DE3017015A1 - STEROIDS, METHOD FOR THEIR PRODUCTION AND PREPARATIONS THEREOF - Google Patents

Description

Our no. 22 928 Be / Hs / gr / Fb

Richardson-Merrell Inc. Wilton, Conn., V.St.A.

Steroids, processes for their manufacture and preparations containing them

The present invention relates to the use of certain steroids for the treatment of acne and oily skin, hairlessness and prostate hypertrophy by preventing testosterone ia reductase.

It is known that the skin is androgen responsive and is an active site of androgen metabolism. The androgen testosterone is metabolized in the skin to dihydrotestosterone (DHT), which is a is more effective androgen than testosterone. As in Arch., Dermatol. 111, 1 * 196 (1975) There is sufficient evidence that DHT is both involved in the development of acne as well as other androgen-related ones

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States is involved. Studies of the urinary flank organ, which is an androgen-dependent valley gland structure, show that DHT stimulates the growth of this structure. It has been found that skin with acne produces 2 to 20 times more DHT than normal skin. It is therefore believed that agents that can block the formation of DHT will be effective in treating acne conditions. Many studies also show that prostate hypertrophy can be treated by administering an agent that prevents the formation of DHT from testosterone, i.e. a testosterone 5α reductase inhibitor. Testosterone is converted to DHT through the enzymatic action of testosterone-5a-reductase. One possible way of - * blocking the formation of DHT is to prevent the activity of testosterone 5a ~ reductase. In the treatment of acne, the activity of the 5α-reductase enzyme is preferably prevented locally, that is to say in the area of the skin afflicted with acne.

It has been widely believed that the as testosterone 5a reductase inhibitors effective steroids would have to have a Δ -3-keto configuration and that therefore the presence of other substituents in ring A would be of little help or even the effect of the Adversely affect compounds as an inhibitor.

For this reason, the numerous compounds disclosed in U.S. Patents 3,917,829 and 4,088 JSO all contain a Δ in ring A. -3-on structure.

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It must be pointed out that the Δ 3-keto-steroids that have been proposed for the inhibition of 5a ~ reductase _s act by way of a competing inhibition and that their effectiveness depends on that a significant, perhaps even significant concentration of the inhibitor in the organ to be treated, that is, for example, in the human skin or in the prostate is maintained. Clearly competitive inhibitors have a lower degree of effectiveness than irreversible or quasi-irreversible inhibitors «.

A theory for the irreversible inhibition of 5α-reductase and A -3-keto-isomerase is offered by US Pat. No. U Ο87,461, to which reference is made in this respect. According to this theory you need a steroid with a potentially reactive group that will take effect _s when to teeffende enzyme's transformation = performs at this time takes place a chemical reaction such as alkylation, directly at the active site of the enzyme or as close thereby that the enzyme is irreversibly inhibited. Propadiene secosteroids are proposed in this patent for the irreversible inhibition of Λ ^ -3-keto-steroid isomerases and testosterone-5ffi-reductase. According to this patent specification, the transformation catalyzed by the enzyme should include a reaction in the C - ^ position.

The present invention relates to the use of certain steroids substituted in the ^ position, which inhibit the activity of 5a-reductase and are therefore suitable for the treatment of acne or oily skin are. It is not known if the inhibition occurred

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irreversible or almost irreversible, i.e. quasi-irreversible is because those substituted in the 4-position Steroids are not easily uncoupled from the enzyme.

It has been found that the compounds of the following general formula are at least quasi-irreversible Inhibitors of 5 <r ~ reductase are:

where R has one of the following meanings:

= 0, -OH, -OCO-alkyl 1-5, -COOH, -CHgOH, -CHO, -

f ^H 3? ^H 3 η

, -CH-COOH, -CH-COO-Alky 1-C ₁ ^ _-6,. O ^

CH, CH, CH, ι 3 ι 3 ι 3

and the 208 isomers of -CH-CH ₂ OH, -CH-CHO, -CH-COOH

CH ₃
or -CH-COO-alkyl-C 1-6.

It is believed that the _{inhibition attributable to the presence of the N 2} substituent at the 4-position accumulates with the competitive inhibition attributed to the presence of a preferred substituent at the 17-position. The substituents in the 17-position, i.e. R in the above formula, are those

such as in U.S. Patents 3,917,829 and 4,088,768 for the inhibition of 5a-reductase previously described.

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Particularly preferred as substituents R are: CH, CH, CH, ι

«3« 3 υ 3

20B-CH-CH ₀ OH ₃ 20B-CH-CHO ₃ 2OB-CH-COOH and

As _s set out there is evidence _s that dihydrotestosterone (DHT) _3, a metabolite of testosterone is j has a stimulating effect on talc glands and is therefore involved in the development of acne agent ^ which prevent the formation of DHT _s are therefore effective for treating acne. The compounds used according to the invention are inhibitors of testosterone-5a-2 ° eductase _{s of} the enzyme _s which converts testosterone into the more effective androgen DHT. For this reason, the compounds according to the invention are suitable for the treatment of acne and oily skin. The . . Compounds are also useful for the treatment of benign prostatic hypertrophy and male hairlessness,

The effectiveness of an enzyme inhibitor is often expressed in its inhibition constants Ki _s as the relation is defined the enzyme catalyzed reaction conditions to inhibitor and substrate concentrations mathematically The derivation of these relationships and the mathematical definition of Ki can be found in standard works of Enzymology "Simply put _s gives Ki quantitatively the unifying power of the inhibitor for the enzyme. The smaller the value of Ki, the greater the unifying effect (affinity). In the case of the substrate, the corresponding value is known as Km, the ratio to the uniting force being roughly the same. The following comparison

017015

shows the increase in unifying power for 5 reductase in compounds of this series compared to that of the substrate (testosterone) and one of the most effective known Inhibitors.

Ki

1.0 χ 10 ' ⁶ M (Km)

Testosterone ^

2.2 χ 10 ~ ^T M

CHa-OH

2.0 χ 10 ' ³ M.

The representative compound according to the present invention then has an affinity for the enzyme which is 50 times larger than that of the substrate and is at least 10 times as effective as the well-known inhibitor. The effectiveness of the compounds according to the invention may be due to their ability to prevent activity

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5a-reductase _s isolated from the rat _{prostate gland s be} proven »If, for example, prostate _{microsomes 9} testosterone-5®-reductase in an amount corresponding to 180 mg fresh tissue and HC -testosterone in a concentration of 2 χ 10 ™ M used ₉ 3 × 10 M (5 « ₉ 20 [beta]) -4-diazo-21-hydroxy-20-methylpregnan-3-one inhibited the conversion of testosterone to DHT and alterstanediol (ADIOL) by a total of 9 %. Under the same conditions, a concentration of 3 10 M inhibited the conversion of testosterone to 5 reduced products by 75 %.

In order to achieve the desired effects against acne or hair loss _s the inventive compounds can be administered orally, parenterally (eg, "intramuscular or subcutaneous) be applied topically or" Topical application is preferred. The compounds according to the invention can be administered to the patient alone or together with other substances in the form of pharmaceutical preparations Amount of the compound to be administered for the effectiveness against acne or hair loss between O ₈ I and 50 mg / kg of body weight per day and preferably between 1 and 30 mg / kg of body weight per day. Single doses for oral or parenteral administration can be, for example, 5 to 200 mg Active ingredient contained »For topiseh © application, the effective amount of compounds according to the invention for the effectiveness against acne or hair loss can be on a percentage basis between O ₃ OOi and 5 % and preferably between 0.005 and 1 % . When applied topically, it can

formulated preparation directly on the area requiring treatment or the mucous membrane of the mouth or nose be applied.

For the treatment of benign prostatic hypertrophy, the compounds according to the invention can be administered to the patient to be treated in a number of ways. When we speak of patients ₉ , we mean male warm-blooded animals such as male rats, male dogs and male humans. The compounds can be administered alone or in conjunction with others. Administration is also possible in the form of pharmaceutical preparations. Administration can be oral or parenteral, such as intravenous, intraperitoneal, intramuscular or subcutaneous, including injection of the active ingredient directly into the prostate. The amount of the compound to be administered varies over a wide range. Depending on the patient to be treated, the complaints to be treated and the mode of administration, the effective amounts of the compound to be administered can vary between 0.1 and 50 mg / kg of body weight per day. They are preferably between 1 and 30 mg / kg body weight per day. Single doses for oral or parenteral administration can contain, for example, 5 to 200 mg of a compound according to the invention. ; ■ "

These dosage ranges represent the amounts of the compound that are effective in reducing the size of the prostate, the amount effective in treating benign ones Prostatic hypertrophy. Connections can be made from

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Onset of hypertrophy of the prostate until symptoms regress and can also be administered preventively be used.

Topical formulations may, for example, in the form of a solution, _s suspension., Emulsion, gel or cream (both of the type oil-in-water such as water-in-oil) carried out, ointments, pastes, jelly or powder. Suitable bases for topical preparation are known to the person skilled in the art and include oily bases such as olive oil, cottonseed oil, petrolatum, mineral oils, silicones such as dimethylpolysiloxane or methylphenylpolysiloxane, lanolins, polyethylene glycol, glycerol monosterate, methyl cellulose and hydroxymethyl cellulose. The topical formulation may contain pharmaceutically acceptable surfactants, wetting agents, dispersants, emulsifiers, penetrants, lubricants, detergents, hardeners, preservatives, fillers, antioxidants, odorants, coolants such as menthol, smoothing agents such as camphor, or dyes such as zinc oxide, contain. Formulations of a solution, suspension or emulsion containing the active ingredient in the form of a finely ground powder can also be used as an aerosol for topical application. The aerosol can be filled under pressure into an aerosol container together with a fibrous or liquid propellant such as dichlorodifluoromethane, dichlorodifluoromethane with dichlorodifluoroethane, carbon dioxide, nitrogen or propane with the usual additives, other solvents or wetting agents, if necessary or desired. The compounds can also be applied in an unpressurized form in an atomizer.

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The following are exemplary pharmaceutical formulations suitable for use with the present Invention can be used:

solution

(5cc-20β) -4-diazo-21-hydroxy-20-methyl-

pregnan-3-one 0.85 g

Alcohol 78.9 ml

Isopropyl myristate 5.0 g

Polyethylene glycol 400 10.02

purified water to 100 ml

Alcohol, isopropyl myristate and polyethylene glycol 400 are put together and the active ingredient is dissolved in it. Purified water is used to make up to 100 ml.

GEL

(a) (5a, 20 [beta]) -4-diazo-21-hydroxy-20-methylpregnan-3-one

(b) alcohol

(c) isopropyl myristate

(d) polyethylene glycol 400

(e) Carbopol 940 (carboxypolymethylene)

(f) triethylamine

(g) purified water to 85 g

The Carbopol 940 is dissolved in isopropyl myristate. To 38 ml of alcohol, 7 ml of purified water and the polyethylene glycol 400 are added and mixed. Both Phases are combined and mixed until well dispersed. With triethylamine it becomes a neutral one pH adjusted. The active ingredient is in the rest of the

0.85 G 78.9 ml 5.0 G 10.0 G 0.75 G rest

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30170

Dissolved alcohol and then mixed well with the rest of the solution. Purified water is used to make up to 85 g and mixed well again «

PEN -

(a) (5 © _s 20β) -lJ-Diazo-21-hydroxy-20-methylpregnan-3-one O _s 85 g

(b) Absolute alcohol x 75 ml

(c) polyethylene glycol ¹ IOQ 10 _fl 0 g

(d) Isopropyl myristate 5 »0 g

(e) stearic acid k _S 3 g

(f) Sodium Hydroxide O ₃ 55 g

(g) purified water to 85 g

The absolute alcohol _s polyethylene glycol 400 and isopropyl myristate are added together "The stearic acid is then eye and the mixture to about 65 ⁰ C heated The sodium hydroxide .If in a small amount of water dissolved _s added and mixed ₀ with water to 85 g padded The active ingredient is then suspended in the pen base and immediately afterwards let the formulation solidify _o

AEROSOL FOAM- · ": -

Ca) (5 © ₉ 2QS) -ii »Diaiso-21 = hydro £ r-20-

methylp5? egnan ~ 3 = on "" I ₈ O g

Cb) propylene glycol '96 O ₉ g.

(e) EmulgiexwachB NF XIV - 3 ₉ O. G

(d) dichlorofluoromethane cryfluorane 6 ₈ 9 g

(20th: 80)

The active ingredient is dissolved in propylene glycol. The emulsifying wax is added and heated to about 70 ⁰ C. The mixture is stirred while cooling to room temperature. A suitable aerosol bottle is filled with this concentrate and 6.9 g of the propellant.

TOFISH CREAM

(a) (5a _s 20β) -Jj-Diazo-21-hydroxy-20-methylpregnan-3-one 1

(b) stearyl alcohol 15

(c) sorbitan monostearate 2

(d) polyoxyethylene sorbitan monostearate 2,3

(e) propylene glycol 5

(f) methyl paraben 0.025 %

(g) propyl paraben 0.015 % (h) purified water balance

POWDER

(a) (5a, 20β) -4-Diazo-21-hydroxy-20-methylpregnan-3-one 1

(b) silicon dioxide, anhydrous 0.5

(c) corn starch, lactose, fine powder remainder

OILY Ointment

(a) (5a _s 20β) -4-Diazo-21-hydroxy-20-methylpregnan-3-one 1

(b) White beeswax 5

(c) Vaseline to 100

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30170-1-

Absorption ointment

(a) (5 <* c, 20 [beta]) -H-diazo-21-hydroxy-20-methylpregnan-3-one 1

(b) cholesterol 3

(c) stearyl alcohol 3

(d) White beeswax 8

(e) Vaseline to 100

WATER-SOLUBLE Ointment

(a) (5dC, 20 [beta]) -4-diazo-21-hydroxy-20-methylpregnan-3-one 1

(b) polyethylene glycol 400 HO

(c) polyethylene glycol 0 to 100

PASTE

(a) (5 ° C, 20 °) -4-diazo-21-hydroxy-20- AEROSOL FOAM 1 methylpregnan-3-one 25th (b) strength 25th (c) zinc oxide to 100 (d) petroleum jelly

(a) (5 © c, 20 [beta]) -4-diazo-21-hydroxy-20-methylpregnan-3-one 1

(b) Emulsifying wax 3

(c) stearyl alcohol 2

(d) diglycol stearate 2

(e) Propylene Glycol 92

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The compounds for treating acne and oily skin can be used in conjunction with other anti-acne preparations, antiseptics, anti-infection agents, keratolytic agents such as resorcinol, comedolytic agents or agents with retinoic acid-like activity, corticoids and other anti-inflammatory agents, ^ thioglycolates , Ethyl lactate or benzoyl peroxide can be used. The following formulations are examples of pharmaceutical preparations for topical use including a compound in conjunction with a keratolytic agent. ■■■ "'.

AEROSOL FOAM .

(a) (5oC, 20 [beta]) -4-diazo-21-hydroxy-20-methylpregnan-3-one 1

(b) resorcinol monoacetate 1

(c) Emulsifying wax3 NP 3

(d) stearyl alcohol 2

(e) diglycol stearate 2

(f) propylene glycol 91

The active ingredient is dissolved in propylene glycol, the emulsifying wax3

added and heated to approximately 70 ° C. While cooling down

is stirred to room temperature. You fill the concentrate in

a suitable aerosol unit and. admits the propellant. ,GEL

(a) (5oc, 20 [beta]) -4-diazo-21-hydroxy-20-methylpregnan-3-one 0.85.g

(b) resorcinol 0.85 g

(c) alcohol 78.9 ml

(d) 13opropyl myristate. 5.0 g

(e) Polyethylene Glycol 400 10.0 g

(f) Carbopol 9 * »0 (carboxypolymethylene) 0.75 g

(g) Triethylamine balance (h) Purified Was ^ gQQ ^ 7/07 43 to 85 g

The Carbopol 940 is dissolved in isopropyl myristate to 38 ml Alcohol is added to 7 ml of purified water and the polyethylene glycol 400 and mixed together. Both phases are combined and mixed until well dispersed o With triethylamine the solution is neutralized = The active ingredient and the resorcinol are dissolved in the rest of the alcohol and added to the solution. It is made up to 85 mg with water and mixed well again.

For oral administration, compounds of the invention into solid or liquid Mittel.formuliert _s can be such as capsules, pills, tablets, powders, solutions, suspensions or emulsions. The compounds can be used in the form of an aerosol with finely divided active ingredient particles or a solution or suspension or emulsion of the active ingredient. The solid dosage form can be a capsule _s such as an ordinary gelatin capsule which can contain the active ingredient a carrier ₉ mu lubricants and inert fillers such as lactose, sucrose or corn starch. The active ingredient can, with known tablet excipients such as lactose _s sucrose or corn starch in combination with binders such as acacia "corn starch or gelatin ₉ release agents _s ,, as stearic acid or magnesium stearate as potato starch or alginic acid _s and a lubricant.

For parenteral use, the formulation of injectable doses of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier, which can be a sterile solution such as water in oil with or without the addition of a surfactant or other pharmaceutically acceptable additives, are examples of usable oils are those from Erdölj oils, and oils of animal _s pf! view or synthetic origin _s such as coconut oil, soybean oil and

Mineral oil. In general, water, table salt, aqueous dextrose and similar sugar solutions, ethanols and glycols, such as propylene glycol or polyethylene glycolj preferred liquid carriers especially for injectables Solutions.

Administration can be in the form of depot injections or implants take place, which are formulated so that a delayed release of the active ingredients is achieved. The active ingredient can pressed into pellets or narrow cylinders and implanted subcutaneously or intramuscularly as a depot injection or implant will. Implants can be inert substances, such as biodegradable polymers and synthetic silicones, such as. Silastic, a silicone rubber made by Dow-Corning Corporation.

The following are examples of pharmaceutical formulations for oral or parenteral administration of those of the invention Active ingredients.

TABLETS .

(a) (5ec, 20 [beta]) -4-diazo-21-hydroxy-20-methylpregnan-3-one 75 g

(b) Lactose I, 26 kg

(c) corn starch 0.3 kg

The active ingredient, lactose and corn starch are mixed together. It is granulated with 10C starch paste and dried to a moisture content of about 2.5ί and sift through a No. 12 mesh screen and then add and mix in:

(a) Magnesium stearate 0.015 kg

(b) corn starch to 1.725 kg

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On a suitable tablet machine was pressed tablets with a weight of 115g per tablet 0 _s,

SOFT GELATINE CAPSULE

(a) 5oc _s 20β) -4-diazo = 21 = hydroxy-20-

methy! pregnan-3 = on O _s 25 kg

(b) Polysorbate 80 O ₃ 25 kg

(c) corn oil to 25 _s 0 kg-are mixed and filled into 5O OOO ₃ soft gelatin capsules.

INTRAMUSCULAR DEPOT INJECTION

Each 1 ml contains the following ingredients;

(a) (5oc _5> 20 [beta]) -4-diazo-21-hydroxy = 20-

methyl! pregnan-3-one 5.0 mg

(b) Anhydrous chlorobutanol 5 _sec 0 mg

(c) aluminum monostearate 50 _sec 0 mg

(d) peanut oil to 1 _s 0 ml ingredients are dissolved or dispersed in the peanut oil «

DEPOT IMPLANT

(a) (5ec _s 20β) -4-diazo-21-hydroxy-20-methylpregnane ~ 3 ⁼ on 5 mg

(b) dimethylsiloxane 240 mg

(c) catalyst remainder

The active ingredient is dissolved in dimethylsiloxane ₉ the catalyst is added and the mass is poured into a suitable monolytic structure «

The active ingredient can also come from a pre-cast polydimethylsiloxane jacket be enclosed.

It is also possible to disperse the active ingredient in a suitable proportion of hydroxyethyl acrylate, which is then polymerized and crosslinked by adding ethylene dimethacrylate and an oxidizing agent _{9 to} obtain a 3-dimensional ethylene glycomethacrylate as a moldable gel.

INTRAMUSCULAR INJECTION SOLUTION

A. Oil type:

(a) (5cC, 20 [beta]) -4-diazo-21-hydroxy-20-methylpregnan-3-one

(b) BHA, BHT aa

(c) peanut or sesame oil

B. Suspension type:

(a) (5oC _a 20β) -4-diazo-21-hydroxy-20-methylpregnan-3-one

(b) sodium carboxymethyl cellulose

(c) sodium bisulfite

(d) water

25 mg O ₉ Ol % w / v

to 1.0 ml

25 mg -. 0.5% w / v 0.02 % w / v,

to 1.0 ml

BUCCAL OR SUBLINGUAL TABLET

(a) (50 ° C, 20 [beta]) -4-diazo-21-hydroxy-20-methylpregnan-3-one

(b) calcium stearate

(c) calcium saccharin

(d) Granular Mannitol

1 %
1 %

0.02 % remainder

The ingredients are mixed and tablets with a weight of 0.115 g each are pressed on a suitable tabletting machine Tablet.

The compounds according to the invention can be prepared from the A -3-keto precursor

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in which R has the meanings already described, are prepared. The substituent R can, however, if this is important for the course of the reaction, be blocked, for example with the formation of a siloxy ether or a ketal. For example, in the reaction scheme below and in Example 1, the substituent at the 17-position is blocked by an ether group created by reaction with tertiary butyldimethylsilyl chloride. For the addition of the 4-benzoyl group, the 17-position then protected After the addition, the blocking will be removed and the substituent R can be brought into the desired form _s such as, for example, oxidized to an aldehyde or an acid oxidation step, followed by esterification, etc. followed before the diazo transfer reaction occurs.

If the substituent E contains an alcohol _s the starting material is the alcohol itself "If R contains an aldehyde, an acid or an ester ₈ the corresponding alcohol is used as the starting material and the alcohol group is later converted into the aldehyde etc."

The alcohol function is protected by the formation of a dimethyl tex t. = Butylsily lether similar to that of EJ Corey et al., J. Am. brazen ,, Soe. S ^ ₀ 6190 (1972) described method.

If the group R is COCH, _s ELOH "the starting material is progesterone _s td.ro ÖIE side chain first protected by formation of the ketal.

-CH ₃

The (protected) 3-keto-A steroid, i.e. compound A. the following reaction scheme is a dissolving metal reduction using lithium in ammonia in aniline under tertiary butyl alcohol as proton donor and at -78 to -33 ° C for 1 to 60 minutes according to the method described by G. Stork et al., J. Am. Chem. Soc. 96, 7114 (1974). The enolation is then determined with trimethylsilyl chloride and the enol ether, i.e. compound B, is isolated.

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The enolate anion is then made from the enol ether using of alkyl lithium such as methyl or butyl lithium in ethers such as tetrahydrofuran or diethyl ether recovered at 0 to 25 ° C within one to 60 minutes and with benzoyl acid chloride or a lower alkyl acid chloride having 1 to 4 carbon atoms for 1 to 20 minutes -100 to -70 ° C in, for example, diethyl ether or tetrahydrofuran (compound C). ~~

Thereafter, the blocking of the alcohol group with P® or an acid, as described by EJ Corey et al., J. Am. Chem. Soc. 94, 619O (1972) or by reaction with a tetrafluoroborate salt, such as the lithium, sodium, zinc, tin, magnesium, silver, potassium, triphenylcarbenium or trialkyloxonium (for example methyl, ethyl , propyl or butyl) tetrafluoroborate in aprotisdien solvents, acetonitrile, dimethylformamide, Dimethy! acetamide, ethers, methylene chloride, chloroform or combinations thereof at temperatures of about 1 to 100 ⁰ C for 1 to 72 hours away. The process leads to the cleavage of the tertiary butyldimethylsilyl ether to give the corresponding alcohols, both primary and secondary "(compound D).

CH,

If R is one of the groups OH, CH ₂ OH or CH-CH ₂ OH or other alcohols according to the definition of R above, the diazo transfer reaction which leads to compound E can follow directly. To this end, equivalent amounts of compound D and a trialkylamine, such as, for example, triethylamine, are treated with sodium hydride and the enolate is obtained. Then p-toluenesulfonyl azide is added to introduce the diazo group, as described by JB Hendrickson et al., J. Org. Chem. 33, 36IO (1968). The reaction is usually carried out in ether or tetrahydrofuran at 0 to 25 ° C and takes one to 24 hours.

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When the substituent R is not the group

ΓΑ

«Ο

or one of the alcohol-containing groups is _fl , the conversion at the 17-position into the desired substituents of this position takes place immediately before the diazo transfer reaction (as in compound D to F and then to G) ₀

The alcohol group may be the aldehyde or ketone by known methods, for example using Pyridinchlorchroraat _g of Eo as J. Corey et al _OJ) Tet. Letts., 2647 (1975) or by Chromferioxid / pyridine (HW Ratcliffe, Org. Syn _"s 1973) or to the corresponding acid using Jones reagent = (R ₀ Bowden et alo _S J. Chem. Soc ₉ 39 (1966 be oxidized) "the acid can be _s converted into ester Alky! wherein one diazomethane for Methylester and saturated with hydrogen chloride gas alcohol" used higher ethyl esters or converted via the acid chloride and the alcohol "for the

Ünn R is the group QCO alkyl ₀ are the compounds obtainable from the alcohol by reaction with a AXkylsäurechlorid having 1 to β carbon atoms or the corresponding anhydride as a solvent in Pyriöin (O to 25 ⁰ C, for 1 to 24 hours).

The diazo transfer reaction can be imaged onto the aldehydes, ketones, and acids (using 2 equivalents Matriumhydrid) _s and ethers are used.

If the substituent R is the group -COCH, one assumes from deia-20-ketal as the starting material for the reaction sequence, wherein the protecting group is prior to the diazo transfer reaction by exchange in acetone or propanone using

Paratuloisulfonic acid as a catalyst at 25 to 60 ° C during removed from one to 24 hours.

The furan i _ j J \

can be done directly without the need for blocking groups can be used and the reaction sequence then goes directly from the starting compound to the desired diazo compound.

The following examples describe the preparation of the 4-diazo compounds according to this invention.

example 1 Testosterone dimethyl t-butylsilyl ether (compound A)

A mixture of testosterone (1.0 g, 3.5 mmol), tert-butyldimethylsilyl chloride (627 mg, 4.2 mmol) and imidazole (287 mg, 4.2 mmol) in dimethylformamide (4 ml) is kept overnight at 40 ° C touched. The mixture is then poured into ice water, the precipitate obtained is filtered off and recrystallized from methanol. Yield 1.35g.

3-trimethylsiloxy-5- «c-dihydro-17ß- (dimethy1-t-butyl) -biloxy-ftndrostä-3-en (compound B)

• 12.0 g (29.8 mmol) of compound A in 70 ml of tetrahydrofuran became ammonia-containing aniline (2.7 g, 29.8 mmol) and Lithium (625 mg, 89 mmol) was given. After an hour the

blue solution treated drop by drop with isoprene until the blue color disappears. The ammonia is evaporated and the residue is dried under vacuum (0.5 mm). 50 ml of tetrahydrofuran are then added, the solution is ^{cooled to 0} ° C. and treated with a solution of 12 ml of trimethylsilyl chloride and 12 ml of triethylamine which has been centrifuged beforehand.

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After 15 minutes the mixture is diluted with pentane and washed with cooled O _s 5m HCl. It is then washed with cooled aqueous sodium bicarbonate _s dried over magnesium sulphate and concentrated "The residue crystallized from ethyl acetate _s yield 6 ₂ 6 g _o (The mother liquors are chromatographed on silica Elution with lO ^ ethyl ether ~ pentane to obtain a fraction. ₉ the Was recrystallized from ethyl acetate and gave 2 _S 2 g.) Melting point 126 ⁰ C ₀

4 ° Benzoyl ~ 5 ° oc ° dihydro-17β- (dimethy1-t-buty1) silyloxy ° androstan-3-one (compound C)

To the enol ether (4 _S 89 g _a 10 _S 27 mmol) in ether (20 ml), methyl lithium (5 _S 5 ml of a 2 _s O 5 M = solution _s H ₉ 3 mmol) is added was added to the solution in a syringe and slowly (1.45 gj 10.3 mmol) was added to a solution of benzoyl chloride in 30 ml of ether at -7O ⁰ C. After 5 minutes, aqueous ammonium chloride is added and the products are isolated by extraction with ether. After the ether has been evaporated off, the residue is recrystallized from carbon tetrachloride; Yield 2 _s 0 g "

4-Benzoyl-5-pC-dihydro-androstan-17fl-ol-3-one (compound D)

The silyl ether (1.64 g _s 3.2 mmol) in 50 ml dichloromethane is treated with trityl fluoroborate (1.27 g _s 3 _S 84 mmol) at 25 ° C. for 1 hour. The solution is then washed with aqueous ammonium chloride, dried and evaporated. The residue is chromatographed on silica gel. By eluting with liquid methanol-chloroform, a fraction _{s was obtained} which was recrystallized from ethyl acetate and pentane (1 _s 0 g).

4-Diazo-5-oc-dihydro-androstan-17ß-ol-3-one (compound E )

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BATH ORIGINAL

The diketone (3.5 mg, 0.8 mffol) in 2.0 ml of tetrahydrofuran was added to sodium hydride (48 mg, a 50% dispersion) in 5 ml of tetrahydrofuran. After 30 minutes, tosylazide (157 mg, 0.8 mWol) in tetrahydrofuran was added and the mixture was stirred at 25 ° C overnight. Ether is then added, the mixture is filtered, washed with water, dried and evaporated. Chromatograph the residue and collect the reaction product eluted with 70% ether-gasoline. By recrystallization from chloroform and hexane, 26 mg of yellow crystals was _s melting point 171 ° C.

Example 2

4 ~ benzoyl-5-cC-dihydro ~ androstan = 17.beta.-ol ~ 3-one by the method described in Example 1 (788 mg, 2 mmol) in ~ 2 mL CH ₂ Cl ₂ to Pyridinchlorehromat (650 mg ₉ 3 mmol ), suspended in 2 ml of CH ₂ CL ₂ at 25 ° C. After 2 hours, ether is added and the solution "decanted This is then filtered through Florisil ₉ the eluate is evaporated and the residue recrystallized from chloroform and heptane.

030047/0743

The triketone (350 mg ₉ 0 _s 8 mmol) in 2 _s 0 ml tetrahydrofuran was added to sodium hydride (48Hg. Of a 50 percent dispersion) in 5 ml tetrahydrofuran. After 30 minutes, tosyl azide (157 mg _s 0 _s 8 mmol) was added in tetrahydrofuran was added and the mixture overnight at 25 ° C for "E.ther is then added, the mixture filtered then _{9 s} getrocteiet washed with water. and evaporated «the residue is chromatographed ₉ the reaction product, which was eluted with 70 percent E.ther gasoline _a collected« recrystallization from chloroform and hexane gave 35 bright yellow crystals «

Example 3

The reaction sequence used in this example is illustrated by the following scheme;

il

-SiO ι

CH ₂ OS14

CH ₂ OSi-L CH ₂ OH

CH ₂ OSi-I-

ϊ HC ₆ H ₅

CH ₂ OH ~

CH ₂ OH

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To the used as the starting material aldehyde (16 ₉ 4 g _fl 50 mmol) in ethanol (250 ml) and tetrahydrofuran (50 ml) at 0 ° C a solution of NaBH ₁₅ (675 mg "12 _S 5 mmol) in ethanol (125 ml) was added dropwise. The mixture is stirred overnight at 25 ° C, then neutralized by addition of glacial acetic acid and concentrated in a rotary evaporator »The residue is taken up in chloroform _a then _s washed with saturated Natriümbicarbonat with brine dried and concentrated" The residue xfird of chloroform and pentane recrystallized. A colorless pesticide (12.6 g, 77 %) with a melting point of 132.5 ° C. was obtained

A mixture of (20- ^ e) -21-hydroxy-20 ~ methylpreg-4-en-3- chloride (Io g _s 30.3 mmol) and imidazole in dimethylformamide (50 ml) is over Stirred at 40 ° C. overnight. The mixture is then poured into ice water. The precipitate obtained is filtered off and recrystallized from methanol. Yield 8 _S 6 go

(20- / £) -21 = Dimethyl - ^ - butylsilyloxy-20-methylpreg-4 ~ en-3 ~ one (2.0 g _s 4.5 mmol) in tetrahydrofuran (20 ml) becomes aniline containing ammonia (420 mg, 4.5 mmol) and lithium (100 mg _s 15 mmol) given. After one hour, the blue solution is treated dropwise with isoprene ₉ until the blue color disappears = the ammonia is then allowed to evaporate and the residue is dried under vacuum (0.5 mm). Tetrahydrofuran (20 ml) is then added to the solution _s cooled to 0 ° C and treated with a solution of trimethylsilyl chloride (4 ml) and triethylamine (4 ml), which were centrifuged as before. After 15 minutes the mixture is diluted with pentane and washed with chilled 0.5 M HCl and then with chilled aqueous sodium bicarbonate, dried (magnesium sulfate) and concentrated.

The residue recrystallized from ethyl acetate gave 1.6 g, melting point 113 ° C.

To the enol ether thus prepared (5.08 g, 9.8 mmol) in ether (20 ml), methyl lithium (5.5 ml ^: a 2.05 molar solution, 11.3 mmol) is added. After one hour at 25 °, the solution is taken up in a syringe and slowly added to a solution of benzoyl chloride (1.5 ¹ l g »1» 27 mmol) in ether (30 ml) at -70 ° C. After five minutes, aqueous ammonium chloride is added and the products are isolated by ether extraction. After evaporation of the ether, the residue was recrystallized from chloroform and heptane and gave 450 mg, melting point 169 C.

The silyl ether- (2O / 3, 5o9-4-benzoyl-21-dimethyl-; t-butylsilyloxy-20-methylpregnan-3-one (1.06 g, 2.0 mmol) in dichloromethane (50 ml) is treated with trityl fluoroborate (660 mg, 2 mmol) treated for 1 hour at 25 ° C. This solution will then washed with aqueous ammonium chloride, dried and evaporated. The residue is chromatographed on silica gel. By eluting with 2 percent methanol-chloroform a fraction was obtained which was recrystallized from ethyl acetate pentane. Yield 50 mg, melting point 236-238 ° C.

(2o / 2, 5 ° t) - ⁱ * -benzoyl-21-hydroxy-20-methylpregnan-3-one (436 mg, 1.0 mmol) in tetrahydrofuran (2.0 ml) is added to sodium hydride (48 mg of a 50% dispersion) in tetrahydrofuran (5 ml). After 30 minutes, tosylazide (196 mg, 1.0 mmol) in tetrahydrofuran is added and the mixture is stirred at 25 ° C. overnight. Man: then add ether, filter the mixture, wash it with water, dry and evaporate. The residue is chromatographed on silica gel and the fraction eluted with 70% ether-gasoline collected. Recrystallization from chloroform and hexane gave yellow crystals. (30 mg)

030047/0743

Melting point 210 ° C (decomposition) des (2 (^ ₉ 5co-4-diazo-21-hydroxy-20-methylpregnan ~ 3-one.

Example 4

On ¹ 4-benzoyl-21-oxo-20-methylpregnan-3 ~ - using · (20 / S ₉ 5 ^ö ^ (2OyS, 5oQ- ^1} -benzoyl-21 ~ carboxylic acid methyl esters 20; M -Benzoyl-5G6-dihydroandrost-3 _s 17 dione; 4-benzoyl-50C-H progesterone, etc., the corresponding 4-diazo steroids can be prepared according to the method of diazo transfer described in Example 2.

Example 4A .

(20 / fl ₃ 5 &) -4-Benzoyl- (20/1, 5aQ -21 "OXo-20-methylpregnan-3-one 872 mg (2 mmol) of the (20/3 $ 5 * &) prepared according to Example 3 = 4 ~ benzoyl-21-hydroxy-g ^ ~ £ ~ r20 methyl compound in dichloromethane (2 ml) is (650 mg, 3 mmol) to pyridinium chlorochromate, suspended in 2 ml of dichloromethane at 25 ° C-- ₉ was added. After 20 ml of ether are added for 2 hours and the solution is decanted, which is then filtered through Plorisil, the eluate is evaporated and the residue is recrystallized from chloroform and heptane.

The diketone (350 mg ₉ 0.8 mmol) in 2 ml Teti _s 0 ^ hydrofuran was added to sodium hydride (48 mg of a 50 »prosentigen dispersion) in 5 ml of tetrahydrofuran. After 30 minutes was added in tetrahydrofuran ₍₉ 8 mmol O) and the mixture overnight at 25 ° C for 157 mg of tosyl azide. Ether is then added, the mixture filtered, washed with mass, dried and evaporated. The residue is chromatographed and the solution eluted with 70% ether-gasoline is collected. Yellow crystals (15 mg) were obtained by recrystallization from chloroform and hexane.

Example 4B

4-Benzoyl-5-06-H-20 - ^ - carbonsäurepregnan-3-one The alcohol of Example 3 (872 mg, 2 mmol) in acetone (5 ml) is mixed with an excess of Jones reagent at 25 ° C 4 Treated for hours. Saturated sodium chloride is then added and the mixture extracted with chloroform. The organic phase is washed well with aqueous sodium chloride, then dried and evaporated. The residue is recrystallized from methanol.

Treatment with ethereal excess diazomethane Night and subsequent evaporation of the solvent resulted in the methyl ester.

■ Treatment of 300 mg of the acid with a saturated Solution of isobutylene in methylene chloride (30 ml) overnight at 25 ° C. with the addition of 2 drops of sulfuric acid as a catalyst, the t-butyl ester was obtained. The implementation, -der .Diazo transfer reaction to the 20/3 carboxylate is im following beirv by converting the t-butyl ester For example, described.

4-Diazo-5-c6-H-20-ß-t-butylcarboxypregnan-3-one The t-butyl ester diketone (400 mg, 0.8 mmol) in 2.0 ml of tetrahydrofuran becomes sodium hydride (48 mg of a 50 percent strength Dispersion) in 5 ml of tetrahydrofuran added. After 30 minutes, tosylazide (157 mg, 0.8 mmol) in tetrahydrofuran is added and the mixture is stirred at 25 ° C. overnight. Ether is then added, the mixture is filtered, washed with water, dried and evaporated. The residue is chromatographed and the reaction product eluted with 70% ether-gasoline is collected. Recrystallization from chloroform and hexane gave yellow crystals (40 mg).

030047/0743

Example 5

The sequence of reactions used in this example is carried out the following scheme explains ι

CH ₂ OH

H ₂ OS H-

C ₆ H

CH ₂ OS? +

6Π5

CH ₂ OH

-SfO
I.

CH ₂ OSH-

CH ₂ OH

17 - ^ - Dimethyl-t-butylsilyIoxymethyl-androst- ^ ~ eh-3-one A mixture of IT ^ -hydroxymethylandrost-Jl-en - ^ - one. (1 »O g» 3.5 nanol), t-butyldimethylsilyl chloride (627 mg, 4.2 mmol) and imidazole (287 mg, 4.2 mmol) in 4 ml of dimethylformamide is stirred at 40 ° C. overnight. The mixture is then poured into ice water, the precipitate obtained is filtered off and recrystallized from methanol. Yield 1.35g.

methyl-androsta-3-en '. ^

12.0 g of the compound obtained by the above procedure (29.8 mmol) in tetrahydrofuran (70 ml) becomes ammonia

containing aniline (2.7 g »29.8 mmol) in lithium (625 mg, 89 mmol) was added. After 1 hour, the blue solution is treated dropwise with isoprene until the blue color disappears. The ammonia is allowed to evaporate and the residue is dried under vacuum (0.5 mm). 50 ml of tetrahydrofuran are then added, the solution is cooled to 0 ° C. and treated with a solution of trimethylsilyl chloride (12 ml) and triethylamine (12 ml) which have previously been centrifuged. After 15 minutes, the mixture is diluted with pentane and first washed with chilled 0.5 M HCl, then with chilled aqueous sodium bicarbonate, dried (magnesium sulfate) and concentrated. The residue crystallizes from ethyl acetate, yield 6.6 g. The mother liquors were chromatographed on silica gel. "By eluting with 10 % ether-pentane, a fraction was obtained which was recrystallized from ethyl acetate, yield 2.4 g. 4-Benzoyl-5-ofc-dihydro-17 /? - dimethyl-t- butylsilyloxy-methyl androstan-3-one

To the enol ether (4.89 g, 10.27 mmol) in ether (20 ml) is methyl lithium (5.5 ml of a 2.05 molar solution, 11.3 mmol) was added. After one hour at 25 ° C

030047/0743

the solution was taken up in a syringe and slowly added to a solution of benzotrichloride (1 ^ 5 g _s 1O ₉ 3 mmol) in ether (30 ml) at 70 ° C. After 5 minutes, aqueous ammonium chloride is added and the products are isolated by ether extraction. After the ether has been evaporated off, the residue is recrystallized from carbon tetrachloride. Yield 2.2g.

The silyl ether (i, _s 64 g 3 ₉ 2 mmol) in dichloromethane (50 ml) is treated with Tritylfluoroborat (1 g ₉ 27 ₉ 3 ₉ 84 mmol) for 1 hour at 25 ° C. The solution is then washed ₉ with aqueous ammonium chloride, dried and evaporated. The residue is chromatographed on silica gel. By eluting with 1% methanol-chloroform gave a Fraktionj, which was recrystallized from ethyl acetate and pentane ₉ mg yield 800th - -

The diketone (350 mg ₉ 0 _s 8 mmol) in tetrahydrofuran (2 ₉ 0 mL) (mg 48 of a 5o percent dispersion) to sodium hydride in 5 ml of tetrahydrofuran was added _o After 30 minutes tosyl azide (157 _s SNG O ₉ S mmol ) in tetrahydrofuran and the mixture was stirred at 25 ° C. overnight. You are dann.Ether to "filtered the Misehung ₉ is washed with water _s dried and evaporated. The residue is chromatographed and the reaction mixture, which has eluted with 70% ether-petrol, is collected. Recrystallization from chloroform and hexane gives yellow crystals (30 mg).

Example 6

The ⁱ i = benzoyl-5e ^ dihydro-17 ~ / l-hydroxymethyl-androstan-3-one can be oxidized to the corresponding 17/3-aldehyde or 17 / & acid esteroids and then converted into the 4-diazo derivative in question »

(A) Methyl-4-benzoyl-5-e & -dihydro-17/3-carboxylate-androstan- 3-one

The alcohol (872 mg, 2 mmol) in 5 ml of acetone is treated with an excess of Jones reagent at 25 ° C. for 4 hours. Saturated sodium chloride is then added and the mixture extracted with chloroform. The organic phase is washed well with aqueous sodium chloride, then dried and evaporated. The residue is recrystallized from methanol to obtain the ßβ carboxylic acid. To prepare the 17 / S-carboxylate ester, for example the methyl ester, the residue is treated with an excess of ethereal diazomethane. After 10 minutes the solvents are evaporated and the residues are recrystallized from methanol.

Methyl-4rdiazo-5 "<'fc-dihydro-androstane-17 / ^ - cai3Oxylat-3-one The diketone (350 mg, 0.8 mmol) in tetrahydrofuran (2.0 ml) is added to sodium hydride (48 mg of a 50 percent dispersion) in 5 ml of tetrahydrofuran.After 30 minutes, tosylazide (157 mg, 0.8 mmol) in tetrahydrofuran is added and the mixture is stirred overnight at 25 ° C. Ether is then added, the mixture is filtered and washed with water , dried and evaporated. The residue is chromatographed, the reaction product eluted with 70% ether-gasoline collected. 30 mg of yellow crystals are obtained by recrystallization from chloroform and hexane. 4-Diazo-5-06-dihydro-androstane-17 ^j /? -carboxylic acid-3-one The 17'yj-carboxylic acid (350 mg, 0.8 mmol) in tetrahydrofuran (2.0 ml) is converted to sodium hydride (96 mg, 2 mmol of a 50 percent dispersion) in tetrahydrofuran (5 ml) After 30 minutes, tosyl (157 mg, 0.8 mmol) in tetrahydrofuran is added and the mixture is stirred overnight at 25 ° C. 60 mg are then added Acetic acid and then ether are added, the mixture is filtered and washed with

030047/0743

Water, dry and evaporate. The residue is chromatographed and the reaction product eluted with 70% ether-gasoline is collected. Recrystallization from chloroform and hexane gives 20 mg of yellow crystals. (B) ^ -Benzoyl-5 ° -® ^ rdihydro-17 ° ^ -carboxaldehyde-edrostan- 3 ~ one

The alcohol (872 mg _s 2 mmol) in dichloromethane (2 ml) is added to pyridine chlorochromate (65 mg _s 3 mmol) suspended in dichloromethane (2 ml) ₅ at 25 ° C. After 2 hours, 20 ml of ether are added and the solution is decanted. This is then filtered through Plorisil, the eluate is evaporated and the residue is recrystallized from chloroform and heptane.

M-Diazo-5- <8 £ rdihydro-androstan-17 /? - carboxaldehyd-3-one The diketone (350 mg _s 0.8 mmol) in 2 ml tetrahydrofuran becomes sodium hydride (H 8 mg of a 50 percent dispersion) added in 5 ml of tetrahydrofuran. After 30 minutes, tosylazide (157 mg, 0 _s, 8 mmol) in tetrahydrofuran is added and the mixture is stirred at 25 ° C. overnight. Ether is then added to _a , the mixture is filtered, washed with water, dried and evaporated. The residue is chromatographed _s eluted with 70% ether-gasoline reaction product collected by recrystallization from chloroform and hexane are obtained 26 mg of yellow crystals.

Example 7

One gram of ji-benzoyl = 5-® £ rdihydro-androstan-17/3 ~ ol-3-one, prepared according to the method of Example 1 in 5 ml of pyridine and 5 ml of acetic anhydride is 10 hours at Maintained 25 ° C and then diluted with ether. The ether solution is made with 1 N HCl, and saturated sodium bicarbonate washed j, then dried, evaporated and the residue recrystallized from ethyl acetate. The 17-acetate was obtained.

M-Diazo-5 - ^ - dihydro-androstane-17-acetyloxy-3-one

The triketone (350 mg _s 0.8 mmol) in tetrahydrofuran (2.0 ml)

is added to sodium hydride ( ¹ 18 mg of a 50 percent dispersion) in 5 ml of tetrahydrofuran. After 30 minutes, tosylazide (157 mg, 0.8 mmol) in tetrahydrofuran is added and the mixture is stirred overnight at 25 ° C. Ether is then added, the mixture is filtered, washed with water, dried and evaporated. The residue is chromatographed and the reaction mixture eluted with 70% ether-gasoline is collected. Recrystallization from chloroform and hexane gives yellow crystals (30 mg).

Example 8

The conversion of progesterone is described in this example.

5-Trimethylsiloxy-5- ° for "H-20-ethylenedioxyprogest-5-en . 20-Ethylenedioxy-progesterone (10.7 g> 30 mmol) in 70 ml of tetrahydrofuran were converted into aniline" containing ammonia (2.7 g, 30 MMoI) and lithium (625 mg, 89 mmol) were added. After 1 hour the blue solution was treated with isoprene dropwise until the blue color disappeared. The ammonia was allowed to evaporate and the residue was dried under vacuum (0.5 mm). Tetrahydrofuran (50 ml) was then added, the solution cooled to 0 ° C and treated with a solution of trimethylsilyl chloride (12 ml) and triethylamine (12 ml) which had previously been centrifuged. After 15 minutes the mixture was diluted with pentane and washed with chilled 0.5 molar HCl and then with chilled aqueous sodium bicarbonate, dried (magnesium sulfate) and concentrated. The residue was crystallized from ethyl acetate, giving 6.0 g. ty-Benzoyl-5-o & -H-20-ethylenedioxy-pregnan-3-one To the enoil ether (Ί, ή g, 10.27 mmol) in 20 ml of ether was methyllithium (5 »5 ml of a 2.05 molar solution , 11.3 mmol) was added. After 1 hour at 25 ° C, the solution is with

was added by syringe, and (g 1, ¹ IS, 10.3 mmol) slowly to a solution of benzoyl chloride in ether at -70 ° C (30 ml). After 5 minutes, aqueous ammonium chloride is added. The products are isolated by extraction with ether. After the ether has been evaporated off, the residue is crystallized from carbon tetrachloride, yield 2.1 g. The acetal (1.1 g) in acetone (100 ml) containing p-toluenesulfonic acid (100 mg) is stirred at 25 ° C. overnight, and the solvent is then evaporated off. The residue is dissolved in ether and washed with aqueous sodium bicarbonate, then dried and evaporated. 800 mg of the triketone are obtained.
^ -Diazo-5-oCrH-t> regnan-3,20-dione

The triketone (355 mg, 0.8 mmol) in tetrahydrofuran (2.0 ml) is added to sodium hydride (Ί8 mg of a 50 percent dispersion) in 5 ml of tetrahydrofuran. After 30 minutes, tosyl azide (157 mg, 0.8 mmol) in tetrahydrofuran * is added and the mixture is stirred overnight at 25 ° C. Ether is then added, the mixture is filtered, washed with water, dried and evaporated. The residue is chromatographed and the reaction product eluted with 70% ether-gasoline is collected. Recrystallization from chloroform and hexane gives 40 mg of yellow crystals.

Example 9

The conversion of ' ¹ I', 5 * Dihydrospiro-randrost ^ 1-ene-17,2 '-3-one ^v is illustrated by the following reaction scheme:

030047/0743

HH

7015

0 C ₆ Hg

H ', 5' -Dihydrospiro fc-trimethylsiloxy-SeC-dihydro-androst-3-en-17,2 '(3' H) furatQ

Cyclic ether (9 8 ₉ g, 30 nunol) in 70 ml tetrahydrofuran was added to ammonia-containing aniline (2.7 g _s 30 mmol) and lithium (625 mg, 89 mmol) was added. After 1 hour, the blue solution is treated dropwise with isoprene until the blue color disappears. The ammonia is then allowed to evaporate and the residue is dried under vacuum (0.5 mm). 50 ml of tetrahydrofuran are then added, the solution is cooled to 0 ° C. and treated with a solution of trimethylsilyl chloride (12 ml) and triethylamine (12 ml) which have previously been centrifuged. After 15 minutes, the mixture is diluted with pentane and washed with chilled aqueous sodium bicarbonate, then dried (magnesium sulfate) and concentrated. The residue crystallized from ethyl acetate. Yield 7.0g.
H ', 5'-Dihydrospiro pt-benzoyl-5 ~ flfc "clihydro-androstane-17» 2 *

To the enol ether (4.5 g, 10.27 mmol) in 20 ml of ether Methyllithium (5 * 5 ml of a 2.05 molar solution, 11.3 mmol)

030047/0743

added =, After 1 hour at 25 ° C, the solution is taken up in a syringe and slowly added to a solution of benzoyl chloride (1 _s iJ5 g _s 10 _S 3 mmol) in 30 ml of ether at -70 ° C. After 5 minutes, aqueous ammonium chloride is added and the products are isolated by ether extraction. After evaporation of the ether, the residue is recrystallized from carbon tetrachloride _s yield 2 _S 2 g.

H ', 5'-Dihydro | Vdiazo-5 ^ -dihydro-androstane-17 ° _S 2'(3'-H) furanJ-3-one

The diketone (320 mg _s 0.8 mmol) in 2 _s 0 ml of tetrahydrofuran is added to sodium hydride (48 mg of a 50 percent dispersion) in 5 ml of tetrahydrofuran. After 30 minutes, tosylazide (157 mg _s 0.8 mmol) in tetrahydrofuran is added and the mixture is stirred at 25 ° C. overnight. Are then added to ether _s the mixture is filtered _three washes with water _s dried and evaporated off. The residue is chroma "" tographierts eluted with f0% ether-gasoline reaction product collected by recrystallization from chloroform and hexane are obtained 35 mg of yellow crystals. Alternatively, the installation and removal, the protective group in the manner done _s that, for example, with an aldehyde begins _s as will be explained briefly below. compound H is protected as an acetal by treatment of one equivalent of the aldehyde with one equivalent of ethylene glycol using acid as catalyst in benzene or toluene at a temperature of about 80 ° to 120 ° C with removal of the excess water _{ for example with the aid of a Dean Stark Palle. The aldehyde protected as acetal is then the dissolving metal reduction using lithium in ammonia in aniline or tertiary butanol as proton donor at -78 ° to 33 ° C for a period of 1 to

Subject to minutes. The enolate ion is made with trimethylsilyl chloride fixed in the manner already described. The enolate anion is then generated using alkyl lithium, such as methyllithium or butyllithiura, in ethers such as tetrahydrofuran or Diethyl ether, at 0 to 25 ° C within 1 to 60 minutes regenerated and treated with benzoyl chloride or a lower alkyl acid chloride for 1 to 20 minutes at -100 ° to -70 ° C in, for example, diethyl ether or tetrahydrofuran implemented so that the compound L is obtained.

The aldehyde function is restored by treatment with acetone or butanone in the presence of a catalytic amount of p-toluenesulfonic acid or a mineral acid for a period of 1 to 24 hours at 25 ° to 50 ° C. Dxe Dxazogruppe can dannYaer introduced the 4-position of the aldehyde derivative directly, or can be the aldehyde first to the corresponding acid by known methods _for example by oxidation with silver oxide, or by Jones-reduction or reduction to the corresponding alcohol by known processes, such as convert the treatment with borohydride in lower alcohols such as ethanol or tetrahydrofuran at 0 ° to C for 1 to 12 hours and then introduce the dxazo group. The diazo transfer is carried out using p 1-toluenesulfonyl azide as described above.

Example 10 (20SS _J 5 ^{<^!)} - 4-diazo-21-oxo-methylpregnan-5-one

(20β) -21-Ethylenedioxy-20-methylpreg-4-en-3-one (2.0 g, 4.5 mmol) in 20 ml of tetrahydrofuran is converted to ammonia-containing aniline (420 mg, 4.5 mmol) and lithium (100 mg,

030G47 / 0743

15 mmol) was added. After 1 hour, the blue solution is treated dropwise with isoprene until the blue color disappears. The ammonia is then allowed to evaporate and the residue is dried under vacuum (0.5 mm). 20 ml. Tetrahydrofuran are then added, the solution is cooled to 0 ° C. and treated with a solution of trimethylsilyl chloride (4 ml) and triethylamine (4 ml) which have previously been centrifuged. After 15 minutes, the mixture is diluted with pentane, washed first with cooled 0.5 molar hydrochloric acid and then with cooled aqueous sodium bicarbonate, dried (magnesium sulfate) and concentrated. The residue crystallizes from ethyl acetate _9, yield 1.6 g.

To the enol ether (5.08 g, 9.8 mmol) in 20 ml of ether, methyl lithium (5.5 ml of a 2 _s 0.5 molar solution _s 11, 3 mmol) is added. After 1 hour at 25 ° C, the solution is taken up in a syringe and slowly added to a solution of benzoyl chloride (1.5M g, 1.27 mmol) in ether (30 ml) at -0 ° C. After 5 minutes, aqueous ammonium chloride becomes. sug added. The products were isolated by ether extraction * After evaporation of the ether, the residue from chloroform and heptane recrystallized _s yield ^ 50 will mg "The acetal (1 g) contains in 200 ml Äceton _s 50 mg of p-toluenesulfonic acid overnight at 25 ° C stirred and then concentrated. The residue crystallizes from dichloromethane and heptane. The aldehyde is obtained in this way.

'.C20ßj 5A) -Ί-Benzoyl-21-oxo-20-methylpregnan-3-one (436 mg, I ₉ O mmol); in 2.0 ml of tetrahydrofuran is added to sodium hydride (48 mg of a 50 percent dispersion) in 5 ml of tetrahydrofuran were added. After 30 minutes, tosylazide (196 mg, 1.0 mmol) in tetrahydrofuran is added and the mixture is stirred at 25 ° C. overnight. Then you give ether

to, the mixture filtered, washed with water, dried and evaporated. The residue is chromatographed on silica gel and the fraction eluted with 70% ether-gasoline is collected. Recrystallization from chloroform and hexane gave 30 mg (20β, 50O-4-diazo-21-oxo-20-methylpregnan-3-one ..

030047/0743

OT ₆ H ₅ or alkyl Cx_

or

alkyl Ci_ ₄

TMSO

> C _e H ₅ or alkyl C

CH ₂ OH

C _e H ₅ or alkyl C _{a- 4}

^: TMS0 means trimethylsilyloxy

0300 * 7/0743

Example 11

CH ₂ OH

Lithium tetrafluoroborate (2.8 g, 30 mmol) was added to the silyl ether (5.5 g, 10 mmol) in 200 ml of methylene chloride and 125 ml of acetonitrile. The mixture was stirred at room temperature for 60 hours. The mixture was then washed with water, aqueous sodium bicarbonate and aqueous common salt solution, dried (magnesium sulfate) and concentrated. Recrystallization of the residue from methylene chloride and heptane gave the alcohol (3.8 g, 86 %).

For: Richardson-Merrell Inc. Wilton, Conn., V.St.A.

Dr.H.phr.Beil Lawyer

030047/0743

Claims (4)

Claims wherein R = O, -OH, -OCO-alkylC ^, -COOH, -CH ₂ OH, -COOAlkylC ₁ _ _6, -COCH _3, f ^H 3? ^H 3 I 1 -CH-COOH, -CH-COOAlkylC _1-6 , O, ^ 'or one CH ₃ CH ₃ of the 20ß-isomers of -CH-CH ₂ OH, -CH-CHO, Ptl CV CH ₃ CH ₃ -CH-COOH or -CH-COOAlkylC _fi means. 2. (5a, 20β) -4-diazo-21-hydroxy-20-methylpregnan-3-one, 3. Preparations for the treatment of acne or oily skin, containing one of the compounds according to Claim 1. 4. Process for the preparation of one of the compounds according to claim 1, characterized in that a compound with the general formula 030047/0743 , jOJ wherein R has the meanings defined above and optionally with the formation of a siloxy ether or a ketal is blocked, reacted with Triraethylsilylchlorid and then with a suitable Treated hydrogenating agent, the resulting compound of the formula then with an alkyl lithium and with benzoyl chloride or a lower alkyl acid chloride with 1-Ί Carbon atoms forming a compound the formula. R " Λ Η C ₆ H ₅ reacts, and this then with sodium hydride or a lower trialkylamine and p-toluenesulfonyl azide converts, the blocking of R being removed, if appropriate, immediately before the diazo transfer reaction. 030047/0743 5 · Process for the preparation of the compounds according to Claim 3, if R is not ΓΊ ' ■ .0 ^, - ' is characterized in that one
a compound of the formula converted into the 18-acetal, this with trimethylsilyl chloride reacted and treated with a suitable hydrogenating agent, the compound of the formula thus formed TMSO with an alkyl lithium and with benzoyl chloride or a lower alkyl acid chloride to form a compound of the formula 030047/0743 converts the aldehyde function by treatment with Recovers acetone or butanone in the presence of a catalytic amount of p-toluenesulfonic acid and the compound obtained with sodium hydride or a lower trialkylamine and p-toluenesulfonazide treated, the aldehyde being converted into the corresponding acid or alcohol, 'as desired. 030047/0743