DE2459467A1 - 4,5 SECO STEROIDS, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS - Google Patents

Description

DIPL.-CHEM. DR. VOLKER VOSf.HIS PATENT ADVERTISER

SIEBERTSTRASSE 4

PHONE: 474075

CABLE ADDRiHSS: BENZENE PATENT MÖNCHEN TELEX 6-23453 VOPAT D.

u.z .: L 123 (Vo / kä) Case: P-522179-S

HE. SQUIBB & SONS, INC., Princeton, New Jersey, V.St.A.

"4,5-seco-steroids, process for their manufacture and pharmaceuticals "

Priority: December 20, 1973, V.St.A., no.427 168 November 8, 1974, V.St.A., No. 522 179

The invention relates to new 4,5-seco-steroids of the general kind

Formula I.

CH ₂ -R ₁

Y- -

(D

Il

in which A is the group -C = CH, -CH = CH ₂ , -CH ₂ CH ₃ or -C-CH ₃ , X ^ is a hydrogen, fluorine, chlorine or bromine atom and.ft,

• a hydrogen, ₀ fluorine, chlorine, bromine or iodine atom, a hydroxyl or ~ OC-R ₂ group P, wherein R ₂ represents a lower alkyl group, lower one is a hydrogen atom,

_{L is an} alkyl radical or an aryl radical, Q is a lower alkyl radical

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or an aryl radical, Y a hydrogen atom and Y ^! represents a hydroxyl group or Y and Y ¹ together represent a carbonyl oxygen atom.

The invention also relates to a process for the preparation of the compounds of general formula I, which is characterized is that a compound of the general formula III

C = O

(III)

in which X ₁ , R ₁ , P, Q, Y and Y 'have the above meanings, treated with p-toluenesulfonylhydrazide in a weakly acidic medium and optionally the compound of the general formula IV obtained.

0- ^

in which X ₁ , R ₁ , P, Y and Y ^{1 have} the above meaning, (a) .partially reduced to the compound of the general formula I in which A represents the group -CH = CH ₉ , or

1 * ~

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-D-

(b) reduced to the compound of the general formula I in which A represents the group -CH ₂ -CH ^, or

(C) hydrated in an aqueous acidic medium in the presence of mercury (II) sulfate to give the compound of the general formula I in which A represents the group -C-CH ₃ .

The lower alkyl radicals are unbranched or branched Residues with 1 to 7 carbon atoms are possible, such as the methyl, ethyl, propyl, isopropyl, tert-butyl and heptyl groups. Alkyl radicals with 1 to 3 carbon atoms are preferred.

The aryl radicals are monocyclic or bicyclic carbocyclic aromatic ring systems with 6 or 10 carbon atoms in question, namely the phenyl or naphthyl group. Preferred are optionally through halogen atoms, such as fluorine, chlorine, bromine or iodine atoms, lower alkyl or alkoxy radicals ihenyl groups substituted with 1 to 7 carbon atoms. The phenyl group is particularly preferred as the aryl radical.

The compounds of general formula I are valuable medicinals. neural substances with anti-inflammatory activity. This could be shown by the reverse passive Arthus skin reaction and the active Arthus reaction in the mouse. The compounds of the general formula I can be administered to reduce joint swelling, tenderness, pain and stiffness in diseases such as rheumatoid arthritis . Surprisingly, in the compounds of general formula I, compared to the corresponding 3-keto-A ⁴ -steroids of general formulas II and VIII, hormonal Ne.ben-

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Effects significantly reduced or absent.

Compounds of the general formula I in which R _{1 is} a hydrogen, fluorine or chlorine atom and X _{1 is} a hydrogen or fluorine atom, can be selected from steroids of the general formula II

(II)

in which JL and X ₁ are as defined above. When the steroids of the general formula II are reacted with hydrogen peroxide in the presence of a base such as sodium or potassium hydroxide, 4,5-epoxy steroids of the general formula III are obtained. The reaction is generally carried out in a polar organic solvent, preferably a lower aliphatic alcohol such as methanol, at temperatures from about 0 to 40 ^° C. and for a period of from 2 to 168 hours, preferably at room temperature for 72 to 120 hours. The 4,5-epoxy steroids of the general formula III are then reacted with p-toluenesulfonylhydrazide to give the 4,5-seco-steroids of the general formula I, in which R _{1 is} a hydrogen, fluorine or chlorine atom, X _{1 is} a hydrogen or Fluorine atom and A denotes an ethynyl group. These compounds have the general formula IV. The reaction is generally carried out in an organic solvent or solvent mixture, for example a halogenated hydrocarbon,

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at temperatures from 0 to 40 ° C for a period of
2 to 24 hours, preferably “at temperatures — from 0 to 30 ^° C. for a period of from 4 to 16 hours.

Compounds of the general formula I in which R _{1 is} a hydrogen, fluorine or chlorine atom, X _{1 is} a hydrogen or fluorine atom and A is an acetyl group, i.e. compounds of the general formula V-

, P Q

(V)

^l 3 -

can be prepared by hydrating a compound of the general formula IV in the presence of mercury (II) sulfate. The reaction is in an aqueous-acidic medium, for example a mixture of formic acid or acetic acid and a lower aliphatic alcohol such as methanol, at temperatures from 0 to 80 ⁰ C for a period of 30 minutes to 24 hours, preferably at temperatures from 50 to 70 ⁰ C for a period of 30 minutes to 2 hours, Gurchge-. leads. '.' ■ '■

The reduction of the compounds of the general formula IV gives compounds of the general formula I in which R _{1 is} a hydrogen, fluorine or chlorine atom, X _{1 is} a hydrogen or

Fluorine atom and A denotes an ethyl group, that is, Verbin-L_J

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fertilize the general formula VI

Y ¹ \ ι I CH ₉
I. -R
1 ^ c- XtJ C = O ._ O Γ I. CH.,
I ² CH.

(VI)

The reduction can be carried out at atmospheric pressure by catalytic hydrogenation be carried out in the presence of palladium or platinum (from platinum oxide). .

The partial hydrogenation of the compounds of the general formula IV gives compounds of the general formula I in which R _{1 is} a hydrogen, fluorine or chlorine atom, X _{1 is} a hydrogen or fluorine atom and A is the vinyl group, i.e. compounds of the general formula VII

(VII)

The hydrogenation can be carried out at atmospheric pressure in the presence of a small amount Amount, for example about 0.1 to 5.0 percent by weight, of a poisoned hydrogenation catalyst, such as with synthetic

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Quinoline-poisoned palladium.

Compounds of the general formula I in which R _{1 is} a Hydroff
xyl- or -OC-Rp, a chlorine, bromine or iodine atom and X ₁ denotes a hydrogen or fluorine atom, can be selected from steroids of the general formula VIII

■ F ^H 2- ° ^H

getting produced. The hydroxyl group in the 21-position of the steroid of the general formula YIII is first blocked with a protective group such as a tetrahydropyranyl group. The reaction of the steroid of the general formula VIII with dihydropyran may be an organic solvent such as benzene, can be carried out at temperatures of 0 to 100 ⁰ C in the absence or presence. The reaction takes about 1 to 24 hours in the presence of an acidic catalyst.

The steroid with the hydroxyl group protected in the 21-position is then oxidized with hydrogen peroxide in the presence of a base. The corresponding 4,5-epoxy compound is obtained, which is then cleaved with an acid to give 21-hydroxy-4,5-epoxysteroid and then reacted in the manner described above to prepare compounds of the general formula I in which R _{1 is} a Hydroxyl group and X ₁

Means hydrogen or fluorine atom. L

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The reaction of compounds of the general formula I in which R _{1 is} a hydroxyl group and X _{1 is} a hydrogen or fluorine atom with a carboxylic acid anhydride of the general formula (RpCO) pO gives the corresponding 21-alkanoyloxy compounds. The reaction is generally performed in an organic solvent such as pyridine, at temperatures from 0 to 40 ⁰ C over a period of 1 to 24 hours, preferably at temperatures of 0 to 3O ⁰ C over a period of 1 to 4 hours is performed.

The reaction of the compounds of general formula I, in which R _{1 is} a hydroxyl group and X _{1 is} a hydrogen or fluorine atom, with a lower alkyl or arylsulfonyl chloride, such as methanesulfonyl chloride or p-tolylsulfonyl chloride, gives the corresponding 21-sulfonates. The reaction is generally carried out in the presence of an organic base, such as pyridine, at temperatures from 0 to 20 ^° C. under anhydrous conditions. The reaction of the 21-sulfonate with an inorganic halide such as potassium fluoride, lithium chloride, lithium bromide or sodium iodide gives the corresponding 21-halogen compounds of the general formula I. The reaction is generally carried out in a polar organic solvent such as dimethylformamide or acetone by 1- carried out refluxing for up to 12 hours, preferably 2 to 4 hours.

Compounds of the general formula I in which X _{1 is} a bromine atom can be prepared from the corresponding compounds of the general formula I in which X _{1 is} a hydrogen atom, Y is a hydrogen atom and Y 'is a hydroxyl group.

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tet, that is, from compounds of the general formula IX

A O

CH,

(IX)

The reaction of the compounds of the general formula IX, in which R ^ denotes a radical other than the hydroxyl group, with a lower alkyl sulfonyl chloride in a polar organic solvent such as dimethylformamide, in the presence of a organic base, such as pyridine, provides Δ ^ 'compounds of the general formula X

(X)

A O

in which Ry means a radical other than the hydroxyl group. The reaction can be carried out at room temperature for a period of time from about 4 to 24 hours, preferably for about 4 to 12 hours.

The 9a-bromine compounds of the general formula I are indicated by -. Reaction of the intermediate of the general formula X with an N-bromamide or N-bromimide of a carboxylic acid or its ■

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Derivatives, for example N-bromoacetamide or an N-bromamide of another lower fatty acid, N-bromosuccinimide or dibromodimethylhydantoin, manufactured. Preferably, the reaction in the presence of perchloric acid or another is proportionate strong acid, such as p-toluenesulfonic acid or trichloroacetic acid, performed with the 11ß-hydroxy compound does not form an ester.

Compounds of the general formula I in which FL is a hydroxyl group and X ^ means a bromine atom - are referenced to the above described manner, but two more steps are required. Before implementing the compounds of general Formula IX with a lower alkyl sulfonyl chloride to produce the Δ 'compounds must protect the 21-hydroxyl group be, for example by reaction with acetic anhydride. After the formation of the 9 ″ bromine compound, the protecting group becomes cleaved for example by reacting with a base.

Compounds of the general formula I in which X ^ is a fluorine, Means chlorine, bromine or iodine atom, can also by reacting a compound of the general formula XI

CH ₂ R ₁ .

OQ

(XI)

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with a hydrogen halide, preferably in an alcohol, free solvent, forming a compound of the general Formula XII

HO

(XII)

in which X ₁ denotes a fluorine, chlorine, bromine or iodine atom and this compound is reacted as described for the compounds of the general formula II.

Compounds of the general formula I in which P and 'Q are methyl groups are preferred. Compounds of the general formula I in which X _{1 represents} a hydrogen or fluorine atom are preferred. Those compounds in which X _{1 is} a fluorine atom are particularly preferred. Furthermore, compounds of the general formula I are preferred in which Y is a hydrogen atom and Y 'is a hydroxyl group. Finally, compounds of the general formula I are preferred in the FL

■ ι »

means a halogen atom. Compounds of the general formula Ii in which R _{1 represents} a chlorine atom are particularly preferred.

The examples illustrate the invention.

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example 1

21 -Chlor-9-fluorine-11β, 16g, 17-trihydroxv-4,5-secoT) regn-3-yn-5,20-dione-16.17-acetonide

a) 21 -Chlor-4,5-epoxy-9-fluorine-11 ß, 16g «IT-trihydroxv ^ ß-pregnane-3,20-dione-16,17-acetonide

A solution of 1.0 g of 21-chloro-9-fluoro-11β, 16a, 17-trihydroxypregn-4-en-3,20-dione-16,17-acetonide in TOO ml of methanol becomes "at ⁰ ° C. with 6 , 2 ml of a 30 percent hydrogen peroxide solution and 4.1 ml of a 4 η sodium hydroxide solution are added. After 150 minutes the slurry is allowed to warm to room temperature and stirred for 15 ms for 18 hours. The slurry is then diluted to 2 liters with water and filtered. 978 mg) is chromatographed on two 1 mm thick silica gel plates with a mixture of chloroform and ethyl acetate in a volume ratio of 5: 1. The iodine-absorbing band that appears above the remaining starting material is cut out and mixed with a mixture of ethyl acetate and methanol in a volume ratio 9: 1 eluted. The eluate is evaporated. Yield 560 mg of a solid. After recrystallization from aqueous ethanol, 409 mg of the title compound with a melting point of 254 to 256 ^° C. are obtained.

b) 21-chloro-9-fluoro-11β, 16q, 17-trihydroxy-4,5-secopregn-3-yne-5,20-dione-16,17-acetonide

A solution of 1.413 g of 21-chloro-4,5-epoxy-9-fluoro-11β, 16a, 17-trihydroxy-5β-pregnane-3,20-dione-16,17-acetonide in 36.9 ml of a mixture of dichloromethane and acetic acid in the volume ratio 1: 1 is cooled to 0 ⁰ C and treated dropwise with a solution of 564.9 mg of p-toluenesulfonyl hydrazide in 36.9 ml of a geminal J

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added dichloromethane and acetic acid in a volume ratio of 1: 1. The mixture is stirred for 2 hours at ⁰ ° C. and for 15 to 18 hours at room temperature, then poured into ice water and extracted several times with diethyl ether. The ether extracts are combined, washed with 10 percent sodium carbonate solution and water and dried over sodium sulfate. The solvent is then distilled off under reduced pressure. 1.36 g of a yellowish product remain, which is chromatographed on a column filled with 20 g of silica gel HF with a mixture of hexane and ethyl acetate in a volume ratio of 6: 1 as the mobile phase. The first 450 ml of the eluate are evaporated under reduced pressure. Yield 1.16 g of a compound which is homogeneous in the thin layer chromatogram. After recrystallization from a mixture of ethyl acetate and hexane 793,4mg of the title compound are obtained, melting at 201 to 203 ⁰ C.

Example 2

21-chloro-9-fluoro-11β, 16a, 17-trihydroxy-4,5-seco-pregnan-3,5,20 trione-16,17-acetonide

A solution of 659.2 mg of 21-chloro-9-fluoro-11β, 16a, 17-trihydroxy-4,5-seco-pregn-3-yne-5,20-dione-16,17-acetonide (prepared according to Example 1) in a mixture of 8.3 ml of 85 percent formic acid and 8.3 ml of 80 percent aqueous methanol is added to a solution of mercury (II) sulfate, which is made up of 50 mg of mercury (II) oxide, 0, 08 ml of sulfuric acid and 1.9 ml · water was prepared. After 30 minutes of standing at 60 ⁰ C, the solution is cooled to 0 ⁰ C, 15 to 18 hours at. left to stand at this temperature and then extra- _j with diethyl ether

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here. The ether extract is mixed with 2 percent sodium carbonate solution and 8 percent aqueous saline solution and dried. The solvent is distilled off under reduced pressure. 670 mg of crude product are obtained, which are combined with 225 mg of crude product from another batch. That combined product is chromatographed on silica gel plates. After developing with a mixture of hexane and ethyl acetate The iodine-absorbing main band is cut out in a volume ratio of 2: 1 and treated with a mixture of ethyl acetate and methanol eluted in a volume ratio of 9: 1. The eluate is evaporated under reduced pressure. The residue becomes from a Recrystallized mixture of ethyl acetate and hexane. Yield 464 mg of a solid, which on a filled with silica gel Column is chromatographed with a mixture of ethyl acetate and hexane in a volume ratio of 4: 1. The eluate is reduced under The pressure was evaporated and the residue was recrystallized from a mixture of hexane and ethyl acetate. Yield 320 mg of the title compound with a melting point of 235 to 236 ° C (decomp.). The product is homogeneous by thin layer chromatography.

Example 3

21-chloro-9-fluoro-11β, 16a, 17-trihydroxy-4,5-seco-pregnane-5,20-dione-16,17-acetonide

A solution of 682.5 mg of 21-chloro-9-fluoro-11β, 16a, 17-trihydroxy-4,5-seco-pregn-3-yne-5,20-dione-16,17-acetonide (prepared according to Example 1) in 15 ml of ethyl acetate is hydrogenated in the presence of 205 mg of a 10 percent palladium-on-charcoal catalyst at atmospheric pressure. After 1 hour, 63 ml of ⁴ hydrogen have been taken up. After 2 hours the catalyst,

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■ - -ν * · 2459A67.

filtered off and the filtrate evaporated under reduced pressure. Yield 630.9 mg of crude product. After recrystallization from a mixture of ethyl acetate and hexane 377.5 mg of the title compound, melting at 219-220, -5 ⁰ C ^ hslten.

· ■. "B e i s ρ i e 1 e 4 to 8

According to Example 1, but using those listed in column I. Steroids, are the products listed in Column II obtain.

example

Column I.

Column II

9-Fludr-1.1 ß, 16a, 17-tri- 9-fluoro-11 ß, 16a, 17-trihydroxy-pregn-4-enxy-4, 5-seco-pregn-3-yne-3,20-dione-i6,17-acetonide 5,20-dione-16,17-acetonide

11β, 16a, 17-trihydroxy- ' pregn-4-en-3,20-dione-16,17 ~ acetonide

9.21 -Difluor-11ß, 16a, 17-trihydroxvOregn-4-ene-3,20-dione-16,17-acetonide

11β, 16a, 17-trihydroxy-4,5-s.eco-pregn-3-yne-5,20-dione-16,17-acetonide

9,21-difluoro-11ß, 16a, 17-trihydroxy-4,5-seco-pregn-3 * in-5,20-dione-16,17- ^ cetonid

21-chloro-9-fluoro-16a, 17-dihydroxypregn-4-en-3,11,20 ^ trione-16,17-acetonide

21-chloro-9-fluoro-16a, 17-dihydroxy-4,5-seco-pregn-3-yn-5,11,20-trione-16,17-acetonide ,

Examples 9-13

According to example 2, but using the in column I. compounds listed (prepared according to Examples 4 to 8), the products listed in column II are obtained.

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Column I Column II

gJ ^ yo- 9-fluoro-11ß, 16a, 17-trihy-

xy-4,5-seco-pregn-3-in-5,20-droxy-4,5-seco-pregnan-

dione-16,17-acetonide 3,5,20- ^ iOn-Io, 17-acetonide

10 11 [beta], 16a, 17-trihydroxy-4,5-11 [beta], 16a, 17-trihydroxy-4,5

seco-pregn-3-in-5,20-dione-seco-pregnan-3,5> 20-trione

16,17-acetonide - 16,17-acetonide

11 g ^ i-Difluor-Hßjiöay ^ -tri- 9,21-Difluor-11ß, 16a, 17-hydroxy-4,5-seco-pregn-3-intrihydroxy-4,5-seco-preg-5,20- dione-16,17-acetonide nan-3,5,20-trione-16,17-

acetonide

12 9-fluoro-16a, 17-dihydroxy-9-fluoro-16a, 17-dihydroxy-4,5-seco-pregn-3-yne-5,11,20-4,5-seco-pregnan-3,5 , 11, trione-16,17-acetonide 20-tetron-16,17-acetonide

13 21-chloro-9-fluoro-16a, 17-di-21-chloro-9-fluoro-16a, 17-hydroxy-4,5-seco-pregn-3-indihydroxy-4,5-seco-pregnan-5 , 11,20-trione-16,17-acetonide 3.5 *, 11.20-tetron-16.17-

acetonide.

Example 14

9-fluoro-11beta, 16a, 17-trihydroxy-4,5-seco-pregnan-5,20-dione 1-6, 17-acetonide
a) 9-Fluoro-4 _t 5-epoxy-11ß _> 16a, 17-trihydroxypregnan-3> 20-dione- 16,17-acetonide

A solution of 9.7 g of 9-fluoro-11ß, 16a, 17-trihydroxypregn-4-en-3,20-dione-16,17-acetonide in 500 ml of methanol is mixed with 30 ml of a 30 percent hydrogen peroxide solution and 20 ml of a 4 η sodium hydroxide solution is added, the mixture is stirred for 4 days and then diluted with ice water. The resulting precipitate is filtered off, dissolved in chloroform, the chloroform solution is dried and evaporated under reduced pressure. The residue is dissolved in 200 ml of a mixture of dichloromethane and hexane in a volume ratio of 1: 1 and chromatographed _{on an L column filled with 150 g of silica gel.} It is mixed with dichloromethane and then j

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chromatographed with a mixture of dichloromethane and ethyl acetate in a volume ratio of 3: 1. The eluate is evaporated. Yield 7.0 g of pure epoxide with a melting point of 258 Ms 260 ^° C. The product is uniform according to thin-layer chromatography.

b) 9-fluoro-11β, 16g, 17-trihydroxy-4,5-seco-pregn-5-yn-5 «20-dione-16,17-acetonide

A solution of 2.44 g of ρ-toluenesulfonylhydrazide in 300 ml of a mixture of dichloromethane and acetic acid in a volume ratio of 1: 1 is at ⁰ ° C. in a solution of 7.0 g (0.016 mol) of the epoxide in 300 ml of the same solvent mixture dripped in. After stirring for 15 to 1 hours at room temperature, the solution is diluted with dichloromethane, washed four times with 1 liter of a 5 percent aqueous sodium carbonate solution each time, dried and evaporated under reduced pressure. The residue is chromatographed on a column filled with 60 g of silica gel and using dichloromethane as the mobile phase. The eluate is evaporated. Yield 4.7 g of the pure title compound with a melting point of 215 to 217 ^° C.

c) 9-fluoro-11 ß, 16a ", 17-trihydroxv-4,5-seco-pregnan-5,20-dione-

16,17-acetonide ■ -

(O _f Oll MoI) /
A solution of 4.7 g / of the compound * obtained in (b) in 300 ml of ethyl acetate is stirred in a hydrogen atmosphere with 500 mg of a 5 percent palladium-on-charcoal catalyst. The hydrogen uptake has ended after 90 minutes. A total of 520 ml (0.0235 mol) of hydrogen has been taken up. After 210 minutes the catalyst is filtered off and the residue is obtained twice from a mixture * of methanol and,

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^ 459467

Recrystallized chloroform. Yield 3.5 g of the title compound with a melting point of 193 Ms 195 ^° C.

Examples 15-18

According to Example 3, but using those listed in column I. Compounds (prepared according to Example 4 to 8), the products listed in column II are obtained.

Example

Column I.

11β, 16a, 17-trihydroxy-4,5-seco-pregn-3-yne-5,20-dione-16,17-acetohid

9,21-difluoro-11β, 16a, 17-trihydroxy-4,5-seco-pregn-3-yne-5,20-dione-16,17-acetonide

9-fluoro-16a, 17-dihydroxy-4,5-seco-pregn-3-yn-5,11, 20-trione-16,17-acetonide

21-chloro-9-fluoro-16a, 17-dihydroxy-4,5-seco-pregn-3-yn-5,11,20-trione-16,17-acetonide

Column II

11β, 16a, 17-trihydroxy-4,5-seco-pregnane-5,20-dione-16,17-acetonide

9,21-difluoro-11β, 16a, 17-trihydroxy-4,5-seco-pregnan-5,20-dione-16,17-acetonide

9-fluoro-16a, 17-dihydroxy-4,5-seco-pregnane-5,11,20-trione-16,17-acetonide

21-chloro-9-fluoro-16a, 17-dihydroxy-4,5-seco-pregnane-5,11,20-trione-16,17-acetonide

Example 19

9-fluoro-11 β, 16q, 17,21-tetrahydroxy-4,5-seco-pregn-3-yn-5 _? 20-dione-16 ,, 17-acetonide
a) 21- (Tetrahydropyran-2-yloxy) -9-fluoro-11β, 16q _? 17-trihydroxy pregn-4-ene-3,20-dione-16,17-acetonide

A suspension of 1 g of 9-fluoro-11β, 16a, 17,21-tetrahydroxypregn-4-en-3,20-dione-16,17-acetonide in 20 ml of dihydropyran mixed with 0.5 ml of an anhydrous solution of hydrogen chloride in Diethyl ether added. The mixture obtained is stirred for 4 hours, then diluted with water and. the precipitated project

509828/1015 ORIGINAL, NSPECTED

. 41 .

filtered off. The title compound is obtained.

b) 21- (tetrahydroxyran-2-yloxy) -9-fluoro-4,5-epoxy-11ß, 16a _t 17-trihydroxv-5ß-pregnan-3 _< 20-dione-16,17-acL- mid "

A solution of 1, 0 g of the compound obtained in (b) in 100 ml of methanol is ^{treated at 0 0} G with 6, 2 ml of a 30 percent strength peroxide solution and 4.1 ml of a 4 η sodium hydroxide solution. After 150 minutes the slurry is allowed to warm to room temperature and stirred for an additional 15 to 18 hours. The slurry is then diluted to 2 liters with water and filtered. The title compound is obtained.

c) 9-fluoro-4,5-epoxy-11β, 16α, 1 · 7,21-tetrahydroxy-5β-pregnane-3,20-dione-16,17-acetonide

'A solution of 1 g of the compound obtained in (b) in 50 ml a mixture of acetic acid and water in a volume ratio of 1: 1 is stirred for 6 hours, soi ann diluted with water and the resulting precipitate is filtered off. It becomes the title compound obtain.

d) '9-Fluoro-11β, 16a, 17,21-tetrahydroxy-4,5-secopregn-3-yn -5,20-dione-16,17-acetonide

A solution of 1.0 g of the compound obtained in (c) in 30 ml of a mixture of dichloromethane and acetic acid in a volume ratio of 1: 1 is ^{cooled to 0} ° C. and treated dropwise with a solution of 500 mg of p-toluenesulfonyl hydrazide in 30 ml of des the same solvent mixture added. The reaction mixture is ^{stirred for 2 hours at 0} ° C. and 15 ms at room temperature for 18 hours, then poured into ice water and washed with diethyl ether j

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extracted. The ether extract becomes more aqueous with 10 percent strength Sodium carbonate solution and water washed over sodium sulfate dried and evaporated under reduced pressure. It what remains is the title compound.

Example 20

9-fluoro-11β, 16rc, 17,21-tetrahydroxv-4,5-seco-pregnan-5,5,20-trione-16,17-acetonide

A solution of 660 mg of 9-fluoro-11β, 16a, 17,21-tetrahydroxy-4,5-seco-pregn-3-yn-5,20-dione-16,17-acetonide (prepared according to Example 19) in one Mixture of 8.3 ml of 85 percent formic acid and 8.3 ml of 80 percent aqueous methanol is converted into a solution of mercury (II) sulfate (prepared from 50 mg of mercury (II) chloride, 0.08 ml of sulfuric acid and 1.9 ml of water ) given. After 30 minutes of standing at 6O ⁰ C, the. Solution cooled to 0 ^° C., left to stand at this temperature for 15 to 18 hours and then extracted with diethyl ether. The ether extract is washed with 2 percent aqueous sodium carbonate solution and 8 percent aqueous sodium chloride solution and dried. After the solvent has been evaporated off under reduced pressure, the title compound remains.

Example 21

9-fluoro-11ß _? 16q, 17,21-tetrahydroxy-4 ^ 5-seco-pregnan-5 _< 20-dione 16,17-acetonide
a) 9-Fluoro-11β, 16α, 17-trihydroxy-21 - / (tetrahydropyran-2-yl) oxy / -prepn-4-en-3,20-dione-16,17-acetonide

A slurry of 16 g of 9-fluoro-11ß, 16a, 17,21-tetrahydroxypregn-4-en-3,20-dione-i6,17-acetonide, 240 ml dioxane and 32 ml _,

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Tetrahydropyran is at room temperature for 2 hours with 500 mg. p-toluenesulfonic acid stirred. Excess 5 percent strength sodium carbonate solution is then added, the mixture is diluted with water and extracted with dichloromethane. The dichloromethane extract is evaporated. The oily residue is dissolved in bichloromethane and chromatographed on a column filled with 100 g of silica gel using dichloromethane as the mobile phase. The eluate is evaporated. Yield 17.8 g of the title compound. After recrystallization from a mixture of acetone and hexane, the compound melts at 218 to 220 ^° C.

b) 4β, 5-epoxy-9-fluorine-11 β, 1 6ce, .17-trihydroxy-21 - / X tetrahydro -

Pvran-2-yl) -oxv7-pregnan-3,20-dione-i6,17-acetonide A solution of 18.32 g of the compound obtained in (a) in 1.8 liters of methanol is mixed with 50 ml of a 30 percent hydrogen peroxide solution and 40 ml of a 4 η sodium hydroxide solution are added and the mixture is stirred for 4 days. The solution is then diluted with water and the resulting precipitate is filtered off. Yield 11.8 "g. The filtrate is extracted with chloroform. The chloroform extract is evaporated. A further 3.0 g of the same compound remain. The two products are combined, dissolved in a mixture of hexane and dichloromethane in a volume ratio of 1: 1 and chromatographed on a column filled with 100 g of silica gel and using dichloromethane as the mobile phase. The eluate is evaporated. Yield 7.0 g of the title compound.

50 9 8 2 8/101 5

c) 4β, 5-epoxy-9-fluoro-11β, 16oc, 17 «21 -tetrahydroxopregnane-5.20dione-16,17-acetonide

A solution of 7.0 g of the compound obtained in (b) in 500 ml of a mixture of acetic acid and water in a volume ratio The mixture is stirred 1: 1 for 5 hours, then diluted with water and extracted with chloroform. The chloroform extract is washed with aqueous sodium bicarbonate solution, dried and evaporated. 5.9 g of the title compound are obtained.

d) 9-fluoro-11β, 16a, 17 "21-tetrahydroxv-4,5-seco-pregn-3-yn-5" 20 dione-16,17-acetonide

A solution of 5.9 g of the compound obtained in (c) in 300 ml of a mixture of acetic acid and dichloromethane in a volume ratio of 1: 1 is mixed with a solution of 2.5 g of p-toluenesulfonyl hydrazide in 300 ml ^{at 0} ° C. while stirring the same solvent added. The resulting solution is stirred for 15 to 18 hours at room temperature, then diluted with dichloromethane, washed with water and aqueous sodium bicarbonate solution and dried. The crude product is chromatographed on a column filled with 60 g of silica gel and using dichloromethane as the mobile phase. The eluate is evaporated. Yield 3.86 g of the title compound,

e) 9-fluoro-11β, 16q, 17,21-tetrahydroxy-4,5-seco-pregnane-5,20-dione-16,17-acetonide

A solution of 3.86 g of the compound obtained in (d) in 500 ml of ethyl acetate is 500 mg in a hydrogen atmosphere a 5 percent palladium-on-charcoal catalyst

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stirs. After 35 minutes, 590 ml of hydrogen have been taken up. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue v / i ^ d recrystallized from methanol. Yield 2.0 g of the title compound with a melting point of 205 ° to 207 ° C.

..Example.game 22

21-chloro-9-fluoro-Hß, 16a, 17-trihydroxy-4, 5-seco-prep; n-3-ene-5,20-dione-16,17-ac etonide

A solution of 3.0 g of 21-chloro-9-fluoro-11β, 16a, 17-trihydroxy-4,5-seco-pregn-3-yn-5,20-dione-16,17-acetonide (prepared according to Example 1) in 250 ml of ethyl acetate containing 60 mg of synthetic quinoline is stirred in the presence of 30 mg of a 5 percent palladium-on-barium sulfate catalyst in a hydrogen atmosphere at normal pressure and room temperature for 15 hours. The catalyst is then filtered off, the filtrate is evaporated and the residue (3.0 g) is dissolved in a mixture of chloroform and hexane in a volume ratio of 1: 1 and placed on a column filled with 60 g of silica gel. The column is eluted with a mixture of chloroform and hexane in a volume ratio of 1: 1. The eluate is evaporated. A mixture of starting steroid and title compound is obtained. After further elution with a mixture of chloroform and hexane and finally with chloroform, the eluate is evaporated. Yield 1.8 g of the title compound, melting after recrystallization from a mixture of ethyl acetate and hexane at 229-230 ⁰ C.

J 509828/101 p

Examples 23 Ms 27 _t

According to Example 22, but using the compounds mentioned in column I (prepared according to Example 4 Ms 8), the products listed in column II are obtained.

example

23

Column I.

9-fluoro-11β, 16α, 17-trihydroxy-4,5-seco-pregn-3-yn-5,20-dione-16,17-acetonide

11β, 16a, 17-trihydroxy

4,5-seco-pregn-3-ln-5,20-dione-16,17-acetonide

9,21-difluoro-11β, 16a, 17-trihydroxy-4,5-secopregn-3-yn-5,20-dione-16,17-acetonide

9-fluoro-16a, 17-dihydroxy-4,5-seco-pregn-3-yn-5,11 » 20-trione-16,17-acetonide

• 27 21-chloro-9-fluoro-16a, 17-dihydroxy-4,5-seco-pregn-

3-yn-5,11,2O-trione-16,17-acetonide

Column II

9-fluoro-11β, 16a, 17-trihydroxy-4,5-seco-pregn-3-ene-5,20-dione-16,17-acetonide

11β, 16a, 17-trihydroxy-4,5-seco-pregn-3-ene-5,20-dione-16,17-acetonide

9,21-difluoro-11β, 16a, 17-trihydroxy-4,5-seco-pregn-3-en-5,20-dione-16,17-acetonide

9-fluoro-16a, 17-dihydroxy-4,5-seco-pregn-3-ene-5,11,20-trione-16,17-acetonide

■ 21-chloro-9-fluoro-16a, 17-dihydroxy-4,5-seco-pregn-i-en-5,11,20-trione-16,17-acetonide

Example 28

21-chloro-11β, 16,17-trihydroxv-4,5-seco-pregnane-3,20-dione-16,17-acetonide
a) 21-chloro-4, 5-e-poxv-11ß, 16 , 17-trihydroxypreg: nan-3, 20-dione

16,17-acetonide

A solution of 10 g of 21-chloro-11.beta., 16,17-trihydroxypregn-4-ene-3,20-dione-16,17-acetonide in 1 liter of methanol at 0 ⁰ C and 31.2 ml of a 30 percent ^ asserstoffperoxidlösung and 20.6 ml of a 4N sodium hydroxide solution are added, the mixture is stirred for 1 hour at ⁰ ° C. and for 3 more hours at room temperature and then in

509828/1015

Poured 3 liters of ice water. The resulting precipitate is filtered off, dissolved in chloroform, the chloroform solution with -5 percent hydrochloric acid and 5 percent aqueous sodium bicarbonate solution washed, dried and evaporated under reduced pressure. The residue is dissolved in dichloromethane and turned on a column filled with 100 g of silica gel and chromatographed using dichloromethane as the mobile phase. The eluate is evaporated. 7.7 g of a mixture of the α- and ß-epoxides are obtained.

b) 21-chloro-11β, 16a, 17-trihvdroxv-4,5-seco-pregn-5-yn -5,20-dione-16,17-acetonide

A solution of 7.7 g (0.017 mol) of the epoxy mixture obtained in (a) in 250 ml of a mixture of dichloromethane and Es-. Acetic acid in a volume ratio of 1: 1 is added ^{dropwise at 0} ° C. with a solution of 2.55 g of ρ-toluenesulfonyl hydrazide in 250 ml of the same solvent. After stirring for 1 hour at ⁰ ° C., the mixture is stirred for a further 3 hours at room temperature, then diluted with 1 liter of a 5 percent strength aqueous sodium bicarbonate solution and dried. The solution is then evaporated. The residue is chromatographed on a column filled with 50 g of silica gel and using chloroform as the mobile phase. The eluate from fractions 3 to 6 is evaporated. Yield 5.7g. After recrystallization from a mixture of methanol and chloroform, 5.1 g of the title compound are obtained. .

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c) 21-chloro-Hβ, 16α, 17-trihydroxy-4,5-seco-pregnan ~ 5,20-dione- 16,17-acetonide

A solution of 5.1 g (0.0117 mol) of the compound obtained in (b) in 510 ml of ethyl acetate is stirred in the presence of 510 mg of a 5 percent palladium-on-charcoal catalyst in a hydrogen atmosphere. After 30 minutes, 590 ml (0.026 mol) of hydrogen have been taken up. After 2 1/2 hours the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is recrystallized from a mixture of acetone and hexane. Yield 4.91 g of the title compound, melting at 153-155 ⁰ C.

5 0 9 8 2 BI 1 0 1 5

Claims (19)

0 ti in which A is the group -C = CH, -CH = CH ₂ , -CH ₂ CH ₃ or -C-CH, X _{1 is} a hydrogen, fluorine, chlorine or bromine atom and R _{1 is} a hydrogen, fluorine -, chlorine, bromine or iodine atom, one II-. Represents a hydroxyl or -OC-IU group, where R _{2 is} a lower alkyl radical, P is a hydrogen atom, a lower alkyl radical or an aryl radical, Q is a lower alkyl radical or an aryl radical, Y is a "hydrogen atom and Y 'is a hydroxyl group, or Y and Y 'together represent a carbonyl oxygen atom. 2. 21-chloro-9-fluoro-11β, 16a, 17-trihydroxy-4,5-seco-pregn-3 in-5,20-dione-16,17-acetonide. 3. 21-chloro-9-fluoro-11β, i-eaj 3,5,20-trione-16,17-acetonide ·. -4,5-secp-pregnan- 4. 21-chloro-9-fluoro-11β, 16a, 17-trihydroxy-4,5-seco-pregnan-5,20-dione-16,17-aeetonide. 50 98 287 1015 5. 21-chloro-9-fluoro-11β, 16α, 17-trihydroxy-4,5-seco-pregn-3-en-5,20-dione-16,17-acetonide. 6. g-Fluoro-11β, 16α, 17-trihydroxy-4,5-seco-pregnane-5,20-dione-16,17-acetonide. 7. 9-Fluoro-11β, 16a _s 17j21-tetrahydroxy-4,5-seco-pregnane-5,20-dione-16,17-acetonide. 8. 21-chloro-11β, 16a, 17-trihydroxy-4,5-seco-pregnane-5,20-dione-16,17-acetonide. 9. A process for the preparation of the compounds according to claim 1, characterized in that a compound of the general formula III (III) Claim 1 specified / in the X ^, R ^, P, Q, Y and Y 'which have in / meaning, treated with p-toluenesulfonylhydrazide in weakly acidic medium and optionally the * compound of the general formula IV obtained 50 9828/1015 • 2459467 - 29 - -Q ■ ^(IV) CH ₂ R ₁
γ «c = o Y- -. / A *
C.
H if in which X ₁ , R ₁ , P, Q, Y and Y ^{1 have} the above meaning, a) partially reduced to the compound of general formula I, in which A represents the group -CH = CH ₂ , or b) reduced to the compound of general formula I in which A represents the group -CHpCH, or c) in an aqueous acidic medium in the presence of mercury (H) sulfate hydrated to the compound of general formula I, in which. A represents the acetyl group. 10. The method according to claim 9 for the preparation of compounds of general formula I, in which R _{1 is} a hydrogen,
Fluorine or chlorine atom, X-, a hydrogen or fluorine atom and A denotes the group -C ^ CH, characterized in that a compound of the general formula III, in which R ^ and X ₁ . have the above meaning treated with p-toluenesulfonylhydrazide. . , 11. The method according to claim 9 for the preparation of compounds of general formula I, in which R _{1 is} a Viasserstoff-,
Fluorine or chlorine atom, X ₁ denotes a hydrogen or fluorine atom and A denotes the acetyl group, characterized in that a compound of the general formula III. with p-toluenesulfo- 509828/1015 2459Λ67 ^π treated nylhydrazid and the product obtained in aqueous acidic medium in the presence of mercury (II) sulfate; hydrated. 12. The method according to claim 9 for the preparation of compounds of the general formula I in which R _{1 is} a hydrogen, fluorine or chlorine atom, X _{1 is} a hydrogen or fluorine atom and A is a vinyl group, characterized in that one is a compound of the general Formula III treated with p-toluenesulfonylhydrazide and the product obtained partially reduced. 13. The method according to claim 9 for the preparation of compounds of the general formula I in which IL is a hydrogen, fluorine or chlorine atom, X _{1 is} a hydrogen or fluorine atom and A is an ethyl group, characterized in that a compound of the general formula III is with Treated p-toluenesulfonylhydrazide and partially reduced the product obtained. 14. The method according to claim 9 for the preparation of compounds of the general formula I in which FL is a hydroxyl group and X _{1 is} a hydrogen or fluorine atom, characterized in that a compound of the general formula III in which R ₁ and X _{1 is} the Have the above meaning treated with p-toluenesulfonylhydrazide. 15. The method according to claim 9 for the preparation of _Q compounds Il of the general formula I, in which R ₁ denotes the group -OC-Rp and X ₁ denotes a hydrogen or fluorine atom, characterized in that ^ 509828/1015 OR ₁ G ₁ NALINSPEcTED that a compound of the general formula III, in which R ^ represents a hydroxyl group and X ^ has the preceding meaning has treated with p-toluenesulfonylhydrazide and the obtained Reacts product with a carboxylic acid anhydride of the general formula 0. 16. The method according to claim 9 for the preparation of compounds of the general formula I in which R ^ is a fluorine, chlorine, bromine or iodine atom and X ^ is a hydrogen or fluorine atom b _t ^. ^ et, characterized in that a compound of the general formula III, in which R ^ represents a hydroxyl group and X ^ has the above meaning, treated with p-toluenesulfonylhydrazide, the product obtained with a lower alkyl or arylsulfonyl chloride and then the product obtained Reacts compound with an inorganic halide. 17. The method according to claim 9 for the preparation of compounds of the general formula I in which X ^ is a bromine atom, characterized in that a compound of the general formula I in which X ^ is a hydrogen atom, Y is a hydrogen atom and Y ^! denotes a hydroxyl group with .ein; lower alkylsulfonyl chloride and then the product obtained is reacted with an N-bromo amide of a carboxylic acid. 18. Process.nach Claim 9 for the preparation of compounds of the general formula I in which X ₁ denotes a fluorine, chlorine, bromine or iodine atom, characterized in that one is a compound of the general formula. 50 9 828/1015 CH ₀ R ₁ I 2 1 C = O O- Claim 1 stated in which R ₁ , P and Q have in / meaning, reacts with a hydrogen halide and the resulting compound of the general formula CH ₀ R ₁ I ^{2 λ} 0 * 0 HO (XII) in which X is a fluorine, chlorine, bromine or iodine atom, with Hydrogen peroxide is oxidized in the presence of a base. 19. Medicament containing a compound according to claim 1 and customary carriers and / or diluents and / or Auxiliary materials. 509828/1015