JPS6140270A - Pyridazinone derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H, n-alkyl or benzyl (substituted to the 4-position of the benzene nucleus); R<2> is n-alkyl, benzyl (substituted to the 4-position of benzene nucleus or alpha-position of benzyl group), cyclohexylmethyl, or pyridylmethyl; the bond between 4- and 5-positions of pyridazinone skeleton is single or double]. EXAMPLE:4,5-Dihydro-6-(4-n-tridecyloxy)phenyl-2(H)-pyridazinone. USE:Medicine having low toxicity and excellent lipid-level lowering action. It remarkably decreases the serum lipid of a rat of hypertriglyceridemia, and increases the HDL-cholesterol level. PREPARATION:The compound of formula I wherein the bond between the 4- and 5-positions of pyridazinone skeleton is single, can be prepared by reacting ethyl 4-substituted-oxybenzoylpropionate of formula II with hydrazine hydrate or N-substituted hydrazine in a mixture of ethanol and hydrochloric acid for 10-15 hr under refluxing.

Description

Detailed Description of the Invention The present invention is based on the general formula [wherein R1 is a hydrogen atom, a straight-chain alkyl group, or a benzyl group with or without a substituent at the 4-position of the benzene nucleus; R2 is a straight-chain alkyl group; It represents a benzyl group, a cyclohexylmethyl group, or a pyridylmethyl group with or without a substituent at the 4-position of the benzene nucleus or at the α-position of the benzyl group, and the bond between the 4- and 5-positions of the pyridazinone skeleton is a single bond or a double bond. The present invention relates to a pyridazinone derivative [I] represented by [representing a heavy bond].

The pyridazinone derivatives shown in [■] above have an excellent lipid-lowering effect, that is, hypertriglyceridemia (hypertriglyceridemia).
It has the effect of significantly lowering serum lipids (triglycerides, total cholesterol, phospholipids), and H
It is a compound that significantly increases DL-cholesterol and has low toxicity, making it useful as a pharmaceutical.

Compound CIE of the present invention can be produced by various methods. For example, ethyl 4-substituted oxybenzoylprobionate represented by the general formula [■] [wherein R2 represents the same as above] is added to a mixture of ethanol and hydrochloric acid, and then hydrazine hydrate or N- After adding the substituted hydrazine, the mixture is heated under reflux for 10 to 15 hours to obtain a dihydropyridazinone derivative represented by the general formula [■] [wherein R1 and 2 are the same as above].

A compound in which R1 in general formula (1'l) is not hydrogen is ace) 2) Alkylated or benzylated with the corresponding halogenide in the presence of potassium carbonate in IJ It can also be manufactured by

In addition, pyridazinone derivatives in which the bond between the 4th and 5th positions are double bonds [IJ is produced by reacting the corresponding dihydropyridazinone derivative [■] with bromine in acetic acid, and then adding water or hydrogen carbonate] It can be produced by adding an aqueous solution and heating and stirring.

In addition, in the above pyridazinone derivative [■], the compound in which R1 is not hydrogen, the compound in which R1 is a hydrogen atom,
It can also be prepared by alkylation or benzylation with the corresponding halide in the presence of potassium carbonate in acetonitrile.

Next, the present invention will be explained in detail with reference to Examples.

Example 1 4.5-dihydro-6-(4-n-)lysosiloxy)
Phenyl-2(H)-pyridazinoneethyl 4-n-
) Lidesyloxybenzoylbrobione) 8.59 was dissolved in ethanol I00me, and hydrazine hydrate 1.5
Add y dropwise while stirring at room temperature. After completion of the dropwise addition, the mixture was heated under reflux for 10 hours while stirring. From now on, the precipitated crystals are collected and re-solidified with ethanol to obtain the desired product 5.69C (yield: 71%) in the form of white plate-like crystals having a melting point of 93-94°C.

Engineering Rvnu"'cm': 3180 (O
H), +720 (C=O).

aX NMR (DMSO-C6) δ: Hydrogen at the 4-position of the pyridazinone ring.

2.4 6 (2H, triplet, J='7H2
), hydrogen at position 5 of birita'dinone ring + 2.
96 (2H1triple tl, r=711(z)
.

Mass m/e: 372 (M+)'-Elemental analysis value (as C2SH56N202) Theoretical value (%; I:
c, 74.15; H, 9,74; N, 7.52 Actual measurement value (a): C, 74,30; a, 9.88; N,
7.50゜Example 2 4.5-dihydro-6-(4-cyclohexyl-methyloxy)phenyl-2(1()-hydecynonethyl 4
- 112 cyclohexylmethyloxybenzoylpropionate is dissolved in 50 rnl of ethanol, and 2.12 liters of hydrazine hydrate is added dropwise with stirring at room temperature. After completion of the dropwise addition, the mixture was heated under reflux for 10 hours while stirring.

From now on, the precipitated crystals are separated and re-solidified using a mixed solvent of ethanol and chloroform to obtain the desired product 6y (yield: 61%) in the form of white plate-like crystals having a melting point of 193-195°C.

Engineering RZ/nuj01am': 3180 (OH)
, +650 (cmo).

aX NMR (DMSO-C6) l: 4 of the pyridazinone ring
position hydrogen.

2, 44 (2H, tri'plet, , T=7H2
), hydrogen at position 5 of pyridazinone ring, 2.92 (2H,
triplet.

J=7H2).

Mass m/e: 286 (M+).

Elemental analysis value (as Cl7H22N202) Theoretical value ((
6): c, 7130; H, 7,74; N, 9.7
8 Actual value ((6): 0% 70.98; Hs 7.I
N iNs 9.88゜Example 6 4.5-dihydro-6-(4-n-)lysosiloxy)phenyl-2(methyl)-pyridazinoneethyl 4-n-)
Lidesyloxybenzoylpropionate 115y is dissolved in a mixture of 10r ethanol:Jme and 5me hydrochloric acid, and methylhydrazine sulfate 492 is added dropwise with stirring at room temperature. After completion of the dropwise addition, the mixture was heated under reflux for 16 hours while stirring. from now on,
The reaction solution is concentrated to dryness under reduced pressure, chloroform and water are added to the resulting solid residue, and the organic layer is thoroughly washed with water. After drying the organic layer with Glauber's salt, it was concentrated to dryness under reduced pressure. The obtained crude crystals are recrystallized from chloroform to obtain the desired product 76y (yield: 68%) as white needle-like crystals having a melting point of 58-59°C.

nujol -1.

Engineering R"max cm -1670 (cmo).

NMR (DMSO-a6) δ: hydrogen at position 4 of pyridazinone ring.

2, 44 (2H, tripHt, , T=7H2),
Hydrogen at position 5 of pyridazinone ring + 2.92 (2H, tr
iplet.

J=7H2).

Mass m/e: 385 (M).

Elemental analysis value (as C24H5BN203) Theoretical value ((
5): c, 74.57; H, 9,9+; Is7.25 actual value ((6): c, 74.71; H, +0.10;
N, 7.04° Example 4 6-(4-n-tridecyloxy)phenyl-2(H
)-pyridazinone 4,5-dihydro-6-(4-
n-)lysosiloxy)phenyl-2(H)-pyridazinone 3y in acetic acid 50+nl! Bromine 14y was added dropwise under stirring at room temperature. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 5 hours. Thereafter, acetic acid is distilled off under reduced pressure, 20 me of water is added to the resulting solid residue, and the mixture is heated and stirred at 80° C. for 2 hours.

The precipitated crystals are separated, air-dried, and then re-solidified in chloroform to obtain the desired product 25y (yield: 85%) in the form of white plate-like crystals having a melting point of 102-104°C.

Engineering Rν+nRc01': 5200 (NH), +72
0 (C=O).

NMR (DMSO-d6) δ: 4-position hydrogen of pyridazinone ring 16, 96 (+ H, doublet, l-7H
2), hydrogen at position 5 of pyridazinone ring, 7.96 (jL
double, ecJ=7H2).

Mass m/e: 570 (M) - elemental analysis value (
C25H34N202) theoretical value ((6): C,
74,55; H, 9,25; N, 7.56 actual value ((
6): C, 74,2+; H, 9,03; N, Otsu 69゜Example 5 6-(4-cyclohexylmethyloxy)phenyl-2(
H)-pyridazinone 4,5-dihydro-6-(4-
Dissolve 4y of cyclohexylmethyloxy)phenyl-2(H)-pyridazinone in 5otne of acetic acid, and dissolve 6.5y of bromine.
is added dropwise while stirring at room temperature. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 6 hours. From now on, acetic acid is distilled off under reduced pressure, and 50% of a saturated sodium bicarbonate solution is added to the resulting solid residue.
Heat and stir at 80°C for 2 hours. From now on, the precipitated crystals are collected, air-dried, and then reconstituted with a mixed solvent of DMF-methanol to obtain the desired product 29 (yield: 86%) as white plate-like crystals having a melting point of 222-224°C.

IRv7'40": 3180 (NH), +660 (
cmo).

NMR (DMSO-d6) δ: hydrogen at position 4 of pyridazinone ring.

6.86 (IH, doublet, J=7H2),
Hydrogen + at position 5 of pyridazinone ring, 7.86 (I HN
doublet.

J=7H2).

Mass m/e: 284 (M+).

Elemental analysis value (as Cl7H2ON202) Theoretical value (%
): C,7L8+ iH,7,09; Is 9.85
Actual value ((6): c, 71.65; u, 715i
Ns 9.61° Examples 6 to 2D The pyridazinone derivatives listed in Table 1 are obtained by performing the reaction and post-treatment according to Examples 1 to 71 above.

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ^2 represents a straight-chain alkyl group, a benzyl group with or without a substituent at the 4-position of the benzene nucleus or the α-position of the benzyl group, a cyclohexylmethyl group, or a pyridylmethyl group, and represents the 4- and 5-positions of the pyridazinone skeleton. The bond represents a single bond or a double bond.] A pyridazinone derivative represented by: