Studies on positive inotropic agents. IV. Synthesis of 5-(3-amino-2-hydroxypropoxy)-3,4-dihydro-8-hydroxy-2(1H)-quinolinone derivatives.

Abstract

Many 5-(3-amino-2-hydroxypropoxy)-3,4-dihydro-8-hydroxy-2(1H)-quinolinone derivatives were synthesized and examined for positive inotropic activity on the canine heart. These compounds were prepared by the reaction of 8-alkoxy-5-(2,3-epoxypropoxy)-2(1H)-quinolinone derivatives and various amines. Among them, 3,4-dihydro-8-hydroxy-543-(1,1,3,3-tetramethylbutylamino)propoxy]-2(1H)-quinolirrone hydrochloride (IIIf) was found to have potent positive inotropic activity with a relatively minor increase in heart rate. Keywordscongestive heart failure; positive inotropic agent; 3,4-dihydro-8-hydroxy-543-(1,1,3,3-tetramethylbutylamino)propoxy]-2(1H)-quinolinone; biological activityWe have been attempting to find positive inotropic agents among compounds bearing a 2(1H)-quinolinone nucleus as candidate drugs for the treatment of congestive heart failure. In the course of our studies, we found that various 2(1H)-quinolinone derivatives showed desirable activity.1,2) We also found that 5-(3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydro-8-hydroxy-2(1H)-quinolinone (8-OH-carteolol) increased cardiac contractile force.3) Here we report the syntheses and biological activities on the canine heart of many 8-OHcarteolol derivatives.Various 5-(3-amino-2-hydroxypropoxy)-3,4-dihydro-8-hydroxy-2(1H)-quinolinone derivatives (III) were synthesized from the epoxide (I)4) by treatment with appropriate amines, followed by hydrolysis of the tetrahydropyranyloxy group (Table I). Treatment of I with methyl iodide in the presence of NaH in dimethyl formamide (DMF) gave 5-(2,3-epoxypropoxy)-3,4-dihydro-1 -methyl-8-(2-tetrahydropyranyloxy)-2(1H)-quinolinone (IV). The 1-methyl derivative (V) was obtained from IV in the same manner as described for the synthesis of III.The 8-benzyloxy derivative (II)4) was converted to 8-benzyloxy-5-(2,3-epoxypropoxy)-2(1H)-quinolinone (VI) by dehydrogenation with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in dioxane. Compound VI was reacted with butylamine in methanol, followed by hydrogenolysis of the benzyloxy group over 10% palladium on charcoal to afford the desired 2(1H)-quinolinone (VII) (Chart 1).Treatment of 3,4-dihydro-5-hydroxy-8-methoxy-2(1H)-quinolinone (VIII)5) with epichlorohydrin followed by reaction with benzylamine gave the quinolinone (XI). Reaction of the 5-acetoxy derivative (IX)4) with 1-bromo-3-chloropropane in methanol in the presence of K2CO3 gave the corresponding chloride (X). 5-(3-Benzylaminopropoxy)-3,4-dihydro-8-hydroxy-2(1H)-quinolinone hydrochloride (XII) was prepared by reaction of X with benzylamine in acetonitrile (Chart 2).

Synthesis and Adrenergic Activity of a New Series of N-Aryl Dicyclopropyl Ketone Oxime Ethers: SAR and Stereochemical Aspects

“…It is also well-known that most of the initial β-blockers contained an isopropyl- or tert -butylamine. Substitution of the nitrogen present within catecholamines by aralkylamines was found to produce β-adrenergic agonists having additional α-adrenolytic properties. , Similarly, it was found that N -aralkyl substitution could also confer α-adrenolytic properties to β-antagonists. , However, to the best of our knowledge, the influence of a direct aromatic substitution on the terminal amine upon adrenergic activity has scarcely been reported excepted in a few articles which described some N -aryl β-blockers which were found to be very weakly potent. , In the present article we describe the synthesis of a series of 31 new N -aryl dicyclopropyl ketone oxime ether derivatives and discuss the results from their examination in in vitro and in vivo β-adrenergic receptor assays.…”

“…9,10 However, to the best of our knowledge, the influence of a direct aromatic substitution on the terminal amine upon adrenergic activity has scarcely been reported excepted in a few articles which described some N-aryl β-blockers which were found to be very weakly potent. 11,12 In the present article we describe the synthesis of a series of 31 new N-aryl dicyclopropyl ketone oxime ether derivatives and discuss the results from their examination in in vitro and in vivo β-adrenergic receptor assays.…”

Synthesis, Antiproliferative, and Antiplatelet Activities of Oxime‐Containing 3,4‐Dihydroquinolin‐2(1H)‐One Derivatives

“…Certain quinolin-2(1H)-one (carbostyril) derivatives have been proved to possess antiplatelet, anti-inflammatory, anti-ulcer, vasodilatory, and phosphodiesterase inhibitory activities. [1][2][3][4][5][6][7][8][9][10][11][12] The cardiovascular and neuroprotective activities of certain 3,4-dihydroquinolin-2(1H)-ones substituted with various side chains have also been reported. 2,7,10,11,13 Recently, we have synthesized and evaluated the cardiovascular activities of certain a-methyleneg-butyrolactones bearing heterocycles such as coumarins, flavones, xanthones, quinolines, and quinolin-2(1H)ones.…”

“…[1][2][3][4][5][6][7][8][9][10][11][12] The cardiovascular and neuroprotective activities of certain 3,4-dihydroquinolin-2(1H)-ones substituted with various side chains have also been reported. 2,7,10,11,13 Recently, we have synthesized and evaluated the cardiovascular activities of certain a-methyleneg-butyrolactones bearing heterocycles such as coumarins, flavones, xanthones, quinolines, and quinolin-2(1H)ones. [14][15][16][17][18] Among these heterocycles, quinolin-2(1H)-ones proved to be the most active against platelet aggregation.…”