EP0522038A1 - Pyrimidines, pyrimidinones et pyridopyrimidines substitues - Google Patents

Pyrimidines, pyrimidinones et pyridopyrimidines substitues

Info

Publication number
EP0522038A1
EP0522038A1 EP91907332A EP91907332A EP0522038A1 EP 0522038 A1 EP0522038 A1 EP 0522038A1 EP 91907332 A EP91907332 A EP 91907332A EP 91907332 A EP91907332 A EP 91907332A EP 0522038 A1 EP0522038 A1 EP 0522038A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
heteroaryl
aryl
cycloalkyl
compound
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.)
Withdrawn
Application number
EP91907332A
Other languages
German (de)
English (en)
Other versions
EP0522038A4 (en
Inventor
Eric E. Allen
William J. Greenlee
Malcolm Maccoss
Arthur A. Patchett
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.)
Merck and Co Inc
Original Assignee
Merck and Co 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
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0522038A1 publication Critical patent/EP0522038A1/fr
Publication of EP0522038A4 publication Critical patent/EP0522038A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • This invention relates to novel substituted pyrimidine, pyrimidinone and pyridopyrimidine
  • the compounds of the invention are also useful as ocular antihypertensives.
  • the compounds of this invention also have central nervous system (CNS) activity. They are useful in the treatment of cognitive dysfunctions including Alzheimer's disease, amnesia and senile dementia. These compounds also have anxiolytic and antidepressant properties and are therefore, useful in the relief of symptoms of anxiety and tension and in the treatment of patients with depressed or dysphoric mental states.
  • CNS central nervous system
  • Renin-angiotensin system plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure.
  • Angiotensin II (A II) an octapeptide hormone is produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs, and is the end product of the RAS•A II is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes.
  • ACE angiotensin converting enzyme
  • One of the possible modes of controlling the RAS is angiotensin II receptor antagonism.
  • non-peptide compounds have been described as A II antagonists.
  • Illustrative of such compounds are those disclosed in U.S. Patents 4,207,324; 4,340,598; 4,576,958; and 4,582,847; in European Patent Applications 028,834; 245,637;
  • This invention relates to novel substituted pyrimidine, pyrimidinone and pyridopyrimidine
  • the compounds of this invention have the general formula (I):
  • the compounds of formula I can also be expressed as compounds having the following formulae (la), (lb), and ((Ic) if R 7 and R 8a are joined)
  • R 1 is (a) -CO 2 R 4 ,
  • -CO 2 -C 1 -C 4 -alkyl or R 4 is H, C 1 -C 6 -alkyl, benzyl or phenyl;
  • R 5 is H, -CH-O-C-R 4 ;
  • E is a single bond, -NR 13 (CH 2 ) s -, -S(O) X (CH 2 ) s - where x is 0 to 2 and s is 0 to 5, -CH(OH)-, -O-, -CO-;
  • R 7 is (a) hydrogen
  • R 8a is (a) aryl
  • R 7 and R 8a when alkyl groups on adjacent atoms may be joined together with the atoms to which they are bound to form a pyridine ring which may be
  • R 27 is C 1 -C 4 -alkyl, Cl, Br, F, I, -CF 3 , aryl or heteroaryl;
  • R 8b is (a) -OH
  • R 9 is H, C 1 -C 5 -alkyl, phenyl or benzyl;
  • R 10 is H, C 1 -C 4 -alkyl
  • R 11 is H, C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 1 -C 4 -alkoxy alkyl, or -CH 2 -C 6 H 4 R 20 ;
  • R 12 is -CN, -NO 2 , -CO 2 R 4 , or -CF 3 ;
  • R 13 is H, C 2 -C 4 -alkanoyl, C 1 -C 6 -alkyl, allyl,
  • R 14 is H, C 1 -C 8 -alkyl, C 1 -C 8 -perfluoroalkyl,
  • R 15 is H, C 1 -C 6 -alkyl
  • R 16 is H , C 1 -C 6 -alkyl , C 3 -C 6 -cycloalkyl , phenyl or benzyl ;
  • R 17 is -NR 9 R 10 , -OR 10 , -NHCONH 2 , -NHCSNH 2 ,
  • R 18 and R 19 are independently C 1 -C 4 -alkyl or taken together are -(CH 2 ) q - where q is 2 or 3;
  • R 20 is H, -NO 2 , -NH 2 , -OH or -OCH 3
  • R 21 is (a) -CO-aryl
  • R 22 is the same as R 8a or -H;
  • R 23 is (a) aryl ,
  • aryl selected from the group consisting of aryl, heteroaryl, -OH, -SH,
  • R 25 is (a) H
  • Z is 0, NR 13 or S; or, a pharmaceutically acceptable salt thereof.
  • alkyl alkenyl
  • alkynyl alkynyl
  • specific names for these generic terms shall mean the straight chain species.
  • butyl shall mean the normal butyl substituent, n-butyl.
  • R 1 is -COOH ; -NH-SO 2 CF 3 ; -CO 2 R 4 ;
  • heteroaryl is an unsubstituted, monosubstituted or disubstituted 5- or
  • substituents are members selected from the group consisting of OH, SH, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, CF 3 , Cl, Br, F, I, NO 2 , CO 2 H, CO 2 -C 1 -C 4 -alkyl, NH 2 , NH(C 1 -C 4 -alkyl) and N(C 1 -C 4 -alkyl) 2 ;
  • R 2a and R 2b are H, F, Cl, CF 3 , C 1 -C 4 -alkyl or
  • R 3a is H, F or Cl
  • R 3b is H, F, Cl, CF 3 , C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy,
  • E is a single bond, -O- or -S-; R 6 is
  • R 2a , R 2b , R 3a and R 3b are each H;
  • X is a single bond.
  • R 1 is -COOH; -NH-SO 2 CF 3 ; CO 2 R 4 ;
  • heteroaryl is an unsubstituted, monosubstituted or disubstituted 5- or 6-membered aromatic ring comprising contain 1 to 3
  • heteroatoms selected from O, N and S and wherein the substituents are members selected from the group consisting of OH, SH, C 1 -C 4 -alkyl,
  • R 3a is H, F or Cl
  • R 3b is H, F, Cl, CF 3 , C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy,
  • R 7 and R 8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which can be substituted with R 26 and R 27 ;
  • R 2a , R 2b , R 3a and R 3b are each H;
  • X is a single bond.
  • R 1 is -COOH; -NH-SO 2 CF 3 ; CO 2 R 4 ;
  • heteroaryl is an unsubstituted, monosubstituted or disubstituted 5-or 6-membered aromatic ring
  • R 2a and R 2b are H, F, Cl, CF 3 , C 1 -C 4 -alkyl or
  • R 3b is H, F, Cl, CF 3 , C 1 -C 4 -alkyl, C 5 -C 6 - cycloalkyl, -COOCH 3 , -COOC 2 H 5 , -SO 2 CH 3 ;
  • E is a single bond, -O- or -S-; R 6 is
  • R 7 and R 8a are as defined above or together with the atoms to which they are bonded may be joined to form a pyridine ring which may be substituted with R 26 and R 27 ;
  • R 2a , R 2b , R 3a and R 3b are each H;
  • FAB-MS Fast atom bombardment mass spectroscopy
  • Intermediate 1 may then be treated with an appropriate R 7 -amidine, guanidine, 0-alkyl or aryl isourea, or S-alkyl or aryl isothiourea, to give the 2,5,6-trisubstituted pyrimidin-4(3H)-one 2.
  • Pyrimidin-4(3H)-one 2 itself may be an A-II antagonist but may also be used as an
  • Scheme 3 illustrates an alternative preparation of pyrimidinone 3.
  • An R 7 nitrile can be converted to an imidate then to an amidine with an R 8a amine. This can then be condensed with ⁇ -ketoester 1 to give 3.
  • Similar procedures also exist for the preparation of isoureas, isothiuronium salts, and guanidines. 4
  • Other methods are also available for the introduction of substituents at the 2-position of the pyrimidine. 5
  • 4-aminopyrimidine 7 The 4-aminopyrimidines such as 7 can be converted to pyrimidin-4(3H)-ones simply by diazotizing them with nitrous acid. 9
  • Scheme 10 illustrates a preparation of a 4-carboxy or 4-carboalkoxy pyrimidine.
  • Ethyl hydrogen malonate can be doubly deprotonated using two equivalents of butyllithium.
  • the dianion can then be used as a nucleophile on which to add the electrophile sidechain to give ethyl ester 11.
  • the ester can then be deprotonated and be added to diethyl oxalate to give the diethyl oxalacetate derivative 12.
  • Scheme 14 illustrates how the pyrimidine ring system can be built onto what would become the 5-sidechain. Conversion of the bromide 18 to a
  • electrophilic sidechain as shown in Scheme 16 or used as electrophiles as illustrated in Scheme 17.
  • N-C-N group amidines, isoureas, isothiuronium salts, etc.
  • C-C-C group generally the ⁇ -keto esters
  • the ⁇ -keto esters may be
  • Scheme 19 provides a route for the
  • imidazole can be achieved upon treatment of acid 26
  • Scheme 20 provides a route to the isomeric acyl sulfonamides 33.
  • bromobenzenesulfonyl chloride 28 may be converted to
  • the compounds of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables and the like as well as topical ocular formulations in the form of
  • hydrochlorothiazide (15-200 mg) chloro- thiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg),
  • Illustrative of the adjuvants which can be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient sich as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintegreen or cherry.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient sich as microcrystalline cellulose
  • a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavoring agent such
  • muscarinic antagonist scopolamine which disrupts learning or are treated with scopolamine and the compound which is to be tested for possible reversal of the scopolamine effect. Twenty-four hours later, the rats are returned to the illuminated chamber.
  • the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • the compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the dosage range will generally be about 5 to 6000 mg. per patient per day which can be administered in single or multiple doses.
  • the dosage range will be about 10 to 4000 mg. per patient per day; more preferably about 20 to 2000 mg . per patient per day.
  • hydrochlorothiazide such as hydrochlorothiazide and consist of hydrochlorothiazide (50 mg) pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Des pyrimidines, des pyrimidinones et pyridopyrimidines substitués représentés par la formule (I) sont utiles comme antagonistes d'angiotensine II lors du traitement de l'hypertension, de l'hypertension oculaire et de certains troubles du système nerveux central; dans ladite formule, K représente -N(R8a)-C(=M) ou -N=C(R8b) où M représente O ou NR22.
EP19910907332 1990-03-30 1991-03-27 Substituted pyrimidines, pyrimidinones and pyridopyrimidines Withdrawn EP0522038A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US50158090A 1990-03-30 1990-03-30
US501580 1990-03-30

Publications (2)

Publication Number Publication Date
EP0522038A1 true EP0522038A1 (fr) 1993-01-13
EP0522038A4 EP0522038A4 (en) 1993-05-26

Family

ID=23994154

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19910907332 Withdrawn EP0522038A4 (en) 1990-03-30 1991-03-27 Substituted pyrimidines, pyrimidinones and pyridopyrimidines

Country Status (4)

Country Link
EP (1) EP0522038A4 (fr)
JP (1) JPH05505609A (fr)
CA (1) CA2079344A1 (fr)
WO (1) WO1991015209A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1925303A2 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale

Families Citing this family (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164407A (en) * 1989-07-03 1992-11-17 Merck & Co., Inc. Substituted imidazo-fused 5-membered ring heterocycles and their use as angiotensin ii antagonsists
DE122010000024I1 (de) * 1990-02-19 2010-07-08 Novartis Ag Acylverbindungen
US5324729A (en) * 1990-03-30 1994-06-28 Merck & Co., Inc. Substituted pyrimidines, pyrimidinones and pyridopyrimidines
US5166206A (en) * 1990-03-30 1992-11-24 Merck & Co., Inc. Substituted pyrimidines, pyrimidinones and pyridopyrimidines
US5250548A (en) * 1990-09-10 1993-10-05 Abbott Laboratories Angiotensin II receptor antagonists
CA2053148A1 (fr) * 1990-10-16 1992-04-17 Karnail Atwal Derives de la dihydropyrimidine
US5260285A (en) * 1990-12-07 1993-11-09 Merck & Co., Inc. Substituted imidazopyridazines as angiotensin II antagonists
US5250521A (en) * 1990-12-07 1993-10-05 Merck & Co., Inc. Substituted pyrazolopyrimidines as angiotensin II antagonists
US5472967A (en) * 1991-02-20 1995-12-05 Synthelabo 4-pyrimidinone derivatives their preparation and their application in therapy
FR2672892B1 (fr) * 1991-02-20 1994-01-14 Synthelabo Derives de 4-pyrimidinones, leur preparation et leur application en therapeutique.
TW274551B (fr) * 1991-04-16 1996-04-21 Takeda Pharm Industry Co Ltd
US5358950A (en) * 1991-07-05 1994-10-25 Laboratoires Upsa Triazolopyrimidine derivatives which are angiotensin II receptor antagonists
FR2678618B1 (fr) * 1991-07-05 1993-11-05 Upsa Laboratoires Nouveaux derives de triazolo pyrimidine antagonistes des recepteurs a l'angiotensine ii; leurs procedes de preparation, compositions pharmaceutiques les contenant.
IT1250749B (it) * 1991-08-02 1995-04-21 Luso Farmaco Inst Composti eterociclici ad attivita' a ii antagonista
IL104756A0 (en) * 1992-02-17 1993-06-10 Ciba Geigy Ag Composition for the treatment of glaucoma
FR2687676B1 (fr) * 1992-02-24 1994-07-08 Union Pharma Scient Appl Nouveaux derives de polyazaindenes antagonistes des recepteurs a l'angiotensine ii; leurs procedes de preparation, compositions pharmaceutiques les contenant.
FR2687677B1 (fr) * 1992-02-24 1996-10-11 Union Pharma Scient Appl Nouveaux derives de polyazaindenes antagonistes des recepteurs a l'angiotensine ii ; leurs procedes de preparation, compositions pharmaceutiques les contenant.
US5387747A (en) * 1992-02-24 1995-02-07 Laboratoires Upsa Triazolopyrimidine derivatives which are angiotensin II receptor antagonists, their methods of preparation and pharmaceutical compositions in which they are present
EP0577025A3 (fr) * 1992-07-01 1998-02-04 Hoechst Aktiengesellschaft Antagonistes du récepteur d'angiotensine-II pour le traitement et la prophylaxie des maladies coronaires du coeur
EP0603712B1 (fr) * 1992-12-22 2001-08-16 Takeda Chemical Industries, Ltd. Composés hétérocycliques avec une activité angiotensine II antagonistique et leur utilisation
IT1263804B (it) * 1993-01-22 1996-09-03 Luso Farmaco Inst Derivati pirimidinonici fusi con eterocicli azotati ad attivita' a ii antagonista
US5491172A (en) * 1993-05-14 1996-02-13 Warner-Lambert Company N-acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents
IL109431A (en) * 1993-05-14 2001-01-11 Warner Lambert Co Pharmaceutical compositions containing n-acyl sulfamic acid esters (or thioesters), n-acyl sulfonamides, and n-sulfonyl carbamic acid esters (or thioesters), for regulating plasma cholesterol concentration, and certain such novel compounds
GB0217431D0 (en) 2002-07-27 2002-09-04 Astrazeneca Ab Novel compounds
US7482355B2 (en) 2002-08-24 2009-01-27 Astrazeneca Ab Pyrimidine derivatives as modulators of chemokine receptor activity
AU2005279045B2 (en) 2004-08-28 2009-11-26 Astrazeneca Ab Pyrimidine sulphonamide derivatives as chemokine receptor modulators
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
MX2009013293A (es) 2007-06-04 2010-02-15 Synergy Pharmaceuticals Inc Agonistas de guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros trastornos.
EP2810951B1 (fr) 2008-06-04 2017-03-15 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
CA2730603C (fr) 2008-07-16 2019-09-24 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase utiles dans le traitement des affections gastro-intestinales, de l'inflammation gastro-intestinale, du cancer gastro-intestinal et d'autres affections
EP2420501A4 (fr) 2009-04-17 2012-08-29 Kowa Co Nouveau composé ayant une structure 3-hétéroarylpyrimidin-4-(3h)-one et préparation pharmaceutique contenant celui-ci
US20120122906A1 (en) * 2009-08-27 2012-05-17 Kowa Company, Ltd. Novel sulfonamide derivative and pharmaceutical product containing same
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
JP2016514670A (ja) 2013-03-15 2016-05-23 シナジー ファーマシューティカルズ インコーポレイテッド 他の薬物と組み合わせたグアニル酸シクラーゼ受容体アゴニスト
JP2016514671A (ja) 2013-03-15 2016-05-23 シナジー ファーマシューティカルズ インコーポレイテッド グアニル酸シクラーゼのアゴニストおよびその使用
EA201592263A1 (ru) 2013-06-05 2016-05-31 Синерджи Фармасьютикалз, Инк. Ультрачистые агонисты гуанилатциклазы c, способ их получения и использования

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0407342A3 (en) * 1989-07-06 1991-07-10 Ciba-Geigy Ag Pyrimidine derivatives
EP0424317A3 (en) * 1989-10-19 1991-09-25 Ciba-Geigy Ag Pyrimidines
EP0435827A3 (en) * 1989-12-28 1991-11-13 Ciba-Geigy Ag Diaza compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1925303A2 (fr) 1999-08-27 2008-05-28 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale
EP2277519A2 (fr) 1999-08-27 2011-01-26 Sanofi-Aventis Deutschland GmbH Utilisation d'antagonistes du récepteur Angiotensin II Type 1 pour prévenir l'accident cérébrovasculaire, le diabète et/ou l'insuffisance cardiaque globale

Also Published As

Publication number Publication date
WO1991015209A1 (fr) 1991-10-17
CA2079344A1 (fr) 1991-10-01
EP0522038A4 (en) 1993-05-26
JPH05505609A (ja) 1993-08-19

Similar Documents

Publication Publication Date Title
WO1991015209A1 (fr) Pyrimidines, pyrimidinones et pyridopyrimidines substitues
US5100897A (en) Substituted pyrimidinones as angiotensin ii antagonists
US5124335A (en) Substituted pyrollo-fused 6 membered heterocycles as angiotensin ii antagonists
US5330987A (en) Substituted pyridopyrimidinones and related heterocycles as angiotensin II antagonists
US5223499A (en) 6-amino substituted imidazo[4,5-bipyridines as angiotensin II antagonists
US5128327A (en) Angiotensin II antagonists incorporating a nitrogen containing six membered ring heterocycle
US5202328A (en) Substituted fused pyrimidinones
US5162325A (en) Angiotensin ii antagonists incorporating a substituted benzyl element
US5126342A (en) Imidazole angiotensin ii antagonists incorporating acidic functional groups
US5246944A (en) Quinoline angiotensin ii antagonists incorporating a substituted benzyl element
US5236928A (en) Imidazole derivatives bearing acidic functional groups at the 5-position, their compositions and methods of use as angiotensin II antagonists
WO1991012001A1 (fr) Agents antagonistes de l'angiotensine ii dans lesquels est incorpore un element de benzyle substitue
US5187159A (en) Angiotensin II antagonists incorporating a substituted 1,3-benzodioxole or 1,3-benzodithiole
JPH05140167A (ja) アンギオテンシンｉｉ拮抗薬としての置換ピラゾロピリミジン及びイミダゾピリダジン
EP0537937A2 (fr) Pyrazino (2,3-D)pyrimidinones substituées comme angiotensin II antagonistes
EP0512870A1 (fr) Quinazolinones substituées portant des groupes fonctionnels acides utiles comme antagonistes d'angiotensin II
JPH0725758B2 (ja) アンギオテンシンｉｉ拮抗薬としての酸性官能基を有する複素環化合物
EP0507594A1 (fr) Quinoléines substituées comme antagonistes d'angiotensine II
US5264439A (en) Quinazolinone, triazolinone and pyrimidinone angiotensin II antagonists incorporating a substituted benzyl element
US5166206A (en) Substituted pyrimidines, pyrimidinones and pyridopyrimidines
US5162340A (en) Substituted 1-(2h)-isoquinolinones bearing acidic functional groups as angiotensin ii antagonists
JPH0597854A (ja) 置換イミダゾ［１，２−ｂ［１，２，４トリアゾールを組み込んだアンギオテンシンＩＩ拮抗剤
US5385894A (en) Disubstituted 6-aminoquinazolinones
WO1991012002A1 (fr) Agents antagonistes de l'angiotensine ii a base d'imidazoles dans lesquels est incorpore un element de benzyle substitue
US5250521A (en) Substituted pyrazolopyrimidines as angiotensin II antagonists

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: 19920923

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): CH DE FR GB IT LI NL

A4 Supplementary search report drawn up and despatched

Effective date: 19930406

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): CH DE FR GB IT LI NL

17Q First examination report despatched

Effective date: 19940722

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

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19981001