JPH02193994A - Pyridazinone derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> represents H or lower alkyl; R<2> represents formula II (R<3> represents mercapto, lower alkylthio, arylthio, etc.), formula III (R<4> represents H or lower alkyl), formula IV (R<5> represents H or lower alkyl), formula V (R<6> represents H, lower alkyl or amino), etc.]. EXAMPLE:4,5-Dihydro-6-(2-mercaptobenzothiazol-5-yl)-5-methyl-3(2H)-pyr idazinone. USE:A cardiac. PREPARATION:A compound expressed by formula VI is reacted with sodium sulfide and sulfur and nitro group thereof is then reduced and further reacted with carbon disulfide to afford a benzothiazole derivative expressed by formula VII, which is subsequently reacted with hydrazine.mono-hydrate to afford the compound expressed by formula I wherein group R<2> represents formula II and group R<3> represents mercapts.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a novel pyridazinone derivative having cardiotonic action or a pharmacologically acceptable acid addition salt thereof.

PRIOR ART Compounds having a viridazinone ring exhibiting cardiotonic action include LY195115 (JP-A-6122080) represented by the following formula, Cl-930 (JP-A-58-74679) represented by the following formula, ( Pimobendan (Japanese Unexamined Patent Publication No. 55-33479) represented by pimobendan (Pimobendan), the compound represented by (US Pat. No. 4,725,686 (Wo 87103,201)), and the following compounds having a pyridone ring. Milrinone (JP-A-57-70868) and the like represented by the formula % (Formula %) have been disclosed.

Problems to be Solved by the Invention Cardiotropic agents have been used as a treatment for chronic heart failure, but none of them has yet been satisfactory in terms of intensity and durability of their effects.

The present invention provides novel pyridazinone derivatives having cardiotonic effects.

Means for Solving the Problems The present invention provides compounds of the formula (I) (wherein R4 represents hydrogen or lower alkyl), (
(wherein R5 represents hydrogen or lower alkyl), [wherein R1 represents hydrogen or lower alkyl and R2 represents formula (A) (wherein R8 represents hydrogen, lower alkyl or amino)] or formula (wherein R8 represents hydrogen, lower alkyl or amino) E) (wherein R' represents mercapto, lower alkylthio, arylthio, lower alkylsulfinyl, arylsulfininobe lower alkylsulfonyl or arylsulfonyl), formula (B) (wherein Ri represents lower alkyl or lower alkoxycarbonyl) , Ra is hydrogen,
(represents lower alkanoyl or lower alkoxycarbonyl)] [hereinafter referred to as compound (1)]. The same applies to compounds of other formula numbers] and pharmacologically acceptable acid addition salts thereof.

In the definition of the polygroup of formula (1), the alkyl moiety in lower alkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, and lower alkoxycarbonyl is a straight or branched carbon atom having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-
Included are butyl, isobutyl, 5ec-butyl, tert-butyl, lowpentyl, isopentyl, neopentyl, n-hexyl, and the like. Examples of the alkyl moiety in arylthio, arylsulfinyl, and arylsulfonyl include phenyl, tolyl, and naphthyl, and lower alkanoyl is a straight or branched alkyl moiety having 1 carbon number.
-4 such as formyl, acetyl, propionyl, n-
Butyryl, imbutyryl, and the like are included, respectively.

Pharmaceutically acceptable acid addition salts of compound (1) include salts with various inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, phosphate, etc. Also, salts with various organic acids, such as formates, acetates, benzoates,
Examples include maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxylate, aspartate, methanesulfonate, and benzenesulfonate.

Next, a method for producing compound (I) will be explained.

Manufacturing method A (wherein R1 and R3 have the same meanings as above) A-1:
Compound (Ia) in which R3 is mercapto (
Compound (II) represented by I aa) (wherein R' has the same meaning as above) (HP 132817
The compound described in -^) is reacted with sodium sulfide and sulfur to reduce the nitro group, and then further reacted with carbon disulfide to form the benzothiazole compound (III).

(In the formula, R' has the same meaning as above.) Next, compound (I aa) can be obtained by reacting compound (III) with hydrazine monohydrate.

A-2: Compound (I a) in which R3 is lower alkylthio (I ab) Compound (I ab) can be obtained by reacting compound (I aa) with a suitable alkylating agent. . Examples of the alkylating agent include alkyl halides, diazoalkanes, and dialkyl sulfates. In addition, the reaction is more preferably carried out in the presence of a suitable base, and examples of the base used include organic bases such as triethylamine, pyridine, and dimethylaminopyridine, and inorganic bases such as potassium carbonate, sodium hydroxide, and silver oxide. It will be done.

A-3: Compound (Iac) in which R3 is arylthio in compound (Ia) Compound (Iac) is a compound (Iac) obtained by the below-mentioned production method A-4 in which R3 is lower alkylsulfonyl and arylhydro It can be obtained by reaction with sulfide or its alkali metal salts such as sodium and potassium.

A-4=Compound (Iad) in which R3 is lower alkyl or arylsulfinyl in compound (Ia) and compound (Iad) in which R3 is lower alkyl or arylsulfonyl
ae) Compound (I ad) and/or (I ae
) can be obtained by oxidizing compound (Iab) or (Iac) with a suitable oxidizing agent.

When metachloroperbenzoic acid, hydrogen peroxide, etc. are used as the oxidizing agent, the sulfinyl compound (lad) is obtained as the main product, and when potassium permanganate or the like is used, the sulfonyl compound (Iae) is obtained as the main product.

Production Method B Suitable α-amino acids include glycine, alanine, valine, leucine, isoleucine, and the like.

Compound (I b) can then be obtained by treating compound (rV) with a dehydrating agent.

Examples of the dehydrating agent include acetic anhydride and phosphorus pentoxide.

Production method C (wherein R' and R4 have the same meanings as above) is:
First, the compound (I ae) obtained in Step-4 of the production method is reacted with an appropriate α-amino acid to form a compound (I ae) represented by the following formula (
IV) and eggplant.

(In the formula, R1 and R4 have the same meanings as above) (In the formula,
R1 and R5 are as defined above) Compound (I c)
is a compound (V) represented by the following formula (wherein R1 has the same meaning as above) and a compound (Vl) represented by the following formula % formula % () (wherein R5 has the same meaning as above) Compound (I c) can be obtained by reacting with, preferably in the presence of a base. Examples of the base include organic bases such as triethylamine and diazabicycloundecene, and inorganic bases such as sodium hydroxide and potassium hydroxide.

Production method D (wherein R9 represents lower alkyl as defined above,
(R1 and R5 have the same meanings as above) Examples of the orthoformic acid lower alkyl ester used include methyl orthoformate, ethyl orthoformate, and the like.

Compound (Id) can then be obtained by reacting the compound (■) with a compound (■) represented by the following formula % (in which R6 has the same meaning as above).

Production method E (wherein R' and R6 have the same meanings as above) is:
First, the compound (Ic) obtained by Production Method C is reacted with a lower alkyl orthoformic acid ester to form a compound (■) represented by the following formula.

Compound (1e) is a compound (IX) represented by the following formula and a compound (X) represented by the following formula ) in the presence of a base if necessary.

Here, the leaving group represented by X includes halogen atoms such as chlorine, bromine, and iodine, and arylsulfonyl such as p-)luenesulfonyl.

As the base, those exemplified in Production Method C can be used in the same manner.

Intermediates and target compounds in each of the above production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. Can be done. Further, the intermediate can also be subjected to the next reaction without being particularly purified.

When you want to obtain the salt of compound (1), if compound (1) is obtained in the form of a salt, you can simply purify it as it is, or if it is obtained in the free form, you can form the salt by a normal method. Bye.

In addition, compound (I) and its pharmacologically acceptable salts are:
It may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

Specific examples of compound (1) obtained by the present invention and their physical properties are shown in Table 1. Note that the compound numbers in the table correspond to the example numbers described later.

Next, the cardiotonic effect of the representative compound (1) will be explained using test examples.

Test Example Anesthetized an adult male and female mixed breed dog weighing 8 to 15 kg by intravenously administering Bendoparbital IJum salt at a rate of 30 mg/kg. Under artificial respiration, a catheter-type pressure transducer was retrogradely inserted into the left ventricle from the left common carotid artery, and the left ventricular pressure was measured.

In addition, peripheral blood pressure was measured using a pressure transducer via a catheter inserted into the femoral artery.

Myocardial contractile force is the maximum value of the first derivative of left ventricular pressure (dp/d
The heart rate was measured by introducing the ECG waveform (lead Ⅰ) into a tachometer using tmax) as an index. Anesthesia was maintained during the measurements by inhalation anesthesia using halothane and laughing gas. At the same time, 0.1 mg of muscle relaxant (pancuronium bromide)
It was continuously infused from the left forelimb vein at a rate of /kg/hour. Using this method, we were able to obtain a stable state of anesthesia for a long period of time.

Test compounds were dissolved in PEG-400 and administered into the right forelimb vein (
1v) at the doses shown in Table 2.

The maximum rate of change in myocardial contractile force, heart rate, and peripheral mean blood pressure from the pre-administration values up to 60 minutes after administration, and the duration of the change in contractile force were determined.

The results are shown in Table 2.

The cardiotonic agent containing the compound (1) in Table 1 or its pharmacologically acceptable acid addition salt can be prepared into commonly applied dosage forms such as tablets, capsules, syrups, injections, drips, and half-open tablets. Orally or intramuscularly, intravenously,
It can be administered parenterally, such as by intra-arterial injection, infusion, or rectal administration via half-opening. Generally known methods are applied to formulate dosage forms for oral or parenteral administration, such as various excipients, lubricants, binders, disintegrants, suspending agents, It may contain an isotonic agent, an emulsifier, etc.

Pharmaceutical carriers used include, for example, water, distilled water for injection, physiological saline, glucose, fructose, white sugar, mannitol, lactose, starch, cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, alginic acid, talc, and citric acid. Examples include sodium acid, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, glycerin fatty acid ester, and the like.

The dosage varies depending on the dosage form, patient's age, weight, symptoms, etc., but for example, it is usually 0.05 to 200 mg/orally.
60 kg/day is appropriate, and in the case of intravenous drip, 0. O1～
It is preferable to use a dose of 5 kg/min within a range that does not exceed the oral dosage limit per day.

The present invention will be explained in detail below using Examples and Reference Examples.

Example 1 3-(4-chloro-3-nitrobenzoyl)acetic acid 5.4
g, sodium sulfide nonahydrate 14.4 g and water 1
The mixture of 00- was stirred at 130°C for 24 hours. Acetic acid was added to adjust the pH to 4.5, extracted with ethyl acetate, dried, and concentrated. Add dimethylformamide (50°C) to the residue, perform 2N hydroxide, and adjust pH to 11.0+ with IJum. Next, carbon disulfide lO- was added and stirred at 60°C for 3 hours. The pH was adjusted to 4.0 with 1N hydrochloric acid and concentrated. The residue was partitioned between water and chloroform, and the organic layer was dried and concentrated. To the resulting residue were further added 50 ml of acetic acid and 5-hydrazine hydrate, and the mixture was stirred at 100°C for 3 hours. The precipitated crystals were washed with water and methanol in that order, and 4,5-dihydro-6-(2mercaptobenzothiazol-5-yl)-5=methyl-3(2H
)-pyridazinone (compound 1) 2.6 g (47%) was obtained.

Example 2゜17.8 g of the compound obtained in Example 1 was mixed with 10 g of methanol.
The mixture was suspended in 0ml+, and 2N sodium hydroxide was added until the raw material was dissolved. 2.1-methyl iodide was added and stirred at room temperature for 20 minutes. Concentrate, add water and collect the precipitated crystals.
4,5-dihydro-5-methyl-6-(2
-methylthiobenzothiazol-5-yl)-3(2H
)-pyridazinone (compound 2) 5.1 g (62%) was obtained.

Example 3 In the same manner as in Example 2, 4.5-dihydro-
0.6 g (52%) of 6-(2-isopropylthiobenzothiazol-5-yl)-5-methyl-3(2H)-pyridazinone (compound 3) was obtained.

Example 4 20.8 g of the compound obtained in Example 2 was dissolved in 20-acetic acid, and 0.6 g of metachloroperbenzoic acid was added thereto at room temperature.
Stir for hours. Add 2N sodium hydroxide to adjust the pH to 1.
The precipitated result was collected and dried to give 4,5-dihydro-5-methyl-(2-methylsulfinylbenzothiazol-5-yl)-3(2H)-pyridazinone (
Compound 4) 0.6g<71%) was obtained.

Example 5 21.0 g of the compound obtained in Example 2 was mixed with 50% 70% acetic acid.
0.8 g of potassium permanganate was added under water cooling, and the mixture was stirred for 3 hours. Hydrogen peroxide solution was added to the reaction solution until it became clear, and the precipitated crystals were collected and dried to give 4,5-dihydro-5-methyl-(2-methylsulfonylbenzothiazol-5-yl)-3(2H )-pyridazinone (compound 5) 0.6 g (54%) was obtained.

Example 6゜Thiophenol 0.32m, sodium methoxide 0.
13 g and 30 g of methanol were stirred at room temperature for 30 minutes. Add 50.5 g of the compound obtained in Example 5,
Stirred at room temperature for 1 hour. Add water and collect the precipitated crystals.
Dried, 4,5-dihydro-5-methyl-6-(2-phenylthiobenzothiazol-5-yl)-3(2H)
-0.27 g (49%) of pyridazinone (compound 6) was obtained.

Example 7゜Compound 5 obtained in Example 5 1.5g, glycine 0.
4 g of potassium carbonate, and 20 g of dimethyl sulfoxide was stirred at 100° C. for 5 hours. The pH was adjusted to 4 with 1N hydrochloric acid and concentrated.

Add 20 ml of pyridine and 5 ml of acetic anhydride to the residue and add 60 ml of pyridine.
The mixture was stirred at ℃ for 2 hours. It was concentrated, water was added, and the precipitated crystals were dried several times to give 4,5-dihydro-6(2,3-dihydroimidazo[2,1-b)benzothiazol-3-one-
6-yl)-5-methyl-3(2H)-pyridazinone (
Compound 7) 0.8g (57%)

Example 8 In the same manner as in Example 7, 4,5-dihydro-6=(2-isopropyl-2,3-dihydroimidazo[2,1 -b) Benzothiazol-3-one-6yl)-5-methyl-3
(2H)-pyridazinone (compound 8) 0.5g (31%
) was obtained.

Example 9 Compound c obtained in Reference Example 3 2.6 g 1 ethyl mercaptoacetate 1.1- and dimethylformamide 30-
2N sodium hydroxide was added to the mixture at room temperature until the reaction solution turned red, and the mixture was stirred for 10 minutes. 60m1 water
The precipitated crystals were dried several times to form 6-(3-amino-2-ethoxycarbonyl-1-benzothiophene-6).
-yl)-4,5-dihydro-5-methyl-3(2H)
3.1 g (93%) of -pyridazinone (compound 9) was obtained.

Example 10 A mixture of 90.7 g of the compound obtained in Example 9 and 20 g of ethyl orthoformate was stirred at 150° C. for 2.5 hours. It was concentrated, 5d of isopropylamine was added, and the mixture was stirred at 40°C for 1 hour. The crystals precipitated by adding water and methanol were dried several times, and 6-(3-isopropyl-38-[1:]
Benzocheno C3゜2-d]pyrimidin-4-one-
7-yl)-4゜5-dihydro-5-methyl-3(2H
)-pyridazinone (compound 10) 0.24g (32%
) was obtained.

Example 11 In the same manner as in Example 10, 6-(3-amino-3H-
[1:l benzocheno[3,2-d)pyrimidine-4-
on-7-yl)-4,5-dihydro-5-methyl-3
(2H)-pyridazinone (compound 11) 0.2g (
29%).

Example 12 110.3 g of the compound obtained in Example 11 was suspended in 50% acetic acid, 0.1 g of sodium nitrite was added, and the mixture was stirred at room temperature for 30 minutes. The crystals precipitated by adding water were collected and dried to give 6-(3H-[1)benzocheno[3,2-
d) Pyrimidin-4-one (7-yl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (compound 1
2) Obtained 0.25g (87%).

Example 13 Compound d3 obtained in Reference Example 4. og, 3.2 ml of ethyl 2-chloroacetoacetate and 30 ml of dimethylformamide! The mixture was stirred at 100°C for 2 hours.

Concentrate, add water and dry the precipitated crystals, 6-
C4-(5-ethoxycarbonyl-4-methylthiazol-2-yl)phenyl]4,5-dihydro-3(2H
)-pyridazinone (compound 13) 2.8g (72%
) was obtained.

Example 14 In the same manner as in Example 13, 6-C4-(5-acetyl-4-methylthiazole -2-yl)phenyl]-45-dihydro-3(2H)-pyridazinone (compound 14) 1.7 g
(48%).

Example 15 In the same manner as in Example 13, compound d was converted to compound e2. obtained in Reference Example 5. 6-C4-(4-ethoxycarbonylthiazol-2-yl)phenylcou 4.5-dihydro-5- by replacing ethyl 2-taloloacetoacetate with 1.1 ml of ethyl bromopyruvate in
Methyl-3(2H)-pyridazinone (compound 15)1.
3g (47%) was obtained.

Reference Example 1 51 g of 3-(4-bromobenzoyl)butyric acid was added little by little to 300 ml of fuming nitric acid while maintaining the internal temperature at 10 to 20° C. and stirred for 2 hours. The reaction solution was poured into 1 liter of ice water and extracted with chloroform. The chloroform layer was washed with water and concentrated. The residue was crystallized from water to obtain 46 g (77%) of 3-(4-bromo-3-nitrobenzoyl)acetic acid (compound a).

Melting point: 111-113°C IR(KBr) cm-': 1700.1
6! J0.160ONMR (CD(1,) pp width: 8.
3.7.9.3.8.3,0°2.5. 1.2 Reference Example 2゜52g of compound a obtained in Reference Example 1 was added to 300ml of acetic acid.
1 and 52 ml of hydrazine l hydrate and add 10
The mixture was stirred at 0°C for 3 hours. Concentrate to about 1/3 volume and add 5 liters of water.
00- was added, the precipitated crystals were removed with P, dried and smoked, and 6-(4-
Bromo-3-nitrophenyl)-4,5-dihydro-5
-Methyl-3(2H)-pyridazinone (compound b) 54
g (100%) was obtained.

Melting point: 196°C IR(KBr)cl': 1720.16
20. 154ONMR (CDCI-) ppm 2
11.2. 8J, 8.0. 3.4゜2.8.2
3i, 1 Reference Example 3 19 g of the compound b obtained in Reference Example 2 was dissolved in 100-dimethylformamide, 6.7 g of cupric cyanide was added, and the mixture was stirred at 110° C. for 2 hours. The reaction solution was cooled and poured into a mixture of 30 ml of ethylenediamine and 200 ml of water, and insoluble matter was removed by filtration.

The p solution was partitioned between water and chloroform, and the chloroform layer was dried and concentrated. The residue was crystallized from chloroform-diethyl ether to give 6-(4-cyano-3-nitrophenyl).
6.9 g (44%) of -4,5-dihydro-5-methyl-3(21()-pyridazinone (compound C)) was obtained.

Melting point; 208-209°C IR(KBr) cm-': 2210.168
0.160ONMR(CDCf-)Ppm: 11.
4.8,7.8J, 3.52.8.2.3.1.1 Reference example 4゜6-(4-cyanophenyl)i5-dihydro3 (2
H)-pyridazinone 6.8 g, methylthioamide 5.1
g and hydrochloric acid saturated dimethylformamide 501nf! The mixture was stirred at 100°C for 2 hours.

Neutralize with IJ (3N hydroxide) and dry the precipitated crystals several times to obtain 4,5-dihydro-6-(4-thiocarbamoylphenyl)-3(2H)-pyridazinone (compound d) 7 .3g (94%) was obtained.

Melting point: 239-240°C IR(KBr) cm-': 1680.
]630. 160ONMR (DMSO-ds)
ppm: 11.0. 9.9. 9.5°8.
0. 7,8. 3.0. 2.5 Reference Example 5゜6-(4-cyanophenyl)-
4.5 using 5.3 g of 6-(4-cyanophenyl)-45-dihydro-5-methyl-3(2H)-pyridazinone in place of 4,5-dihydro-3(2H)-pyridazinone.
-dihydro-5~methyl6-<4-thiocarbamoylphenyl)-3(2H)pyridazinone (compound e)5.
0 g (94%) was obtained.

Melting point: 239-242°C IR(KBr) am-': 1680.1
640.160ONMR (DMSOdJ ppm: 1
1.0.9.9.9.5゜8.0.7.8.3.5.2
．． 8.2J, 1.1 Effects of the Invention The compound (I) of the present invention and its pharmacologically acceptable salts exhibit excellent cardiotonic action and are useful as cardiotonic agents.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents hydrogen or lower alkyl, and R
^2 has the formula ▲ mathematical formula, chemical formula, table, etc. ▼ (wherein R^3 represents mercapto, lower alkylthio, arylthio, lower alkylsulfinyl, arylsulfinyl, lower alkylsulfonyl or arylsulfonyl), formula ▲ mathematical formula, There are chemical formulas, tables, etc.▼ (In the formula, R^4 represents hydrogen or lower alkyl),
Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^5 represents hydrogen or lower alkyl),
Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^6 represents hydrogen, lower alkyl, or amino) or Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^7 is lower alkyl or lower alkoxycarbonyl, and R^8 represents hydrogen, lower alkanoyl or lower alkoxycarbonyl] and pharmacologically acceptable acid addition salts thereof.