JPH0873491A - Triamcinolone derivative - Google Patents

Abstract

PURPOSE: To obtain the subject new derivative which is a specific triamucinolone derivative having a triamucinolone acetonide parent nucleus, having antiinflammatory actions without exercising systemic effects, causing slight side effects and having high safety and useful for an external preparation, etc., for treating dermatopathy. CONSTITUTION: This new triamcinolone derivative of formula I (A is H or F; B is H or a 1-7C acyl; R<1> is H or a 1-2C hydrocarbon; R<2> is a 2-3C hydrocarbon or may be linked with R<1> to form a ring; R<3> is methyl, ethyl, pivaloyloxymethyl, ethoxycarbonyloxyethyl or phthalidyl), has antiinflammatory actions and high safety, hardly has recognizable systemic effects, causes slight side effects and is useful for an external preparation, etc., for treating dermatopathy. The derivative is obtained by reacting a triamcinolone of formula II with an ester carbonyl of formula III, providing an acetal derivative, then, as necessary, acylating the resultant acetal derivative with acetic anhydride, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to triamcinolone derivatives, particularly to triamcinolone derivatives useful in the treatment of skin diseases.

[0002]

BACKGROUND OF THE INVENTION [0002] Topical steroids are very widely used in the treatment of skin diseases, and many external ointments are commercially available. Topical ointment allows the drug to act only on the area where it is applied,
Although it is ideal that there is no effect on the whole body, continuous application of steroid ointment causes systemic effects such as suppression of pituitary and adrenal cortex functions due to transdermal absorption, in addition to local side effects applied It is known. Therefore, there is a demand for the development of topical steroids having a small systemic effect.

[0003]

Means for Solving the Problems As a result of intensive studies from the above viewpoint, the present inventor has found that a derivative having triamcinolone acetonide as a nucleus is effective as a steroid agent having little systemic effect. The invention was completed.

The triamcinolone derivatives that the present inventors have found to be effective are as follows.

[0005]

[Chemical 4] More specifically, the triamcinolone derivative is as follows.

[0006]

[Chemical 5]

[0007]

[Function] In order to verify the efficacy of the triamcinolone derivative, an ointment for external use of this compound was prepared, and croton oil ear edema model, which is a typical dermatitis model, and inflammation model at a relatively deep part, which are systemic by continuous administration. The effect of topical application was compared with existing steroids using a paper disk granuloma model, which can be examined at the same time.

The cyclohexanonecarboxylic acid derivatives of triamcinolone according to the present invention, TCP-1, TCP-
2 and 3 samples of TLP, which is a levulinic acid derivative, were compared and examined for anti-inflammatory effect by external application as an ointment using existing ointments such as triamcinolone acetonide and betamethasone valerate. ,
TCP-2 and TLP showed a dose-dependent inhibitory effect on croton oil mouse ear edema. Although the effect was weaker than that of triamcinolone acetonide, the inhibitory effect was almost the same as that of betamethasone valerate. Meanwhile, pa
Triamcinolone acetonide suppressed the growth of granulation by per disk in a dose-dependent manner, but TCP-1, TC
No effect was observed with P-2 and TLP. At the same time, the effect on the whole body by continuous administration for 7 days was also examined. As a result, betamethasone valerate and triamcinolone acetonide showed dose-dependent organ atrophy, whereas TCP-1, TCP-2 and TLP had no effect.

[0009] More specifically, the inventors have shown that Ton
elli's method (Tonelli, G., Thibault, L. and Ringler,
I .: Endocrinology 77 625 (1965)), but the method using this mouse ear is a method that has been conventionally used for testing corticosteroids. B which is a control drug against the inflammatory reaction caused by croton oil
V, HA and HB were suppressed in a dose-dependent manner. On the other hand, T
For CP-1, TCP-2, TLP and TA, which is the nucleus of these compounds, a dose-dependent inhibitory effect was observed for all compounds in 0.01-0.1% formulations. The degree of suppression is TC
P-1, TCP-2, and TLP were weaker than TA. Comparing the clinically applied doses, it was confirmed that the inhibitory effect was almost the same as that of BV, which is very often used in clinical practice.

A paper disk was embedded under the skin, and an ointment was applied to the skin on the top of the paper to study the effect on the granulation growth. At the same time, the effect on the whole body of continuous administration for 7 days was also examined. TCP-1, TCP-2, and T
LP showed no suppressive effect on granulation growth, but TA suppressed it in a dose-dependent manner. On the other hand, we examined thymus, adrenal gland and spleen weight as indicators of systemic side effects. TCP
-1, TCP-2, and TLP had no effect, but TA showed a significant dose-dependent inhibitory effect, especially in thymus weight at clinical dose 43.3%
Atrophy was observed. From these results, TCP-1, T
Although CP-2 and TLP were not observed to suppress granulomas, it was revealed that they did not affect the thymus and the like.

The inhibitory effect on granuloma is that the paper disk is inserted in the upper part of the muscle under the subcutaneous tissue, and the ointment applied to the epidermis shows the effect of the drug that penetrates the skin and the subcutaneous tissue. It is believed that those that affect sexuality have a strong effect. That is, a drug such as TA that is well absorbed in the blood circulation has a strong effect. However, drugs that are well absorbed into the blood circulation have a large effect on the whole body and have strong side effects such as adrenal gland, thymus weight reduction, and suppression of body weight gain. On the other hand, an ester form such as betamethasone valerate penetrates well through the skin, but it is retained in local tissues, has little transfer to blood circulation, and has weak systemic side effects. TCP-1, TCP-2 and TLP
Shows an effect on the inflammatory reaction of croton oil ear edema at the superficial application site, and in the granulomatous experiment, the inhibitory effect on the inflammatory reaction at a location away from the application site is weak and almost all systemic side effects are observed. Therefore, it is considered that it has an anti-inflammatory effect at the site of application and is absorbed to hydrolyze the ester group in the body fluid to lose its effect.

[0012]

【Example】

{Synthesis} The triamcinolone derivative according to the present invention is synthesized by combining triamcinolone with a predetermined ester carbonyl compound and reacting it with an acid catalyst (FIG. 3, FIG. 4; Example 1-1, Example 2-). 1, Example 3-
1, Example 4-1). In this case, as the acid catalyst used in the acetalization reaction, sulfonic acids, hydroiodic acid, hydrohalic acid such as hydrochloric acid, perchloric acid, sulfuric acid,
Inorganic acids such as boron trifluoride and aluminum chloride, Lewis acids and the like are considered. The acetal body obtained by the reaction of triamcinolone with a predetermined ester carbonyl body may optionally acylate the hydroxyl group at the 21-position to obtain a 21-acetate body (Fig. 3, Fig. 4; Examples). 1-2, Example 1-3, Example 2-2, Example 3-
2, Example 4-2).

The synthetic route of the triamcinolone derivative according to the present invention is shown below. In the examples, all NMR are proton NMR, all in CDCl ₃ , JNM-F
Measured with X90Q.

[Example 1] [Example 1-1; Synthesis of acetal (1,2) of triamcinolone and 4-oxocyclohexanecarboxylic acid vivaloyloxymethyl ester (PivER1)] 4-oxocyclohexanecarboxylic acid viva Dissolve 80 mg of loyloxymethyl ester in 3 ml of dichloromethane, add 76 mg of triamcinolone and then 1 drop of 70% perchloric acid, and stir for 6 hours. The reaction solution was added with sodium hydrogen carbonate solution to stop the reaction, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated to give 15 g of silica gel and a developing solution (ethyl acetate: chloromethane =).
Chromatography with 1: 1). As a result, two isomers of an acetal body (1) (Rf 0.6, 13 mg, mp125 ° C) and an acetal body (2) (Rf 0.5, 13 mg, mp138 ° C) were obtained.

[Α] ²⁰ _D + 70.6 ° (C 1.0 CHC
l ₃ ) NMR δ (ppm) of acetal (1) 0.89 (3H, s, 18-CH ₃ ), 1.20 (9H, s, pivaloyl-
_{CH 3), 1.56 (3H,} s, 19-CH 3), 5.77 (2H, s, pivaloyloxy-CH
₂ ), 6,11 (1H, s, 4-H), 6.39 (1h, d, J = 10.3,2-H), 7.25 (1
H, d, J = 10.3,1-H). The NMR of the acetal body (2) was the same as that of the isomer acetal body (1).

[Example 1-2: 21 of acetal (1)]
-Synthesis of Acetate Form (TCP-1)] 13 mg of acetal (1) is dissolved in 300 mg of dichloromethane and 200 mg of pyridine, 100 mg of acetic anhydride is added thereto, and the mixture is left at room temperature overnight. Then, the reaction solution was diluted with ethyl acetate, washed successively with 10% sulfuric acid, sodium hydrogen carbonate solution and water, the organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and hexane was added to the residual solution to give mp157-1.
12 mg of 21-acetate (TCP-1) at 60 ° C was obtained.

NMR of TCP-1 δ (ppm) 0.94 (3H, s, 18-CH ₃ ), 1.22 (9H, s, pivaloyl-
CH ₃ ), 1.56 (3H, s, 19-CH ₃ ), 2.20 (3H, s, 21-acetoxy-CH
₃ ), 4,91 (2H, s, 21-CH ₂ ), 5.77 (2H, s, pivaloyloxy-CH
₂ ), 6.11 (1H, s, 4-H), 6.40 (1H, d, J = 10.3Hz, 2-H), 7.26 (1
H, d, J = 10.3 Hz, 1-H). [Example 1-3; Synthesis of 21-acetate body (TCP-2) of acetal (2)] 13 mg of acetal (2) was used as Example 1-2. By the same treatment, 12 mg of 21-acetate body (TCP-2) having an mp of 255-260 ° C. was obtained.

NMR of TCP-2 δ (ppm) 0.94 (3H, s, 18-CH ₃ ), 1.20 (9H, s, pivaloyl-
CH ₃ ), 1.56 (3H, s, 19-CH ₃ ), 2.20 (3H, s, 21-acetoxy-CH
₃ ), 4,91 (2H, s, 21-CH ₂ ), 5.77 (2H, s, pivaloyloxy-CH
₂ ), 6.19 (1H, s, 4-H), 6.40 (1H, d, J = 10.3Hz, 2-H), 7.26 (1
H, d, J = 10.3Hz, 1-H). [Example 2] [Example 2-1; Synthesis of acetal form (5) of triamcinolone and levulinic acid pivaloyloxymethyl ester (PivER2)] Lebrin 300 mg of acid pivaloyloxymethyl ester is dissolved in 5 ml of dichloromethane, 150 mg of triamcinolone and 3 drops of 70% perchloric acid are added thereto, and the mixture is stirred for 6 hours. Then, a sodium hydrogen carbonate solution was added to the reaction solution to stop the reaction, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated, and 20 g of silica gel, a developing solution (ethyl acetate: dichloromethane =
Chromatography with Rf0.
80 mg of acetal form (5) of 5 and mp75-80 ° C was obtained.

[Α] ²⁰ _D + 35.7 ° (C 1.0 CHC
l ₃ ) NMR δ (ppm) of acetal (5) 0.89 (3H, s, 18-CH ₃ ), 1.20 (9H, s, pivaloyl-
CH ₃ ), 1.58 (3H, s, 19-CH ₃ ), 5.57 (2H, s, pivaloyloxy-CH
₂ ), 6.14 (1H, s, 4-H), 6.34 (1H, d, J = 10.3,2-H), 7.21 (1H,
d, J = 10.3,1-H). [Example 2-2; Synthesis of 21-acetate body (TLP) of acetal (5)] 80 mg of acetal (5) was dissolved in 1 ml of dichloromethane and 500 mg of pyridine, and Add 200 mg of acetic anhydride and let stand overnight at room temperature. Then, the reaction solution was diluted with methyl acetate, washed successively with 10% sulfuric acid, sodium hydrogen carbonate solution and water, the organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and hexane was added to the residual solution to give mp 80-85. ℃ acetate body (TLP)
80 mg was obtained.

[Α] ²⁰ _D + 55.1 ° (C 1.0 CHC
l ₃ ) TLP NMR δ (ppm) 0.93 (3H, s, 18-CH ₃ ), 1.19 (9H, s, pivaloyl-
CH ₃ ), 1.56 (3H, s, 19-CH ₃ ), 2.19 (3H, s, 21-aceloxy-CH
₃ ), 4.90 (2H, s, 21-CH ₂ ), 5.77 (2H, s, pivaloyloxy-CH
₂ ), 6.11 (1H, s, 4-H), 6.37 (1H, d, J = 10.3Hz, 2-H), 7.24 (1
H, d, J = 10.3 Hz, 1-H). [Example 3] [Example 3-1; Synthesis of acetal compound (7) of triamcinolone and 4-oxocyclohexanecarboxylic acid methyl ester (ER3)] 4 -Oxocyclohexanecarboxylic acid methyl ester 200 mg dichloromethane 3 ml
And triamcinolone 103 mg and 70%
Add 40 mg of perchloric acid and shake for 10 minutes to obtain a clear solution. The reaction solution was neutralized with sodium hydrogen carbonate solution, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, concentrated, and subjected to chromatography using 15 g of silica gel and a developing solution (ethyl acetate: hexane = 1: 1). , 70 mg of an Rf 0.55 acetal compound (7) was obtained. mp145-150 ° C NMR of acetal (7) δ (ppm) 0.89 (3H, s, 18-CH ₃ ), 1.55 (3H, s, 19-CH ₃ ),
3.66 (3H, s, ester-CH ₃ ), 6.15 (1H, s, 4-H), 6.34 (1H, d, J = 1
0.3Hz, 2-H), 7.24 (1H, d, J = 10.3Hz, 1-H). [Example 3-2; 21-acetate body (8) of acetal (7)] Acetal (7) 50mg It is dissolved in 1 ml of dichloromethane and 500 mg of pyridine, 250 mg of acetic anhydride is added thereto, and the mixture is left at room temperature overnight. Then, the reaction solution was diluted with ethyl acetate, washed successively with 10% sulfuric acid, sodium hydrogen carbonate solution and water, the organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and hexane was added to the residual solution to give 21. -50 mg of crystals of the acetate form (8) were obtained.

Mp145-150 ° C. NMR of 21-acetate (8) δ (ppm) 0.94 (3H, s, 18-CH ₃ ), 1.54 (3H, s, 19-CH ₃ ),
2.18 (1H, s, acetyl-CH ₃ ), 3.67 (3H, s, ester-CH ₃ ), 4.89
(2H, s, 21-CH ₂ ), 6.125 (1H, s, 4-H), 6.34 (1H, d, J = 10.3H
z, 2-H), 7.26 (1H, d, J = 10.3Hz, 1-H). [Example 4] [Example 4-1; of triamcinolone and 4-oxocyclohexanecarboxylic acid ethyl ester (ER4)] Synthesis of acetal body (9)] 200 mg of 4-oxocyclohexanecarboxylic acid ethyl ester and triamcinolone were treated in the same manner as in Example 3-2 to obtain acetal body (9) and Rf0.
57 was obtained in an amount of 75 mg.

Mp 140-145 ° C. NMR of acetal (9) δ (ppm) 0.89 (3H, s, 18-CH ₃ ), 1.24 (3H, t, J = 7.0Hz, et
hyl-CH ₃ ), 1.55 (3H, s, 19-CH ₃ ), 4.15 (2H, q, J = 7.0Hz, et
hyl-CH ₂ ), 6.16 (1H, s, 4-H), 6.34 (1H, d, J = 10.3Hz, 2-H),
7.21 (1H, d, J = 10.3Hz, 1-H) [Example 4-2; 21-acetate body (10)] 50 mg of acetal body (9) was treated in the same manner as in Example 3-2,
21-acetate body (10) 5 having an mp of 115 to 122 ° C
0 mg was obtained.

NMR of 21-acetate (10) δ (ppm) 0.94 (3H, s, 18-CH ₃ ), 1.25 (3H, t, J = 7.0Hz, e
thyl-CH ₃ ), 1.55 (3H, s, 19-CH ₃ ), 4.14 (2H, q, J = 7.0Hz, e
thyl-CH ₂ ), 4.92 (2H, s, 21-CH ₂ ), 6.15 (1H, s, 4-H), 6.36
(1H, d, J = 10.3Hz, 2-H), 7.25 (1H, d, J = 10.3Hz, 1-H). [Synthesis of Raw Material] [Synthesis of Raw Material 1; 4-oxocyclohexanecarboxylic acid pivaloyloxy Method for producing methyl ester (PivER1)] 300 mg of pivalic acid chloromethyl ester was dissolved in 3 ml of dimethylformamide, and sodium iodide 3 was added thereto.
00 mg; 4-oxocyclohexanecarboxylic acid 150
mg and 200 mg triethylamine were added, 20
After standing at ℃ for 5 days, dilute the reaction mixture with ethyl acetate,
The organic layer is dried and concentrated by sequentially washing with a sodium hydrogen carbonate solution and water. The residual liquid was subjected to chromatography using 20 g of silica gel and a developing liquid (hexane: ethyl acetate = 5: 1) to obtain 120 mg of an oily substance of Rf0.5 (coloring with iodine on TLC).

NMR δ (ppm) 1.22 (9H, s, pivaloyl-
CH ₃ ), 2.16 (4H, m, 2-H ₂ , 6-H ₂ ), 2.39 (4H, m, 3-H ₂ , 5H
₂ ), 2.80 (1H, m, 1-H), 5.84 (2H, s, pivaloyloxy-CH ₂ ). [Synthesis of raw material 2; production method of levulinic acid pivaloyloxymethyl ester (PivER1)] Reference Example 1 150-levulinic acid instead of 4-oxocyclohexanecarboxylic acid
The same treatment was performed using mg to obtain 100 mg of an oily substance having Rf 0.6.

NMR δ (ppm) 1.22 (9H, s, pivaloyl-
CH ₃ ), 2.21 (3H, s, acetyl-CH ₃ ), 2.70 (4H, m, -CH ₂ CH ₂
-), 5.76 (2H, s, pivaloyloxy-CH ₂ ). {Drug efficacy test} [Materials used] ・ Drugs used TCP-1, TCP-2, TLP, and comparative drug are all white petrolatum (Wako Pure Chemical) Was used to make an ointment. Triamcinolone acetonide (Wako Pure Chemical Industries), hydrocortisone butyrate (Sigma), hydrocortisone acetate (Wako Pure Chemical Industries) were formulated as 0.001%, 0.01%, 0.1%, 1% formulations, and betamethasone valerate 0.0012%, 0.012%, 0.12%, 1.2% formulation was prepared. TC
P-1, TCP-2, and TLP are compared with triamcinolone acetonide, so the formulation should have the same concentration as triamcinolone acetonide in terms of mother nucleus.
The formulations were 5%, 0.15%, and 1.5%.

-Used animals As the used animals, male ddY mice and SD rats are used.
Purchased from Japan SLC Co., Ltd. Room temperature 23 ± 1 ℃, humidity 55
Only healthy animals were bred under the condition of ± 10% and used for the experiment.

[Test Method] -Effect of croton oil on ear edema Method of Tonelli et al. (Tonelli, G., Thibault, L. and Ringle
r, I .: Endocrinology77 625 (1965)). That is, 6 male ddY mice having a body weight of 25 to 30 g were made into one group, and 20 mg of the ointment to be tested was applied to the back surface of the right ear.
30 minutes after application of ointment 30 μl of 4% croton oil ether solution
Was dripped. Four hours after dropping the croton oil, the mouse was killed with ether, and both ears were punched out with a 6 mm cork borer, and the weight was measured. As a result, the edema rate of the right ear with respect to the untreated ear weight on the left side was calculated and compared with the control group.

[Effect of granuloma proliferation by paper disc method] Experiment according to the method of Hisagi et al. (Kouhei Hisaki, Tomohisa Shibuya, Noboru Tsurumi, Hajime Fujimura: The Journal of the Japanese Pharmacological Society, 77, 73-85 (1981)). I went. That is, 5 male SD rats having a body weight of 150 g to 170 g per group were shaved on the back with hair clippers. A midline incision was made on the back, and one paper disk (diameter 8 mm, thickness 1 mm, weight 30 ± 1 mg: Toyo Tan Paper), which had been weighed and sterilized, was inserted subcutaneously in both shoulder glands, and the wound was sutured. In addition, penicillin G potassium after surgery to prevent infection
2,000 units were injected intramuscularly. 50 mg for base and test drug
It was rubbed on the skin above the paper disk insertion part carefully (30 seconds).

A plastic neck shackle was placed to prevent the rat from licking the drug application site. This operation was repeated once a day for 7 days, and the day after the final application, the rat was sacrificed after blood collection under ether anesthesia, and the granulation was carefully removed. In addition, the thymus, spleen and adrenal gland were removed and the wet weight was measured. The granulation was dried at 40 ° C. for 24 hours, and then its dry weight was weighed.

[Test Results] -Results for ear edema due to croton oil Effect of TCP-1, TCP-2, and TLP on croton oil ear edema in mice, and betamethasone valerate (B
V), hydrocortisone acetate (HA) and hydrocortisone butyrate (HB) were shown in FIG. 1 and Table 1 for the effects on mouse croton oil ear edema.

As is clear from these, BV, HA and HB showed a dose-dependent inhibitory effect in the range of 0.01 to 1.0%, while TCP-1, TCP-
2. TLP and triamcinolone acetonide (TA), which is the mother nucleus of these compounds, showed a dose-dependent inhibitory effect at 0.01-1.0%. Moreover, the potency of all three drugs was weaker than that of TA. Furthermore, there was almost no difference in activity among the three compounds.

Next, the results of 0.1% formulation (calculated as mother nucleus) used as a clinical dose are shown in FIG. From these results, it can be seen that the strength of the effect of this drug was almost the same as that of BV, although the strength of the effect of all three compounds was weaker than that of the mother nucleus TA in comparison of clinical doses.

[0033]

[Table 1] -Results on the growth of granulomas by the paper disk method Table 2 shows the effects on the growth of granulomas surrounding the paper disks. As shown in these, TCP-1, T
CP-2 and TLP did not have a significant inhibitory effect on the growth of granuloma, but TA, which is the nucleus, had a dose-dependent inhibitory effect, and a 1% formulation had a significant inhibitory effect.

The effect on the weight of each organ is shown in Table 2.
With respect to thymus, spleen and adrenal weight, BV and TA showed dose-dependent atrophy of all organs, and TA thymus atrophy was particularly prominent, with 0.1% ointment 43.3% and 1% ointment 89.1.
Although a suppressive effect of 0.1% was observed, in contrast to this, TC
P-1, TCP-2, and TLP showed almost no effect on organ weight.

[0035]

[Table 2]

[0036]

From the above results, the triamcinolone derivative (TCP-1, TCP-2, and TL) according to the present invention is obtained.
P) has almost the same efficacy as BV against superficial inflammation and almost no effect on the whole body, suggesting that it may be a highly safe external drug with few side effects. It was

[Brief description of drawings]

FIG. 1 Effect of TCP-1, TCP-2 and TLP on croton oil ear edema of mice, and croton oil ear edema of mice of betamethasone valerate (BV), hydrocortisone acetate (HA) and hydrocortisone butyrate (HB) on mice. It is a figure showing the effect to.

FIG. 2 is a diagram showing the results of 0.1% preparations (converted to mother nucleus) used as clinical doses.

FIG. 3 is a flow chart showing a synthetic route of a triamcinolone derivative according to the present invention.

FIG. 4 is a corresponding chart showing a synthetic route of a triamcinolone derivative according to the present invention.

Claims (3)

[Claims] 1. A triamcinolone derivative represented by the following formula: 2. A triamcinolone derivative represented by the following formula: 3. A triamcinolone derivative represented by the following formula: