JPH04108730A - Allergic disorder therapeutic agent - Google Patents

Abstract

PURPOSE:To provide the title therapeutic agent having both leukotriene and thromboxane A2 antagonismic actions, containing a phloroglucinol derivative as active ingredient. CONSTITUTION:The objective therapeutic agent containing, as active ingredient, a compound of formula I [R is of formula II (R<2> is alkyl) or H; R<1> is alkyl]. This compound can be prepared by adding phloroglucinol to a mixed solution of the corresponding fatty acid and BF3-Et2O complex followed by reaction at 100 deg.C in an argon stream. For the present therapeutic agent, a patient needed for the therapy of an allergic disorder is administered with a single dosage of 1-1000mg of the active ingredient in several portions a day with a total of 3-3000mg thereof for one day.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to a therapeutic agent for allergic diseases.

[Prior Art] Allergic diseases refer to diseases caused by allergies. Allergic reactions are classified from type ■ to type V, depending on the types of cells and antibodies involved, the type of reaction, etc. Among them, type I allergic reactions occur most frequently and are involved in almost all allergic reactions.

Diseases caused by type I allergies include bronchial asthma, allergic rhinitis, urticaria, and anaphylaxis-1 seasonal conjunctivitis. In this type of allergy, the body is sensitized to the antigen, producing IgE antibodies, and the IgE antibodies are produced.
The gE antibody binds to the IgE receptor of mast cells and basophils, and the re-invading antigen acts on it, producing chemical mediators such as histamine, leukotrienes, prostaglandins, thromboxane, and platelet activating factor (PAF). is released and symptoms occur.

In this way, chemical mediators related to allergies
There are many types of allergy, and these are involved in a complex manner, resulting in an allergic lesion with one main symptom. Therefore, it is thought that an ideal anti-allergic drug would have a variety of chemical mediator-antagonistic effects. .

Traditionally, therapeutic agents for allergic diseases include: ■Drugs that inhibit the release of chemical mediators from mast cells;
Drugs that suppress the biosynthesis of chemical mediators in mast cells, ■Drugs that antagonize chemical mediators on cell receptors where chemical mediators act, and ■Functionally antagonize the action of chemical mediators. Examples include drugs. ■Examples include antihistamines, etc.
Examples of ■ are lipoxygenase inhibitors, thromboxane A2 synthase inhibitors, etc. Examples of ■ are leukotriene antagonists, PAF antagonists, anticholinergics, etc., and examples of ■ are β2 stimulants, among others. Many of the drugs listed in ■, ■, and ■ are currently in the stage of clinical trials (Kenji Tasaka, Kagaku to Kogyo, Vol. 42, No. 8, pp. 55-59, 1989).

It has been established that leukotrienes or thromboxane A2 are important chemical mediators in allergic diseases including bronchial asthma in humans, but at present there are no antagonists that act together effectively against these mediators. Not discovered. There are many chemical mediators involved in allergies, and these are involved in a complex manner, resulting in allergic lesions with one main symptom. Therefore, anti-allergy drugs that have antagonistic effects on a variety of chemical mediators are recommended. is considered ideal.

(Problems to be Solved by the Invention) Therefore, an object of the present invention is to provide a therapeutic agent for allergic diseases having both leukotriene and thromboxane A2 antagonistic effects.

[Means for Solving the Problems J] As a result of intensive research, the present inventors discovered that phloroglucinol derivatives having a specific structure are excellent leukotrienes (LT).
, ) has an antagonistic effect and thromboxane A, (TXA, ) has an antagonistic effect and has completed the present invention.

That is, the present invention.

A therapeutic agent for allergic diseases containing as an active ingredient a phloroglucinol derivative represented by the general formula [I] (branched alkyl group) or hydrogen atom, where R is a straight-chain or branched alkyl group. provide.

[Effects of the Invention] The phloroglucinol derivative represented by the above formula [I], which is the active ingredient of the therapeutic agent of the present invention, has an effect on the receptors of leukotriene or thromboxane A2, which are chemical mediators in allergic diseases. Since it strongly antagonizes the mediator, it can be effectively used in the treatment of allergic diseases.

Detailed Description of the Invention] The therapeutic agent of the present invention is preferably a phloroglucinol derivative represented by the above-mentioned formula [I]. a straight-chain or branched alkyl group, R2 is hydrogen or has 1 to 5 carbon atoms
of straight-chain or branched alkyl groups.

- The phloroglucinol derivative represented by formula [I] is
Phloroglucinol with the corresponding fatty acid, OF, Et
In addition to the ZO complex mixture, under an argon stream,
It can be synthesized by reacting at 100°C. At this time, the mixing ratio of phloroglucinol and fatty acid is preferably about stoichiometric.If the mixing ratio of phloroglucinol and fatty acid is 12-2 in molar ratio, the general formula [
I] Recovery of 6 products in which those in which R is hydrogen are mainly produced, and when R is 1.4 to 6, mainly those in which R is ketone are produced;
For purification, after cooling the reaction mixture, it was added dropwise to an aqueous potassium acetate solution, i'jJ4 was extracted with ethyl acetate, the ethyl acetate layer was dried, and then subjected to silica gel column chromatography (hexane-ethyl acetate = 5 = 1). This can be done by separating the

The therapeutic agent of the present invention is administered to patients in need of allergic disease treatment at a dose of 1 to 1000 mg of the active ingredient per dose.
The dosage range is generally 3 to 30% of the active ingredient per day in several divided doses.
It can be administered at a total daily dose of 3000 mg. Of course, the dosage can vary depending on the patient's weight, symptoms, and other factors recognized by those skilled in the art.

In addition to the active ingredient, the therapeutic agent of the present invention includes a pharmaceutically acceptable vehicle, carrier, excipient, and diluent.

They may be combined in unit dosage form with binders, preservatives, stabilizers, flavoring agents, and the like as required by generally accepted pharmaceutical practice. The amount of active ingredient in these compositions or preparations is adjusted accordingly to obtain a suitable dosage within the indicated range.

The route of administration of the therapeutic agent of the present invention is not particularly limited, but it is preferably administered orally or by inhalation. However, in case of emergency, subcutaneous, intramuscular or intravenous administration is also possible.

Examples of the form of the therapeutic agent of the present invention include tablets,
Examples include capsules, powders, inhalation solutions, and injection solutions.

The acute toxicity of the compound of the present invention is 3 to 1 Onag/kg.
(mice, intravenous administration).

Hereinafter, the present invention will be explained in more detail based on Examples.

However, the present invention is not limited to the following examples. [Example] Synthesis of diacetyl phloroglucinol 5 ml of acetic acid and 15 g of phloroglucinol were added to 11 ml of F3-ether complex, and the mixture was heated under an argon stream. The reaction was carried out at 100° C. for 2 hours. After cooling, 5.5 g of potassium acetate was added dropwise to 100 ml of water while stirring the reaction solution. A white precipitate formed after standing was removed by filtration, the filtrate was extracted with ethyl acetate, and the solvent was distilled off. The residue was subjected to silica gel chromatography (starting solvent: hexane-ethyl acetate = 5:1) to obtain 1.55 g of diacetyl phloroglucinol as pale yellow crystals. Yield is 5
It was 87%.

m, p,: 161-163℃ 1, R (Ilr in ν, c+n-'l: 2800
-3200.1600HN M R (CD s OD,
270MHz) δ:1'6.44 (s, 3 old, 6.05 (s, H+1.2.90 fs, 6)
1]"C-NMR (CD, OD, 270M
Hzl δ: 2050, 172.4, 169.9
, 104.8, 95.7, 32.9 Song 11 Synthesis of raw diisobutyryl phloroglucinol 11 ml of isobutyric fi and 500 μl of phloroglucinol were added to 5 liters of F,-ether complex, Example 1 Diisobutyrylphloroglucinol was obtained as a yellow oil in the same manner as above, and the yield was 78.7%.

I R(v"'c+a-'l: 3200-3
400.1600'H-NMR (CDC1, 270M
Hzlδ: 16.34 fs, 3 old, 5.90 (s
, IH), 3.96 (11,2 old.

1.21 fd, 12H, J=10Hz)"C-NMR
(CDCI N, 270M) 121 δ: 21
1.9.172.3.103.5.95.6.39.3
．． 19.1 m day Synthesis of dibutyrylphloroglucinol F,-ether complex 5 + sl to n-butyric r111 proverb 1
and 0.5 g of phloroglucinol were added in the same manner as in Example 1 to obtain yellow crystals of dibutyrylphloroglucinol. The yield was 76.3%.

m, p,: 126-128℃ IR (ν@r, cm-'l: 3100-33
00.1620'H-NMR (CDCI, 2
70klHzlδ.

16.20 (s, 3H1,5,58(s, 1
) II.

3.06 ft, 4H, J=7.0 Hzl, 1.7
2 fm, 4H1,1,01(t, 6H,J=7
．． 0Hz) 'C-NMR (CDCI, , 270MHzl
δ.

206.9. 1?1.9. 113.9. 95.5
．． 46.1. Synthesis of di(3-methyl-butyryl) phloroglucinol F, -ether complex 1.011 ml and phloroglucinol 0.0 ml were added. Add 5g,
Di(3-methyl-butyryl)phloroglucinol was obtained in the same manner as in Example 1.

Melting point = 124-126℃ UV L"" 331 nm (sl (log t
=3.531.272 nwflog E =4.53
1,205 n+s (log ε; 4.01lI R
(KBr) 3100-3300.1620.1
200'HNMR (COC: Is, 2701+IHz
l δ: 16.32 (s, 3H).

5.90 (s, IMl, 2.97 fd
, 4M1. 2.25 (m, 2H1°1.
01 fd, 12H, J = 7.0 Hz 1m Synthesis of di(2-methyl-propanoyl)phloroglucinol P,-ether complex 5.0 ml with 1.0 wil of 2-methylpropanoic acid and phloroglucinol 05 g of rucinol was added and the same procedure as in Example 1 was carried out to obtain oily di(2-methyl-propanoyl)phloroglucinol.

UV Et” 332 nmlsl flag
t=3.63), 272 r+n+flag
t, =4.601.204 nm (log t
;4.1011 R(KBr) 3200-34
00. 1600. 1200H-NMR (CDC1,
, 270MHzl δ: 16.34 (s, 3
H1゜5.90 fs, IHL, 3.96i garden,
2H1,1,211d, 12)! .

Synthesis of dibrovanoyl phloroglucinol 1 ml of propanoic acid and 0.5 g of phloroglucinol were added to 5.0 ml of the F,-ether complex, Example 1. Dibrobanoylphloroglucinol was obtained in the same manner as above.

Melting point: 152-154℃ UV L"" 330 rvisl frog ε
: 3.581.271 nm (log t = 4.58
1.205 n+w (log t, :4.0511
R(KBr) 2800-3200.1600
'H-NMR (CDCIs, 2701Hzl δ:
16.18 (s, 3) 11°5.8Q (s,
IHL, 3.14fq, 4H,J=7.0Hzl
, 1.18 (t, 6H, J = 7.0 Hz 1 1 Mu5 Nibutyryl phloroglucinol synthesis 5.0 ml of F,-ether complex was mixed with alcohol #1-(1*
Butyrylphloroglucinol was obtained in the same manner as in Example 1 by adding I and 0.5 g of phloroglucinol.

Melting point: 180-181℃ UV L"" 287 n+w (sl frog
a=4.171.227 rv(log t =4.
041.206 nm (log E =4.021
1 R(KBr) 3300-3400.121
0'HNMR (CDsOD, 270 MHz) δ
: 5.87 (s, 2H1゜3.10 (t, 2
H, J=7.0 Hz), 1.76 fs, 2H)
, 1.111t, 3H, J=7.0 ) 1z
1) Synthesis of hexanoylphloroglucinol 16 liters of hexanoic acid and 1.7 g of phloroglucinol were added to 10 ml of F,-ether complex, and hexanoyl phloroglucinol was prepared in the same manner as in Example 1. Obtained.

Melting point: 104-106°C UV 287 nmfsl (log
! =4.38), 227 r++s(log E =
4.281.207 nm (log t =4.22
]IR(KBr) 3200-3400.16
40.1200') I-NMR (CDsOD, 270
MHz) δ: 5.9 (1(s, 2H1°3.
08 ft, 2H, J=7.0 Hzl, 1
．． 68 fm, 2H1,1, 42fm, 4H1,1
,02(t, 3H, J=7.0 HzlK5) Synthesis of 2-methyl-butyrylphloroglucinol F,
- 1 i of 2-methylbutane to 5.0 ml of ether complex
11. Oml and 0.5 g of phloroglucinol were added and the same procedure as in Example 1 was carried out to obtain oily 2-methyl-butyrylphloroglucinol.

UV 288 nm (sl (log c
;4.201.228 nmIggt +4.08
1.206 nIl(log t +4.091T
R(KBr)3200-3400.16
20.1210'f(-NMR(CDJo, 270
MHz) δ 5.99 Is, 2)1).

385 (厘, l)++, 1.84 + layer,
JHI, 1.40 fm, IH).

1.16 1d, 3H, J=7.0 Hz),
0.92ft, 3H,J=7.0zl Synthesis of 2-methyl-propanoylphloroglucinol P,-ether complex8. Oyal 2-methylpropanoic acid 1. 2-methyl-propanoylphloroglucinol was obtained in the same manner as in Example 1 by adding Oml and 1.5 g of phloroglucinol.

Melting point: 263-65℃ UV: 287 nm (sl (log E)
+4.191.227 nta(log E;4.
081.206 nm (log! +4.0611
R(KBr) 3200-3400.161.
5.1210'H-NMRfcD, OD, 270
MHz) δ: 5.90 fs, 2H1゜4.0
8 (m, IH, J=7 Hzl real JC sex).

Synthesis of 3-methyl-butyrylphloroglucinol F,
-1 3-methylbutanoic acid to 8.0 ml of ether complex
．． 0 ml and 1.5 g of phloroglucinol were added in the same manner as in Example 1 to obtain 3-methyl-butyrylphloroglucinol.

Melting point: 96-99℃ UV! t” 288 nm (sl
(log C+4.101.227 nmflo
g E +3.99), 206 nm (log t
, +4. oolIR(KBr) 3200-
3400.1620.1210H-NMRfcD,OD
, 270 MHz δ: 5.92 (s, 2
)1t.

3.04 (+1.2H, J=7.21(zl, 2.
32 (m, 1)tl, 1.07(d, 6H,J
=7.2 Hzl Synthesis of dihexanoyl phloroglucinol 1.6 @l of hexanoic acid and 1.7 g of phloroglucinol were added to 10 l of the F,-ether complex, and the mixture was prepared as in Example 1. Similarly,
Dihexanoylphloroglucinol was obtained.

Melting point 285-87℃ LIV Et0H331nmfsl frog
E ==3.591.271 rvflog [:
+4.56+, 205 nm (log ε24.0
911 R (KBr) 3200-3400
．． 1640. 1200'H-NMRf(:DxOD
, 270 MHz) δ: 5.92 [3, IH
).

3.16 ft, 4H, J=7.2 Hzl,
1.81 fq, 4H, J=7.2)1z)
, 1.53 fm, 8H], 1.09
(T, 6H, j = 7.2 Hz) Leukotriene antagonism After making an incision on the contralateral side of the membranous part of the trachea isolated from a guinea pig, cut out one segment perpendicular to the trachea and cut three pieces in succession. and indomethacin 10-'M at 37°C (D9iO-
)' solution (NaC1: 137mM, KCI: 2.7mM
, CaClt: 1.8 mW, MgCIz: 1.1
sM, NaHPO, : 0.41, NaHCO, : 12
．． A load of 0.5 g was applied and suspended in a Magnus tube filled with [l mu, glucose +5.6 mM). A gas of 95% O2-5% Co, 1 gas was aerated into the Magnus tube, and smooth muscle contraction was induced by an isotonic transtube "f-(TD)".
-112S, Nihon Kohden) via polygraph (JD-
1125, Nihon Kou N). Test drug (Example 1
~ Compounds obtained in 12) are leukotrienes (L T
) D a (manufactured by Cayman Chemica 1)
Incubate for 20 minutes before adding 3 x 10-'M. The inhibition rate was calculated from the contraction rate when the test drug was added, with the contraction when leukotriene D4 alone was added as 100%.

The results are shown in Table 1.

Thromboxane A2 After making an incision on the contralateral side of the membranous part of the trachea isolated from a guinea pig, cut out one segment at a time perpendicular to the running direction, and place three pieces in succession into a Magnus tube filled with Tyrode's solution at 37°C with 0.5
In a 6-Magnus tube suspended under a load of 95% 0
A 2-5% CO8 gas mixture was vented and smooth muscle contractions were recorded as described above. The test drugs (compounds A-G) are stable thromboxane A 2 U46619 (9,11-
Dideoxy-9α,11a-methanoepoxy-PGFz
, manufactured by Cay*anChemica1, 13 x 10
Incubation was performed for 20 minutes before the addition of Ll-46619.
It was calculated from the contraction rate when the test drug was added. Table 1 shows the results.
Shown below.

Table 1 From Table 1, it was found that the compound of the present invention has leukoto-1 and thromboxane A2 antagonistic activity.

Claims (4)

[Claims] (1) General formula [ I ] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] (However, R in the formula ▲ There are mathematical formulas, chemical formulas, tables, etc.)
(R^2 is a straight-chain or branched alkyl group) or a hydrogen atom, and R^1 is a straight-chain or branched alkyl group) Allergies containing phloroglucinol derivatives as active ingredients Sexual disease treatment. (2) In the above general formula [I], R^1 is a linear or branched alkyl group having 1 to 5 carbon atoms, and R^2 is hydrogen or a linear or branched alkyl group having 1 to 5 carbon atoms. The therapeutic agent according to claim 1, which is an alkyl group. (3) The therapeutic agent for allergic disease according to claim 1 or 2, wherein the allergic disease is a disease caused by type I allergy. (4) The therapeutic agent for allergic disease according to claim 3, wherein the allergic disease is bronchial asthma or anaphylaxis.