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WO1989006535A1 - 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 ESTERS Download PDF

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Publication number
WO1989006535A1
WO1989006535A1 PCT/US1989/000047 US8900047W WO8906535A1 WO 1989006535 A1 WO1989006535 A1 WO 1989006535A1 US 8900047 W US8900047 W US 8900047W WO 8906535 A1 WO8906535 A1 WO 8906535A1
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WIPO (PCT)
Prior art keywords
alkyl
aryl
cycloalkyl
substituted
piperazinyl
Prior art date
Application number
PCT/US1989/000047
Other languages
French (fr)
Inventor
Karnail Atwal
Original Assignee
E.R. Squibb & Sons, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US07/145,007 external-priority patent/US4870072A/en
Priority claimed from US07/145,004 external-priority patent/US4859676A/en
Application filed by E.R. Squibb & Sons, Inc. filed Critical E.R. Squibb & Sons, Inc.
Publication of WO1989006535A1 publication Critical patent/WO1989006535A1/en

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    • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Cardiovascular activity is exhibited by compounds having formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is (1) or (2); R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -(CH2)n-Y1, or halo substituted alkyl; R3 is hydrogen, alkyl, cycloalkyl, aryl, -(CH2)n-Y2, -(CH2)p-Y3, 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)p-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, (3), carboxyl, alkoxycarbonyl, (4), (5), (6) or (7); Y2 is cycloalkyl, aryl, carbamoyl, (3), carboxyl, alkoxycarbonyl, (4), or (5); Y3 is hydroxyl, alkoxy, aryl-(CH2)m-O-, mercapto, alkylthio, aryl-(CH2)m-S-, (6), (7), 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.

Description

2-OXO-1-SUBSTITUTED PYRAZOLO [1 ,5-a] PYRIMIDINE-6-CARBOXYLIC ACID ESTERS
Brief Description of the Invention Compounds having the formula
Figure imgf000003_0001
and pharmaceutically acceptable salts thereof, are cardiovascular agents. In formula I, and throughout the specification, the symbols are as defined below.
R1 is
Figure imgf000003_0002
R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or halo substituted alkyl;
Figure imgf000003_0003
R3 is hydrogen, alkyl, cycloalkyl, aryl, or halo substituted alkyl;
Figure imgf000004_0001
R4 is aryl;
R5 is hydrogen, alkyl, cycloalkyl, aryl, or arylalkyl and R6 is hydrogen, alkyl, cycloalkyl, or halo substituted alkyl,
Figure imgf000004_0009
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,
Figure imgf000004_0003
or halo substituted alkyl;
Figure imgf000004_0002
Y1 is cycloalkyl, aryl, hydroxyl, alkoxy, mercapto, alkylthio, ,
Figure imgf000004_0005
Figure imgf000004_0004
amino, substituted amino, carbamoyl, (substituted
carboxyl, alkoxycarbonyl, ;
Figure imgf000004_0006
Y2 is cycloalkyl, aryl, carbamoyl,
(substituted amino )
Figure imgf000004_0007
carboxyl, alkoxycarbonyl,
Figure imgf000004_0008
Y3 is hydroxyl, alkoxy, a
Figure imgf000005_0001
mercapto, alkylthio,
Figure imgf000005_0002
Figure imgf000005_0003
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
Figure imgf000008_0001
that is, 3-amino-5-pyrazolone, is reacted with a keto ester having the formula
Figure imgf000008_0002
to provide a compound of the formula
Figure imgf000008_0003
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
Figure imgf000009_0004
and R6 is hydrogen.
To prepare the compounds of formula I where
R1 is
Figure imgf000009_0003
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
Figure imgf000009_0002
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
Figure imgf000009_0001
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
Figure imgf000010_0001
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.
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001

Claims

What is claimed is:
Compounds having the formula
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof wherein
Figure imgf000020_0002
R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, -(CH2) -Y1, or halo substituted alkyl;
R3 is hydrogen, alkyl, cycloalkyl, aryl, or halo substituted alkyl;
Figure imgf000020_0003
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,
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000021_0003
Y2 is cycloalkyl, aryl, carbamoyl,
(substituted amino )- alkoxycarbonyl,
Figure imgf000021_0004
Figure imgf000021_0005
Y3 is hydroxyl, alkoxy,
Figure imgf000021_0009
mercapto, alkylthio,
Figure imgf000021_0006
ammo or substituted ammo ;
Figure imgf000021_0007
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
Figure imgf000021_0008
R2 is alkyl (especially methyl);
R3 is alkyl; and,
R4 is substituted phenyl.
3. A compound in accordance with claim 1 wherein
R1 is
Figure imgf000022_0001
R2 is methyl;
R3 is isopropyl; and,
R4 is 3-nitrophenyl.
4. A compound in accordance with claim 1 wherein
R1 is
Figure imgf000022_0002
R2 is methyl; R3 is isopropyl; and, R4 is 3-nitrophenyl.
5. A compound in accordance with claim 1 wherein
R1 is
Figure imgf000022_0003
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
Figure imgf000023_0001
or a pharmaceutically acceptable salt thereof wherein
R1 is
Figure imgf000023_0002
R2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or halo substituted
Figure imgf000023_0003
alkyl;
R3 is hydrogen, alkyl, cycloalkyl, aryl,
Figure imgf000023_0004
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,
Figure imgf000023_0005
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,
Figure imgf000024_0001
or halo substituted alkyl;
Figure imgf000024_0002
Y1 is cycloalkyl, aryl, hydroxyl, alkoxy, mercapto, alkylthio,
Figure imgf000024_0003
Figure imgf000024_0004
amino, substituted amino, carbamoyl, (substituted
Figure imgf000024_0005
carboxyl, alkoxycarbonyl,
Figure imgf000024_0006
;
Figure imgf000024_0007
Y2 is cycloalkyl, aryl, carbamoyl,
(substituted amιno
Figure imgf000024_0008
carboxyl, alkoxycarbonyl,
Figure imgf000024_0009
Y3 is hydroxyl, alkoxy,
Figure imgf000024_0010
mercapto, alkylthio,
Figure imgf000024_0012
amino or substituted amino;
Figure imgf000024_0011
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.
PCT/US1989/000047 1988-01-19 1989-01-05 2-OXO-1-SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE-6-CARBOXYLIC ACID ESTERS WO1989006535A1 (en)

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
US145,007 1988-01-19
US145,004 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

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036422A1 (en) * 1999-11-19 2001-05-25 Abbott Laboratories Tricyclic dihydropyrimidine potassium channel openers
EP1242383A1 (en) * 1999-11-12 2002-09-25 GPI NIL Holdings, Inc. Aza compounds having neuronal activity
US6538000B1 (en) 1999-11-19 2003-03-25 Abbott Laboratories Tricyclic dihydropyrimidine potassium channel openers
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use

Citations (2)

* Cited by examiner, † Cited by third party
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

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUT42077A (en) * 1985-06-03 1987-06-29 Squibb & Sons Inc Process for producing diesters of 2-tioxo- or 2-oxo-pyrimidine-1,5-dicarboxylic acid and 1-acyl-pyrimidine-5-carboxylic acids and esters
EP0217142A3 (en) * 1985-09-30 1988-01-07 Yoshitomi Pharmaceutical Industries, Ltd. A polyazaheterocyclic compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0380592A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1242383A1 (en) * 1999-11-12 2002-09-25 GPI NIL Holdings, Inc. Aza compounds having neuronal activity
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use
WO2001036422A1 (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

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EP0380592A1 (en) 1990-08-08

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