DE1618191A1 - New formyl-19-nor-steroids, their derivatives and a process for their preparation - Google Patents

Description

New "complete" for the journal of the opening script certain registration documents - us. Sign: 21 084-BR / ro

CIBA AKTIENGESELLSCHAFT, BASEL (SWITZERLAND)

P 16 18 191.2
Case 566

Germany

Heue Pormy-l-19-nor-sterQide, your derivatives land Process for their manufacture. ·

The present invention relates to new formyl-19-nor-steroids and their derivatives, in particular the 3-Qxo-4-formyl- ^ '-steroids and the 3-QxQ ~ 5-formyl-4β _> 10-.eyclo-19- nor-steroids, as well as a process for their production by loading

4th
clearing of 3jl9-Dioxo-A -steroids »

The new method is characterized in that

4th
one 3,19-Dioxo- ^ -steroide of the partial formula

0Ö38 8S / 2135

which contain no further free oxo groups are irradiated, the new formyl steroids obtained are isolated and, if desired, the 3-oxo-Jf-formyl-A ·· steroid, which is predominantly in its enol form, is esterified and / or the aeetal groups present in the compounds obtained sets free, existing ether or ester groups saponified to free hydroxyl groups and / or existing free hydroxyl groups esterified, etherified or oxidized * I- ■ * ■ /; /o.1. '·: ■ · ,: ~ ^τ ,. ··

• · The, present procedure is eg »B, by the present Partialscheina illustrated

CHOIR
008885/2135

wherein R is hydrogen or the residue of a lower alkanecarboxylic acid stands.

The irradiation of the 3,19-Bioxo-

ä -steroide is beneficial in organic solvents e.g. in aliphatic and / or cycloaliphatic)! Hydrocarbons, such as pentane, hexane, cyclohexane or methylcyclohexane, aliphatic or cyclic ethers, such as diethyl ether or dioxane. but especially in alcohols e.g. torment fuel or ethanol.

Artificial bare is suitable as a light source strong, natural light «It is preferable to use ultraviolet light, as it is from low mercury or primarily high pressure burners or strong sunlight. The irradiation is preferably carried out at temperatures between 0-80 ° «It is useful under Nitrogen atmosphere carried out in a quartz vessel, in which the light source is arranged centrally and with water chilled wlrdf "

The reaction mixture obtained on irradiation is worked up in a customary manner, for example. by chromatography on silica gel and / or by crystallization, in particular fractional crystallization. The by-products obtained are the well-known, highly effective, unsübstltuierfcen 3-0χο-Δ ^^ ⁰ '-19-ηοΓ-8ΐβΓ0ΐαβ, which can easily be converted into 3-Oxo-l9-nor-A - during work-up.

0 09885/2135 BADOBSGiNAL

rearrange steroids.

Any esters or protective groups present in the formyl-19-nor-steroids obtained, such as ketals, for example, can be hydrolytically cleaved and free hydroxyl groups can be oxidized to oxo groups. On the other hand, the process products with free oxy groups can be converted into their esters or ethers in a manner known per se, so z = B _s by acylation with carboxylic acid anhydrides or carboxylic acid halides.

The starting materials for the present

4th
drive 3il9-Dioxo-A steroids used are known or can be produced by methods known per se. They preferably belong to the series of androstanes, pregnanes, cholans, cholestanes, furostanes and cardanolides and, in addition to the groups mentioned, can have further substituents such as alkyl, for example methyl groups, halogen atoms, functionally modified oxo groups and / or free, esterified or etherified hydroxyl groups. Furthermore, they can also have further double bonds, for example in the 6,7 position.

The pormyl-19-norsteroids obtained according to the process are new and also form an object of the present invention. They are a new class of biological effective steroids or are important intermediates in the production of such. For example, the 4-

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Formyl-19-nor compounds by catalytic reduction in transfer the well-known highly effective 4-Fiethyl-19-nor-steroids.

Compounds of the formulas are particularly valuable

where- A- for the sub-formulas

and

(in)

and

CHOIR ₁

are, FU is hydrogen or a carboxylic acid radical, - in particular a lower aliphatic carboxylic acid radical, Hp an oxo group or a free, esterified or etherified ß-position hydroxyl group and a hydrogen atom or a lower aliphatic hydrocarbon radical, E * two hydrogen atoms, a lower alkyl! together with a hydrogen atom or a free, esterified or etherified hydroxyl group together with a hydrogen atom ". .-> or a methylene group, E ^ a
: ■■ "« «- '- ^ L 003085/4435

free or ketalysed oxo group or a hydrogen atom and a free, esterified or etherified hydroxyl group, Rc and Rg are a hydrogen atom or a free, esterified one or etherified hydroxyl group. The remainders R ^, R_ and Rg can together also represent a bis-alkylenedioxy radical, in particular the bis-methylenedioxy radical.

The compounds of the formula II in which R is a hydrogen atom or a lower one are particularly suitable aliphatic carboxylic acid residue, R is a keto group or a free or esterified with a lower aliphatic carboxylic acid hydroxyl group together with a hydrogen atom or a lower alkyl, such as methyl or Aethy1-, a lower alkenyl, such as vinyl, allyl or methallyl, or a lower alkynyl, such as ethynyl or propynyl radical and R, represent two hydrogen atoms.

In the esters mentioned above are the acid residues, especially those of aliphatic, cycloaliphatic, araliphatic, aromatic, heterocyclic carboxylic acids with 1-15 carbon atoms, e.g. pormates, acetates, propionates, Butyrates, methyl acetates, capronates, valerianates, decanoates, Cyclopentylpropionate, Tetrahydrobenzoate, Phenylpropionate, Benzoates, foruates, trifluoroacetates, ethyl and methyl carbonates.

Formyl-19-ηοΓ-steroids, which are in the 17-position Side chain of the cholan, cholestan, spirpstan or cardanolide series can, if desired, according to their own

009085/2135

known methods in the pharmacologically highly effective Androstane and pregnane abbreviations, for example acylolytic, oxidative and / or microbiological route "being transformed., '

The new pharmacologically active compounds can be used as medicaments in human or veterinary medicine, for example in the form of pharmaceutical preparations. These include the new compounds together with pharmaceutical, organic or inorganic, solid or liquid carriers that are used for enteralj z «.B. oral, parenteral or topical © "gift, suitable sinä.-Pür.dle formation of the same, köismea solofae substances in questioned the string of the new Verbtriäungöä.» iöfet - '^ eagtsreni. as s gelatin, milk sugar * starch ^ "" Magaesiiim vegetable gels , Beszylalleöhöle, - "Öusani, - Vaseline _s cholesterol tmd aadeye known medicament carriers. The pharmaceutical preparations know in solid form, for example "as tablets, coated tablets or capsules, or in liquid or semi-liquid form as suspensions, emulsions." Ointments or creams are present. "If necessary, these pharmaceutical preparations are sterilized and, if necessary, contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers. They can also contain other therapeutically valuable substances" Their manufacture takes place ia-'be-

- 009BBS / 2.135 -.

known way.

The procedure is described in more detail in the following examples. The temperatures are in degrees Celsius specified.

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Example 1:

4 3 g 3. _r 19-Dioxo-17-acetoxy-A -androsten be

dissolved in 150 ml of ethanol and placed in a quartz vessel Room temperature under nitrogen for 5 hours with a Low-pressure mercury burner irradiated. The reaction mixture is evaporated in vacuo, the residue is dissolved in ether and washes the ethereal solution with 1 hour aqueous sodium hydroxide solution. The essential solution is evaporated and the residue in benzene acetic ester (4: 1) solution on silica gel chromatographierto First 58O mg of 19-mortestosterone acetate are obtained, after crystallization from aetone petroleum ether melts at 124 °. Mixed melting point, IR spectrum and thin-layer chromatograms are similar to those of a 19-nor-testosterone acetate, obtained in another way, identiseh, (according to thin-layer chromatogram of the primary reaction solution however, the 3-0xo-17ß-acetoxy-Δ is primarily formed -estrene, which is isomerized during work-up).

Later benzene acetic ester (4: l) fractions consist of 620 mg of unchanged starting material. Finally, 725 mg of 3-oxo-5β-formyl-17β-aeetoxy-4a, 10a-cyclQ-19-norandrostane, which melts at 135 ° after two crystallizations from acetone-petroleum ether, are eluted. Εα1 _β = + 60 ° (e = 0 ^ 32). IR: 2720, 1725 »1250 cm" ¹ .

You acidify the base cheese solution, pull it

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- ίο -

with ether and evaporate the ether. This gives 0.6 g of a mixture of 3-0xo-4-formyl-17β-acetoxy-A- ^{: >>} ^ and residues and its isomeric 4-hydroxymethylene compound. The mixture is acetylated in 100 ml of anhydride-pyridine (1: 1) solution overnight at room temperature. It is evaporated in vacuo and the residue is chromatographed in benzene / ethyl acetate (4; l) solution on silica gel. This gives 470 mg of I-oxo - ^ - acetoxymethylene-rfß-acetoxy-A-19-nor-androsten, which melts at 152-155 ° after two crystallizations from acetone-petroleum ether. [oJ _D = + 228 ° (c = 0.56). IR: 1765, 1725, I695 / 1620, 1590, 1250, 1175 cm " ^1. W: 230 (II250), 297 (5870) The starting material used in this example

3,19-DlQXo-17β-acetoxy-A-android can be obtained, for example, as follows will: '

11 * 8 S 3,17-Dioxo-19-hydroxy-A -androsten be dissolved in 150 ml of tetrahydrofuran and added bie 20 ° with stirring a solution of 11.8 g lithium aluminum tritertiary butoxyhydride given in 100 ml of tetrahydrofuran. The mixture is stirred at 20 ° for 3/4 hours and then mixed with it Seige aqueous glacial acetic acid, diluted with ethyl acetate and works on as usual. The resulting crude product is acetylated in 250 ml of acetic anhydride / pyridine (1: 1) mixture Night at room temperature. The crude product obtained after evaporation in vacuo becomes neutral with methylene chloride Aluminum oxide (activity III) filtered and the evaporated

009885/2135

1818191

- 11 - ■ ■■; -;

Eluate then recrystallized from Aeeton petroleum ether.

4 This gives 7.2 g of 3-oxo-17β, 19-diacetoxy-A -androsten

from>. 97-100 °. [a3 _B =.> 133 ° (c «0.51). IR: 1725, 1675, 1623, 1255 cm " ^1. '- ^: " ■■. · - ■ "-'V--'

2 g of this acetate are hydrolyzed in 450 ml of 90% aqueous methanol with 1.2 mol of equivalent sodium bicarbonate at the boiling point for 1 hour. Water is added as soon as crystallization begins, the crystals formed after cooling are used, washed with plenty of water, dried and recrystallized from acetone fatty acid. This gives 1.6 g of 3 ^ 0xo-l7ß * acetoxy-19-hydroxy-A -androsten from P. 162-163 ° » W _n * *? 6 ° (e, * 0.9p). IR: 36OO /

1675, I623, 1255 enf ¹ . -

5g of the compound thus obtained are mixed in 75 ial dimethylformamide with 6.1 ml of 8-n chromic acid in sulfuric acid and 8-n wSssriger% 1/2 hours at 4o left ^Q>. An aqueous solution of sodium sulfate is added until crystallization begins. The crystals are filtered off, washed with water and dried. After recrystallization from aeetone petroleum ether, 4.0 g of 3,19-Jioxo-17β-acetoxy -. ^ Androsteti vom "I3I-132 ⁰ , CaIj ₅ " + 143 ° (c = 0.68), IR? 2800 _# 1T25, 1675 ^, 1622> 1255 a " ¹ .

009885/2135

Example 2ί

4 6 2 g 3ü9-Dloxo-1Tß-acetoxy-A * -androstadien

irradiated in 350 »1 ethane oil in a quartz vessel at room temperature under nitrogen for T hours with a low-pressure mercury burner: The reaction mixture is evaporated in vacuo, the residue is taken up in ether and washed with 1N aqueous sodium hydroxide solution. The ethereal portion is evaporated, taken up in benzene-ethyl acetate (4: 1) and chromatographed on silica gel. First 320 mg of 3-oxo-17β-acetoxy-A '^ * -östratriene are obtained, which after three crystallizations from acetone-petroleum ether melts at 117-118 °. IR: 1725, 1703, 1635, 1255 cnf ¹ . Further benzolessigester- (4sl) -fraktionell provide 420 mg of 3-oxo-17ß-aceto3ty-4a, 10a-cyclö-19-nor-Δ -androsten, which melts after two recrystallization from acetone-petroleum ether at 128-129 ° «IRt 1725 (wide), 1255 cm " ¹ .

Later fractions give 374 mg of unchanged starting material and the last benzolesslgester- (4il) eluates consist of 51 mg of 3-oxo-5ß-formyl-17ß-acetoxy-4a, lOa-cyclo-19-ηοΓ-Δ -androsten, which after four Crystallizations from acetone-petroleum ether at 16-164 ° melts »IR: 2730, 1725-17ΟΟ, 1255 cm" ¹ .

The basic What * '' ¹ -3 - "'J HF: - ^r: undressed ri CNIR ^ Fauert and with ether, the ethereal solution is then evaporated.

0 0 9 8 8 5/2135 BAD OBiGlNAL

and acetylated directly overnight with 50 ml of an acetic anhydride-pyridine (1: 1) mixture at room temperature. It is evaporated in vacuo and the residue is chromatographed on silica gel. 470 mg of 3-oxo-4-acetoxymethylene-17β-acetoxy-A- ^ ■ ' -19-norandrostadiene, which after three recrystallization from acetone-hexane at 155-157 °, is eluted with benzene acetic ester (4; 1) mixture melts. IR: 1766.1725 * I699,

The starting material used in this example

can be obtained e.g. as follows:

■ '■ "' -% 0.5 g of 3-oxo-17β-acetoxy-19-hydroxy-A-android

are mixed with 1 g of chloranil in 25 ml of tertiary butanol Stir refluxed for 5 hours. After cooling it will filtered off and the piltrate evaporated in vacuo. One takes the residue in ethyl acetate, the solution washes under Ice cooling successively with 2 N sodium hydroxide solution μηά plenty of water and evaporate the organic phase. The residue is taken up in methylene chloride solution and filtered over neutral aluminum oxide (effectiveness III), evaporates.

and recrystallized from acetone-petroleum ether. You get so

k 6 the 3-oxo-17ß-acetoxy-19-hydroxy-A '-androstadien vom

P. 149-151 ⁰ · IRj 3620, 1720, I655, 1617, 1585, 1257 cm " ¹ "', 150 mg of this compound are taken up in a little pyridine and added to a suspension of 150 mg of chromium trioxide in pyridine Hours are worked up as usual and the crude product obtained is filtered in

009885/2135 /

Methylene chloride over neutral aluminum oxide (activity III). Crystallization of the evaporated eluates from acetone-petroleum ether yields 12 mg of 3,19-dioxo-17β-acetoxy-A 'androstadiene with a melting point of 64 °. [a] _β = + 38.5 ° (c = 0.52). IR: 1720, 1660, 1615, 1588, 1255 cm " ¹ .

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Claims (1)

Patent claims: 1. Process for the production of new formyl-19-norsteroids and their derivatives, characterized in that ji ■■ '■ ".. ■■ -'" ■ "_; ■ - ■■ '-" ■ man 3,19-Β1οχο-Δ -steroids of the partial formula which contain no further free oxo group, irradiated, the new formyl steroids obtained are isolated and, if desired, the J-oxo - ^ - formyl-A ^ ^1Ö '-sterGid present predominantly in its enol form is esterified and / or acetal groups present in the compounds obtained In freedom, existing ether or ester groups saponified to free hydroxyl groups and / or existing free hydroxyl groups esterified, etherified or oxidized " 2. The method according to claim 1, characterized : it net that one 3, -19-Dioxo-A -steroids of the Androstan-, Pregnan-, Cholan, Cholestan, Furostan, Spirostan or Cardanolide series used as starting materials. 3 · The method according to claim 1, characterized in that it is marked M. ■ t ä n τ _Γ ^ια " ^η 1ο ^ ο-Α -stci-noMe der} -ovm« l - BADORlGtNAL 009885/2135 used as starting materials, in which R _{3 is} a ketalized oxo group or a free, esterified or etherified ßständig hydroxyl group and a hydrogen atom or a lower aliphatic hydrocarbon radical and'PU two hydrogen atoms, a lower alkyl radical together with a hydrogen atom or a free, esterified or etherified hydroxyl group together with represent a hydrogen atom or a methylene group. Process according to Claim 1, characterized in that 3jlSHDioxo-Δ steroids of the formula used as starting materials, where R ₁ ^ a ketalized oxo group or a hydrogen atom and a free, esterified or etherified hydroxyl group, R ₅ and Rg a hydrogen atom or a free, esterified or etherified hydroxyl. 0 0 9885/2135 group or the radicals R ^, R ₁ - and R ^ stand for a bisalkylenedioxy group. . 5. The method according to claim 1, characterized in that that one ^, l ^ Dioxo-lT-acetQxy- ^ -androsteö as a starting material used* · 6. Verfanren according to claim 1, 'characterized in that one uses 3,19-dioxo-17-acetoxy- ^ - *' -androstadiene as the starting material. 7. New formyl-19-nor - steroids whose ring A is one of the Formulas, 'λ or 0
CHOIR | where R, hydrogen or a carbonic acid residue, correspond. 3 B " New Pormyl-19-nor-steroids of the general formula where A is one of the sub-formulas or CHOIR ₁ and where FL is hydrogen or a carboxylic acid residue, R an oxo group or a free, esterified or etherified ß permanent hydroxyl group together with a hydrogen atom or a lower aliphatic hydrocarbon radical and R two hydrogen atoms, a lower alkyl radical together with a hydrogen atom or a free, esterified or etherified hydroxyl group together with a hydrogen atom or represent a methylene group. 009885/2135 9. New formyl-19-nor-steroids according to claim 8, wherein R _{1 is} hydrogen or a lower alkanoyl residue, R is hydrogen and PL · a lower alkanoyloxy group together. 'means with a hydrogen atom. . New formyl-19-nor-steroids of the general formula CH ₂ S ₅ where Ä for one of the sub-formulas or CHORUS ^ and wherein R _{1 is} hydrogen or a carboxylic acid residue, R. is a free or ketalized oxo group or a hydrogen atom and a free, esterified or etherified hydroxyl group 9885/2135 FL and R ^ - a hydrogen atom or a free, esterified or 5 ο mean etherified hydroxyl group or in which R ^, R ₄ . and R together represent a bis-alkylenedioxy group. 00 9 88 5/2135