JPS5855157B2 - Pregnane 2-bromo-6 beta-fluoro-3-keto-1,4-steroid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel group of 2-bromo-6-fluoropregnanes.

More particularly, the present invention describes the effects of the present invention in certain known physiologically active steroids, e.g.
2-Bromo-6β of the pregnane series has valuable pharmacological properties, especially anti-inflammatory and anti-rheumatoid arthritis effects, with significantly reduced side effects such as IJ stagnation, calcium loss, adrenal and pituitary suppression, etc. -Relating to a method for producing fluoro-3-keto Δ1°4-steroid.

Many of the novel compounds of this invention can be administered by both topical and systemic routes.

For experts in steroid chemistry, 2-bromo-
It is well known in the literature that 3-ke)-6β-fluoro-Δ4-pregnane derivatives are very unstable and epimerization gives the corresponding 2-bromo-6α-fluoro derivatives.

Alarmingly, we found that 2-bromo-3keto-6
It has been found that β-fluoro-pregnane can be stabilized in its 6β-epimer form by appropriate introduction of a Δ1°4 double bond system.

The valuable new pharmacologically effective product 2-bromo-6β-fluoro-Δ1°4-flexnadiene derivative thus obtained and the process for its preparation are the object of the present invention, as detailed below.

The novel compound of the present invention has the general formula (wherein, It can be an α-methyl group or a β-methyl group, R' can be hydrogen or an acyl group having 2 to 8 carbon atoms, R can be hydrogen or 2 to 8 Z is an α-hydroxyl group; and when R' is hydrogen, the corresponding 16
16α-acyl derivatives with α·17α-acetonides and organic carboxylic acids having 2 to 8 carbon atoms were prepared.

It has also been confirmed that when 16α-hydroxyl, 17α- and 21-hydroxyl groups are esterified (if 16α-hydroxyl is present), their effects are significantly enhanced.

A further object of the present invention is a number of new and interesting processes for the preparation of new compounds of formula (I) via a series of novel intermediates not yet described in the literature.

As detailed below, the above method is based on the general formulas (n) and (R'), where Ac is an acetyl group and R' has 2 to 8 carbon atoms. acyl group, Z can be hydrogen, α-methyl group or β-methyl group).

The above Bq major intermediates ① and R' can be prepared according to reaction scheme &1 with slight variations as indicated in the scheme.

The starting material is represented by the formula where Ac and Z have the above definitions.

The starting material may be prepared essentially as described in U.S. Pat. No. 2,841,600 from the corresponding 5α,6α-epoxide-3-ethylene ketal by reacting it with a 70% aqueous hydrogen fluoride solution.

A large number of new products and intermediates can be prepared from the main intermediates (n) and (R') according to the novel process of the present invention as shown in Reaction Scheme Part 2.

Of all the compound numbers shown in both Scheme A1 and Scheme 20, Arabic numerals indicate only intermediates and Roman numerals indicate final products and/or important useful intermediates.

When the compound (■) dissolved in dioxane is reacted with bromine in the presence of sodium acetate, either the 2,2-dibromo-derivative (■) or the 2-fromo derivative (■) is produced depending on the amount of bromine used during the reaction. can get.

Compound (2) can be obtained by further brominating compound (2).

Compound (1) is then converted to the corresponding 2-promoted 4-pregnagene (2).

This exchange can be carried out by treatment with lithium chloride and dimethylformamide at 110-120°C.

Compound (1) is converted to the 11α-mesyl-derivative (2) by reaction with methanesulfonyl chloride in pyridine.

When the above 11α-mesyl-derivative ① dissolved in acetic acid is heated to 100-110°C with sodium acetate, the corresponding 2-bromo-6β-fluoro-4·901)-pregnatriene-17α· represented by the structural formula (n) is produced. 21
Diol-3.20-dione is obtained.

Alternatively, the main intermediate (n) is compound ① at 120°C.
The corresponding 2-bromo-2-pregnene-derivative ■ was obtained by reaction with dimethylformamide and lithium carbonate at 100°C, which was converted into the corresponding 11α mesyl-derivative ■, and finally the compound ■ was reacted with lithium chloride and lithium carbonate at 110 °C. It can be obtained by reacting with dimethylformamide to produce the desired main intermediate (n).

The corresponding 17.alpha.-acyl-derivatives 2' can be prepared by converting compound 1 to the anhydride of an organic acid having 2 to 8 carbon atoms (
For example, it can be produced by acylation with acetic anhydride, propionic anhydride, valeric anhydride).

Alternatively, compound ■' can be prepared by the same acylation procedure shown for compound ■ to obtain the corresponding 17-acyl-derivative ■, which is then reacted with acetic acid and sodium acetate to give compound ■'. can be done.

An alternative method for preparing compound (1) consists of acylating compound (1) to obtain compound (2) and heating this with lithium chloride and dimethylformamide at 110° C. to obtain compound (2).

Yet another method for preparing ■' is to reflux compound ■ with acetic acid containing 1% water to form compound Q (formed), which is acylated to obtain compound e; and heating with dimethylformamide to finally obtain the desired compound (1).

Any novel product of the invention of the general formula (2) can be prepared according to reaction scheme Layer 2 from the two main intermediates (1) and (2).

The main intermediate ① is converted into the corresponding 9α-bromo 11β-hydroxy compound O according to methods known per se.

From the compound [phase], the corresponding 9β・11β-epoxy-
Either 21-acetate 0 or the corresponding 9β.11β-epoxy-21 alcohol@ can be prepared.

In the formula, Ac is -C0Cn3, and R' is H or 2-
an acyl group having 8 carbon atoms, R being hydrogen or selected from the group consisting of organic mono- or di-carboxylic acids having 2 to 8 carbon atoms, metasulfobenzoic acid and phosphoric acid It can be an acyl residue.

Reaction of compound 0 with a 70% aqueous hydrogen fluoride solution at a temperature of 15 DEG to -5 DEG C. gives the corresponding 9.alpha.-fluoro-11.beta.hydroxy-21-acetate-) (III).

Under the same conditions the compound @ corresponds to 9α-fluoro11β
-Hydroxy-21-alcohol (IV).

Compound (1) can be prepared from compound (2) by acetylation, and conversely, compound (1) can be prepared by hydrolyzing compound (2) with potassium carbonate in methanol.

Compound (1) can be prepared by converting compound (1) into a 17α·21-ortho-ester, hydrolyzing this ortho-ester to obtain a 17α-acetyl ester, and subsequently acylating the 21-position.

Compound (1) can be prepared using compound (1) as a starting material according to other methods known per se from the literature.

Corresponding 9 from intermediate ■′ in the same way as from intermediate ■
α-fluoro-11β hydroxy-21-acetate-
17α-acyle) (VI) is prepared via the corresponding bromohydrin [phase] and 9β·11β-epoxide 0.

Reaction of the main intermediate (2) dissolved in acetic acid with N-chlorosuccinimide and lithium chloride gives the corresponding 9α.11β-dichloro-derivative (2).

Heating the main intermediate n' (z=hydrogen) with potassium acetate and dimethylformamide at 120 DEG C. forms the corresponding Δ16-derivative [phase].

The latter compound dissolved in aqueous acetone solution was heated to -10°C.
Treatment with potassium permanganate in the presence of formic acid gives the corresponding 16.alpha..17.alpha.-dihydroxy-derivative [phase].

Reaction of the latter compound with N-chloro-succinimide and lithium chloride in acetic acid gives the corresponding 9α-
11β-dichloro-derivative ① is formed.

The corresponding 16α-acylate (■A) is obtained by acylation of compound ■ dissolved in pyridine with the anhydride of an acid having 2 to 8 carbonate atoms, and compound ■ is prepared in the presence of perchloric acid. By reacting with acetone, the corresponding 16α/17α acetonide (■B) is produced.

Bromohydrin 0 and 9β/11β from compound [phase]
- Corresponding 9α- via epoxide [phase] and [phase]
Fluoro 11β-hydroxy-21-acetate (IX
) and 9α-fluoro-11β-hydroxy-21 alcohol (X) are obtained.

Acylation of compound (1) dissolved in pyridine with an anhydride of an organic acid having 2 to 8 carbon atoms gives the corresponding 16α-acyle (IXA).

The corresponding 16α by reacting compounds ■ and X with acetone in the presence of peroxyacid.

17α-acetonide (IXB) and (XA) can be produced.

When each of epoxide 0.0.0 and [phase] oyohi [phase] is treated with 36% concentrated hydrochloric acid at 0°C, the corresponding 9α
-Chloro-11β-hydroxy derivative is produced.

The 11β-hydroxy-derivatives ■, ■, ■, IXA, and IXB are known per se in the steroid field.
It can be converted to the corresponding 11-keto-derivative by oxidation with rO3.

Next, the method of carrying out the present invention will be explained with reference to the following examples, but these examples are merely described for illustrative purposes and are not intended to limit the present invention.

Example 1 2,2-dibromo-6β-fluoro-pregnane 5α.
11α·17α·21-tetraol 3·20-dione-21-acetate (compound ■, Z=H) 1v 6β-fluoro-pregnane-5α·11α·17α·21-tetraol-3 in 15 ml dioxane・20-dione 21-acetate (compound of
Z=H) and 0.5 P of anhydrous sodium acetate are stirred with 11 bromine at 25-28°C.

The reaction mixture is kept at 25-28° C. with stirring for an additional 5 minutes, then it is poured into 10077 Il of water with stirring.

The precipitate thus obtained is filtered, washed with water and dried.

1v of crude product ■ is obtained. It is purified by recrystallization from benzene.

Infrared spectrum (in Nujol): 3350.346
0.3330,1725.1240CrrL-1゜Example 2 2-furomo6β-fluoro-pregnane 5α・11α
・17α・21-tetraol 3・20-dione-21
-Acetate (Compound ■, Z=H) Compound ■ is obtained by operating as described in Example 1, except using half the amount of bromine as in Example 1, and crystallized from methanol-chloroform. Infrared spectrum (Nujol) 3520.3420.3230,17
60,1720.1225CTL' is shown.

Example 3 2.2-Schiff'lomo6β-fluoropregnan-5
α・11α・17α・21-tetraol-3・20-
Dione-21-acetate (Compound ■ obtained from Compound ■, Z=H) Bromination of Compound ■ according to the method described in Example 2 yields Compound ■, which is similar to the sample obtained according to Example 1. It shows the same characteristics as.

Example 4 2-furomo6β-fluoro-1,4-pregnagen-11α,17α,21-trimyl-3,20-dione 21-acetate (compound, Z=I() 10 ml of dimethyl kept at 100°C 1r of 2,2-dibromo-6β-fluoro-pregnane-5α·11α·17 is added to a suspension of 1i of anhydrous lithium chloride in formamide with continuous bubbling of dry nitrogen.
α·21-tetraol-3·20-dione 21-acetate ■ is added with stirring.

The reaction mixture is heated to 110-120° C. for 1 hour, then it is cooled to 20° C. and poured with stirring into 100 ml of cold water.

The precipitate is filtered once, washed with water and dried.

0.6f of the compound ■ is obtained, which has the following properties.

MeOH Ultraviolet spectrum: λ -252mμ aX Infrared spectrum (Nujol): 3410.17401
1725.1660.1635.1600cfrL' Example 5 2-furomo6β-fluoro-1-pregnagen-1
1α・17α・21-trio-rou 3・20-dione 1
1-mesylate 21-acetate (compound ■, Z=H) 5 in 25 ml of pyridine cooled to 10°C
31 nl of methanesulfonyl chloride was gradually added to the solution of compound (1) while stirring.

The reaction mixture is kept at -5° C. with stirring for 30 minutes and then poured into 250 ml of cold water.

The precipitate thus obtained is filtered once, washed with water and dried.

The desired compound 6z is obtained.

, MeOH ultraviolet spectrum, λ -249 mμ aX infrared spectrum (Nujol): 3575.3300.
175011725.1665.1640.1600.
1350crrL-1 Example 6 2-furomo6β-fluoro-1,4,901) flefnatriene-17α,21-diol 3,20-dione 21-acetate (compound ■, Z=H) 7.5'i in a suspension of compound ■? of anhydrous sodium acetate.

The reaction mixture is heated to 110° C. with stirring for 1 hour, then it is cooled to 20° C. and poured slowly into 250 ml of ice water.

The precipitate thus obtained is filtered once, washed with water and dried.

3.52 of 2-bromo-6β-fluoro4.9(1
1) -7'lecnatriene-17α・21-diol-
3,20-dione 21-acetate (compound ■, Z=
H) is obtained, which exhibits the following properties:

Ultraviolet spectrum: λM80H: 246mμax Infrared spectrum (Nujol): 3550.3470.
3350.174011725.1670.1640.
1600G near rL” Example 7 2-bromo-6β-fluoro-1-pregneno 5α・1
1α・17α・21-tetraol 3・20-dione
21-Acetate (Compound ■, Z=H) 5 g of 2,2 dibromo- 6β-
Fluoro-pregnane-5α・11α・17α・21-
Tetraol-3.20dione 21-acetate is added with stirring.

The reaction mixture was heated to 120° C. for 30 minutes with stirring;
It is then cooled to 20° C. and poured into 250 ml of water.

Neutralize the lithium carbonate by slowly adding acetic acid.

The resulting suspension is filtered, the crude product is washed with water and dried.

3.751 of compound (2) is obtained.

MeOH.

Ultraviolet spectrum: λ, 258mμ ax Infrared spectrum (nujol): 3520°3400.
326011760.1720.1670.1590c
rfL' Example 8 2-furomo6β-fluoro-1-pregneno5α・1
1α・17α・21-tetraol 3 ・20-dione 11-fusylate 21-acetate (compound ■, Z=H
) From compound (1), compound (2) is prepared by operating in the same manner as in Example 5, which exhibits the following properties.

, MeOH.

Ultraviolet spectrum, λ, 258 mμaX Infrared spectrum (Nujol): 3570.3530.
3440.3330, 1740.1720.1685.
1600.1350 cm 1 Example 9 2-furomo6β-fluoro-1,4,901) pregnatriene-17α,21-diol-3,20-dione 21-acetate (from compound ■, Z=H1 compound ■) Under nitrogen atmosphere 5z of 2-bromo-6β-fluoro-1-prechnene-5α·11α·17α·21- was added with stirring to a solution of 5 g of anhydrous lithium chloride in 50 ml of dimethylformamide kept at 100°C.
Tetraol-3.20 dione 11. - Mesylate 21
- Add acetate.

The reaction mixture was incubated for 30 min with stirring under nitrogen atmosphere.
heated to 0°C, then cooled to 20°C, and
Pour into 00ml of cold water.

The precipitate obtained is filtered once, washed with water and dried.

Product IIA showed the same properties as the sample obtained according to the method of Example 6.

Example 10 2-furomo6β-fluoro-1,4,9αυ flexnatriene-17α,21-diol 3,20-dione
17,21-Cyasade (Compound II'A1R' obtained from compound ■ via compound ■ = acetyl) 1 g of 2-bromo-6β-fluoro4pregnagen-11α·17α·21-trio-3·20-dione 11-mesylate 21 acetate (compound ■) 4
Dissolve in a mixture consisting of 4 TLl of ethyl acetate, 7.5 ml of acetic anhydride and 0.05 ml of 70% perchloric acid.

The reaction mixture was kept at room temperature for 30 minutes and then transferred to a 60 m
Pour into a separatory funnel containing a cold solution of IJum (131 parts bicarbonate in 1 part water) and shake well.

Separate the organic layer and concentrate in vacuo to obtain the corresponding crude 17α.
A semi-solid residue consisting of ~acetate ■ is obtained.

This residue is combined with 10 ml of glacial acetic acid and added with 1.
51 of anhydrous sodium acetate is added.

The reaction mixture was heated to 110 °C and at this temperature an additional 3
After holding for 0 minutes, it was cooled to 20°C and 50ml
pour into the water.

The precipitate obtained is filtered once, washed with water and dried.

Compound ■'A is obtained which exhibits the following properties.

Ultraviolet spectrum, λ -247 mμ, E1%,
MeOH maxlcIrL -245, [, αJD--81° (C-1, in dioxane) Infrared spectrum (nujol): 1740° 1675.
1650.1605.1235crIL'Example 11 2-70mo6β-fluoro-1,4,90D pregnatriene-17α,20-diol 3,20-dione
17,21-diacetate (compound n'A obtained from compound ■ via compound ■, R' = acetyl) Starting from 2g of compound ■ and operating as shown in Example 10, the following The corresponding 5.alpha..17.alpha.-diacetate (compound 2) of 2.2P is obtained which exhibits the properties.

, MeOH ultraviolet spectrum, λ -259mμ ax infrared spectrum (Nujol): 1730.1690.
1590 cm -1 2.2 g of the obtained compound (1) are dissolved in 22 rrLl of dimethylformamide.

22 g of lithium chloride are added and the reaction mixture is heated to 110° C. for 30 minutes, which is subsequently worked up as described in Example 9.

1.31 compound ■'A is obtained. Example 12 2-furomo6β-fluoro-1,4,9(11) pregnatriene-17α,21-diol 3,20-dione 17,21-diacetate (compound II'A obtained from compound IIA, R'= Starting from the compound HA of 1z and proceeding as shown in Example 1o, a product of 11g is obtained which exhibits the same properties as the compounds ■'A prepared according to Examples 1o and 11. .

Example 13 2-bromo-6β-fluoro-9β·11β oxide-
1,4-pregnagene-17α,21-diol-3
・20-dione-17,21-diacetate (compound 0
, R'-acetyl, Z=H) 101 of compound II'A is suspended in 1001 nl of tetrahydrofuran and treated with 10 ml of 7% perchloric acid and 5z of N-bromoacetamide at 10°C.

After 1 hour, excess bromine is removed using an aqueous sodium sulfite solution.

The resulting solution is slowly poured into 11 pieces of cold water.

The corresponding bromohydrin (compound 0) is passed through once.

This can be used in the next step for epoxide production.

Suspension of 15 g of wet bromohydrin 0 in 150 rrLl of acetone □Add 15 g of potassium acetate.

The reaction mixture is refluxed for 1 hour, then it is cooled to room temperature and poured into 500 ml of cold water.

The precipitate is filtered once, washed with water and dried.

The desired compound 0 of 4z is obtained which exhibits the following properties.

, MeOH UV spectrum, λ = 252-253 mμ, aX 1% E1clrL = 210, [α)D = 76.5° (c = 1
% in dioxane) Infrared spectrum (Nujol): 1755.1740.
1670.1600. 1235cm 1 Example 14 2-Flomo6β・9α-difluoro-1-4 flexnadiene-11β・17α・21-)diol-3・20
-dione-17,21-diacetate (compound VIA,
R' = acetyl) 7 of 10rIll cooled to 10°C
Add 22 epoxide '0 to 0% hydrogen fluoride with stirring.
Add after 5 minutes.

The reaction mixture is kept under the above conditions for a further 30 minutes and then poured into cold aqueous ammonia solution.

The precipitate obtained is filtered once, washed with water and dried.

22 crude compounds VIA are obtained. Crystallization from methanol gives a pure product of 1.31 with the following properties:

, MeOH UV spectrum, λ = 246 mμ, E1% m
ax 1(]240 Infrared spectrum (nujol): 3500°1760.
1730,1700.1675.165011615.
1240crrL'[α)D--46° (c=0.5
, in dioxane), melting point 312-315°C, molecular weight 55
9.5 Analysis value: CC25H2B rF207 Calculation value (: 53.68%, R5, 22%, Br14
．． 29%, F6.8% Actual value C53, 65%, R5, 13%, Br14.0
%, F6.65% N, M, R1 confirms the presence of 2-bromo-3-ketoΔ1°4 and the epimeric β-configuration of the 6-fluoro-substituent.

δ(Me2SO) 0.87 (3H,s, 18CH
3) 1.55 (3H, d, 19CH3) 1.97 (3H, 51 CH3COO-) 2.06 (3H, s.

CH3COO-) 4.77 (2H,51 CO-□CH2C)-CO) 6.47 (IH, d, = C(4)-H) 7.84 (
IH,s,=C(1)-H)p,p-m Example 15 2-7" Romo6β-fluoro=9α・11βcyclo1・4-pregnagen-17α・21-diol-
3,20-dione-17,21-diacetate (compound ■A, R'=acetyl) 1? in 40 ml of glacial acetic acid. Compound I ['A and 0.5P N-chloro- in a solution of 4v lithium chloride
Add succinimide with stirring.

The reaction mixture is kept at 15-20° C. with stirring for a further 3 hours, then it is poured into cold water.

The precipitate is filtered once, washed with water and dried.

The crude product is crystallized from aqueous acetone to obtain pure compound vIIA of 0.5P with the following properties:

Ultraviolet spectrum, λ = 244 mμ, E1%,
MeOH maXICrrL = 215 Infrared spectrum (nujol'): 1760.174
5.1675.1650.1610.1230cm
(a) D=+0.2° (c=1 in dioxane), melting point -268-272°C.

Example 16 2-7” lomo6β-fluoro-1,4,9(lυ・1
6-bregnatetraen-21-ol-3,20-dione 21-acetate (compound [phase]) 600 rIL maintained at 100°C with continuous bubbling of dry nitrogen
To a suspension of 50 grams of anhydrous sodium acetate in 1 liter of dimethylformamide is added 5z of compound ■'A with stirring.

The reaction mixture is heated to 120° C. and maintained at this temperature under a nitrogen atmosphere while stirring for a further 4 hours.

After cooling to 20°C, do not stir the reaction mixture after the reaction.
．． Pour into −l of cold water.

The precipitate obtained is filtered, washed with water and dried.

A compound [phase] of 4z is obtained. MeOH1% UV spectrum λ = 244 mμ, E1cIrL
aX 520 Infrared spectrum (Nujol): 1740°1665.
1610,1595.1235.1215CrIL'
(α) D=+37.2° (c=1 in dioxane) melting point -232-235°G.

Example 17 2-Bromo-6β-fluoro4.9(11)pregnatriene-16α.17α.21-trio-3.
20-dione 21-acetate (compound [phase]) Compound 51 [phase] in 200 ml pure acetone and 1.5 ml 99% formic acid cooled to 10°C
A solution of 2,31 potassium permanganate in 100 TILl of acetone containing 20% water is rapidly added to the solution with vigorous stirring.

After 2 minutes, 10% aqueous sodium bisulfite solution is added until excess potassium permanganate is completely removed.

The resulting suspension is filtered once to remove formed salts, and the clear liquid is concentrated in vacuo to a small volume.

Filter the precipitate to obtain 4.2S' compound [phase]. Ultraviolet spectrum: λ -248, E1% -2゜75 eOH maXlcrrL Infrared spectrum (Nujol'): 3410.172
5.1660.1600.123ka "1 [α, 1D=-
49° (c=1 in dioxane), melting point = 180-18
6℃.

Example 18 2-furomo6β-fluoro-9α·11β dichloro-
1,4-pregnagene-16α,17α,21-trio-3,20-dione 21-acetate (compound ■
) Starting from compound [phase], compound (1) is obtained by operating as shown in Example 15.

When crystallized from methanol it has the following properties:

Ultraviolet spectrum: λM00H-247mμ, E1%ma
x 1cm238 Infrared spectrum (Nujol): 3540°3260.
1745.1720.1665.1605.1230c
rrL' (a) p=+60° (c=1 in dioxane), mp=146-148°C.

Example 19 2-furomor6β-fluoro-9α·11β-dichloro-1,4-pregnagene-16α·17α·21-trio-3·20-dione 16·21-diacetate (compound ■A) 5 ml of pyridine Compound 1 of 1z dissolved in is treated with 0.5 ml of acetic anhydride at 0°C.

The reaction mixture is allowed to stand for 1 hour and then poured into 100 ml of ice water.

Filter the precipitate, wash with water and dry.

Compound 1,1z A is obtained. Ultraviolet spectrum: λ
=247mμ, E1%eOH maXICrrL =227 Infrared spectrum (nujol): 3450°1730.
1665.1640, 1610.1230C1rL-1
[α, lp=+300 (c=1, in dioxane), melting point=155-157°C.

Example 20 2-furomo6β-fluoro-9α・11β-cyclo1・4-pregnagen-16α・17α, 21-)
Liol-3,20-dione 21-acetate 16,1
7-Acetonide (Compound 1 B) To a suspension of 11 Compound 1 in 507711 acetone is added 0.25 rnl of 70% perchloric acid.

The reaction mixture is left at 15-20° C. for 1 hour, then it is neutralized with sodium bicarbonate.

After washing off the salt, the liquid is concentrated in vacuo to a small volume and cooled to facilitate precipitation of the crude acetonide.

0.6 crystallized from acetone aqueous solution and exhibits the following properties:
A pure compound of P (■B) is obtained.

MeOH1% Ultraviolet spectrum: λ -247mμ, E1crrL
aX = 225 Infrared spectrum (nujol): 1750°1730.
1670, 1610, 123 (g) "1, [α) D=
+66.5° (C-1 in dioxane), melting point -150
~153℃.

Example 21 2-furomo6β,9α-difluoro-1,4pregnagen-11β,16α,17α,21-tetraol 3,20-dione 21-acetate (Compound ■) Starting from compound [Yes], compound 0 and Compound (1) can be produced by operating as shown in Examples 0 and 0 via [Phase].

, MeOH UV spectrum, λ-246, E1%=max
1crrL38 Infrared spectrum (Nujol): 3400.1730
゜1665.1600.1230crrt-11Cα)
D-19° (c=0.5, in dioxane), melting point=2
47-251℃.

Analytical value: C23H27BrF207 Calculated value F=7.14% Actual value F=7.10% Example 22 2-bromo-6β・9α-difluoro-1,4flexnaciene-11β・16α・17α・21-tetraol-3 -20-Dione 16,21-diacetate (Compound IXA) Compound IXA can be prepared by starting from Compound (1) and operating as shown in Example 19.

Ultraviolet spectrum: λM00H-245mμ, E1%=210゜maXlc
IrL infrared spectrum (Nujol): 3450°1730.
1670.1640, 1605.1235crrL” Example 23 2-furomo6β-9α-difluoro-1-4 pregnagen-11β・16α・17α・21-tetraol-3・20-dione 21 acetate 16・17-acetonide (compound IXB) Compound IXB can be prepared by starting from compound (1) and operating as shown in Example 20.

e OH ultraviolet spectrum: λ -245mμ, E1%ma
XICrrL 221 Infrared spectrum (Nujol): 3500.1760
．． 1730, 1670 1640L610. 1235
77L-1Ccl: lp=+0.2° (c=1 in dioxane), melting point -148-151°C.

Example 24 2-furomo6β-fluoro-16α-methyl 4.9
01) -Pregnatriene-17α・21-diol-
3,20-dione 17,21-diacetate (compound II'B) 6β-fluoro-16α-methyl-fregnan-5α・
Starting from 11α·17α·21-tetraol 3·20-dione 21-acetate (compound Z-αCH3), Example 1.2.3.4.5.6.7.8.9.10
．． Compound II'B can be prepared by operating according to the methods described in 11 and 12.

Ultraviolet spectrum: λMeOH=246mμ, E1%ma
x 1 cm=251 Infrared spectrum (Nujol): 1740°1725.
1675.1650.1605.1230.1250c
IrL-1, melting point = 218-222°C.

Example 25 2-70mo 6β-fluoro-9α·11β dichloro-
16α-methyl-1,4-pregnagene-17α,2
1-Diol 17.21'Diacetate (Compound 1B) Compound 1B can be prepared by starting from Compound 1'B and operating as shown in Example 15.

, MeOH 1% UV spectrum, λ = 244 mμ, E1crrL
ax 196 infrared spectrum) L/(nujol): 1735.157
0.1605.1235crIL-1, melting point = 242 ~
246℃.

Example 26 2-furomo 6β・9α-difluoro-16α methyl-
1,4-pregnagen-11β, 17α, 21-trio-ru 3,20-dione 17,21-diacetate (
Compound VIB) Starting from compound II'B, Example 13
Compound vtB can be prepared by operating as shown in and 14.

Ultraviolet spectrum: λ -246mμ, E1%eOH max 1cm233 Infrared spectrum (Nujol): 3480.1755.
1730.1710.1675.1650.1615.
1235CrIL' [α) D= -53° (c-
1 in dioxane), melting point -288-290°C.

Example 27 2-furomo 6β-fluoro-9α·11β dichloro-
16β-methyl-1,4-pregnagene-17α,2
1-diol-3,20 dione 17,21-diacetate (compound ■C) 6β-fluoro-16β-methyl-7regnan 5α,1
1α・17α-21-tetraol 3・20-dione 2
Starting from 1-acetate (compound 1, Z=βCH3), Examples 1.2.3.4.5.6.7.8.9.10.
By operating according to the methods described in Examples 11 and 12, compound ■'C is obtained, from which compound ■C can be prepared according to the method of Example 15.

, MeOH1% Ultraviolet spectrum, λ -244 mμ, El.

max =224, [α].

−+17.5° (c=1 in dioxane) Example 28 2-bromo-6β·9α-difluoro-16β-methyl-1,4-pregnagene-ILβ·17α·21-trio-3,20-dione 17,21-diacetate (compound VIC) Starting from compound ■'C, Example 13
Compound vic can be produced by operating as shown in and 14.

Ultraviolet spectrum: λ, 245, E1%-MeOH
.

maXlcIrL 21 Infrared spectrum (Nujol): 3460.1740
．． 1760,16701165011600.1240
crrL' EXAMPLES Two Biological Tests The local anti-inflammatory effect of the novel products of the invention was determined by a pure leukoblastoma test.

This study was conducted in adult male rats (S
Prague Dawley) was used at a ratio of 10 animals per group, and the method of Winter and Porter (J, A
m, Pharm.

Ass, Sci, md, , 46.515.195
7)).

This method consists of subcutaneous implantation of sterile cotton pellets.

The pellets used were 5-open sections cut from dental windings each measuring approximately 45 m9.

Two pellets were inserted subcutaneously into each animal's abdomen on either side.

After 7 days, the pellets were removed and the exudate weight was recorded as a measure of granuloma formation.

The degree of granulation-like inhibition indicates the anti-inflammatory effect of the test compound.

Test compounds were administered topically (compound absorbed into pellets prior to implantation) as well as orally (administered daily).

For topical administration, test compounds were dissolved in 95% ethanol, and for oral administration, compounds were suspended in a conventional vehicle consisting of carboxymethyl cellulose and Tween 80.

Fluocinolone acetonide, a well-known topical anti-inflammatory steroid, was used as a comparison product and its action was evaluated by four components: local anti-inflammatory action, topical thymol (thymo
lytic) action, oral anti-inflammatory action and oral thymol action, each of which was conventionally equal to 1.

The results are shown in Table I. In the table, "Compound 14" is the compound described in Example 14, that is, 2-furomo 6β・9α
-difluorote 4-pregnagene-11β/17α
・21-trio-rou 3・20-dione-17α・21
-diacetate, "Compound 15" is Example 15
The compound described in 2-furomoloβ-fluoro-
9α・11β-cycloloto 4-pregnagen-17
α・21-diol 3・20-dione-17α・21-
Represents diacetate.

The above data show that after topical administration, the new compound exhibited a significant anti-inflammatory effect that was 10 times higher than fluocinolone acetonide.

Furthermore, it is noted that the thymol effect, one of the well-known side effects of anti-inflammatory corticosteroids, is five times lower in the case of the new compound than in fluocinolone acetonide.

The test compound appears to have a significantly favorable therapeutic index compared to the reference standard.

All tested products showed a higher anti-inflammatory effect with stronger inhibition of granulomas, but less undesirable side effects, such as thymol action, than that observed for fluocinolone acetonide as a control substance. It was noticeably small.

These remarkable pharmacological properties make it clear that the novel halopregnanes of the present invention are very useful anti-inflammatory agents.

They can be used in the treatment of humans and livestock, such as in the treatment of various types of inflammatory skin diseases, psoriasis and other allergic diseases.

Usual dosages vary depending on the disease, the product used, the individual being treated and the route of administration, but range from o, ooi to about 0.
Contains an amount of 200% by weight of the specified active ingredient.

Depending on the route of administration, various pharmaceutical compositions containing the active ingredient can be prepared.

For topical administration, the active ingredients may be formulated in conventional compatible vehicles used to prepare ointments, creams, emulsions, drops and sprays.

The novel technical matters disclosed by the present invention will be summarized below.

1. General formula (wherein,
can be a methyl group, R' can be hydrogen or an acyl group having 2 to 8 carbon atoms, R can be hydrogen or an organic group having 2 to 8 carbon atoms; 2-bromo-6β
-Fluoro-1,4-pregnagen-17α,21-
Diol 3.20-dione.

2. General formula [wherein, X can be a keto group, a β-hydroxyl group, or a chlorine atom, Y can be a fluorine atom or a chlorine atom, and R has the same meaning as in 1 above. ,
R2 represents a hydroxyl group and R3 represents OR'(R' can be hydrogen or an acyl group having 2 to 8 carbon atoms), or R2 and R3 together---OCH3 \ / 2-Bromo-6β-fluoro4 represented by / ＼ -OCH3]
-Pregnagen-17α・21diol-3・20-
Zeon.

3. A compound represented by the general formula (wherein Ac is an acetyl group and Z is hydrogen, an α-methyl group or a β-methyl group) is heated to 100 to 120°C with lithium chloride and dimethylformamide under a nitrogen atmosphere. △1° to a 2,2 cyfromo-3-keto-5α-hydroxy 6β-fluoro-pregnane derivative, which consists of heating to obtain a compound represented by the general formula (wherein Ac and 2 have the meanings given above). A method for producing a compound represented by the above formula (2) by simultaneously introducing four double bonds.

4. 2-bromo-3-keto-6β fluoro-pregnane represented by the general formula (wherein Ac and 2 have the same meanings as above) is heated to 100 to 120°C with lithium chloride and dimethylformamide under a nitrogen atmosphere. 2-Flomo-3-keto-6β-fluoro-△1° represented by the general formula (wherein Ac and Z have the same meanings as above) by heating
said 2, consisting of producing 4-pregnagene;
-bromo-3-keto 6β-fluoro-pregnane
- Methods of stabilization in the form of epimers.

5. (A) Acetic anhydride at room temperature) 6β-fluoro-pregnane 5α.
11α·17α·21-tetraol 3·20-dione 21-acetate is reacted with bromine and (B) 2 in dimethylformamide in the presence of anhydrous lithium chloride under nitrogen atmosphere according to paragraphs 3 and 4 above.・2-
Dibromo6β-fluoro-pregnane-5α・11α・
17α・21-tetraol-3・20-dione-21
-Heat the acetate to 100-120°C to obtain 2-bromo-6β-fluoro-1,4 pregnagen-11α,1.
7α·21-trio-3·20-dione-21-acetate was obtained, (qThe latter intermediate was subjected to reaction with methane-sulfonyl chloride in the presence of anhydrous pyridine to give (D
) 2-bromo-6β-fluoro-1,4 pregnagene- in ethyl acetate in the presence of 70% perchloric acid at room temperature.
11α·17α·21-4liol-3·20-dione-11-mesylate-21-acetate was reacted with acetic anhydride to form 2-bromo-6β-fluoro4- Pregnagen-11α・17α・21-trio-3・20-dione-11-mesylate 17・21-diacetate 1
2-Bromo-6β-fluoro-1,4,9 (11) consisting of a step of heating to 00 to 120°C to obtain the desired compound
-7'regunatriene-17α・21-diol-3・
A method according to the above items 3 and 4 for producing 20dione-17.21-diacetate.

6, (A) 2-furomo6β-fluoro-1,4,9α
D-pregnatriene-17α・21-diol-3・
20-Dione-17,21-diacetate is reacted with perchloric acid and N-furomoacetamide, (B) the corresponding furomohydrin is refluxed in acetone in the presence of potassium acetate, and (q cold 2-furomo6β- Fluoro-9β-1
1β oxide-1, 4-pregnagen-17α, 21
2-Bromo-6β·9α-difluoro-1 consisting of a step of reacting -diol-3·20-dione-17·21-diacetate with 70% hydrogen fluoride to obtain the desired compound.
・4-Pregnagen-11β・17α・21-)
Method for producing IJol 3,20-dione-17,21-diacetate.

7. 2-bromo-6β-fluoro4,9(11)-pregnatriene-17α,21-diol-3,20- in glacial acetic acid in the presence of N-chloro-succinimide
From reacting dione-17,21-diacetate with lithium chloride, 2-7''romo6β-fluoro-
9α・11β dichloro-1,4-pregnagene-17
α・21-diol-3・20-dione-17・21-
Manufacturing method of diacetate.

8(A) 2-bromo6β-fluoro4.9(11)-pregnatriene-17α.21 in dimethylformamide in the presence of anhydrous potassium acetate under nitrogen atmosphere.
-diol-3,20-dione-17,21-diacetate was heated to 100120'C, (B) the obtained 2-
Bromo 6β-fluoro 4.9a1).16-bregnatetraen-21-ol 3.20-dione 21-acetate is reacted cold with potassium permanganate in acetone in the presence of formic acid to form (C) chloride. 2bromo-6β-fluoro4 in aqueous acetic acid in the presence of lithium
9(1)-7'regunatriene-16α・17α・21
-trio-3.20-dione-21-acetate was reacted with N-chloro-succinimide, and the obtained 2
-Flomo6β-fluoro-9α・11β-dichloro-
2-Bromo6β-fluoro-9α, which consists of reacting 1,4-pregnagene 16α·17α·21-tri-3·20dione-21-acetate with acetone in the presence of perchloric acid to obtain the desired compound.・11β-
Dichloro-1,4-pregnagene 16α・17α・2
1-trio-ru 3.20dione-21-acetate-
Method for producing 16/17-acetonide.

9. (A) 2-Bromo6β-fluoro4.9(11)-pregnatriene-17α in dimethylformamide in the presence of anhydrous potassium acetate under nitrogen atmosphere.
-21-diol-3.20=dione-17.21-diacetate is heated to 100-120°C, and (B) the obtained 2-bromo6β-fluoro-1.4.9(11).
16-phlebnatetraen-21-ol-3・20-
Dione-21-acetate is reacted cold with potassium permanganate in the presence of acid in acetone to form (C) 2-bromo-6β-fluoro4.901) phlebnatriene-16α.17α.21-trio-ru. Reacting 3,20-dione-21-acetate with N-furomoacetamide and perchloric acid, (D) refluxing the corresponding bromohydrin in acetone in the presence of potassium acetate, and (EP2
Bromo-6β-fluoro-9β・11β-oxytote 4-pregnagen-16α・17α・21-trio-
3.20-dione 21-acetate was mixed with 70% hydrogen fluoride to obtain (F'') 2-bromo-6β.9
α-difluoro-1,4-pregnagene-11β·1
2-Bromo-6 consisting of a step of reacting 6α·17α·21-tetraol-3·20-dione-21-acetate with acetone in the presence of perchloric acid to obtain the desired compound.
β・9α-difluoro-1,4-pregnagene-11
β・16α・17α・21-tetraol-3・20-
Method for producing dione-21-acetate-16/17 acetonide.

Claims (1)

[Claims] 16β-fluoro-pregnane-5α, 11α, 17α
・21-tetraol-3,20-dione 21-acetate is brominated to produce 2,2-dibromo-6β-fluoro-
Pregnane-5α, 11α, 17α, 21-tetraol-3, 20-dione-21-acetate, which was then heated to form 2furomo6β-fluoro-1,4-pregnagen-11α, 17α, 21-trio. -Lou 3・
20-dione-21-acetate was obtained, which was then mesylated to obtain 2-bromo-6β-fluoro-1.4
-Pregnagene-11α・17α・21-trio-3・20-dione-11-mesylate-21-acetate is acylated to 2bromo-6β-fluoro-1,4
-7” Regnasien-11α・17α・21-Trio-
2-Flomo 6β-fluoro 4.901 consisting of obtaining and heating Ru 3.20-dione-11-mesylate-17-arale-4-21-acetate.
)-pregnatriene-7α,21 diol-3・2
Method for producing 0-dione-17-acylate-21-acetate. 26β-fluoro-pregnane-5α·11α. 17α・21-tetraol-3・20-dione 21-
Brominating acetate to produce 2,2-dibromo-6β-fluoroprecnan-5α, 11α, 17α, 21-tetraol-3, 20-dione 21-acetate,
Next, this is heated to produce 2-furomo6β-fluoro-1.
4-Pregnagen-11α・17α・21-trio-
3.20-dione-21-acetate was obtained, which was then mesylated to obtain 2-furomo6β-fluoro-1.4-pregnagene-11α, 17α. Acylation of 21-trio-3,20-dione-11-mesylate-21-acetate to produce 2bromo-6β-
Fluoro-1-4-7” Regnasien-11α/17α
・21-trio-3.20-dione-11-mesylate-17-arale-4-21-acetate was obtained and heated to give 2-bromo-6β-fluoro-1.4.
9αυ pregnatriene-17α・21-diol-3
20-dione-17,21-diacetate, then this 17,21-diacetate was reacted with N-promoacetamide in the presence of perchloric acid, and the resulting bromohydrin was treated with potassium acetate. corresponding 9
A β·11β-epoxy derivative was obtained which was then reacted with hydrogen fluoride to obtain 2-bromo-6β·9α-difluoro-1
・4-Pregnagen-11β・17α・21-trio-3・20-dione-17・21-diacetate or the above-mentioned 2-fromo 6β-fluoro r:1-
1.4.901)-pregnatriene-17α.21-
Diol-3,20-dione-17,21-diacetate was reacted with Nchloro-succinimide in the presence of lithium chloride and acetic acid to give 2-bromo-6β-fluoro-
9α・11β-cyclo1・4-pregnagen-1
A process for producing a compound having the formula (wherein X represents a β-hydroxyl group or a chlorine atom and Y represents a fluorine atom or a chlorine atom), the process comprising obtaining 7α.21-diacetate.