JPS6242960A - Novel hydrazone derivative and drug containing same as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [A is 4-thienylidene, 4-oxanilidene, 1-methyl-4-piperidinylidene, cyclopentylidene, etc.; R<1> is (chlorosubstituted)phthalazinyl and R<2> is H or R<1> is chlorophenyl and R<2> is methyl]. EXAMPLE:1-[2-(4-Thienylidene)hydrazino]phthalazine. USE:An anti-inflammatory drug and an antiallergic. Useful as a drug for preventing and remedying various inflammatory diseases such as rheumatism, arthritis, etc., and allergic diseases such as asthma, etc. PREPARATION:A compound shown by the formula A=0 is reacted with a compound shown by the formula II in the absence of a solvent or in the presence of an inert solvent to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel hydrazone derivatives and anti-inflammatory and anti-allergic medicines containing at least one of them as an active ingredient.

More specifically, the present invention provides [wherein A is 4-thianylidene, 4-oxanilidene,
1-Methyl-4-pi is lysinylidene, cyclohexylidene, cyclohexylidene, cyclooctylidene, 1,5
-dimethyl-4-hexenylidene, -ethylprohylidene, 1-propylbutylidene, 1-methylthiomethyl-2-methylthioethylidene, 1-1-lifluoromethylbenzylidene, 3.5-) -t-butyl-4
-Hydroxybenzylidene, or 3,5-dihydroxybenzylidene group, R1 represents a phthalazinyl group, chloro-substituted phthalazinyl group or chlorophenyl group, and R2 represents d, a hydrogen atom when R1 is a phthalazinyl group or a chloro-substituted phthalazinyl group. Expressed ~,
When R1 is a chlorophenyl group, it represents a methyl group]
The present invention relates to a novel hydrazone derivative represented by the following formula, and an anti-inflammatory and anti-allergic drug characterized by containing at least one of these as an active ingredient.

The present invention will be explained in detail below, but first, the method for producing the compound according to the present invention will be described.
The compound represented by 1) is a compound represented by the general formula (rT) A = OfIT) (wherein A represents the same meaning as defined above) and the general formula (m) H2N-N-R' (m
) (wherein R1 and R2 have the same meanings as defined above.

) in the absence of a solvent or in the presence of an inert solvent.

This reaction is a conventional reaction used to synthesize hydrazone from an aldehyde or ketone compound and a hydrazine compound.

Examples of solvents used in this reaction include lower alcohols such as methanol, ethanol, pro, and Q-nol, and tJ4
t, hydrocarbon solvents such as benzene, toluene, etc., rosinated hydrocarbon solvents such as methylene chloride, chloroporm, 1,2-dichloroethane, carbon tetrachloride, etc., ether solvents such as ethyl ether, tetrahydrofuran, dioxane, dimethyl Examples include polar solvents such as formamide and dimethylacetamide. These solvents may be used alone or as a mixed solvent of two or more.

Although the target compound can be obtained at a temperature ranging from -10°C to ]OO'C, heating or cooling is usually not required and the reaction can be carried out satisfactorily at room temperature. In addition, as is generally known, the condensation reaction with inorganic acids such as hydrochloric acid and sulfuric acid, or methanesulfonic acid 1. The reaction can be promoted by adding an organic acid such as Qradluenesulfonic acid or acetic acid as a catalyst.

The compound represented by the general formula 〇) obtained here has 8
There are two types of isomers: isomer and diisomer.

The present inventors synthesized various new hydrazone compounds represented by formula (T) 1-1 and investigated their anti-inflammatory effect and release-inhibiting effect of a slow-reacting anaphylactic substance (SR8-A). , the hydrazone compound represented by the general formula (■) has an edema-suppressing effect in the carrageenan-induced footprint edema model, as shown in Table 1 below, and as shown in Table 2 below. As shown in Figures 1 to 1, it was found that the compound had no effect on suppressing the release of SRS-A caused by stimulation of the lungs of sensitized guinea pigs. The present invention (・) 2 is based on such knowledge 1. According to the present invention - IJ:
JL Compound 1 has anti-inflammatory and anti-allergic effects, such as rheumatoid arthritis, various inflammatory diseases such as arthropathy, and allergenic diseases such as asthma, for prevention and treatment. Jl was found to be useful as a medicine.

The hydrazone compound C11 represented by the general formula (1) is a new compound created by the present inventors, and of course, it is not known that these compounds have anti-inflammatory or anti-allergic effects, and such knowledge is , which was first obtained by the present inventors.

+'+fJ The compound of general formula (I) can be administered to mammals including humans, but generally it can be prepared in various pharmaceutically acceptable pharmaceutical compositions. As a second, it can be administered orally or parenterally.

For formulation, the compound of general formula (1) can be used in the form of a linguistically acceptable salt. ? c, 7
1-1 to T et al.'s compound, I'1? ) j alone, also 1.
<Nido 11, 6-1, a business group, [3, 711, and 71 compounds, 1, soil k, 14 other medicine activities, 14 [blended with ingredients, 7 may also be used.

In the form of 1, C1, 1 compound is added with suitable additives, such as lactose, Manny Soto, Tou F: o condensone, mil/isodenzone, crystal cell 1-
excipients such as cellulose u4f+, gum arabic, gelatin, disintegrants such as basil/isodenzone, carpogysimebrucell r1-sodium, etc.
1. Magnenium stearate melt? ”+'fσ'
By combining <i'i11, etc.; θ5 to 1/i'', tablets, powders, and drugs can be prepared.

Forms of parenteral administration include Vaseline, Q-Loughin, Zolasubux, Salmon ointment, Hydrophilic ointment, ¥1
It can also be combined with water vaseline, hydrophilic plastibase, etc. to make a soft □I'1.f, or mixed with an emulsion base or a water-soluble base to form a suppository.

Dose 8 dose fd: h+ = age, symptoms, treatment effect, 1 g! j
Although it varies depending on the method and administration period, it is usually 0.5 to 1.5 mg/kg for oral [-] or rectal administration.
It is best to administer the drug once to three times a day within the range of 1 to 3 times per day.

The compounds according to the present invention will be described in detail below, with examples and biological activity data of the obtained compounds, but the present invention is not limited by the examples. .

In the description of TLC in the examples, the type of solvent is indicated by a symbol in parentheses.
This shows the Rf value of F254).

Regarding TLC, each description of A-13 described and the type of solvent are as follows.

A:],]2--dichloroethane:ethyl acetate:1,2-')chloroethane=1:4(
Volume ratio) C; rr;
] °8(〃 )J); rr:
1. ethylamine] (1:1.(/')
1) 0 when measured by liquid film method
Any absorption between 0 and 1700z+-1? - Kui τ - Dimensions. , Example 1 1 (2(・1-Janilidene・)hydrazino]phthalantane■-hydrazinophthalani) , / 320 mq (2
) and 1-oxitubuan 21F1 mg (2 m
30me of Methanol L was added to M), and after stirring overnight, the methanol in the reaction mixture was concentrated under reduced pressure and 7/4-
Afterwards, pick up the precipitated crystals. 1-[2 of pale yellow ligated crystals
(・1-dyanylide]/)hydrazino]phthalanone 23
2 rnq was obtained.

Yield Old (related) Melting point: 14d, 8-1115, 1°C (methanol) Ma, ss Subecle: m/e = 258.
230.225.197.184゜Example 2 1-chloror+-4-42-(4-thiagoichisuden)hydrazinophthalazine-]O- 1-chloro-4-hydrazinophthalazine and 4- 1-chloro-4,-(2-(4-thianylidene)hydrazinocyphthalazine was obtained by the method according to Example 1 using oxothiane.

Yield: 68 Melting point: 195.3-195.5°C (decomposition) (methanol) Mass distillation m/e=294.292
．． 266.264.233.231.220.218゜Example 3 1-chloro-4-(2-cyclohexylidene)hydrazinophthalazine L Example using 1-chloro-4-hydrazinophthalazine and cyclohexanone 1-chloro-4-(2-cyclohexylidene)hydrazinophthalazine was obtained by the method according to 1.

Yield, 56% Melting point: 1.20.2-121.0 (decomposition) Mass
Svectorni m/e=276.274.233.231
．． 220.228゜Example 4 ]-chloro-4-42-(1-methylthiomethyl-2-
Methylthioethylidene) hydrazinocyphthalazine C/- 1-chloro-4-(2-() -] Methylthiomethyl-2-methylthioethylidenehydrazinocyphthalazine was obtained.

Yield: 63 Melting point: 94. ．． 8~96.1°C Mass spectrum/l/: m/e = 328.3
26.267.265゜Example 5 1-chloro-4-(2-(4-octylidene)hydrazinocyphthalazine L Based on Example 1 using 1-chloro-4-hydrazinophthalazine and 4-oxooxane 1-chloro-4-C2-(4-octylidene)hydrazinocyphthalazine was obtained by the method described above.

Yield: 60% Melting point: 144.8-145.3°C (decomposition) Mass
Suburitoru: m/e=278.276.220.2
18゜Example 6 1-chloro-4-(2-cyclooctylidene)hydrazinophthalazine 1-chloro-4-(2-cyclooctylidene)hydrazinophthalazine was prepared by a method based on Example 1 using 1-chloro-4-hydrazinophthalazine and cyclooctanone. -4-(2-cyclooctylidene)hydrazinophthalazine was obtained.

Yield Near 9T Melting point: 128.7-129°C (ethanol) Mas
s spectrum two m/θ-304, 302, 233, 23
1,221,220,219,218° Example 7 1-Chloro-4,-(2-cyclotakutinyritene)hydrazinophthalazine t 1-chloro-4-hydrazinophthalazine 410-]. 4
-mg (2,1mM) and Schiff (r-'e, 7-tanone) 82 mq (21mM) in 30 ml methanol
was added and stirred for 4 hours. After that, methanol in the reaction mixture was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wako Gel C-200). 1-
Chloro-4(2-cyclopentylidene)hydrazinophthalazine 3587I''/ was obtained.

Yield 66 Polymer melting point: 138.1 °C (decomposition) to 1.37.4 (1,
, 2-dichloroethane-ethanol) Ma 8 (3 sd ctor: m/e=262.260
．． 2; U3.2: Moon, 225° Example 8 1-Chloro-4-(2-(1,5-:)methyl-4-hexenylidene)hydrasifthalasif I ]-chloro-4-hydrazinophtha radin and 6-methyl-
The oily substance 1-chloron-4-[2-(1,5-
U methino (-71-hexenylidene) hydrasiftarasif! I was.

Yield: 86 Ma, ss, + (vector: m/e -: (old, 3
02.289.287.22o1218゜Example S) 1,-[2(3,4-dihydroxybenzylidene)hydrazinocyphthalazine]-According to Example 1 using hydrazinophthalazine and 3,4 dihydroxybenzaldehyde 1- depending on the method
[2-(3,4-dihydroxybenzylidene) hydradanophthalazine.

Yield °76 °C Melting point: 265.8 °C (decomposition) Mass spectrum: m/e-zso, 279.17
1゜Example 1. (1 1-[2-(3,5-di-1-butyl-4hydroxybenzylidene]hydrazino]phthalazine 1-hydrasifthalasif 403 mLj (2,5mM) and 3,5
-di-t-butyl-4-hydroxybenzaldehyde 4
907q (2.5mM) was added with 40ml of methanol, and after stirring overnight, the methanol was distilled off under reduced pressure, and the residue was recrystallized with ethanol-hexane.
-(2-(3,5-di-t-phthyl-4-hydroxybenzylidene)hydrazinocyphthalazine 520 mg was obtained.

Yield: 52 Melting point: 240-240.3°C MaSs spectrum: m/e = 377.376
．． 375.36], 172° Example 11 ■=Zicrow 4. - (2-(1-)lifluoromethylbenzylidene)hydrazinocyphthalazine C/- 1-chloro-4-hydrazinophthalazine 201 mg (
1mM) and α, α, α-trinoloroacetofe/
71.83mji+ (1mM) contains metal/-21)
After adding 20 mg of methanesulfonic acid and heating under reflux for 22 hours, methanol was concentrated, and the residue was mixed with 30 mg of water.
1 was added thereto, the mixture was made neutral with a saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate. The extract is treated with sodium sulfate.
After removing a large amount of sodium sulfate, ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel C-200) to obtain yellow crystals of 1-chloro-4-(2- 72 mg of (1-1-lifluoromethylbenzylidene)hydra)nokophthalazine was obtained.

Yield: 20% Melting point = 182-183°C (1,2-dichloroethane-
Hexane) Mass, Z, Actor; m/e=352.350
．． 283.281゜Example 12 Thian-4-one methyl(4-chlorophenyl)hydrazone 1-methyl-1-(4-chlorophenyl)hydrazine 2
30 mg (1,5mM) and 4-oxothiane 152
my (1,5mM) in 1,2-dichloroethane 1
After stirring for 24 hours, 1.2-') chloroethane was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wako Gel C-200) to obtain an oily substance, thian-4-one methyl (4 -Chlorophenyl) hydrazone 226"J t obtained.

Yield: 59% TLC: Rf = 0.25 (A) Mass speckle: m/e = 256.254.143.1
42.141.140゜IR Slot: 1640.1590.1485.12
65.1090.940 cm-1゜Example 13 Oxan-4-onemethyl(4-chlorophenyl)hydrazone Method according to Example 12 using 1-methyl-1,-(4-chlorophenyl)hydrazine and 4-oxooxane An oily substance, oxan-4-onemethyl(4-chlorophenyl)hydrazone, was obtained.

Yield, 74th section TLC: Rf = 0.21- (c) Mass '2 l-le: m/e = 240.238.144
．． 143.142.1 old, 11].

Ding R Suskutorni ] 635, 1590. 1490,
J465, 1450.1385.1280.1225
．． 1175.1090.1005.9950.

Example 14 1-Methyl-4-piperidoneMethyl(4-chlorophenyl)hydrazone H3 1-Methyl-1-(,110lophenyl)hydrazine and 1-methyl-4-pi were prepared by the method according to Example 12 using lydone. An oily product of 1-methyl-4-piperidonemethyl(4-chlorophenyl)hydrazone was obtained.

Yield near 1% TLC: Rf=' 0.19 (D)Mass spectrum 2m/θ-253,251,193,143,1
42,141, ] 40゜Engine R S Takutor: 1635.1590, 1-490.1
375.1270°1135.1.090 cm-'.

Example 15 = 21- 4-hebutanone methyl(4,-1)'lorophenyl)hydrazone 1,- By the method based on Example 12 using methyl-1-(4,-chlorophenyl)hydrazine and 4-hezotanone Oily substance 4~heptanomef /I/ (4-
chlorophenyl) hydrazone.

Yield: 60% TLC: Rf = 0.54 (A) Mass,
ect/l/: m/e=254.252.144.1
43.142.141゜IR System: 1620.1590, ]490.14
70.1450.1300, ], 1. OOcm-1° Example 16 cyclooctanonemethyl(4-chlorophenyl)hydrazone 1-methyl-1,-(4,-ri[Golov J-Nino 1-)
By using hydrazine and cyclooctane in accordance with the method of Example 12, an oily product of Schiff [+octanone methinot] was prepared.
-(4-' chlorophenyl b)+: F razone 4-' obtained.

Yield 51V TLC: Rf = 0.52 (C) lAa, ss ξ) /l/: m/e = 266.264.
14・1.143.1・12.141°IR somictor 1.6], 0. ], I590I
490, I480.1465.1450.1. /1.4
0.1305, ], ], 0(1cm”.

Example 17 3-wave nonmethyl (1-chlorophenyl) hydrazine and I
1 3-gtanonemethyl(1-chlorophenyl)hydrazone of oily substance 1 was prepared by the 17/zeta force method according to Example 12 using 10 tons of pentanone. 0.37(A) hia,ss spectrum/lz:111/θ-226,
2211, 154, 157, 143, 142, 111]
, 1 old).

Ii (spectrum 1630.1590.1) (),
], 460,1305.11, C1 (1 cm'.

Example 18 Cyclo l\xanoneme J le (4-ri l'7 rj fue;
-l) hydrazone 1-methyl-(4-ly(10-soenyl)hydrazine and cyclopentanone were used in accordance with Example 12 to obtain an oily product of Schiff
Fuconi:-ru) Hydrazono obtained.

Yield: 65% TLC: Rf20.60 (B) Mass, 7
．． Vector: m/θ2 238.236.1112.1 Old.

IF spectrum: 1630. [590,]I49
01.44.5.3305.1180.1]05.10
95 az.

Example 19 Cyclopentanone methyl (4-chlorophenyl) hydrazone], an oily product of cyclopentanone methyl ( 4-chlorophenyl)hydrazino was obtained.

Yield: 81 TLC: Rf = 0.4.5 (Mass spectrum: rule = 224.22
2.142.1 Old, I40° IR spectrum: 164.
011590.1490.1,320,1,305.1
090 on-1,, Example 20 - Chloro, 1. - [2-(], -:]lI-chillino■co1lidenehydrazinophthalazine1-ri[,I Tll]-- in Example 1 using -1-hydrazinophthalazine and cyclo-ξnthanone My base
TJ rho 4-[2-(1-ethinotozolo-1-lidene)hydrazinophthalazine was obtained by the method described above. .

Yield, 69 TLC: Rf = 0.76 (B) Mass Ritter III/θ = 264.262.235.233
,]78゜Example 21 After thoroughly mixing 1-chloro-4(2-7chlorohexylidene)hydrazinophthalazine 57.5f and microcrystalline senorose 307, l. 207
The mixture was further mixed and passed through a 5-bow sieve, and then mixed with 2.57 g of sodium carboxymethylcellulose and 57 g. of magnesium stearate to form capsules.

Example 22 ■-Chloro 4-- A mixture of 507 g of (2-(4-thianylidene)hydrazinophthalazine), 157 crystalline cellulose, 14.5 S' of lactose, and 187 g of dried potato starch was mixed with 12 g of water and 2 g of hydroxyzorobyl cellulose. After kneading, the mixture was extruded through a 16-mesh mesh, dried at 40°C, and granulated.

Next, this was mixed uniformly with 0.57 mg of magnesium stearate, and tableted by a conventional method to obtain 1 in 2001 ng of one tablet.
Tablets containing 007ff@I-rioo-4-[2(4-thianylidene)hydrazinophthalazine.

The novel compound represented by the general formula (I) according to the present invention has anti-inflammatory and anti-allergic effects, but the anti-inflammatory effects were found to be significantly anti-allergic in a carrageenan footprint edema suppression test. is 5R8-
Confirmed by A release inhibition test.

The following is the carrageenan footprint edema suppressing effect, and SR8.
- Tests related to the inhibitory effect on A release and examples of acute toxicity tests are listed.

■) Carrageenin foot dance: edema suppression effect experiment was conducted on male Wistar rats (body weight 110-150).
y) with 6 animals per group. The test compound was suspended in a 5% gum arabic aqueous solution, and 0.5
It was administered orally at the rate of me/100 f body weight. After 1 hour, apply 1 carrageenan subcutaneously to one hind leg.
I received a me injection and developed inflammation. 3 hours after onset of inflammation, hind legs 1U! :
The edema volume was measured, and the inhibition rate was calculated from the following formula.

Table 1 Carrageenin footprint edema inhibition rate Dosage, Ibuzolofen, Test compound 1.2.5.8.
12.13 was orally administered at 25 μ/kg, test compound 17.
18.19 is 11001n/kg oral administration a) Significant difference test (-y, P(0,05,44p<o,
ol) 2) Effect of inhibiting BRB-A release Anti-ovalbumin rabbit serum was administered to the ear veins of guinea pigs to sensitize them. After 24 hours, they were sacrificed by exsanguination, and their lungs were removed and cut into pieces of 2M or less.

250 mf/lung section with 2.375 ml of Tyrode's solution
Add 5 μt of the test compound at the desired concentration and heat at 37°.
After 15 min incubation at C, 10 Tq
/ ml of ovalbumin OA was added, and after further incubation at the same temperature for 10 minutes, the reaction was immediately cooled on ice to stop the reaction, and gauze filtration was performed to obtain a white filtrate. The inhibition rate of 5R8-A release in this F solution was determined by measuring ileal contraction by the Magnus method in the presence of atropine and pyrilamine.
Calculated. In addition, in this test, it was confirmed that ileal contraction was suppressed by a test using FPL 557]2, a specific antagonist of 5R8-A.

Table 2 SR8-A release inhibition rate 3) Acute toxicity d-cl Using N strain male mice, 1-chloro-4-[
2-(4-thianylidene)hydrazinophthalazine 5
% gum arabic aqueous solution, and this was
After oral administration at a dose of 7 kg, no deaths were observed when observed 168 hours later.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, A is 4-thianylidene, 4-oxanylidene,
1-Methyl-4-piperidinylidene, cyclopentylidene, cyclohexylidene, cyclooctylidene, 1,5
-dimethyl-4-hexenylidene, 1-ethyl-propylidene, 1-propylbutylidene, 1-methylthiomethyl-2-methylthioethylidene, 1-trifluoromethylbenzylidene, 3,5-di-t-butyl-4-hydroxybenzylidene or 3,5-dihydroxybenzylidene group, R^1 represents a phthalazinyl group, chloro-substituted phthalazinyl group, or chlorophenyl group, and R^2 is a hydrogen atom when R^1 is a phthalazinyl group or a chloro-substituted phthalazinyl group. and when R^1 is a chlorophenyl group, it represents a methyl group]. 2. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, A is 4-thianylidene, 4-oxanylidene,
1-Methyl-4-piperidinylidene, cyclopentylidene, cyclohexylidene, cyclooctylidene, 1,5
-dimethyl-4-hexenylidene, 1-ethyl-propylidene, 1-propylbutylidene, 1-methylthiomethyl-2-methylthioethylidene, 1-trifluoromethylbenzylidene, 3,5-di-t-butyl-4-hydroxybenzylidene or 3,5-dihydroxybenzylidene group, R^1 represents a phthalazinyl group, chloro-substituted phthalazinyl group, or chlorophenyl group, and R^2 is a hydrogen atom when R^1 is a phthalazinyl group or a chloro-substituted phthalazinyl group. and when R^1 is a chlorophenyl group, it represents a methyl group.