JPH01258671A - 5-(1h-imidazol-1-yl)-3(2h)-pyridazinone derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> is H, 1-14C alkyl, (halogen-substituted)benzyl, cinnamyl, naphthoxyethyl or (halogen-substituted) phenoxyethyl; R<2> is H or 1H-imidazolyl-1-yl; R<3> is H or (halogen-substituted) phenyl] or an acid addition salt thereof. EXAMPLE:5-(1H-imidazol-1-yl)-6-phenyl-3(2H)-pyridazinone. USE:A drug useful as antithrombotic drug and antifungal agent having low toxicity and effective as a preventive and remedy of cerebral thrombosis, cerebral embolism, peripheral arterial and venous embolism and mycotic infection. PREPARATION:For example, a 5-chloro-6-phenyl-3(2H)-pyridazinone derivative shown by formula II (R<4> and R<5> are H or Cl) is reacted with an excess amount of imidazole preferably in a solvent at 50-180 deg.C for 1-8hr to give a compound shown by formula I wherein R<1> is H and R<3> is (halogen-substituted) phenyl.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention provides novel 5
-(IH-imidazol-1-yl)-3(2H)-pyridazinone derivatives and acid addition salts thereof.

[Conventional technology]

6-(1(IH-imidazol-1-yl)phenyl)
-3(2H)-pyridazinone derivatives (JP-A-58-74
679) is known to have antithrombotic and cardiotonic effects.

Also, Pharmazie, 32
, 555 (1977), it was reported that 3(2H)-pyridazinone derivatives have antibacterial activity.

However, there is nothing to suggest about 5-(11(-imidazol-1-yl)-3(2H)-pyridazinone derivatives or their antithrombotic and antifungal effects).

[Problems to be solved by the present invention]

The purpose of the present invention is to achieve medicinal efficacy as an antithrombotic agent and an antifungal agent.
Our goal is to provide new compounds with excellent safety.

Means for Solving Problem C] The present invention provides the following - 5-(l H-
The present invention relates to (imidazol-1-yl)-3(2H)-pyridazinone derivatives and acid addition salts thereof.

do1 (wherein, R1 is a hydrogen atom, an alkyl group of C, -C,,
benzyl group, which may be substituted with a halogen atom,
Indicates a cinnamyl group, a naphthoxyethyl group, or a phenoxyethyl group that may be substituted with a halogen atom. R2 represents a hydrogen atom or a 1-1-imidazol-1-yl group. (R3 represents a hydrogen atom or a phenyl group which may be substituted with a halogen atom.) Specifically, R' in the above definition is a hydrogen atom, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group. basis,
Hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-chlorobenzyl group , 3-chlorobenzyl group, 4-chlorobenzyl L2
, 4-dichlorobenzyl group, cinnamyl Li(1-naphthoxy)ethyl group, l-(2-naphthoxy)ethyl group,
Examples include 2-phenoxyethyl group and 2-(2°4-dichlorophenoxy)ethyl group.

111 - More preferred embodiments of the compound of the present invention represented by formula (1) include those in which R' has the same meaning as above, and R2 and R1 are as follows.

R2 is a hydrogen atom, R3 is a phenyl group, 4-chlorophenyl or c2. 4-) A compound in which a chloro-1-coffenyl group is preferred, or a compound in which R2 is an IH-imidazol-1-yl group and R3 is a hydrogen atom is preferred.

Acids that can form acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acetic acid, propionic acid, acid, malonic acid, succinic acid, and glutaric acid. , adipic acid, malic acid, maleic acid, fumaric acid, citric acid, benzoic acid, methanesulfonic acid, and other organic acids, but hydrochloric acid is preferred because it forms particularly good crystals with the compound of the present invention.

The compounds of the present invention can be easily produced by the methods shown in [Reaction Formulas-1 and 2] below.

(In the formula, R' has the same meaning as above, R4 and R
5 represents a hydrogen atom or a chlorine atom) Step A That is, the above-mentioned compound (Ia) of the present invention is prepared by Tory (D
(French Published Patent No. 1352099)
) 5-chloro-6-phenyl-3 (
It can be produced by reacting the 2H)-pyridazinone derivative (I+) with imidazole. Examples of the solvent used in this reaction include ethers such as tetrahydrofuran, dioxane, and ethylene glycol diethyl ether; acetonitrile; , N-dimethylformamide is preferably used. The reaction temperature is usually 50 to 180°C5
Preferably, the temperature is 100-150°C, and the reaction time is 1
-8 hours, preferably 3-5 hours. In addition, in this reaction, inorganic bases such as sodium carbonate and potassium carbonate, tertiary amines such as triethylamine and N,N-dimethylaniline, and bases such as sodium hydride and potassium tert-butoxy can be used. Preferably, an excess of imidazole is used. The ratio of compound [II] and imidazole used is usually 2 to 2 of the former.
~5 times the molar amount is used.

Step B Next, the compound [1b] of the present invention is prepared by adding an alkyl halide or a benzyl halide m(R'-x
(In the formula, R1 has the same meaning as above, X is a chlorine atom,
)] representing a bromine atom or an iodine atom in the presence of a base. The base, solvent, reaction temperature and reaction time to be used may be in accordance with the above-mentioned step A, and the ratio of compound (Ia) and alkyl halides or hensyl halides to be used is usually 1 to 1 to 10% of the former to the latter.
It is 3 times the mole, preferably 1.2 times the mole.

(III) (Ic) (wherein R
' has the same meaning as above, and X represents a chlorine atom, a bromine atom, or an iodine atom. ) Also, the compound of the present invention (I c
) is the method of Schonbek et al.
Monatsch
efte fur Chemie), 99.

15 (1968)) 4,5-dihalogeno-3(2H)-pyridazinone derivative [III]
The 0-unit reaction, which can be produced by reacting imidazole with imidazole, may also be carried out in accordance with the above-mentioned step A.

In addition, the acid addition salt of formula (1) above can be easily produced according to a conventional method.

The thus obtained compound (1) of the present invention exhibits antithrombotic and antifungal effects and is low in toxicity, and therefore is useful for the prevention and treatment of cerebral thrombosis, cerebral embolism, peripheral arterial/venous occlusion, mycosis, etc. It is useful as a medicine and can be administered orally in solid form such as tablets, granules, or capsules, or as an external preparation such as ointment, jelly, cream, powder, solution, emulsion, or spray. It is preferable to use it as There are no particular difficulties in preparing these formulations, and known methods may be followed.

Oral administration of the compound of the present invention to crabs varies depending on age, body weight, symptoms, etc., but is usually about 10 to 10 per 10 for adults.
It may be increased or decreased as appropriate within the range of 11000III. The concentration of the compound (1) of the present invention in the external preparation is preferably in the range of 0.1 to 5%.

[Example] Example 1 10.33 g of 5-chloro-6-phenyl-3(2H)-pyridazinone and 2 g of imidazole io were heated and stirred in N,N-dimethylformamide at 140° C. for 4 hours. After 6 hours, 200 ml of water was added and left overnight. The precipitated crystals were collected by filtration, washed with water, and then recrystallized from dioxane-ethanol to obtain colorless prism product 5.
-(IH-imidazol-1-yl)-6-phenyl-
7.5 g (yield 63%) of 3(2H)-pyridazinone was obtained. Melting point 245-246°C.

rRν8↓01cm-': 3 1 4 0 (NI
P).

1650 (C=0).

MS (m/z): 238 (M”).

Examples 2-3 The corresponding starting compounds were treated in the same manner as in Example 1 to obtain the compounds shown in Table 1 at a good yield of 1%.

Table 1 Example 4 2.38 g of 5-(1!■-imidazol-1-yl)-6-phenyl-3(2H)-pyridazinone.

1.98g hexylbromide and 1.3g potassium carbonate
8 g was added to 50 ml of dioxane and heated under reflux for 4 hours. After 6 days, the precipitate was collected by filtration, and the solvent was distilled off under residual pressure. The residue was dissolved in methylene chloride, washed with water, dried, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 5d of 20% ethanolic hydrochloric acid solution and dried under reduced pressure.

The residue was recrystallized from acetone-diethyl ether to give 3.3 g of 2-hexyl-5-(IH-imidazol-1-yl)-6-phenyl-3(2H)-pyridazinone monohydrochloride as a pale yellow prism. (yield 92%). Melting point 1
44-145°C YuI Rv3A"cm-': 1
660 (C=O).

MS (m/z): 322 (M').

Examples 5 to 16 The corresponding starting compounds were treated in the same manner as in Example 4 to obtain the compounds shown in Table 2 in good yields.

Example 17 6.1 g of 4.5-dichloro-2-decyl-3(2H)-pyridazinone and 5.44 g of imidazole were heated and stirred in N,N-dimethylformamide at 140°C for 4 hours. After removing the solvent under reduced pressure,
The residue was dissolved in 5% hydrochloric acid 100% and extracted with ethyl acetate.The aqueous layer was adjusted to pH with 40% aqueous sodium hydroxide solution.
10, and the precipitated oil was extracted with methylene chloride. The methylene chloride extract was washed with water, dried, and then dried under reduced pressure.

Dissolve the residue in 10 d of 20% ethanolic hydrochloric acid solution,
After condensation under reduced pressure, 6.2 g of dihydrochloride of 2-decyl-4,5-(IH-imidazol-1-yl)-3(2H)-pyridazinone ( A yield of 70% was obtained.

IR+z;S Aotcr': l 6 6 5 (C
=O).

MS (II/Z): 368 (M”).

Examples 18-22 The corresponding raw material compounds were treated in the same manner as in Example 17 to obtain the third
The compounds shown in the table were obtained in good yields.

Table 3 Formulation example 1 Compound of the present invention 50 ■ Lactose
200■Crystalline cellulose
40 ■ Magnesium stearate 5 rn
g The above mixture is mixed according to a conventional method and tableted to prepare tablets containing 50 mg of the active ingredient per tablet.

Formulation Example 2 Compound of the present invention 50mg milk tJ!
90mg corn starch
60mg talc
30■ Magnesium stearate 10 mg The above mixture is granulated according to a conventional method to obtain granules.

[Pharmacological experiment]

(1) Platelet aggregation inhibitory effect The platelet aggregation inhibitory effect of the compound of the present invention is expressed by pons (G, V,
R, Born)'s method [Nature,
927-929 (1962)).

That is, citrated rabbit blood was collected and centrifuged to separate blood Wi (PPP) with a high platelet concentration and plasma (PPP) with a low platelet concentration.

Next, test compound 1 dissolved in dimethyl sulfoxide
．． After adding 5 μP to 270 μl of PRP and incubating at 37° C. for 1 minute, arachidonic acid or collagen was added to induce aggregation. Platelet aggregation was measured using NKK hematotracer, and the 50% inhibitory concentration (IC6° (μM)) of the test compound was determined from the concentration inhibition rate curve.

Note that aspirin was used as a control drug, and the results of representative examples are shown in Table 4.

Table 4 (2) Measurement of Minimum Inhibition 4 degrees (MIC) for various fungi Using Sabouraud dextrose medium, MIC was determined by agar 4Ii and dilution method according to the Japanese Society of Chemotherapy standard method (revised in 1980). .

Note that clotrimazole was used as a control drug, and the results of representative examples are shown in Table 5.

Table 5 a) (C,a,): Candida albicans (C
andida albicans) I F 0 1
060, (T, m,): Trichophyton sentag
rophyLes) I F O6124, (A, ν,
): Astroderma banpleosegemy (Arthr
oderma vanbreuseghemii)S
M 7420°b) CTZ: Clotrimazl
e).

(3) Acute toxicity test The test compound was suspended in 0.5% carboxymethylcellulose solution, and DDY male mice weighing 20-25 g (1
Table 6 shows the results of 0 representative cases in which the 50% lethal dose (1, D, .) was calculated from the cumulative mortality rate for 7 days after administration.

(Effects of the Invention) The compound of the present invention exhibits stronger activity than aspirin in an in vitro platelet aggregation inhibition test,
In addition, it showed the same level of activity as clotrimazole in MIC measurement experiments against various fungi.

Furthermore, it was confirmed to have low toxicity in animal experiments.

The compound of the present invention is characterized by excellent effects as an antithrombotic or antifungal agent.

Claims (3)

[Claims] (1) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R^1 is a hydrogen atom, an alkyl group of C_1 to C_1_4, or benzyl which may be substituted with a halogen atom. R^2 represents a hydrogen atom or a 1H-imidazole-
Indicates a 1-yl group. R^3 represents a hydrogen atom or a phenyl group which may be substituted with a halogen atom. ) 5-(1H-imidazol-1-yl-)-3 represented by
(2H)-pyridazinone derivative or acid addition salt thereof. (2) In the general formula [I], R^1 is a hydrogen atom, C
_1 to C_1_4 indicates an alkyl group, a benzyl group, a cinnamyl group, a naphthoxyethyl group that may be substituted with a halogen atom, or a phenoxyethyl group that may be substituted with a halogen atom, and R^2 is a hydrogen atom. and R^3 is a phenyl group which may be substituted with a halogen atom. (3) In the general formula [I], R^1 is C_1 to C_
1_4 represents an alkyl group, a benzyl group or a phenoxyethyl group that may be substituted with a halogen atom, and R
^2 is a 1H-imidazol-1-yl group, and R
The compound according to claim 1, wherein ^3 is a hydrogen atom.