JPH032181A - Tetrazole derivative and antiallergic agent - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> represents H, (aryl- substituted) lower alkoxycarbonyl or (aryl-substituted) lower alkyl; R<2> represents aryl or (aryl-substituted) lower alkyl]. EXAMPLE:1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)- N-(1H- tetrazol-5-yl)-1,8-naphthylidine-3-carboxamide. USE:An antiallergic agent. PREPARATION:An enoxacin compound expressed by formula II is reacted with a compound expressed by the formula R<1>-X (X represents halogen) to form a carboxylic acid compound expressed by formula III. This compound or a reactive derivative in the carboxyl group thereof is reacted with an aminotetrazole compound expressed by formula IV or a reactive derivative at the amino group thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a tetrazole derivative obtained by modifying the chemical structure of enoxacin, which has antiallergic activity, and an antiallergic agent containing the derivative as an active ingredient.

[Prior art and problems to be solved by the invention] Disodium cromoglycate (DSCG), chlorpheniramine ma-leate, tranilast, etc. are known as compounds having anti-allergic activity, and are used as medicines. has been done. However, these are not satisfactory in terms of side effects, oral absorption, and efficacy.Therefore, it has been desired to develop an antiallergic agent that does not have the above-mentioned drawbacks.

[Means for Solving the Problem] As a result of extensive research into anti-allergic agents, the inventors discovered that enoxacin, which is known as an anti-bacterial agent, also has anti-allergic effects, and that it can be used as a starting material. The inventors have discovered that the derivative has even higher anti-allergic activity even when administered orally, and has confirmed that it has fewer side effects.The present invention has been completed as a result of various studies on the derivative.

[Structure of the Invention] The present invention provides an enoxacin compound represented by the formula:
(wherein R1 is H, a lower alkoxycarbonyl group optionally substituted with an aryl group or a lower alkyl group optionally substituted with an aryl group) is reacted with a halogen compound represented by and R2 represents an aryl group or a lower alkyl group optionally substituted with an aryl group) or salts thereof. The above compound is produced by reacting an aminotetrazole compound of the formula or a reactive derivative thereof at the amino group with the carboxylic acid compound (rv) or a reactive derivative at the carboxyl group thereof. The present invention also provides an anti-allergic disease treatment agent containing the tetrazole derivative shown in (1) or a salt thereof as an active ingredient.

[Description of the Invention] The terms used in this specification are explained as follows.

The term "lower" includes groups having 1 to 6 carbon atoms, unless otherwise specified.

The term "lower alkyl" refers to straight chain or branched saturated hydrocarbon residues having 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms, more preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl,
Isopropyl, butyl.

Includes isobutyl, t-butyl, pentyl and hexyl.

The IH-tetrazolyl group represented by the formula is in a tautomeric relationship with the 2H-tetrazolyl group represented by the formula. Therefore, the above two groups are substantially the same, and isomers containing the above groups are considered to be the same compound. Therefore,
All isomers containing the above group in the molecule are included within the scope of the present invention, but in this specification, for convenience of description, only the expression "rlH-tetrazolyl" is used.

The term "salts" includes pharmaceutically acceptable non-toxic salts. These include metal salts such as alkali metal salts (e.g. sodium salts, potassium salts, etc.) and alkaline earth metal salts (e.g. calcium salts, magnesium salts, etc.) and inorganic bases such as ammonium salts and amine salts (e.g. trimethylamine salts, triethylamine salt, brocaine salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, N-methylglucamine salt, monoethanolamine salt, jetanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt, organic base salts such as phenethylbenzylamine salts, basic amino acid salts (eg, arginine salts, lysine salts, etc.). These salts can be prepared in conventional manner, for example from the corresponding acids and bases or by salt exchange.

Among enoxacin compounds (II) as starting materials, enoxacin in which R2 is ethyl, for example, is a known substance and can be produced by the method described in Japanese Patent Publication No. 57-10109.

The method for producing the tetrazole derivative of the present invention represented by formula (1) will be described in detail as follows.

(In the formula, RI, R2 and X have the same meanings as above.) Compound (IV) is produced by reacting enoxacin compound (II) with a halogen compound (III) according to a known method. A compound of formula (I) is then prepared by reacting a compound of formula (tV) or a reactive derivative thereof at the carboxyl group with an aminotetrazole compound (V) or a reactive derivative thereof at the amino group.

For compounds of formula (IV), reactive derivatives at their carboxyl groups include acid halides, acid anhydrides, active esters and active amides. Among these, acid chloride is frequently used as the acid halide. Acid anhydrides include symmetrical acid anhydrides and mixed acid anhydrides;
The latter includes, for example, dialkyl phosphoric acid mixed acid anhydrides, dialkyl phosphorous acid mixed acid anhydrides, alkyl carbonic acid mixed acid anhydrides,
Included are aliphatic carboxylic acids (eg, pivalic acid, trichloroacetic acid, etc.), mixed acid anhydrides, and the like. As the active ester, methyl ester, ethyl ester, cyanomethyl ester, p-nitrophenyl ester, ester with N-hydroxysuccinimide, etc. are used. As the active amide, amides with imidazole, dimethylimidazole, triazole, etc. are used.

Regarding the compound of formula (V), reactive derivatives at the amino group include Schiff bases with aldehydes (e.g., acetaldehyde, isopentanal, benzaldehyde, etc.), reaction products with silyl compounds (e.g., trimethylsilyl chloride, trimethylsilylacetamide, etc.) A reaction product with a phosphorus compound (for example, phosphorus trichloride, phosphorus oxychloride, etc.) is used.

When the compound of formula (IV) is used in the form of the free carboxylic acid or its salt, it is advantageous to carry out the reaction in the presence of a condensing agent. 5OC12, 5O2C as a condensing agent
12, PCh, PCl5. POCIs, PBr
=, or N,N'-dicyclohexylcarbodiimide (DCC), N-cyclohexyl-N
o-morpholinoethylcarbodiimide, N,N'-diisopropylcarbodiimide, CIC02C1 (3, Cl
0(hCJs, BrC(hCJ, (fJIscO
) io, N-ethylbenzisoxazolium salt, 2-chloro-1-methylpyridium salt, N,N'-carbonyldiimidazole (CDI), etc. are used.

This reaction is usually carried out in an inert solvent. As the inert solvent, dioxane, methylene chloride, chloroform, ether, tetrahydrofuran (THF), acetone, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, acetonitrile, benzene, toluene, xylene, etc. are used.

An example of a preferred reaction method is as follows.

First, carboxylic acid compound (IV) or its salt is dissolved in an inert solvent, and a condensing agent is added thereto. If the condensing agent is a halogenating agent, the addition is advantageously carried out under water cooling;
In the case of other condensing agents, the reaction can be carried out either under water cooling or without water cooling (that is, at room temperature). The reaction mixture is kept at room temperature or under heating, such as boiling temperature, for 0.5 to 3 hours.

The active form of the acid thus produced! React with aminotetrazole compound (V) with or without LiLi. This reaction is carried out in an inert solvent, if necessary in the presence of a base, to produce the target compound (1). The base may be any base that can capture hydrogen halide, such as tertiary amines (triethylamine, dimethylaniline, pyridine, etc.). aminotetrazole compound (
V) can also serve as a base. When the reaction is carried out at room temperature to boiling point temperature for 0.5 to 5 hours, the target substance can be obtained in good yield.

Since the tetrazole conductor of the formula (R) has excellent antiallergic activity, it is useful as a medicine for treating (preventing, alleviating, and treating allergic diseases).

When administered for prophylactic and/or therapeutic purposes,
The compound (1) of this invention as an active ingredient is mixed with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral administration or external use to prepare a conventional pharmaceutical preparation. It can be administered in the form of Such formulations can be solid, such as capsules, tablets, dragees, ointments, suppositories, or liquid, such as solutions, suspensions, and emulsions.

If necessary, auxiliaries, stabilizers, wetting agents, emulsifiers, buffers and other conventional additives can also be added to the above formulations.

The dosage for the above uses will vary depending on the age of the patient, the condition, the compound used, the method of administration and the treatment desired. However, generally about 0.1 to 1000 (preferably 0.5 to 1000)
Satisfactory results are obtained when a dose of 1.sob) mg/kg is administered, preferably in divided doses 2 to 4 times a day or in the form of a depot preparation.

[Examples] The present invention will be described below with reference to Reference Examples, Examples, Formulation Examples, and Test Examples, but the technical scope of the present invention is not limited thereto.

Reference Example 1 5 g (14.4 mmol) of 1-ethyl-6-fluoro-14-dihydro-enoxacin was added to 175 ml of dry DMF.
1.73 g (17.3 mmol) of K HCOs and 1.08 ml (17.3 mmol) of CH3I were added sequentially, and the mixture was reacted at 50° C. for 3.5 hours.

After water was added to the reaction mixture to dissolve it, it was extracted four times with chloroform. The organic layer was washed twice with a saturated NaCl aqueous solution, dried using anhydrous Na25O4, and after distilling off the solvent, to remove DMF, ether was added under cooling with water for crystallization, followed by washing. The obtained solid was collected by suction filtration and dried to give 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl).
-1,8-naphthyridine-3-carboxylic acid white crystals 8
65 mg (yield 18%) was obtained.

mp282-28.8°C (decomposition) IR (KB', cm-'); 1730maX Enoxacin 1. Dry Og (2,88 mmol) D
Suspended in 35 ml of MF, then 345.4 ml of KHCOs
g (3.45 mmol), C2H510,279m
1 (3.45 mmol) were added one after another and reacted at room temperature for 4 hours.

Approximately 150 ml of water was added to the reaction mixture to dissolve it, and the organic layer extracted with chloroform (2001111) was diluted with saturated Na
After washing with C1 aqueous solution, it was dried using anhydrous Na and SO2. After evaporating the solvent (leaving a small amount of DMF), under water cooling,
After about 12,011 g of ether was added and stirred for a while, the precipitated solid was collected by suction filtration. The filtrate was washed with ether and dried to give 1-ethyl-6-fluoro-1,4-
237.6 mg (yield 24%) of white crystals of dihydro-4-year-old xo-7-(4-ethyl-1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid were obtained.

mp184~187℃ JR (u", cm-'); 1740.1720
(shoulder) ax't NMR (CDCh+ DMSO-ds, δ) 8.7
Ns, IH, naphthyridine-H) 7.95 (dd,
l) l, naphthyridine-formerly 4.70-4.20 (I
n, 2H,-CthCl(,) 4.13-3.70
(m, 4H,7CLLCHs, piperagiline
-Hn 2.80-2.23 (m, 6H, piperazine-H
) 1.67-0.93 (1, 8) 1. -CH2CH3
X2') TLC, Rf value~OJI (II:H(:I
s: CthOl+ = 9:1) 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-+, S
-naphthyridine-3-carboxylic acid 150 mg (0,
45 mmol) and N,N'-carbonylshiimidazo)L, (CD I > toLtmg (0, lower mmol) were dissolved in 10 ml of dry DMF by heating to 130 t, and reacted at 130°C for 1 hour. Under the same conditions. Below,
5-aminotetrazole 114.5 mg (1,35
Add 1 ml of a dry DMF solution of 1 mmol), lower the temperature to 70 t, and react for 3 hours. After distilling off the solvent from the reaction mixture, add chloroform to the residue, heat it a little, and collect the insoluble matter by suction filtration. Unreacted 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-1,8-naphthyridine-3
-Carboxylic acid removed. The filtrate was dissolved in methanol under heating and allowed to stand until the temperature returned to room temperature. When the precipitated solid was collected by suction filtration and dried, 1-ethyl-6-fluoro-1,4
-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-N-(I H-tetrazol-5-yl)
40.7 mg (yield 23%) of pale yellow crystals of -1,a-naphthyridine-3-carboxamide was obtained.

mp 2F 5-278℃ (decomposition) MS (lIl/Z); 401 (M"),
44 (BP) TLCi Rf value 40.07 (TLC plate: Merck Art5735 Ethanol: Ethyl acetate: Triethylamine Milo:
4: 3) 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-1,8
-naphthyridine-3-carboxylic acid 200 rng (0
, 57 mmol) and CD I 139.6 mg (0,8
6 mmol) in 7 ml of dry DMF and heated to 70°C.
The reaction was carried out for 1 hour. Under the same conditions, 146.5 mg (1,72 mmol) of 5-aminotetrazole was dried in D.
2 ml of MF solution was added and reacted at 70°C for 3.5 hours.

After distilling off the solvent from the reaction mixture, chloroform was added to the residue, and the mixture was heated a little and the insoluble materials were collected by suction filtration. The filtrate was dissolved in methanol under heating, and then left to stand until the temperature returned to room temperature. The precipitated solid was collected by suction filtration and dried to give 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-
7-(4-ethyl-1-piperazinyl)-N-(IH-
Tetrazol-5-yl)-1,8-naphthyridine-3
- Carboxamide pale yellow solid 94.7 mg (yield 4
0%) was obtained.

mp294-296℃ (decomposition) MS (m/z); 415 (M''), 84 (
BP) TLC, Rf value 0.18 (TLC plate, Mercktriethylamin 25.0On+g 49.00mg 3B, OQmg 5.00mg 1.00mg Art5735 manufactured by Ethanol: Ethyl acetate: N=6:4:3) Formulation example 1 (1) Target substance of Example 2 (2) Lactose crystalline cellulose corn starch (3) Hydroxypropyl cellulose (4) ECG505 (carboxymethyl cellulose calcium) (5) Magnesium stearate (6) Talc 2.00 mg 1.00 mg 1. 00mg Total 120mg (1) + (2) was kneaded with a 5% aqueous solution of (3), dried, sized, (4), (5), and (6) were added and mixed, and tableted at 120o+g ( φ7 mm) to make tablets.

Formulation example 2 (1) Target substance of Example 2 50.00 mg
(2) Lactose 124.50m
g Cornstarch 2Q, OOmg (3
) Hydroxypropyl cellulose 2. OOmg(4)
Light anhydrous silicic acid 1.50mg (5)
Magnesium stearate 2.00mg total 20
0 mg (1) + (2) + (3) was kneaded with a 5% aqueous solution of (4), then dried and sized. Furthermore, (5) is added and mixed, and 200 mg is filled into No. 3 hard capsules.

Test Example 1 (Experimental Materials and Methods) Animals Used: Male Wistar rats (7 weeks old) were purchased from the Shizuoka Experimental Animal Agricultural Cooperative, and used for the experiment after one week of preliminary breeding.

Preparation of antiserum: Journal of Immunology 106.1002-10
11 (1971) was followed.

An extract of Ascaris soum (^5carfs 5uulQ) was dinitrophenylated and administered together with (DNP-As) killed Bordetella pertussis to four subcutaneous sites in the paws of male Quister rats for additional sensitization. Three days later, blood was collected, serum was separated, and used as DNP-As antiserum. The titer of the antiserum was determined by rat 48-hour PCA and was found to be 1:200.
Met.

48-hour PCA: A 35-fold diluted solution of anti-DNP-As serum was administered intradermally to two sites on the right side of the rat's back, which had been shaved in advance, for sensitization. After 48 hours, 1 ml of a 0.5% Evans blue saline solution containing 500 μg of DNP-As was administered into the tail vein to induce a reaction. After 30 minutes, the head was decapitated, the dorsal skin was peeled off, and 2 yM of sensitized area and 1 control area were cut out.
978) (7) The leaching amount of Evans Blue, which was used as a reaction index, was quantified according to the method. That is, IN-potassium hydroxide aqueous solution 1a11 was added to the cut skin at 37°C.
Incubate for 16 hours to lyse the skin tissue. 0
．． After adding and mixing 9 ml of a 6N-phosphoric acid-acetone (5:13) mixture, the mixture was centrifuged at 3000 rpm for 15 minutes, and the absorbance of the supernatant at 620 nm was measured to quantify leached Evans Blue. The compound (1) of the present invention was suspended in 0.5% tragacanth and orally administered 1 hour before the reaction induction.

The results of oral administration are shown in Table 1. These results show that the compound of the present invention clearly suppresses allergic reactions and has a strong anti-PCA effect.

It should be noted that even when the target substance of the present invention was administered in large quantities to rats, no death occurred.

Table 1 The object compound (I) of the present invention exhibits excellent antiallergic activity.

Claims (2)

[Claims] (1) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 is H, a lower alkoxycarbonyl group that may be substituted with an aryl group, or a lower alkyl group that may be substituted with an aryl group. (R^2 represents an aryl group or a lower alkyl group optionally substituted with an aryl group) or a salt thereof. (2) An anti-allergic agent containing the compound (I) or its salts described in claim (1) as an active ingredient