JPS5817480B2 - Corticosteroid 21- Ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing novel corticosteroid 21-ester derivatives.

More specifically, the present invention relates to the general formula (I) [wherein R represents a lower alkyl group or a lower alkoxy group, or two R's together represent -CH=CH-
CH=CH-.

X is -CH2-CR(CH3)- or -CH-C(C)
(3) - represents an organic carboxylic acid and 21
General formula (II), characterized in that R and X are the same as defined above.

Z is from 21-hydroxycorticosteroid to part 2
The present invention relates to a method for producing a corticosteroid 21-ester derivative represented by the formula (representing a group formed by removing the 1-position hydroxyl group).

Specific examples of the lower alkyl group represented by R include methyl, ethyl propyl, etc., and specific examples of the lower alkoxy group represented by R include methoxy, ethoxy, propoxy, etc.

It is known that 21-hydroxycoliticosteroids (hereinafter simply referred to as corticosteroids) have an inhibitory effect on antibody production and are useful as immunosuppressants for various immune diseases.

However, conventionally known corticosteroids not only suppress cell-mediated immunity but also suppress the production of antibodies in the blood, so they can reduce the host's resistance to infectious diseases etc. based on the production of antibodies in the blood. It has been known.

Therefore, when administering corticosteroids to prevent diseases originating from cellular immune phenomena, it has often been necessary to use antibacterial agents such as antibiotics in combination.

The inventors of the present application have successfully synthesized a number of novel steroid compounds, and as a result of various studies on their pharmacological effects, the target compound of the method of the present invention represented by the above general formula ("II)" suppresses the production of antibodies in the blood. Its action is extremely low compared to general corticosteroids, and its cell-mediated antibody suppressing effect is several times more potent than that of corticosteroids. It was found that there is virtually no need to take into account the reduction of the underlying resistance to pathogenic bacteria.

Therefore, it can be said that the present invention has been completed by successfully separating the functions.

In addition, stabilizing effects of drugs on tissue cell and somosomal membranes have been known as one of the mechanisms of immunosuppressive action or anti-inflammatory action of drugs. It was also found that the compound's stabilizing effect on lysosomal membranes is extremely strong compared to common corticosteroids.

The method of the present invention is carried out by condensing the carboxyl group of an organic carboxylic acid represented by the general formula CI) with the 21-position hydroxyl group of a corticosteroid to form an ester bond.

Such corticosteroids are in particular corticosteroids, such as corchicin, hydrocorcin, dexamethasone, prednisolone, methylprednisolone, triamcinolone, betamethasone, paramethasone, f/1 grednisone, betamethasone 17-valerate.

Triamsifron 16.1 Fudiacetate 6 Noamsifuron 16.1 Fuacetonide and any other 21
-Probably hydroxycorticosteroids.

Conventionally, manual engraving in which a carboxyl group and a hydroxyl group are condensed has been well established, and the method of the present invention can also be carried out by incorporating this method.

That is, the method of the present invention uses carboxylic acid of general formula (I) or its carboxy! This is carried out by reacting a reactive derivative at the hydroxyl group with a corticosteroid or a reactive derivative at the 21-position hydroxyl group thereof.

Examples of reactive derivatives of carboxylic acids of the general formula CI)D include acid halides such as acid chlorides and acid bromides, acid anhydrides, such as mixed acid anhydrides with acetic acid (acetic acid, etc.).

When reacting the reactive derivative of the carboxylic acid with a corticosteroid, the solvent may be, for example, in pyridine,
It is preferable to carry out the reaction at about -20°C to 60°C.

Reactive derivatives of corticosteroids include halides at the 21-position hydroxyl group (e.g. iodides, bromides,
chloride), tosylate, and mesylate; when using reactive derivatives of these corticosteroids,
The organic carboxylic acids of the general formula CI) are preferably used in the form of salts such as alkali metal salts such as sodium and potassium salts and alkaline earth metal salts.

Examples of the solvent in this case include dimethyl sulfoxide, dimethyl formamide, and acetone.

The reaction temperature may be the same as above. In addition to the hydroxyl group at position 21, corticosteroids may have hydroxyl groups at other positions, but the hydroxyl group at position 21 is usually preferentially esterified, so if normal reaction conditions are followed, by-products will not be formed. does not actually occur.

After the reaction is completed, the target product can be collected by means known per se.

The compound of the present invention is used in the same manner as prednisolone, for example, for immunological diseases such as rheumatic fever, rheumatic arthritis, and generalized erythematous lupus.

However, when using the compounds of the present invention, there is virtually no need to take precautions to reduce resistance to pathogenic bacteria.

In the following examples, raw material compounds are abbreviated as follows.

2-Methyl-3-,-(5-carboxy-3'-methyl-2'-pentenyl)-1,4-naphthoquinone Abbreviation
KAcid-1 2,3,5-trimethyl-6-(5'-carboxine-3
-Methyl-2-hentenyl)-1,4-benzoquinone Abbreviation EAcid-■ 2.3,5-1-limethyl-6-,-(5'-hydroxy-3'=methylpentyl)-1,4-benzoquinone Abbreviation dihydroEAcid-■ 2,3-dimethoxy-5-methyl-6-(5'-carboxy-3'-methyl-2'-pentenyl)-1,4-benzoquinone Abbreviation QAc id-■ Example I KAcid -- I (1g) of benzene (10ml
) Add oxalyl chloride (0.5ml) to the solution 30
Heat separately for a minute.

The reaction solution was evaporated to dryness under reduced pressure, and the resulting residue was added dropwise to a solution of prednisolone (1.2 g) in pyridine (10 ml) while stirring under ice cooling.

After the addition, the reaction solution is poured into ice water and extracted with ethyl acetate, and the extract is washed with water, cold diluted hydrochloric acid, and water sequentially and dried.

The residue obtained by distilling off the solvent was dissolved in a small amount of chloroform and poured into a column of silicic acid (30 g).
1), KAcid-1 (0.47 g) is recovered.

Then, when chloroform-ethanol (97:3) is passed, prednisolone 21-2-methyl-3-(5'-carboxy-trimethyl-27-hentenyl)-1,4-naphthoquinone ester is eluted.

When Motoichi is recrystallized from acetone-water, m r 149
A pale yellow silky crystal (1 g) of -16'5°C is obtained.

Br Infrared absorption spectrum λ cl-11=”:345
0aX (OH) 1730 (ester) 1710 (2C
position CO) 1660 (3rd position CO, quinone) elemental analysis
C39C59FI4408 Calculated value C71,10H7,04 Actual value C71,24H7,07 Example 2 EAcid --((2g) Tokiza IJ Le/)
The acid chloride obtained from IJ (1, ml) was dissolved in dry chloroform (15 ml) and dissolved in a solution of prednisolone (3,11 g) in dry chloroform (40 tnl) and pyridine (20 ml) at -20°-10°C. Add dropwise over 1 hour while cooling.

After the dropwise addition, the mixture was stirred at nitrogen temperature for 2 hours, poured into ice water, and extracted three times with chloroform (100 ml).

The extract was washed successively with dilute hydrochloric acid, 20% sodium bicarbonate, and water, dried, and then the solvent was distilled off.

Recrystallization of the residue from acetone-water gives mp 133-
Yellow needle-shaped crystals of prednisolone 21-2゜3゜5-trimethyl-6-(5-carboxy-3'-methyl-2-pentenyl)-1゜4-benzoquinone ester at 139°C (
2.81 g) is obtained.

Br Infrared absorption spectrum λ c seedling-1: 3430aX (OH), 1.730 (ester), 1708 (C
20th position CO), 16651,1643 (C3 position CO quinone) Elemental analysis C3□H4608・H2O (636,75,
) Calculated value C69,79H7,60 Actual value C69,70H7,54 Example 3 The acid chloride obtained from dihydro E Ac1d-1 (539 mg) and oxalylchloride (0.5 ml) was mixed with prednisolone (0,601 g). The residue obtained by the reaction in the same manner as in Example 2 was dissolved in a small amount of chloroform, poured into a column of silicic acid (20 g), and then dissolved in hexane-chloroform (
1:1), dihydroE Ac1d-1 was recovered first, and then prednisolone 21-2゜3゜5-trimethyl-6-(5-carboxy-3'-methylpentyl)-1゜4-benzoquinone ester was eluted. The mixture was evaporated to dryness under reduced pressure to obtain 55 g of yellow powder.

Br Infrared absorption spectrum λ an-”: 3450ex (OH'l), 1745 (ester>, 1725 (C2
0 position CO) 1655.1640 (C3 position CO quinone) Mass spectrum C3□H4808 (620,75):
m/e = 620 (molecular ion); Example 4 The acid chloride obtained from E Ac1d -■ (0,192 g) and oxalylchloride (0,3 ml) was mixed with dexamethasone (0,336 g) and Example 2. The reaction solution obtained in the same manner was evaporated to dryness, and the resulting residue was dissolved in a small amount of chloroform to precipitate unreacted dexamethasone (19
When the filtrate was poured into a tower containing silicic acid (10 g) and eluted with chloroform, unreacted E Ac was removed.
1d-I (0,091 g was recovered, followed by dexamethasone 21-2゜35-trimethyl-6-(5'-hydroxy-37-methyl-2-pentenyl゛)-1゜4
-Benzquinone ester is eluted and evaporated to dryness under reduced pressure to give a yellow powder (0.12 g).

Br Optical external absorption spectrum λ, Cm”: 345 Q
ax (OH), 1745 (ester), 1725 (CO at C20 position), 1655.1640 (CO quinone at C3 position) Mass spectrum C38H4,06F (650,75
): m/e = 650 (molecular ion) Example 5 Prednisolone (0.36 g) was dissolved in chloroform (,'
5 ml) and pyridine (2 ml) while stirring under ice water.
(0.4 g) of acid chloride in chloroform (1
0 ml) solution dropwise.

After stirring at room temperature for 1 hour, the reaction solution was poured into ice water and extracted with chloroform.

The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silicic acid column chromatography to obtain prednisolone 21-2.3-dimethoxy- as a yellow oil. 5-methyl-6
-(5-carboxy-3'-methyl-2'-pentenyl)-1°4-benzoquinone ester (o, 4 g) was obtained.

The chemical structure of the target product is based on the carbonyl and quinone nucleus of the 3rd carbon atom of prednisolone (1636 cm! and 1
It was confirmed by infrared absorption spectrum at <1720 cm'' based on the carbonyl at position 20 of 650 cmL prednisolone.

Reference example 1 Direct effects on enzymes in rat hepatic isosomes and effects on lysosomal membranes were reported by Watanabe et al.
nn, Bull, '22187 (1974) [
I followed the method.

That is, it was measured from the direct effect on β-glucuronidase and acid phosatase obtained from lysosomes and the effect on leakage of these enzymes from lysosomes.

As a result, as shown in Table 1, the compound of the present invention did not inhibit line seam enzymes, and as shown in Table 2, unlike prednisolone, a raw material corticosteroid, and prednisolone acetate, a general acid ester, enzyme leakage occurred. was found to have a strong membrane stabilizing effect.

Reference Example 2 The effect of sheep red blood cells as an antigen on antibody production in mouse blood was determined using conventional methods (e.g., "Immunology and Allergy Experimental Methods" edited by Toraji Shindo, "Bunkodo").

(Tokyo, 30, 191971), 103 sheep red blood cells were intraperitoneally administered as an antigen to refractory mice (10 animals per group to 6 weeks of ddYSLC), and a suspension of gum arabic as a specimen was administered subcutaneously for 7 consecutive days. Blood antibody titers were measured by hemagglutination reaction at 1 week, 2 weeks, and 3 weeks after antigen administration.

As a result, as shown in Table 3, almost no suppression of the blood antibody titer was observed in the group administered equimolar amounts of the compound of the present invention compared to the group administered with the raw material corticosteroid (prednisolone).

Reference example 3 Graft-versus-host reaction was determined by Simonsen (Progr.

Allergyt volume 6, page 349.

(1972) and Daley et al. (Biochem, Ph.
armanool, vol. 18, 2163. 196
The tile cells of female C57BL/6XDB mice were transformed into female cells (C,57BL/6XDB human/2) following the method of
F, intravenously transferred to mice (BDF, abbreviated as mouse) 1
Mice were killed on day 0 or day 11, and the weight of the tiles was measured.

The specimen was intraperitoneally administered as a suspension of gum arabic for 4 days from 4 days after the cell transfer to BDF1 mice to which the tile cells had been transferred.

As a result, as shown in Table 4, the raw material corticosteroid (
It was found that the compound of the present invention significantly inhibits graft-versus-host reaction compared to prednisolone).

Claims (1)

[Scope of Claims] 1 General formula [wherein R represents a lower alkyl group or a lower alkoxy group, or two R's together represent -CH=CH-
Represents CFI-CH-. K is -CH2-CH(CH3)- or -CH=C(CH
3) A general formula characterized by condensing an organic carboxylic acid represented by - with a 21-hydroxycorticosteroid [wherein R and Z is 21-droxycorticosteroid
A method for producing a corticosteroid 21-ester derivative represented by the formula (representing a group formed by removing a hydroxyl group).