WO1991012001A1 - 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 Download PDF

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Publication number
WO1991012001A1
WO1991012001A1 PCT/US1991/000993 US9100993W WO9112001A1 WO 1991012001 A1 WO1991012001 A1 WO 1991012001A1 US 9100993 W US9100993 W US 9100993W WO 9112001 A1 WO9112001 A1 WO 9112001A1
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Prior art keywords
alkyl
aryl
substituted
group
unsubstituted
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PCT/US1991/000993
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English (en)
Inventor
William J. Greenlee
Arthur A. Patchett
David Hangauer
Thomas Walsh
Kenneth J. Fitch
Ralph A. Rivero
Daljit S. Dhanoa
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Merck & Co., Inc.
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Publication of WO1991012001A1 publication Critical patent/WO1991012001A1/fr

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    • 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.

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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.
PCT/US1991/000993 1990-02-13 1991-02-11 Agents antagonistes de l'angiotensine ii dans lesquels est incorpore un element de benzyle substitue WO1991012001A1 (fr)

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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP0527534A1 (fr) * 1991-08-13 1993-02-17 Merck & Co. Inc. Dérivés de la quinoline et de l'azaquinoline comme antagonistes de l'angiotensine II
EP0539086A2 (fr) * 1991-10-24 1993-04-28 American Home Products Corporation Dérivés de la pyrimidine condensés et leur utilisation comme antagonistes de l'angiotensine II
US5240938A (en) * 1991-02-13 1993-08-31 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted pyridoimidazolyl ring
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
WO1994021259A1 (fr) * 1993-03-19 1994-09-29 Merck & Co., Inc. Quinazolinones remplacees par des derives d'acide phenoxyphenylacetique
GB2277446A (en) * 1993-03-19 1994-11-02 Merck & Co Inc Quinazolinones useful as endothelin antagonists
US5373015A (en) * 1991-10-14 1994-12-13 Imperial Chemical Industries Plc Fused pyridine derivatives useful as angiotensin II antagonists
WO1995002596A1 (fr) * 1993-07-15 1995-01-26 Pfizer Inc. Composes azacycliques-heterocycliques en tant qu'antagonistes du recepteur de l'angiotensine ii
US5449682A (en) * 1990-02-13 1995-09-12 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted benzyl element
LT3612B (en) 1992-08-29 1995-12-27 Boots Co Plc Therapeutic agents
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
WO1996040258A2 (fr) * 1995-06-07 1996-12-19 G.D. Searle & Co. Therapie mixte a base de spironolactone et d'un antagoniste de l'angiotensine ii pour le traitement de l'insuffisance cardiaque globale
EP0749974A1 (fr) * 1994-03-08 1996-12-27 Otsuka Pharmaceutical Factory, Inc. Derive de diester phosphonique
WO1999007687A1 (fr) * 1997-08-05 1999-02-18 Agrevo Uk Limited Derives pesticides de 4-benzyl-1,2,4-triazolin-5-one
EP1722788A2 (fr) * 2004-03-08 2006-11-22 Wyeth a Corporation of the State of Delaware Modulateurs de canaux ioniques
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
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C 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
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
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US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
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WO1994000450A1 (fr) * 1992-06-25 1994-01-06 Zeneca Limited Derives de chromane utilises comme antagonistes d'angiotensine ii
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
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DE4327256A1 (de) * 1993-08-13 1995-02-16 Bayer Ag Sulfonylbenzyl-substituierte Benzimidazole, Verfahren zu ihrer Herstellung und ihre Verwendung in Arzneimitteln
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US5449682A (en) * 1990-02-13 1995-09-12 Merck & Co., Inc. 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
US5177095A (en) * 1990-02-13 1993-01-05 Merck & Co., Inc. Triazole 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
EP0527534A1 (fr) * 1991-08-13 1993-02-17 Merck & Co. Inc. Dérivés de la quinoline et de l'azaquinoline comme antagonistes de l'angiotensine II
US5373015A (en) * 1991-10-14 1994-12-13 Imperial Chemical Industries Plc Fused pyridine derivatives useful as angiotensin II antagonists
EP0539086A2 (fr) * 1991-10-24 1993-04-28 American Home Products Corporation Dérivés de la pyrimidine condensés et leur utilisation comme antagonistes de l'angiotensine II
EP0539086A3 (en) * 1991-10-24 1993-06-16 American Home Products Corporation Condensed pyrimidine derivatives and their use as angiotensine ii antagonists
LT3612B (en) 1992-08-29 1995-12-27 Boots Co Plc Therapeutic agents
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
GB2277446A (en) * 1993-03-19 1994-11-02 Merck & Co Inc Quinazolinones useful as endothelin antagonists
US5401745A (en) * 1993-03-19 1995-03-28 Merck & Co., Inc. Quinazolinones substituted with phenoxyphenylacetic acid derivatives
US5420133A (en) * 1993-03-19 1995-05-30 Merck & Co., Inc. Quinazolinones substituted with phenoxyphenylacetic acid derivatives
WO1994021259A1 (fr) * 1993-03-19 1994-09-29 Merck & Co., Inc. Quinazolinones remplacees par des derives d'acide phenoxyphenylacetique
WO1995002596A1 (fr) * 1993-07-15 1995-01-26 Pfizer Inc. Composes azacycliques-heterocycliques en tant qu'antagonistes du recepteur de l'angiotensine ii
US5789415A (en) * 1993-07-15 1998-08-04 Pfizer Inc. Azacyclic-heterocyclic compounds as angiotension II receptor antagonists
EP0749974A4 (fr) * 1994-03-08 1997-12-17 Otsuka Pharma Co Ltd Derive de diester phosphonique
US5798344A (en) * 1994-03-08 1998-08-25 Otsuka Pharmaceutical Factory, Inc. Phosphonic ester derivatives of quinazolinones
EP0749974A1 (fr) * 1994-03-08 1996-12-27 Otsuka Pharmaceutical Factory, Inc. Derive de diester phosphonique
US6984633B2 (en) 1995-06-07 2006-01-10 G.D Searle & Co. Method to treat cardiofibrosis with a combination therapy of an angiotensin II antagonist and epoxymexrenone
WO1996040258A3 (fr) * 1995-06-07 1997-01-23 Searle & Co Therapie mixte a base de spironolactone et d'un antagoniste de l'angiotensine ii pour le traitement de l'insuffisance cardiaque globale
WO1996040255A3 (fr) * 1995-06-07 1997-01-23 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
WO1996040258A2 (fr) * 1995-06-07 1996-12-19 G.D. Searle & Co. Therapie mixte a base de spironolactone et d'un antagoniste de l'angiotensine ii pour le traitement de l'insuffisance cardiaque globale
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
WO1999007687A1 (fr) * 1997-08-05 1999-02-18 Agrevo Uk Limited Derives pesticides de 4-benzyl-1,2,4-triazolin-5-one
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
EP1722788A2 (fr) * 2004-03-08 2006-11-22 Wyeth a Corporation of the State of Delaware Modulateurs de canaux ioniques
EP1722788A4 (fr) * 2004-03-08 2008-02-13 Wyeth Corp Modulateurs de canaux ioniques
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C 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
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
EP2810951A2 (fr) 2008-06-04 2014-12-10 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
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation

Also Published As

Publication number Publication date
JPH05503530A (ja) 1993-06-10
JPH05504969A (ja) 1993-07-29
CA2075627A1 (fr) 1991-08-14
EP0515535A1 (fr) 1992-12-02
EP0517812A1 (fr) 1992-12-16
EP0517812A4 (en) 1995-10-18
EP0515535A4 (en) 1996-01-17
WO1991011999A1 (fr) 1991-08-22
CA2075637A1 (fr) 1991-08-14

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