4,5-dihydro-4,4-dialkyl-6-(substituted)phenyl-3(2H)-pyridazinones useful as cardiotonic agents

Novel 4,5-dihydro-4,4-dialkyl-6-(substituted)phenyl-3(2H)-pyridazinones having unexpected activity for use as cardiotonic and antihypertensive agents.

BACKGROUND OF THE INVENTION 
Substituted 4,5-dihydro-6-(substituted)phenyl-3(2H)-pyridazinones and 
6-(substituted)phenyl-3(2H)-pyridazinones useful as cardiotonic agents are 
the subject of U.S. Pat. No. 4,353,905 and U.S. application Ser. No. 
477,695 filed Mar. 22, 1983 now 4,734,415. Additional references are cited 
therein to other known compounds. 
SUMMARY OF THE INVENTION 
The present invention relates to novel 
4,5-dihydro-4,4-dialkyl-6-(substituted)phenyl-3(2H)-pyridazinone compounds 
having unexpectedly superior activity as cardiotonic agents of the formula 
##STR1## 
wherein Q is oxygen or sulfur; R.sub.2 and R.sub.3 are independently 
hydrogen or lower alkyl; R.sub.4 and R.sub.5 are independently lower 
alkyl; Y is H, halogen, lower alkyl, lower alkoxy, or a group such as 
##STR2## 
where R.sub.d and R.sub.e are independently H, lower alkyl, 
(CH.sub.2).sub.n R.sub.f where R.sub.f is a benzene ring optionally 
substituted by halogen, hydroxy, lower alkyl, lower alkoxy, and CF.sub.3, 
and n is zero to three, and A is any of the groups from a-e, and is 
attached to the 3- or 4-position of the phenyl ring: 
##STR3## 
wherein R.sub.1, R', and R are independently hydrogen or lower alkyl, 
CH.sub.2 OH, SCH.sub.3, SOCH.sub.3, SO.sub.2 CH.sub.3, hydroxyalkyl, 
halogen, (CH.sub.2).sub.k NR" R"', wherein k is zero to two and R" and R"' 
are independently hydrogen or lower alkyl, wherein lower alkyl contains 
one to six carbon atoms; or, when attached to the 4- and 5-positions of 
the imidazole ring, may be taken together to form a (i) 5-, 6-, or 
7-membered ring which may also contain a nitrogen atom, (ii) benzene ring 
which is optionally substituted by halogen, hydroxy, lower alkyl, and 
lower alkyloxy, and (iii) pyridine ring; X is a bond, (CH.sub.2).sub.n or 
O(CH.sub.2).sub.n wherein n is one to four; 
##STR4## 
wherein 
(i) W=L=Z=CH 
(ii) W=Z=N and L=CH or 
(iii) L=Z=N and W=CH; and X is a bond, (CH.sub.2).sub.n or 
O(CH.sub.2).sub.n+1 wherein n is 1 to 4; 
##STR5## 
wherein R.sub.6 is hydrogen, alkyl, COR.sub.7 where R.sub.7 is a benzene 
ring optionally substituted by halogen, lower alkyl, hydroxy, lower 
alkoxy, and CF.sub.3 or (CH.sub.2).sub.n R.sub.7 where n is zero to four 
and R.sub.7 is the same as defined above; or 
##STR6## 
wherein R.sub.8 and R.sub.9 are independently hydrogen, lower alkyl, aryl, 
hydroxy, lower alkoxy, NHR.sub.17 where R.sub.17 is hydrogen, lower alkyl 
or lower alkanoyl, CO.sub.2 R.sub.18 where R.sub.18 is hydrogen or lower 
alkyl, OCOBR.sub.10 where R.sub.10 is alkyl, aryl or heteroaryl and B is a 
direct bond or NH, or R.sub.8 and R.sub.9 taken together, are carbonyl or 
ethylenedioxy; 
##STR7## 
wherein represents a double or single bond between two carbon atoms; 
R.sub.11 is hydrogen or lower alkyl; M is NH, O, or S, and X is either a 
direct bond or NH; or 
##STR8## 
where X, M, and R.sub.11 are the same as defined above; or 
e. A=NHPR.sub.12 R.sub.13 wherein P is a bond or carbonyl; R.sub.12 is 
lower alkyl, straight or branched; R.sub.13 is H, NR.sub.14 R.sub.15 
wherein R.sub.14 and R.sub.15 are individually hydrogen, lower alkyl 
straight or branched or taken together to form a 5-, or 6-, or 7-membered 
ring or a group as defined as 1a-1c: or S(O).sub.n R.sub.16 where n is 
zero to two and R.sub.16 is lower alkyl straight or branched, phenyl; 
and the pharmaceutically acceptable acid addition salts thereof. 
Preferred compounds of formula I of the present invention are the compounds 
of formula I wherein Q is oxygen, Y is hydrogen, and A is 
##STR9## 
wherein R, R.sub.1, and R.sub.2 are independently H or lower alkyl, 
R.sub.1 and R.sub.2 may be taken together to form a (i) five or six 
membered ring and (ii) benzene ring; or A is NHPR.sub.12 R.sub.13 wherein 
P is carbonyl, R.sub.12 is lower alkyl, and R.sub.13 is hydrogen and is 
attached to the four-position of the phenyl ring. 
Most preferred compounds of the present invention are 
4,5-dihydro-4,4-dimethyl-6-[4-(1H-imidazol-1-yl)phenyl]3(2H)pyridazinone 
and 
N-[4-(1,4,5,6-tetrahydro-5,5dimethyl-6-oxo-3-pyridazinyl)phenyl]-acetamide 
. 
The present invention further relates to a cardiotonic composition for 
increasing cardiac contractility, said composition comprising an effective 
amount of a compound of formula I as defined above and a pharmaceutically 
acceptable carrier. 
The present invention also relates to the method for increasing cardiac 
contractility in a patient requiring such treatment which comprises 
administering orally or parenterally in a solid or a liquid dosage form to 
such patient an effective amount of a compound of formula I as defined 
above. 
The present invention relates to a pharmaceutical composition which also 
decreases blood pressure, said composition comprising an effective amount 
of a compound of formula I as defined above and a pharmaceutically 
acceptable carrier. 
Finally, the present invention relates to the method of decreasing blood 
pressure in a patient requiring such treatment which comprises 
administering to such patient an effective amount of a compound of formula 
I as defined above. 
DETAILED DESCRIPTION OF THE INVENTION 
The detailed description of a cardiotonic composition and the 
pharmaceutical composition, which may be used for the compound of formula 
I above in combination with a pharmaceutically acceptable carrier, but not 
considering the unexpected activity of the present invention may be found 
in the above noted U.S. Pat. No. 4,353,905 and U.S. application Ser. No. 
477,695 filed Mar. 22, 1983, which therefore, are hereby incorporated by 
reference. In the same manner the method of using the present compounds of 
formula I for increasing cardiac contractility and decreasing blood 
pressure can be ascertained from U.S. application Ser. No. 477,695 filed 
Mar. 22, 1983, when appropriately noting the unexpectedly relative 
activity of the present formula I compounds. The relative activity is as 
set out hereinafter. 
The compounds of the present formula I are also useful in both the free 
base form and in the form of acid addition salts as described in U.S. 
application Ser. No. 477,695. 
The terms "lower" in reference to alkyl and alkoxy, as well as "halogen" 
are as defined in U.S. application Ser. No. 477,695. 
The relative activity showing unexpectedly superiority for the compounds of 
the present invention compared to those of the closest compounds of U.S. 
application Ser. No. 477,695 is shown in the following table. 
TABLE 
__________________________________________________________________________ 
##STR10## 
% Change 
Compound Dose Myocardial 
Heart Blood 
Ex. R.sub.3 
R.sub.4 
R.sub.5 
(mg/kg) 
Contractility 
Rate Pressure 
__________________________________________________________________________ 
H H H 0.01 9 -4.0 -2.0 
0.03 32 -4.0 -6.0 
0.10 57 -1.0 -10.5 
0.31 87 2.0 -21.5 
n = 1 
H CH.sub.3 
H 0.01 0.5 -1.0 0 
0.03 -2.0 -4.5 -1/-1 
0.10 8.0 -4.5 0/-1 
0.31 26.5 -1.5 -5/-9.5 
1.0 61.0 3.0 -7/-14.5 
1* H CH.sub.3 
CH.sub.3 
0.01 15.0 1.5 -1/-1.5 
n = 1 0.03 34.0 4.0 -6/-10 
0.10 70.0 17.0 -11/-16.5 
0.31 101.5 21.5 -22/-34 
1.0 99.0 30.5 -21.5/-31.5 
n = 5 
CH.sub.3 
H H 0.01 50.6 .+-. 11.2 
6.0 .+-. 5.3 
-1.7 .+-. 1.1 
n = 5 0.03 124.0 .+-. 29.4 
25.2 .+-. 8.2 
-7.4 .+-. 1.3 
n = 6 0.10 148.5 .+-. 22.5 
43.8 .+-. 12.0 
-19.0 .+-. 1.3 
n = 4 0.31 118.5 .+-. 31.7 
47.5 .+-. 15.5 
-35.2 .+-. 1.3 
n = 3 1.0 58.6 .+-. 12.9 
33.3 .+-. 13.3 
-45.0 .+-. 4.9 
n = 1 
CH.sub.3 CH.sub.3 
H H 0.01 1 0 1/0 
0.03 5 0 -1/-2 
0.1 20 1 -1/- 2 
0.31 73 5 -8/-9 
1.0 98 15 -15/-17 
__________________________________________________________________________ 
n = number of tests 
*Compound of the present invention 
The test procedure for methods of use of the present invention, are as 
described in U.S. application Ser. No. 477,695.

The following Example further illustrates the present invention without, 
however, limiting thereto. 
EXAMPLE 1 
4,5-Dihydro-4,4-dimethyl-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone 
Imidazole (0.70 g, 0.013 mol) and methyl 
.alpha.,.alpha.-dimethyl-4-fluoro-.gamma.-oxobenzene butanoate (2.85 g, 
0.012 mol) are dissolved in dimethyl sulfoxide (12.0 ml) in which freshly 
pulverized potassium carbonate (5.80 g, 0.042 mol) is suspended. The 
resulting mixture is stirred and heated at 100.degree.-110.degree. for 12 
hours. The mixture is then cooled to room temperature and poured into 100 
ml of ice water and stirred for ten minutes. The solid is filtered to give 
2.14 g of methyl 
.alpha.,.alpha.-dimethyl-4-(1H-imidazol-1-yl)-.gamma.-oxobenzene 
butanoate, mp 89.degree.-93.degree. C. 
Methyl-.alpha.,.alpha.-dimethyl-4-(1H-imidazol-1-yl).gamma.-oxobenzene 
butanoate (1.8 g, 0.0066 mol) is dissolved in ethanol (25 ml) and 1.0 ml 
of 54% aqueous hydrazine is added. The resulting mixture is refluxed for 
ten hours, then another 0.5 ml aqueous hydrazine is added and the mixture 
is refluxed for an additional four hours. 
The solution is evaporated to dryness and the residue is triturated with a 
small volume of ice-cold ethanol and collected on a suction funnel to give 
1.2 g of the title compound, mp 199.degree.-200.degree. C. 
Calcd. for C.sub.15 H.sub.16 N.sub.4 O; C, 67.14; H, 6.01; N, 20.89. C, 
66.91; H, 5.88; N, 20.74.