DE1916134A1 - 3,16beta, 17beta-OEstriol derivatives and processes for their preparation - Google Patents

Description

DR. ELISABETH JUNG, DR. VOLKER VOSSIUS. DIPL.-ING. GERHARD COLDEWEY PATENT LAWYERS 1 9 1 R 1 3 A

8 MONCHEN23 ■ S I E G ES STRASSE 28 ■ TELEPHONE 34 SO 67 ■ TELEGRAM ADDRESS: INVENT / M DNCH EN

TELEX 5 29 686

ι ß. MAR. eat;

U ₀ ZoS E 143 (ho / Vo / kä)

IBF-B-30

SGS-D-IO

SOGIETE GEISRALS DE 1113CHSPlCHES ET D ^j APPLICATIOHS SCIEKTIFIQUES

·· ΡΟΟΒΠΑΟ O.A. ■ Paris, France

"3jl6ß _p 27ß ~ Qstriolü $ rivafea usid process su their production"

Priority j 29 ο Kars 1968 "France, Hr ₀ 146 076

The invention relates to new 3pl6ß _i 17ß = estriol derivatives of the general formula I *. ·

(D

In which R is a Jiiedei? Er iilkylrestt, preferably the methyl or ethyl group ρ and Fr is a hydrogen atom or the aoyl radical of an aliphatic, cycloaliphatic or mixed aliphatic cycloaliphatic carboxylic acid with 2 to 18 carbon atoms, or both radicals R "suüamraen form an acetonide group ₀ The acetone oils have the general formula II 9098 8 6/16 57

SAD ORIGINAL

in which R has the above meaning * -.

The compounds of the invention include the 3-alkoxy-16-epiostriols and their 16β _? 17. i3 dieters, diesters and ketals, including the 3-methoxy and 3-lthoxy-16ß, 17ß-Ö8triol [16,17- ^ aCe tonids.

The invention relates to a .ferner, Ter-propelled en aur preparation of the compounds of the general formula I ₈ which is characterized in that t

a) Oestrone with I3op.?cpenyl acetate to the 3 _? 17-Piacetoxyöetra ~ l, 3 _f 5 ~ (Io) jl6-tetraen umsetaH-p

b) the product obtained is oxidized with lead tetramcetate in a mixture of acetic acid and acetic anhydride to give 3 _B 16ß-Diaeetöxyöstra-1,3,5 (10) = triene «17 = one,, w,

c) this compound "" reduced with potassium anhydride ssura 3 _f l6ß _e 17ß- "Trihydroxyöstra-1,3,5 (10Atrien,

d) the product obtained with a lower dialkyl sulfate

auia 3-alkoxy-X6 ~ epiestriol and this compound optionally with an aliphatic, cycloaliphatic or mixed aliphatic-cycloaliphatic carboxylic acid with 2 to 18 Esterified or optionally carbon atoms or their reactive derivative converted into acetonide with acetone «,

The Beie ^ ele - explain the invention »

909 8 86/1657

BATH

example 1

Manufacture of

A) Preparation of 3 , IT-Biacetox yö stya _r l _T 3 » _T !> (10), 16-tetraene 210 oil Ieopropenyl acetate with 30 β oestrone and then with 9 ml of a catalyst solution (10 ml isopropenyl acetate and 0.2 ml sulfuric acid) was added "the solution is boiled for 1 hour under reflux and _P anschlieseend be within 1 hour 60 ml of Löeungsiaittele abdeetilliex'tc the Reaktlonsgemiech is displaced yet times with 120 BLL isopropenyl acetate and 6 ml Katalyaatorlösung and the volume reduced by distillation to half

The solution is then or twice with 300 «400 ml ether, washed the Ktherextrakt with 200 al of saturated, ice-cold Hatriumbicarbonatlösung and then gewaschenο neutral with water, the ether solution is decanted, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at 25 ⁰ C for Irockene evaporated.

The residue is digested with 150 ml of methanol, filtered and washed with 50 ml of methanol, then dissolved in methylene chloride, evaporated to dryness and treated again with 100 ml of methanol. Yield 29 g (73 % of theory) from Fc 148 to 150 ^° C .; Λ * / £?. * 90 _f 9 ° _o

B) Preparation of 3,16ß-dlacetoxyöB tra-1,3 »5 (i p) -triene-r7-" On 29 g of the product from stage (A) ground in a solution of 580 ml of acetic acid and 29 ml of acetic anhydride dissolved The solution is mixed with 42 g of freshly prepared lead tetracetate moist with acetic acid. «The solution is stirred for 2 hours / then

909886/1657

BATH ORIGINAL

it »4 · - '·

allowed to stand after 18 hours at Hardly temperature anschlieeeerid at 45 ⁰ C under reduced pressure, concentrated, then taken up in 800 ml of benzene, washed twice with [200 ml of water and twice · with 250 ml 5 # hydrochloric Natriumbioarbonatlösung and anschlieesend washed neutral with water, The verecniedenen Waschfraktionell are extracted with 600 ml of benzene * The benzene extracts are combined tmd concentrated "is obtained 30 g of crude product from the F _e 148 bis'149 ⁰ Gj [d] ^ + 130 ° (ethanol) ₀

G) Preparation of 3rl6ßpl7ß ~ grihydror> .y (3s tra- »l _B 3 _< , 5 (10) -triene 30 [beta] of the product obtained in stage (B) dissolved in 500 ml of methanol and admixed with 30 g of coli borohydride the solution stirred for 18 hours toi room temperature gelasßen and then neutralized with "acetic acid and aur dryness evaporated the residue is taken up in 300 ml of water _P filtered, washed with Waseer and dried After UmkriBtallisation from methanol, filtering drying and treatment with 150 ml of acetone is obtained 14 g of product from P, 265 to 27O ⁰ C that the analysis preparation melts at 267 to 269 ⁰ Cj / X ^ ⁹ + ^as ° (ethanol) «

"W ₀ Ro Biggerstaff and T ₀ F = Gallagher ^ J .. Org ₀ Chemistry 22 (1957) _ρ page 1220, give a melting point of 265 to 289 ⁰ Go

I)) Production of ^ ~ Hethox7 ^ 16ß ₍ , 17ß ~ dihydroa: y43stra-l, 3 _> 5 (10) ~ trien

14 gdes product obtained in step (C) in 280 ml of methanol and 1 liter of 5 - ^ - dissolved strength Natriumhydroxydlösuhg and heated to 70 ⁰ C .. over 15 minutes 84 ml of dimethyl sulphate is added stirring tinter *. Tray 1-s-tündigejE stirring at 70 ⁰ C v / ei'tere 336 ml 5 ^ * - owned Hatriumhydroxydlösung and 84 ml Dimethi / l "sulphate within yen '" minutes access roads as:.? N, _e The solution is

9 09886/165 7

BAD ORiGiNAL

1 Stunde'bei 70 ° 0 is stirred Then the W allowed to cool solution »» filtered with water until neutral and dried "Naoh repeated Umkristalliaation from a mixture of benzene and hexane to obtain 10 g of the product of 9, 138 bia 142 ⁰ C ₀ The melting point of an analysis preparation is 141 to 142 ° Co. The mixed melting point with an authentic sample is not lowered

G E

O ₁₉ H ₂₆ O ₃ ; over ₀ : 75 * 46; 8th

? 75.29; 8th

The product is also tested together with an authentic sample by means of thin-tech chromatography on silica gel with benzene containing 8 φ methanol, and then with ethyl acetate (50 Jt) -cyclohexane (45 ^) - methanol (5 ^) as the mobile phase.

A sample is acetylated and identified again by determining the melting point and by means of thin-layer chromatography. The 3-methoxy-16β, 17β = -diacetoxyöstra-1,3 »5- (10) -triene has a melting point of 126 to 127 ° C _e

« 71 C. H about <> 71 , 46; 7 _# 82j gef, , 36: 7.96,

When using diethyl sulfate instead of dimethyl sulfate in Step (D) one obtains the 3-itthoxy-16-epiÖstriol from P. 171 bis

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BATH

Preparation of 3 ° "Metho; cy ~ -l6fi .17fl diacetO3cyögtra-" l.3 ■ 5 (10) trien ~ 1 g 3 "-methoxy-l6ß, 17-clihydroiyÖstra-l _{t 3?} 5 (10) -triene in 5 ml of anhydrous pyridine You · solution is 3 al ^{v /} offset friech distilled EssigBäureanhydrid and practice? Left at night. The solution is then poured into 50 ml of water ^; sen, rubbed and the precipitate left to crystallize. The crystals are washed with water, dried and recrystallized from ethanol. Yield 1.15 g of product from I ¹ . € 12 »° G (capillary tube)«

t 71, gefps 71, -:

Manufacture of 3 ~ methoxy-l6fl, 17fl-'di »undecanoy3 o3arö« ^< fcjrfc »

1 g of 3-methoxy-16ß, 17ß- * dihydroxyBsträ * l _f 3,5 (10) -triene is dissolved in 5 ml of anhydrous pyridine · 3 ml of undeoanoic acid chloride are added dropwise in a bubbler and then the solution is toei for 1 hour The reaction mixture is then poured into 50 ml of water and extracted with ether. The ether solution is washed with aqueous Hatriunt bicarbonate solution: and dried over sodium sulfate. After the ether has evaporated, the residue is absorbed in petroleum ether and taken up with methanol failed. After recrystallization of the product from a mixture of petroleum ether and methanol, a total of Ip5 g of Ϊ is obtained. 51 bio 52 ⁰ O (capillary tube).

· ■ ^, 909888/1657

/ BATH

t 76 «Mt C. 7 - H *
• 76 10.40; ber. 10.41. gef «

Case 4

Preparation of 3-Methox.y ~ 16ß _B 17ft-ai- (3'- cyclohexylpropionyl oxy) -gstra-1.5,5 (lQ) -triene

1 g of 3-methoxy-16ß _f 17ß-dihydrojLy, Uetre.-l _f 5 _t 5 (10) -triene is dissolved in 5 ml of anhydrous fyridine, treated with 3 g of 2 -cyclohexylpropionic acid chloride and left to stand overnight. The solution is then poured into 50 ml of water . gemäse Beiopiel 3 reclaimed The Hückatand of Ätheresrtrakte- is of benzene and acetone anschlieosend auo mlrristallisiert ^ ^ After twice recrystallizing from a C'eiiiuch of methanol and acetone, O _f 95 the product from P. 90 ⁰ G (capillary tube) ,,

HC ₃₇ Il ₅₄ O ₅ ; her .: 76.77; 9 _? 4O;

found: 77.0; 9 »43c

Example 5

Manufacture of 3-methoxy-l6ß , 17fl-di-pentanoy loxyöB-fcrcv-l "5 ₁ 5 ( 10 ) 7

1 g 3 ~ Ilethozy-l6 £ - _{f-17e'dihydroxyöstra li3-r} (10) '- trien is dissolved in anhydrous Pyridia and gemäas Example 4 2 g Pentaneäureohlorid added. After working up, a light oil is obtained that smelled of pentanoic acid. The product cannot crystallize

90988 6/16 5 7

BAD OBIGlNAU

ΖΓΛ f ^ J CV

l \ f "A mii" 1 6-

Dedication of 5

^ ΤΤΒ-τ-ΓΓ »»! ».»! '- ■ in ι ill ι nmii. *! iiw · ι in ir

4 B _{3-Methoxy-l6ß>} 17-dihydroxyöstr & -l, 3, £ '(l0} -triene be in a mixture of 200 ml of acetone and 300% vasserfreiem ml of petroleum "ether <Kp" 45 to 5O ⁰ C) dissolved after Zugabo of 1 g of p-ToluoXßulfonsäure is that mixture a "Stund®" boiled under reflux for ₉ wherein a water-petroleum ether-g-eaisch is trapped in a water separator for _«o Subsequently, the calculated amount of freshly fused and pulverized Efätriumacetat 30 minutes under stirring, neutralized Hie crystals are _f abzentrifu- yaws and the solution is evaporated aur dryness Hex residue is washed with water and umkristallisiertο from acetone 3.5 g of Auebeute IO 156 ° Cc

CH

C ₂₂ H ₅₀ O ₅ J calc .: 77 _f l6 ;. 8 _S 82;

It is known that the estrogens have a trophic effect on the epithelial tissue and the connective tissue and inhibit the secretion of the sebum glands. However, because of their unwanted hormonal side effects, such as bleeding in the irau and feminization in men _s they have not heretofore been used in medicine

It was surprisingly discovered that the new compounds of the invention in comparison to the "known drugs" have and at the same time considerably fewer hormonal side effects an increased affinity for the mucous membranes

and the skin have :, - ■

90988 6/16 5 7

o ~ 9 .-.

This "discovery is based on a series of plagues that resulted from the following Yergleieh requests "

Attempt a

In experiments with eleven estrogens, _P shows that 3-methyl oxy and the 3-etho: & y-16-e.piö3t: egg have by far the weakest estrogenic effect »furthermore, it is evident that the affinity for the skin in the 3-methyl ether derivative is twice as large as other. estrogen: aen _s -lie have no ether group in the 3 ~ position _β

The oestrogenic effect of the Tß-ÖBtratriol is 600 times as high ν / ie dia of I6 ~ epiestri oil-5 ~ aiethyl ether in eubcutaneous use.

■ Tersucli ^ G
Pauor of the OES &E'UF, bsini castrated Eattenv; eibchen In dieseiu- Tsrsiioh se IGTE to ₉ that the estrogens Y / irkirag of Q8tradiol - 5-Gensoe.ts at iatrainuslculäser application 300 ~ AIAL, and the estrogenic v / MPACT of estrone in subcutaneous use is 10 "to 30 times as high as that of 3" methoxy- = 16-QpiÖstriol8 in subcutaneous use. Application ο

J-MB the above experiments it can be seen that awischen ^ the compounds of the invention and other _t although very similar steroids ,, significant biological differences.

■ f-; a aftigi. oiöb. further that the steroids of the invention praktxüch lceino b.oriionalen side effect, exhibit s, is inversely

909886/16 57

BATH ORIGINAL

■ - ίο -

& UR dansack standing Ys-rsueiian ersichtläcib. _e that the compounds of the invention, a © affinity for the skin include, the oils of the other estrogenic uai more than twice überstsigtf and DASA "/ onnectivity significant VJIrkungen bsi tan & ier application gsgeii" V $ rä7icleniiig3a iinö. Srkraiikimgen des

have ice hsarboclens and connective tissue *

i d »2r skin" oeim "aging dog

P Known eats aicii the .alteruBg eggs flaut anrcJi yerwechsel der Epitüelsellsiii, and 3'wa :? through the generation sc-lisimingens see you siar! tea rose füliren teönnezio

An older chicken was treated daily for a month with a gsriagsn hsngs of a sage _s the 1? Ϊ́ 3 ~ Kethosy = 16 = -8piöstriöl ent- = malt and applied to the skin yus? De _o Bszzach i-; ar the proportion of abnormal lines ? especially of the neerotiaoiiea cells ^ iaeignificantly declined, vährsnd bsi ITerwsiuUu ^. iron Yergleicnssul) - stanaen who were not dealt with degenerative revenge *

¥ grsuch_ £.

CtQg ₁ activity of _n galgdrfisea

lach der τοη WoSoBullough and E ₀ B ₀ Laurence In J ₀ Derraatolo 35 (1960) _E page 3? besoiiriefeensn Methods are mänaliciie mice 23 Sage ait of Tos-stelienö under (D) said ointment treated ₀ The ialgdrusen the 'Here only 2 _P contained after 94 ropes compared to 5 * 11 at nleiitbeliandelten iieren and 6j, 18 in yaw, the only with the Ointment condition treated

909886/1657

At ά &&. The experiments described in the preliminary stages were: fepioestriol was used. In practice, that insufficient solubility liaf be fiddled _s this link for memclie Anwendungsswecke Ih oil has · "There were daber the eiitepreonenden 16fl, l? _Fl-r diester produced a '/ esentlieh better ÖUöslichkeit

It was checked whether these substances of the invention have the same properties \ i ± e the lower ^ "Alkoicy-IG-epiestriole _f \ χηά züiea: soi-zohl with regard to a strong inhibition of the sebum glands as well as to the practically fine / iormonal love effects

It wufde the duration of Öetrus measured by _f each have the same Doeie (10 rag) S-Met ^ ioxy-IG-epiöstriols whose 3.6ß _f 17ß · Di "" ndecylat, _l6ß? 17ß-Di-3 ⁱ -cycloii-3; c5'lpropioK.at baWc the _P acetonide caused vmrde _t Sb it was established that the ethers and the acetonide have even lower estrogenic effects "all iG-iipiöstriel * there with ilines no estrogenic irrigation occurs at all, while 16.-epiestriol causes an uterus of 1 1/2 days' duration »

The 3-Kethyläther be 16-Epiöstriols sov / ie 16ßj.l7ß ° acetonide and its various l6ß _r 17S master are of Bpithelgev / ebeSf used the HaarliOöens and connective tissue of the in human medicine for the treatment of various diseases of the mucous membranes lolcalen ₉

Regardless of whether _P as a carrier 5;. 53 Crsäie _{f f} ointment lotion * one viässs owned Älko ^ ^or;? -'- lyc6rin-i.iC3uri-; _r v .-:.: ic X-öei'iig on dsr ¹ basis

9098Ö6 / 165 7 ^v

■ - 12.- ·

of propylene · = · or ethylene gljrlsöl or an oil solution was used, sioli in no case showed the slightest deceitful, clinical or "biological effect, neither with the nor with the Ifexi2i _f even at doses of 10 mg per day over 18 months and 20 mg per Sag over 5 months _β pass same applies to the antigonadotrope effect was studied on animals in Parabiose (a castrated male and one female) ₀ -

b) Effectiveness

Ό For diseases of the skin and hair In the tests according to the examples below, the active ingredient in jporm was used in various pharmaceutical preparations

A cream, d _e h. in the form of an emulsion in a continuous oil phase with a content of 1% of the 3-ethyl ether of 16-epi-vestriol _p its acetonide or one of its loßjlTß-dieaters. The cream was used to treat diseases of the hairless skin a bit twice a day used for a period of at least 14 days to a maximum of 3 months.

Ale lotion, d _P h _o emulsion in a continuous aqueous phase with a Wirkstoffgenalt of 1 #, The lotion for the treatment of diseases of the hairless skin and dee scalp once or twice daily over a period of 14 days to 18 months used in the form of

As an aqueous alcohol-glycerine solution with an active ingredient content of 1 $> for the treatment of diseases of the scalp once a day =: · loaned over a period of 14 days to 15 months «,

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In a first group of clinical trials there were 63 patients treated. The treatment was successful in 44 cases and 19 Cases unsuccessful.

Below is the breakdown of the results given diseases egg 'bare skin _p in particular seborrhea 6 MUe successful? 3 unsuccessful, Dsrmatosenj, especially different © types of acne: 19 successes, "10 failures ,.

Diseases of the connective tissue _P alone or predominantly (elastoses ₉ solar atrophy fold)?
8 successes, no failures, _etc.

Rote StreifSHj,, -jsdoeh not caused by disease of the Adrenal glands;

2 successes, 1 failure,

Seborrhoischs disorders Baar soil _β with and without hair loss
10 successes, 4 failures "

-ν

Another series of experiments on 20 patients concerned presenile or senile changes in the skin of the face. The result of the treatment was clearly positive in 14 cases ^ the skin of the face was visibly rejuvenated «.

ß) diseases der_ verse chiedenen ^ mucous membranes The preparations were in the form of an oil solution used with an active ingredient concentration of 1 to ^5c SSO Treatment was switched bie twice daily over a period of 14 days to 3 months "

9 098 8 67 1657

BAD OBlGiNAL

25 patients suffered βά a atropliisolien or dystrophieciien state of Schlsimhäu.te the upper JLtejnwege, mouth and throat; some suffered from inflammation and had an-. having a bad smell from the mouth or iiaae * The treatment was successful in 18 cases

A further 10 patients were women "who suffered from atrophy of the vulvovaginal scitleim hair after menopause, which was characterized by a high susceptibility to infections and in some cases due to this. expressed annoying or even painful complaints. laeii a treatment over different periods of time, ia δ cases a cure xw.ä in 2 cases a visible improvement was achieved.

The conditions of use of the compounds of the invention in the Human therapies can be summarized as follows

P roduction in _i P ogBi eiiie ^ Cr eme

a) Vex the active ingredient is ^ a Sräger NaOH nature of feeiian "delnden Erkrankuag Tuad dee Änwendungsrljytliinu ^ in a Konsen trätion of C 5 _S MS 10 incorporated fi,

b) The carrier used must be pharmaceutically acceptable and the following properties of light penetration, variable

U) 'emulsion in continuous oil paste iWaBser-in ^ oil) ^ or f) emulsion in continuous aqueous phase (oil-in. Water);

c) The preparation is applied to the skin once or twice a day. worn and lightly massaged in »

90 9 886 / 18S7

■ - 15 -

P räpara tig fforta a lotion

a) The active ingredient is incorporated of the support depending on the type disease treated and the & du & gerhythiBZS Asne in a concentration of 0 5 _fi Ma 10 to #

b) The carrier used must be pharmacologically acceptable and have the following properties:

e () easy penetration, variable, ι

ii) emulsion in continuous oil phase (water-in-oil) or j) emulsion in continuous aqueous phase (oil-in-water);

c) Depending on the liquid in the preparation, this is applied to the hairless Apply to skin or scalp once or twice a day and lightly massaged in <>

Preparation in gorro a non-greasy one

a) The active ingredient is incorporated into the liquid carrier, depending on the nature of the disease to be treated and the Äaweaduagerhytluau8 in a concentration of 0.5 to 10 ^.

b) The carrier consists of a mixture of water pharraakologisch acceptable "ethanol, glycerol, ethylene glycol or propylene glycol and optionally essential oils (eucalyptol, menthol Eampfer _c),

c) The preparation is applied to the scalp once or twice a day applied and lightly massaged in.

90988 6/1657

Preparation In i'orm _a fatty one . Solution

a) The active ingredient wird.einempharinakolögiseh acceptable FET -th Lösun & srjiittel incorporated depending on the disease being treated and the au bie Rörperetelle to be treated in concentrations of 0.5 10%. " _:

b) Use in the mucous membranes (conjunctiva, · Ha8enschleimliäute _}, mouth and throat mucous membranes. Kas and pharynx mucous membranes, vagina _f rectum) by dropping or in powder form, once or twice a day. . -. . "..-.'-. ■ .- ··. '.

In präpar at _n the form of gels

a) The active ingredient is incorporated into aero gel in a concentration of U ₁ S to 10 $ , v / o if the gel is fat and concentration: depends on the nature of the disease to be treated and the part of the body treated. , ·..

b) Use for the treatment of hairless skin, dee Haaiw. soil or mucous membranes _o application. once or several times a day _; ,. gegebenenfallsι under slight Einmaseiereii, _-;

BATH

Claims (1)

In fJ.er R a lower alkyl radical, preferably the methyl or Ethyl group »and R is a hydrogen atom or the acyl radical of a aliphatic, - c.yoloaliphatic or like aliphatic cycloaliphatic Eats carboxylic acid with 2 to 18 carbon atoms, or the two radicals R together form an acetonide group, 2ο Process for the preparation of the compounds according to claim characterized in that one a) converts oestrone with I3opropenylaoetat to 3 _f 17-diacetoxyb \ 8tra-li, 38 5 (lü), 16-tetraene, b) the product obtained is oxidized with lead tetraacetate in a mixture of sesetic acid and acetic anhydride to 3 _i 16e> dlacetoxyuetral, 3,5 (10) -trien-17-one, c) this compound with potassium borohydride sun 3, 16β _; 17S-Trihydroxyöetra-1,3,5UO) -trlen reduced, d) the product obtained is reacted with a lower dialkyl sulfate sum 3-alkoxy-> 16-eplBetriol and the compound optionally esterified or optionally with an aliphatic, cycloaliphatic or mixed aliphatic-cycloaliphatic carboxylic acid with 2 to 18 carbon atoms or its reactive derivative converted into the acetonide with acetone _o 909886/165 7 "^;' ^: ' ■■ χ i« ft B 'B ^{ri y} BATH ORIGINAL