JPS597200A - 6alpha-methylpredonisolone 17alpha-ester compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R is ethyl, propyl, or butyl). EXAMPLE:6alpha-Methylpredonisolone 17alpha-butylate (11beta, 12-dihydroxy-17alpha-butylyloxy- 6alpha-methylpregna-1,4-diene-3,20-dione). USE:Having high local antiphlogistic action, usable for remedying clinically various kinds of dermatoses, also usable for asthmas, allergoses. A compound wherein R is propyl has especially improved action. PROCESS:6alpha-Methylpredonisolone shown by the formula II is reacted with an orthoesterifying reagent shown by the formula RC(OR')3 (R' is lower alkyl) to give 17alpha,21-cyclic ortho ester compound shown by the formula III, which is subjected to ring opening reaction using an acid, to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel derivatives of 6α-methylpredoni/lono.

In recent years, a large number of corticosteroids have been clinically used as adrenocortical hormone agents for the purposes of anti-rheumatic, anti-inflammatory, anti-allergic, and anti-shock effects. In particular, recently, regarding the anti-inflammatory effect of corticosteroids, their application as a locally effective topical drug is more widespread than that of an oral drug, and the topical use of each weight = 1 lucosteroid is not a clinical scale, but a -. It is also commercially available for use. There are many types of corticosteroids, including hydrocortisone, which is considered to be the basic substance. i'1. is considerably modified, such as those with the introduction of a heavy bond, or those with an esterified hydroxyl group or an acetonidized hydroxyl group. There are a number of compounds that have been designed by design, especially corticosteroid compounds in which fluorine atoms have been introduced into the 9th or 6th positions of the steroid nucleus. Although such compounds are certainly excellent corticosteroids with strong physiological activity, on the other hand, those with fluorine atoms introduced have safety issues, and clinical use of these compounds is limited. requires appropriate management by a physician. Furthermore, considering internal metabolism and excretion1111, even though it is a topical drug, it is difficult to say that there are no safety problems depending on the period of use and amount of use3. Considering the actual situation of inflammatory corticosteroids [7. Obtaining a novel corticosteroid compound that has a chemical structure similar to natural corticosteroids that does not have a fluorine atom in the steroid core, and has excellent anti-inflammatory effects. After much deliberation, we succeeded in creating three useful new compounds. That is, the present invention provides 6α-methylprednisolone 17α-propionate (11β,21-dihydroxy/-6α-methyl-17α-pro/!?noylox/pregna-1,4-diene-3,2('l-dione)
(hereinafter referred to as compound I), 6α-methylprednisolone 17α-butyrate (11β+21-'; hydroquine-17α-butyryluoquine-6α-methylpregna-1
+4-diene-3,2(1-dione) (hereinafter compound 11)
It is written as ) and 6α-methylprednisolone 17α-
The present invention provides valerate (IIβ, 21-dihydroxy/-6α-methyl-17α-valeryl oquinopregner 1,4-diene:'!, 2+1-dione) (hereinafter referred to as compound 1] 1).

Prednisolone is △1 body of hydrocortisone,
Mineralocorticoid activity, a side effect of hydrocortisone, is low. A methyl group introduced into the 6-position of prednisolone is 6α-methylprednisolone, which is a compound with 15-20 orders of magnitude higher activity than prednisolone, and is used as a corticosteroid in addition to oral medication.
Especially acute and chronic disease; ξcytic leukemia (lyl
It is a highly safe drug with remarkable effects on m-phocytic leukemia).

Compound ■, Compound 11, and Compound II+ all have more pronounced local anti-inflammatory effects than their parent compounds, and as is clear from the efficacy test results described below,
Some steroids have been found to have better effects than commercially available topical steroids. In particular, compound 1 has particularly excellent local anti-inflammatory effects.

Hereinafter, Compound I, Compound 11 and Compound I of the present invention
I+ will be explained by illustrating its manufacturing method.

6α=Methylprednisolone (1) general formula, RC(OH2)3 ・−・・
... (2) (In the formula, R represents an ethyl group, a propyl group, or a butyl group, and R' represents a lower alkyl group such as a methyl group or an ethyl group.)
．． 7α, 21-cyclic orthoester compound (
3), and then subjected to ring-opening reaction to obtain the desired 1
A 7α-monoester compound (4) is obtained.

The formula for these reaction steps is as follows.

C) (3cl(,.

fl)
f3+H (4) 17α, 2]-When producing the cyclic or-I ester compound (3), generally d, M)+! is added to dimethylformamide. I! To the 6α-methylprednisolone (+1), add the orthoesterifying reagent (2) and p-+-luenesulfonic acid (approximately 1/10-J/2 (l), and stir in a stream of argon or nitrogen for 30 minutes. Compound 3) can be easily obtained by heating at 70' to 110°C for minutes to several hours.Next, a small amount of pyridine or dilute 1x acid sodium aqueous solution is added to this anti+5 solution at room temperature. After adding r'ii'' acid edyl or methylene chloride, the organic layer is separated and washed with water. When pyridine, a, and potassium solution are added to the reaction solution after the reaction in 1 and 2,
It is possible to suppress the decomposition of the produced orthoester compound (3) and improve the yield. After drying the above-mentioned extract with ethyl acetate or methylene chloride over anhydrous sodium sulfate, it is filtered, the P solution is concentrated, and the resulting residue is subjected to a recrystallization operation using acetone/xane] do. If this crystallization operation is difficult, compound (3) may be purified by column chromatography using silica gel impregnated with triethylamine. On the other hand, compound (3) as a crude product obtained as described above may be provided as is for the next reaction.

The obtained 17α,21-cyclic orthoester compound (3
) Usually, an acid is used for the ring-opening reaction, but this reaction is carried out very smoothly. Usually, a 21-monoester compound is produced as a by-product in addition to the desired I7α-monoester compound (4). In order to selectively obtain the 17α-monoester compound (4), the acidity used is preferably about pH 2 to 4.

Usually oxalic acid is used, but good results are obtained when a buffer solution ('pH 3-4) is used. The present inventors discovered that this 17α
It has been found that by using iodine in the ring-opening reaction of 3) to the 21-cyclic orthoester compound, the desired 17α-monoester compound (11) can be obtained in a low yield. The target 17α-monoester compound (
In order to obtain only 4), column chromatography using silica gel is usually used, but preparative thin 1/Δ chromatography (silica gel) can also be used. 1 isolated and purified in this way
The chemical profile of 7α-mononisalide (4) was determined by infrared absorption spectrum (IR), nuclear magnetic resonance spectrum (NMR), and dynamic phase separation (MS).

Compound 1, Compound 1 and Compound +n l-J provided by the present invention are all potent local anti-inflammatory compounds.
'1. It has a number of clinically important diseases, including acute and chronic eczema, seborrheic eczema, I-B dermatitis, childhood eczema, contact dermatitis, It can be used for the treatment of dry skin, etc., and can also be used for the treatment of sundae, kuzhan 1, allergies, etc. The new compound according to the present invention may be prepared in various dosage forms depending on the type of drug used, i.e., soft/IM, cream, liquid liniment, liquid liniment, patch b, or powder. used.

The local anti-inflammatory effects of Compound Ⅰ, Compound II, and Compound '1ylII+ provided by the present invention are extremely excellent, and this can be evaluated by the vasoconstriction test method (ξ Sochi test method). . The test results are listed below along with the test method.

Efficacy Test Compound 1, Compound 11 and Compound 111 were prepared in a control and test compound, respectively, in a white petrolatum-based ointment with a concentration of 0,0% (W/W). did. These soft test pieces were randomly divided into adhesive bones for patch tests (Fin Chamber, manufactured by Ebitest (Finland)), and a fixed amount (approx. 2 (lrnfl) was applied to the flexor side of the forearm of 10 healthy adult males.
], remove the bond wound/eye after 16 hours. After gently washing away the drug remaining on the skin with soap, the cauldron whiteness was judged by two judges 2 and 6 hours later.

Judgment is based on pallor level: 10+ (with egg), + (moderate), ±(
1 longitude) and = (invalid), each with 3
Point, 2 point, ] point and 0 point, examinee, examiner 10
Collection of results, ¥t L, 2 people! r-11 fixed person's 1/- average 1st shift - c't output L ~ (maximum value 30.
0).

The results are shown below.3 // As shown in this table, Compound ■, Compound ■, and Compound Il+ far exceeded the effect of 6α-methylprednisolone, and moreover, Compound 1 and Compound II i- J
It shows the same or better effect than commercially available beta-mezzanono-17α-valerate.

The following describes the compound's proboscis according to the present invention and its production example (l
Detailed explanation of the roughness.

Example 1 6α-methylprednisolone 17α-propionate (compound ■) (a) 6α-methylprednisolone], 1:l (:(
mM) in dimethylformamide/l me K'/&
Oak, this, ethyl orthozolopione-1.1.06
f (6mM) and p-toluenesulfonic acid (1,02
67 ((1,15mM) was added, and in an argon atmosphere, 8
Heat with PM stirring for 1.51f4 at 0'C, then
To this reaction solution at room temperature was added ethyl acetate] (Hl m, e and] 0% aqueous sodium carbonate solution (1.5 nte),
Add another 50 ml of water. Shake this mixture well;
After separating the ethyl acetate layer, it was mixed with water: 3 (] me
Wash twice with water and dry with anhydrous sodium sulfate. Then, the P solution is concentrated by 1Pi filtration. The resulting product was recrystallized from ether to give 6α-methylprednisolone 17α,21-ethyl orthopropionate (as colorless needles), 28F (yield: 12.8%).

The properties and various analysis data of this compound are as follows.

m-1), 160.0-i64. o 'C (decomposition) I
RνWRp c7++ ”: :335(1(
OH), 172(+ (c=o), 16
45 (c=o).

MSm/z: 459 (M++]), 7158
(M'), April, 430.41-3.395, ;U56
．． 3111297.279.237.161, 36,
]: U5 (Base Beak), 12], 57゜Elemental analysis value (C27H3+30 (as 1) Calculated value (correspondence) C
,70,71; H,8,: 5゜ Real 1flll 1 shift (%) C,70,59; H,8,/+7
.

Dissolve 320 mg of this 6α-methylprednisolone]7α,2]-ethyl orthopropionate in 80ml of methanol, and add 1.5ml of 2N-7 uric acid. ．． Add 5mg, 4
Heat at 0'C for 10 minutes. Next, this reaction solution was concentrated in a reduced volume, and 50 me of ethyl acetate was added to the residue.
Wash this twice with water:
After drying the ethyl acid layer over anhydrous sulfuric acid and sodium, the Wagyu acid product obtained by concentration was subjected to preparative thin layer chromatography on a gel gel.6α-methylprednisolone/! 7α-propionate 2: 5H nog (yield 78.
3rd Section) was I (1st Section).

This compound is a colorless crystalline solid7);
The structure was confirmed from the above physical properties and the results of each (111 analysis).

Rf value: 0.52 (Noriki Gel, Mouthpiece, Benopi//Ethanol-4/1).

IR maxc771: U4.0(1(Of(), +7
25 (C=O), 17]5(C=O),] C6(1
゜N Ivt RδpI)m(CDC,/:,):
(1,08(3H,S, 18th CH3), 113(
3H, t, J = 811z, CH2CH3),
1.17 (3H, t.

J = 6llz, C6(1-CH3), I,
i16 (3H,s, 19th position CH3), 2.31 (
2H, Q, J=8117. , CH2CH3), 4.
28 (2H.

S, C2l-CH2), /1.48 (J II,
br, C11-CH), 6.01(l H, br
, s, C4,-CH), (i, 26 (] H, d
, J = 1011z.

C2--CH), 7, :U2 (I H, d
, J=H month, C), -CH).

MSm/z: 4 (U1 (M-'-1-)
), 43(1(M”), 413,4]2.39
9.35G, 327.325.297.279.239
．． 161, ■: 36.135 (base beak), 121
．． 57゜Elemental analysis [Direct (C25H3406L 11 Li Direct f%) C, 69,74;
H, 7, 96.

Actual value f%) C, 69,58; H, 8,15.

(b) 6α-methylprednisolone (1,37/I f
(]mM) in 4 nte dimethylformamide, and ethyl orthopropione-1-0,352i
? (2mM) and p-1/l/:r-7sufu1/
Add 0.017y (0.1mM) of fonic acid,
The mixture was heated and stirred in a nitrogen stream for 1 hour at 'C. Next, viridi 71me is added to this reaction solution at room temperature, and further 60 ml, 1 of agglomerated methylene is added, and this organic layer is washed three times with 30 r. of water and then dried over anhydrous 112 sodium sulfate. Then, the residue obtained by filtering and concentrating the P solution was recrystallized from ether-hexane to give 0.394 f of 6α-methylprednisolone 17α,21-ethyl orthopropionate (yield: 86,0%). )was gotten.

The physical properties and analysis results of this product completely matched those of the product subjected to q4+ in (a) above17.

Next, this 6α-methylprednisolone 17α, 21-
Ethyl orthopropione-h 0.229 F (0,
5mM) was added to 4 me of methylene chloride, iodine (HIP) was added to this under stirring, and the reaction was allowed to proceed at room temperature for 30 minutes.Then, this reaction solution was concentrated in a vacuum chamber, and the obtained The 411 product was subjected to preparative thin layer chromatography (solica gel) and 1 was purified to give 6(x-methylprednisolone 17α-propionate (1,1:(6ii')
(Yield 63, 3rd batch) was obtained. The results of this study and each analysis were consistent with those listed in (a,) above.

Real MQ N2 6α-methylprednisolone 17α
-Buty 1 no 1 (compound 1) 6α-methylprednisone 1.50F (4mM)
was dissolved in dimethylformamide I (lrne), and ethyl orthobutyrate 1.52fi' (8mM) was added to this.
and p-toluenesulfonic acid 0.034? (0,2
m'M) was added, and the mixture was heated and stirred at 78°C for 1 hour in an argon stream. This reaction was then added with ethyl acetate 6 (1 ml) and 1 ml of 10% sodium carbonate at room temperature.
The organic layer is washed three times with water 3 (l me). After drying with anhydrous sodium sulfate, it is filtered and the F solution is concentrated. When recrystallized, 6α-methylprednisolone 1
7α,21-ethyl orthobutyrate, as colorless needle crystals 1. s4g (yield 97.4%) was obtained.

The raw material and analysis results of this product are as follows.

m, p, ], 64. ．． 0 ~ 166.0°C (decomposition)
(c=o), 1645 (c=0).

MS m/z: 473 (M++1
), 472 (M +), 427, ;U56.311.297.279.161.136.13
5 (base peak), ]21.71° Elemental analysis value (028H4oO6) Calculated value (%l C,7], 16; H,8,53
.

Actual position] 1st shift (%) C, 71, C13; 11.8
．． 7J.

This 6α-methylprednisolone + 7α,21-ethyl orthobutyrate (1,2:Hi'j (0,5mM
) was dissolved in 6 rugs of methanol, and 2N-N-N-O-O,F5rne was added thereto at 4(]'C and heated for 10 minutes.Then, the solvent was distilled off under reduced pressure, and the resulting residue was When subjected to gel column chromatography and sipped with semi-blue water, 6α-methyloledonisolone 17α-butyrate was obtained as a colorless solid (1,15
4,';Z (yield 69, /I) was obtained.

Although this product is an amorphous solid, the following physical properties and various analyzes confirmed its structure.

Rf value: (152 (Nricagel, p-subonodoben7ane/ethanol-47'J).

■R, ding r,, layer 3/l0(1(OH), 1720
(C=0), ]715 (C=O), 1655 (C-
0),, NMRδl:lI)m(CI)Cta)
: (1,418(:u)(+”+18th CH
3) , 0.416-1.05 (: UH, m, Cl
2CH2CH3), 1.13 (3H.

d+ J”' 6 +17., C6,
-CHz3. ), 1.48 (3H,8
, 19th CH3), 4.28 (2)], e, C
2+ -CH2), 4.50 (I H, br.

C11-CH), 6.03 (I H+ br-8+
C4CH), 6.27 (I H, a, J = lO1l
z, 9z-(Jl), 7.35 (IH,d.

J-1 (lHz, Cl, -CH).

MS m/z: 445 (M″-11), 444.
(M+), 427.426, old 3, ;U56,32
7, 325, 297, 279, 161, 13fi
(Base peak), 1; 35.12], 71° Elemental analysis value (C26H3606) Calculated value (%) C, 70,25; H, 8,16.

Actual measurement value (C, 70, 16; H, 8,: only).

Example: 6α-Methylprednisolone 17α-valerate (for compound) 6α-Methylprednisolone 0.374. ? was dissolved in 3 rrte of dimethylformamide, 0.324 S' of methyl orthovalerate was added thereto, and 0.017 f of p-toluenesulfonic acid was completely processed in an argon stream. -) Heating (stirring) at 0°C for 5 hours. Then, at room temperature, 50 ml of ethyl acetate and 5 ml of 10% sulfur and lithium carbonate water MWO were added, followed by 30 m of water, The ethyl acetate layer was separated, washed twice with 30 rttl of water, and dried over 15 ml of anhydrous sodium sulfate.This was filtered and the crude product obtained by condensing 7 ml of 19. The product was partitioned by chromatography using triethylamine-impregnated chromatography to give (iα-methylpredochlorono-17α,21-methylorthovalerate) as a colorless amorphous solid (+, 43 : U7 (yield 9J,
Section 7) Obtained. The analysis data for each category of this item is as follows.

■R,W:; CTn-], , U4(10(C
H), +72() (c=o), ] C65
(C=O).

MSm/Z: (17:4 (M'+J), /
+72 (M”), 44], 356.207.279.1
61, J: U6, C35 (base beak), +21.8
5゜Elemental analysis value (C281 (4006) total polish, value C%) C,71,16i H,8,53
゜Actual (Rule 11t'j (%) C,71,2:U:
H, 8, 69.

Next, this 6α-megolprednisolone 17α, 21
-Methyl orthovalerate/lz 8 me and bath water/l (1'C plus 1?li
'l. Add 0.5me of 2N-7 oxalic acid to this,
After stirring for 0 minutes at 1 KN, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to preparative thin layer chromatography (Ricagel).
Valerate is 0.187 y as a colorless amorphous solid
(yield: 81.7%).

The structure of this product was confirmed from the following physical properties and analysis results.

Rf value: 0.53 (Nrica gel, single spot, benzene/ethanol = 4/I).

IRν Bonzo l-1: 3400 (OH), 172
0 (C=O), 1715 (C=0), 165
5 (C=O).

NMRδppm (CDCt3): 0.95
(3H, 8. 18th position CH・3), 0, 88 −
1, 25 (3H, m, CH2CH2CH
2CH3), 1.11 H+ d+ J” 6 1
+z, c6ke CH3), 1.52 (3H, E
l.

19th CH3), 4. , 28 ( 2 H, S, C
21-CH2), 4.52( ], H, 'br
, C11-CH), 6.02 ( ]H,, 'b
r, s, C4-CH), 6, 24 (]
H, d, J = IOflz, C2-CB),
7.38 (lH.

d, J = 1. OIIz, Cl-CH).

MS m/z: 459 (M++1), 458
(M+), 441, 440, 427, 356, 32
7, 325, 297, 281, 279, 161, 1:J
．． 6 (base beak), 135, +21, 85.

Elemental analysis (direct (C27H38(+6)h1°s♀
Value (%) C, 70.72; H. 8.35
8 real C for A1 White - (person in charge) C, 7 (+
．． 50; It, 8.5: Uh.

! Licensed by 1 person; Attorney, Takashi Minami, Attorney for the company
Author: June 3, 1952 Kazuo Wakasugi, Commissioner of the Patent Office 1. Description of the case 1960 Patent Application No. 1/G 0// 2 Name of the invention O: α-Methylprednisolone/7α-ester compound 3
Relationship with the case of the person making the amendment Patent Applicant Address: Kamijujo A-2g-a, Kita-ku, Tokyo Name: 4th Director, Ota Pharmaceutical Co., Ltd. Address: Mutual Daiichi Building 6, 3-2 Kojimachi, Chiyoda-ku, Tokyo Subject Contents of amendment in section 7 of the Detailed Explanation of the Invention in the Specification/7 Negative The statement of "Compound ■" in the fifth line from the bottom is corrected to "F-Compound ■."

that's all 912-

Claims (1)

[Claims] General formula] (wherein ■ is n groups selected from the group consisting of ethyl group, propyl group, and butyl group) 6α-
Methyl pretonyl 17α-ester compound.