JPH0499794A - Novel 21-substituted steroid compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to novel steroid compounds.

[Prior art and problems to be solved by the invention] Steroids are important therapeutic agents indispensable for the treatment of skin diseases. Its scope of application covers a wide range of inflammatory diseases, such as contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular eczema, Widal lichenosis, housewife's eczema, prurigo and insect bites, drug eruption, and poisoning. Eruption, epidermis, palmar pustulosis, lichen planus, glossy lichen, pilaris rubra, pityriasis rubrum, erythema, erythroderma, supradiscal erythematous lupus, lichen planus, pityriasis pilaris. It is widely used in a wide range of conditions, including healing, Juhring's herpetiform dermatitis, alopecia areata, palmar vitiligo, sarcoidosis, keloids, hypertrophic scars, chronic adrenocortical insufficiency, rheumatism, bronchial asthma, and ulcerative colitis. It is used.

However, many of the patients to whom these steroids are applied have intractable skin that requires long-term administration over a wide area of the body, so doctors have to devise ways to administer steroids (e.g., using sealed bandages) and how to administer steroids to patients. Despite this guidance, side effects are still a problem. For example, local side effects such as skin atrophy, steroid healing, steroid rosacea, depigmentation, and infections may occur, and in rare cases, systemic side effects such as Cushing's symptoms, growth retardation in children, and osteoporosis may also occur.

In order to solve these problems, steroid compounds in which the 21st position is substituted with an alkylthio group derived from an alkanethiol have also been reported;
S., Simons, B., Thompson, an.
dD, Johnson, Bioche+n1str
y, 18.4915 (1979), M, Pan5
．． J. Robinson, LoMercor,
B. Thompson.

and S, S, Simons, J, 5teroi.
d, Biochem, 23°261<1985
), JP-A-63-60995, JP-A-63215
No. 695], it could not be said to be fully satisfactory in terms of the strength of pharmacological action and reduction of side effects.

Therefore, it has been desired to develop a steroid compound that has strong pharmacological effects that can bring about early recovery in patients with these refractory skin conditions, and that has extremely few side effects.

[Means to solve the problem]

Under these circumstances, the present inventors conducted extensive research and found that the 21st position represented by Formation (1) below was substituted with an amide alkanethiol, etc. derived from an aminoalkanethiol and a protected amino acid or an acid anhydride. The present invention was completed based on the discovery that the steroid compound shown above exhibits a high anti-inflammatory effect and has extremely few side effects.

That is, the present invention relates to the following general formula (I), with the following blanks (in the formula, R1 represents a hydroxyl group or an acyloxy group having 1 to 6 carbon atoms, R3 represents a hydrogen atom or a lower alkyl group, or R1 and one A lower alkylidenedioxy group may be formed in combination. R5 is an acyl group having 1 to 6 carbon atoms or N-
Indicates an acyl group derived from a protected amino acid, X and Y
represent hydrogen atoms or halogen atoms which may be the same or different, Zl represents an oxygen atom, sulfur atom or imino, Z2 represents an oxygen atom or imino, and n represents an integer of 1 to 6.

1.2 The wavy line indicates that the configuration can be either α or β.
A dashed line between positions indicates that there may be a double bond. ) 21-substituted steroid compounds are provided.

In general formula (I), the acyloxy group having 1 to 6 carbon atoms represented by R1 includes formylglycine, acetoxy group,
Examples include propionyloxy group, butanoyloxy group, pentanoyloxy group, hexanoyloxy group, and the like.

The lower alkyl group represented by R2 has 1 to 5 carbon atoms.
A straight or branched alkyl group, specifically a methyl group,
Examples include ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group, and amyl group. Also R
The lower alkylidenedioxy group formed by 1 and R2 together includes isopropylidenedioxy group, 3-
Examples include pentylidenedioxy group.

Examples of the acyl group having 1 to 6 carbon atoms represented by R5 include formyl group, acetyl group, propionyl group, butanoyl group,
Examples include pentanoyl group and hexanoyl group. Examples of N-protected amino acids with acyl groups derived from N-protected amino acids include N-acetylglycine, N-formylglycine, N-acetylleucine, N-formylleucine, N-acetylphenylalanine, N-formylphenylalanine, Examples include N-acetylmethionine and N-formylmethionine. Further, the halogen atom represented by XSY includes chlorine, fluorine, bromine, or iodine atom.

The 21-substituted steroid compound of the present invention can be produced, for example, according to the following reaction formula (A) or (B).

The following margins (in the formula, R,, R2, x, y, z, , Z2 and n have the same meanings as above. R, / represent an acyl group having 1 to 6 carbon atoms, and R1 and R6 are the same - or a hydrogen atom or a straight or branched alkyl group having 1 to 5 carbon atoms, which may be different.) In other words, the 21-[(aminoalkyl)thio]steroid compound represented by the -form (II) and the general The steroid compound (Ia) of the present invention can be produced by reacting the acid anhydride represented by the formula (I[[) in the presence or absence of an amine.

Here, the raw material 21-[(aminoalkyl)thio]
Steroid compound (II) can be prepared, for example, by the method of Simmons et al.

Thompson, and D. F. Johns.
on, Biochea+118°4915 (1979
), S, S, Simons, Jr., M.
Pan5. and D, F., Johnson, J.
Org, Chem, 45, 3084 (198
It can be synthesized by 0>E etc.

The reaction is carried out using 300 to 10 equivalents of acid anhydride (I) to 214(minoalkyl)thio]steroid compound (I[), in the presence or absence of an amine, at 30 to 50°C, preferably from 0 to This is carried out by stirring at 30°C for 30 minutes to 8 hours. As the acid anhydride, for example, acetic anhydride, but-9-pionic anhydride, etc. can be used, and as the amine, for example, pyridine, triethylamine, etc. can be used.

The following margins [wherein R, SR,, xSy, z, Z, and n have the same meanings as above. R, II represents an acyl group derived from an N-protected amino acid, R6 represents an amino acid protecting group (e.g. acyl group, t-butoxycarbonyl group, etc.),
R1 represents a group derived from an amino acid (for example, a hydrogen atom, a straight or branched lower alkyl group, a 2-methylthioethyl group, or a benzyl group). ] That is, a 21-[(aminoalkyl)thio]steroid compound represented by the formula (II) is reacted with a carboxylic acid derivative such as a protected amino acid represented by the general formula (rV) in the presence of an appropriate dehydration condensation agent. By doing so, the steroid compound (Ib) of the present invention can be produced.

The reaction was carried out using a 2l-4(aminoalkyl)thio]steroid compound (■), 1 to 10 equivalents of a carboxylic acid derivative (TV), and 1 to 10 equivalents of a dehydration condensing agent alone or in the presence of a basic catalyst. , in a solvent that does not participate in the reaction, -1
This is carried out by stirring at 0 to 100°C, preferably 10 to 50°C, for 30 minutes to 8 hours. Examples of the dehydration condensation agent include N,N-dicyclohexylcarbodiimide; examples of the basic catalyst include 4-pyrrolidinopyridine, dimethylaminopyridine, and pyridine; and examples of the solvent, such as ethyl acetate and methylene chloride. etc. can be used respectively.

The steroid compound (I) obtained by these reactions can be separated and purified from the reaction mixture by known methods such as column chromatography and recrystallization.

〔Example〕

Next, the present invention will be further explained with reference to Examples and Test Examples.

Example 1 21-[2= (acetylamino)ethylthio]-9-
Fluoro-11β,17-cyhydroxy-16β-methylpregna-1,4-diene-3°20-dione (compound number 1): 150 ml of acetic anhydride! Add 2 liters of water at room temperature while stirring well.
-(2-aminoethylthio)-9-fluoro11β,1
7-cyhydroxy-16β-methyl pregna-1,4-
4.00 g of diene-3,20-dione was added. After this, the reaction was completed by stirring at room temperature for 15 hours. The resulting reaction product was cooled to -10°C, and 150ml of ethanol was added! was slowly added dropwise and stirred for 30 minutes, then the solvent was removed and the residue was extracted with chloroform. The organic layer was washed successively with distilled water and saturated saline, dried over anhydrous sodium sulfate,
This was filtered.

Thereafter, the solvent was removed, and the residue was subjected to silica gel column chromatography, eluted with chloroform:methanol, the solvent was distilled off, and recrystallized from ethyl acetate:chloroform. ) Ethylthio]-9-fluoro-11β,17-dihydroxy-16β methylpregna-1,4-diene-3,20-
0.29 g of dione (compound number 1) was obtained.

NilR(DMNllR(Dδ(ppm): 0, 83
-2.71 (m, IIH) 0,95 (d, 3H
, J=7Hz) 1, 16 (s, 3H) 1.50 (s, 3H) 2, 14 (s, 3) 1) 3, 31-3.52 (m, 4H) 4, Of (d, IH , J=8)1z)4,08
(d, IH, J=8Hz) 4, 29-4.30 (m
, 1) 1) 4,88 (s, IH) 5,30 (d, LH, J=4Hz) 5,53 (s
, IH) 6,00 (s, 1) 1) 6,22 (d, LH, J=10Hz) 7.28 (
d, l) I, J=10) 1z) IRv max (
KBr) (Crn-'): 3480, 2940.
1662. 1616. 1420. 1306.
1244°1042, 886. 704. 666 Example 2 9-fluoro-11β,17-cyhydroxy-16β-
Methyl-21-[2-(propionylamino)ethylthio]pregner 1.4-diene 3.20-dione (compound number 2): 21-(aminoethylthio)-9-fluoro-11β,
17-dihydroxy-16βτ methylpregna-1,4
From 5.00 g of -diene-3,20-dione and 62-propionic anhydride, 0.42 g of the title compound was obtained in the same manner as in Example 1.

NMR (DMSO-d,) δ (ppm): 0, 84-
2.69 (+0.13H)0, 93 (d, 3H,
J=7)1z)1,00 (t, 3H, J=7Hz)
1,20 (s, 3H) 1,50 (s, 3 days) 3,30-3.54 (+n, 4H) 4,02 (d
, IH, J=7Hz) 4, 16 (d, LH, J=
7Hz) 4,23-4.40 (m, IH) 4,87 (s, LH) 5,30 (d, LH,J=5Hz>5,58 (s
, IH) 6,00. (s, LH) 6, 23 (d, 1N, J=10Hz) 7, 27
(d, IH, J=10Hz) IRνmax (KBr)
(cm-'): 3496, 2944. 2876,
1662. 1620. 1466, 1302°11
70, 1064,946,768,704 Example 3 9-fluoro-21-(2-[(2-formylamino)
-4-Methylthiooxobutylcoaminoethylthio)-
11β,17-cyhydroxy-16β-methylpregna-1,4-diene-3°20-dione (compound number 3)
: 3.45 g of N-formyl-methionine was suspended in 100 ml of dry ethyl acetate, and while stirring well at room temperature, 2l-(2-aminoethylthio)-9-fluoro-1
1β,17-dihydroxy-16β methylpregna-1
, 3.00 g of 4-diene-3,20-dione was dissolved in dry ethyl acetate to make 20 rn!, and 4.12 g of dicyclohexylcarbodiimide was dissolved in dry ethyl acetate to make 40 rn! ! .

The closed ones were added one after another. After this, the reaction was completed by stirring at room temperature for 4 hours.

The obtained reaction product was filtered to remove the precipitate, and the organic layer was washed successively with distilled water and saturated brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was removed, and the residue was subjected to silica gel chromatography, eluted with chloroform:methanol, the solvent was distilled off, and recrystallized from acetone:n-hexane.
21-(2-[(2-formylamino)-4-methylthiooxobutylcoaminoethylthio)-11β.

17-cyhydroxy-16β-methylpregna1.4-
Diene-3,20-dione (compound number 3) 0.24g
was gotten.

NMR (DMSO-da) δ (ppm): 0, 97
(s, 3H) 1,03 (d, 3)1. J=7Hz) 1, 36-
3.47 (o+, 18H) 1, 49 (s, 3H
) 2,03 (s, 3H) 3,54 (d, 1)1. J=17Hz) 3.75
(d, LH, J=17Hz) 4.16 (d, L
H, J=1011z) 4, 32-4.43 (m, I
H) 5.18 (s, IH) 5,24 (s, LH) 6,00 (s, LH) 6,20 (d, LH, J=10Hz) 7,28 (
d, IH, J=10Hz) 8, 02 (s, 18) 8, 14 (t, LH, J= 6) 1z) 8, 27 (d
, LH, J=8Hz)IRv max (KBr)
(Cm-'): 3352, 2944. 1664
．． 1622. 1532. 1444. 1390°1302.1244.1048.776.708 Example 4 21- (2-C(2-acetylamino)-4methylthiooxobutyl]aminoethylthio)=9-fluoro-
11β,17-cyhydroxy-16β-methylpregna-1,4-diene-3°20-dione (Compound No. 4)
: 2l-(2-aminoethylthio)-9-fluoro-11
β,17-cyhydroxy-16β-methylpregna-1
,4-diene-3°2Q-dione and 7.01 g of N-acetyl-methionine, 0.61 g of the title compound was obtained in the same manner as in Example 3.

NMR (DMSOJa) δ (ppm): 0, 97 (
s, 3H) 1,03 (d, 3H, J=7Hz) 1,38-3.
43 (m, 18H) 1, 50 (s, 3ft) 1, 85 (s, 3fl) 2, 03 (s, 3H) 3, 54 (d, 1) 1. J=17Hz)3,75
(d, 1)1. J=17Hz)4.16 (d,
1)1. J=10Hz) 4, 22-4.34 (m,
IH) 5,19 (s, II() 5,25 (s, IH) 6,01 (s, IH) 6,21 (d, LH,J=10Hz)7,28 (
d, IH, J=10Hz) 8,00 (s, IH) 8,03 (s, LH) TRv max (KBr) (cm -'): 3
328, 2924. 2852. 1618. 15
80. 146B, 1438°1312, 118
8. 1060. 722,642 Test Example The anti-inflammatory effect was tested by the following method.

The results are shown in Table 1.

(Test method) The abdomen of a DDY male mouse (approximately 30 g) was shaved, and 7%
A solution of 0.15 cm of picryl chloride in ethanol was applied to the shaved area. After 6 days, apply 1% chlorinated picryl olive oil solution to the front and back of the right ear for 20 days. d of the compound of the present invention and the comparative drug (hydrocortisone) to induce inflammation.
A 0-3M solution (base; ethanol/propylene glycol-7/3) 40I was applied to the front and back of the right auricle. In the control group, only the base was applied instead of the test solution. trigger 2
After 4 hours, remove the layers, cut both ears, and punch (φ9 mm>
The sample was punched out and the weight of the auricle was measured. As an index of the anti-inflammatory effect of each steroid, the inhibition rate of the test solution against the weight increase of the right auricle based on the base was calculated using the following formula.

Edema suppression rate (%) = 100- Weight difference with the untreated left auricle (■) Comparison of the average value of the weight difference between the left and right auricles in the test solution treated group and the average value of the weight difference between the left and right auricles in the control group to which only the base was applied. A t-test was used for the test.

Table 1 [Effects of the Invention] The 21-substituted steroid compound (I) of the present invention has a strong anti-inflammatory effect, so it can be used to treat contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummular eczema, and Widal. Lichen habit, housewife's eczema, prurigo, insect bites, drug eruption, poison eruption, rolling swelling, palm! ! Pyorrhea, lichen planus, glossy lichen, pityriasis pilaris, Gibell's rosacea, erythema, erythroderma, supradiscal erythematous lupus, lichenoid lichen, Juhring's herpes dermatitis, alopecia areata,
It can be used for the prevention, treatment, and treatment of palmar vitiligo, sarcoidosis, keloids, hypertrophic scars, chronic adrenal cortex insufficiency, rheumatism, bronchial asthma, ulcerative colitis, etc.
Moreover, it has extremely few side effects.

that's all

Claims (1)

[Claims] 1. The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (I) (In the formula, R_1 represents a hydroxyl group or an acyloxy group having 1 to 6 carbon atoms, and R_2 represents hydrogen. It may represent an atom or a lower alkyl group, or may be combined with R_1 to form a lower alkylidenedioxy group. R_3 represents an acyl group having 1 to 6 carbon atoms or an acyl group derived from an N-protected amino acid. ,
X and Y represent a hydrogen atom or a halogen atom which may be the same or different, Z_1 represents an oxygen atom, a sulfur atom or imino, Z_2 represents an oxygen atom or imino, and n represents an integer of 1 to 6. The wavy line indicates that the configuration may be either α or β, and the broken line between the 1st and 2nd positions indicates that there may be a double bond. ) A 21-substituted steroid compound represented by: