JPH09255669A - New benzylidene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new benzylidene derivative that has allergic reaction inhibitory actions, particularly allergic reaction inhibitory actions of both types I and IV. SOLUTION: This compound is a compound of formula I (R<1> and R<2> are each H, a halogen, halogen-substitutable lower alkyl, lower alkoxy, OH, lower alkoxycarbonyl, etc.; a lower alkylene in whose chain R<1> and R<2> in combination of them may be replaced with O) or its salt, for example, (z)-N-(5- phenylmethylene-4,5-dihydro-4-oxo-2-thiazolyl) guanidine. The compound of formula I is obtained an aldol condensation of a substituted benzaldehyde of formula II and a compound of formula III (X is a halogen) in a solvent (e.g. acetic acid) in the presence of a base (e.g. sodium acetate) at 0 deg.C or higher temperature, preferably at 0-300 deg.C, for 1-24hr. This compound is efficient in cure of allergic diseases of both immediate type and delayed type such as contact dermatitis, atopic dermatitis, bronchial asthma, rheumatoid arthritis.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to contact dermatitis, atopic dermatitis, bronchial asthma and the like having an allergic reaction suppressing action, particularly a type I allergic reaction suppressing action and a type IV allergic reaction suppressing action. The present invention relates to a novel benzylidene derivative or a salt thereof which is useful as a prophylactic / therapeutic agent for allergy or as a prophylactic / therapeutic agent for autoimmune diseases such as rheumatoid arthritis.

[0002]

BACKGROUND OF THE INVENTION Regarding benzylidene derivatives, benzylidene derivatives having a guanidino group are described in Bioorg. M
ed. Chem. Lett. , 3 (8) 1729-17.
34 (1993), J. Med. Chem. , 37
(2) 322-328 (1994) and Japanese Patent Laid-Open No. 4-2.
21371 has been reported to have inhibitory activity against 5-lipoxygenase, cyclooxygenase, or both. However, these compounds are specified as a phenol derivative having a large steric hindrance, in which the phenyl group moiety is 3,5-di (t-butyl) -4-phenol. Furthermore, these compounds are only disclosed for use as anti-inflammatory agents with inhibitory activity against 5-lipoxygenase and cyclooxygenase.

[0003]

The conventional anti-allergic agents are mainly used to suppress type I allergic reaction and have been used for immediate allergic diseases. These therapeutic agents include
Although steroids and immunosuppressants are used, their use is limited due to their strong side effects, and it is hard to say that they are sufficient in terms of safety. INDUSTRIAL APPLICABILITY The novel benzylidene derivative of the present invention has an allergic reaction-suppressing action, and particularly has a type I allergic reaction-suppressing action and a type IV allergic reaction-suppressing action, and therefore can be used for both immediate-type and delayed-type allergic diseases. In addition, the type IV allergic reaction inhibitory action is considered to be deeply involved in the development of autoimmune diseases such as atopic dermatitis.

[0004]

Therefore, the present inventors have developed a drug having an excellent allergic reaction inhibitory action, in particular, a type I allergic reaction inhibitory action and an IV type allergic reaction inhibitory action, and having few side effects. As a result of intensive studies aimed at achieving the above, it was found that a benzylidene derivative having a phenyl ring with less steric hindrance achieves the intended purpose, and the present invention was completed. The benzylidene derivative of the present invention has the following general formula (I)

[0005]

[Chemical 1]

(In the formula, R ¹ and R ² are each independently a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a halogen atom, a lower alkenyl group, a lower alkoxy group, a hydroxyl group, a lower alkoxycarbonyl group. , A lower alkylcarbonyloxy group, a lower alkoxycarbonylalkenyl group, or a lower alkylene chain in which R ¹ and R ² together may be substituted with one or more oxygen atoms.). It relates to a derivative or a salt thereof. The substituent R ¹ or R ² in the general formula (I) will be specifically described. The halogen atom is fluorine, chlorine, bromine or iodine.
Examples of the lower alkyl group which may be substituted with a halogen atom include a linear or branched one having 1 to 10 carbon atoms, preferably one having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl and n. -Propyl, iso-propyl, n-butyl, iso-butyl, t-butyl group and the like. These lower alkyl groups are one or two of the halogen atoms described above.
May be substituted with one or more, for example, a lower alkyl group substituted with one or two or more fluorine atoms or chlorine atoms, more specifically, trifluoromethyl group, trifluoroethyl group, trichloroethyl group. Etc. Examples of the lower alkenyl group include linear or branched unsaturated ones having 2 to 10 carbon atoms, preferably those having 3 to 8 carbon atoms, and examples thereof include allyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl and the like. Examples of the lower alkoxy group include those having the above lower alkyl group, and examples thereof include methoxy, ethoxy, n-propoxy, iso-propoxy,
Examples include n-butoxy, iso-butoxy and t-butoxy groups. Examples of the lower alkoxycarbonyl group include those having the above lower alkyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an iso-propoxycarbonyl group,
Examples thereof include an n-butoxycarbonyl group, an iso-butoxycarbonyl group and a t-butoxycarbonyl group. Examples of the lower alkylcarbonyloxy group include those having the aforementioned lower alkyl group, and examples thereof include an acetoxy group and an ethylcarbonyloxy group. Examples of the lower alkoxycarbonylalkenyl group include the above-mentioned lower alkenyl groups substituted with a lower alkoxycarbonyl group having the above-mentioned lower alkyl group, and these substitution positions are not particularly limited, for example, an ethoxycarbonylpropenyl group, 4-methoxycarbonyl-1-butenyl group, 4-ethoxycarbonyl-1-butenyl group and the like can be mentioned. The lower alkylene chain in which R ¹ and R ² together may be substituted with one or more oxygen atoms is a linear or branched alkylene chain having 3 to 10 carbon atoms, preferably 3 to 5 carbon atoms. And one or more, preferably two or more, of carbon atoms in the alkylene chain may be substituted with oxygen atoms. For example, propylene group, butylene group,
There is a methylenedioxy group and the like, and a methylenedioxy group is preferable.

The salts of the present invention include organic acid salts,
Inorganic acid salts, metal salts and the like can be used. As these salts, pharmaceutically acceptable salts are preferable.
The salts of the present invention include, for example, hydrochlorides, sulfates, nitrates, inorganic acid salts such as phosphates, maleates, fumarates, oxalates, succinates, malonates, lactates,
Organic acid salts such as citrate and methanesulfonate.
Base addition salts include, but are not limited to, hydroxides, carbonates and bicarbonates of ammonia, sodium, lithium, potassium, calcium and the like.

The compound of the present invention has a cis form and a trans form with respect to the double bond bonded to the thiazolone ring. Although any of these may be used, the cis form (Z form) is preferable. When it has an asymmetric carbon, it may be a racemate or an optically active substance. The compounds of the invention can also be used in the form of solvates, especially hydrates.

The compound of the present invention can be obtained in good yield according to the following production method, but the scope of the present invention is not limited to these.

[0010]

[Chemical formula 2] (Note: Reaction formula 1 is included.)

(In the formula, R ¹ and R ² have the same meanings as described above, and X means a halogen atom.) The compound represented by the general formula (I) is generally represented by the reaction formula 1. A substituted benzaldehyde represented by the formula (II),
It can be produced by aldol condensation with a compound represented by the general formula (III). That is, the substituted benzaldehyde represented by the general formula (II) and the compound represented by the general formula (III) are mixed with, for example, methanol, ethanol, benzene, toluene, xylene, dimethylformamide, acetic acid or a mixed solvent thereof, or the like. In an active solvent, in the presence of a base such as sodium acetate, potassium acetate, ammonium acetate, piperidine, morpholine and pyridine, 0 ° C or higher, preferably 0 to 300 ° C, more preferably 0 ° C to 1 at the boiling point of the solvent used. By reacting for 24 hours, the compound represented by the general formula (I) can be obtained. Also,
The compound represented by the general formula (III) used as a starting material is represented by the following reaction formula 2:

[0012]

[Chemical 3] (Note: Reaction formula 2 is included.)

(In the formula, X means a halogen atom.)
Org. Synth. , III, 751 (1955).

The present invention also relates to general formula (I)

[0015]

[Chemical 1]

(In the formula, R ¹ and R ² are each independently a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted with a halogen atom, a lower alkenyl group, a lower alkoxy group, a hydroxyl group, a lower alkoxycarbonyl group. , A lower alkylcarbonyloxy group, a lower alkoxycarbonylalkenyl group, or a lower alkylene chain in which R ¹ and R ² together may be substituted with one or more oxygen atoms.). It also relates to a pharmaceutical composition comprising a derivative or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention may further contain a pharmaceutically acceptable carrier. INDUSTRIAL APPLICABILITY The pharmaceutical composition of the present invention has an allergic reaction-suppressing action, in particular, type I allergic reaction-suppressing action and type IV allergic reaction-suppressing action, allergic rhinitis, measles, eczema / dermatitis, infectious allergy, tuberculin It is useful as a prophylactic / therapeutic agent for allergies such as reaction, contact dermatitis, atopic dermatitis, bronchial asthma, etc., and as a prophylactic / therapeutic agent for autoimmune diseases such as rheumatoid arthritis. Therefore, the present invention also relates to an antiallergic agent comprising a benzylidene derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. When the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is used as a medicine, the dose varies depending on the symptoms, age, sex, body weight or administration method of the administration subject. For example, when orally administered to an adult, the dose of the compound represented by the general formula (I) or a salt thereof is usually 1 to 1000 mg, preferably 10 to 500 mg. As a degree, about 1 to several times a day is administered. The administration method is not particularly limited, but usually, it can be stably administered systemically or locally, orally or parenterally.

The pharmaceutical composition of the present invention, together with known excipients and the like, can be prepared by conventional methods such as tablets, capsules, powders, fine granules, suppositories, injections, creams, gels and ointments. Agents, patches (plasters, poultices, reservoir patches), aerosols, and the like can be prepared as needed. For example, as excipients, lactose, sucrose, starches, crystalline cellulose, silicic acid anhydride, calcium phosphate, etc., as binders, polyvinylpyrrolidone, hydroxypropylcellulose, etc., and as disintegrants, carboxymethylcellulose, hydroxypropyl, etc. Cellulose or the like can be used, and as the lubricant, talc, stearic acid, stearate or the like can be used. In addition to these,
Furthermore, if necessary, wetting agents, suspension aids, sweetening agents, aromatic agents, coloring agents, preservatives and the like which are usually used for preparations can be added. In addition, after the preparation of tablets, granules and the like, the preparation (eg, film coating, sugar coating) can be performed by using other additive for the preparation. The coating material may also contain other additives such as colorants, flavoring agents and processing aids.

[0018]

EXAMPLES The present invention will be specifically described below with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. Reference Example N- (4,5-Dipidro-4-oxo-2-thiazolyl) guanidine hydrochloride 10 g of guanylthiourea and 10.9 g of ethyl chloroacetate
Was dissolved in 100 ml of ethanol and refluxed for 3 hours with stirring. After cooling, the precipitated crystals were filtered and washed with ethanol to obtain 11.5 g (yield 70%) of N- (4,5-dihydro-4-oxo-2-thiazolyl) guanidine hydrochloride. Melting point 240 ° C (decomposition)

Example 1 (Z) -N- (5-phenylmethylene-4,5-dihydro-4-oxo-2-thiazolyl) guanidine benzaldehyde 1.1 g ,. N- (4,5-dihydro-4-oxo-2-thiazolyl) guanidine hydrochloride 2 g
And 2.95 g of sodium acetate were dissolved in 10 ml of acetic acid, and the mixture was stirred at 80 ° C. for 1 hour. After cooling, the reaction solution was poured into ice water and stirred for 1 hour. The precipitated crystals are filtered, washed with water,
After drying, recrystallization from ethanol gave (Z) -N-
1.1 g of (5-phenylmethylene-4,5-dihydro-4-oxo-2-thiazolyl) guanidine (yield 43
%) Was obtained. Melting point 264 ° C. (decomposition) Elemental analysis C ₁₁ H ₁₀ N ₄ OS.0.8H ₂ O Calculated value C 50.68 H 4.48 N 2
1.49 Found C 50.72 H 4.53 N 2
1.61 ¹ H-NMR (DMSO-d ₆ ) 7.33 to 7.59
(M, 6H, ArH, olefin), 7.79-8.
80 (brs, 4H, -NH)

Then, the compounds of Examples 2 to 17 were obtained according to the methods of Reference Examples and Examples. Example 2 (Z) -N- {5- (4'-methylphenylmethylene)
-4,5-dihydro-4-oxo-2-thiazolyl} guanidine 58% yield mp two hundred seventy-nine to two hundred eighty-three ° C. (decomposition) Elemental analysis _{C 12 H 12 N 4 OS ·} 0.8H 2 O Calculated C 52.46 H 4.99 N 2
0.39 found C 52.32 H 4.71 N 2
0.25 ¹ H-NMR (DMSO-d ₆ ) 2.34 (s, 3
_{H, -CH 3), 7.29 (} d, 2H, J = 8.10H
z, ArH) 7.45 (d, 2H, J = 8.10 Hz,
ArH) 7.54 (s, 1H, olefin) 7.82
~ 8.64 (brs, 4H, -NH)

Example 3 (Z) -N- {5- (4'-isopropylphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine Yield 27% Melting point 268-271 ° C (decomposition) ) elemental analysis _{C l4 H 16 N 4 OS ·} 0.8H 2 O calculated C 55.54 H 5.86 N 1
8.50 Found C 55.34 H 5.72 N 1
8.46 ¹ H-NMR (DMSO-d ₆ ) 1.20 (s, 3
_{H, -CH 3), 1.23 (} s, 3H, -CH 3),
2.48~2.51 (m, 1H, -C H (C
_{H 3) 2), 7.34~7.54 (} m, 5H, ArH,
olefin, 7.60-8.68 (brs, 4H,
-NH)

Example 4 (Z) -N- {5- (4'-chlorophenylmethylene)
-4,5 Jibidoro oxo-2-thiazolyl} guanidine yield 61% mp two hundred and eighty-seven to two hundred ninety ° C. (decomposition) Elemental analysis _{C 11 H 9 N 4 OSC1 ·} 0.8H 2 O Calculated C 44.76 H 3.62 N 1
8.98 Found C 44.52 H 3.51 N 1
8.85 ¹ H-NMR (DMSO-d ₆ ) 7.53 to 7.60
(M, 5H, ArH, olefin), 7.76-8.
80 (brs, 4H, -NH)

Example 5 (Z) -N- {5- (4'-hydroxyphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine Yield 18% Melting point 273 ° C (decomposition) Element analysis _{C 11 H 10 N 4 O 2} S · 0.8H 2 O calculated C 47.75 H 4.23 N 2
0.24 found C 47.61 H 4.15 N 2
0.32 ¹ H-NMR (DMSO-d ₆ ) 6.86 to 6.91
(M, 2H, ArH), 7.38 to 7.43 (m, 2
H, ArH), 7.49 (s, 1H, olefin),
6.92-8.60 (brs, 4H, -NH), 9.9
2 (s, 1H, -OH)

Example 6 (Z) -N- {5- (4'-methoxyphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine Yield 50% Melting point 264-267 ° C (decomposition) ) elemental analysis _{C 12 H 12 N 4 O 2} S · 0.8H 2 O calculated C 49.58 H 4.72 N 1
9.27 Found C 49.30 H 4.54 N 1
9.25 ¹ H-NMR (DMSO-d ₆ ) 3.81 (s, 3)
_{H, -OCH 3), 7.06 (} d, 2H, J = 8.90
Hz, ArH), 7.52 (d, 2H, J = 8.90H
z, ArH), 7.54 (s, 1H, olefin),
7.63-8.82 (brs, 4H, -NH)

Example 7 (Z) -N- {5- (4'-acetoxyphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine Yield 29% Melting point 235 ° C (decomposition) Element analysis _{C 13 H 12 N 4 O 3} S · 0.8H 2 O calculated C 48.99 H 4.30 N 1
7.58 Found C 48.84 H 4.13 N 1
7.48 ¹ H-NMR 2.28 (s, 3H,-
OOCCH ₃ ), 7.26 (d, 2H, J = 8.64H
_{z, ArH), (DMSO-} d 6) 7.58
(S, 1H, olefin), 7.61 (d, 2H, J
= 8.64 Hz, ArH), 7.39 to 8.40 (br
s, 4H, -NH)

Example 8 (Z) -N- {5- (4'-methoxycarbonylphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine Yield 66% Melting point 282-285 ° C ( Decomposition) Elemental analysis C ₁₃ H ₁₂ N ₄ O ₃ S.0.8H ₂ O Calculated value C 48.99 H 4.30 N 1
7.58 Found C 48.75 H 3.22 N 1
_{^{7.56 1 H-NMR (DMSO-}} d 6) 3.87 (s, 3
_{H, -OCH 3), 7.61 (} s, 1H, olefi
n), 7.69 (d, 2H, J = 8.37Hz, Ar
H), 8.04 (d, 2H, J = 8.37Hz, Ar
H), 7.25 to 8.52 (brs, 4H, -NH)

Example 9 (Z) -N- {5- [4 '-(E) -ethoxycarbonylpropenylphenylmethylene] -4,5-dihydro-
4-oxo-2-thiazolyl} guanidine Yield 35% Melting point 255 ° C (decomposition) Elemental analysis C ₁₇ H ₁₈ N ₄ O ₃ S.0.8H ₂ O Calculated value C 54.77 H 5.30 N 1
5.03 measured value C 54.50 H 5.12 N 1
4.91 ¹ H-NMR (DMSO-d ₆ ) 1.28 (t, 3
H. _{J = 7.02Hz, -OCH 2 CH 3} ), 2.09
_{(S, 3H, -CH 3)} , 4.22 (q, 2H, J =
_{7.02Hz, -O CH 2 CH 3)} , 7.57~7.6
5 (m, 6H, ArH, olefin), 7.26-
8.40 (brs, 4H, -NH)

Example 10 (Z) -N- {5- (3'-trifluoromethylphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine Yield 62% Melting point 248-251 ° C (decomposition) elemental analysis _{C 12 H 9 N 4 OSF 3} · 0.8H 2 O calculated C 43.85 H 3.25 N 1
7.04 measured value C 43.74 H 3.07 N 1
7.14 ¹ H-NMR (DMSO-d ₆ ) 7.66 (s, 1
H, olefin, 7.72 to 7.89 (m, 4H,
ArH), 7.15 to 8.60 (brs, 4H, -N
H)

Example 11 (Z) -N- {5- (2 ', 4'-dichlorophenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine Yield 70% Melting point 294-298 ° C (Decomposition) Elemental analysis C ₁₁ H ₈ N ₄ OSC1 ₂ · 0.8H ₂ O Calculated value C 40.09 H 2.94 N 1
6.99 Found C 40.26 H 2.82 N 1
6.84 ¹ H-NMR (DMSO-d ₆ ) 7.73 (s, 1
H, olefin, 7.55-7.63 (m, 3H,
ArH), 7.89-8.72 (brs, 4H, -N
H)

Example 12 (Z) -N- {5- (3 ', 4'-dihydroxyphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine Yield 32% Melting point> 300 ° C (Decomposition) Elemental analysis C ₁₁ H ₁₀ N ₄ O ₃ S.0.8H ₂ O Calculated value C 45.14 H 3.99 N 2
0.77 Found C 45.33 H 3.76 N 2
0.61 ¹ H-NMR (DMSO-d ₆ ) 6.82 to 6.99
(M, 3H, ArH), 7.40 (s, 1H, oref
in), 7.60 to 8.72 (brs, 4H, -N
H), 9.27 (brs, 2H, -OH)

Example 13 (Z) -N- {5- (4'-hydroxy-3'-methoxyphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine Yield 30% Melting point 277 ° C. (decomposition) elemental analysis _{C 12 H 12 N 4 O 3} S · 0.8H 2 O calculated C 49.31 H 4.14 N 1
9.17 Found C 49.25 H 4.09 N 1
9.23 ¹ H-NMR (DMSO-d ₆ ) 3.82 (s, 3
_{H, -OCH 3), 6.87~7.15 (} m, 3H, A
rH), 7.50 (s, 1H, olefin), 7.2
3 to 8.30 (brs, 4H, -NH), 9.50
(S, 1H, -OH)

Example 14 (Z) -N- {5- (3'-hydroxy-4'-methoxyphenylmethylene) -4,5-dipidro-4-oxo-2-thiazolyl} guanidine Yield 48% Melting point 263 ~277 ℃ (decomposition) elemental analysis _{C 12 H 12 N 4 O 3} S · 0.8H 2 O calculated C 49.31 H 4.14 N 1
9.17 Found C 49.57 H 4.34 N 1
9.04 ¹ H-NMR (DMSO-d ₆ ) 3.82 (s, 3
_{H, -OCH 3), 7.02 (} s, 3H, ArH),
7.44 (s, 1H, olefin), 7.70-8.
75 (brs, 4H, -NH), 9.18 (s, 1H,
-OH)

Example 15 (Z) -N- {5- (3 ', 4'-dimethoxyphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine Yield 42% Melting point 273-276 ° C. (decomposition) elemental analysis _{C 13 H 14 N 4 O 3} S · 0.8H 2 O calculated C 48.68 H 4.90 N 1
7.47 Found C 48.94 H 4.77 N 1
7.58 ¹ H-NMR (DMSO-d ₆ ) 3.21 (s, 3
_{H, -OCH 3), 3.81 (} s, 3H, -OC
_{H 3), 7.06~7.17 (m,} 3H, ArH),
7.54 (s, 1H, olefin), 7.64-8.
70 (brs, 4H, -NH)

Example 16 (Z) -N- {5- (3 ', 4'-methylenedioxyphenylmethylene) -4,5-dihydro-4-oxo-2
- thiazolyl} guanidine yield 41% mp two hundred and sixty-six to two hundred and seventy ° C. (decomposition) Elemental analysis _{C 12 H 10 N 4 O 3} S · 0.8H 2 O Calculated C 47.30 H 3.84 N 1
8.39 Found C 47.53 H 3.95 N 1
8.41 ¹ H-NMR (DMSO-d ₆ ) 1.91 (s, 2
_{H, -OCH 2 O -),} 6.09 (s, 1H, Ar
H), 7.02 to 7.13 (m, 2H, ArH), 7.
50 (s, 1H, olefin), 7.60 to 8.70
(Brs, 4H, -NH)

Example 17 (Z) -N- {5- (4'-acetoxy-3'-methoxyphenylmethylene] -4,5-dihydro-4-oxo-2-thiazolyl} guanidine Yield 21% Melting point 147 ° C. (decomposition) elemental analysis _{C 14 H 14 N 4 O 4} S · 0.8H 2 O calculated C 48.21 H 4.51 N 1
6.06 found C 48.10 H 4.42 N 1
5.91 ¹ H-NMR (DMSO-d ₆ ) 3.83 (s, 3
_{H, -OCH 3), 3.84 (} s, 3H, -OOCCH
₃ ), 6.55 to 7.72 (m, 4H, ArH, ole
fin), 7.32 to 8.50 (brs, 4H, -N
H)

Example 18 (Z) -N- {5- (4'-hydroxy-3'-methoxyphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine hydrochloride (Z)- A solution of 1 g of N- {5- (4'-hydroxy-3'-methoxyphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine in 100 ml of tetravidrofuran was treated with ethereal hydrogen chloride. .
After removing the solvent, by recrystallization from methanol,
0.95 g (yield 89%) of (Z) -N- {5- (4'-hydroxy-3'-methoxyphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine hydrochloride was obtained. Obtained. Melting point 246 ° C (decomposition) Elemental analysis C ₁₂ H ₁₂ N ₄ O ₃ S.HCl Calculated value C 43.84 H 3.99 N 1
7.04 found C 44.00 H 4.03 N 1
7.18 ¹ H-NMR (DMSO-d ₆ ) 3.83 (s.3)
_{H, -OCH 3), 6.99~7.21 (} m, 3H, A
rH), 7.74 (s, 1H, olefin), 8.6
9 (brs, 5H, -OH, -NH)

Thereafter, the compounds of Examples 19 and 20 were obtained in the same manner as in the method of Example 18. Example 19 (Z) -N- {5- (4'-hydroxy-3'-methoxyphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine methanesulfonate Yield 86% Melting point 169-172 ° C. (decomposition) Elemental analysis C ₁₂ H ₁₂ N ₄ O ₃ S.CH ₃ SO ₃ H Calculated value C 40.19 H 4.15 N 1
4.42 Found C 40.10 H 4.32 N 1
4.51 ¹ H-NMR (DMSO-d ₆ ) 3.80 (s.3)
_{H, -OCH 3), 6.95~7.21 (} m, 3H, A
rH), 7.74 (s, 1H, olefin), 8.4
9 (brs, 5H, -OH, -NH)

Example 20 (Z) -N- {5- (4'-hydroxy-3'-methoxyphenylmethylene) -4,5-dihydro-4-oxo-2-thiazolyl} guanidine sodium salt Yield 82% Melting point> 300 ° C. (decomposition) Elemental analysis C ₁₂ H ₁₂ N ₄ O ₃ S.Na Calculated value C 45.71 H 3.84 N 1
7.77 Found C 45.60 H 3.92 N 1
7.51 ¹ H-NMR (DMSO-d ₆ ) 3.65 (s.3)
_{H, -OCH 3), 6.23~6.87 (} m, 3H, Λ
rH), 7.36 (s, 1H, olefin), 7.7
6 (brs, 4H, -NH)

Next, pharmacological test examples and pharmacological data showing that the compound of the present invention has an effect on type I allergy and type IV allergy are shown.

Test Example 1 Experimental method (a) Compound 48 / 80-induced histamine release reaction test from rat peritoneal mast cells A peritoneal cell suspension was obtained from Wistar rats. After incubating the suspension at 37 ° C. for 4 minutes, a compound 48/80 solution was added to induce a reaction, and the amount of histamine released during the reaction for 10 minutes was measured. In addition,
Inventive compound was added to DMSO solution at 1 × 10 ⁻⁷ M or 1
It was dissolved so as to have a ^{concentration of} × 10 ^-6 M, and added 3 minutes before the reaction was initiated, to the peritoneal cell suspension. The inhibition rate (%) was calculated by the following calculation formula.

[0041]

[Equation 1]

Test Example 2 Experimental method (b) Antihistamine action Ha in Tyrode solution kept at 32 ° C
The ileum of an rtley type guinea pig was suspended and histamine (pure concentration 10 ⁻⁷ g / ml) was added to measure ileum contraction. The compound of the invention was added to the DMSO solution at 1 × 10 5.
Dissolve to ⁻⁶ M, 1 minute before the reaction
It was added to liquid de. The inhibition rate (%) was calculated by the following calculation formula.

[0043]

[Equation 2]

Test Example 3 Experimental method (c) Mouse mixed lymphocyte reaction Using mitomycin C-treated Balb / C mouse spleen cells and DBA2 mouse spleen cells, BrdU incorporation was measured by ELISA after 4 days of mixed culture. did. The compound of the invention was dissolved in a DMSO solution at 1 × 10 ⁻⁶ M or 3 × 10 ⁻⁶ M and added to the culture solution at the same time when the mixed culture was started. The inhibition rate (%) was calculated by the following calculation formula.

[0045]

(Equation 3)

Test Example 4 Experimental method (d) Mouse picryl chloride-induced delayed hypersensitivity reaction Picbyl chloride was subcutaneously administered to Balb / C mice for sensitization, and after 7 days, picryl chloride was applied to the auricles to react. Caused. After 24 hours, the thickness of the auricle was measured, and the thickness before the reaction was subtracted to obtain the expansion. The compound of the invention was suspended in 0.5% CMC-Na at 10 mg / kg and orally administered immediately before and 16 hours after the induction of the reaction.
The inhibition rate (%) was calculated by the following publishing formula.

[0047]

(Equation 4)

The results obtained by the above experimental methods (a) to (d) are shown in Table 1 below.

[0049]

[Table 1]

From these results, the compounds of the present invention
It was confirmed that it has a type II allergic reaction inhibitory action and a type IV allergic reaction inhibitory action (cellular immunity).

[0051]

The novel benzylidene derivative of the present invention is
Since it has an allergic reaction-suppressing action, particularly a type I allergic reaction-suppressing action and a type IV allergic reaction-suppressing action, it is useful in the pharmaceutical industry as a therapeutic agent for both immediate-type and delayed-type allergic diseases.

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Claims (3)

[Claims] 1. A compound of the general formula (I) (In the formula, R ¹ and R ² are each independently a hydrogen atom, a halogen atom, a lower alkyl group optionally substituted with a halogen atom, a lower alkoxy group, a hydroxyl group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group,
A lower alkoxycarbonylalkenyl group or a lower alkylene chain in which R ¹ and R ² together may be substituted with one or more oxygen atoms. ) A benzylidene derivative or a salt thereof represented by: 2. General formula (I): wherein R ¹ and R ² are each independently
Hydrogen atom, halogen atom, lower alkyl group optionally substituted by halogen atom, lower alkoxy group, hydroxyl group, lower alkoxycarbonyl group, lower alkylcarbonyloxy group, lower alkoxycarbonylalkenyl group, or
R ¹ and R ² together mean a lower alkylene chain optionally substituted by one or more oxygen atoms. ) An anti-allergic agent comprising a benzylidene derivative or a salt thereof. 3. A pharmaceutical composition comprising the benzylidene derivative according to claim 1 or a salt thereof.