Abstract:
Cardiovascular activity is exhibited by compounds having the formula ##STR1## or a pharmaceutically acceptable salt thereof wherein R 1  is ##STR2## or ##STR3## and R 2 , R 3  and R 4  are as defined herein.

Description:
BRIEF DESCRIPTION OF THE INVENTION 
     Compounds having the formula ##STR4## and pharmaceutically acceptable salts thereof, are cardiovascular agents. In formula I, and throughout the specification, the symbols are as defined below. 
     R 1  is ##STR5## or ##STR6## 
     R 2  is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, --(CH 2 ) n  -Y 1 , or halo substituted alkyl; 
     R 3  is hydrogen, alkyl, cycloalkyl, aryl, --(CH 2 ) n  --Y 2 , --(CH 2 ) p  --Y 3 , or halo substituted alkyl; 
     R 4  is aryl; 
     R 5  is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R 6  is hydrogen, alkyl, cycloalkyl, --(CH 2 ) n  --Y 2 , --(CH 2 ) p  --Y 3  or halo substituted alkyl, or R 5  and R 6  taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperizinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl or 1-pyrrolidinyl, 1-piperidinyl, or 1-azeipinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy; 
     R 7  is alkyl, cycloalkyl, aryl, --(CH 2 ) n  --Y 2 , --(CH 2 ) p  --Y 3  or halo substituted alkyl; 
     Y 1  is cycloalkyl, aryl, hydroxyl, alkoxy, aryl--(CH 2 ) m  --O--, mercapto, alkylthio, aryl--(CH 2 ) m  --S--, amino, substituted amino, carbamoyl, (substituted amino) ##STR7## carboxyl, alkoxycarbonyl, ##STR8## or ##STR9## 
     Y 2  is cycloalkyl, aryl, carbamoyl, ##STR10## carboxyl, alkoxycarbonyl, ##STR11## or ##STR12## 
     Y 3  is hydroxyl, alkoxy, aryl--(CH 2 ) m  --O--, mercapto, alkylthio, aryl--(CH 2 ) m  --S--, ##STR13## amino or substituted amino; 
     m is 0 or an integer of 1 to 6; 
     n is an integer of 1 to 6; and 
     p is a integer of 2 to 6. 
     Listed below are definitions of various terms used to describe the compounds of this invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group. 
     The terms &#34;alkyl&#34; and &#34;alkoxy&#34; refer to both straight and branched chain groups. Those groups having 1 to 8 carbon atoms are preferred. 
     The term &#34;halo substituted alkyl&#34; refers to alkyl groups (as described above) in which one or more hydrogens have been replaced by chloro, bromo or fluoro groups. Exemplary groups are trifluoromethyl, which is preferred, pentafluoroethyl, 2,2,2-trichloroethyl, chloromethyl, bromomethyl, etc. 
     The term &#34;aryl&#34; refers to phenyl and substituted phenyl. Exemplary substituted phenyl groups are phenyl groups substituted with one, two or three alkyl, alkoxy, alkylthio, halo, nitro cyano, trifluoromethyl, or difluoromethoxy groups. 
     The terms &#34;alkenyl&#34; and &#34;alkynyl&#34; refer to both straight and branched chain groups. Those groups having 2 to 8 carbon atoms are preferred. 
     The term &#34;cycloalkyl&#34; refers to those groups having 3, 4, 5, 6 or 7 carbon atoms. 
     The term &#34;halo&#34; refers to chloro, bromo, fluoro and iodo. 
     The term &#34;substituted amino&#34; refers to a group of the formula --NZ 1  Z 2  wherein Z 1  is hydrogen, alkyl, or aryl--(CH 2 ) m  -- and Z 2  is alkyl or aryl--(CH 2 ) m  -- or Z 1  and Z 2  taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, or 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The compounds of formula I, and the pharmaceutically acceptable salts thereof, are cardiovascular agents. They act as calcium entry blocking vasodilators and are especially useful as hypotensive agents. Thus, by the administration of a composition containing one (or a combination) of the compounds of this invention, the blood pressure of a hypertensive mammalian (e.g., human) host is reduced. A single dose, or two to four divided daily doses, provided on a basis of about 0.1 to 100 milligrams per kilogram of body weight per day, preferably from about 1 to about 50 milligrams per kilogram per day, is appropriate to reduce blood pressure. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular or intravenous routes can also be employed. 
     As a result of the calcium entry blocking activity of the compounds of formula I, and the pharmaceutically acceptable salts thereof, it is believed that such compounds in addition to being hypotensive agents may also be useful as anti-arrhythmic agents, anti-anginal agents, anti-fibrillatory agents, anti-asthmatic agents, anti-ischemic agents, and in limiting myocardial infarction. 
     The compounds of this invention can also be formulated in combination with a diuretic, or a beta-adrenergic agent, or angiotensin converting enzyme inhibitor. Suitable diuretics include the thiazide diuretics such as hydrochlorothiazide and bendroflumethiazide, suitable beta-adrenergic agents include nadolol, and suitable angiotensin converting enzyme inhibitors include captopril. 
     The compounds of formula I can be formulated for use in the reduction of blood pressure in compositions such as tablets, capsules or elixirs for oral administration, or in sterile solutions or suspensions for parenteral administration. About 10 to 500 milligrams of a compound of formula I is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained. 
     To prepare the compounds of formula I, a compound of the formula ##STR14## that is, 3-amino-5-pyrazolone, is reacted with a keto ester having the formula ##STR15## to provide a compound of the formula ##STR16## The reaction is preferably heated in the presence of an organic solvent, such as dimethylformamide. 
     Reaction of compound IV with a compound having the formula 
     
         R.sub.5 --N═C═O                                    V 
    
     in solvents, such as tetrahydrofuran and pyridine, to provide the compounds of formula I wherein R 1  is ##STR17## and R 6  is hydrogen. 
     To prepare the compounds of formula I where R 1  is ##STR18## and R 6  is other than hydrogen, the compound of formula IV can be treated with phosgene or 4-nitrophenylchloroformate followed by an amine of the formula R 5  R 6  NH. The reaction is preferably run in the presence of an organic base, such as pyridine, and triethylamine. 
     To prepare the compounds of formula I where R 1  is ##STR19## a compound of formula IV, in a solvent, such as dichloromethane, and an organic base, such as pyridine, is reacted with a compound of the formula ##STR20## 
     The compounds of formula I that contain a basic or acid group form acid addition and basic salts with a variety of inorganic and organic acids and bases. The pharmaceutically acceptable salts are preferred, although other salts may also be useful in isolating or purifying the product. Such pharmaceutically acceptable acid addition salts include those formed with hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, acetic acid, maleic acid, etc. Pharmaceutically acceptable basic salts include alkali metal salts (e.g. sodium, potassium and lithium) and alkaline earth metal salts (e.g. calcium and magnesium). The salts can be obtained by reacting the product with an equivalent amount of the acid in a medium in which the salt precipitates. 
     Preferred compounds of this invention are those wherein: 
     R 1  is ##STR21## or ##STR22## 
     R 2  is alkyl (especially methyl), R 3  is alkyl and R 4  is substituted phenyl. 
     The following examples are specific embodiments of this invention. 
    
    
     EXAMPLE 1 
     4,7-Dihydro-5-methyl-7-(3-nitrophenyl)-2-oxopyrazolo[1,5-a]pyrimidine-1,6-(2H)dicarboxylic acid, bis(1-methylethyl) ester 
     A. 1,2,4,7-Tetrahydro-5-methyl-7-(3-nitrophenyl)-2-oxopyrazolo[1,5,-a]pyrimidine-6-carboxylic acid, 1-methylethyl ester 
     A mixture of 3-amino-5-pyrazolone (3.57 g, 36.1 mmole) and 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, 1-methylethyl ester (10 g, 36.1 mmole) in dry dimethylformamide (30 ml) was heated at 70° C. under argon for 24 hours. The reaction mixture was allowed to cool to room temperature and then diluted with ether. The resultant precipitate was filtered off and recrystallized from isopropanol to provide 4.23 g of the title A compound in crystalline form, m.p. 254°-256° C. 
     Analysis calc&#39;d for C 17  H 18  N 4  O 5  : C, 56.98; H, 5.06; N, 15.63; Found: C, 57.18; H, 5.10; N, 15.70. 
     B. 4,7-Dihydro-5-methyl7(3-nitrophenyl)-2-oxopyrazolo[1,5-a]pyrimidine-1,6(2H)dicarboxylic acid, bis(1-methylethyl) ester 
     The suspension of the title A compound (1.43 g, 4.0 mmol) in dichloromethane (10 mL) and pyridine (2 mL) was treated at 0° C. under argon with isopropylchloroformate (0.6 mL, 5.2 mmol). After the addition was finished, the cooling bath was removed and the reaction was allowed to stir at room temperature for 1 hour. The resulting solution was diluted with ethyl acetate and was washed wtih 1N hydrochloric acid, water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed and the residue was purified by flash chromatography. The fractions containing the desired product were collected and evaporated. The residue was crystallized from ether-hexanes to yield 370 mg of a colorless solid. This material was combined with another batch of the same product and crystallized from isopropyl ether-dichloromethane to give the title compound as a colorless solid, m.p. 162°-164° C. 
     Analysis calc&#39;d for C 21  H 24  N 4  O 7  : C, 56.75; H, 5.44; N, 12.60; Found: C, 56.92; H, 5.34; N, 12.31. 
     EXAMPLE 2 
     1,2,4,7-Tetrahydro-5-methyl-1-[[(1-methylethyl)amino]carbonyl]-7-(3-nitrophenyl)-2-oxopyrazolo-[1,4-a]pyrimidine-6-carboxylic acid, 1-methylethyl ester 
     The suspension of the title A compound from Example 1 (1.43 g, 4.0 mmol) in tetrahydrofuran (10 mL) and pyridine (1mL) was treated at 0° C. under argon with isopropylisocyanate (0.33 mL, 3.35 mmol). After the addition was finished, the cooling bath was removed and the reaction was allowed to stir at room temperature for 5 hours. The resulting solution was diltued with ethy acetate and was washed with 1N hydrochloric acid, water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed and the residue was crystallized from ether-hexanes to yield 1.04 g of the title compound as a colorless solid, m.p. 172°∝174° C. (sinters at 167° C.). 
     Analysis calc&#39;d for C 21  H 25  N 5  O6: C, 56.87; H,, 5.68; N, 15.80; Found: C, 57.18; H, 5.66; N, 15.56. 
     EXAMPLE 3 
     1,2,4,7-Tetrahydro-5-methyl-7-(3-nitrophenyl)-2-oxo-1-[(propylamino)carbonyl]pyrazolo[1,5-a]pyrimidine-6-carboxylic acid, 1-methylethyl ester 
     The suspension of the title A compound from Example 1 (0.75 g, 2.0 mmol) in tetrahydrofuran (10 mL) and pyridine (1 mL) was treatetd at 0° C. under argon with n-propylisocyanate (0.24 mL, 2.5 mmol). After the addition was finished, the cooling bath was removed and the reaction was allowed to stir at room temperature for 5 hours. The resulting solution was diluted with ethyl acetate and was washed with 1N hydrochloric acid, water and brine. After drying over anhydrous magnesium sulfate, the solvent was removed and the residue was crystallized from ether-hexanes to yield 701 mg of a colorless solid. The product was recrystallized from dichloromethane-isopropyl ether to yield 601 mg of the title compound, m.p. 160°-163° C. 
     Analysis calc&#39;d for C 21  H 25  N 5  O 6  : C, 56.87; H, 5.69; N, 15.80; Found: C, 56.94; H, 5.62; N, 15.68. 
     EXAMPLES 4-25 
     Using the procedures outlined above and in Examples 1-3, the following additional compounds of formula I within the scope of the present invention can be made. ##STR23## 
     
         __________________________________________________________________________Ex.No. R.sub.2    R.sub.3           R.sub.4    R.sub.5       R.sub.6__________________________________________________________________________ 4 CH.sub.3    CH.sub.2 CH.sub.3                                        ##STR24##    H 5 CH.sub.3           ##STR25##                             ##STR26## CH.sub.3      CH.sub.3 ##STR27##           ##STR28##                             ##STR29## CH.sub.3 CH.sub.2 CH.sub.2                                                     H 7 CH.sub.2 CH.sub.2 OCH.sub.3          CH.sub.2 CH.sub.3                             ##STR30## CH.sub.3 CH.sub.2                                                     H ##STR31##     CH.sub.2 CH.sub.3                             ##STR32## CH.sub.3      H 9 CH.sub.2 CH.sub.3          CH.sub.2 CH.sub.2 OCH.sub.3                             ##STR33## CH.sub.2 CH.sub.2 CH.sub.2                                       CH.sub.2 ##STR34##     CH.sub.2 CH.sub.3                             ##STR35## CH.sub.2 CH.sub.2 SCH.sub.2                                       CH.sub.211 CH.sub.3           ##STR36##                             ##STR37##                                        ##STR38##    H12 CH.sub.3           ##STR39##                             ##STR40## CH.sub.3      CH.sub.2                                                     CH.sub.313 CH.sub.2 CH.sub.2 CH.sub.3          CH.sub.3                             ##STR41##                                        ##STR42##    H14 CH.sub.2 CH.sub.3           ##STR43##                             ##STR44##                                        ##STR45##__________________________________________________________________________Ex. No.R.sub.2        R.sub.3         R.sub.4     R.sub.7__________________________________________________________________________15   CH.sub.3 CH.sub.2               CH.sub.3                                ##STR46##                                            ##STR47##16   CH.sub.3                ##STR48##                                ##STR49##                                            ##STR50##17   CH.sub.2 CH.sub.2 OCH.sub.3               CH.sub.2 CH.sub.3                                ##STR51##  CH.sub.2 CH.sub.318 ##STR52##     CH.sub.2 CH.sub.3                                ##STR53##                                            ##STR54##19   CH.sub.2 CH.sub.3                ##STR55##                                ##STR56##  CH.sub.2CH.sub.2 CH.sub.3                                           520   CH.sub.3                ##STR57##                                ##STR58##  CH.sub.2 CH.sub.321 ##STR59##     CH.sub.2 CH.sub.3                                ##STR60##  CH.sub.322 ##STR61##     CH.sub.3                                ##STR62##  CH.sub.2 CH.sub.2                                           OCH.sub.323   CH.sub.3       CH.sub.2 CH.sub.3                                ##STR63##                                            ##STR64##24   CH.sub.3                ##STR65##                                ##STR66##  CH.sub.325   CH.sub.3       CH.sub.2 CH.sub.2 CH.sub.3                                ##STR67##  CH.sub.2 CH.sub.2__________________________________________________________________________                                           CH.sub.3