GB2031404A - Pyridazinone compounds - Google Patents

Pyridazinone compounds Download PDF

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GB2031404A
GB2031404A GB7840864A GB7840864A GB2031404A GB 2031404 A GB2031404 A GB 2031404A GB 7840864 A GB7840864 A GB 7840864A GB 7840864 A GB7840864 A GB 7840864A GB 2031404 A GB2031404 A GB 2031404A
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oxo
methyl
hydrogen atom
lower alkyl
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Welfide Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Pyridazinones of the formula: <IMAGE> or pharmaceutically acceptable acid addition salts thereof, wherein A is methylene, ethylene or a vinylene, in the case where A is ethylene or vinylene, it may be substituted with alkyl; B = C < is O = C < or H2C <; R<1> is hydrogen, alkyl, alkanoyl, alkylsulfonyl, or an optionally substituted benzoyl group; R<2> is hydrogen, alkyl, hydroxy alkyl, carbamoylalkyl, naphthyloxyalkyl, oxalkyl, or a (R<6>) (R<7>)N-(CH2)n- group, where each of R<6> and R<7> is hydrogen or alkyl or R<6> and R<7> together with the adjacent nitrogen atom form a heterocycle, and n is 2 or 3; R<3> is hydrogen; R<4> is hydrogen, alkyl, hydroxymethyl or alkanoyloxymethyl; and R<5> is hydrogen or alkyl; or R<3> and one of R<4> and R<5> together form a single bond. The compounds inhibit platelet aggregation and have antihypertensive activity.

Description

SPECIFICATION Pyridazinone compounds This invention relates to pyridazinone compounds which are therapeutically useful as antithrombotic and antihypertensive drugs.
According to the present invention, there is provided a pyridazinone compound of the formula:
or a pharmaceutically acceptable acid addition salt thereof, wherein A is a methylene group, an ethylene group or a vinylene group, in the case where A is an ethylene group or a vinylene group, it may be substituted with a lower alkyl group (e.g. methyl, ethyl, propyl or butyl); B = is O = C < or H2C < ;R1 is a hydrogen atom, a lower alkyl group (e.g. methyl, ethyl, propyl or butyl), an alkanoyl group (e.g. acetyl, propionyl or butyryl), an alkylsulfonyl group (e.g. methanesulfonyl or ethanesulfonyl) or a benzoyl group which may be substituted by at least one substituent at any position(s) on the phenyl nucleus, each substituent being independently selected from a halogen atom (e.g. fluorine, chlorine or bromine), a lower alkyl group (e.g. methyl, ethyl, propyl or butyl) and a lower alkoxy group (e.g. methoxy or ethoxy); R2 is a hydrogen atom, an alkyl group (e.g.
methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl or docosyl), a hydroxy lower alkyl group (e.g. hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl), a carbamoylalkyl group (e.g. carbamoylhexyl, carbamoyloctyl, carbamoyldecyl or carbamoylundecyl), a naphthyloxyalkyl group (e.g. naphthyloxymethyl or 2naphthyloxyethyl), an oxalkyl group (e.g. 3-oxobutyl or 4-oxopentyl) or a (R6) (R7)N(CH2)n group, where each of Re and R7 is a hydrogen atom or a lower alkyl group (e.g. methyl, ethyl, propyl or butyl) or R6 and R7 together with the adjacent nitrogen atom form a heterocycle (e.g. pyrrolidine, piperidine, morpholine, piperazine or N-methylpiperazine) and n is 2 or 3; R3 is a hydrogen atom;R4 is a hydrogen atom, a lower alkyl group (e.g. methyl, ethyl, propyl or butyl), a hydroxymethyl group or a lower alkanoyloxymethyl group (e.g. acetoxymethyl, propionyloxymethyl or butyryloxymethyl); and R5 is a hydrogen atom or a lower alkyl group (e.g. methyl, ethyl, propyl or butyl); or R3 and one of R4 and R5 together form a single bond.
Preferable compounds of the formula (I) are those wherein A is an ethylene group or a vinylene group which may be substituted by a lower alkyl group; B = C < is O = C < ; R1 is a hydrogen atom or a lower alkyl group; R2 is a hydrogen atom, an alkyl group or a (RB)(R7)N--(CH,),,- group, where each of R6 and R7 is a hydrogen atom or a lower alkyl group or R6 and R7 together with the adjacent nitrogen atom form a heterocycle and n is 2 or 3; R3 is a hydrogen atom; R4 is a hydrogen atom, a lower alkyl group, a hydroxymethyl group or a lower alkanoyloxymethyl group; and R5 is a hydrogen atom or a lower alkyl group.
More preferable compounds of the formula (I) are those wherein A is an ethylene group which may be substituted by a lower alkyl group; B = C < is O = C < ; R1 is a hydrogen atom or a lower alkyl group; R2 is a hydrogen atom, a lower alkyl group or a (RB)(R7)N--(CH,),,- group, where each of Re and R7 is a hydrogen atom or a lower alkyl group or R6 and R7 together with the adjacent nitrogen atom form a heterocycle and n is 2 or 3; R3 is a hydrogen atom; R4 is a hydrogen atom, a lower alkyl group a hydroxymethyl group or a lower alkanoyloxymethyl group; and R5 is a hydrogen atom.
The compound of formula (I) can be prepared by reacting a compound of the formula:
wherein each symbol is as defined above, or a functional derivative (e.g. an ester or an acid anhydride) thereof or compound of the formula:
wherein each symbol is as defined above, with a compound of the formula: R2NHNH2 (IV) wherein R2 is as defined above, or hydrate thereof, thereafter the product obtained, if desired, is esterified, alkylated, acylated, sulfonated, dyhydrogenated or converted into a pharmaceutically acceptable acid addition salt.
The reaction of the compound of formula (II) with the compound of formula (IV) is usually carried out without a solvent or in an inert solvent such as water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, dioxane, benzene, toluene, chloroform, dimethylformamide or a mixture thereof at room temperature or under heating.
The reaction of the compound of formula (Ill) with the compound of formula (IV) is preferably carried out by heating under reflux for 1 to 20 hours in a solvent such as methanol, ethanol or isopropanol.
The compound of formula (I) wherein R4 is a lower alkanoyloxymethyl group can be prepared by esterifying the compound of formula (I) wherein R4 is a hydroxymethyl group. The reaction is advantageously carried out by heating under reflux for 1 to 10 hours in the presence of a base such as triethylamine or pyridine in an inert solvent such as chloroform, dimethylformamide or tetrahydrofuran.
The esterifying agent, for example, includes acetic acid, propionic acid, butyric acid or a functional derivative (e.g. an acid anhydride or an acid halide) thereof.
The compound of formula (I) wherein R2 is other than a hydrogen atom can be prepared by alkylating the compound of formula (I) wherein R2 is a hydrogen atom. The reaction is preferably carried out at a temperature of from 0 to 1 00 C for 1 to 10 hours in the presence of a suitable deacidifying agent such as sodium hydride, sodium methoxide or sodium amide in a solvent such as dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone or tetrahydrofuran.
The alkylating agent includes an alkyl halide (e.g. methyl iodine, ethyl bromide, butyl bromide, octyl bromide or docosyl bromide), a hydroxy lower alkyl halide (e.g. 3-hydroxypropyl bromide or 2hydroxyethyl bromide), a carbamoylalkyl halide (e.g. 1 0-carbamoyldecyl bromide), a naphthyloxyalkyl halide (e.g. 2-(2-naphthyloxy)ethyl bromide), an oxoalkyl halide (e.g. 4-oxopentyl bromide), (R6)(R7)N- (CH2)n-Hal, wherein R6, R7 and n are as defined above and Hal is a halogen atom, such as 2dimethylaminoethyl bromide, 3-dimethylaminopropyl bromide, 2-morpholinoethyl bromide or 3piperidinopropyl bromide), or a corresponding organic sulfonate (e.g. methyl methanesulfonate or methyl p-toluenesulfonate) or sulfate (e.g. dimethyl sulfate).
The compound of formula (II) wherein B = C < is H2C < and R1 is an alkanoyl group, an alkylsulfonyl group or a benzoyl group which may be substituted by at least one substituent at any position(s) on the phenyl nucleus, each substituent being independently selected from a halogen atom, a lower alkyl group or a lower alkoxy group can be prepared by reacting a compound of the formula (I) wherein B + C Q2 is H2C < and R1 is a hydrogen atom with an acylating agent such as an acid anhydride or an acid halide or an alkylsulfonyl halide such as methanesulfonyl chloride.The reaction is advantageously carried out in a suitable solvent such as benzene, toluene, chloroform or dioxane, if desired, in the presence of a deacidifying agent such as sodium carbonate, potassium carbonate, pyridine which can also be used as a solvent or triethylamine.
The compound of formula (I) wherein B = C < is H2t < and R' is a hydrogen atom can be prepared by hydrolysing a compound of the formula (I) wherein B = C < is H2 < and Rr is an alkanoyl group, an alkylsulfonyl group or a benzoyl group which may be substituted by at least one substituent at any position(s) on the phenyl nucleus, each substituent being independently selected from a halogen atom, a lower alkyl group or a lower alkoxy group. The hydrolysis is preferably carried out by heating under reflux in the presence of sodium hydroxide in an alcohol.
The compound of formula (I) wherein R3 and one of R4 and R5 together form a single bond can be prepared by dehydrogenating a compound of the formula (I) wherein R3 is a hydrogen atom, R4 is a hydrogen atom, a lower alkyl group, a hydroxymethyl group or a lower alkanoyloxymethyl group and R5 is a hydrogen atom and a lower alkyl group. The reaction is preferably carried out at a temperature of from 0 to 1000C for several hours to scores of hours in the presence of a dehydrogenating agent such as bromine or chlorine with or without an inert solvent such as chloroform, dichloroethane, benzene, toluene or acetic acid.
The compound of formula (I) wherein A is a vinylene group which may be substituted by a lower alkyl group can be prepared by dehydrogenating a compound of the formula (I) wherein A is an ethylene group which may be substituted by a lower alkyl group. The reaction is preferably carried out at room temperature or under reflux for several hours to scores of hours in the presence of a dehydrogenating agent such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone, 2,3,5,6-tetrachloro-1 ,4-benzoquinone or palladium-carbon in an inert solvent such as methanol, benzene, toluene, xylene or dioxane.
The compounds of the present invention can be converted in a conventional manner into the corresponding acid addition salts with various inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, maleic, fumaric, oxalic and citric acids.
The starting compounds of formulas (II) and (III) can be prepared by such a conventional manner as described in the following reaction scheme:
Examples of Starting Compounds (1) 4-Oxo-4-(1 -methyl-2-oxoindolin-5-yl)-3-methylbutanoic acid, melting at 180-1 820C; (2) 4-Oxo-4-(1-methyl-2-oxoindolin-5-yl)butanoic acid, melting at 236-2400C; (3) 4-Oxo-4-(indolin)-5-yl)-3-methylbutanoic acid, melting at 1 93-1 950C; (4) 4-Oxo-4-( 1 ,2,3,4-tetrahydroquinolin-6-yl)-3-methylbutanoic acid; (5) 4-Oxo-4-( 1 ,4,4-tri methyl-2-oxo- 1 ,2,3,4-tetrahydroquinolin-6-yl)-3-methylbutanoic acid, melting at 133-1350C;; (6) 4-Oxo-4-(4-methyl-2-oxo- ,2,3,4-tetrahydroquinolin-6-yl)-3-methylbutanoic acid, melting at 172-1 740C; (7) 4-Oxo-4-( 1 ,4,4-trimethyl-2-oxo-1 ,2,3,4-tetrahydroquinolin-6-yl)butanoic acid, melting at 194-1 970C; (8) 4-(1 -Ethyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6-yi)carbonyl-y-butyrolactonet melting at 135-1 380C; and (9) 4-(1-Methyl-2-oXo-1,2,3,4-tetrahydroquinolin-6-yl)carbonyl-F-butyrolactone, melting at 142-1 44cC.
The compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof have inhibitory activities on platelet aggregation and antihypertensive activities as shown, for example, by the following tests: Testing Methods I. Inhibitory activity on platelet aggregation in rats and rabbits A group of ií- 6 rats (250--300 g) or 3 rabbits (3-3.5 kg) was used. The citrated blood was obtained 2 hours after the oral treatment with test compounds. The platelet aggregation of platelet richplasma was induced by addition of 1.5 x 10-5 M adenosine diphosphate (final concentration) and was measured with a Born type six channel aggregometer (G.V.R. Born, J. Physiol. 162, 67 (1962)). Results are shown in the following Table I as the percent inhibition of the aggregation as compared with the control group.
II. Antihypertensive activity in spontaneously hypertensive rats A group of 5 spontaneously hypertensive rats (300-350 g) was used. Tail blood pressure was determined by a rat tail manometer (NARCO, PE-300) without anesthesia immediately before and 5 hours after the oral treatment with test compounds. The rat was warmed at 400C for 10 minutes. The apparatus detects blood flow pulses in the tail by a pulse sensor. The arterial blood flow was interrupted by applying pressure to the tail through a pneumatic cuff. The blood flow reappeared when the cuff pressure was decreased. The value was approximately equal to the maximum blood pressure. Results are shown in the following Table I as mmHg in a decrease of maximum blood pressure at 5 hours after the treatment.
Test Compounds Compound A: 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) 1 -methyl-1 ,2,3,4- tetrahydroquinolin-2-one Compound B: 6-(5-Acetoxymethyl-3-oxo-2,3 ,4,5-tetrahydropyridazin-6-yl)- 1-methyl- 1,2,3,4 tetrahydroquinolin-2-one Compound C: 6-(5-Methyl-3-oxo-2,3 ,4,5-tetrahydropyridazin-6-yl)- 1 ,4,4-tri methyl- 1,2,3,4 tetrahydroquinolin-2-one Compound D: 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1,4-dimethyl- 1,2,3,4 tetrahydroquinolin-2-one Compound E: 6-( 5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) 1 ,4,4-trimethyl-1 2,3,4- tetrahydroquinolin-2-one Compound F: 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1 -methyl-1 2,3,4- tetrahydroquinolin-2-one Compound G: 6-(5-Ethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1-ethyl-i ,2,3,4-tetrahydroquinolin- 2-one Compound H: 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -ethyl- 1,2,3,4- tetrahydroquinolin-2-one Compound l: 6-(5-Acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1-ethyl- 1,2,3,4- tetrahydroquinolin-2-one Compound J: 6-( 5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1-ethyl-1,2.3,4- tetrahydroquinolin-2-one Compound K: 6-[5-Methyl-2-(2-morpholinoethyl)-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]- i-methyl- 1 ,2,3,4-tetrahydroquinolin-2-one hydrochloride hemihydrate RESULTS TABLE I
Percent inhibition of platelet aggregation Decrease of tail Dose blood pressure Compound (mg/kg, p.o.) Rat Rabbit (mmHg) in SHR 0.03 62 93+2(SE) 0.10 61 A 0.30 .23 1.0 56 3 51 85+6 31 B 30 62 3 59 93+1 48 C 30 63 0.1 38 D 0.3 78+6 16 3.0 71 10 43 E 30 48+16 3 62 F 30 92 G 3 34 H 3 46 3 46 30 47 J 3 35 K 3 51 75+8 45 The inhibitory agents of platelet aggregation are useful in the prophylaxis or therapy of plateletinduced thromboembolism, and in modifying other platelet-mediated phathologic processes such as atherosclerosis in human beings. Therefore, these agents are useful as the drugs for treatment of the patients with following diseases or disorders: (i) cerebrovascuiar disorders such as transient ischemic attacks, transient monocular blindness or completed stroke, (ii) ischemic heart diseases such as a myocardial infarction, (ii) thrombosis in other arteries, (iv) microcirculatoly thrombosis and (v) venous thrombosis. These agents are also used for patients with prosthetic heart valves or arterio-venous shunts, and are useful as anti hypertensive drugs.
The compound of formula (I) and pharmaceutically acceptable acid addition salts thereof can be administered safely as antithrombotic or antihypertensive drugs, either alone or in the form of a pharmaceutical preparation with a suitable and conventional carrier or adjuvant, administered orally, without harmful side effects to the patients.
The pharmaceutical composition can take the form of tablets, granules, powder or capsules, for oral administration, of injectable solution for subcutaneous or intramuscular administration. The choice of carrier is determined by the preferred form of administration, the solubility of the compounds and standard pharmaceutical practice.
FORMULATION EXAMPLE 10 mg tablets are prepared from the following compositions: Compound A 10.0 mg Lactose 32.0 mg Microcrystalline cellulose 4.7 mg Corn starch 12.0 mg Magnesium stearate 0.3 mg Talc 1.0 mg 60.0 mg The oral daily dose of the compounds of formula (I) or pharmaceutically acceptable acid addition salts thereof for human adults usually ranges from 0.1 to 100 mg, but it may vary depending upon the age, body weight, and/or severity of the conditions to be treated as well as the responses to the medication.
The present invention is further explained by way of the following illustrative examples: EXAMPLE 1 A solution of 7 g of 4-oxo-4-(1 -methyl-2-oxoindolin-5-yl)butanoic acid and 3 ml of hydrazine hydrate in 70 ml of dimethylformamide was heated on a water bath for 4 hours. The precipitated crystals were filtered off and recrystallized from dimethylformamide to give 4.0 g of 5-(3-oxo-2,3,4,5- tetrahydropyridazin-6-yl)- 1 -methylindolin-2-one as pale yellow prisms, melting at 2 6 1 --2640 C.
EXAMPLE 2 A solution of 27 g of 4-oxo-4-(indolin-5-yl)-3-methylbutanoic acid hydrochloride and 1 5 ml of hydrazine hydrate in 200 ml of ethanol was heated under reflux on a water bath for 2 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The precipitated crystals were filtered off, washed with water and recrystallized from ethanol to give 20 g of 5-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)indoline as white crystals, melting at 187-1 890C.
EXAMPLE 3 To a solution of 5-(5-methyi-3-oxo-2,3,4,5-tetrahydropyridazin-6-yí)indoline in 100 ml of chloroform was added 5 ml of triethylamine with stirring. To the mixture was added dropwise 3 ml of acetic anhydride. After maintaining at room temperature for one hour, the reaction mixture was concentrated under reduced pressure. The residual crystals were filtered off, washed with water and recrystallized from ethanol to give 4.3 g of 5-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1- acetylindoline as white crystals, melting at 258-261 0C.
The following compounds can be prepared in an analogous manner mentioned in the above Examples: 5-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)indolin-2-one, melting at 3400 C with decomposition; 5-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)indolin-2-one, melting at 27 60C; 5-( 5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -methylindolin-2-one, melting at 213--214"C; 5-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -methanesulfonylindoline, melting meting at 230-2320C 6-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -acetyl- 1 ,2,3,4-tetrahydroquinoline, melting at 2100C; 6-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 ,2,3,4-tetrahydroquinoline, melting at 1 66-1 680 C;; 6-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -(4-fluorobenzoyl)- 1 ,2,3,4-tetrahydroquinoline, 6-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -(3,4-dichlorobenzoyl)- 1,2,3,4-tetrahydroquinoline; 6-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -(4-methoxybenzoyl)- 1 ,2,3,4-tetrahydroquinoline; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1 ,2,3,4-tetrahydroquinoline, melting at 154-1 570C; 6-( 5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -acetyl-1 ,2,3,4-tetrahydroquinoline, melting at 175-1 780C; 6-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -(4-methylbenzoyl)- 1 ,2,3,4-tetrahydroquinoline;; 5-(5-Butyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)indoline; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 methyl ,2,3,4-tetrahydroquinolin-2-one, melting at 166-1 680C; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 ,2,3,4-tetrahydroquinolin-2-one, melting at 300-3050C with decomposition; 6-( 5-Methyl-3-oxo-2 ,3,4,5-tetrahydropyridazi n-6-yl)- 1 -(4-chlorobenzoyl)- 1,2,3,4tetrahydroquinoline, melting at 236--2380C; and 6-( 5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -methyl-1 ,2,3,4-tetrahydroquinoline, melting at 164-1 650C.
EXAMPLE 4 A solution of 2.72 g of 4-oxo-4-(1 -methyl-2-oxo-l ,2,3,4-tetrahydroquinolin-6-yl)-3- methylbutanoic acid and 1.5 g of 2-hydrazinoethanol in 30 ml of ethanol was heated under reflux on a water bath for 2 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The precipitated crystals were filtered off and recrystallized from isopropanol to give 2.5 g of 6-[2-(2-hydroxyethyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]- 1-methyl 1 ,2,3,4-tetrahydroquinolin-2-one as colorless crystals, melting at 171-1 730C.
EXAMPLE 5 To a solution of 5.4 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1 -methyl-1,2,3,4- tetrahydroquinolin-2-one in 50 ml of dimethylformamide was added 1.1 g of 50% sodium hydride. After stirring for about 30 minutes, 2.4 g of ethyl bromide was added and the mixture was stirred at about 400C for one hour. The reaction mixture was poured into 200 ml of water and extracted with 100 ml of ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure.
The residue was recrystallized from ethanol to give 3.7 g of 6-(2-ethyl-5-methyl-3-oxo-2,3,4,5tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-2-one as colorless crystals, melting at 170-1 720C.
The following compounds can be prepared in an analogous manner mentioned in the above Examples: 6-[2-(2-Naphthyloxy)ethyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazi n-6-yl]- 1 -methyl-1,2,3,4- tetrahydroquinolin-2-one, melting at 127-1290C; 5-[2-(2-Hydroxyethyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]-indoline, melting at 1 17-1200C; 6-(2-Butyl-5-methyl-3-oxo-2 ,3 ,4,5-tetra hydropyridazi n-6-yl)- 1 -methyi- 1,2,3,4tetrahydroquinolin-2-one, melting at 109-11 00C; 6-(5-Methyl-2-octadecyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1-methyl- 1,2,3,4- tetrahydroquinolin-2-one, melting at 66--700C;; 6-(2-Docosyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1-methyl- 1 2,3,4- tetrahydroquinolin-2-one, melting at 65-67 0C; 6-(5-Methyl-2-pentadecyl-3-oxo-2,3,4,5-tetrahydropyridazi n-6-yl )- 1 -methyl-1 ,2,3,4- tetrahydroquinolin-2-one, melting at 68.5--70.50 C; 6-[2-(4-Oxopentyl )-5-methyl-3-oxo-2 ,3,4, 5-tetra hydropyrid azi n-6-yl] - 1-methyl-I 1,2,3,4- tetrahydroquinolin-2-one, melting at 80--83 C; 6-[2-(10-Carbamoyldecyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-ylj-1 -methyl-1 ,2,3,4- tetrahydroquinoline-2-one, melting at 77-81 C;; 6-(2-Heptadecyl-5-methyl-3-oxo-2,3,4,5-tetra hydropyridazin-6-yl)- 1-methyl- 1 2,3,4- tetrahydroquinolin-2-one, melting at 76--780C; 6-(2-Hexadecyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -methyl- 1,2,3,4- tetrahydroquinolin-2-one, melting at 70-71 OC; and 5-(2-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -methylindolin-2-one, melting at 200-2030C.
EXAMPLE 6 To a solution of 3 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1 ,4,4- trimethyl-1 ,2,3,4-tetrahydroquinolin-2-one in 30 ml of dimethylformamide was added 0.9 g of 50% sodium hydride. After stirring for about 30 minutes, 1.7 g of 2-morpholinoethyl chloride was added and the mixture was stirred at about 500C for one hour. The reaction mixture was poured into 200 ml of icecold water and extracted with 1 50 ml of chloroform. The extract was dried over potassium carbonate and concentrated under reduced pressure. To the residue was added alcoholic hydrogen chloride and the precipitated crystals were filtered off.Recrystallization from isopropanol gave 2.5 g of 6-[5-methyl 2-(2-morpholinoethyl)-3-oxo-2,3 ,4,5-tetrahydropyridazin-6-yl]- 1 ,4,4-trimethyl- 12,3,4- tetrahydroquinolin-2-one hydrochloride, melting at 243--2460C.
The following compounds can be prepared in an analogous manner mentioned in the above Example: 6-[5-Methyl-2-(2-morpholinoethyl)-3-oxo-2,3,4,5-tetrahydropyridazin-6-ylj- 1 methyl-1 ,2,3,4-tetrahydroquinolin-2-one hydrochloride hemihydrate, melting at 221-2290C; 6-[5-Methyl-2-(3-piperidinopropyl)-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]- 1 - methyl-1 ,2,3,4-tetrahydroquinolin-2-one hydrochloride, melting at 232--2330C; 6-|5-Methyl-2-(3-4-methylpiperazin- 1 -yl)-3-oxo-2 ,3,4,5-tetrahydropyridazin-6-ylj- 1 -methyl-1 ,2,3,4-tetrahydroquinolin-2-one dihydrochloride, melting at 257--2590C with decomposition;; 6-[2-(2-Dimethyla minoethyl)-5-methyl-3-oxo-2,3 ,4,5-tetrahydropyridazin-6-yl- 1 ,4,4-trimethyl-1 ,2,3,4-tetrahydroquinolin-2-one, hydrochloride, melting at 237-2390C with decomposition; and 6-[2-(3-Di methyla minopropyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6- yl]-1 ,4,4-trimethyl-1 ,2,3,4-tetrahydroquinolin-2-one hydrochloride hydrate, melting at 220--2240C.
EXAMPLE 7 A mixture of 20 g of 4-oxo-4-(1 ,4,4-trimethyl-2-oxo- 1 ,2,3,4-tetrahydroquinolin-6-yl)-3- methylbutanoic acid,10 g of hydrazine hydrate and 200 ml of ethanol was heated under reflux for one hour. After cooling, the precipitated crystals were filtered off and recrystallized from ethanol to give 1 5.1 g of 6-(5-methyl-3-oxo-2 ,3,4,5-tetrahydropyridazin-6-yl)- 1 4,4-trimethyl- 1,2,3,4tetrahydroquinolin-2-one, melting at 238-241 OC.
EXAMPLE 8 To a mixture of 6 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1 ,4,4-trimethyl- 1 ,2,3,4-tetrahydroquinolin-2-one and 60 ml of dimethylformamide was added 1.8 g of sodium hydride.
After 30 minutes, 4.6 g of butyl bromide was added to the mixture and the whole mixture was stirred for one hour. After completion of the reactipn, the mixture was poured into ice-cold water and the precipitated crystals were filtered off and recrystallized from a mixture of ethanol and water to give 5.2 g of 6-(2-butyl-5-methyl-3-oxo-2,3 ,4,5-tetrahydropyridazin-6-yl)- 1 ,4,4-tri methyl- 1,2,3,4tetrahydroquinolin-2-one, melting at 1 37-1 390C.
EXAMPLE 9 To a mixture of 12 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-4-methyl-1 ,2,3,4- tetrahydroquinolin-2-one and 200 ml of acetic acid was added dropwise 8.4 g of bromine. The mixture was heated with stirring at 60-700C for 3 hours and then the solvent was distilled off under reduced pressure. To the residue was added water and the precipitated crystals were filtered off.
Recrystallization from acetic acid gave 6.5 g of 6-( 5-methyl-3-oxo-2,3-dihydropyridazin-6-yl)-4-methyl1 ,2,3,4-tetrahydroquinolin-2-one, melting at above 3000 C.
EXAMPLE 10 A mixture of 5.4 g of 6-( 5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -methyl-1 ,2,3,4- tetrahydroquinolin-2-one, 5.5 g of 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone and 500 ml of benzene was heated under reflux for 48 hours. After cooling, the precipitated crystals were filtered off. The filtrate was washed with a 10% sodium hydroxide solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue and the crystals were combined and purified by using a column chromatograph.The resulting crystals were recrystallized from methanol to give 1.5 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -methyl-1 ,2-dihydroquinolin-2-one, melting at 248-251 ?C.' The following compounds can be prepared in an analogous manner mentioned in the above Examples:: 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1 ,4-dimethyl-l ,2,3,4-tetrahydroquinolin-2one, melting at 223-2250C; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-4-methyl- 1 ,2,3,4-tetrahydroquinolin-2-one, melting at 275-2780C; 6-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 4,4-trimethyl- 1 ,2,3-4-tetrahydroquinolin-2-one, melting at 233-2350C; 6-(2,5-Dimethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 ,4,4-trimethyl- 1,2,3,4tetrahydroquinolin-2-one, melting at 1 65-1 690C;; 6-( 5-Methyl-3-oxo-2,3-dihydropyradazin-6-yl)- 1,4,4-tri methyl- ,2,3,4-tetra hydroqui nolin-2-one, melting at 270-2740C; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yI)- 1,4-di ,4-dimethyl-1 ,2-dihydroquinolin-2-one; 6-(5-Methyl-3-oxo-2,3-dihydropyridazin-6-yl)-1 -methyl- ,2-dihydroquinolin-2-one; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -ethyl-4-methyl- 1 ,2 ,3 ,4- tetrahydroquinolin-2-one; 6-(5-Ethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 ,4,4-trimethyl-1 ,2,3,4-tetrahydroquinolin-2one;; 6-(2-Ethyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 ,4,4-trimethyl- 1 2,3,4- tetrahydroquinolin-2-one; 6-(5-Ethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1 ,4-dimethyl-1 ,2-dihydroquinolin-2-one; 6-( 5-methyl-2-propyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 ,4-dimethyl- 1 2-dihydroquinolin- 2-one; 6-(2,5-Dimethyl-3-oxo-2,3-dihydropyridazin-6-yl)- 1 4-dimethyl- 1 ,2-dihydroquinolin-2-one; and 6-(5-M ethyl-3-oxo-2,3,4, 5-tetra hydropyridazi n-6-yl)-1 -butyl-4,4-di methyl- 1 ,2,3,4- tetrahydroquinolin-2-one.
EXAMPLE 11 A solution of 4.9 g of 4-( 1 -methyl-2-oxo-i ,2,3,4-tetrahydroquinolin-6-yl)-carbonyl-y- butyrolactone and 3.0 ml of 85% hydrazine hydrate in 50 ml of ethanol was heated under reflux overnight. The reaction mixture was concentrated under reduced pressure and ice-cold water was added to the residue. After the mixture was allowed to stand, the precipitated crystals were filtered off and recrystallized from water to give 2.5 g of 6-(5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6- yl)-l-methyl-l ,2,3,4-tetrahydroquinolin-2-one as colorless prisms, melting at 201--2040C.
EXAMPLE 12 A solution of 13.6 g of 6-(5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1 -methyl 1 ,2,3,4-tetrahydroquinolin-2-one, 5.8. g of acetic anhydride and 10 ml of triethylamine in 300 ml of chloroform was heated under reflux on a water bath for 3 hours. The reaction mixture was washed with water, dried over potassium carbonate and concentrated under reduced pressure. The residue was dissolved into a small amount of ethyl acetate. After the solution was allowed to stand, the precipitated crystals were filtered off and recrystallized from isopropanol to give 7.3 g of 6-(5-acetoxymethyl-3-oxo 2,3,4,5-tetrahydropyridazin-6-yl)-l -methyl-l ,2,3,4-tetrahydroquinolin-2-one as needles, melting at 149-1 530C.
The following compounds can be prepared in an analogous manner mentioned in the above Examples: 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1,2,3,4tetrahydroquinolin-2-one, melting at 325-3300C; 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1,4,4-trimethyl- 1 ,2,3,4-tetrahydroquinolin-2-one, melting at 241--243 C; 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1-ethyl- 1,2,3,4tetrahydroquinolin-2-one, melting at 198--200 C; 6-(5-Acetoxymethyl-3-oxo-2,3,4,5-tetra hydropyridazi n-6-yí )- 1 -ethyl- 1,2,3,4- tetrahydroquinolin-2-one, melting at 1 57-1 590C;; 6-(5-Hydroxymethyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1-methyl1 ,2,3,4-tetrahydroquinolin-2-one, melting at 21 8-21 9 CC; 6-(5-Acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -methyl- 1,2,3,4- tetrahydroquinolin-2-one, melting at 230--2320C; 6-(5-Butyryloxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 -methyl- 1,2,3,4- tetrahydroquinolin-2-one, melting at 93--980C; 6-(5-Hydroxymethyl-2-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1 -methyl1,2,3,4-tetra hydroquinolin-2-one; 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 ,4-di methyl- 1,2dihydroquinolin-2-one; ; 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1 ,4-dimethyi- 1,2,3,4-tetrahydroquinolin-2-one, melting at 222--2230C: 6-(2-Butyl-5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- i-methyl- 1 ,2,3,4-tetrahydroquinolin-2-one; and 6-( 5-Acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1,4-dimethyl 1,2,3,4-tetrahydroquinolin-2-one.

Claims (15)

1. A pyridazinone compound of the formula:
or a pharmaceutically acceptable acid addition salt thereof, wherein A is a methylene group, an ethylene group or a vinylene group, in the case where A is an ethylene group or a vinylene group, it may be substituted with a lower alkyl group; B = C < is O = C < or H2C < ;R' is a hydrogen atom, a lower alkyl group, an alkanoyl group, an alkylsulfonyl group or a benzoyl group which may be substituted by at least one substituent at any position(s) on the phenyl nucleus, each substituent being independently selected from a halogen atom, a lower alkyl group and a lower alkoxy group; R2 is a hydrogen atom, an alkyl group, a hydroxy lower alkyl group, a carbamoylalkyl group, a naphthyloxyalkyl group, an oxoalkyl group or a (Fl6)(Fl7)N(CH2) group, where each of R6 and R7 is a hydrogen atom or a lower alkyl group or R6 and R7 together with the adjacent nitrogen atom form a heterocycle and n is 2 or 3; R3 is a hydrogen atom;R4 is a hydrogen atom, a lower alkyl group, a hydroxymethyl group or a lower alkanoyloxymethyl group; and R5 is a hydrogen atom or a lower alkyl group; or R3 and one of R4 and R5 together form a single bond.
2. A compound as claimed in Claim 1, wherein A is an ethylene group or a vinylene group which may be substituted by a lower alkyl group; B = C < is O = C < ; R' is a hydrogen atom or a lower alkyl group; R2 is a hydrogen atom, an alkyl group or a (R6)(Fl7)N(CH2) group, where each of R6 and R7 is a hydrogen atom or a lower alkyl group or RB and R7 together with the adjacent nitrogen atom form a heterocycle and n is 2 or 3; R3 is a hydrogen atom; R4 is a hydrogen atom, a lower alkyl group, a hydroxymethyl group or a lower alkanoyloxymethyl group; and R5 is a hydrogen atom or a lower alkyl group.
3. A compound as claimed in Claim 1, wherein A is an ethylene group or an ethylene group substituted with a lower alkyl group; B = C < is O = C < 2; R1 is a hydrogen atom or a lower alkyl group; R2 is a hydrogen atom, a lower alkyl group or a (Fl6)(R7)N(CH2) group, where each of R6 and R7 is a hydrogen atom or a lower alkyl group or R6 and R7 together with the adjacent nitrogen atom form a heterocycle and n is 2 or 3; R3 is a hydrogen atom; R4 is a hydrogen atom, a lower alkyl group, a hydroxymethyl group or a lower aikanoyloxymethyl group; and R5 is a hydrogen atom.
4.6-(5-Methyl-3-oxo-2,3,4,5-tetra hydropyridazin-6-yl)- 1 -methyl- 1,2,3,4- tetrahydroquinolin-2-one.
5. 6-(5-Methyl-3-oxo-2,3,4,5-tetra hydropyridazin-6-yl)- 1 ,4-dimethyl- 1,2,3,4tetrahydroquinolin-2-one.
6. 6-( 5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 ,4,4-trimethyl-i ,2,3,4- tetrahydroquinolin-2-one.
7. 6-( 5-Acetoxymethyl-3-oxo-2,3 ,4,5-tetrahydropyridazin-6-yl)- 1-methyl- 1,2,3,4tetrahydroquinolin-2-one.
8. 6-( 5-Hydroxymethyl-3-oxo-2 ,3,4, 5-tetrahydropyridazin-6-yl)- 1 -methyí- ,2,3 ,4- tetrahydroquinolin-2-one.
9. 6-[5-Methyl-2-(2-mornholinoethyl)-3-oxo-2,3,4,5-tetrahydrnpyndazin-6-yl)-1- methyl-l ,2,3,4-tetrahydroquinolin-2-one.
10. 6-(5-Ethyl-3-oxo-2,3A,5-tetrahydrnpyndazin-6-yl)1 -ethyl-1 ,2,3,4- tetrahydroquinolin-2-one.
11.6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- -ethyl- 1,2,3,4- tetrahydroquinolin-2-one.
12.6-(5-Acetoxymethyl-3-oxo-2,3,4,5-tetrahydrnpyridazin-6yl) 1-ethyl-1.2,3,4- tetrahydroquinolin-2-one.
13.6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazì 1-ethyl-I ,2,3,4- tetrahydroquinolin-2-one.
14.6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)- 1 ,4,4-trimethyl- 1 ,2,3,4-tetrahydroquinolin-2-one.
1 5. 6-(2,5-Dimethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yI)- 1 ,4,4-trimethyl1 ,2,3,4-tetrahydroquinolin-2-one.
1 6. A pharmaceutically acceptable acid addition salt of the compound as claimed in any one of Claims 2 to
15.
GB7840864A 1978-10-17 1978-10-17 Pyridazinone compounds Withdrawn GB2031404A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0052016A1 (en) * 1980-11-11 1982-05-19 Otsuka Pharmaceutical Co., Ltd. Carbostyril compounds, compositions containing same and processes for preparing same
EP0178876A1 (en) * 1984-10-15 1986-04-23 Eli Lilly And Company Pyridazinone inotropic agents
EP0188917A1 (en) * 1984-12-24 1986-07-30 Warner-Lambert Company 6-Substituted-2(1H)-quinolinones and related compounds having use as cardiotonic, antihypertensive, and antithrombotic agents
EP0259871A1 (en) * 1986-09-12 1988-03-16 Roche Diagnostics GmbH Indolinones substituted by heterocycles, process for their preparation and medicines containing them
US4840955A (en) * 1984-12-24 1989-06-20 Warner-Lambert Company 6-substituted-2(1H)-quinolinones and related compounds having use as cardiotonic, antihypertensive, and antithrombotic agents

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0052016A1 (en) * 1980-11-11 1982-05-19 Otsuka Pharmaceutical Co., Ltd. Carbostyril compounds, compositions containing same and processes for preparing same
EP0178876A1 (en) * 1984-10-15 1986-04-23 Eli Lilly And Company Pyridazinone inotropic agents
US4617302A (en) * 1984-10-15 1986-10-14 Eli Lilly And Company Inotropic agents
EP0188917A1 (en) * 1984-12-24 1986-07-30 Warner-Lambert Company 6-Substituted-2(1H)-quinolinones and related compounds having use as cardiotonic, antihypertensive, and antithrombotic agents
US4840955A (en) * 1984-12-24 1989-06-20 Warner-Lambert Company 6-substituted-2(1H)-quinolinones and related compounds having use as cardiotonic, antihypertensive, and antithrombotic agents
EP0259871A1 (en) * 1986-09-12 1988-03-16 Roche Diagnostics GmbH Indolinones substituted by heterocycles, process for their preparation and medicines containing them
US4870077A (en) * 1986-09-12 1989-09-26 Boehringer Mannheim Gmbh Heterocyclic substituted indolinones

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