrochloric acid solution. The solution is refluxed for 30 minutes and, after cooling, an excess of ethyl acetate is added. The organic phase is washed with water for neutral reaction, dried over anhydrous magnesium sulfate and evaporated to dryness to give 0.2 g of a white solid which is recrystallized from petroleum ether (boiling range 60 - 80 ° C) to give 0 16 g of androst-4-ene-16,16-dimethyl-3,17-dione in the form of white needles, mp 164 - 165 ° C.
På lignende måde fremstilles de nedenfor anførte forbindelser:Similarly, the compounds listed below are prepared:
Eksempel 6a.Example 6a.
Androst-4-en-16,16-diallyl-3,17-dion, smeltepunkt 118 - 120°C (af petroleumsether med kogeinterval 60 - 80°C).Androst-4-ene-16,16-diallyl-3,17-dione, m.p. 118-120 ° C (of petroleum ether with boiling range 60 - 80 ° C).
Eksempel 6b.Example 6b.
Androst-4-en-16,16-dibenzyl-3,17-dion, smeltepunkt 150 - 152°C (af petroleumsether med kogeinterval 60 - 80°C).Androst-4-ene-16,16-dibenzyl-3,17-dione, m.p. 150 - 152 ° C (of petroleum ether with boiling range 60 - 80 ° C).
Eksempel 6c.Example 6c.
Androst-4-en-16,16-di-n-butyl-3,17-dion, i form af en tyk olie med infrarøde carbonylabsorptioner ved 1680 og 1720 cmAndrost-4-ene-16,16-di-n-butyl-3,17-dione, in the form of a thick oil with infrared carbonyl absorptions at 1680 and 1720 cm
Eksempel 6d.Example 6d.
Androst-4-en-16,16-diethyl-3,17-dion, i form af en halvkrystalliseret olie med infrarøde carbonylabsorptioner ved 1680 og 1720 cm 17 143767Androst-4-ene-16,16-diethyl-3,17-dione, in the form of a semi-crystallized oil with infrared carbonyl absorptions at 1680 and 1720 cm 17
EkSempel 7· OCOCHj o' 0,158 g androst-4-en-16,16*-dimethyl-17|3-ol-3-on opløses i 4 ml tørt benzen, og der tilsættes 0,14 g tørt pyridin og 0,12 g ace-tylchlorid. Blandingen koges under tilbagesvaling i 30 minutter, afkøles og hældes ud i et overskud af ethylacetat. Ethylacetatopløsningen vaskes med fortyndet saltsyre og derefter med vand, før den tørres over vandfrit magnesiumsulfat. Ved filtrering og inddampning af filtratet til tørhed fås 0,156 g af et fast stof, som omkrystal-liseres af petroleumsether (kogeinterval 60 - 80°C), hvorved der fås 0,100 g androst-4-en-16,16-dimethyl-17|3-ol-3-on-acetat i form af hvide nålé med smeltepunkt 153 - 155°C.Example 7 · OCOCH 2 O 0.158 g of androst-4-ene-16,16 * -dimethyl-17 | 3-ol-3-one is dissolved in 4 ml of dry benzene and 0.14 g of dry pyridine and 0.12 are added. g of acetyl chloride. The mixture is refluxed for 30 minutes, cooled and poured into an excess of ethyl acetate. The ethyl acetate solution is washed with dilute hydrochloric acid and then with water before being dried over anhydrous magnesium sulfate. Filtration and evaporation of the filtrate to dryness afforded 0.156 g of a solid which was recrystallized from petroleum ether (boiling range 60 - 80 ° C) to give 0.100 g of androst-4-ene-16,16-dimethyl-17 | 3-ol-3-one acetate in the form of white needles, m.p. 153 - 155 ° C.
På lignende måde fremstilles følgende forbindelse:Similarly, the following compound is prepared:
Eksempel 7a.Example 7a.
Androst-4-en-16,16-dimethyl-17f3-ol-3-on-hexanoat, smeltepunkt 105 -107°C (af methanol).Androst-4-ene-16,16-dimethyl-17β-ol-3-one-hexanoate, mp 105 -107 ° C (of methanol).
Eksempel 8.Example 8.
^,'CH3 0,5 g androst-5-en-3,3-ethylendioxy-16,16-dimethyl-17-on opløses i 18 143757 tørt ether og holdes under nitrogenatmosfære. Et stort overskud af methyllithium (20 ml af en 1,75M opløsning i hexan) tilsættes i løbet af 10 minutter. Der dannes øjeblikkelig et bundfald. Blandingen omrøres i 2 timer ved stuetemperatur, før den overskydende mængde methyllithium sønderdeles ved forsigtig tilsætning af vand. Produktet ekstraheres med ethylacetat, og den organiske fase vaskes med vand, tørres over vandfrit magnesiumsulfat og inddampes til tørhed, hvorved der fås 0,51 g af et hvidt fast stof. Dette faste stof omkrystalliseres af petroleumsether (kogeinterval 60 - 80°C), hvorved der fås 0,40 g androst-5-en-3,3-ethylendioxy-16,16,17a-trime-thyl-17p-ol i form af hvide krystaller med smeltepunkt 170 - 171°C.CH3 0.5 g of androst-5-ene-3,3-ethylenedioxy-16,16-dimethyl-17-one is dissolved in dry ether and kept under a nitrogen atmosphere. A large excess of methyl lithium (20 ml of a 1.75M solution in hexane) is added over 10 minutes. A precipitate is formed immediately. The mixture is stirred for 2 hours at room temperature before the excess amount of methyl lithium is decomposed by gentle addition of water. The product is extracted with ethyl acetate and the organic phase is washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness to give 0.51 g of a white solid. This solid is recrystallized from petroleum ether (boiling range 60 - 80 ° C) to give 0.40 g of androst-5-ene-3,3-ethylenedioxy-16,16,17a-trimethyl-17β-ol in the form of white crystals, melting point 170 - 171 ° C.
Eksempel 9. OHExample 9. OH
I -3 x/ 'CH3 1,1 g androst-5-en-3,3-ethylendioxy-16,16,17a-trimethyl-173-ol opløses i 50 ml methanol, og der tilsættes 10 ml 2,5N saltsyreopløsning. Blandingen koges under tilbagesvaling i 15 minutter. Produktet ekstraheres med ethylacetat, og den organiske fase vaskes til neutral reaktion med vand. Efter tørring over vandfrit magnesiumsulfat og filtrering inddampes filtratet til tørhed, hvorved der fås 0,94 g af et råt fast stof. Dette faste stof omkrystalliseres af petroleumsether (kogeinterval· 60 - 80°C), hvorved der fås 0,54 g androst-4-en-16,16,17a-trimethyl-170-ol-3-on i form af hvide flåger med smeltepunkt 165 - 166°C.Dissolve 1.1 g of androst-5-ene-3,3-ethylenedioxy-16,16,17a-trimethyl-173-ol in 50 ml of methanol and add 10 ml of 2.5N hydrochloric acid solution. The mixture is refluxed for 15 minutes. The product is extracted with ethyl acetate and the organic phase is washed to neutral with water. After drying over anhydrous magnesium sulfate and filtration, the filtrate is evaporated to dryness to give 0.94 g of a crude solid. This solid is recrystallized from petroleum ether (boiling range · 60 - 80 ° C) to give 0.54 g of androst-4-ene-16,16,17a-trimethyl-170-ol-3-one in the form of white flakes with mp 165 - 166 ° C.
19 1437 5719 1437 57
Farmakologisk beskrivelse.Pharmacological description.
1. Androgenisk/anabolisk forsøg og anti-androgenisk forsøg.1. Androgenic / Anabolic Test and Anti-Androgenic Test.
Den anvendte metode var dybest set den af Hershberger et al. i Proc.The method used was basically that of Hershberger et al. in Proc.
Soc. Exp. Biol. Med., 8_3, 175, (1953) beskrevne metode med mindre modifikationer.Soc. Exp. Biol. Med., 8_3, 175, (1953), with minor modifications.
Ikke-kønsmodne hanrotter med en vægt på 50 - 60 g blev kastreret under nembutal-anæstesi.- Dyrene fik medikament i 4 dage begyndende på 5. dagen efter kastreringen. Dyrenes kropsvægt blev målt i den periode, hvor de fik medikament. Den 10. dag efter kastreringen blev dyrene dræbt, og vægten af sædblæren, den ventrale prostata, levator ani-musklen og thymus blev målt, ligesom hele kropsvægten blev målt.Non-sexually mature male rats weighing 50 - 60 g were castrated under nembutal anesthesia.- The animals were given medication for 4 days beginning on the 5th day after castration. The body weight of the animals was measured during the period of drug administration. On the 10th day after castration, the animals were killed and the weight of the sperm bladder, ventral prostate, levator ani muscle and thymus was measured, as was the whole body weight.
Disse data blev derefter sammenlignet med data fra kontroldyr. Forbindelserne blev formuleret som opløsninger eller suspensioner i arachisolie, og de blev indgivet subcutant.These data were then compared with data from control animals. The compounds were formulated as solutions or suspensions in arachis oil and administered subcutaneously.
Androgenisk/anabolisk forsøg.Androgenic / anabolic experiment.
Til dette forsøg blev forbindelserne givet i en dosis på 50 mg/kg subcutant, og resultaterne blev sammenlignet med kontroldyr, som subcutant fik testosteron i en dosis på 1 mg/kg. Begge rækker data blev sammenlignet med data fra kastrerede kontroldyr, som ikke fik medikament.For this experiment, the compounds were given at a dose of 50 mg / kg subcutaneously, and the results were compared with control animals given subcutaneously with testosterone at a dose of 1 mg / kg. Both rows of data were compared with data from castrated control animals that did not receive medication.
Anti-androgenisk forsøg.Anti-androgenic trial.
Til dette forsøg blev forbindelserne administreret i en dosis på 50 mg/kg subcutant jævnsides med testosteron i en dosis på 1 mg/kg subcutant for at bestemme inhiberingsgraden i sammenligning med kontroldyr, som fik testosteron i en dosis på 1 mg/kg subcutant. Begge rækker data blev sammenlignet med data fra kastrerede kontroldyr, som ikke fik medikament. Resultaterne er anført i nedenstående tabel I.For this experiment, the compounds were administered at a dose of 50 mg / kg subcutaneously equivalently with testosterone at a dose of 1 mg / kg subcutaneously to determine the degree of inhibition compared to control animals receiving testosterone at a dose of 1 mg / kg subcutaneously. Both rows of data were compared with data from castrated control animals that did not receive medication. The results are given in Table I below.
143757 20143757 20
Tabel ITable I
Forbindelse Androgenisk respons, Anti-androgeniske data, fremstillet styrke i procent i procent inhibering ifølge ek- forhold til testoste- sempel nr. ron sædblære prostata sædblære prostata 5 0,15 0,36 12,1 14,4 6. - - 17,8 35,0 9 --6,5 19,7 cyproteron- acetat 20 mg/kg - - 54,0 56,5 2. Androgen-fortrængningsforsøg.Compound Androgenic Response, Anti-Androgenic Data, Percent Percent Inhibition Prepared Strength According to Test Specimen No. Ron Sperm Prostate Sperm Prostate 5 0.15 0.36 12.1 14.4 6. - 17, 8 35.0 9 - 6.5 19.7 cyproterone acetate 20 mg / kg - - 54.0 56.5 2. Androgen displacement test.
33
Forbindelsernes evne til at fortrænge [ H]-5a-dihydrotestosteron fra cytosol-androgenbindende proteiner med høj affinitet, der var isoleret fra rotteprostata og -epididymis, blev undersøgt in vitro under anvendelse af den af W.I.P. Mainwaring, F.R. Mangan, P.A. Feherty og M. Freifeld i Molecular and Cellular Endocrinology, 1974, 1, 113 -128 angivne metode.The ability of the compounds to displace [H] -5α-dihydrotestosterone from high affinity cytosol androgen binding proteins isolated from rat prostate and epididymis was investigated in vitro using that of W.I.P. Mainwaring, F.R. Manganese, P.A. Feherty and M. Freifeld in Molecular and Cellular Endocrinology, 1974, 1, 113 -128.
0,1 ml's prøver af cytosol inkuberedes natten over i nærværelse af -in i 5 x 10 M [ H]-5a-dihydrotestosteron (47 Ci/millimol, The Radiochemical Centre, Amersham), enten alene eller sammen med den forbindelse, som skulle afprøves, i en koncentration på 5 x 10 -7 -7 5 x 10 og 2,5 x 10 M. Forbindelsernes evne til at fortrænge 3 [ H]-5a-DHT fra bindingsproteinerne kunne ses som en formindskelse af antallet af impulser, der var bundet i den overstående væske. Resultaterne er anført i nedenstående tabel II.0.1 ml of cytosol samples were incubated overnight in the presence of -in in 5 x 10 M [H] -5α-dihydrotestosterone (47 Ci / millimole, The Radiochemical Center, Amersham), either alone or in conjunction with the compound to be was tested, at a concentration of 5 x 10 -7 -5 x 10 and 2.5 x 10 M. The ability of the compounds to displace 3 [H] -5a-DHT from the binding proteins could be seen as a decrease in the number of pulses that was bound in the supernatant fluid. The results are given in Table II below.
Tabel IITable II
33
Procent fortrængning af [ H]-5a-dihydrotestosteron fra androgen- bindende proteiner 3 -10Percent displacement of [H] -5α-dihydrotestosterone from androgen-binding proteins 3-10
[ H]-5a-DHT koncentration 5 x 10 M[H] -5a-DHT concentration 5 x 10 M
21 14375721 143757
Forbindelse 2,5 x 10 5,0 x 10 5,0 x 1Q-Sl prosta- epi- pro- epi- pro- epi- ta didy- stata didy- stata didy- mis mis mis 5 36 0 50 4 81 64 6 16 0 27 0 80 48 9 32 0 46 4 88 81 DHT 86 72 86 75 90 83 3. Inhibering af testosteron-5a-reductase.Compound 2.5 x 10 5.0 x 10 5.0 x 1Q-Sl prosta-epi-pro-epi-pro-epi-didy-state didy-state didy-mis mis 5 36 0 50 4 81 64 6 16 0 27 0 80 48 9 32 0 46 4 88 81 DHT 86 72 86 75 90 83 3. Inhibition of testosterone 5α reductase.
44
Bestemmelsen af dette enzyms aktivitet (/^ -3-ketosteroid-5a-reduc-tase blev udført i det væsentlige som beskrevet af W.I.P. Mainwaring og F.R. Mangan, J. Endocrinology, 1973, 5JJ, 121 - 139.The determination of the activity of this enzyme (β-ketosteroid-5α-reductase) was performed essentially as described by W.I.P. Mainwaring and F.R. Mangan, J. Endocrinology, 1973, 5JJ, 121-139.
Den procentvise omdannelse af testosteron (T) til 5a-dihydrotesto-steron (DHT) i dette system lå i området mellem 15 og 30%, afhængig af de forskellige formuleringer. Inhibering af omdannelsen blev konstateret ved en reduktion i antallet af impulser pr. minut, der var knyttet til DHT.The percentage conversion of testosterone (T) to 5α-dihydrotestosterone (DHT) in this system ranged from 15 to 30%, depending on the different formulations. Inhibition of the conversion was found by a reduction in the number of pulses per second. minute associated with DHT.
% omdannelse = -CP11), D.HT- x ioo%% conversion = -CP11), D.HT- x10%
cpm T + cpm DHTcpm T + cpm DHT
% omdannelse uden forbindelse - % omdannelse med fc?r-% inhibering = ---ffXa&Slae % omdannelse uden forbindelse (cpm = antal impulser pr. minut)% conversion without connection -% conversion with fc? r-% inhibition = --- ffXa & Slae% conversion without connection (cpm = number of pulses per minute)
Resultaterne fremgår af nedenstående tabel III og tabel IV.The results are shown in Table III and Table IV below.
Tabel IIITable III
143757 22143757 22
Forbindelse % inhibering af 5a-reductase -5Compound% inhibition of 5α-reductase -5
forbindelse i 1 x 10 Mcompound in 1 x 10 M
5 30,0 (3) 6 23,1 (2) 9 27,3 (2)30.0 (3) 6 23.1 (2) 9 27.3 (2)
Tabel IVTable IV
Forbindelse % inhibering af 5a-reductase -4Compound% inhibition of 5α-reductase -4
koncentration 1 x 10 Mconcentration 1 x 10 M
androst-4-en-16,16-dime- thyl-170-ol-3-on 58,0 (7) androst-4-en-16,16-dime- thyl-3,17-dion 56,8 (3) androst-4-en-16,16,17a-tri- methyl-17p-ol-3-on 48,9 (3) andro s t-4-en-16,16-dimethyl- 17β-ο1-3-οη-17-me- thylether 52,7 (3) androst-4-en-16,16-dime-thyl-173-ol-3-on-17-ben- zylether 41,2 (3) androst-4-en-16,16-dime-thyl-173-ol-3-on-17-hexa- noat 65,4 (3) androst-4-en-16,16-diethyl- 173-ol-3-on 44,7 (3) 23 143757androst-4-ene-16,16-dimethyl-170-ol-3-one 58.0 (7) androst-4-ene-16,16-dimethyl-3,17-dione 56.8 ( 3) androst-4-ene-16,16,17a-trimethyl-17β-ol-3-one 48,9 (3) andro-t-4-ene-16,16-dimethyl-17β-α1-3 -οη-17-methyl ether 52,7 (3) androst-4-ene-16,16-dimethyl-173-ol-3-one-17-benzyl ether 41,2 (3) androst-4 -en-16,16-dimethyl-173-ol-3-one-17-hexanoate 65,4 (3) androst-4-ene-16,16-diethyl-173-ol-3-one 44 , 7 (3) 23 143757
Tabel IV fortsat androst-4-en-16,16-diethyl- 3.17- dion 28,1 (3) androst-4-en-16,16-diallyl- 17β-ο1-3-οη 27,6 (3) androst-4-en-16,16-diallyl- 3.17- dion 15,0 (3) androst-4-en-16,16-dibenzyl- 3.17- dion 26,4 (3) ( ) tallene i paranteserne anqiver antallet af forsøg.Table IV continued androst-4-en-16,16-diethyl-3.17-dione 28.1 (3) androst-4-en-16,16-diallyl-17β-ο1-3-οη 27,6 (3) androst -4-en-16,16-diallyl-3.17-dione 15.0 (3) androst-4-en-16,16-dibenzyl-3.17-dione 26.4 (3) () The numbers in the parentheses indicate the number of attempts .
4. Forbindelsernes indvirkning på den testosteron-inducerede vækst af et organ på siden af en hamster.4. The effect of the compounds on the testosterone-induced growth of an organ on the side of a hamster.
Hos kastrerede hanhamstere eller uopererede hunhamstere kan flankeorganet (en talgkirtel) stimuleres til vækst ved topisk applikation af testosteron. Testosteron omdannes i denne kirtel til 5a-dihydrotestosteron (S. Takayashu og K. Adachi, Endocrinology, 1972, 90 73 - 80), som nu antages at være den aktive androgen i de fleste androgenafhængige receptororganer. Forbindelsernes evne til at inhibere denne stimulering blev undersøgt i det væsentlige under anvendelse af den af W. Voigt og S.L. Hsia, Endocrinology, 1973, 92, 1216 - 1222,angivne metode.In castrated male hamsters or unoperated female hamsters, the flank organ (a sebaceous gland) can be stimulated for growth by topical application of testosterone. Testosterone is converted in this gland to 5α-dihydrotestosterone (S. Takayashu and K. Adachi, Endocrinology, 1972, 90 73-80), which is now believed to be the active androgen in most androgen-dependent receptor organs. The ability of the compounds to inhibit this stimulation was examined essentially using that of W. Voigt and S.L. Hsia, Endocrinology, 1973, 92, 1216 - 1222, stated method.
Voksne hanhamstere blev kastreret af scrotal vej . 1 uge senere blev de opdelt i grupper på hver 4 dyr og behandlet på følgende måde: en gruppe blev ikke behandlet. En anden gruppe fik kun acetone på flankeorganet på venstre side af dyret og acetone indeholdende 4^ug testosteron pr. dag på højre sides flankéorgan. Andre grupper fik acetone alene på den venstre sides flankeorgan og acetone indeholdende 4yUg testosteron plus 4 00^,ug forbindelse pr. dag på højre sides flankeorgan.Adult male hamsters were castrated by the scrotal pathway. 1 week later, they were divided into groups of 4 animals and treated as follows: one group was not treated. Another group received only acetone on the flank of the animal on the left side and acetone containing 4 µg of testosterone per day. day on the right flank organ. Other groups received acetone alone on the left side flank and acetone containing 4 µg testosterone plus 4 µg / µg compound per day. day on the right flank.
Efter 3 ugers behandling blev dyrene dræbt, og organerne blev målt og placeret i fixativ til histologisk undersøgelse. >After 3 weeks of treatment, the animals were killed and the organs measured and placed in fixative for histological examination. >
Claims (4)
Priority Applications (1)
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DK102480A DK102480A (en) | 1975-03-21 | 1980-03-10 | INTERMEDIATES FOR THE PREPARATION OF 16,16 DIALKYL STEROIDS |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB11819/75A GB1538227A (en) | 1975-03-21 | 1975-03-21 | 16,16-disubstituted steroids of the androstene series |
GB1181975 | 1975-03-21 |
Publications (3)
Publication Number | Publication Date |
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DK123476A DK123476A (en) | 1976-09-22 |
DK143757B true DK143757B (en) | 1981-10-05 |
DK143757C DK143757C (en) | 1982-03-22 |
Family
ID=9993275
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DK123476A DK143757C (en) | 1975-03-21 | 1976-03-19 | ANALOGY PROCEDURE FOR THE PREPARATION OF 16,16-DISUBSTITUTED 3-OXOANDROSTEN |
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JP (2) | JPS51118756A (en) |
AT (1) | AT357700B (en) |
AU (1) | AU501246B2 (en) |
BE (1) | BE839751A (en) |
CA (1) | CA1069498A (en) |
CH (2) | CH621560A5 (en) |
DE (1) | DE2610497C2 (en) |
DK (1) | DK143757C (en) |
FR (2) | FR2304345A1 (en) |
GB (1) | GB1538227A (en) |
IE (1) | IE42308B1 (en) |
IL (2) | IL49132A (en) |
NL (1) | NL184111C (en) |
SE (2) | SE7603410L (en) |
ZA (1) | ZA761324B (en) |
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GB1602960A (en) * | 1977-05-25 | 1981-11-18 | Beecham Group Ltd | Process for preparing 16,16-disubstituted steroids of the androstene series |
DE2943778A1 (en) * | 1979-10-26 | 1981-05-07 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | 17-Alpha:alkyl-4,15-androstadiene-3-one derivs. - topical antiandrogens effective against acne, seborrhoea, alopecia and hirsutism |
DE3514272A1 (en) * | 1985-04-17 | 1986-10-23 | Schering AG, 1000 Berlin und 4709 Bergkamen | DERMATICA |
JPS63300153A (en) * | 1987-05-29 | 1988-12-07 | 日本碍子株式会社 | Building enamel panel |
GB9021546D0 (en) * | 1990-10-04 | 1990-11-21 | Beecham Group Plc | Novel composition |
WO1992007586A1 (en) * | 1990-10-31 | 1992-05-14 | Beecham Group Plc | Topical composition with retinoid penetration enhancer |
GB9205194D0 (en) * | 1992-03-10 | 1992-04-22 | Smithkline Beecham Plc | Novel composition |
JPWO2003051903A1 (en) * | 2001-12-19 | 2005-04-28 | 中外製薬株式会社 | Androstane derivatives having substituents at the 7- and 17-positions |
CN108558975B (en) * | 2018-04-26 | 2021-03-02 | 昆明理工大学 | 12 beta-hydroxy-androstane 4, 14-diene-16-ketone compound and application thereof |
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US3853926A (en) * | 1973-05-29 | 1974-12-10 | Searle & Co | 17{62 -hydroxy-16,16-dimethylester-4-en-3-one |
-
1975
- 1975-03-21 GB GB11819/75A patent/GB1538227A/en not_active Expired
-
1976
- 1976-03-01 IE IE412/76A patent/IE42308B1/en unknown
- 1976-03-02 IL IL49132A patent/IL49132A/en unknown
- 1976-03-12 DE DE2610497A patent/DE2610497C2/en not_active Expired
- 1976-03-15 FR FR7607328A patent/FR2304345A1/en active Granted
- 1976-03-16 AT AT191376A patent/AT357700B/en not_active IP Right Cessation
- 1976-03-18 SE SE7603410A patent/SE7603410L/en not_active Application Discontinuation
- 1976-03-18 BE BE165323A patent/BE839751A/en not_active IP Right Cessation
- 1976-03-19 JP JP51030741A patent/JPS51118756A/en active Granted
- 1976-03-19 CA CA248,260A patent/CA1069498A/en not_active Expired
- 1976-03-19 DK DK123476A patent/DK143757C/en active
- 1976-03-19 NL NLAANVRAGE7602949,A patent/NL184111C/en not_active IP Right Cessation
- 1976-03-19 AU AU12207/76A patent/AU501246B2/en not_active Expired
- 1976-03-22 CH CH354376A patent/CH621560A5/en not_active IP Right Cessation
- 1976-04-04 ZA ZA761324A patent/ZA761324B/en unknown
-
1979
- 1979-03-09 CH CH228479A patent/CH631996A5/en not_active IP Right Cessation
- 1979-03-13 SE SE7902256A patent/SE7902256L/en not_active Application Discontinuation
- 1979-10-19 IL IL58505A patent/IL58505A0/en unknown
-
1980
- 1980-02-26 FR FR8004184A patent/FR2445340A1/en active Granted
-
1985
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Also Published As
Publication number | Publication date |
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IL49132A0 (en) | 1976-05-31 |
FR2304345A1 (en) | 1976-10-15 |
DK143757C (en) | 1982-03-22 |
JPS6355488B2 (en) | 1988-11-02 |
CH621560A5 (en) | 1981-02-13 |
IL49132A (en) | 1980-05-30 |
JPS625920B2 (en) | 1987-02-07 |
AT357700B (en) | 1980-07-25 |
BE839751A (en) | 1976-09-20 |
ZA761324B (en) | 1977-02-23 |
NL184111C (en) | 1989-04-17 |
SE7603410L (en) | 1976-09-22 |
SE7902256L (en) | 1979-03-13 |
FR2304345B1 (en) | 1980-11-07 |
IE42308B1 (en) | 1980-07-16 |
IL58505A0 (en) | 1980-01-31 |
FR2445340B1 (en) | 1983-02-11 |
CH631996A5 (en) | 1982-09-15 |
DE2610497C2 (en) | 1986-10-16 |
DK123476A (en) | 1976-09-22 |
JPS51118756A (en) | 1976-10-18 |
NL7602949A (en) | 1976-09-23 |
JPS61178920A (en) | 1986-08-11 |
NL184111B (en) | 1988-11-16 |
GB1538227A (en) | 1979-01-10 |
AU1220776A (en) | 1977-09-22 |
AU501246B2 (en) | 1979-06-14 |
IE42308L (en) | 1976-09-21 |
CA1069498A (en) | 1980-01-08 |
ATA191376A (en) | 1979-12-15 |
FR2445340A1 (en) | 1980-07-25 |
DE2610497A1 (en) | 1976-10-07 |
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