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WO1993018035A1 - Antagonistes des recepteurs de l'angiotensine ii - Google Patents

Antagonistes des recepteurs de l'angiotensine ii Download PDF

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Publication number
WO1993018035A1
WO1993018035A1 PCT/US1993/001105 US9301105W WO9318035A1 WO 1993018035 A1 WO1993018035 A1 WO 1993018035A1 US 9301105 W US9301105 W US 9301105W WO 9318035 A1 WO9318035 A1 WO 9318035A1
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Prior art keywords
loweralkyl
hydrogen
substituted
halo
alkoxy
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PCT/US1993/001105
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English (en)
Inventor
Thomas M. Zydowsky
Biswanath De
Kazumi Shiosaki
Fatima Z. Basha
Martin Winn
John F. Debernardis
Thomas W. Von Geldern
Diane M. Yamamoto
Saul H. Rosenberg
Daniel J. Kerkman
Steven A. Boyd
Anthony K. L. Fung
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Abbott Laboratories
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Publication of WO1993018035A1 publication Critical patent/WO1993018035A1/fr

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/26Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32Nitrogen atom
    • C07D473/34Nitrogen atom attached in position 6, e.g. adenine
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
    • C07D473/40Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D513/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04Ortho-condensed systems

Definitions

  • This invention relates to compounds and compositions which block angiotensin II receptors, processes for making such compounds, synthetic intermediates employed in these processes and a method of treating
  • the present invention also relates to compositions and a method for treating glaucoma, preventing or treating atherosclerosis, preventing or treating stroke and treatment of a variety of obesity-related disorders with such compounds.
  • the present invention also relates to compositions and a method for treating CNS disorders.
  • renin-angiotensin system is one of the important blood pressure regulating systems.
  • the RAS functions as shown in the scheme below.
  • Low renal perfusion pressure stimulates the juxtaglomerular cells of the kidney to produce the proteolytic enzyme renin.
  • This enzyme acts on a circulating protein, angiotensinogen, cleaving off a decapeptide angiotensin I.
  • Angiotensin I is then cleaved to the octapeptide angiotensin II by angiotensin converting enzyme (ACE).
  • ACE angiotensin converting enzyme
  • Angiotensin II is the most powerful pressor substance in the RAS.
  • Angiotensin II binds to vascular smooth muscle receptors and induces vasoconstriction, but has little or no stimulating action on the heart.
  • Inhibitors of renin for example enalkiren
  • inhibitors of ACE for example, captopril and enalapril
  • ACE inhibitors have reported side effects including cough and skin rash.
  • Peptidyl and non-peptidyl angiotensin II receptor antagonists are known.
  • the peptidyl compound saralasin or [Sar 1 ,Ala 8 ] angiotensin II has been found to be a potent antagonist of the actions of angiotensin II.
  • Saralasin has several disadvantages. Because it is a peptide, saralasin has very poor oral bioavailability. The use of saralasin, therefore, is limited to administration to hospitalized patients by continuous intravenous infusion. Saralasin is also known to cause an initial increase in blood pressure after intravenous administration due to its activity as an angiotensin receptor agonist. Therefore, non-peptidyl angiotensin II receptor antagonists are preferred.
  • L, L', M and M' are independently selected from
  • heterocyclic ring wherein the heterocyclic ring contains 1 , 2, 3 or 4 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom or 2 nitrogen atoms and 1 oxygen atom or 1 oxygen atom and 1 sulfur atom and wherein the 5- membered heterocyclic ring is unsubstituted or susbstituted with a substituted selected from amino, alkylamino, dialkylamino, hydroxy, alkoxy, thioalkoxy, halo, loweralkyl and halo-substituted loweralkyl,
  • R 7 is loweralkyl, halo-substituted loweralkyl or -NR 7b R 7c wherein R 7b and R 7c are independently selected from hydrogen and loweralkyl and R 7a is loweralkyl, halo- substituted loweralkyl, amino, alkylamino, dialkylamino or -COOH;
  • R 50 and R 51 are independently selected from hydrogen, loweralkyl, hydroxy, alkoxy, hydroxy- substituted loweralkyl, alkoxy-substituted loweralkyl, alkoxy- substituted alkoxy and -S(O) 2 R 50a wherein R 50a is loweralkyl or aryl, or R 50 and R 51 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered aliphatic heterocycle;
  • R 53a is hydrogen or a carboxy-protecting group
  • R 54 is selected from hydrogen, loweralkyl, -C(O)R 56 , -C(O)NR 56 R 57 and -S(O) 2 R 58 wherein R 56 is selected from hydrogen, loweralkyl and aryl and R 58 is selected from lower alkyl and halo-substituted loweralkyl and wherein R55 and R57 are independently selected from hydrogen, loweralkyl, hydroxy and alkoxy;
  • R 1 and R 1 ' are hydrogen, but R 1 and R 1 ' are not both hydrogen;
  • the bicyclic heterocycle comprising at least one
  • the 6-membered ring of the bicyclic heterocycle comprising 0, 1 , 2 or 3 nitrogen atoms or 1 nitrogen atom and 1 oxygen atom or 1 nitrogen atom and 1 sulfur atom or 1 oxygen atom and 1 sulfur atom or 2 oxygen atoms or 2 sulfur atoms or 1 oxygen atom or t sulfur atom, the remaining ring atoms being carbon atoms and the 6-membered ring comprising 0, 1 , 2 or 3 double bonds; the 5-membered ring of the bicyclic heterocycle comprising 0, 1 , 2 or 3 nitrogen atoms or 1 nitrogen and 1 oxygen atom or 1 nitrogen and 1 sulfur atom or 1 oxygen atom and 1 sulfur atom or 1 sulfur atom or 1 oxygen atom, the remaining ring atoms being carbon atoms and the 5-membered ring comprising 0, 1 or 2 double bonds; the nitrogen atoms of the bicyclic heterocycle can be substituted with a substituent R 2 wherein at each occurrence R 2 is independently selected from hydrogen, loweral
  • the bicyclic heterocycle can be substituted with one, two or three substituents independently selected from R 3 and R 4 , R 3 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle and R 4 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle, wherein
  • R 10 is loweralkyl, halo- substituted loweralkyl, -PO 3 H 2 or-NR 1 1 R 12 wherein R 11 and R 12 are independently selected from hydrogen and loweralkyl and
  • R 20 is loweralkyl, halo- substituted loweralkyl or -NR 27a R 27b wherein R 27a and R 27b are independently selected from hydrogen, -OH and loweralkyl and R 21 is loweralkyl, halo-substituted loweralkyl, amino, alkylamino, dialkylamino or -COOH,
  • R 28a alkoxy and -S(O) 2 R 28 a wherein R 28a is loweralkyl or aryl, or R 25 and R 26 taken together with the nitrogen atom to which they are attached form a 5- to 7- membered aliphatic heterocycle;
  • R 31 is selected from hydrogen, loweralkyl and aryl and R 33 is selected from loweralkyl and halo- substituted loweralkyl and wherein R 30 and R 32 are
  • R 59 is loweralkyl, halo-substituted loweralkyl or aryl
  • D is (ii) a bicyclic heterocycle comprising a 5-membered ring fused to a 5-membered ring, the bicyclic heterocycle comprising at least one
  • heteroatom selected from N, O and S; each of the 5-membered rings of the bicyclic heterocycle independently comprising 0, 1 , 2 or 3 nitrogen atoms or 1 nitrogen and 1 oxygen atom or 1 nitrogen and 1 sulfur atom or 1 oxygen atom and 1 sulfur atom or 1 sulfur atom or 1 oxygen atom, the remaining ring atoms being carbon atoms and each of the 5-membered rings
  • the bicyclic heterocycle can be substituted with one or two substituents independently selected from R 3 and R 4 , R 3 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle and R 4 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle, wherein R 3 and R 4 are defined as above; or D is
  • R 3 and R 4 are defined as above;
  • Preferred compounds of the invention are compounds wherein D is a substituted purinyl group, a substituted pyrazolopyrimidinyl group, a substituted triazolopyrimidinyl group, a substituted thiazolopyrimidinyl group, a substituted oxazolopyrimidinyl group, a substituted pyrrolopyyrimidinyl group, a substituted thienopyrimidinyl group, a substituted furopyrimidinyl group, a substituted benzofuranyl group, a substituted isoxazolopyridinyl group or a substituted pyrrolopyridinyl group.
  • loweralkyl refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.
  • alkenyl refers to a branched or straight chain comprising two to ten carbon atoms which has one or more carbon-carbon double bonds, including vinyl, propenyl, butenyl and the like.
  • alkynyl refers to a branched or straight chain comprising two to ten carbon atoms which has one or more carbon-carbon triple bonds, including ethynyl, propynyl, butynyl and the like.
  • cycloalkyl refers to an alicyclic group comprising from 3 to 7 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkylalkyl refers to a loweralkyl radical to which is appended a cycloalkyl group, including cyclopentylmethyl,
  • alkylene refers to a 1 to 10 carbon straight or branched chain di-radical, including -CH 2 -,
  • halo-substituted loweralkyl refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen, including chloromethyl, fluoroethyl, trifluoromethyl, pentafluoroethyl and the like.
  • hydroxy-substituted loweralkyl refers to a loweralkyl radical to which is appended one or two hydroxy (-OH) groups.
  • halogen or halo as used herein refers to I, Br, Cl or F.
  • alkoxy refers to R 34 O- wherein R 34 is a loweralkyl or benzyl group.
  • Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy, benzyloxy and the like.
  • thioalkoxy refers to R 35 S- wherein R 35 is a loweralkyl or benzyl group.
  • alkoxy-substituted loweralkyl refers to a loweralkyl radical to which is appended an alkoxy group.
  • thioalkoxy-substituted loweralkyl refers to a a loweralkyl radical to which is appended a thioalkoxy group.
  • Representative thioalkoxy-substituted loweralkyl groups include
  • hydroxy-substituted loweralkyl refers to a loweralkyl radical to which is appended one or two hydroxy (-OH) groups.
  • carboxy-substituted loweralkyl refers to a loweralkyl radical to which is appended a carboxy group (-COOH), including carboxymethyl, carboxyethyl and the like.
  • alkoxycarbonyl refers to -C(O)OR 36 wherein R 36 is a carboxy-protecting group.
  • alkoxycarbonyl-substituted loweralkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group.
  • alkoxy-substituted alkoxy refers to an alkoxy radiacl to which is appended another alkoxy radical, including
  • alkylamino refers to -NHR 37 wherein R 37 is a loweralkyl group.
  • dialkylamino refers to -NR 38 R 39 wherein R 38 and R 39 are independently selected from loweralkyl.
  • alkanoyloxyaikyl refers to a loweralkyl radical to which is appended -OC(O)R 40 wherein R 40 is loweralkyl.
  • aroyloxyalkyl refers to a loweralkyl radical to which is appended -OC(O)R 41 wherein R 41 is aryl.
  • alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group.
  • alkoxycarbonyloxyalkyl refers to a loweralkyl radical to which is appended -OC(O)OR 42 wherein R 42 is loweralkyl or cycloalkyl.
  • alkoxycarbonylaminoalkyl refers to a loweralkyl radical to which is appended -NHC(O)OR 43 wherein R 43 is loweralkyl.
  • alkylaminocarbonyiaminoalkyl refers to a loweralkyl radical to which is appended -NHC(O)NHR 44 wherein R 44 is loweralkyl.
  • alkanoylaminoalkyl refers to a loweralkyl radical to which is appended -NHC(O)R 45 wherein R 45 is loweralkyl.
  • heterocyciiccarbonyloxyalkyl refers to a loweralkyl radical to which is appended -OC(O)R 46 wherein R 46 is a
  • aryl refers to a phenyl or a C 9 or C 10 bicyclic carbocyclic ring system having one or more aromatic rings, including naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • Aryl groups can be
  • arylalkyl refers to a loweralkyl radical to which is appended an aryl group.
  • Representative arylalkyl groups include benzyl, phenylethyl, fluorobenzyl, fluorophenylethyl and the like.
  • aliphatic heterocycle refers to a saturated cyclic group containing 5 to 7 ring atoms and, in particular, at least 1 nitrogen atom in the ring and optionally 1 additional heteroatom selected from S, S(O) 2 , O and N, with the remaining ring atoms being carbon atoms.
  • the ring can be substituted on a carbon atom or a heteroatom, for example, with loweralkyl, alkoxy or alkoxy-substituted alkoxy.
  • Representative aliphatic heterocycles include, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, S,S-dioxothiomorpholine,
  • heterocyclic group or “heterocyclic” as used herein rn the context of the terms “heterocyclic-substituted loweralkyl” and “5- to 7-membered aliphatic heterocycle” refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur, or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one nitrogen and one sulfur atom; or one nitrogen and one oxygen atom; wherein the
  • 5-membered ring has 0-2 double bonds and the 6- or 7-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur heteroatoms can optionally be oxidized; wherein the nitrogen heteroatom can optionally be quatemized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another 5-, 6- or 7-membered heterocyclic ring independently as defined above.
  • Heterocyclics include indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl,
  • benzothiazolyl benzoxazolyl, furyl, thienyl, triazolyl, benzothienyl,
  • heterocyclic-substituted loweralkyl refers to a loweralkyl radical to which is appended a heterocyclic group.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise carbamates, amides, N-alkyl derivatives, amino acetal derivatives, N-benzyl derivatives, imine derivatives, enamine derivatives and N-heteroatom derivatives. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc),
  • carboxy-protecting group refers to a carboxy group which has been esterified with one of the commonly used carboxylic acid protecting ester groups employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out.
  • Carboxy-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis” pp. 152-186 (1981 ), which is incorporated herein by reference.
  • a carboxy-protecting group can be used as a prodrug whereby the carboxy-protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium
  • carboxy-protecting groups are C 1 to C 8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like), benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like, dialkylaminoalkyl (e.g., dimethylaminoethyl and the like), alkanoyloxyalkyl groups such as pivaloyloxymethyl or propionyloxymethyl and the like, aroyloxyalkyl, such as benzoyloxyethyl and the like,
  • alkoxycarbonylalkyl such as methoxycarbonylmethyl
  • alkoxycarbonyloxyalkyl such as t-buyloxycarbonyloxymethyl and the like
  • alkoxycarbonylaminoalkyl such as t-butyloxycarbonylaminomethyl and the like
  • alkylaminocarbonylaminoalkyl such as methylaminocarbonylaminomethyl and the like
  • alkanoylaminoalkyl such as acetylaminomethyi and the like
  • heterocycliccarbonyloxyalkyl such as 4-methylpiperazinylcarbonyloxymethyl and the like
  • dialkylaminocarbonylalkyl such as dimethylaminocarbonylmethyl and the like
  • (5-(loweralkyl)-2-oxo-1 ,3-dioxolen-4-yl)alkyl such as (5-t-butyl-2-oxo-1 ,3-dioxolen-4-yl)
  • R 3 is bonded to either the 5-membered ring or the 6-membered ring and R 4 is bonded to either the 5-membered ring or the 6-membered ring.
  • the compounds of formula I When the compounds of formula I contain one asymmetric carbon atom, they can exist as pure enantiomers or mixtures of enantiomers. When the compounds of formula I contain more than one asymmetric carbon atom, they can exist as diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.
  • the present invention includes within its scope all of the isomeric forms.
  • the terms "R” and "S” configuration used herein are as defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem (1976) 45, 13-30.
  • the compounds of this invention can be prepared by the processes illustrated in Schemes I through XVIII. It should be understood that substituents A, D, E, G, R 1 , R 2 , R 3 , R 4 , etc. as used herein correspond to the groups identified by formula (I).
  • P is a protecting group. In the course of synthesis, certain groups present in the molecule, particulary carboxylic acid and tetrazole groups, are protected and deprotected as necessary.
  • protecting group is well known in the art and refers to substituents on functional groups of compounds undergoing chemical transformation which prevent undesired reactions and degradations during a synthesis; see, for example, T.H.
  • Suitable carboxy-protecting groups include t-butyl and benzyl groups.
  • Suitable tetrazole nitrogen-protecting groups include
  • the compounds of formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic synthesis that the functionality present on the heterocycle and other portions of the molecule must be consistent with the chemical transformation proposed. This will frequently necessitate judgment as to the order of synthetic steps, protecting groups required and deprotection conditions. Throughout the following section, not all compounds of formula (I) falling into a given class may necessarily be prepared by all methods described for that class. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods described must then be used.
  • Schemes I - XV illustrate methods of preparing compounds of the invention comprising various -G-E- substituents.
  • Reaction Scheme I illustrates a method of preparing compounds wherein -G-E- is -N(R 5 )-.
  • a biphenylamine of Formula 82 is alkylated under standard conditions (e.g., R 5 -X' wherein X' is a leaving group) and then reacted with a chloro-heterocycle to give a compound of Formula 81.
  • Scheme II
  • Reaction Scheme III illustrates a method of preparing compounds wherein -G-E- is -S- .
  • a biphenyl thiol of Formula 85 is reacted with a chloro-heterocycle to give a compound of Formula 84.
  • a biphenylmethylamine of the Formula 86 is reacted with a chloro-heterocycle in the presence of a base, such as triethylamine or lithium
  • Reaction Schemes VIA and VIB illustrate alternative methods of preparing compounds wherein -G-E- is -CH(R 5 )-O-.
  • a compound of Formula 93 having a leaving group X' e.g., mesylate
  • a compound of Formula 95 is reacted with a hydroxy-substituted heterocyclic in the presence of a base to give a compound of Formula 95.
  • secondary alcohol 92 whose preparation is illustrated in Scheme XXII, is reacted with a chloro-heterocycle in the presence of a base to give a compound of Formula 95.
  • the ketone is reacted with the desired Wittig reagent (e.g., Pr-P(Ph) 3 ) to give an intermediate oiefin which is reduced with hydrogen in the presence of a catalyst (e.g., platinum or palladium) to afford a compound of Formula 103.
  • the desired Wittig reagent e.g., Pr-P(Ph) 3
  • a catalyst e.g., platinum or palladium
  • Schemes XVI-XVII illustrate methods of preparing compounds of the invention comprising various bicyclic heterocyclic groups (D).
  • Scheme XVI discloses the synthesis of a compound of the invention comprising a substituted pyrrolopyridine (in particular, 4- ⁇ N-propyl-N-[(2'-[1H- tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -1 ,3-dioxo-1 ,3-dihydropyrrolo[3,4- c]pyridine and 4- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ - 1 ,3-dioxo-2-hydroxy-1 ,3-dihydropyrrolo[3,4-c]pyridine).
  • a substituted pyrrolopyridine in particular, 4- ⁇ N-propyl-N-[(2'-[1H- tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -1 ,3-d
  • Scheme XVII discloses the synthesis of a compound of the invention comprising a substituted pyrroloisoxazole (in particular, ethyl 3- ⁇ N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -4H-pyrrolo[3,4-c]isoxazole-5(6H)-carboxylate).
  • P 1 is hydrogen or an N-protecting group
  • R 1 " is R 1 as defined above, -NO 2 , -CN or an N-protected tetrazolyl group wherein the tetrazole is N-protected with a trityl group, a
  • Preferred intermediates of formula II are those wherein A is a bond; L, L', M and M' are hydrogen; and R 1 " is a tetrazolyl group or an N-protected tetrazolyl group.
  • R 1 " is R 1 as defined above, -NO 2 , -CN or an N-protected tetrazolyl group wherein the tetrazole is N-protected with a trityl group, a
  • Preferred intermediates of formula III are those wherein A is a bond; L, L', M and M' are hydrogen; and R 1 " is a tetrazolyl group or an N-protected tetrazolyl group.
  • Example 1A The compound resulting from Example 1A (2.5 g, 15 mmol) was taken up in phosphorous oxychloride (16 mL) and heated at reflux for three hours. The mixture was allowed to cool to ambient temperature and the volume reduced by one half under reduced pressure. The residue was diluted with diethyl ether (50 mL), and the solids which formed were collected by filtration and discarded. The filtrate was evaporated under reduced pressure to give a reddish oil which was distilled (80-81 °C at 0.75 mm Hg) to give the product as a colorless oil (1.16 g, 48% yield).
  • Example 1 D To the compound resulting from Example 1 D (0.28 g, 1.36 mmol) dissolved in tetrahydrofuran (1 mL) was added 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (1 mL). The solution was cooled to 0 °C and lithium hexamethyldisilazide (1.4 mL of a 1M solution in THF) was slowly added. The ice-bath was removed and the solution stirred for 10 minutes. The reaction mixture was re-cooled in the ice-bath and butyl iodide (0.74 g, 0.46 mL, 4.02 mmol) was added.
  • DMPU 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
  • Example 1E The compound resulting from Example 1E (220 mg, 0.84 mmol) was dissolved in tetrahydrofuran (1.5 mL) and cooled to 0 °C in an ice bath. Lithium hexamethyldisilazide (0.85 mL of a 1M solution in THF) was added dropwise over one minute. The bath was removed and the solution stirred for 30 minutes. The bath was replaced and N-triphenylmethyl-5-[2-(4'-bromomethyl-biphenyl)]tetrazole (83% pure, 563 mg, 0.84 mmol), prepared by the procedure described in European Patent Application No. 291, 969, in tetrahydrofuran (1 mL) was added dropwise over one minute.
  • Example 1 F The compound resulting from Example 1 F (183 mg, 0.25 mmol) was dissolved in THF (1 mL) and EtOH (1 mL). p-Toluene sulfonic acid (50 mg) was added and the reaction stirred overnight at ambient temperature. The solvent was removed under reduced pressure and the residue dissolved in MeOH (2 mL). Sodium hydroxide (2 mL of a 5 N solution) was added and the cloudy solution stirred at ambient temperature. After three hours thin layer chromatography indicated that starting material was still present. The reaction mixture was heated at 70 °C for 2.5 hours. The solution was cooled to ambient temperature and the solvents removed in vacuo.
  • N-Triphenylmethyl-5-[2-(4'-bromomethyl-biphenyl)]tetrazole (6.00 g, 10.7 mmol), prepared by the procedure described in European Patent Application No. 291 ,969, was dissolved in 55 mL of tetrahydrofuran. n- Butylamine (40 mL) was added and the mixture kept at ambient
  • Example 2B The compound resulting from Example 2B (500 mg, 0.75 mmol) was dissolved in tetrahydrofuran (25 mL) to which acetic acid (25 mL) and water (2 mL) had been added. The solution was refluxed for 2 hours and then concentrated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with ethanol in methylene chloride to provide the title compound as a colorless amorphous solid (150 mg, 47%).
  • Example 2A To a solution of the compound resulting from Example 2A (4.8 mmol) in dimethylformamide (8 mL) was added triethylamine (1 mL) and 6-chloro-9-(tetrahydro-2-pyranyl)purine (1.5 g, 6.3 mmol). The reaction was heated for 6 hours at 65 °C and then stirred overnight at ambient temperature. The reaction mixture was worked up by the procedure described in Example 2B to give an oil. Flash chromatography on silica gel eluting with ethyl acetate in hexanes afforded the title compound as a yellow amorphous solid (2.4 g, 79%). MS (DCI/NH 3 ) m/e 752 (M+H) + .
  • N-Triphenylmethyl-5-[2-(4 , -bromomethyl-biphenyl)]tetrazole (6.00 g, 10.7 mmol), prepared by the procedure described in European Patent Application No. 291 ,969, was dissolved in 55 mL of tetrahydrofuran. n-Propylamine (40 mL) was added and the mixture kept at ambient
  • Example 4B The compound resulting from Example 4B (500 mg, 0.71 mmol) was deblocked using the procedure described in Example 2C. Flash
  • Example 4A 6-(N-Propyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino)-9H-purine
  • 6-chloro-9-(tetrahydro-2-pyranyl)purine by the procedure described in Example 2B to provide an amorphous solid (950 mg, 56%).
  • This compound was deprotected by the procedure described in Example 3B to afford the title compound as an amorphous solid (250 mg, 53%).
  • Example 6A To the compound resulting from Example 6A (1.73 g, 6.59 mmol) in dimethylformamide (30 mL) at 0 °C was added 1.0 M sodium
  • Example 10 5- ⁇ N-Butyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ - [1 ,2,3]triazolo[1 ,5-alpyrimidine-6-carboxylic acid
  • the compound resulting from Example 8C is hydrolyzed by the procedure described in Example 7 to give the title compound.
  • Example 10
  • Example 2A To a solution of the compound resulting from Example 2A (2.25 mmol) in dimethylformamide (3 mL) was added triethylamine (1 mL) and 6-chloro-8-methylpurine (0.39 g, 2.3 mmol), prepared by the procedure described in J. Chem. Soc. Perkin Trans. 1, 879 (1984). The mixture was heated at 60 °C for 16 hours and then an additional portion of 6-chloro-8-methylpurine (160 mg, 0.954 mmol) was added. After 26 hours, the reaction was worked up by the procedure described in Example 2B.
  • Example 10A A solution of the compound resulting from Example 10A (240 mg, 0.35 mmol) in tetrahydrofuran (10 mL) was treated with p-toluene sulfonic acid monohydrate (100 mg, 0.53 mmol) and the mixture was stirred at ambient temperature for 12 hours. An additional aliquot of p-toluene sulfonic acid monohydrate (100 mg, 0.53 mmol) was added and the solution was heated at 60 °C for 4 hours. Potassium carbonate (280 mg, 2 mmol) was added and volatiles were removed under reduced pressure. Water (100 mL) was added to the residue and the solid was removed by filtration. The filtrate was acidified with acetic acid and the solid collected by filtration.
  • Example 11 A A solution of the compound resulting from Example 11 A (430 mg, 2.5 mmol) in tetrahydrofuran (15 mL) was treated with triethylamine (1 mL) and the compound resulting from Example 2A (2.5 mmol). After stirring at ambient temperature for 10 hours, the volatiles were removed under reduced pressure and the residue obtained worked up by the procedure described in Example 2B. The residue obtained was purified by flash chromatography on silica gel eluting with ethyl acetate in hexane to afford the title compound as an amorphous solid (1.05 g, 61%). MS (FAB) m/e 683 (M+H) + .
  • Example 11B To the compound resulting from Example 11B (300 mg, 0.44 mmol) dissolved in 10 mL of tetrahydrofuran was added p-toluene sulfonic acid monhydrate (92 mg, 0.48 mmol). The reaction was stirred at 55 °C for 3 hours. Solid potassium carbonate (200 mg) and 1 mL of water were added. The volatiles were removed under reduced pressure and water (75 mL) was added to the residue. The solid was removed by filtration and the filtrate was acidified with acetic acid. The aqueous layer was extracted with ethyl acetate (150 mL). The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate.
  • p-toluene sulfonic acid monhydrate 92 mg, 0.48 mmol
  • Example 12A The compound resulting from Example 12A (1.00 g, 1.4 mmol) was mixed with 12 mL of triethylamine and 500 mg of 10% palladium on carbon in 150 mL of ethyl acetate. The mixture was stirred for 36 hours under 1 atmosphere of hydrogen. Additional aliquots of 10% palladium on carbon (500 mg) were added at 12 and 24 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue obtained was suspended in ethyl acetate (200 mL), washed with saturated brine and dried over sodium sulfate. The filtered solution was concentrated in vacuo.
  • Example 12B The compound resulting from Example 12B (330 mg, 0.5 mmol) was deprotected according to the procedure described in Example 2C. The residue obtained was purified by flash chormatography on silica gel eluting with formic acid and water in ethyl acetate. The residue obtained was recrystallized from methylene chloride and hexane to afford the title compound as an amorphous solid (150 mg, 68%).
  • 6-Chloro-7-(tert-butyloxycarbonylmethyl)-7H-purine To a solution of 6-chloropurine (2.00 g, 12.9 mmol) in anhydrous dimethylformamide (10 mL) was added potassium carbonate (3.00 g) followed by tert-butylchloroacetate (2.00 g, 13.3 mmol). After stirring at ambient temperature for 14 hours, the reaction mixture was poured into saturated aqueous ammonium chloride solution (150 mL) and extracted with ethyl acetate (5 ⁇ 100 mL). The combined organic extracts were washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to afford an orange oil. The reaction was repeated using 3.00 g of 6-chloropurine and the products were combined.
  • Example 4A A solution of the compound resulting from Example 4A (3 mmol) in dimethylformamide (5 mL) was treated with triethylamine (1 mL) and the compound resulting from Example 13A (900 mg, 3.3 mmol). After stirring at 55 °C for 18 hours, the reaction was worked up by the procedure described in Example 2B. Flash chromatography on silica gel eluting with ethyl acetate in methylene chloride provided the title compound as a yellow amorphous solid (1.52 g, 76%). MS (FAB) m/e 768 (M+H) + .
  • Example 14A The compound resulting from Example 14A (770 mg, 1 mmol) was deprotected by the procedure described in Example 13C except that the solution was refluxed for 2 hours. Work up as described in Example 13 and flash chromatography on silica gel eluting with formic acid and water in ethyl acetate provided the title compound as an off-white amorphous solid (275 mg, 60%).
  • Example 15B The compound resulting from Example 15B (950 mg, 1.3 mmol) was deblocked according to the procedure described in Example 2C.
  • Example 15A The compound resulting from Example 2A and 4-chlorothieno[2,3- d]pyrimidine, prepared according to the procedure described in Bull. Chim. Soc. Fr. 587 (1975), are reacted according to the procedure described in Example 15A to give 4- ⁇ N-butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ thieno[2,3-d]pyrimidine.
  • Example 15A The compound, resulting from Example 2A and 4-chloro-6-methyl-furo[2,3-d]pyrimidine, prepared according to the procedure described in Bull. Chem. Soc. Fr. 4344 (1969), are reacted according to the procedure described in Example 15A to afford 4- ⁇ N-butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -6-methyl-furo[2,3-d]pyrimidine.
  • Example 2B purified by flash chromatography on silica gel to afford 4- ⁇ N-butyl-N-[(2 , -[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -6-chloro-3-methyl-isoxazolo[5,4-b]pyridine.
  • Example 2A To the compound resulting from Example 2A (2.5 mmol) dissolved in dimethylformamide (3 mL) was added the compound resulting from Example 25A (600 mg, 2.5 mmol) and 4-methylmorpholine (1 mL). The mixture was heated for 27 hours at 65 °C. During the heating, additional portions of the compound resulting from Example 25A (150 mg, 0.6 mmol) were added at 9 hours and 21 hours. Normal work up afforded an orange oil which was purified by flash chromatography on silica gel eluting with ethyl acetate in hexane.
  • Example 25B The compound resulting from Example 25B (170 mg, 0.224 mmol) was deblocked according to the procedure described in Example 10B with the modification that potassium acetate replace potassium carbonate in the neutralization step.
  • the crude product was dissolved in ethyl acetate and treated with hexane to produce the title compound as a colorless solid (66 mg, 57%).
  • Grignard formation was effected by treatment of magnesium (1.2 equivalents) in tetrahydrofuran with dibromoethane (0.05 equivlants) followed by heating to reflux and then adding a solution of the protected compound from above in tetrahydrofuran.
  • the reaction mixture turned brown and after 4 hours, most of the metal had been consumed.
  • the Grignard reagent was cooled in a dry ice/acetone bath and then transferred via cannula into a -70 °C solution of trimethyl borate (2.5 equivalents) ( ⁇ 2 M in tetrahydrofuran). Upon completion of the addition, the cooling bath was removed and the mixture allowed to warm to ambient temperature. The solution was diluted with ether (4 volumes), washed with 3 N
  • hydrochloric acid ensuring that the aqueous layer was pH 2 or lower.
  • the pH was then adjust to 10 by the addition of 1 N sodium hydroxide and the ether layer was discarded.
  • the aqueous solution was cooled to 0 °C, carefully acidified to pH 2 with 3 N hydrochloric acid and extracted with ether.
  • the combined organic extracts were dried over sodium sulfate and concentated in vacuo to about 20% of volume whereupon the boronic acid crystallizes in 36% yield.
  • the compounds of the present invention can be used in any combination.
  • salts derived from inorganic or organic acids.
  • Pharmaceutically acceptable salts are described in Berge, et al., J. Pharmaceutical Sciences 66 1-19 (1977). These salts include but are not limited to the following:
  • dodecylsuifate ethanesulfonate. glucoheptonate, glycerophosphate
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid, methanesulfonic acid and citric acid.
  • Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases. The salts can be prepared in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting the free base function with a suitable acid or by reacting the acidic function with a suitable base.
  • the compounds of the present invention are useful for blocking the interaction of angiotensin II with angiotensin II receptors and for treating hypertension, edema, renal failure, congestive heart failure, glaucoma, psoriasis, benign prostatic hypertrophy, diabetic nephropathy, diabetic retinopathy, or to prevent atherosclerosis or for treating gastrointestinal disorders associated with enhanced contractility and/or motility of intestinal smooth muscle or for treating contractile disorders of the uterus (including premature contractions, dysmenorrhea and the like) or for treating or preventing stroke, cerebral vasospasm or cerebral infarction or for treating CNS disorders (depression, schizophrenia, anxiety or cognitive disorders (Alzheimer's disease, amnesia and senile dementia)) in a human or other mammal.
  • the compounds of the invention are also useful for enhancing intimal wound closure and for reducing luminal thrombogenicity in a human or other mammal.
  • EDTA ethylenediamine tetraacetic acid
  • the buffer contained no cocaine, propanolol or steroid.
  • the pH of the buffer was 7.40 at 37°C when saturated with 5% carbon
  • the tissues were cleaned of extraneous connective tissue, cut into 3 mm rings, and suspended within a 10 mL tissue bath. All dilutions of peptide preparations were made with 0.3% aqueous BSA. The tissues were primed with 55 mM potassium chloride. Tissues were pre-loaded with 1 g of tension. Tension was recorded on a model 7 Grass polygraph using FT03 transducers. At the end of the equilibrium period, a control cumulative concentrationcontractile response curve for angiotensin II (A II: 1 X 10 -10 - 10 -8 M) was obtained. The tissue was washed several times until the baseline was reached. Forty five minutes later, test compound (antagonist) was added and the tissue was incubated for 30 minutes.
  • test compound antagonist
  • concentration-response curve for A II was then repeated in the presence of the test compound.
  • One dose of antagonist was tested per tissue only.
  • a dose of 1 mM of test compound was used, for a full pA 2 experiment multiple doses were used depending upon the potency of the antagonist.
  • the pA 2 value therefore is a measure of the effectiveness of the compound as an antagonist.
  • the data in Table 1 show that the compounds of the invention are potent antagonists at the angiotensin II receptor.
  • Table 1 pA2 Values from Isolated Rabbit Aorta Assay
  • the total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 25 mg/kg body weight or more usually from 0.1 to 15 mg/kg body weight.
  • Single dose compositions can contain such amounts or submultipies thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in multiple doses or in a single dose of from 10 mg to 1000 mg.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the compounds of the present invention can be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit
  • Topical administration can also involve the use of transdermal administration such as transdermal patches.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water.
  • Such compositions can also comprise adjuvants, such as wetting agents; emulsifying and suspending agents; sweetening, flavoring and perfuming agents.
  • sterile injectabie aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectabie solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulation can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • the most common way to accomplish this is to inject a suspension of crystalline or amorphous material with poor water solubility
  • the rate of absorption of the drug becomes dependent on the rate of dissolution of the drug which is, in turn, dependent on the physical state of the drug, for example, the crystal size and the crystalline form.
  • Another approach to delaying absorption of a drug is to administer the drug as a solution or suspension in oil.
  • Injectable depot forms can also be made by forming microcapsule matrices of drugs and
  • biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly-orthoesters and polyanhydrides.
  • the depot injectables can also be made by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration can include capsules, tablets, pills, powders, prills and granules.
  • the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • the dosage forms can also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings and other release-controlling coatings.
  • Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such exipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical
  • compositions can optionally contain opacitying agents and can also be of a composition that they release the active ingredient(s) only, or preferably, in a certain part of the intestinal tract, optionally in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as can be required.
  • Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels can contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,
  • polyethylene glycols silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
  • powdered tragacanth malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl iaurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
  • Ringer's solution ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations.
  • Wetting agents, emuisifiers and lubricants such as sodium lauryl sulfate and
  • magnesium stearate as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgement of the formulator.
  • the compounds of the present invention can be administered alone or in combination or in concurrent therapy with other cardiovascular agents
  • renin inhibitors independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, potassium channel activators, antiserotoninergic agents, thromboxane synthetase inhibitors, renin inhibitors and other agents useful for treating (in a human or other mammal) hypertension, edema or congestive heart failure.
  • ACE angiotensin converting enzyme
  • potassium channel activators potassium channel activators
  • antiserotoninergic agents antiserotoninergic agents
  • thromboxane synthetase inhibitors renin inhibitors and other agents useful for treating (in a human or other mammal) hypertension, edema or congestive heart failure.
  • diuretics include hydrochlorothiazide, chlorothiazide, acetazoiamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene,
  • Representative adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranolol, timoiol, carteolol and the like or a pharmaceutically acceptable salt thereof.
  • vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside, flosequinan and the like or a pharmaceutically acceptable salt thereof.
  • Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof.
  • Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.
  • Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof.
  • antiserotoninergic agents include ketanserin and the like or a pharmaceutically acceptable salt thereof.
  • renin inhibitiors include enalkiren, A-72517, PD-134672 or Ro 42-5892 and the like or a pharmaceutically acceptable salt thereof.
  • cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, guanabenz, reserpine and the like or a pharmaceutically acceptable salt thereof.
  • the compound of formula I and the other cardiovascular agent can be administered at the recommended maximum clinical dosage or at lower doses.
  • Dosage levels of the active compounds in the compositions of the invention can be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient.
  • the combination can be administered as separate compositions or as a single dosage form containing both agents.

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Abstract

Composés de la formule (I) qui sont des antagonistes des récepteurs de l'angiotensine II.
PCT/US1993/001105 1992-03-04 1993-02-04 Antagonistes des recepteurs de l'angiotensine ii WO1993018035A1 (fr)

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