Claims
- 1. A compound having the formula
- wherein X is (CH.sub.2).sub.n wherein n is 1 or 2, or CR.sub.4 .dbd.CR.sub.5 wherein R.sub.4 and R.sub.5 are independently hydrogen or lower alkyl; R and R.sub.1 are independently hydrogen or lower alkyl; R.sub.2 and R.sub.3 are independently lower alkyl or R.sub.2 and R.sub.3 are taken together with the carbon to which each is attached to form a ring having three to six carbons, inclusive.
- 2. A compound of claim 1 wherein X is (CH.sub.2).sub.2.
- 3. A compound of claim 1 wherein R, R.sub.2 and R.sub.3 are methyl and R.sub.1 is hydrogen.
- 4. A compound of claim 1 wherein the specific embodiment is 6-(4,5-dihydro-4,4-dimethyl-5-oxo-1H-pyrazol-3-yl)-3,4-dihydro-1-methyl-2(1H)-quinolinone.
- 5. A pharmaceutical composition for treatment of congestive heart failure, hypertension, or thrombosis comprising a cardiotonic, antihypertensive, or antithrombotic effective amount of a compound as claimed in claim 1 in admixture with a pharmaceutically acceptable carrier.
- 6. A method for increasing cardiac contractility, in a patient requiring such treatment, which comprises administering an effective amount of a pharmaceutical composition according to claim 5.
- 7. A method for lowering blood pressure in a patient requiring such treatment, which comprises administering an effective amount of a pharmaceutical composition according to claim 5.
- 8. A method for decreasing platelet aggregation in a patient requiring such treatment which comprises administering an amount of a pharmaceutical composition according to claim 5.
SUMMARY OF THE INVENTION
This is a continuation of U.S. Ser. No. 846,410 filed Mar. 31, 1986 abandoned which is a continuation of U.S. Ser. No. 685,639 filed Dec. 24, 1984 abandoned.
BACKGROUND OF THE INVENTION
The present invention relates to 6-substituted-2(1H)-quinolinone and related compounds having usefulness for the treatment of congestive heart failure and the therapy of thromboembolic diseases.
Cardiotonic agents having the structure XXX are disclosed in U.S. application Ser. No. 497,316 now U.S. Pat. No. 4,526,982 issued July 2, 1985. However, such agents of formula XXX do not make the novel quinolinones of the present invention obvious. Additionally, compounds of formula XX may be found in British Pat. No. 2,031,404 having antithrombotic and antihypertensive use. Again the combination of cyclic groups in the present invention is not taught.
The present invention relates to novel 6-substituted-2(1H)-quinolinone and related compounds useful as cardiotonic, antihypertensive, and antithrombotic agents having the structural formula I wherein X is (CH.sub.2).sub.n wherein n is 1 or 2, or CR.sub.4 =CR.sub.5 wherein R.sub.4 and R.sub.5 are independently hydrogen or lower alkyl; R and R.sub.1 are independently hydrogen, lower alkyl, or aralkyl; R.sub.2 and R.sub.3 are independently lower alkyl or R.sub.2 and R.sub.3 are taken together with the carbon to which each is attached to form a ring containing three to six carbons, inclusive.
Lower alkyl in the present invention means alkyl of from one to six carbons, inclusive. Aralkyl means optionally substituted phenyl attached through an alkyl of from one to three carbons, inclusive. The substituted phenyl includes one to three substituents such as alkyl of from one to six carbons, inclusive, alkoxy of from one to six carbons, inclusive, hydroxy, halogen, and the like. Halogen herein may be particularly chloro, fluoro, bromo, trifluoromethyl, and iodo, but preferably fluoro, trifluoromethyl, or chloro, the alkyl or alkoxy may be straight or branched hydrocarbons.
The present invention further relates to a method for treating congestive heart failure, hypertension, or diseases advantageously treated with platelet aggregation inhibitors such as thromboembolism in a patient which comprises administering orally or parenterally in a solid or liquid dosage form to such patient an effective amount of compounds having the structure I as defined above. The method of treatment increases cardiac contractility, decreases hypertension, and inhibits platelet aggregation in a patient requiring such treatment.
Another aspect of the present invention relates to a pharmaceutical composition for increasing cardiac contractility for lowering blood pressure or for inhibiting platelet aggregation, said composition comprising an effective amount of a compound of formula I as defined above and a pharmaceutically acceptable carrier.
The process for producing the quinolinone compounds of formula I comprises reacting an appropriately substituted quinolinone having the formula II wherein X, R, R.sub.2, and R.sub.3 are as defined above and Alk is alkyl of from one to four carbon atoms, and preferably methyl or ethyl, with R.sub.1 NHNH.sub.2 wherein R.sub.1 is as defined above. The reaction temperature is preferably at the boiling point of the solvent, that for example, may be an alcohol such as methanol or ethanol. See Scheme I.
The preparation of a compound for formula II is generally accomplished as shown in Scheme II. 6-Acetyl-3,4-dihydro-1-methyl-2(1H)-quinolinone of formula IV or appropriate compound having the desired X may be used as a starting material. The starting material is prepared by following the procedure described in Japan. Kokai 76,115,480 (Chem. Abs. 86, 121190W, 1977). Steps I and II of Scheme II are generally within ranges of reaction parameters determined by skill in the art from those shown as Preparations I and II respectively, hereinafter. The alkylation step II for a compound of formula I where R is lower alkyl may precede step I or be omitted as determined by convenience and desired end product.
The alkylation step shown as step II in Scheme II may be accomplished in one step or in a step-wise manner depending on whether R.sub.2 and R.sub.3 are the same or different. That is, the appropriate alkyl ester of .beta.-oxobezenepropionic acid is reacted with lower alkyl halide; such as iodide, chloride, or bromide, in the presence of sodium hydride in a polar aprotic solvent, such as dimethylformamide. The preferred halide is iodide.
The compounds of formula II wherein R, R.sub.1, and R.sub.2 are different can also be prepared from compounds of formula IV by following steps shown in scheme III.
The reaction conditions of Scheme II or III are within the ordinary skill of the art.
Preferred compounds of the present invention include compounds of formula I wherein X is (CH.sub.2).sub.2. Also preferred are compounds of formula I wherein R, R.sub.2, and R.sub.3 are methyl.
A particularly preferred compound of the present invention is 6-(4,5-dihydro-4,4-dimethyl-5-oxo-1H-pyrazol-3-yl)3,4-dihydro-1-methyl-2(1H)-quinolinone.
The compounds of formula I where R.sub.1 is hydrogen may exist in tautomeric form; for example as illustrated by I.sup.1 .revreaction.I.sup.2. Also covered in the invention are tautomeric forms where R is hydrogen and X is CR.sub.4 .dbd.CR.sub.5 as shown by I.sup.3 .revreaction.I.sup.4.
The following Examples will further illustrate the invention without, however, limiting it thereto.
US Referenced Citations (6)
Foreign Referenced Citations (3)
| Number |
Date |
Country |
| 126651 |
Nov 1984 |
EPX |
| 1466547 |
Mar 1977 |
GBX |
| 2031404 |
Apr 1980 |
GBX |
Continuations (2)
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Number |
Date |
Country |
| Parent |
846410 |
Mar 1986 |
|
| Parent |
685639 |
Dec 1984 |
|
Patent Grant
4840955
