JPS6087283A - Pyridazinone derivative and its salt - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R is 1-6C alkyl; A is 1-2 N-containing 5-membered, 6-membered heterocyclic ring or quinolyl which may contain substituent group; n is 1-4; dotted line is single bond, or double bound) and its salts. EXAMPLE:6-[4-(N-(4-pyridyl methyl-N-acetyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone. USE:A cardiac. PREPARATION:A compound shown by the formula II is reacted with a compound shown by the formula III in the presence of a catalyst such as p-toluenesulfonic acid, etc. in a solvent such as N,N-dimethyl-formamide, benzene, toluene, or a mixed solvent of them under reflux to give a compound shown by the formula IV. The reaction product is reduced by contact hydrogenation, etc. to give a compound shown by the formula V, which is reacted with an acid chloride shown by the formula RCOX (X is halogen) and acylated to give a pyridazinone derivative shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyridazinone derivatives or salts thereof useful as cardiotonic agents.

Cardiac inotropes have the effect of directly acting on the heart to strengthen its contractile force, and various drugs have been used to treat heart failure.

However, many of these cardiotonic drugs have the disadvantages that their safety range is extremely narrow and they cause arrhythmia, and their inotropic effects are temporary and are not suitable for oral administration.

The present inventors have conducted extensive searches for compounds that can exhibit a sufficiently long-lasting effect as a cardiotonic agent, and have finally arrived at the present invention.

That is, the gist of the present invention is the following general formula (1);
/ If so, it contains two nitrogen atoms! Represents a membered ring, a multicyclic group, or a quinolyl group, and each ring has an alkyl group with a carbon number/~g, a cyan group, a hydroxyl group, an alkoxy group with a carbon number of 7 or more, an amine group, a carbon # ! It may have at least seven substituents selected from an alkylamino group having I/- and an acylamino group having from - to Z carbon atoms. n represents an integer from / to , and the dotted line represents a - double bond or a pyridazinone derivative or a salt thereof.

Hereinafter, one aspect of the present invention will be explained in detail.

In the above general formula (1), specific examples include methyl, ethyl, n-propyl, i-furovir, n-butyl, t-7'-tyl, pentyl, hexyl, etc., with carbon number/~g
(preferably /~g) alkyl groups are mentioned.

A specific example of A is, for example, 1,2-pyridyl.

3-pyridyl% goupyridyl% 3-dihydropi 3
- Lysyl, -1pyrrolyl, 3-pyrrolyl, 3-pyridazinyl, derpyridazinyl, 2-pyrimidinyl, derbyrimidinyl,! -pyridinyl, 3-dihydropyridazinyl,
2-imidazolyl.

Gooimidazolyl! -imidazolyl, 4t-quinolyl, etc., and may have at least 7 t substituents on the ring. As the substituent, an alkyl group having 7 to 7 carbon atoms such as methyl, ethyl, propyl, phtyl, pentyl, and hexyl; a cyan group; a hydroxyl group; Amino group: alkylamino groups with carbon number l-d such as methylamino, ethylamino, propylamino, and butylamino; and acylamino groups with carbon numbers - to y such as acetylamino, propionylamino, and butyrylamino. However, particularly preferred are alkyl groups having 7 or more carbon atoms such as methyl and ethyl, hydroxyl groups, and amine groups.

Specific examples of the pyridazinone 04 represented by the general formula (1) include the following.

4- 〇H3 0H.

0H8 an.

0H1 -G- Oh.

Oh.

Oh.

Oh.

-Just- 0H.

Also included within the scope of the present invention are pharmaceutically acceptable salts of the above compounds. Examples of the above-mentioned salts include inorganic acids such as phosphoric acid, hydrochloric acid, and sulfuric acid, and diorganic acid salts of oxalic acid and lactic acid.

Next, a method for producing the compound of the present invention will be explained.

The pyridazinone derivative used in the method of the present invention is, for example, 1
It can be synthesized by the following route.

(If) H (IV) (I) (In the above formula, X represents) .

n and R are as defined in general formula (I). ) The reaction between compound (If) and compound (■) is carried out in the presence of a catalyst such as p-)luenesulfonic acid, in a mixed solvent such as N,N-dimethylformamide, benzene, toluene, etc. This is done under reflux. reaction time is 0
, 6 to 1 hour, preferably -]]- It is preferable to carry out the reaction while removing the produced water from the system by azeotropy. Compounds (1) and (m) used
The amount of Z0 is approximately equimolar.Then, the amount of the obtained compound (I
Compound (V) can be obtained by reducing V) by a catalytic hydrogenation method or the like.

Catalytic hydrogenation is carried out in a solvent such as N,N-dimethylformamide at θ°C to /θθ°C under normal pressure or pressure in the presence of a catalyst such as palladium-black or palladium-carbon. Reaction time: By reacting with hydrate (■) to acylate.

When the desired pyridazinone derivative (I) is obtained, -co θ~/! in a solvent such as amide, pyridine, 2,4t, t-collidine, or a mixed solvent thereof. Carry out at θ°C.

The reaction time is O0t~! time (T), acid chloride (Vl) or 1 is the use of acid anhydride (■) 1
2- The amount is /~y mol per 1 mol of compound (V).

In addition, the obtained pyridazinone derivative (1) is phosphoric acid,
Inorganic acids such as hydrochloric acid, sulfuric acid, or oxalic acid.

Reaction with organic acids such as lactic acid yields pharmaceutically acceptable salts.

The pyridazinone derivative (1) or a salt thereof thus obtained can be purified by a conventional method such as column chromatography.

When the compound according to the present invention is used as a cardiotonic agent, it can be administered by an appropriate oral or parenteral administration method. ' In this case, the forms provided include, for example, powders, granules, dragees, pills, capsules, liquids, etc. for oral administration, and suppositories, suspensions, solutions, etc. for parenteral administration. Examples include emulsions, ampoules and injection solutions. Of course, a combination of these can also be provided.

For formulation, conventional methods in this field can be used.

Furthermore, the amount of the compound of the present invention to be administered as a cardiotonic drug depends on age, gender, body weight, sensitivity differences, and administration method.

The decision is made by the doctor, taking into consideration the timing and interval of administration, the degree of the medical condition, the nature, preparation, and type of the pharmaceutical preparation, and the type of active ingredient.

For example, in the case of oral administration of 1 g, /daily p, o, i ~ /θ Misaki /
A dosage of 41 S degrees body weight is chosen, but is of course not limited to this.

The present invention will be described in more detail below using Examples and the T-groove side, but the present invention is not limited to the following Examples without exceeding the gist thereof.

Example / (za-[gu(N-(4t-pyridyl)methyl-N-
acetyl)aminophenyl] -y, t-dihydro-j
(,2H)-pyridazinone) (a) j-(p-aminophenyl)-Q, ? -dihydro-4-3(,2H)-pyridazinone/ /, ♂f.

Isonicotinaldehyde 10rd, p-) Luenesulfonic acid jOwy, mixture of toluene/60- and N,N-dimethylformamide 701111 7500-76
The reaction was carried out at 0°C for 3 hours (during the reaction, water produced by co-layer dehydration was removed from the system.) 1. After cooling the reaction solution, 300 wt of ethyl ether was added and the precipitated crystals were removed. I took it. After drying, t-(a-(4t-pyridyl)methylideneaminophenyl)-4t,t-dihydro-3(,zH
)-pyridazinone 23. -! I got 2.

(b) Compound 23.269 obtained in (a) was mixed with triethylamine 2- and N,N-dimethylformamide 2-
Suspend in a solution of 00d and further! Chipalladium-Chensuide J
,? f was added, and catalytic hydrogenation was carried out at room temperature and under normal pressure. After collecting the theoretical amount of hydrogen, remove the catalyst and pour the P liquid into ice water.
The precipitated crystals were collected in a furnace. What is the yield of dried rice? / /, Q? Met. The crude crystals were purified by column chromatography (silica gel, solvent: chloroform-THF) to obtain pure 6-[cou(4t-pyridyl)methylaminophenyl]-! -Dihydro? (,2H
)-pyridazinone/, 20.2f was obtained.

(C) To the compound obtained in (b)/39,2. ri, 6-
A mixture of collidine, 21d and acetic anhydride θ, jII+/ was reacted at 730°C for 3 hours, and one reaction solution was directly subjected to column chromatography (silica gel% bath medium: riproform-THF) to obtain the target product O-[ Gu(N-(cupyridyl)methyl-N-acetyl)aminophenyl]-4t
, j-dihydro-j(2H)-pyridacy/one 0,4t4
I got it.

Engineering R (KBr): / t! j crn-' Example λ (6-[Cu(N-(2-(/-methyl)pyrrolyl)methyl-N-acetyl)aminophenyl)"*Tajhydro J(jH)-pyridazinone) Production (a) Implementation Under the same conditions as in example (a), using %/-methylpyrrole-cocarbaldehyde j, 2.29 instead of isonicotinaldehyde, 6-[gu(,2-
(i-methyl)pyrrolyl)methylideneaminophenyl)
-y,j-dihydro-3(coH)-pyridazinone 7,
! ≦2 was obtained.

(1)) Compound 2F obtained in (a) was added to Example/(
+)) was subjected to catalytic hydrogenation under the same conditions as -(g-(s-(
/-methyl)pyrrolyl)methylaminophenyl]-ri,
! -dihydro 3(,2H)-pyridazinone obtained j f.

(Q) To the compound obtained in (kl)/4F, Example/
Acetylation was performed under the same conditions as in (C) to obtain the desired dihydro-,? (2H)-Pyridazinone O, Tada 2 was obtained.

Engineering R (KBr): /6416. /176 cm-
'Example 3 (6-[gu(N-(couquinolyl)methyl-N-acetyl)aminophenyl)-a,t-dihydro-3(,
(a) Production of 1g-[gu(4t-quinolyl ) Methylideneaminophenyl]-4t,j-dihydro-3(
H)-pyridazinone/da,6θ2 was obtained.

(1)) The compound / 3.7 Of obtained in (a) was subjected to catalytic hydrogenation under the same conditions as in Example / (1)).
[Gu(41-quinolyl)methylaminophenyl]-gu,! -dihydro-3(,zH)-pyridazinone/2.9
I got 02.

(Q) The compound /, /jt obtained in (b) is acetylated under the same conditions as in (C) of Example /, and used as the objective. 6-[gu(N-(guquinolyl)methyl-)
N-acetyl)aminophenyl two 4t,! -dihydro-J(,2H)-pyridazinone 0.39 f was obtained.

Engineering R (KBr): / t t, Otm-'Reference Example/ The usefulness of the pyridazinone derivative in the present invention as a cardiotonic agent was tested by a method using a large excised papillary muscle cross-perfusion specimen.

Canine isolated papillary muscle cross-perfusion specimens were prepared using the method of Endo and Hashimoto [American Journal of Physiology (Amer.
ican J, Physiol, ) 2/♂ volume, /
the law of nature! ? - / 3 pages, / 92θ year medical examination].

The compounds obtained in Examples/~3 were dissolved in a solvent, and they were moved close to the specimen, and the effect on the contractile force of papillary muscles was recorded. The results are shown in Table 1.

Continuation of page 1 ■Int, CI,' Identification symbol Internal reference number 665-

Claims (1)

[Claims] (1) The following general formula (■): (In the above formula, R represents an alkyl group with carbon number/~g, A#'i,/or a !-membered ring or a 6-membered ring containing one nitrogen atom) Represents a heterocyclic group or a quinolyl group, A
The number of carbon atoms per ring is an alkyl group, a cyano group, or a hydroxyl group. It may have at least seven substituents selected from an alkoxy group having a carbon number of ~g, an amino group, an alkyl axi) group having a carbon number of ~da, and a 7-syl amino group having a carbon number of ~da. nFi/~Da is an integer, and a dotted line represents a -multiple bond or a double bond. ) Pyridazinone derivatives or salts thereof.