EP0380592A1 - 2-OXO-1-SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE-6-CARBOXYLIC ACID ESTERS - Google Patents
2-OXO-1-SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE-6-CARBOXYLIC ACID ESTERSInfo
- Publication number
- EP0380592A1 EP0380592A1 EP89901760A EP89901760A EP0380592A1 EP 0380592 A1 EP0380592 A1 EP 0380592A1 EP 89901760 A EP89901760 A EP 89901760A EP 89901760 A EP89901760 A EP 89901760A EP 0380592 A1 EP0380592 A1 EP 0380592A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- aryl
- cycloalkyl
- substituted
- piperazinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- cardiovascular agents are cardiovascular agents.
- the symbols are as defined below.
- R 1 is R 2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or halo substituted alkyl;
- R 3 is hydrogen, alkyl, cycloalkyl, aryl, or halo substituted alkyl;
- R 4 is aryl
- R 5 is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R 6 is hydrogen, alkyl, cycloalkyl, 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-piperazinyl, 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, or halo substituted alkyl
- Y 1 is cycloalkyl, aryl, hydroxyl, alkoxy, mercapto, alkylthio, , amino, substituted amino, carbamoyl, (substituted
- Y 2 is cycloalkyl, aryl, carbamoyl,
- Y 3 is hydroxyl, alkoxy, a
- alkyl and “alkoxy” refer to both straight and branched chain groups. Those groups having 1 to 8 carbon atoms are preferred.
- halo substituted alkyl 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.
- aryl 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.
- alkenyl and alkynyl refer to both straight and branched chain groups. Those groups having 2 to 8 carbon atoms are preferred.
- cycloalkyl refers to those groups having 3, 4, 5, 6 or 7 carbon atoms.
- halo refers to chloro, bromo, fluoro and iodo.
- substituted amino 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, l-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.
- 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.
- 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.
- the substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular or intravenous routes can also be employed.
- hypotensive agents 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.
- 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.
- reaction is preferably heated in the presence of an organic solvent, such as dimethylformamide.
- R 6 is 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.
- R 1 is 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
- 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).
- alkali metal salts e.g. sodium, potassium and lithium
- 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 2 is alkyl (especially methyl), R 3 is alkyl and R 4 is substituted phenyl.
Abstract
Les composés de la formule (I) ou leur sel pharmaceutiquement acceptable ont une activité cardiovasculaire. Dans cette formule R1 représente (1) ou (2); R2 représente un hydrogène, un alkyle, un alkényle, un alkynyle, un cycloalkyle, un aryle, -(CH2)n-Y1, ou un alkyle à substitution halo; R3 représente hydrogène, alkyle, cycloalkyle, aryle, -(CH2)n-Y2, -(CH2)p-Y3, ou un alkyle à substitution halo; R4 représente un aryle; R5 représente un hydrogène, alkyle, cycloalkyle, aryle, ou arylalkyle et R6 représente un hydrogène, alkyle, cycloalkyle, -(CH2)n-Y2, -(CH2)p-Y3 ou un alkyle à substitution halo, ou R5 et R6, pris ensemble avec l'atome d'azote auquel ils sont rattachés représentent 1-pyrrolidinyle, 1-pipéridinyle, 1-azépinyle, 4-morpholinyle, 4-thiamorpholinyle, 1-pipérazinyle, 4-alkyl-1-pipérazinyle, 4-arylalkyle-1-pipérazinyle, 4-diarylalkyle-1-pipérazinyle ou 1-pyrrolidinyle, 1-pipéridinyle, ou 1-azéipinyle substitué avec alkyle, alkoxy, alkylthio, halo, trifluorométhyle ou hydroxy; R7 représente alkyle, cycloalkyle, aryle, -(CH2)n-Y2, -(CH2)p-Y3 ou alkyle à substitution halo; Y1 représente cycloalkyle, aryle, hydroxyle, alkoxy, aryl-(CH2)m-O-, mercapto, alkylthio, aryl-(CH2)m-S-, amino, amino substitué, carbamoyle, (3), carboxyle, alkoxycarbonyle, (4), (5), (6), ou (7); Y2 représente un cycloalkyle, aryle, carbamoyle, (3), carboxyle, alkoxycarbonyle, (4), ou (5); Y3 représente hydroxyle, alkoxy, aryl-(CH2)m-O-, mercapto, alkylthio, aryl-(CH2)m-S-, (6), (7), amino ou amino substitué; m est égal à 0 ou à un nombre entier compris entre 1 et 6; n est un nombre entier compris entre 1 et 6; et p est un nombre entier compris entre 2 et 6.The compounds of formula (I) or their pharmaceutically acceptable salt have cardiovascular activity. In this formula R1 represents (1) or (2); R2 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, - (CH2) n-Y1, or halo substituted alkyl; R3 represents hydrogen, alkyl, cycloalkyl, aryl, - (CH2) n-Y2, - (CH2) p-Y3, or halo substituted alkyl; R4 represents aryl; R5 represents hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R6 represents hydrogen, alkyl, cycloalkyl, - (CH2) n-Y2, - (CH2) p-Y3 or halo substituted alkyl, or R5 and R6, taken together with the nitrogen atom to which they are attached represent 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-azeipinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy; R7 represents alkyl, cycloalkyl, aryl, - (CH2) n-Y2, - (CH2) p-Y3 or halo substituted alkyl; Y1 represents cycloalkyl, aryl, hydroxyl, alkoxy, aryl- (CH2) mO-, mercapto, alkylthio, aryl- (CH2) mS-, amino, substituted amino, carbamoyl, (3), carboxyl, alkoxycarbonyl, (4), ( 5), (6), or (7); Y2 represents cycloalkyl, aryl, carbamoyl, (3), carboxyl, alkoxycarbonyl, (4), or (5); Y3 represents hydroxyl, alkoxy, aryl- (CH2) m-O-, mercapto, alkylthio, aryl- (CH2) m-S-, (6), (7), amino or substituted amino; m is 0 or an integer from 1 to 6; n is an integer between 1 and 6; and p is an integer between 2 and 6.
Description
2-OXO-1-SUBSTITUTED PYRAZOLO [1 ,5-a] PYRIMIDINE-6-CARBOXYLIC ACID ESTERS
Brief Description of the Invention Compounds having the formula
and pharmaceutically acceptable salts thereof, are cardiovascular agents. In formula I, and throughout the specification, the symbols are as defined below.
R1 is
R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or halo substituted alkyl;
R3 is hydrogen, alkyl, cycloalkyl, aryl, or halo substituted alkyl;
R4 is aryl;
R5 is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R6 is hydrogen, alkyl, cycloalkyl, or halo substituted alkyl,
or R5 and R6 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-azeipinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy;
R7 is alkyl, cycloalkyl, aryl,
or halo substituted alkyl;
Y1 is cycloalkyl, aryl, hydroxyl, alkoxy, mercapto, alkylthio, ,
amino, substituted amino, carbamoyl, (substituted
carboxyl, alkoxycarbonyl, ;
Y2 is cycloalkyl, aryl, carbamoyl,
(substituted amino )
carboxyl, alkoxycarbonyl,
Y3 is hydroxyl, alkoxy, a
mercapto, alkylthio,
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 an 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 "alkyl" and "alkoxy" refer to both straight and branched chain groups. Those groups having 1 to 8 carbon atoms are preferred.
The term "halo substituted alkyl" 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 "aryl" 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 "alkenyl" and "alkynyl" refer to both straight and branched chain groups. Those groups having 2 to 8 carbon atoms are preferred.
The term "cycloalkyl" refers to those groups having 3, 4, 5, 6 or 7 carbon atoms.
The term "halo" refers to chloro, bromo, fluoro and iodo.
The term "substituted amino" refers to a group of the formula -NZ1Z2 wherein Z1 is hydrogen, alkyl, or aryl-(CH2)m- and Z2 is alkyl or aryl-(CH2)m- or Z 1 and Z2 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, l-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
that is, 3-amino-5-pyrazolone, is reacted with a keto ester having the formula
to provide a compound of the formula
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
V R5-N=C=O
in solvents, such as tetrahydrofuran and pyridine, to provide the compounds of formula I wherein R1
is
and R6 is hydrogen.
To prepare the compounds of formula I where
R1 is
and R6 is other than hydrogen, the compound of formula IV can be treated with phosgene or 4-nitrophenylchloroformate followed by an amine of the formula R5R6NH. 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
R1 is
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
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:
R1 is
R2 is alkyl (especially methyl), R3 is alkyl and R4 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'd for C17H18N4O5:
C, 56.98; H, 5.06; N, 15.63; Found: C, 57.18; H, 5.10; N, 15.70.
B. 4,7-Dihydro-5-methyl-7-(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 with 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'd for C21H24N4O7:
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 (1 mL) 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 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 1.04 g of the title compound as a colorless solid, m.p. 172-174°C (sinters at 167°C).
Analysis calc'd for C21H25N5O6:
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 treated 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'd for C21H25N5O6:
C, 56.87; H, 5.68; 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.
Claims
What is claimed is:
Compounds having the formula
or a pharmaceutically acceptable salt thereof wherein
R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -(CH2) -Y1, or halo substituted alkyl;
R3 is hydrogen, alkyl, cycloalkyl, aryl, or halo substituted alkyl;
R4 is aryl;
R5 is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R6 is hydrogen, alkyl, cycloalkyl, -(CH2)n-Y2, -(CH2)p-Y3 or halo substituted alkyl, or R5 and R6 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-azeipinyl substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy; R7 is alkyl, cycloalkyl, aryl, -(CH2)n-Y2, -(CH2) -Y3 or halo substituted alkyl;
Y1 is cycloalkyl, aryl, hydroxyl, alkoxy, aryl-(CH2)m-O-, mercapto, alkylthio, aryl-(CH2)m-S-, amino, substituted amino, carbamoyl, (substituted
carboxyl, alkoxycarbonyl, Y2 is cycloalkyl, aryl, carbamoyl,
(substituted amino )- alkoxycarbonyl, Y3 is hydroxyl, alkoxy,
mercapto, alkylthio, ammo or substituted ammo ; m is 0 or an integer of 1 to 6 ; n is an integer of 1 to 6 ; and p is an integer of 2 to 6 .
2 . A compound in accordance with claim 1 wherein
R1 is alkyl
R2 is alkyl (especially methyl);
R3 is alkyl; and,
R4 is substituted phenyl.
3. A compound in accordance with claim 1 wherein
R1 is
R2 is methyl;
R3 is isopropyl; and,
R4 is 3-nitrophenyl.
4. A compound in accordance with claim 1 wherein
R1 is R2 is methyl; R3 is isopropyl; and, R4 is 3-nitrophenyl.
5. A compound in accordance with claim 1 wherein
R1 is
R2 is methyl; R3 is isopropyl; and, R4 is 3-nitrophenyl.
6. A compound in accordance with claim 1 having the name 4,7-dihydro-5-methyl-7-(3-nitrophenyl)-2-oxopyrazolo[1,5-a]pyrimidine-1,6(2H)-dicarboxylic acid, bis (1-methylethyl) ester.
7. A compound in accordance with claim 1 having the name 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.
8. A compound in accordance with claim 1 having the name 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.
9. A.method for reducing the blood pressure of a mammalian host in need thereof which comprises administering to said host an effective amount of a compound having the formula
or a pharmaceutically acceptable salt thereof wherein
R1 is
R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or halo substituted alkyl;
R3 is hydrogen, alkyl, cycloalkyl, aryl, or halo substituted alkyl;
R4 is aryl;
R5 is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R6 is hydrogen, alkyl, cycloalkyl, or halo substituted alkyl, or R5 and R6 taken together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, l-piperazinyl, 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;
R7 is alkyl, cycloalkyl, aryl, or halo substituted alkyl; Y1 is cycloalkyl, aryl, hydroxyl, alkoxy, mercapto, alkylthio, amino, substituted amino, carbamoyl, (substituted carboxyl, alkoxycarbonyl, ; Y2 is cycloalkyl, aryl, carbamoyl,
(substituted amιno carboxyl, alkoxycarbonyl,
Y3 is hydroxyl, alkoxy,
mercapto, alkylthio, 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 an integer of 2 to 6.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/145,007 US4870072A (en) | 1988-01-19 | 1988-01-19 | 2-oxo-1-substituted pyrazolo[1,5-A]pyrimidine-6-carboxylic acid esters as blood pressure reducing agents |
| US145004 | 1988-01-19 | ||
| US145007 | 1988-01-19 | ||
| US07/145,004 US4859676A (en) | 1988-01-19 | 1988-01-19 | 2-Oxo-1-sulfonyl pyrazolo(1,5-a) pyrimidine-6-carboxylic acid esters |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0380592A1 true EP0380592A1 (en) | 1990-08-08 |
| EP0380592A4 EP0380592A4 (en) | 1991-10-09 |
Family
ID=26842566
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19890901760 Ceased EP0380592A4 (en) | 1988-01-19 | 1989-01-05 | 2-oxo-1-substituted pyrazolo 1,5-a¨pyrimidine-6-carboxylic acid esters |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP0380592A4 (en) |
| WO (1) | WO1989006535A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6417189B1 (en) * | 1999-11-12 | 2002-07-09 | Gpi Nil Holdings, Inc. | AZA compounds, pharmaceutical compositions and methods of use |
| US7253169B2 (en) | 1999-11-12 | 2007-08-07 | Gliamed, Inc. | Aza compounds, pharmaceutical compositions and methods of use |
| CA2391291A1 (en) * | 1999-11-19 | 2001-05-25 | Abbott Laboratories | Tricyclic dihydropyrimidine potassium channel openers |
| US6538000B1 (en) | 1999-11-19 | 2003-03-25 | Abbott Laboratories | Tricyclic dihydropyrimidine potassium channel openers |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0204317A2 (en) * | 1985-06-03 | 1986-12-10 | E.R. Squibb & Sons, Inc. | 2-Thio or oxo-4-aryl or heterocyclo-1,5(2H)-pyrimidinedicarboxylic acid diesters and 3-acyl-5-pyrimidinecarboxylic acids and esters |
| EP0217142A2 (en) * | 1985-09-30 | 1987-04-08 | Yoshitomi Pharmaceutical Industries, Ltd. | A polyazaheterocyclic compound |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2593890A (en) * | 1948-08-11 | 1952-04-22 | Gen Aniline & Film Corp | 3, 3'-bis |
| US4746656A (en) * | 1986-07-21 | 1988-05-24 | E. R. Squibb & Sons, Inc. | 1,2,4,7-tetrahydro-2-oxopyrazolo[1,5-a]pyrimidine derivatives |
-
1989
- 1989-01-05 EP EP19890901760 patent/EP0380592A4/en not_active Ceased
- 1989-01-05 WO PCT/US1989/000047 patent/WO1989006535A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0204317A2 (en) * | 1985-06-03 | 1986-12-10 | E.R. Squibb & Sons, Inc. | 2-Thio or oxo-4-aryl or heterocyclo-1,5(2H)-pyrimidinedicarboxylic acid diesters and 3-acyl-5-pyrimidinecarboxylic acids and esters |
| EP0217142A2 (en) * | 1985-09-30 | 1987-04-08 | Yoshitomi Pharmaceutical Industries, Ltd. | A polyazaheterocyclic compound |
Non-Patent Citations (1)
| Title |
|---|
| See also references of WO8906535A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1989006535A1 (en) | 1989-07-27 |
| EP0380592A4 (en) | 1991-10-09 |
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