WO1989006535A1 - ESTERS DE L'ACIDE 2-OXO-1-SUBSTITUE PYROZOLO[1,5-a]PYRIMIDINE-6-CARBOXYLIQUE - Google Patents

ESTERS DE L'ACIDE 2-OXO-1-SUBSTITUE PYROZOLO[1,5-a]PYRIMIDINE-6-CARBOXYLIQUE 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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WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
cycloalkyl
substituted
piperazinyl
Prior art date
Application number
PCT/US1989/000047
Other languages
English (en)
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/fr

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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.

Landscapes

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

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.
PCT/US1989/000047 1988-01-19 1989-01-05 ESTERS DE L'ACIDE 2-OXO-1-SUBSTITUE PYROZOLO[1,5-a]PYRIMIDINE-6-CARBOXYLIQUE WO1989006535A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US145,007 1988-01-19
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
US07/145,004 US4859676A (en) 1988-01-19 1988-01-19 2-Oxo-1-sulfonyl pyrazolo(1,5-a) pyrimidine-6-carboxylic acid esters
US145,004 1988-01-19

Publications (1)

Publication Number Publication Date
WO1989006535A1 true WO1989006535A1 (fr) 1989-07-27

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1989/000047 WO1989006535A1 (fr) 1988-01-19 1989-01-05 ESTERS DE L'ACIDE 2-OXO-1-SUBSTITUE PYROZOLO[1,5-a]PYRIMIDINE-6-CARBOXYLIQUE

Country Status (2)

Country Link
EP (1) EP0380592A4 (fr)
WO (1) WO1989006535A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001036422A1 (fr) * 1999-11-19 2001-05-25 Abbott Laboratories Ouvreurs de canaux potassiques du type dihydropyrimidine tricyclique
EP1242383A1 (fr) * 1999-11-12 2002-09-25 GPI NIL Holdings, Inc. Composes aza a activite neurale
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 (fr) * 1985-09-30 1988-01-07 Yoshitomi Pharmaceutical Industries, Ltd. Composé polyazahétérocyclique

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 (fr) * 1999-11-12 2002-09-25 GPI NIL Holdings, Inc. Composes aza a activite neurale
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use
WO2001036422A1 (fr) * 1999-11-19 2001-05-25 Abbott Laboratories Ouvreurs de canaux potassiques du type dihydropyrimidine tricyclique
US6538000B1 (en) 1999-11-19 2003-03-25 Abbott Laboratories Tricyclic dihydropyrimidine potassium channel openers

Also Published As

Publication number Publication date
EP0380592A1 (fr) 1990-08-08
EP0380592A4 (en) 1991-10-09

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