Method of producing derivatives of 6 alpha-methyl hydrocortizon

专利摘要:

公开号:SU1255053A3
申请号:SU833673658
申请日:1983-12-05
公开日:1986-08-30
发明作者:Аннен Клаус；Петцольдт Карл；Лаурент Хенри；Вихерт Рудольф；Хофмайстер Хельмут；Вендт Ханс；Альбринг Манфред
申请人:Шеринг Аг (Фирма)；
IPC主号:

专利说明:

The invention relates to methods for producing new 6c derivatives: -methyl-hydrocortisone of the general formula
BUT
Where
R, 1-oxoalkyl C — C — octyl R, current or benzoyl residue; i -oxo-pkilny With, -C-residual,
possessing topical activity in various skin diseases.
The purpose of the invention is to obtain new derivatives of bo-methylhydrocortisone, which have advantages in terms of fracological compared to the known,
PRIOR 1. A solution of 1.0 g of 17-β-acetoxy-11 / 3,21-dioxy-6c4-methyl-4-β-pregnep-3,20-dione in 20 ml of pyridine is mixed with 3 ml of butyric acid and stirred for 2 hours. room temperature. The reaction is then poured into 150 ml of chilled 8% sulfuric acid and stirred for another 5 hours, and the initially separated oil crystallizes. It is sucked off, washed with water and dried b h at 80 ° C in a vacuum drying cabinet. For purification, the crude product is recrystallized from a mixture of acetone and diisopropyl ether.
. 940 ml of 17 acetoxy-21-butyryl-hydroxy-1p hydroxy-6o; methyl-4-β-pregnene-3,20-dione are obtained with a melting point of mp. 98-102
And pmme R 2. A solution of 1.0 g i 1 p, 21 -dioxy-6c:.-Methyl-1 7-propionyl oxy-4 - pregnen-3,20-diop in 10 i-ш pyridine is mixed with 5 ml of propionic anhydride for 2 hours at room temperature. The mixture is then introduced into a solution of sodium chloride, in ice-cold water, filtered off with silica and, after usual processing, the crude product is purified. Onto 65 g of silica gel with methyl chloride / gradient (acetone).
0
five
0
five
0
0
five
0
5 Yield 11 p-hydroxy-6cc-methyl-1 7, 21-dipropionoxy-4-pregnen-3,20-dione is 1.08 g; m.p. 210 ° C
Example 3: Analogously to Example 1 1, 0 g 1, 1, 1-dioxy-6c; -methyl-17-β-propionyloxy-4-pregnen-3, 20-dione is reacted with 5 ml of anhydride oil After precipitation, the mixture is extracted with ice-cold water with sodium chloride, extracted with methylene chloride, distilled with steam and treated as usual. The crude product is purified by crystallization from a mixture of acetone and hexane,
21-Butyryloxy-1 1/5-hydroxy-β-bc-methyl-1 7-propionyloxy-4-pregnen-3.20 dione Vuhod is 912 mg; m.p. ,
Example 4
a) A solution of 5.0 g of 21-acetoxy-1 1/3, 1 7-dioxy-bo-methyl-4-pregnen-3,20-dione in 25 ml of pyridine at -15 ° C
3 ml of trifluoroacetic anhydride are mixed dropwise and stirred for 10 minutes. at. The mixture is introduced into a solution of sodium chloride in ice water, and the precipitate is filtered off. The residue is dissolved in methylene chloride, washed until neutral and after drying over sodium sulfate, the center is vacuum centered.
The yield of 21-acetoxy-1 7-hydroxy-6-obmet-11-trifluoroacetoxy-4-pregnen-3., 20-dione is 5.1 g.
b) 3.7 g of the crude product obtained according to example 4a in 45 ml of dithylene-glcol dimethyl ether and 5.5 ml of propionic anhydride are mixed together with 5.9 g of 4-dimethyl-aminopyridine for 18 hours at room temperature.
After the usual treatment, they are made
3.9 g of 2G-acetoxy-6c; -methyl 17-pro I pionyloxy-1 1 / -trifluoroacetoxy-4-pregnen-3, 20-dione.
c) 3.0. g 21-acetoxy-6c -methyl-17-β-propionyloxy-1 1 | 5-trifluoroacetoxy-. -4-pregnen-3, 20-dione in 50 ml of methanol and 2.5 ml of triethylamine are stirred at room temperature for 4 hours. The crude product is purified on a .300 g of sipicagel using a methylene chloride acetone gradient (0-15% acetone).
3
 1.2 g of 2 1-acetoxy-Py-oxy-6ot methyl-1 7-propnonyloxy-4-β-pregnen-3,20-dione was isolated.
Example Under the conditions of Example 2, 1.0 g of 1 7-butyryloxy-M, 21-dioxy-6l-methyl-4-pregnen-3,20-dione is reacted with acetic anhydride, treated and purified. The yield of 21-acetoxy-7-butyryloxy-11 |} -oxy-6 (H.-methyl-4-pregnen-3,20-dione is 1.02 g.
Example 6. 1.0 g of 17-butyryl-oxy-11 / i, 21-dioxy-6ot-mitshl-4-preg nen-3,20-dione, as in Example 2, leads to a reaction with propionic anhydride, and clean.
Get I, g 17 butyryloxy-1-hydroxy-5-methyl-21-propionyloxy-4-β-pregnen-3,20-dione; m.p. 175 ° C.
Example 7.1 g of 7-butyryl-hydroxy-1 / E, 21-dioxy-6-C-methyl-4-pregnen-3,20-dione under the conditions of example 3 is brought into contact with oily anhydride and the like obrabatgoat way. The crude product is recrystallized from a mixture of acetone and hexane.
860 mg of 17,21-dibutyrylos-1 1p-hydroxy-6cC-methyl-4-pregnen-3,20-dione with m.p. 103 ° C.
Froze 1.0 g of 17-butyryl si-1 1 p, 21-dioxy-bob-methyl-4-pregn 3,20-dione in pyridine is reacted with 5 ml of valeric anhydride as in Example 3.
After the usual treatment and purification of 65 g of silica gel using a methylene chloride acetone gradient (0–15% acetone), 980 mg of 17-bu tiryloxy-1 IP-oxy-6 (X-methyl-21 –ryloxy-4-pregnane) are isolated. -W, 20-dione.
EXAMPLE 9. Under conditions, with a measure of 3 1.0 g 1 G | The 21-dioxy-7-propyloxy-6o-methyl-4-pregnen-3,20-dione is reacted with isobutyric anhydride, processed and purified.
The yield of 11 p -oxy-21-isobutyryloxy-6oh. Methyl-l 7-propionyloxy-4-pregene-3,20-dione is 870 mg.








Example 10. Analogously to Example 2 1, 0 g 1 1 |), 21-dioxy-6o6-methyl-17-55 valeryloxy-4-pregnen-3, 20-dione is reacted with acetic anhydride, treated and purified.
ten
15
20
25
550534
980 mg of 21-acetoxy-1 1/5-β-oxy-6cC-methyl-1 7-shaft eroxy-4-pregnen-3, 20-dione were isolated.
EXAMPLE 11 Under the conditions of Example 5, 2 1.0 g of 11p, 21-DIOXI-17-isobutyryl-oxy-bo; -methyl-4-pregnen-3, 20-dione are reacted with anhydride. propionic acid, process and opp.
This gives 985 mg of 11/5-hydroxy-1 7-isobutyryloxy-6) with: -methyl-21-propionyloxy-4-pregnen-3, 20-dione.
Example 12. Analogously to Example 2, 2.2 g of 1 7-benzoshloxy-i 1 0.2-di-oxy-6a: - methyl 4-pregnen-3,20-dione is reacted with acetic anhydride and treated, - as usual, the crude product is purified on 350 g of silica gel using a methylene chloride acetone gradient (0-8% acetone). 1.6 g of 21-acetoxy- 1.7 benzoyl-si-Tr-hydroxy-by-methyl-4-pregnenZ, 20-dione was isolated; m.p. 210 C.
Example 13. 1.0 g, 21-diox-6a, -methyl-7-trimethylacetoxy-4-β-pregnene-3,20-dione under the conditions of example 2 is reacted with propionic anhydride, treated and purified similarly
described,
940 mg of 11 /) -oKCH-6oi-Methyl-2I-propionyloxy-7-trimethylacetoxy-4-pregnen-3, 20-dione are obtained.
Example 14. Under the conditions of example 8: 500 mg of 17-acetoxy-1p, 21-dioxy-6a; -methyl-4-pregnen-3, 20-dione are converted into 480 mg 17 with 1.5 ml of acetic anhydride, 17 21-diacetoxy-1B-hydroxy-6y-methyl-4-pregnen-3,20
-dione with so pl. 130-135 C.
Example 15. Under the conditions of Example 1, 500 mg of 17-acetoxy-11p, 21-β-dioxy-β-methyl-4-pregnen-3.20-β-dione is converted into 490 mg of G 7 by reacting with 1.5 ml of propionic anhydride in pyridine. acetoxy-si 1 1 | -oxy-6ob-methyl-2 I-propionic - hydroxy-4-pregnen-3, 20-dione with m.p. 99-103 ° C.
Pharmacological, data
The topical (local) activity of the compounds was determined using a vasoconstriction test as follows.
The test was performed on groups of 8 healthy experimental subjects of both sexes, which over the past two weeks did not receive local treatment with corticosteroids. After removing the layer of corneum
until slush lusidum on the backs of the experimental
(20-40 outline tezaplenki) applied
0.1 I finished product on the field
4 cm in size without occlusal
in szk.
Vasoconstriction was visually evaluated after 8 hours by the following degrees of action: I - absolute blanching 2 - slight residual erythema; 3 - moderate erythema, intensity of erythema in the average range of treated and intact skin; 4 - erythema with slight lightening; 5 - no pale or increased erythema.
The individual estimates were averaged.
In a series of experiments, difluctolone-21-valerianate (6 °,;; -difluoro-1 I p-hydroxy-6a-methyl-21-valyloxy-1,4-pregnadiadien-3, 20 was used as a comparative substance. -dion -DFV).
Accordingly, the difference between the average degree of action of DFV, obtained as a result of separate research, and the test substance, was determined. Positive deviations, indications of a more favorable assessment of the test substance as compared to DFV, and negative ones - unfavorable. The table below shows the observation results that were obtained by treating the experimental subjects with a preparation containing 0.001 and 0.00001% of the active substance.
Vasoconstrictor Test
Substance
I Concentration - after 8 h 1%,%
3
-1.6 -0.3
0,001 0,00001

21-Aietoksn-P 3, 0, 4
1 7os-dphydroxy-bl-methyl-0, 00001-0.3
-, 4-pregnadi Continuation Table
R 2
j
10 15
20 25
30 5
0
five
0
five
en-3,20-dione (known)
11p, 21-dihydroxy-1 tiryloxy-4-β-pregnen-3.20-β-dion (active substance of the Alpha-zone trade preparation)
1 1 /, 21-Dihydroxy-bc-methyl-1 7 | x; -propionroxy-4-Pregnen-3, 20-dione
21-Acetoxy-1 lp-hydroxy-6 p-methyl-1 7ci-propionyloxy-4-pregnen-3,
1 1 (3-Hydroxy-6ob-methyl-1 7l, 21-dipropionyl-oxy-4-pregnen-3,20-dione
1 7p, -Butyryloxy-11 /, 21-dihydroxy-6cg-methyl-4-pregnen-3,20-dione 21-Acetoxy-1 7ci- - butyryloxy- -1lp-hydroxy-6 with, -methyl-4- -pregnen-3,20- -dione
1 / 3,21-Dihydroxy-si-17s2-isobutyryloxy-6c 1.-methyl-4-pregnen-3,20-diop
11p, 21-dihydroxy-6os-methyl-1 7ci--trshtetylacetoxy-4-pregnene-3, 20-dione
0.001-0.4
0.00001 -0.2
0,0010,3
0.00001 + 1.1
0.001-0.1
0.00001 + 1.4
0.001 + 0.1
0.00001-1.9
0.001-0.1
0.00001 + 1.1
0,, 1
0.00001 + 1.6
0.001 + 0.3
0.00001 + 1.4
0.001 + 0.1
0.00001 + 1.6
0.001-0.4
0, 00001 +0.9
21-Acetoxy-17- 0.001-0.2-benzoyloxy-n / 5-hydrox-0.00001 +1.4 -6ci-MeTHn-4-β-pregnen-3.20-dion

权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING b derivatives of ob-methylhydrocortisone total where R _f - 1-oxoalkyl C ₂ -C a residue or benzoyl residue;
R ₂ is 1-oxoalkyl C _g ~ C _$ .-Residue, characterized in that bsb-methylhydrocortisone-1 7-acylate of the general formula where R ₍ has the indicated meanings, is esterified at the 21-position with alkane carboxylic anhydride from 2-5 -carbon atoms with the subsequent selection of the target products.
SU 1255053__A3_

类似技术:

---

公开号 | 公开日 | 专利标题

---

KR950004901B1|1995-05-15|Steroid derivatives

---

RU2065864C1|1996-08-27|Glycyrhetic acid derivatives, and process for preparation thereof

---

SU1255053A3|1986-08-30|Method of producing derivatives of 6 alpha-methyl hydrocortizon

---

HU192868B|1987-07-28|Process for producing particularly antiasthmatic medicine preparations

---

US4379093A|1983-04-05|Process for preparing high purity ursodeoxycholic acid

---

US5238837A|1993-08-24|Superoxide dismutase derivatives

---

US4186143A|1980-01-29|Chenodeoxycholic acid recovery process

---

DK159686B|1990-11-19|ANALOGY PROCEDURE FOR THE PREPARATION OF 6ALFA METHYL COTICOIDS

---

CA1324134C|1993-11-09|Process for preparing |-2-| acetic acids and 2-| acetic acids and esters thereof, useful as mucoregulator and antihyschaemic drugs

---

EP0082818A1|1983-06-29|Process to obtain human lipids and lacto-N-norhexaosyl ceramide

---

SU890979A3|1981-12-15|Method of preparing corticoids

---

US4349543A|1982-09-14|Histolytic agents and their use

---

JP3578412B2|2004-10-20|Novel benzanilide-type compounds and drugs used for promoting blood circulation

---

US3681405A|1972-08-01|Novel 21,21-dichlorosteroids

---

US4103025A|1978-07-25|Novel terpenes

---

CA1196910A|1985-11-19|Process for preparing new 7-substituted 3-keto.delta.4 or .delta.1-4 steroid derivatives

---

EP0251039A1|1988-01-07|Esters of salsalate with guaiacol, for treating phlogistic bronchopneumopathies

---

EP0386538A2|1990-09-12|Process for preparing high purity 3-alpha-7-beta-dihydroxycholanic acid

---

Sakiyama et al.1964|The betaines of 3-hydroxyproline. Assignment of configuration and inhibition of acetylcholinesterase

---

US4329295A|1982-05-11|24-Cyclopropylcholene-3β, 22-diols and esters thereof

---

CA1041479A|1978-10-31|Chenodeoxycholic acid

---

BLICKENSTAFF et al.1961|Some reactions of methyl 3α-hydroxy-12α-methoxy-9 |-cholenate

---

EP0507348B1|1997-07-09|Superoxide dismutase derivatives

---

Cavalla et al.1951|181. Lanosterol. Part XI. Reduction of ketones in the lanosterol series

---

EP0437552A1|1991-07-24|Alkyl derivates in 17/21 of 19-nor progesterone

同族专利:

---

公开号 | 公开日

---

PT74183B|1983-05-18|

---

FI72729C|1987-07-10|

---

US4912098A|1990-03-27|

---

DE3169460D1|1985-04-25|

---

DD208812A5|1984-04-11|

---

CS231199B2|1984-10-15|

---

CS231197B2|1984-10-15|

---

EP0054786A1|1982-06-30|

---

DD202580A5|1983-09-21|

---

FI814126L|1982-06-24|

---

AU7854981A|1982-07-01|

---

YU103283A|1983-10-31|

---

FI72729B|1987-03-31|

---

YU103383A|1983-12-31|

---

CS231200B2|1984-10-15|

---

YU102083A|1983-10-31|

---

CS221883A2|1984-02-13|

---

DK159324B|1990-10-01|

---

PL238739A1|1983-05-09|

---

RO83669B|1984-08-30|

---

NO156409B|1987-06-09|

---

BG38337A3|1985-11-15|

---

NO814394L|1982-06-24|

---

BG38338A3|1985-11-15|

---

CS8109720A2|1984-02-13|

---

YU103183A|1983-10-31|

---

ES8401988A1|1984-01-16|

---

IE52511B1|1987-11-25|

---

ES8307896A1|1983-08-01|

---

EP0054786B1|1985-03-20|

---

AT12237T|1985-04-15|

---

PL130894B1|1984-09-29|

---

PL130895B1|1984-09-29|

---

RO83669A|1984-06-21|

---

IL64614D0|1982-03-31|

---

GB2089809B|1984-09-26|

---

HU186460B|1985-08-28|

---

JPS57167999A|1982-10-16|

---

IL64614A|1985-06-30|

---

ES508325A0|1983-08-01|

---

GB2089809A|1982-06-30|

---

ZA818907B|1982-11-24|

---

PT74183A|1982-01-01|

---

CA1185234A|1985-04-09|

---

SU1245264A3|1986-07-15|

---

CS222081A2|1984-02-13|

---

PL238741A1|1983-05-09|

---

ES8302027A1|1983-02-01|

---

PL238738A1|1983-05-09|

---

PL234367A1|1983-02-28|

---

YU293181A|1983-10-31|

---

JPH0257559B2|1990-12-05|

---

PH17637A|1984-10-18|

---

AU548999B2|1986-01-09|

---

ES521498A0|1984-01-16|

---

GR76975B|1984-09-04|

---

DK571981A|1982-06-24|

---

DK159324C|1991-02-25|

---

NO156409C|1987-09-30|

---

ES510339A0|1983-02-01|

---

CS221781A2|1984-02-13|

---

PL238740A1|1983-05-09|

---

CS231198B2|1984-10-15|

---

CS231188B2|1984-10-15|

---

CS221981A2|1984-02-13|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US3141876A|1956-08-02|1964-07-21|Upjohn Co|3-keto-6-methyl-4-pregnene-3, 20-diones and a method for the production thereof|

---

US3176032A|1958-04-18|1965-03-30|Syntex Corp|17alpha, 21-diacyloxy derivatives of 6alpha-methyl-delta1, 4-pregnadien-3, 20-dione and of 6alpha-methyl-delta4-pregnen-3, 20-dione|

---

JPS6040439B2|1978-03-29|1985-09-11|Taisho Pharma Co Ltd|

---

DE2848423A1|1978-11-08|1980-05-29|Merck Patent Gmbh|HYDROCORTISONESTER, PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND METHOD FOR THE PRODUCTION THEREOF|DE3133081A1|1981-08-18|1983-03-10|Schering Ag, 1000 Berlin Und 4619 Bergkamen|NEW 6METHYLPREDNISOLONE DERIVATIVES, THEIR PRODUCTION AND USE|

---

DE3227312A1|1982-07-19|1984-01-19|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW 6.16 DIMETHYL CORTICOIDS, THEIR PRODUCTION AND USE|

---

DE3243482A1|1982-11-22|1984-05-24|Schering AG, 1000 Berlin und 4709 Bergkamen|NEW 6METHYL CORTICOIDS, THEIR PRODUCTION AND USE|

---

DE3427486A1|1984-07-23|1986-01-30|Schering AG, Berlin und Bergkamen, 1000 Berlin|METHOD FOR PRODUCING 6METHYLSTEROIDS|

---

CN102401624B|2010-09-10|2014-07-16|珠海格力电器股份有限公司|Stepping motor stroke position detection device and detection control method|

---

CN102964414A|2012-12-14|2013-03-13|中国科学院上海有机化学研究所|Synthesis method of 17-position steroid carboxylic ester|

---

EP3006453A1|2014-10-08|2016-04-13|Cosmo Technologies Ltd.|17alpha-monoesters and 17alpha,21-diesters of cortexolone for use in the treatment of tumors|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

DE3049400|1980-12-23|

---