EP0515535A1 - Agents antagonistes de l'angiotensine ii dans lesquels est incorpore un element de benzyle substitue - Google Patents

Agents antagonistes de l'angiotensine ii dans lesquels est incorpore un element de benzyle substitue

Info

Publication number
EP0515535A1
EP0515535A1 EP91905007A EP91905007A EP0515535A1 EP 0515535 A1 EP0515535 A1 EP 0515535A1 EP 91905007 A EP91905007 A EP 91905007A EP 91905007 A EP91905007 A EP 91905007A EP 0515535 A1 EP0515535 A1 EP 0515535A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
substituted
group
unsubstituted
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Withdrawn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
EP91905007A
Other languages
German (de)
English (en)
Other versions
EP0515535A4 (en
Inventor
William J. Greenlee
Arthur A. Patchett
David Hangauer
Thomas Walsh
Kenneth J. Fitch
Ralph A. Rivero
Daljit S. Dhanoa
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 EP0515535A1 publication Critical patent/EP0515535A1/fr
Publication of EP0515535A4 publication Critical patent/EP0515535A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and 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
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms

Definitions

  • Angiotensin II (A II), is an octapeptide hormone 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
  • RAS reninangiotensin system
  • a II receptor antagonism Several peptide analogs of A II are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by partial agonist activity and lack of oral absorption [M. Antonaccio. Clin. Exp.
  • 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; 4,582,847; and
  • This invention is directed to substituted heterocycles attached through a methylene bridge to novel substituted phenyl derivatives to give
  • compounds of the Formula I which are angiotensin II antagonists and are useful in the treatment of hypertension and congestive heart failure.
  • the compounds of the invention are useful as ocular antihypertensives.
  • the compounds of this invention contain a heterocyclic moiety which is substituted at the specified positions and to which a methylene bridge connecting a novel substituted phenyl group as defined by the lower portion of Formula I, is attached.
  • compositions of these novel compounds as the sole therapeutically active ingredient and in combination with diuretics and other antihypertensive agents, including beta blockers, angiotensin converting enzyme inhibitors, calcium channel blockers or a combination thereof are disclosed and claimed. Further, methods of treating hypertension and congestive heart failure are described and claimed.
  • the compounds of this invention 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.
  • these compounds exhibit antidopaminergic properties and are thus useful to treat disorders that involve dopamine dysfunction such as schizophrenia.
  • the compounds of this invention are especially useful in the treatment of these conditions in patients who are also
  • hypertensive or have a congestive heart failure condition hypertensive or have a congestive heart failure condition.
  • This invention relates to compounds of the general Formula I :
  • R 1 is:
  • aryl wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
  • L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom
  • M is O, S or NR 15 ;
  • R 2 is:
  • R 7a and R 7b are independently
  • R 7a and R 7b when R 7a and R 7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;
  • R 8a and R 8b are independently
  • a substituent selected from the group consisting of: -CON(R 2a ) 2 , -heteroaryl, -S(O) x -R 21 , -tetrazol-5-yl, -CONHSO 2 R 21 , -SO 2 NH-heteroaryl, -SO 2 NHCOR 21 , -PO(OR 2 ) 2 , -PO(OR 2a ) 2 , -SO 2 NH-CN,
  • X is:
  • R 11 and R 12 are independently:
  • R 13 is :
  • disubstituted aromatic 5 or 6 membered ring which can contain one or two heteroatoms selected from the group consisting of N, O, S, and wherein the substituents are members selected from the group consisting of -OH, -SH, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyloxy, -CF 3 , Cl, Br, I, F, or NO 2 ;
  • R 16 is
  • substituents are V and W, (9 ) (C 1 -C 10 )-alkyl-S(O) n ,
  • V and W are each independently selected from:
  • M 1 is M or -C(O)-; and z is 0 or 1; and r and t are 0 to 2; and
  • R 17 and R 18 are each independently selected from:
  • N, O, or S such as pyrrolidine, morpholine, or piperazine
  • heteroaryl is a 5 or 6 membered aromatic ring containing one or two heteroatoms selected from the group consisting of O, N, or S,
  • R 21 is:
  • R 1 is:
  • L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom
  • M is O, S or NR 15 ;
  • R 2 is:
  • R 7a and R 7b are independently
  • R 8a and R 8b are independently
  • a substituent selected from the group consisting of: -CON(R 2a ) 2 , -heteroaryl, -S(O) x -R 21 , -tetrazol-5-yl, -CONHSO 2 R 21 , -SO 2 NH-heteroaryl, -SO 2 NHCOR 21 , -PO(OR 2 ) 2 , -PO(OR 2a ) 2 , -SO 2 NH-CN,
  • R 11 and R 12 are independently:
  • R 13 is:
  • aryl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of Cl, Br , I, F,
  • disubstituted aromatic 5 or 6 membered ring which contains one or two heteroatoms selected from the group consisting of N, O, S, and wherein the substituents are members selected from the group consisting of -OH, -SH, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyloxy -CF 3 ,
  • R 16 is
  • V and W are selected from:
  • R 17 and R 18 are independently
  • N, O, or S such as pyrrolidine, morpholine, or piperazine
  • heteroaryl is a 5 or 6 membered aromatic ring containing one or two heteroatoms selected from the group
  • R 21 is:
  • R 1 is:
  • B is a single bond; and n is 0 to 2; and J 1 and L are connected together to form a 6-carbon aromatic ring substituted with R 7a , R 7b , R 8a and R 8b ; or J 1 and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom not at J 1 , substituted with R 7a , R 7b , R 8a and R 8b ; and
  • L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom; and J 2 is -C(R 17 )-; and
  • M is O, or NR 15 ; and R 2 is:
  • R 2a is:
  • R 7a and R 7b are independently
  • R 8a and R 8b are independently
  • R 9 and R 10 are independently:
  • X is:
  • R 11 and R 12 are independently:
  • R 13 is:
  • (k) -SO 2 NHCO-(C 1 -C 8 )-alkyl wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: -OH, -SH, -O(C 1 -C 4 )-alkyl, -S-(C 1 -C 4 )-alkyl, -CF 3 , Cl, Br, F, I, -NO 2 , -CO 2 H, -CO 2 -(C 1 -C 4 )-alkyl, -NH 2 ,
  • disubstituted aromatic 5 or 6 membered ring which can contain one or two heteroatoms selected from the group consisting of N, O, S, and wherein the substituents are members selected from the group consisting of: -OH, -SH, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkyloxy -CF 3 ,
  • V and W are selected from:
  • R 17 and R 18 are independently
  • R 21 is:
  • alkyl substitutents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
  • alkenyl and alkynyl substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon double bond or triple bond, respectively, such as vinyl, allyl and 2-butenyl.
  • Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each which may be substituted or unsubstituted with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
  • the alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge.
  • aryl substituent recited above represents phenyl or naphthyl.
  • heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, for example, pyridyl, thienyl, furyl,
  • Preferred compounds of the present invention which are illustrative of subclasses of Formula lb are:
  • DIHYDROTRIAZOLONES DIHYDROTRIAZOLONES
  • antagonists of Formula I consist of a heterocyclic component
  • alkylation may take place at more than one nitrogen atom of the heterocycle, and in these cases,
  • the alkylation step produces a fully-assembled antagonist of Formula I, except that functional groups in the alkylating agent or in the heterocycle may be present in protected form and require deprotection steps to be carried out to complete the synthesis. In other cases, the alkylation is carried out with a
  • a substituted benzyl element is introduced at the beginning of, or during the preparation of the heterocyclic element. Routes of this type are illustrated in Part II below. In most cases where this general approach is used, the substituted benzyl component which is introduced during the synthesis of the heterocycle must be subjected to further
  • this substituted benzyl component is designated as "-CH 2 Ar,” and is usually introduced by an alkylation step with a substituted benzyl halide or pseudohalide designated ArCH 2 -Q (where Q is, for example, Cl, Br, I, F, OTs, or OMs), or is introduced by a route which starts with a substituted benzylamine, designated
  • ArCH 2 NH 2 The required substituted benzylamine derivatives may be prepared by standard methods, for example from the substituted benzylic halides or pseudohalides ("ArCH 2 -Q"). Substituted benzyl
  • PART I are illustrated by those listed below in Table 1.
  • Substituted benzyl amines which are useful in the preparation of the alkylated heterocycles described in PART I are illustrated by those listed below in Table 2. In cases where these benzylic halides, pseudohalides and amines are not commercially
  • the compounds of this invention may be resolved using techniques known in the art.
  • the diastereomeric salts or esters of the enantiomers are separated and the desired compound is the more active stereoisomer.
  • the compounds of this invention, their pharmaceutically acceptable salts and their prodrug forms are included within the scope of this invention.
  • FAB-MS Fast atom bombardment mas spectroscopy
  • An appropriately substituted anthranilonitrile is acylated using the requisite acyl chloride.
  • the resulting amide is alkylated with sodium hydride and the appropriate alkyl halide (or pseudohalide).
  • the resulting tertiary amide is then rearranged/cyclized with basic hydrogen peroxide 1 .
  • 2-Substituted quinazolinones may be prepared from substituted anthranilonitriles as described in the literature and illustrated in Scheme I-2.
  • the appropriately substituted anthranilonitrile is acylated using the requisite acyl chloride then cyclized using basic hydrogen peroxide. 1
  • Scheme I-4 illustrates the general preparation of 2,3-disubstituted quinazolin-4- (3H)-ones of Formula la, wherein B is a single bond and K 1 is -C(O)-.
  • B is a single bond
  • K 1 is -C(O)-.
  • 2-substituted quinazolinone (see Scheme I-2 or Scheme I-3) is alkylated using sodium hydride and the appropriate alkyl halide (or pseudohalide). This reaction sometimes gives some O-alkylated product, generally less than 20% of the isolated reaction products.
  • anthranilic acids may be acylated and cyclized by heating them in DMF with an acyl chloride,
  • triethylamine and DMAP may also be prepared by heating an appropriately
  • the necessary alkyl amine may then be prepared from the alkyl halide (or pseudohalide) using the standard literature procedures (Scheme I-6). 5 Then, the amine and the 3,1,4-benzoxazone are heated together to give the desired 2,3- disubstituted quinazolinone 2 (Scheme I-7). SCHEME I-5
  • Substituted 2-alkylthioquinazolin-4(3H)-ones wherein K 1 is -C(O)- and B is -S- may be prepared from their corresponding substituted anthranilic acids as shown in Scheme I-8.
  • the amine from Scheme I-6 can be converted to its isothiocyanate upon treatment with thiophosgene. This may then be reacted with an appropriately substituted anthranilic acid to give the desired 3-alkyl-2-mercapto-quinazolin-4(3H)-one.
  • 6 A second alkylation of the mercapto group then gives the desired 2-alkylthio- 3-alkylquinazolin-4(3H)-one.
  • Scheme I-10 illustrates a possible route to the isomeric 1,2-disubstituted quinazolin-4(1H)-ones wherein J 1 is -C(O)- and where B is -S- or -O-.
  • An anthranilonitrile can be acylated with an alkyl haloformate or an alkylthiol haloformate. 10 This may then be deprotonated and alkylated with the
  • Scheme I-11 illustrates the method by which a 2-amino-3-alkylquinazolinone can be made.
  • the 2-mercaptoquinazolinone (14) shown in Scheme I-8 can be treated with sulfuryl chloride to give the corresponding 2-chloroquinazolinone.
  • Scheme I-12 illustrates the method by which a 2-amino-1-alkylquinazolinone can be made.
  • the products from Scheme I-10 can be used as a synthetic intermediate if the initial R 1 is a protecting group such as benzyl or t-butyl. 14
  • Deprotection and subjection of the resulting 2-mercapto-1-alkylquinazolinone to the same conditions used in Scheme I-11 will result in the formation of the desired 2-amino-1-alkylquinazolin-4(1H)-one.
  • the sulfide may be displaced directly by an R 1 amine as shown in Scheme I-13 (R 1 -S- and R 1 -NH 2 may or may not have the same R 1 ).
  • N-protected derivative 25 The nitro group of 25 may be reduced to the amine 26 by reduction with hydrogen over palladium on carbon.
  • the amine (26) may then be reacted with a variety of reagents known to form derivatives of amines such as alkyl- or
  • chloroformate is best carried out in the presence of a strong base such as sodium hydride to deprotonate the amine. This anion then reacts readily with chloroformates to give the substituted carbamates 27.
  • the carbamate (27) may be isolated, then deprotonated with lithium bis(trimethylsilyl)amide and alkylated to give the N,O-disubstituted
  • carbamates 28 may be carried out in one flask by first deprotonating the aniline (i.e. with sodium hydride in DMF), reacting the anion with an acyl halide or chloroformate, then treating the intermediate with an equivalent of a strong base such as lithium bis(trimethylsilyl)amide and finally adding an alkylating agent to obtain 28.
  • the carbamoyl-substituted quinazolinones 27 and 28 may be cleanly deprotected under acidic conditions such as trifluoroacetic acid-anisole to afford the heterocycles 29 and 30 respectively.
  • Scheme I-15 illustrates the reaction of amine 25 with isocyanates to give disubstituted ureas
  • Tetrasubstituted and trisubstituted ureas such as 34 and 35 may be prepared from the benzyl
  • Trisubstituted ureas (32) may be
  • the urea-substituted quinazolinones 32 and 33 may be cleanly deprotected under acidic conditions such as trifluoroacetic acid-anisole to afford the heterocycles 34 and 35 respectively.
  • the amine 26 (Scheme I-14) may be derivatized or converted to other functional groups using chemical procedures well known to those skilled in the art. After the appropriate 6-substituent has been constructed the protecting group may be removed by treatment with trifluoroacetic acid in the presence of anisole as illustrated in Schemes I-14 through I-16. The heterocycles obtained in this manner may be incorporated into Angiotensin II Antagonists of general Formula la as described in Part II.
  • the compounds of Formula lb can be prepared by a variety of methods typified by those described below in Schemes I-17to I-28.
  • N 1 and N 2 of the triazole ring are derived from hydrazine or a
  • N 4 of the triazole and the 4-(arylmethyl) substituent are derived directly or indirectly from a suitably substituted benzylamine (or isocyanate or isothiocyanate) or from a benzyl halide (or methanesulfonate, p-toluenesulfonate, etc.).
  • reaction Schemes described below are reasonably general, it will be understood by those skilled in the art of organic synthesis that one or more functional groups present in a given compound of Formula lb may render the molecule incompatible with a particular synthetic sequence. In such a case an alternative route, an altered order of steps, or a strategy of protection and deprotection may be employed. In all cases the particular reaction conditions (including reagents, solvent, temperature, and time) should be chosen so that they are consistent with the nature of the functionality present in the molecule.
  • R 16 Q represents an alkylating agent in which R 16 is typically a functionalized or unfunctionalized alkyl or aralkyl group, while Q is a leaving group such as chloro, bromo, iodo, methanesulfonate, or
  • M is O or S.
  • the isocyanate 2 itself is obtainable by well-known methods from various sources, including the (arylmethyl)amine (by phosgene treatment), the arylmethyl halide (by treatment with cyanate anion), and the arylacetic acid or derivative (via Curtius rearrangement of the acyl azide). Upon heating in the presence of
  • Reaction Scheme I-18 A highly useful alternative route to 4 is shown in Reaction Scheme I-18. This approach has been described by M. Pesson, S. Dupin, and M.
  • (arylmethyl)amine 10 (typically at temperatures from 70-150°C).
  • 4 can be alkylated to give the trisubstituted triazolinone 5.
  • Reaction Schemes I-17 and I-18 are not suitable for the introduction of most aryl or heteroaryl substituents at N 2 .
  • the procedures of Reaction Schemes I-19 to I-22 are especially well suited for the synthesis of compounds of Formula lb having aryl or heteroaryl substituents at N 2 , since the triazolinone ring is constructed with the N 2 -substituent in place, whereas the N 4 -substituent is introduced subsequently by alkylation.
  • Reaction Scheme I-19 presents a route patterned after that reported by K. Yabutani, K.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à des hétérocycles substitués, qui sont fixés par l'intermédiaire d'un pont de méthylène à de nouveaux dérivés de phényle substitué, représentés par la formule (I), et qui sont utiles comme agents antagonistes de l'angiotensine II.
EP91905007A 1990-02-13 1991-02-11 Angiotensin ii antagonists incorporating a substituted benzyl element Withdrawn EP0515535A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US47978690A 1990-02-13 1990-02-13
US479786 1990-02-13

Publications (2)

Publication Number Publication Date
EP0515535A1 true EP0515535A1 (fr) 1992-12-02
EP0515535A4 EP0515535A4 (en) 1996-01-17

Family

ID=23905431

Family Applications (2)

Application Number Title Priority Date Filing Date
EP91905007A Withdrawn EP0515535A4 (en) 1990-02-13 1991-02-11 Angiotensin ii antagonists incorporating a substituted benzyl element
EP91905733A Withdrawn EP0517812A4 (en) 1990-02-13 1991-02-11 Angiotensin ii antagonists incorporating a substituted benzyl element

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP91905733A Withdrawn EP0517812A4 (en) 1990-02-13 1991-02-11 Angiotensin ii antagonists incorporating a substituted benzyl element

Country Status (4)

Country Link
EP (2) EP0515535A4 (fr)
JP (2) JPH05503530A (fr)
CA (2) CA2075637A1 (fr)
WO (2) WO1991011999A1 (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 (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5449682A (en) * 1990-02-13 1995-09-12 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted benzyl element
US5240938A (en) * 1991-02-13 1993-08-31 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted pyridoimidazolyl ring
US5177095A (en) * 1990-02-13 1993-01-05 Merck & Co., Inc. Triazole angiotensin II antagonists incorporating a substituted benzyl element
US5183810A (en) * 1990-02-13 1993-02-02 Merck & Co., Inc. Imidazole angiotensin II antagonists incorporating a substituted benzyl element
US5246944A (en) * 1991-08-13 1993-09-21 Merck & Co., Inc. Quinoline angiotensin ii antagonists incorporating a substituted benzyl element
SG42942A1 (en) * 1991-09-10 1997-10-17 Tanabe Seiyaku Co Imidazopyridine derivatives and process for preparation thereof
US5187159A (en) * 1991-10-07 1993-02-16 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted 1,3-benzodioxole or 1,3-benzodithiole
GB9121727D0 (en) * 1991-10-14 1991-11-27 Ici Plc Heterocyclic compounds
TW226375B (fr) * 1991-10-24 1994-07-11 American Home Prod
US5442062A (en) * 1991-10-24 1995-08-15 The Upjohn Company Imidazole derivatives and pharmaceutical compositions containing the same
WO1994000450A1 (fr) * 1992-06-25 1994-01-06 Zeneca Limited Derives de chromane utilises comme antagonistes d'angiotensine ii
GB9218449D0 (en) 1992-08-29 1992-10-14 Boots Co Plc Therapeutic agents
CA2139930A1 (fr) * 1992-07-10 1994-01-20 Alan Martin Birch Derives du dioxycyclobutene comme antagonistes de l'angiotensine ii
DE4302956A1 (de) * 1993-02-03 1994-08-04 Bayer Ag Substituierte Imidazo(4,5-b)pyridine und Benzimidazole
US5300668A (en) * 1993-03-10 1994-04-05 Pfizer Inc. Certain esters of 1-(4-X-methylphenyl)cyclopent-3-ene-1-carboxylic acid, wherein X is a trialkylsilyloxy, bromo or hydroxy group, as intermediates
US5420133A (en) * 1993-03-19 1995-05-30 Merck & Co., Inc. Quinazolinones substituted with phenoxyphenylacetic acid derivatives
US5401745A (en) * 1993-03-19 1995-03-28 Merck & Co., Inc. Quinazolinones substituted with phenoxyphenylacetic acid derivatives
US5334598A (en) * 1993-03-19 1994-08-02 Merck & Co., Inc. Six-membered ring fused imidazoles substituted with phenoxyphenylacetic acid derivatives
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
AP9400651A0 (en) * 1993-07-15 1995-12-30 Pfizer Azacyclic-heterocyclic compounds as angiotensin II receptor antagonists.
DE4327256A1 (de) * 1993-08-13 1995-02-16 Bayer Ag Sulfonylbenzyl-substituierte Benzimidazole, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln
ES2079315B1 (es) * 1994-02-24 1996-10-16 Uriach & Cia Sa J Nuevas imidazopiridinas.
US5798344A (en) * 1994-03-08 1998-08-25 Otsuka Pharmaceutical Factory, Inc. Phosphonic ester derivatives of quinazolinones
ES2152396T3 (es) * 1994-04-06 2001-02-01 Shionogi & Co Derivado del acido fenilacetico con sustitucion en gamma, su procedimiento de obtencion y bactericida agricola que lo contiene.
ATE216261T1 (de) * 1995-06-07 2002-05-15 Searle & Co Kombinationstherapie zur behandlung des kongestiven herzversagens mit spironolacton und angiotensin ii-antagonist
WO1996040255A2 (fr) * 1995-06-07 1996-12-19 G.D. Searle & Co. Procede de traitement de la fibrose cardiaque par une combinaison therapeutique d'un antagoniste de l'angiotensine ii et d'un antagoniste de l'aldosterone epoxy-steroide
GB9716446D0 (en) * 1997-08-05 1997-10-08 Agrevo Uk Ltd Fungicides
CA2336714A1 (fr) 1998-07-06 2000-01-13 Bristol-Myers Squibb Company Biphenyl sulfonamides en tant que doubles antagonistes de recepteurs d'angiotensine et d'endotheline
US6174912B1 (en) 1998-08-21 2001-01-16 Dupont Pharmaceuticals Company Nitrogen substituted imidazo[4,5-C]pyrazoles as corticotropin releasing hormone antagonists
GB0328295D0 (en) * 2003-12-05 2004-01-07 Muscagen Ltd Therapeutic compounds
AU2005231123A1 (en) * 2004-03-08 2005-10-20 Wyeth Ion channel modulators
ME02005B (fr) 2005-09-14 2012-08-31 Takeda Pharmaceuticals Co Inhibiteurs de la dipeptidyl peptidase permettant de traiter le diabete
CA2622642C (fr) 2005-09-16 2013-12-31 Takeda Pharmaceutical Company Limited Inhibiteurs de dipeptidylpeptidase
TW200838536A (en) 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
AU2008261102B2 (en) 2007-06-04 2013-11-28 Bausch Health Ireland Limited Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
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
JP2011520969A (ja) * 2008-05-19 2011-07-21 シェーリング コーポレイション 二環式ヘテロ環誘導体およびｇｐｒ１１９モジュレーターとしてのその使用
CA2930674A1 (fr) 2008-06-04 2009-12-10 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
JP2011528375A (ja) 2008-07-16 2011-11-17 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 胃腸障害、炎症、癌、およびその他の障害の治療のために有用なグアニル酸シクラーゼのアゴニスト
WO2010137336A1 (fr) 2009-05-29 2010-12-02 興和株式会社 NOUVEAU DÉRIVÉ D'ACIDE α-PHÉNOXYBENZÈNEACÉTIQUE ET PRÉPARATION PHARMACEUTIQUE LE CONTENANT
WO2011138657A1 (fr) * 2010-05-04 2011-11-10 Glenmark Pharmaceuticals S.A. Composés oléfiniques à substitution aryle en tant qu'inhibiteurs de la pde10a
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
CA2905438A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
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
JP6606491B2 (ja) 2013-06-05 2019-11-13 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ｃの超高純度アゴニスト、その作成および使用方法
TWI731317B (zh) * 2013-12-10 2021-06-21 美商健臻公司 原肌球蛋白相關之激酶（ｔｒｋ）抑制劑

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3962244A (en) * 1971-01-23 1976-06-08 Hoechst Aktiengesellschaft Benzene sulfonyl ureas
US4420487A (en) * 1978-04-10 1983-12-13 The Purdue Frederick Company Diuretic and antihypertensive benzimidazoles
NZ192392A (en) * 1978-12-19 1983-02-15 M Ishikawa 3-(substituted (phenyl or pyridyl)) -3,4-dihydroquinazolin-4-ones
US4728741A (en) * 1985-01-08 1988-03-01 Smithkline Beckman Corporation 1-substituted-2-mercapto benzimidazole compounds and intermediates
US4772600A (en) * 1986-06-09 1988-09-20 A. H. Robins Company, Inc. Fused imidazoheterocyclic compounds and pharmaceutical compositions
EP0260621A3 (fr) * 1986-09-18 1989-03-15 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft 3-Aryluracides-énoléthers et leur utilisation comme herbicides
JPH07107056B2 (ja) * 1987-01-30 1995-11-15 日清製粉株式会社 ４（３ｈ）−キナゾリノン誘導体、その製造方法およびそれを有効成分とする抗潰瘍剤
AU2328188A (en) * 1987-09-23 1989-04-18 Ciba-Geigy Ag Heterocyclic compounds
GB8904174D0 (en) * 1989-02-23 1989-04-05 British Bio Technology Compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO9112001A1 *

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
WO1991011999A1 (fr) 1991-08-22
EP0517812A1 (fr) 1992-12-16
CA2075627A1 (fr) 1991-08-14
EP0517812A4 (en) 1995-10-18
CA2075637A1 (fr) 1991-08-14
EP0515535A4 (en) 1996-01-17
JPH05503530A (ja) 1993-06-10
JPH05504969A (ja) 1993-07-29
WO1991012001A1 (fr) 1991-08-22

Similar Documents

Publication Publication Date Title
WO1991012001A1 (fr) Agents antagonistes de l'angiotensine ii dans lesquels est incorpore un element de benzyle substitue
US5162325A (en) Angiotensin ii antagonists incorporating a substituted benzyl element
US5264439A (en) Quinazolinone, triazolinone and pyrimidinone angiotensin II antagonists incorporating a substituted benzyl element
US5100897A (en) Substituted pyrimidinones as angiotensin ii antagonists
US5246944A (en) Quinoline angiotensin ii antagonists incorporating a substituted benzyl element
EP0515546A1 (fr) Antagonistes de triazole angiotensine ii incorporant un element de benzyle substitue
US5238942A (en) Substituted quinazolinones bearing acidic functional groups as angiotensin ii antagonists
US5175164A (en) Angiotensin ii antagonists incorporating a substituted indole or dihydroindole
US5252574A (en) Angiotensin II antagonists incorporating a substituted thiophene or furan
US5240928A (en) Substituted quinazolinones as angiotensin II antagonists
EP0522038A1 (fr) Pyrimidines, pyrimidinones et pyridopyrimidines substitues
US5236928A (en) Imidazole derivatives bearing acidic functional groups at the 5-position, their compositions and methods of use as angiotensin II antagonists
WO1993012095A1 (fr) Agents antiangineux a base de quinazolinone
US5183810A (en) Imidazole angiotensin II antagonists incorporating a substituted benzyl element
US5177095A (en) Triazole angiotensin II antagonists incorporating a substituted benzyl element
US5162340A (en) Substituted 1-(2h)-isoquinolinones bearing acidic functional groups as angiotensin ii antagonists
US5166206A (en) Substituted pyrimidines, pyrimidinones and pyridopyrimidines
WO1991012002A1 (fr) Agents antagonistes de l'angiotensine ii a base d'imidazoles dans lesquels est incorpore un element de benzyle substitue
US5385894A (en) Disubstituted 6-aminoquinazolinones
US5240938A (en) Angiotensin II antagonists incorporating a substituted pyridoimidazolyl ring
US5436259A (en) Substituted 1,2,4-triazolin-3-one compounds bearing acidic functional groups as balanced angiotensin II antagonists
US5292741A (en) Macrocycles incorporating quinazolinones

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: 19920808

AK Designated contracting states

Kind code of ref document: A1

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

A4 Supplementary search report drawn up and despatched

Effective date: 19951201

AK Designated contracting states

Kind code of ref document: A4

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

RBV Designated contracting states (corrected)

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

17Q First examination report despatched

Effective date: 19970211

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: 19980901