EP0380592A1 - ESTERS DE L'ACIDE 2-OXO-1-SUBSTITUE PYRAZOLO[1,5-a]PYRIMIDINE-6-CARBOXYLIQUE - Google Patents

ESTERS DE L'ACIDE 2-OXO-1-SUBSTITUE PYRAZOLO[1,5-a]PYRIMIDINE-6-CARBOXYLIQUE

Info

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
Application number
EP89901760A
Other languages
German (de)
English (en)
Other versions
EP0380592A4 (en
Inventor
Karnail Atwal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ER Squibb and Sons LLC
Original Assignee
ER Squibb and Sons LLC
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 ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
Publication of EP0380592A1 publication Critical patent/EP0380592A1/fr
Publication of EP0380592A4 publication Critical patent/EP0380592A4/en
Ceased legal-status Critical Current

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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (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.
EP19890901760 1988-01-19 1989-01-05 2-oxo-1-substituted pyrazolo 1,5-a¨pyrimidine-6-carboxylic acid esters Ceased EP0380592A4 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US145004 1988-01-19
US145007 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

Publications (2)

Publication Number Publication Date
EP0380592A1 true EP0380592A1 (fr) 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 (fr)
WO (1) WO1989006535A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7253169B2 (en) 1999-11-12 2007-08-07 Gliamed, Inc. Aza compounds, pharmaceutical compositions and methods of use
US6417189B1 (en) * 1999-11-12 2002-07-09 Gpi Nil Holdings, Inc. AZA compounds, pharmaceutical compositions and methods of use
EP1242422A1 (fr) * 1999-11-19 2002-09-25 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

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0204317A2 (fr) * 1985-06-03 1986-12-10 E.R. Squibb & Sons, Inc. Diesters d'acides 2-thio ou oxo-4-aryl ou hétérocyclyl-1,5(2H)-pyrimidinedicarboxyliques et esters d'acides 3-acyl-5-pyrimidinecarboxyliques
EP0217142A2 (fr) * 1985-09-30 1987-04-08 Yoshitomi Pharmaceutical Industries, Ltd. Composé polyazahétérocyclique

Family Cites Families (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

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0204317A2 (fr) * 1985-06-03 1986-12-10 E.R. Squibb & Sons, Inc. Diesters d'acides 2-thio ou oxo-4-aryl ou hétérocyclyl-1,5(2H)-pyrimidinedicarboxyliques et esters d'acides 3-acyl-5-pyrimidinecarboxyliques
EP0217142A2 (fr) * 1985-09-30 1987-04-08 Yoshitomi Pharmaceutical Industries, Ltd. Composé polyazahétérocyclique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO8906535A1 *

Also Published As

Publication number Publication date
WO1989006535A1 (fr) 1989-07-27
EP0380592A4 (en) 1991-10-09

Similar Documents

Publication Publication Date Title
EP0572437B1 (fr) Derives de 2,4-diaminoquinazolines stimulant l'activite anti-tumorale
EP0234830B1 (fr) Acides 2-(imino substitué)-6-aryl-3,6-dihydro-1,5(2H)-pyrimidine-carboxyliques substitués en position 4 et analogues
AU592569B2 (en) 2-thio or oxo-4-aryl or heterocyclo-1,5 (2h)- pyrimidinedi-carboxylic acid diesters and 3-acyl-5- pyrimidinecarboxylic acids and esters
US4855301A (en) 1,2,3,4-Tetrahydro-6-substituted-4-aryl(or heterocyclo)-3-((substituted amino)carbonyl)-2-thioxo (or oxo)-5-pyrimidinecarboxylic acids and esters
JP2020516666A (ja) アポトーシス誘発剤
CA1317597C (fr) Esters de l'acide 3,6-dihydro-1,5(2h) -pyrimidinecarboxylique
EP0236902B1 (fr) 1,2,3,4-Tétrahydro-4-aryl(ou hétérocyclo)-2-thioxo(ou oxo)-5-carboxy-pyrimidine substituées en position 3 et en position 6 et leurs esters
US4684655A (en) 1,2,3,4-tetrahydro-6-substituted-4-aryl-3-substituted-2-thioxo(or oxo)-5-pyrimidinecarboxylic acids and esters and use thereof to lower blood pressure
US4769371A (en) Dihydropyrimidine carboxylic acid esters
EP0237347B1 (fr) Acides et esters 1,2,3,4-tétrahydro-6-substitués-4-aryl(ou hétérocyclo)-3-[(amino substitué)-carbonyl]-2-thioxo(ou oxo)-pyrimidiniques
US4728652A (en) 2-substituted thio or oxy-4-aryl or heterocyclo-5-carboxy-1,4-dihydropyrimidines, composition containing them, and method of using them to reduce blood pressure
EP0202654A2 (fr) Dérivés de 5-carboxy-1,4-dihydropyrimidine
US4140788A (en) N-Substituted imidazolecarboxamide derivatives
JPH08231546A (ja) ９−置換２−（２−ｎ−アルコキシフエニル）−プリン−６−オン類
CA1331177C (fr) Esters de l'acide 3-oxo-1,2,4-triazolo [4,3-a]pyrimdine-6-carboxylique
US4746656A (en) 1,2,4,7-tetrahydro-2-oxopyrazolo[1,5-a]pyrimidine derivatives
JPH06501023A (ja) 抗腫瘍活性を増強するためのピリミジン誘導体
EP0380592A1 (fr) ESTERS DE L'ACIDE 2-OXO-1-SUBSTITUE PYRAZOLO[1,5-a]PYRIMIDINE-6-CARBOXYLIQUE
FR2613717A1 (fr) Derives d'acides pyrimidinecarboxyliques, a action therapeutique
WO2019235553A1 (fr) Dérivé d'azétidine, et promédicament de celui-ci
DE69813886T2 (de) Naphthalin derivate
EP0086647B1 (fr) Pyrimidines, leur préparation et compositions pharmaceutiques les contenant
EP3105232B1 (fr) Triazolobenzodiazépines substituées
US4870072A (en) 2-oxo-1-substituted pyrazolo[1,5-A]pyrimidine-6-carboxylic acid esters as blood pressure reducing agents
NZ534229A (en) Phenylpyrimidine amines as ige inhibitors

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19891115

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

A4 Supplementary search report drawn up and despatched

Effective date: 19910819

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17Q First examination report despatched

Effective date: 19920603

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 19940619

RTI1 Title (correction)

Free format text: 2-OXO-1-SUBSTITUTED PYRAZOLO??1,5-A PYRIMIDINE-6-CARBOXYLIC ACID ESTERS