WO1993018035A1 - Angiotensin ii receptor antagonists - Google Patents

Angiotensin ii receptor antagonists 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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French (fr)
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/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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
    • C07D401/12—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic 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
    • C07D491/02—Heterocyclic 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
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic 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
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic 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
    • C07D513/02—Heterocyclic 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
    • C07D513/04—Ortho-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 ***e, 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.

Abstract

Compounds are disclosed having formula (I). The compounds of the invention are angiotensin II receptor antagonists.

Description

ANGIOTENSIN II RECEPTOR ANTAGONISTS
Technical Field
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
hypertension, edema, renal failure, benign prostatic hypertrophy, diabetic nephropathy, Alzheimer's disease or congestive heart failure with such compounds. 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.
Background of the Invention
Blood pressure is regulated by a multitude of interrelated factors involving neural, vascular and volume-related effects. The renin-angiotensin system (RAS) 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). 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.
Figure imgf000004_0001
Inactive Fragments
Inhibitors of renin (for example enalkiren) and inhibitors of ACE (for example, captopril and enalapril) have clinical efficacy in treating hypertension and congestive heart failure. ACE inhibitors, however, have reported side effects including cough and skin rash.
Peptidyl and non-peptidyl angiotensin II receptor antagonists are known. The peptidyl compound saralasin or [Sar1 ,Ala8] angiotensin II has been found to be a potent antagonist of the actions of angiotensin II. Saralasin, however, 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.
Disclosure of the Invention
In accordance with the present invention, there are compounds of the formula I:
wherein
A is
(i) a covalent bond,
(ii) -O-,
(iii) -C(O)-,
(iv) -CH2-,
(v) -S-, -S(O)- or-S(O)2-;
E-G is
(i) -N(R5)-,
(ii) -O-,
(iii) -S-,
(iv) -N(R5)-CH(R5)-,
(v) -O-CH(R5)-,
(vi) -S-CH(Rs)-,
(vii) -C(R5')(R5)-CH(R5)-,
(viii) -CH(R5)-C(R5 ,)(R5)-.
(ix) -CH(R5)-N(R5)-,
(x) -CH(R5)-O-,
(xi) -CH(R5)-S-,
(xii) -N(R5)-N(R5)-,
(xiii) -C(R5)=C(R5)- or
(xiv) -CH(R5)-C(R5')(R5)-N(R5)- wherein at each occurrence R5 is
independently selected from hydrogen, loweralkyl, alkoxy-substituted loweralkyl, halo-substituted loweralkyl, carboxy-substituted loweralkyl, heterocyclic-substituted loweralkyl, alkenyl, alkynyl, cycloalkyl or cycloalkyialkyi and Rs' is hydrogen, halo, hydroxy, carboxy, alkoxy or thioalkoxy;
L, L', M and M' are independently selected from
(i) hydrogen, (ii) loweralkyl,
(iii) halo-substituted loweralkyl,
(iv) halo,
(v) -CN,
(vi) -NO2,
(vii) -OH,
(viii) hydroxy-substituted loweralkyl,
(ix) alkoxy-substituted loweralkyl,
(x) -NH2,
(xi) alkylamino,
(xii) dialkylamino,
(xiii) -SH,
(xiv) alkoxy and
(xv) thioalkoxy; R1' are independently selected from
(i) tetrazolyl,
Figure imgf000007_0001
or ,
Figure imgf000007_0002
Figure imgf000007_0003
,
(iv) -NH-C(=N(R50a))(R51a) wherein R50a is hydrogen, -CN or -NO2 and R51a is hydrogen, loweralkyl, alkylamino, dialkylamino, alkoxy or thioalkoxy,
(v) -NH(R51b) wherein R51b is a 5-membered aromatic 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,
(vi) -COOR6 or -CH2COOR6 wherein R6 is hydrogen or a carboxy- protecting group or
(vii) -NHS(O)2R7 or -CH2NHS(O)2R7 or -NHC(O)R7a or
-CH2NHC(O)R7a wherein R7 is loweralkyl, halo-substituted loweralkyl or -NR7bR7c wherein R7b and R7c are independently selected from hydrogen and loweralkyl and R7a is loweralkyl, halo- substituted loweralkyl, amino, alkylamino, dialkylamino or -COOH;
(viii) -C(O)NR50R51 or -CH2C(O)NR50R51 or -NHC(O)NR50R51
or -CH2NHC(O)NR50R51 or-NHC(S)NR50R51 or
-CH2NHC(S)NR50R51 wherein R50 and R51 are independently selected from hydrogen, loweralkyl, hydroxy, alkoxy, hydroxy- substituted loweralkyl, alkoxy-substituted loweralkyl, alkoxy- substituted alkoxy and -S(O)2R50a wherein R50a is loweralkyl or aryl, or R50 and R51 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered aliphatic heterocycle;
(ix) -CH2OR52 wherein R52 is selected from hydrogen, loweralkyl and -C(O)R53 wherein R53 is hydrogen, loweralkyl or aryl;
(x) -CH(OH)R52a or -C(O)Rs2a wherein R52a is loweralkyl, halo- substituted loweralkyl, -CF2COOR53a or -CH2COOR53a
wherein R53a is hydrogen or a carboxy-protecting group,
(xii) -CH2NR54R55 wherein R54 is selected from hydrogen, loweralkyl, -C(O)R56, -C(O)NR56R57 and -S(O)2R58 wherein R56 is selected from hydrogen, loweralkyl and aryl and R58 is selected from lower alkyl and halo-substituted loweralkyl and wherein R55 and R57 are independently selected from hydrogen, loweralkyl, hydroxy and alkoxy;
(xiii) -SO3H, -OSO3H or -CH2SO3H,
(xiv) -OPO3H2, -PO3H2 or -CH2PO3H2,
(xv) -SO2NR50R51 or -CH2SO2NR50R51 wherein R50 and R51
are defined as above and
(xvi) -C(O)NHSO2R60, -C(O)NHC(O)R60 or -C(O)NHNHSO2R60 wherein R60 is loweralkyl, halo-substituted loweralkyl or aryl;
with the proviso that one of R1 and R1' is hydrogen, but R1 and R1' are not both hydrogen;
and
D is
(i) a bicyclic heterocycle comprising a 6-membered ring fused to a
5-membered ring, the bicyclic heterocycle comprising at least one
heteroatom selected from N, O and S; 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 R2 wherein at each occurrence R2 is independently selected from hydrogen, loweralkyl, carboxy-substituted loweralkyl or alkoxycarbonyl-substituted loweralkyl; the nitrogen atoms of the bicyclic heterocycle can be oxidized; one or two carbon atoms of the bicyclic heterocycle can be
substituted with an oxo (=O) substituent and the sulfur atoms of the bicyclic heterocycle can be substituted with one or two oxo (=O) substituents; the bicyclic heterocycle can be substituted with one, two or three substituents independently selected from R3 and R4, R3 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle and R4 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle, wherein
R3 is
(i) hydrogen,
(ii) loweralkyl,
(iii) halo,
(iv) halo-substituted loweralkyl,
(v) thioalkoxy,
(vi) alkoxy-substituted loweralkyl,
(vii) thioalkoxy-substituted loweralkyl,
(viii) aryl,
(ix) arylalkyl,
(x) -NO2,
(xi) -COOR8 wherein R8 is hydrogen or a carboxy-protecting group,
(xii) -OR9 wherein R9 is hydrogen, loweralkyl, halo-substituted
loweralkyl, aryl, arylalkyl, heterocyclic-substituted loweralkyhor -C(O)R10 wherein R10 is loweralkyl, halo- substituted loweralkyl, -PO3H2 or-NR1 1R12 wherein R11 and R12 are independently selected from hydrogen and loweralkyl and
(xiii) -NR13R14 or -CH2NR13R14 wherein R13 and R14 are
independently selected from (1) hydrogen, (2) lower
alkyl, (3) arylalkyl, (4) -C(O)R15, (5) -S(O)2R15 wherein R15 is loweralkyl or halo- substituted loweralkyl and
(6) -R16-R17 wherein R16 is alkylene and R17 is
(a) -NR18R19 wherein R18 and R19 are independently
selected from hydrogen and loweralkyl or
(b) unsubstituted or loweralkyl substituted aziridinyl,
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridinyl or pyrimidinyl, or R13 and R14 taken together with the nitrogen atom to
which they are attached form a 5- to 7-membered aliphatic
heterocycle and R4 is
(i) hydrogen,
(ii) loweralkyl,
(iii) halo-substituted loweralkyl,
(iv) -CN,
(v) -NO2,
(vi) -NH2,
(vii) -NH-C(=N(R25a))(R26a) wherein R25a is hydrogen, -CN or -NO2 and R26a is hydrogen, loweralkyl, alkylamino, dialkylamino, alkoxy or thioalkoxy,
(viii) -NH(R26b) wherein R26b is a 5-membered aromatic 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 substitutent selected from amino, alkylamino, dialkylamino, hydroxy, alkoxy, thioalkoxy, halo, loweralkyl and halo-substituted loweralkyl, (ix) -CHO or -CH(=N-OH),
(x) tetrazolyl,
(xi) -NHS(O)2R20 or -CH2NHS(O)2R20 or -NHC(O)R21 or
-N(OH)C(O)R21 or-CH2NHC(O)R21 or -CH2N(OH)C(O)R21 wherein R20 is loweralkyl, halo- substituted loweralkyl or -NR27aR27b wherein R27a and R27b are independently selected from hydrogen, -OH and loweralkyl and R21 is loweralkyl, halo-substituted loweralkyl, amino, alkylamino, dialkylamino or -COOH,
(xii) -CH(OH)R22 or -C(O)R22 wherein R22 is loweralkyl, halo- substituted loweralkyl, -CF2COOR23 or -CH2COOR23 wherein R23 is hydrogen or a carboxy-protecting group,
(xiii) -COOR24 or -CH2COOR24 wherein R24 is hydrogen or a
carboxy-protecting group,
(xiv) -C(O)NR25R26 or -CH2C(O)NR25R26 or -NHC(O)NR25R26
or -CH2NHC(O)NR25R26 or -NHC(S)NR25R26
or -CH2NHC(S)NR25R26 wherein R25 and R26 are
independently selected from hydrogen, loweralkyl,
hydroxy, alkoxy, hydroxy-substituted loweralkyl,
alkoxy-substituted loweralkyl, alkoxy-substituted
alkoxy and -S(O)2R28a wherein R28a is loweralkyl or aryl, or R25 and R26 taken together with the nitrogen atom to which they are attached form a 5- to 7- membered aliphatic heterocycle;
(xv) -CH2OR27 wherein R27 is selected from hydrogen,
loweralkyl and -C(O)R28 wherein R28 is hydrogen,
loweralkyl or aryl;
(xvi) -CH2NR29R30 wherein R29 is selected from hydrogen,
loweralkyl, -C(O)R31 , -C(O)NR31 R32 and -S(O)2R33
wherein R31 is selected from hydrogen, loweralkyl and aryl and R33 is selected from loweralkyl and halo- substituted loweralkyl and wherein R30 and R32 are
independently selected from hydrogen, loweralkyl,
hydroxy and alkoxy;
(xvii) -SO3H, -OSO3H or -CH2SO3H,
(xviii) -OPO3H, -PO3H2 or-CH2PO3H2,
(xix) -SO2NR25R26 or -CH2SO2NR25R26 wherein R25 and R26
are defined as above and
(xx) -C(O)NHSO2R59. -C(O)NHC(O)R59 or -C(O)NHNHSO2R59
wherein R59 is loweralkyl, halo-substituted loweralkyl or aryl;
or 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
independently comprising 0, 1 or 2 double bonds; the nitrogen atoms of the bicyclic heterocycle can be substituted with a substituent R2 wherein at each occurrence R2 is independently selected from hydrogen, loweralkyl, carboxy-substituted loweralkyl or alkoxycarbonyl-substituted loweralkyl; the nitrogen atoms of the bicyclic heterocycle can be oxidized; one or two carbon atoms of the bicyclic heterocycle can be substituted with an oxo (=O) substituent and the sulfur atoms of the bicyclic heterocycle can be
substituted with one or two oxo (=O) substituents; the bicyclic heterocycle can be substituted with one or two substituents independently selected from R3 and R4, R3 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle and R4 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle, wherein R3 and R4 are defined as above; or D is
or
Figure imgf000013_0001
Figure imgf000013_0002
wherein R3 and R4 are defined as above;
or a pharmaceutically acceptable salt or prodrug thereof.
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.
Representative bicyclic heterocycle substituents of the compounds of this invention are:
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
and the like.
The term "loweralkyl" as used herein 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.
The term "alkenyl" as used herein 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.
The term "alkynyl" as used herein 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. The term "cycloalkyl" as used herein refers to an alicyclic group comprising from 3 to 7 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term "cycloalkylalkyl" as used herein refers to a loweralkyl radical to which is appended a cycloalkyl group, including cyclopentylmethyl,
cyclohexylmethyl and the like.
The term "alkylene" as used herein refers to a 1 to 10 carbon straight or branched chain di-radical, including -CH2-,
-CH(CH3)-, -CH2CH2CH2-, -CH(CH3)CH2CH2- and the like.
The term "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.
The term "hydroxy-substituted loweralkyl" refers to a loweralkyl radical to which is appended one or two hydroxy (-OH) groups.
The term "halogen" or "halo" as used herein refers to I, Br, Cl or F.
The term "alkoxy" refers to R34O- wherein R34 is a loweralkyl or benzyl group. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy, benzyloxy and the like.
The term "thioalkoxy" as used herein refers to R35S- wherein R35 is a loweralkyl or benzyl group.
The term "alkoxy-substituted loweralkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxy group.
The term "thioalkoxy-substituted loweralkyl" as used herein refers to a a loweralkyl radical to which is appended a thioalkoxy group. Representative thioalkoxy-substituted loweralkyl groups include
methylthiomethyl, methylthioethyl, ethylthioethyl, propylthiomethyl and the like.
The term "hydroxy-substituted loweralkyl" as used herein refers to a loweralkyl radical to which is appended one or two hydroxy (-OH) groups.
The term "carboxy-substituted loweralkyl" as used herein refers to a loweralkyl radical to which is appended a carboxy group (-COOH), including carboxymethyl, carboxyethyl and the like. The term "alkoxycarbonyl" as used herein refers to -C(O)OR36 wherein R36 is a carboxy-protecting group.
The term "alkoxycarbonyl-substituted loweralkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group.
The term "alkoxy-substituted alkoxy" as used here refers to an alkoxy radiacl to which is appended another alkoxy radical, including
methoxymethoxy, methoxy ethoxy, ethoxyethoxy and the like.
The term "alkylamino" as used herein refers to -NHR37 wherein R37 is a loweralkyl group.
The term "dialkylamino" as used herein refers to -NR38R39 wherein R38 and R39 are independently selected from loweralkyl.
The term "alkanoyloxyaikyl" as used herein refers to a loweralkyl radical to which is appended -OC(O)R40 wherein R40 is loweralkyl.
The term "aroyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended -OC(O)R41 wherein R41 is aryl.
The term "alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group.
The term "alkoxycarbonyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended -OC(O)OR42 wherein R42 is loweralkyl or cycloalkyl.
The term "alkoxycarbonylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended -NHC(O)OR43 wherein R43 is loweralkyl.
The term "alkylaminocarbonyiaminoalkyl" as used herein refers to a loweralkyl radical to which is appended -NHC(O)NHR44 wherein R44 is loweralkyl.
The term "alkanoylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended -NHC(O)R45 wherein R45 is loweralkyl.
The term "heterocyciiccarbonyloxyalkyl" as used herein refers to a loweralkyl radical to which is appended -OC(O)R46 wherein R46 is a
heterocyclic group. The term "aryl" as used herein refers to a phenyl or a C9 or C10 bicyclic carbocyclic ring system having one or more aromatic rings, including naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can be
unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, halo-substituted loweralkyl, alkoxy, thioalkoxy, alkoxycarbonyl, hydroxy, halo, mercapto, nitro, amino, alkylamino, dialkylamino, carboxaldehyde, carboxy and carboxamide.
The term "arylalkyl" as used herein refers to a loweralkyl radical to which is appended an aryl group. Representative arylalkyl groups include benzyl, phenylethyl, fluorobenzyl, fluorophenylethyl and the like.
The term "aliphatic heterocycle" as used herein 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,
4-methoxymethoxypiperidine and the like.
The term "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,
pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,
isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl, benzothienyl,
homopiperazinyl, homopiperidinyl, homomorpholinyl and the like.
Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substitutents independently selected from hydroxy, halo, oxo (=O), amino, alkylamino, dialkylamino, alkoxy, thioalkoxy, carboxy, alkoxycarbonyl, loweralkyl, cycloalkyl, -OSO3H and halo-substituted loweralkyl.
The term "heterocyclic-substituted loweralkyl" as used herein refers to a loweralkyl radical to which is appended a heterocyclic group.
The term "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),
benzyloxycarbonyl (Cbz) and the like.
As used herein, the term "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. In addition, 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
Series, American Chemical Society (1975). Such carboxy-protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. No. 3,840,556 and 3,719,667, the disclosures of which are incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of
"Bioreversible Carriers in Drug Design: Theory and Application", edited by E.B. Roche, Pergamon Press:New York (1987). Representative carboxy-protecting groups are C1 to C8 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,
cyclohexyloxycarbonylmethyl and the like, 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)methyl and the like and (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1 ,3-dioxolen-4-yl)methyl and the like.
When used herein, a formula such as
Figure imgf000027_0001
represents a bicyclic heterocycle where R3 is bonded to either the 5-membered ring or the 6-membered ring and R4 is bonded to either the 5-membered ring or the 6-membered ring.
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.
In addition, in the compounds of the invention, combinations of substituents and/or variables (i.e., A, D, E, G, R 1, R2, R3, R4, etc.) are permissible only if such combinations result in stable compounds.
In general, 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, R1, R2, R3, R4, 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. The term "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. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York (1981) for methods of introducing and removing appropriate protecting groups. Suitable carboxy-protecting groups include t-butyl and benzyl groups. Suitable tetrazole nitrogen-protecting groups include
triphenylmethyl (Tr), benzyl, t-butyl, methoxymethyl, benzyloxymethyl, p-nitrobenzyl, 1-ethoxyethyl and the like.
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.
Scheme I
Reaction Scheme I illustrates a method of preparing compounds wherein -G-E- is -N(R5)-. According to Scheme I, a biphenylamine of Formula 82 is alkylated under standard conditions (e.g., R5-X' wherein X' is a leaving group) and then reacted with a chloro-heterocycle to give a compound of Formula 81. Scheme II
According to Scheme II, compounds wherein -G-E- is -O- are prepared by coupling a hydroxy-substituted heterocycle with a bromo-biphenyl
compound of Formula 80 in the presence of a copper salt to give a compound of Formula 83. Scheme III
Reaction Scheme III illustrates a method of preparing compounds wherein -G-E- is -S- . According to Scheme XX, a biphenyl thiol of Formula 85 is reacted with a chloro-heterocycle to give a compound of Formula 84.
Scheme IV
Reaction Schemes IVA and IVB illustrate alternative methods of
preparing compounds wherein -G-E- is -CH2-N(R5)- . According to Scheme
IVA, a biphenylmethylamine of the Formula 86 is reacted with a chloro-heterocycle in the presence of a base, such as triethylamine or lithium
hexamethyldisilazide, to give a compound of Formula 87. Alternatively, according to Scheme IVB, a chloro-heterocycle is reacted with a primary amine to give a compound of Formula 88. This secondary amine is reacted with a biphenylmethyl bromide 89 to give a compound of Formula 87.
Scheme V
According to Scheme V, compounds wherein -G-E- is -CH(R5)-NH- are prepared by oxidizing a compound of Formula 90 to aldehyde 91. Addition of an organometallic reagent ( e.g., R5-M is propyl-Grignard reagent, yields secondary alcohol 92. The alcohol is converted to a leaving group (e.g., X' is a mesylate) which is displaced with a heterocyclic amine to afford a compound of Formula 94. Scheme VI
Reaction Schemes VIA and VIB illustrate alternative methods of preparing compounds wherein -G-E- is -CH(R5)-O-. According to Scheme VIA, a compound of Formula 93 having a leaving group X', e.g., mesylate, is reacted with a hydroxy-substituted heterocyclic in the presence of a base to give a compound of Formula 95. Alternatively, according to Scheme VIB, 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. Scheme VII
According to Scheme VII, compounds wherein -G-E- is -CH(R5)-S- are prepared by reacting a compound of Formula 93, whose preparation is illustrated in Scheme XXII, with a thiol-substituted heterocycle in the presence of a base to give a compound of Formula 96.
Scheme VIII
According to Scheme VIII, compounds wherein -G-E- is -CH2-CH(R5)- are prepared by reacting a heterocyclic aldehyde of Formula 97 with a Wittig reagent (CH2=P(Ph)3) to yield vinyl-heterocycle 98. Oiefin epoxidation with m-chloroperoxybenzoic acid affords epoxide 99. Epoxide 99 is opened with a Grignard reagent 100 prepared from the corresponding biphenylbromide. The resulting alcohol 101 is oxidized (e.g., Swern oxidation) to afford ketone 102. 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.
Scheme IX
According to Scheme IX, compounds wherein -G-E- is -CH(R5)-CH2- are prepared by converting a biphenyl aldehyde of the Formula 91 to a halo-alkylated compound of the Formula 93A (X' is halogen). Compound 93A is converted into Wittig reagent 110 using triphenylphosphine and a suitable base. This Wittig reagent is reacted with heterocyclic aldehyde 97 to give a compound of the Formula 111. This olefin is reduced with hydrogen in the presence of a catalyst such as platinum or palladium to give a compound of the Formula 112.
Scheme X
According to Scheme X, compounds wherein -G-E- is -N(R5)-CH2- are prepared by alkyalting amine 82 with R5CI in the presence of a base. The resulting amine 82a is reductively aminated with aldehyde 97 to give a compound of the Formula 114. Scheme XI
According to Scheme XI, compounds wherein -G-E- is -NH-CH(R5)- are prepared by reacting a heterocyclic nitrile 115 with an alkyl Grignard reagent (e.g., propylmagnesium bromide) and then hydrolyzing the intermediate imine to give a ketone of the Formula 116. Reductive amination with a biphenylamine 82 yields a compound of the Formula 117.
Scheme XII
According to Scheme XII, compounds wherein -G-E- is -O-CH(R5)- are prepared by reacting a heterocyclic aldehyde with an organometaliic reagent (e.g., R5-M is propylmagnesium bromide) to produce a secondary alcohol of the Formula 120. The alcohol is converted to a leaving group (for example, mesylate) and then is coupled with the biphenyl alcohol in the presence of a base to afford a compound of the Formula 121.
Scheme XIII
According to Scheme XIII, compounds wherein -G-E- is -S-CH(R5)- are prepared by converting a secondary alcohol to a leaving group (e.g., X' is mesylate) and then displacing it with biphenyl thiol 85 in the presence of a base to afford a compound of the Formula 123.
Scheme XIV
According to Scheme XIV, compounds wherein -G-E- is -NH-N(R5)- are prepared by converting a biphenylamine 82 into a urea of the Formula 124. The urea is reacted with bromine in the presence of a base to yield hydrazine 125. Alkylation with an alkyl bromide (e.g., R5X' is propyl bromide), followed by displacement of a chloro heterocycle with the secondary amine 125, affords a compound of the Formula 126. Scheme XV
According to Scheme XV, compounds wherein -G-E- is -N(R5)-NH- are prepared by first converting amine 82a to urea 130. Urea 130 is converted to hydrazine 131 by treatment with bromine in base. Hydrazine 131 is reacted with chloro-heterocycle D-Cl to afford a compound of the Formula 132.
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000034_0002
Figure imgf000034_0003
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000036_0002
Figure imgf000036_0003
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000039_0001
Figure imgf000039_0002
Figure imgf000039_0003
Figure imgf000040_0001
Figure imgf000040_0002
Schemes XVI-XVII illustrate methods of preparing compounds of the invention comprising various bicyclic heterocyclic groups (D).
Scheme XVI
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). 3,5-Dichloro-1-methyl- 2-(1H)-pyrazinone, prepared according to the method of Vekemans, Pollers- Wieers and Hoornaert, J. Het. Chem.20, 919 (1983), is combined in ethanol with 1.0 equivalent of N-triphenylmethyl-5-[2-(4'-propylaminomethylbiphenyl)]tetrazole, prepared by the procedure described in Example 72B, and 2.0 equivalents of ethyldiisopropylamine to afford a compound of the Formula 201. Compound 201 is dehalogenated using 10% palladium on carbon in 1 :1 ethanol/ethyl acetate to give the des-chloro compound 202. Diels-Alder cycloaddition of compound 202 with dimethyl acetylenedicarboxylate (3 equivalents, neat) at 140 °C according to the method of Tutonda et al., Tet.
Letters 27, 2509 (1986) provides a compound of the Formula 203. Diester 203 is heated in a sealed tube with ethanolic ammonia at 100 °C overnight to give an imide of the Formula 204. Acid catalyzed detritylation affords a compound of the Formula 205.
Alternatively, heating a compound of the Formula 203 in a sealed tube with hydroxylamine in ethanol at 80 °C overnight affords the corresponding N-hydroxyimide 206. Acid catalyzed detritylation affords a compound of the Formula 207.
Scheme XVII
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). A compound of the Formula 210, ethyl 3-amino-4H-pyrrolo[3,4-c]isoxazoie-5(6H)-carboxylate, prepared according to the procedure described in J. Med. Chem. 11, 453 (1968), is reacted with lithium bis(trimethylsilyl)amide and n-butyl iodide according to the procedures described in Example 6A to give the 3-butylamino compound of the Formula 211. Compound 211 is alkylated with N-triphenylmethyl-5-[2-(4'-bromomethyl-biphenyl)]tetrazole and lithium bis(trimethylsilyl)amide also by the procedure described in Example 6A to give a compound of the Formula 213. Tosic acid detritylation affords a compound of the Formula 214.
Figure imgf000042_0001
Figure imgf000043_0001
Intermediates useful for the preparation of the novel compounds of this invention include a compound of the formula (II):
Figure imgf000044_0001
wherein A, L, L', M, M' and R5 are defined as above;
P1 is hydrogen or an N-protecting group; and
R1" is R1 as defined above, -NO2, -CN or an N-protected tetrazolyl group wherein the tetrazole is N-protected with a trityl group, a
t-butyl group, a benzyl group, a benzyloxymethyl group or a methoxymethyl group.
Preferred intermediates of formula II are those wherein A is a bond; L, L', M and M' are hydrogen; and R1" is a tetrazolyl group or an N-protected tetrazolyl group.
Other intermediates useful for the preparation of the novel compounds of this invention include a compound of the formula (III):
Figure imgf000045_0001
wherein A, L, L', M and M' are defined as above; and
R1" is R 1 as defined above, -NO2, -CN or an N-protected tetrazolyl group wherein the tetrazole is N-protected with a trityl group, a
t-butyl group, a benzyl group, a benzyloxymethyl group or a methoxymethyl group.
Preferred intermediates of formula III are those wherein A is a bond; L, L', M and M' are hydrogen; and R1" is a tetrazolyl group or an N-protected tetrazolyl group.
Intermediates of the formula II wherein A is a covalent bond, L, L', M, and M' are hydrogen and R1" is a tetrazolyl group (i.e., compound 306) can be prepared as illustrated in Scheme XVIII. Aldehyde 300 (X" is halogen) can be reductively aminated to provide amine 301a. Protection of the amino group (for example, P1 = trityl), followed by Grignard formation, provides compound 302. Reaction of 302 with oxazoiine 303 provides biphenyl 304. Reaction of biphenyl 304 with POCl3 provides nitrile 305. Nitrile 305 can then be
elaborated to tetrazole 306 (for example, by reaction with sodium azide).
Figure imgf000046_0001
The foregoing may be better understood from the following examples, which are presented for the purpose of illustration and not intended to limit the scope of the inventive concept.
Example 1
2-{N-Butyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-6,7-dihydro- 5H-[1]-pyrindine-3-carboxylic acid Example 1A
Ethyl 2-cyano-3-hydroxyacrylate sodium salt
Sodium (2.4 g, 105 mmol) was added portionwise to ethanol (40 mL). After complete dissolution, the solution was warmed to 50-60 °C and ethyl cyanoacetate (11.3 g, 0.10 mol) was added dropwise over two minutes. A white precipitate formed immediately upon addition. The mixture was stirred for an additional 10 minutes at 60 °C, and then ethyl formate (6.4 g, 0.10 mol) was added to the warm mixture. The mixture was heated to reflux, at which time the solids dissolved. After approximately three hours at reflux, a white precipitate formed. The resulting slurry was kept at reflux for three more hours and then allowed to cool to ambient temperature overnight. The white solid was collected by filtration, washed with cold ethanol and dried in vacuo at 50 °C to give the product as a white solid. (7.8 g, 48% yield). For analytical purposes, a small amount of the product (~25 mg) was neutralized with phosphoric acid, extracted with ethyl acetate, dried over sodium sulfate, and evaporated under reduced pressure to give a yellow oil which solidified on standing. 1H NMR (CDCI3, 300 MHz) d 1.38 (t, J = 7Hz, 3H), 4.37 (q, J = 7Hz, 2H), 7.87 (bs, 1 H), 12.8 ( s,1 H). Example 1B
Ethyl 2-cyano-3-chloroacrylate
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). 1H NMR (CDCI3, 300 MHz) d 1.37 (t, J = 7Hz, 3H), 4.36 (q, J = 7Hz, 2H), 8.05 (s, 1H).
Example 1C
Ethyl 2-cyano-3-[(2-pyrrolidin-1-yl)-cyclopent-2-enyl]-acrylate
To 1-pyrrolidino-1-cyclopentene (0.99 g, 1.10 mL, 7.3 mmol) dissolved in methylene chloride (20 mL) was added triethylamine (0.74 g, 1.0 mL, 7.3 mmol). The solution was then cooled to -20 °C. The compound resulting from Example 1B (1.16 g, 7.3 mmol) was added dropwise over five minutes and then the solution was stirred at -20 °C for one hour. After warming to ambient temperature, the solution was washed with water (2 mL), dried over magnesium sulfate and evaporated under reduced pressure to give a red solid (2.0 g) which was used without further purification.
Example 1D
Ethyl 2-amino-6,7-dihydro-5H-[1]pyrindine-3-carboxylate The compound resulting from Example 1C (2.0 g) was suspended in ethanoiic ammonia (20 mL) and stirred at ambient temperature for four days. The solid was collected by filtration and washed with diethyl ether. The resulting bright yellow solid was added to a sodium ethoxide solution prepared from sodium (0.25 g) dissolved in ethanol (25 mL). The mixture was heated at reflux for 1.5 hours during which time the solution turned dark red. The solvent was removed under reduced pressure and the residue obtained was dissolved in ethyl acetate (50 mL), washed with water (2 × 50 mL), dried over sodium sulfate and evaporated under reduced pressure to give the product as an orange solid (0.83 g, 55% yield), which was used without further purification. 1H NMR (CDCl3, 300 MHz) d 1.38 (t, J = 8Hz, 3H), 2.84 (m, 4H), 4.32 (q, J = 9Hz, 2H), 6.34 (bs, 2 H), 7.96 (s, 1H). MS (DCI/NH3) m/e 207 (M+H)+.
Example 1E
Ethyl 2-(n-butylamino)-6,7-dihydro-5H-[1]pyrindine-3-carboxylate
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. After the addition was complete, the bath was removed and the solution stirred at ambient temperature overnight . The reaction mixture was evaporated and dissolved in ethyl acetate (25 mL). The ethyl acetate solution was washed with water (25 mL) and brine (25 mL), dried and concentrated under reduced pressure to give a yellow solid. Purification by flash
chromatography on silica gel eluting with 10% ethyl acetate in hexane afforded the desired product as a yellow oil (175 mg, 49% yield). 1H NMR (CDCI3, 300 MHz) d 0.96 (t, J = 7Hz, 3H), 1.36 (t, J = 7Hz, 3H), 1.44 (m, J = 8Hz, 2H), 1.57 (bs, 1 H), 1.62 (m, J = 8Hz, 2H), 2.07 (p, J = 8Hz, 2H), 2.79 (t, J = 8Hz, 2H), 2.88 (t, J = 8Hz, 2H), 3.51 (t, J = 7Hz, 2H), 4.29 (q, J = 7Hz, 2H), 7.93 (s, 1 H). MS (DCI/NH3) m/e 263 (M+H)+. Example 1F
Ethyl 2-{N-butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4- yl)methyl]amino}-6,7-dihydro-5H-[1]-pyrindine-3-carboxylate
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. The bath was removed and the solution was stirred overnight at ambient temperature during which time the solution turned black. The solvent was evaporated under reduced pressure, and the residue obtained was dissolved in ethyl acetate, washed with water (5 mL), brine (5m L), and 1N phosphoric acid (5 mL), dried over sodium sulfate and evaporated under reduced pressure to give a yellow oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane afforded the product as a yellow foam (188 mg, 30% yield). 1H NMR (CDCI3, 300 MHz) d 0.70 (t, J = 7Hz, 3H), 1.16 (m, 2H), 1.33 (t, J =7Hz, 3H), 1.45 (m, 2H), 2.10 (m, J = 8Hz, 2H); 2.84 (t, J = 8Hz, 4H), 3.22 (m, 2H), 4.30 (q, J = 7Hz, 2H), 4.58 (bs, 2H), 6.9 (d, J = 8Hz, 6H), 7.06 (q, J = 8Hz, 4H), 7.23 (m, 8H), 7.44 (m, 4H), 7.77 (bs, 1 H), 7.88 (dd, J = 8Hz, 1Hz, 1H).
Example 1G
2-{N-Butyl-N-[(2'-[N-trinhenylmethyl-1 H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino}-6,7-dihydro-5H-[1]-pyrindine-3-carboxylic acid
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. The residue was taken up in water (5 mL) and extracted with ethyl acetate (2 × 5 mL). The organic layer was acidified with 1M phosphoric acid, extracted with ethyl acetate (2 × 10 mL), dried over sodium sulfate and evaporated under reduced pressure to give a pale yellow solid. The solid was triturated with hexanes, filtered and dried overnight in vacuo at 60 °C to afford 103 mg (89% yield) of the title compound. 1H NMR (CDCI3, 300 MHz) d 0.90 (t, J = 7Hz, 3H), 1.40 (m, 2H), 1.55 (bm, 2H), 2.26 (t, J = 8Hz, 2H), 3.10 (m, 4H), 3.66 (bm, 2H), 4.45 (bm, 2H), 6.92 (m, 4H), 7.20-7.60 (m, 4H), 7.93 (d, J = 8Hz, 2H), 8.32 (s, 1 H). MS (FAB) m/e 469 (M+H)+, 491 (M+Na)+. Anal calcd for C27H28N6O2: C, 69.21 ; H, 6.02; N, 17.94. Found: C, 69.08; H, 5.87; N, 17.00.
Example 2
9-Methyl-6-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methynaminc}-9H- purine
Example 2A
N-Butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4- yl)methyl]amine
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
temperature for 2 hours. The solution was concentrated at reduced pressure and the residue obtained taken up in chloroform. The solution was washed with dilute potassium hydroxide solution, dried over potassium carbonate and concentrated under reduced pressure to afford the title compound. 1H NMR (CDCI3, 300 MHz) d 0.89 (t, J = 7Hz, 3H), 1.25-1.38 (m, 2H), 1.42-1.52 (m, 2H), 2.60 (t, J = 7Hz, 3H), 3.68 (s, 2H), 6.85-6.95 (m, 4H), 7.08 (s, 2H), 7.20-7.51 (m, 16H), 7.92 (dd, J = 8Hz, 2Hz, 1 H).
Example 2B
9-Methyl-6-{N-butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino}-9H-purine
A solution of the compound resulting from Example 2A (3 mmol) in tetrahydrofuran (25 mL) was treated with triethylamine (1 mL) and 9-methyl-6-chloropurine (800 mg, 4.75 mmol). The reaction mixture was stirred for 24 hours at 50 °C. An additional portion of 9-methyl-6-chloropurine (400 mg) was added and heating was continued for an additional 48 hours. The volatiies were removed in vacuo and the residue obtained dissolved in ethyl acetate (200 mL). The organic solution was washed with saturated aqueous brine, dried over sodium sulfate and sodium carbonate, filtered and concentrated in vacuo. The residue obtained was flash
chromatographed on silica gel eluting with ethyl acetate in hexanes to afford the title compound as an amorphous solid (1.1 g, 65%). MS (FAB) m/e 682 (M+H)+.
Example 2C
9-Methyl-6-{N-butyl-N-[(2'-[1 H-tetrazol-5-yl]binhenyl-4-yl)methyl]amino}-9H- purine
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%). 1H NMR (DMSO-d6, 300 MHz) d 0.87 (t, J = 5Hz, 3H), 1.30 (m, 2H), 1.60 (m, 2H), 3.70 (bs, 2H), 3.72 (s, 3H), 4.10 (bs, 1 H), 5.05 (bs, 1 H), 5.50 (bs, 1H), 7.03 (d, J = 6Hz, 2H), 7.20 (d, J = 6Hz, 2H), 7.55 (m, 2H), 7.65 (m, 2H), 8.13 (s, 1H), 8.26 (s, 1H). MS (DCI/NH3) m/e 440 (M+H)+. Example 3
6-(N-Butyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-9H-purine
Example 3A
6-{N-Butyl-N-[(2'-[N-triphenylmethyl- 1H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino}-9H-purine
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/NH3) m/e 752 (M+H)+.
Example 3B
6-(N-Butyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino)-9H-purine To the compound resutling from Example 3A (752 mg, 1 mmol) dissolved in tetrahydrofuran (50 mL) was added water (1.25 mL) and 12 M hydrochloric acid (1.25 mL). The solution was heated at 60 °C for 1 hour. The reaction was concentrated under reduced pressure and the residue obtained dissolved in methylene chloride (200 mL). The solution was extracted with saturated aqueous sodium bicarbonate. The combined aqueous extracts were washed with diethyl ether (100 mL) and then acidified with acetic acid and extracted with methylene chloride (3 × 100 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was crystallized from methylene chloride (25 mL) and hexane (250 mL). The solid was removed by filtration and dried to afford the title compound as a colorless amorphous solid (256 mg, 60%). 1H NMR (DMSO-d6, 300 MHz) d 0.78 (t, J = 4.5Hz, 3H), 1.20 (m, 2H), 1.50 (m, 2H), 3.80 (bs, 2H), 5.20 (bs, 2H), 6.95 (d, J = 6Hz, 2H), 7.13 (d, J = 6Hz, 2H), 7.45-7.55 (m, 4H), 8.02 (s, 1H), 8.16 (s, 1 H). MS (DCI/NH3) m/e 426 (M+H)+.
Example 4
2-Chloro-6-{N-propyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}- 9H-purine
Example 4A
N-Propyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4- yl)methyl]amine
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
temperature for 2 hours. The solution was concentrated at reduced pressure and the residue obtained taken up in chloroform. The solution was washed with dilute potassium hydroxide solution, dried over potassium carbonate and concentrated under reduced pressure to afford the title compound. 1H NMR (CDCI3, 300 MHz) d 0.89 (t, J = 7Hz, 3H), 1.50 (sextet, J = 7Hz, 2H), 2.55 (t, J = 7Hz, 2H), 3.68 (s, 2H), 6.85-6.95 (m, 4H), 7.08 (s. 2H), 7.20-7.50 (m, 16H), 7.92 (dd, J = 8Hz, 2Hz, 1H).
Example 4B
2-Chloro-6-{N-propyl-N-[(2'-[N-triphenylmethyl-1 H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino)-9H-purine
To a solution of the compound resulting from Example 4A (2.3 mmol) in dimethylformamide (3 mL) was added triethylamine (1 mL) and 2,6-dichloropurine (600 mg, 3.2 mmol). The solution was heated for 12 hours at 50 °C and then additional 2,6-dichloropurine (600 mg) was added.
Following an additional 2 hours at 50 °C, the reaction was worked up by the procedure described in Example 2B to afford an amorphous solid.
Flash chromatography on silica gel eluting with ethyl acetate in hexane afforded the title compound as an off-white amorphous solid (1.15 g, 84%): MS (FAB) m/e 688 (M+H)+.
Example 4C
2-Chloro-6-{N-pronyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}- 9H-purine
The compound resulting from Example 4B (500 mg, 0.71 mmol) was deblocked using the procedure described in Example 2C. Flash
chromatography on silica gel eluting with ethanol in methylene chloride containing acetic acid afforded the title compound as a colorless,
amorphous solid (165 mg, 50%). 1H NMR (DMSO-d6, 300 MHz) d 0.87 (t, J = 7.5Hz, 3H), 1.62 (m, 2H), 3.30 (bs, 1H), 3.48 (bs, 1 H), 4.08 (bs, 1 H), 4.90 (bs, 1H), 5.55 (bs, 1 H), 7.05 (d, J = 8Hz, 2H), 7.20 (m, 2H), 7.50-7.70 (m, 4H), 8.15 (s, 1H). MS (DCI/NH3) m/e 446 (M+H)+.
Example 5
6-(N-Propyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino)-9H-purine The compound resulting from Example 4A was reacted with 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%). 1H NMR (DMSO-d6, 300 MHz) d 0.87 (t, J = 4.5Hz, 3H), 1.62 (m, 2H), 4.05 (bs, 2H), 5.05 (bs, 1H), 5.50 (bs, 1H), 7.02 (d, J = 6Hz, 2H), 7.20 (d, J = 6Hz, 2H), 7.50-7.70 (m, 4H), 8.10 (s, 1H), 8.20 (s, 1H). MS (FAB) m/e 412 (M+H)+.
Example 6
Ethyl 7-[N-butyl-N-[[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl]amino]pyrazolo[1 ,5-a]pyrimidine-6-carboxylate Example 6A
Ethyl 7-(N-butylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate
To ethyl 7-aminopyrazolo[1 ,5-a]pyrimidine-6-carboxylate (3.70 g, 17.9 mmol, prepared by the procedure of Makisumi, Y., Chem. Pharm. Bull. 10, 620 (1962), in dimethylformamide (90 mL) at 0 °C was added 1.0 M sodium bis(trimethylsilyl)amide in tetrahydrofuran (18 mL, 18 mmol). After 1 hour 1-iodobutane (2.2 mL, 19 mmol) was added, and the mixture was stirred at ambient temperature for 24 hours. The mixture was diluted with ethyl acetate and the solution washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. Chromatography of the residue obtained on silica gel eluting with 15% ethyl acetate in hexane afforded 1.73 g (37%) of the desired product as an oil. TLC (20% ethyl acetate/80% hexane ) Rf = 0.27. 1 H NMR (CDCI3, 300 MHz) d 0.98 (t, 3H), 1.40 (t, 3H), 1.56-1.42 (m, 2H), 1.80-1.65 (m, 2H), 4.43-4.30 (m, 4H), 6.42 (d, 1H), 7.98 (d, 1H), 8.68 (s, 1H), 9.67 (bs, 1H).
Example 6B
Ethyl 7-[N-butyl-N-[[2'-(N-triohenylmethyl-1H-tetrazol-5-yl)biphenyl-4- yl]methyl]amino]pyrazolo[1 ,5-alpyrimidine-6-carboxylate
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
bis(trimethylsilyl)amide in tetrahydrofuran (7.2 mL, 7.2 mmol). After 1 hour, triphenylmethyl-5-[2-(4'-bromomethylbiphenyl)]tetrazole (4.00 g, 6.03 mmol, 84% pure), prepared by the procedure of Aldrich, P. E. etal. European Patent Application 291 ,969, was added. The mixture was stirred at ambient temperature for 24 hours and at 50 °C for 18 hours. The mixture was diluted with ethyl acetate, and the solution was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. Chromatography of the residue obtained on silica gel eluting with 14% ethyl acetate in hexane afforded 182 mg (4%) of the desired product as a foam. TLC (20% ethyl acetate/80% hexane ) Rf = 0.17. 1H NMR (CDCI3, 300 MHz) d 0.78 (t, 3H), 1.25-1.10 (m, 2H), 1.38 (t, 3H), 1.60-1.46 (m, 2H), 3.67 (t, 3H), 4.40 (q, 2H), 4.57 (s, 2H), 6.66 (d, 1H), 7.55-6.80 (m, 22H), 7.95-7.89 (m, 1H), 8.14 (d, 1H), 8.77 (s, 1H).
Example 6C
Ethyl 7-[N-butyl-N-[[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl]amino]pyrazolo[1 ,5-a]pyrimidine-6-carboxylate
The resultant compound from Example 6B (174.2 mg, 0.236 mmol) in 15:15:1 acetic acid/tetrahydrofuran/water (6 mL) was heated at reflux for 1 hour. The mixture was evaporated under reduced pressure and chased with several portions of toluene. Chromatography of the residue obtained on silica gel eluting with 2.5-4% methanol in chloroform afforded 94.7 mg (81%) of the title compound as a foam. TLC (10% methanol/90%
chloroform ) Rf = 0.37. 1H NMR (CDCI3, 300 MHz) d 0.86 (t, 3H), 1.35-1.10 (m, 2H), 1.37 (t, 3H), 1.72-1.55 (m, 2H), 3.40 (t, 2H), 4.38 (q, 2H), 4.98 (s, 2H), 6.64 (d, 1H), 7.22-7.10 (m, 4H), 7.46-7.38 (m, 1H), 7.63-7.51 (m, 2H), 8.17 (d, 1H), 8.29-8.22 (m, 1H), 8.54 (s, 1 H).
Example 7
7-[N-Butyl-N-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]amino]pyrazolo[1 ,5- a]pyrimidine-6-carboxylic acid
The resultant compound from Example 6 (74.3 mg, 0.150 mmol) in 1 M aqueous potassium hydroxide solution (1.5 mL) was stirred for 46 hours at ambient temperature. The mixture was acidified with 6 M hydrochloric acid and filtered. The resulting solid was dissolved in tetrahydrofuran, dried over sodium sulfate and evaporated under reduced pressure.
Chromatography of the residue on silica gel eluting with 5% methanol and 1% acetic acid in chloroform afforded 35.4 mg (50%) of the desired product as an amorphous solid. TLC (1% acetic acid/5%methanol/94% chloroform) Rf = 0.22. 1H NMR (CDCI3, 300 MHz) d 0.90 (t, 3H), 1.20-1.40 (m,2H), 1.52- 1.66 (m, 2H), 3.51-3.68 (m, 2H), 4.88 (s, 2H), 6.67 (s, 1H), 6.97 (d, 2H), 7.03 (d, 2H), 7.37 (dd, 1 H), 7.47-7.62 (m, 2H), 8.17 (dd, 1 H), 8.23 (d, 1 H), 8.78 (s, 1H). MS (DCI/NH3) m/e 469 (M+H)+. Example 8
Ethyl 7-{N-butyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}- [1,2,3]triazolo[ 1, 5-ao]pyrimidine-6-carboxylate
Example 8A
Ethyl 7-(n-b_]tylarrιino)-f1.2.3]trlazolo[1,5-a]pyrimidine-6-carboxylate Using the procedure described in Example 6A and replacing ethyl 7-aminopyrazolo[1,5-a]pyrimidine-6-carboxylate with ethyl 7-amino[1 ,2,3]-triazolo[1,5-a]pyrimidine-6-carboxylate, prepared using the method of Urleb, U. et al., Heterocycles 24, 1899 (1986), affords the title compound.
Example 8B
Ethyl 5-{N-butyl-N-[(2'-[N-triphenylmethyl- 1H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino}-[1,2,3]triazolo[1 ,5-a]pyrimidine-6-carboxylate
Using the procedure described in Example 6B with the
resultant compound from Example 8A gives the title compound.
Example 8C
Ethyl 5-(N-butyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}- [1 ,2,3]triazolo[1 ,5-a]pyrimidine-6-carboxylate Using the procedure described in Example 6C with the resultant compound from Example 8B gives the title compound.
Example 9
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
6-{N-Butyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-8-methyl-9H- purine
Example 10A
6-(N-Butyl-N-[(2'-[N-triphenylmethyl-1 H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino}-8-methyl-9H-Purine
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. The residue obtained was purified using flash chromatography on silica gel eluting with ethanol in methylene chloride to provide the title compound as an amorphous solid (250 mg, 16%). MS (FAB) m/e 682 (M+H)+.
Example 10B
6-{N-Butyl-N-{(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-8-methyl-9H- purine
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. Flash chromatography on silica gel eluting with ethanol and acetic acid in methylene chloride afforded the title compounds as an amorphous solid (90 mg, 58%) after recrystallization from ethyl acetate in hexane. 1H NMR (DMSO-d6, 300 MHz) d 0.87 (t, J = 7.5Hz, 3H), 1.30 (m, 2H), 1.55 (m, 2H), 2.42 (s, 3H), 3.80 (bs, 2H), 5.25 (bs, 2H), 7.03 (d, J = 8Hz, 2H), 7.16 (d, J = 8Hz, 2H), 7.50-7.70 (m, 4H), 8.13 (s, 1H), 12.70 (bs, 1H). MS (DCI/NH3) m/e 440 (M+H)+.
Example 11
7-(N-Butyl-N-[(2'-[ 1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1-methyl-1H- [1 ,2,3]triazolo[4,5-d]pyrimidine
Example 11 A
4-Chloro-1-methyl-1H-[1 ,2,3]triazolo[4,5-d]pyrimidine A suspension of 5-amino-6-chloro-4-methyiaminopyrimidine (1.6 g,
10 mmol) in 30 mL of water was treated with 25 mL of acetic acid. The solution was diluted with 50 mL of water and solid sodium nitrile (760 mg,
11 mmol) was added. After stirring at ambient temperature for 15 minutes, an additional portion of sodium nitrite (140 mg, 2 mmol) was added.
Stirring was continued for 15 minutes after which time the reaction mixture was diluted with 250 mL of water. Solid sodium acetate was added to adjust the pH to 5 and then the solution was extracted with ethyl acetate (2 × 250 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale yellow solid (1.2 g, 70%). 1H NMR (CDCI3, 300 MHz) d 4.38 (s, 3H), 8.95 (s, 1H).
Example 11 B
7-{N-Butyl-N-[(2'-[N-triphenylmethyl-1 H-tetrazol-5-yl]biohenyl-4- yl)methyl]amino}-1-methyl-1H-[1 ,2,3]triazolo[4,5-d]pyrimidine
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 1 1 C
7-{N-Butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino }- 1-methyl- 1H-
[ 1,2,3]triazolot[4,5-d]pyrimidine
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. The filtered solution was concentrated under reduced pressure and the residual acetic acid removed by azeotropic distillation with toluene. The residue was recrystallized from ethyl acetate and hexane to afford the title compound as an amorphous solid (120 mg, 61%). The 300 MHz 1H NMR spectrum was found.to be consistent with the proposed structure. MS (FAB) m/e 441 (M+H)+. Anal calcd for C23H24N10: C, 62.71 ; H, 5.49; N, 31.80. Found: C, 62.82; H, 5.54; N, 31.68.
Example 12
6-{N-Propyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-7-methyl- 7H-purine Example 12A
2,8-Dichloro-6-{N-propyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5- yl]biphenyl-4-yl)methyl]amino}-7-methyl-7H-purine To a solution of the compound resulting from Example 4A (4.33 mmol) in dimethylformamide (5 mL) was added triethylamine (1 mL) and 2,8-dϊchloro-7-methylpurine (1.00 g, 4.3 mmol). After stirring for 24 hours at ambient temperature, the reaction was worked up according to the procedure described in Example 2B. Flash chromatography on silica gel eluting with ethyl acetate in hexane afforded the title compound as a yellow amorphous solid (2.00 g, 75%). MS (FAB) m/e 736 (M+H)+.
Example 12B
6-{N-Propyl-N-[(2'-[N-triphenylmethyl-1 H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino}-7-methyl-7H-purine
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. Flash chromatography on silica gel eluting with isopropanol and acetic acid in methylene chloride afforded the title compound as an amorphous solid (340 mg, 36%). MS (FAB) m/e 668 (M+H)+.
Example 12C
6-{N-Propyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-7-methyl- 7H-purine
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%). 1H NMR (DMSO-d6, 300 MHz) d 0.87 (t, J = 7.5Hz, 3H), 1.68 (m, 2H), 3.40 (m, 2H), 3.80 (s, 3H), 4.80 (s, 2H), 7.07 (d, J = 9Hz, 2H), 7.28 (d, J = 9Hz, 2H), 7.52-7.70 (m, 4H), 8.57 (s, 1H), 8.63 (s, 1H). MS (DCI/NH3) m/e 426 (M+H)+.
Example 13
6-{N-Propyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-9- (carboxymethyl)-9H-purine
Example 13A
6-Chloro-9-(tert-butyloxycarbonylmethyl)-9H-purine and
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.
Purification by flash chromatography on silica gel eluting with ethyl acetate in hexane provided the title compound (6.4 g, 75%). TLC (75% ethyl acetate/25% hexane) Rf = 0.69. MS (DCI/NH3) m/e 269 (M+H)+, 286 (M+H+NH3)+.
Also obtained was the isomeric 7-substituted compound, 6-chloro-7- (tert-butyloxycarbonylmethyl)-7H-purine, (1.3 g, 15%). TLC (75% ethyl acetate/25% hexane) Rf = 0.28. MS (DCI/NH3) m/e 269 (M+H)+, 286 (M+H+NH3)+. Example 13B
6-{N-Propyl-N-[(2'-[N-triphenylmethyl-1 H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino}-9-(tert-butyloxycarbonylmethyl)-9H-purine
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 13C
6-{N-Propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-9- (carboxymethyl)-9H-purine
A solution of the resultant compound from Example 13B (770 mg, 1 mmol) in tetrahydrofuran (75 mL) was treated with 12 M hydrochloric acid (3 mL) and water (2 mL). The solution was heated at 65 °C for 1.5 hours and then concentrated under reduced pressure. Water (100 mL) was added to the residue and solid sodium hydroxide was added to adjust the pH to 11. The solid was removed by filtration and the filtrate acidified with formic acid. The solid was collected by filtration and purified by flash chromatography on silica gel eluting with water and formic acid in ethyl acetate. The residue obtained was treated with toluene in methanol and concentrated in vacuo to affordjhe title compound as an amorphous solid (225 mg, 48%). 1H NMR (DMSO-d6, 300 MHz) d 0.87 (t, J = 7Hz, 3H), 1.65 (m, 2H), 3.30 (bs, 2H), 5.01 (s, 2H), 5.02 (bs, 1 H), 5.40 (bs, 1 H), 7.02 (d, J = 8Hz, 1 H), 7.21 (d, J = 8Hz, 2H), 7.50-7.70 (m, 2H), 8.16 (s, 1H), 8.23 (s, 1 H). MS (DCI/NH3) m/e 470 (M+H)+.
Example 14
6-{N-ProPyl-N-[(2,-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-7- (carboxymethyl)-7H-purine Example 14A
6-{N-Propyl-N-[(2'-[N-trinhenylmethyl-1H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino}-7-(carboxymethyl)-7H-purine A solution of the compound resulting from Example 4A (3 mmol) in dimethylformamide (5 mL) was treated with triethylamine (1 mL) and the 7-substituted isomer resulting from Example 13A (900 mg, 3.34 mmol). After stirring at 55 °C for 18 hours, an additional aliquot of the 7-substituted isomer (200 mg, 0.74 mmol) was added. Heating at 55 °C was continued for 24 hours at which time the reaction mixture was worked up by the procedure described in Example 2B. The residue obtained was purified by flash chromatography on silica gel eluting with ethyl acetate to afford the title compound as an amorphous solid (850 mg, 42%). MS (FAB) m/e 768 (M+H)+.
Example 14B
6-{N-Propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-7- (carboxymethyl)-7H-purine
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%). 1H NMR (DMSO-d6, 300 MHz) d 0.71 (t, J = 7.5Hz, 3H), 1.52 (m, 2H), 3.20 (m, 2H), 4.58 (s, 2H), 5.13 (s, 2H), 7.01 (d, J = 8Hz, 2H), 7.13 (d, J = 8Hz, 2H), 7.48-7.66 (m, 4H), 8.47 (s, 1 H), 8.51 (s, 1H). MS (DCI/NH3) m/e (M+H)+.
Example 15
9-Benzyl-6-(N-propyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}- 9H-purine Example 15A
9-Benzyl-6-chloropurine
The reaction of 6-chloropurine (5.00 g, 32.3 mmol), benzyl bromide (6.1 g, 35.6 mmol) and potassium carbonate (13.8 g, 100 mmol) in dimethylformamaide (10 mL) according to the procedure described in Example 13A provided the title compound as a colorless solid (4.5 g, 57%).
Example 15B
9-Benzyl-6-{N-propyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4- yl)methyl]amino}-9H-Purine
To a solution of the compound resulting from Example 4A (2.53 mmol) in dimethylformamide (8 mL) was added triethylamine (3 mL) followed by the compound resulting from Example 15A (680 mg, 2.5 mmol). After stirring at 60 °C for 6 hours, the reaction was worked up according to the procedure described in Example 2B. Purification by flash
chromatography afforded the title compound as a yellow amorphous solid (980 mg, 52%).
Example 15C
9-Benzyl-6-[N-propyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}- 9H-purine
The compound resulting from Example 15B (950 mg, 1.3 mmol) was deblocked according to the procedure described in Example 2C.
Purification by flash chromatography eluting with ethanol and acetic acid in methylene chloride followed by recrystallization of the residue from methylene chloride and hexane afforded the title compound as an off white amorphous solid (570 mg, 89%). 1H NMR (DMSO-d6, 300 MHz) d 0.87 (t, J = 7Hz, 3H), 1.63 (m, 2H), 3.45 (bs, 1H), 4.05 (bs, 1 H), 5.00 (bs, 1 H), 5.40 (s, 2H), 5.50 (bs, 1 H), 7.05 (d, J = 8Hz, 2H), 7.20 (d, J= 8Hz, 2H), 7.25-7.45 (m, 5H), 7.50-7.70 (m, 4H), 8.26 (s, 1H), 8.32 (s. 1H). Example 16
2-Methyl-7-{N-butyl-N-[(2'-[1H-tetrazcl-5-yl]biphenyl-4- yl)methyl]aminp}thiazolo[5,4-d]pyrimidine
Reaction of the compound resulting from Example 2A and 2-methyl-7-chlorothiazolo[5,4-d]pyrimidine, prepared according to the procedure described in Chem. Pharm. Bull.16, 352 (1958), according to the procedure described in Example 15B affords 2-methyl-7-{N-propyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}thiazolo[5,4-d]pyrimidine.
The above compound is deblocked according to the procedure described in Example 2C to afford the title compound.
Example 17
2-Methyl-7-{N-butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino}oxazolo[5,4-d]pyrimidine
Reaction of the compound resulting from Example 2A and 7-chloro-2-methyloxazolo[5,4-d]pyrimidine, prepared according to the procedure described in Chem. Pharm. Bull, 8, 137 (1960), according to the procedure described in Example 15B affords 2-methyl-7-{N-propyl-N-[(2'-[N-triphenylmethyl-1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}oxazolo[5,4-d]pyrimidine.
The above compound is deblocked according to the procedure described in Example 1 G to afford the title compound.
Example 18
4-(N-Butyl-N-[(2'-[1H-tetrazol-5-yl]binhenyl-4-yl)methyl]amino}-1H- pyrazolo[3,4-d]pyrimidine
The reaction of the compound resulting from Example 2A and 4- methylmercapto-6-chloropyrazolo[3,4-d]pyrimidine, prepared according to J. Am. Chem. Soc. 79, 6407 (1957), according to the procedure described in Example 15B affords 4-{N-propyl-N-[(2'-[N-triphenylmethyl-1 H-tetrazol-5- yl]biphenyl-4-yl)methyl]amino}-1 H-pyrazolo[3,4-d]pyrimidine. The above compound is deblocked according to the procedure described in Example 2C to afford the title compound.
Example 19
4-(N-Butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-7-methyl-7H- pyrrclo[2,3-d]pyrimidine
Reaction of the compound resulting from Example 2A and 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine, prepared according to the procedure described in Chim. Ther. 6(6), 427 (1971), according to the procedure described in Example 15A affords 4-{N-butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-7-methyl-7H-pyrrolo[2,3-d]pyrimidine.
The above compound is deblocked according to the procedure described in Example 2C to afford the title compound.
Example 20
4-{N-Butyl-N-[(2'-[1H-tetrazol-5-yl]hiphenyl-4-yl)methyl]amino}thieno[2,3- d]pyrimidine
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.
The above compound is deblocked according to the procedure described in Example 2C to afford the title compound.
Example 21
4-(N-Butyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-6-methyl- furo[2,3-d]pyrimidine
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.
The above compound is deblocked according to the procedure described in Example 1 G to afford the title compound.
Example 22
7-{N-Butyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino]benzofuran A mixture of 7-aminobenzofuran hydrochloride, prepared according to the procedure described in J. Med. Chem. 16 717 (1973), n-butyl iodide, and potassium carbonate are heated until the starting benzofuran is consumed. The reaction mixture is diluted with methylene chloride and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography to afford 7-butylaminobenzofuran.
A solution of the above compound in dimethylformamaide is treated with potassium carbonate and N-triphenylmethyl-5-[2-(4'-bromomethylbiphenyl)]tetrazole, prepared as described by P.E. Aldrich, et al., in
European Patent Application Number 291969. Stirring is continued at ambient temperature until the reaction is judged complete by TLC. The reaction is worked up following the procedure described above to afford 6-{N-butyl-N-[(2,-[N-triphenylmethyl-1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}benzofuran.
The above compound is deblocked according to the procedure described in Example 1G and purified by flash chromatography on silica gel to afford the title compound.
Example 23
4-{N-Butyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-3-methyl- isoxazolo[5,4-b]pyridine
A solution of the compound resulting from Example 2A, triethylamine, and 4,6-dichloro-3-methylisoxazolo[5,4-b]pyridine, prepared according to the procedure described in J. Hetero. Chem. H, 435 (1977), in
tetrahydrofuran are stirred at ambient temperature until the starting amine is consumed. The reaction is worked up according to the procedure
described in Example 2B and 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.
A solution of the above compound in dioxane is treated with hydrazine hydrate. Stirring is continued until the starting material is consumed. The reaction mixture is concentrated under reduced pressure and toluene is added. This solution is treated with 2 N sodium hydroxide solution and air is bubbled into the reaction mixture until the starting material is consumed. The organic layer is separated, washed with water, dried over calcium chloride and concentrated in vacuo to afford 4-{N-butyl-N-[(24N-triphenylmethyl-1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-3-methyl-isoxazolo[5,4-b]pyridine.
The above compound is deblocked according to the procedure described in Example 2C to afford the title compound.
Example 24
7-(N-Butyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1 ,3-dioxo-2- phenyl-1 ,3-dihydropyrrolo[3,4-c]pyridine-6-carboxylic acid
The reaction of n-butyl iodide, potassium carbonate and 7-amino-6-ethoxycarbonyl-1 ,3-dioxo-2-phenyl-1 ,3-dihydropyrrolo[3,4-c]pyridine, prepared according to the procedure described in Chem. Pharm. Bull. 31, 3460 (1983), according to the procedure described in Example 22 affords ethyl 7-butylamino-1 ,3-dioxo-2-phenyl-1 ,3-dihydropyrrolo[3,4-c]pyridine-6-carboxylate.
The above compound is treated with potassium carbonate and N-triphenylmethyl-5-[2-(4'-bromomethyl-biphenyl)]tetrazole, prepared as described by P.E. Aldrich, etal., in European Patent Application Number 291969, by the procedure described in Example 22. Work up and flash chromatography on silica gel affords ethyl 7-{N-butyl-N-[(2'-[N- triphenylmethyl-1 H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-1,3-dioxo-2- phenyl-1 ,3-dihydropyrrolo[3,4-c]pyridine-6-carboxylate. The above compound is deblocked and hydrolyzed by the procedure described in Example 1 G to afford the title compound.
Example 25
9-Methyl-8-phenyl-6-{N-butyl-N-[(2'-[1 H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino}-9H-purine
Example 25A
6-Chloro-9-methyl-8-phenyl-9H-Purine
A mixture of trimethyl orthobenzoate (10 mL) and 5-amino-6-chloro-4-methylaminopyrimidine (1.00 g, 6.3 mmol), prepared according to J. Am. Chem. Soc. Zϋ. 490 (1957), was heated for 72 hours at 150 °C. The cooled solution was concentrated in vacuo and the residue purified by fiash chromatography on silica gel eluting with ethyl acetate in hexane to afford the title compound as a light yellow solid (980 mg, 64%).
Example 25B
9-Methyl-8-phenyl-6-{N-butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5- yl]biphenyl-4-yl)methyl]amino}-9H-purine
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.
Further purification was achieved using flash chromatography eluting with ethyl acetate in methylene chloride to afford the title compound as a colorless amorhpous solid (190 mg, 10%). Example 25C
9-Methyl-8-phenyl-6-{N-hutyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4- yl)methyl]amino}-9H-purine
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%). 1H NMR (DMSO-d6, 300 MHz) d 0.90 (t, J = 8Hz, 3H), 1.32 (m, 2H), 1.63 (m, 2H), 3.60 (bs, 1H), 3.85 (bs, 1H), 4.20 (s, 3H), 5.03 (bs, 1H), 5.13 (bs, 1H), 7.02 (d, J = 9Hz, 2H), 7.12 (d, J = 9Hz, 2H), 7.50-7.70 (m, 7H), 7.76 (bs, 2H), 8.28 (s, 1H).
Example 26
5-[2-(4,-N-Propylaminpmethyl-biphenyl)]tetrazole hydrochloride
Example 26A
N-Benzyloxymethyl-5-(2-bromophenyl)tetrazole
5-(2-Bromophenyl)-[1H]-tetrazole was nitrogen-protected as the benzyloxymethyl (BOM) ether by reaction of a solution of the tetrazole in anhydrous dimethylformamide with technical grade BOM-chloride and anhydrous potassium carbonate. The reaction was complete in less than 60 minutes and the work up involved filtration through Celite and
evaporation of the solvent under reduced pressure. The residue obtained was purified by chromatography to afford the title product in 70% yield as an oil which crystallized on standing.
Example 26B
N-(4-Bromobenzyl-N-propylamine
To 4-bromobenzaldehyde (100 g, 0.54 mol) and n-propylamine (36.3 g, 0.60 mol) in methanol (100 mL) was added 5% platinum on carbon (1.00 g). This mixture was shaken in a Parr hydrogenation reactor overnight to complete formation of the Schiff base. The reaction was then hydrogenated under 4 atmospheres of hydrogen until the theoretical uptake of hydrogen had been consumed. The catalyst was removed by filtration through a 0.45 m nylon frit and washed with methanol. The filtrate was concentrated under reduced pressure and the residue obtained dissolved in ether (500 mL). The ether solution was washed with water (2 × 100 mL), 10% sodium bicarbonate solution (2 × 100 mL). and water (2 × 100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the crude title compound (121.34 g). GC-MS showed this material to be 98.5% pure product containing 1.5% of the desbromo compound; the yield is 96.93% based on the GC purity of the product obtained. A sample of this material was purified by bulb-to-bulb distillation (bath temperature 130-150 °C, 0.18 torr). 1H NMR (CDCI3, 300 MHz) d 0.92 (t, J = 7.4 Hz, 3H), 1.36 (bs, 1H), 1.53 (tq, J1 = J2 = 7.4Hz, 2H), 2.57 (t, J = 7.4Hz, 2H), 3.74 (s, 2H), 7.20 (d, J = 9Hz, 2H), 7.44 (d, J = 9Hz, 2H). IR (film) 1430, 1060 cm-1. MS (DCI/NH3) m/e 228, 230 (M+H)+.
Example 26C
4-[(N-tert-Butyloxycarbonyl-N-propylamino)methyl]phenyl boronic acid To the compound resulting from Example 26B in methylene chloride at 0 °C was added triethylamine (2 equivalents) and di-fert-butyl-dicarbonate (1.05 equivalents). The cooling bath was removed and the mixture allowed to warm to ambient temperature. The solution was diluted with a suitable solvent (ether or hexane), washed with 2 N hydrochloric acid, dried over sodium sulfate and concentrated in vacuo. The Bocprotected compound was obtained as a colorless oil in quantitative yield and was used without further purification.
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.
Example 26D
N-Benzyloxymethyl-5-{2-[4'-(N-propyl-N-tert- butyloxycarbonylamino)methyl-biphenyl]}tetrazole To palladium tetrakis(triphenylphosphine) (0.05 equivalents) dissolved in toluene was added a solution of the compound resulting from Example 26A (1 equivalent). After 10 minutes, a 2 M aqueous solution of sodium carbonate was added followed by the compound resulting from Example 26C dissolved in the minimum amount of ethanol. The two-phase mixture was rapidly stirred under reflux for 2.5 hours and then cooled to ambient temperature. The solution was diluted with ether and the organic phase was dried over sodium sulfate and concentrated in vacuo to afford a brown oil. Filtration through silica gel eluting with 35% ether in hexanes afforded the title compound as a coioriess oil (87%).
Example 26E
5-[2-(4'-N-Propylaminomethyl-biphenyl)]tetrazole hydrochloride To the compound resulting from Example 26D (1.00 g, 1.94 mmol) dissolved in 1 mL of absolute ethanol at ambient temperature was added a solution of anhydrous hydrogen chloride (g) dissolved in ethanol (5 mL, 11.2 M). There was observed an immediate evolution of carbon dioxide which lasted about 90 minutes; also during this time a heavy white
precipitate appeared. After 3 hours, the solvent was removed in vacuo and the residue triturated with 8 mL of ethyl acetate. The white solid was then dried in vacuo at 60 °C to afford the title compound (553 mg, 86%).
The compounds of the present invention can be used in
the form of 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:
acetate, ad i pate, alginate, citrate, ascoΦate, aspartate, benzoate,
benzenesulfonate, bisulfate, bo rate, butyrate, camphorate,
camphorsulfonate, citrate, digluconate, cyclopentanepropionate,
dodecylsuifate, ethanesulfonate. glucoheptonate, glycerophosphate,
hemisulfate, heptonate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maieate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, phosphate, 3-phenyl-propionate, picrate, pivalate, propionate, stearate, succinate, tart rate,
thiocyanate, toluenesulfonate (tosylate), undecanoate and valerate.
Examples of 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.
The ability of the compounds of the invention to block the interaction of angiotensin II with angiotensin II receptors can be demonstrated as described below.
ANGIOTENSIN II FUNCTIONAL ASSAY: Antagonism of Contraction of Rahhit Aorta
The protocol reported by AT Chiu and P.Timmermans (P.C. Wong, et al. Hypertension, 13, 489-497 (1989)) was followed with a few modifications. Female New Zealand White rabbits weighing 2-5 kg were sedated with carbon dioxide and then sacrificed. Main abdominal aortas were removed and placed in Krebs-Henseleit buffer at room temperature.
Krebs-Henseleit buffer
Buffer Component mM Concentration
sodium chloride 119.00
potassium chloride 4.70
potassium dihydrogen phosphate 1.20
calcium chloride 2.50
sodium bicarbonate 20.00
magnesium sulfate 1.50
dextrose 11.00
EDTA* disodium calcium salt 0.01
* EDTA = ethylenediamine tetraacetic acid The buffer contained no ***e, propanolol or steroid.
The pH of the buffer was 7.40 at 37°C when saturated with 5% carbon
dioxide/95% oxygen.
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. The 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. For single dose shift experiments a dose of 1 mM of test compound was used, for a full pA2 experiment multiple doses were used depending upon the potency of the antagonist.
All responses to the control agonist were calculated as a percentage of the maximum response. These points in duplicate were plotted and analyzed according to standard Schild analysis (H.O. Schild, British J Pharmacology and Chemotherapy, 2, 189-206 (1947). The pA2 values calculated for the compounds of the invention are shown in Table 1. The pA2 value is the negative logarithm of the [A]2 value. [A]2 is the concentration of antagonist which necessitates doubling the agonist concentration in order to achieve the agonist effect which was measured in the absence of antagonist.
The pA2 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
Example pA2
2 8.08
3 8.17
5 7.92
10 8.81
11 7.97
13 8.14
Sar, -1, Thr-8 AII (SARILE) 9.02
The ability of the compounds of the invention to lower blood pressure in vivo in renal artery ligated rats can be demonstrated according to the method disclosed by Cangiano, et al., J. Pharmacol. Exp. Ther. 208 310 (1979)).
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. In general, 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.
It will be understood, however, that the total daily usage of the
compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. 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
formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches. The term 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.
Injectable preparations, for example, 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. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. in addition, 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. in order to prolong the effect of a drug, it is often desirable to slow the absorption of a drug from subcutaneous or intramuscular injection. 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.
Solid dosage forms for oral administration can include capsules, tablets, pills, powders, prills and granules. In such solid dosage forms 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. In the case of capsules, tablets and pills, 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
formulating art. They 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. Examples of 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.
Sprays can additionally contain customary propellants such as
chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such 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
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.
Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazoiamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene,
chlorthalidone and the like or a pharmaceutically acceptable salt thereof.
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.
Representative 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.
Representative antiserotoninergic agents include ketanserin and the like or a pharmaceutically acceptable salt thereof.
Representative renin inhibitiors include enalkiren, A-72517, PD-134672 or Ro 42-5892 and the like or a pharmaceutically acceptable salt thereof.
Other representative 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.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

Claims

CLAIMS What is claimed is:
1. A compound of the formula:
Figure imgf000084_0001
wherein
A is
(i) a covalent bond,
(ii) -O-,
(iii) -C(O)-,
(iv) -CH2-,
(v) -S-, -S(O)- or-S(O)2-;
E-G is
(i) -N(R5)-,
(ii) -O-, (iii) -S-,
(iv) -N(R5)-CH(R5)-,
(v) -O-CH(R5)-,
(vi) -S-CH(R5)-,
(vii) -C(R5')(R5)-CH(R5)-,
(viii) -CH(R5)-C(R5 ,)(R5)-,
(ix) -CH(R5)-N(R5)-,
(x) -CH(R5)-O-,
(xi) -CH(R5)-S-,
(xii) -N(R5)-N(R5)-,
(xiii) -C(R5)=C(R5)- or
(xiv) -CH(R5)-C(R5')(R5)-N(R5)- wherein at each occurrence R5 is
independently selected from hydrogen, loweralkyl, alkoxy-substituted loweralkyl, halo-substituted loweralkyl, carboxy-substituted loweralkyl, heterocyclic-substituted loweralkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl and R5' is hydrogen, halo, hydroxy, carboxy, alkoxy or thioalkoxy; and M' are independently selected from
(i) hydrogen,
(ii) loweralkyl,
(iii) halo-substituted loweralkyl,
(iv) halo,
(v) -CN,
(vi) -NO2,
(vii) -OH,
(viii) hydroxy-substituted loweralkyl,
(ix) alkoxy-substituted loweralkyl,
(x) -NH2,
(xi) alkylamino,
(xii) dialkylamino,
(xiii) -SH, (xiv) alkoxy and
(xv) thioalkoxy; R1' are independently selected from
(i) tetrazolyl,
or
Figure imgf000086_0002
,
Figure imgf000086_0001
Figure imgf000086_0003
,
(iv) -NH-C(=N(R50a))(R51a) wherein R50a is hydrogen, -CN or -NO2 and R51a is hydrogen, loweralkyl, alkylamino, dialkylamino, alkoxy or thioalkoxy,
(v) -NH(R51b) wherein R51b is a 5-membered aromatic 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,
(vi) -COOR6 or -CH2COOR6 wherein R6 is hydrogen or a carboxy- protecting group or
(vii) -NHS(O)2R7 or -CH2NHS(O)2R7 or -NHC(O)R7a or -CH2NHC(O)R7a wherein R7 is loweralkyl, halo-substituted
loweralkyl or -NR7bR7c wherein R7b and R7c are independently selected from hydrogen and loweralkyl and R7a is loweralkyl, halo- substituted loweralkyl, amino, alkylamino, dialkylamino or -COOH;
(viii) -C(O)NR50R51 or -CH2C(0)NRδθR51 or -NHC(O)NR50R51
or -CH2NHC(O)NR50R51 or-NHC(S)NR50R51 or
-CH2NHC(S)NR50R51 wherein R50 and R51 are independently selected from hydrogen, loweralkyl, hydroxy, alkoxy, hydroxysubstituted loweralkyl, alkoxy-substituted loweralkyl, alkoxysubstituted alkoxy and -S(O)2R50a wherein R50a is loweralkyl or aryl, or R50 and R51 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered aliphatic heterocycle;
(ix) -CH2OR52 wherein R52 is selected from hydrogen, loweralkyl and -C(O)R53 wherein R53 is hydrogen, loweralkyl or aryl;
(x) -CH(OH)R52a or-C(O)R52a wherein R52a is loweralkyl, halo- substituted loweralkyl, -CF2COOR53a or -CH2COOR53a
wherein R53a is hydrogen or a carboxy-protecting group,
(xii) -CH2NR54R55 wherein R54 is selected from hydrogen, loweralkyl, -C(O)R56, -C(O)NR56R57 and -S(O)2R58 wherein R56 is selected from hydrogen, loweralkyl and aryl and R58 is selected from lower alkyl and halo-substituted loweralkyl and wherein R55 and R57 are independently selected from hydrogen, loweralkyl, hydroxy and alkoxy;
(xiii) -SO3H, -OSO3H or -CH2SO3H,
(xiv) -OPO3H2, -PO3H2 or -CH2PO3H2,
(xv) -SO2NR50R51 or -CH2SO2NR50R51 wherein R50 and R51
are defined as above and
(xvi) -C(O)NHSO2R60, -C(O)NHC(O)R60 or -C(O)NHNHSO2R60 wherein R60 is ioweralkyl, halo-substituted loweralkyl or aryl;
with the proviso that one of R1 and R1' is hydrogen, but R 1 and R1' are not both hydrogen;
and D is
(i) a bicyclic heterocycle comprising a 6-membered ring fused to a
5-membered ring, the bicyclic heterocycle comprising at least one
heteroatom selected from N, O and S; 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 1 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 R2 wherein at each occurrence R2 is independently selected from hydrogen, ioweralkyl, carboxy-substituted loweralkyl or alkoxycarbonyl- substituted loweralkyl; the nitrogen atoms of the bicyclic heterocycle can be oxidized; one or two carbon atoms of the bicyclic heterocycle can be substituted with an oxo (=O) substituent and the sulfur atoms of the bicyclic heterocycle can be substituted with one or two oxo (=O) substituents; the bicyclic heterocycle can be substituted with one, two or three substituents independently selected from R3 and R4, R3 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle and R4 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle, wherein
R3 is
(i) hydrogen,
(ii) loweralkyl,
(iii) halo,
(iv) halo-substituted loweralkyl,
(v) thioalkoxy, (vi) alkoxy-substituted loweralkyl,
(vii) thioalkoxy-substituted ioweralkyl,
(viii) aryl,
(ix) arylalkyl,
(x) -NO2,
(xi) -COOR8 wherein R8 is hydrogen or a carboxy-protecting group,
(xii) -OR9 wherein R9 is hydrogen, ioweralkyl, halo-substituted
loweralkyl, aryl, arylalkyl, heterocyclic-substituted loweralkyl or -C(O)R10 wherein R10 is ioweralkyl, halo- substituted loweralkyl, -PO3H2 or -NR11R12 wherein R11 and R12 are independently selected from hydrogen and loweralkyl and
(xiii) -NR13R14 or -CH2NR13R14 wherein R13 and R14 are
independently selected from (1 ) hydrogen, (2) lower
alkyl, (3) arylalkyl, (4) -C(O)R15, (5) -S(O)2R15 wherein R15 is loweralkyl or halo- substituted loweralkyl and
(6) -R16-R17 wherein R16 is alkylene and R17 is
(a) -NR18R19 wherein R18 and R19 are independently
selected from hydrogen and loweralkyl or
(b) unsubstituted or loweralkyl substituted aziridinyl,
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, pyridinyl or pyrimidinyl,
or R13 and R14 taken together with the nitrogen atom to
which they are attached form a 5- to 7-membered aliphatic
heterocycle and
(i) hydrogen,
(ii) loweralkyl,
(iii) halo-substituted loweralkyl,
(iv) -CN,
(v) -NO2.
(vi) -NH2, (vii) -NH-C(=N(R25a))(R26a) wherein R25a is hydrogen, -CN or -NO2 and R26a is hydrogen, loweralkyl, alkylamino, dialkylamino, alkoxy or thioalkoxy,
(viii) -NH(R26b) wherein R26b is a 5-membered aromatic 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 substitutent selected from amino, alkylamino, dialkylamino, hydroxy, alkoxy, thioalkoxy, halo, loweralkyl and halo-substituted loweralkyl, (ix) -CHO or-CH(=N-OH),
(x) tetrazolyl.
(xi) -NHS(O)2R20 or -CH2NHS(O)2R20 or -NHC(O)R21 or
-N(OH)C(O)R21 or -CH2NHC(O)R21 or -CH2N(OH)C(O)R21 wherein R20 is loweralkyl, halo- substituted loweralkyl or -NR27aR27b wherein R27a and R27b are independently selected from hydrogen, -OH and loweralkyl and R21 is loweralkyl, halo-substituted ioweralkyl, amino, alkylamino, dialkylamino or -COOH,
(xii) -CH(OH)R22 or -C(O)R22 wherein R22 is loweralkyl, halo- substituted loweralkyl, -CF2COOR23 or -CH2COOR23
wherein R23 is hydrogen or a carboxy-protecting group,
(xiii) -COOR24 or -CH2COOR24 wherein R24 is hydrogen or a
carboxy-protecting group,
(xiv) -C(O)NR25R26 or -CH2C(O)NR25R26 or -NHC(O)NR25R26
or -CH2NHC(O)NR25R26 or-NHC(S)NR25R26
or -CH2NHC(S)NR25R26 wherein R25 and R26 are
independently selected from hydrogen, loweralkyl,
hydroxy, alkoxy, hydroxy-substituted loweralkyl,
alkoxy-substituted loweralkyl, alkoxy-substituted
alkoxy and -S(O)2R28a wherein R28a is loweralkyl or aryl, or R25 and R26 taken together with the nitrogen atom to which they are attached form a 5- to 7- membered aliphatic heterocycle; (xv) -CH2OR27 wherein R27 is selected from hydrogen,
loweralkyl and -C(O)R28 wherein R28 is hydrogen,
loweralkyl or aryl;
(xvi) -CH2NR29R30 wherein R29 is selected from hydrogen,
ioweralkyl, -C(O)R31 , -C(O)NR31 R32 and -S(O)2R33
wherein R31 is selected from hydrogen, loweralkyl and aryl and R33 is selected from loweralkyl and halo- substituted loweralkyl and wherein R30 and R32 are
independently selected from hydrogen, loweralkyl,
hydroxy and alkoxy;
(xvii) -SO3H, -OSO3H or-CH2SO3H,
(xviii) -OPO3H, -PO3H2 or -CH2PO3H2,
(xix) -SO2NR25R26 or -CH2SO2NR25R26 wherein R25 and R26
are defined as above and
(xx) -C(O)NHSO2R59, -C(O)NHC(O)R59 or -C(O)NHNHSO2R59
wherein R59 is loweralkyl, halo-substituted loweralkyl or aryl;
or 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
independently comprising 0, 1 or 2 double bonds; the nitrogen atoms of the bicyclic heterocycle can be substituted with a substituent R2 wherein at each occurrence R2 is independently selected from hydrogen, loweralkyl, carboxy-substituted loweralkyl or alkoxycarbonyl-substituted loweralkyl; the nitrogen atoms of the bicyclic heterocycle can be oxidized; one or two carbon atoms of the bicyclic heterocycle can be substituted with an oxo (=O) substituent and the sulfur atoms of the bicyclic heterocycle can be substituted with one or two oxo (=O) substituents; the bicyclic heterocycle can be substituted with one or two substituents independently selected from R3 and R4, R3 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle and R4 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle, wherein R3 and R4 are defined as above; or D is
or
Figure imgf000092_0001
Figure imgf000092_0002
wherein R3 and R4 are defined as above;
or a pharmaceutically acceptable salt or prodrug thereof.
2. The compound of Claim 1 wherein A is a covalent bond, L, L', M, M' and R 1' are hydrogen, -G-E- is -CH2-N(R5)- and D is a substituted purinyl group.
3. A compound of the formula:
Figure imgf000093_0001
wherein
A is
(i) a covalent bond,
(ii) -O-,
(iii) -C(O)-,
(iv) -CH2-,
(v) -S-, -S(O)- or -S(O)2-;
E-G is
(i) -N(R5)-,
(ii) -O-,
(iii) -S-,
(iv) -N(R5)-CH(R5)-,
(v) -O-CH(R5)-,
(vi) -S-CH(R5)-,
(vii) -C(R5')(R5)-CH(R5)-, (viii) -CH(R5)-C(R5')(R5)-,
(ix) -CH(R5)-N(R5)-,
(x) -CH(R5)-O-,
(xi) -CH(R5)-S-,
(xii) -N(R5)-N(R5)-,
(xiii) -C(R5)=C(R5)- or
(xiv) -CH(R5)-C(R5')(R5)-N(R5)- wherein at each occurrence R5 is
independently selected from hydrogen, loweralkyl, alkoxy-substituted loweralkyl, halo-substituted loweralkyl, carboxy-substituted loweralkyl, heterocyclic-substituted loweralkyl, alkenyl, alkynyl, cycloalkyl or cycloalkyialkyi and R5' is hydrogen, halo, hydroxy, carboxy, alkoxy or thioalkoxy; L, L', M and M' are independently selected from
(i) hydrogen,
(ii) loweralkyl,
(iii) halo-substituted loweralkyl,
(iv) halo,
(v) -CN,
(vi) -NO2,
(vii) -OH,
(viii) hydroxy-substituted loweralkyl,
(ix) alkoxy-substituted loweralkyl,
(x) -NH2,
(xi) alkylamino,
(xii) dialkylamino,
(xiii) -SH,
(xiv) alkoxy and
(xv) thioalkoxy; R1 and R1 ' are independently selected from
(i) tetrazolyl, or
Figure imgf000095_0002
,
Figure imgf000095_0001
Figure imgf000095_0003
,
(iv) -NH-C(=N(R50a))(R51a) wherein R50a is hydrogen, -CN or -NO2 and R51a is hydrogen, loweralkyl, alkylamino, dialkylamino, alkoxy or thioalkoxy,
(v) -NH(R51b) wherein R51b is a 5-membered aromatic 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 substitutent selected from amino, alkylamino, dialkylamino, hydroxy, alkoxy, thioalkoxy, halo, loweralkyl and halo-substituted ioweralkyl,
(vi) -COOR6 or -CH2COOR6 wherein R6 is hydrogen or a carboxy- protecting group or
(vii) -NHS(O)2R7 or -CH2NHS(O)2R7 or -NHC(O)R7a or
-CH2NHC(O)R7a wherein R7 is loweralkyl, halo-substituted
loweralkyl or -NR7bR7c wherein R7b and R7C are independently selected from hydrogen and loweralkyl and R7a is loweralkyl, halo- substituted loweralkyl, amino, alkylamino, dialkylamino or -COOH;
(viii) -C(O)NR50R51 or -CH2C(O)NR50R51 or -NHC(O)NR50R51 or -CH2NHC(O)NR50R51 or -NHC(S)NR50R51 or
-CH2NHC(S)NR50R51 wherein R50 and R51 are independently selected from hydrogen, loweralkyl, hydroxy, alkoxy, hydroxy- substituted loweralkyl, alkoxy-substituted loweralkyl, alkoxy- substituted alkoxy and -S(O)2R50a wherein R50a is loweralkyl or aryl, or R50 and R51 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered aliphatic heterocycle; (ix) -CH2OR52 wherein R52 is selected from hydrogen, loweralkyl and
-C(O)R53 wherein R53 is hydrogen, loweralkyl or aryl;
(x) -CH(OH)R52a or -C(O)R52a wherein R52a is loweralkyl, halo- substituted loweralkyl, -CF2COOR53a or -CH2COOR53a
wherein R53a is hydrogen or a carboxy-protecting group,
(xii) -CH2NR54R55 wherein R54 is selected from hydrogen, loweralkyl, -C(O)R56, -C(O)NR56R57 and -S(O)2R58 wherein R56 is selected from hydrogen, loweralkyl and aryl and R58 is selected from lower alkyl and halo-substituted loweralkyl and wherein R55 and R57 are independently selected from hydrogen, loweralkyl, hydroxy and alkoxy;
(xiii) -SO3H, -OSO3H or -CH2SO3H,
(xiv) -OPO3H2, -PO3H2 or -CH2PO3H2,
(xv) -SO2NR50R51 or -CH2SO2NR50R51 wherein R50 and R51
are defined as above and
(xvi) -C(O)NHSO2R60, -C(O)NHC(O)R60 or -C(O)NHNHSO2R60 wherein R60 is loweralkyl, halo-substituted loweralkyl or aryl;
with the proviso that one of R1 and R1' is hydrogen, but R1 and R1' are not both hydrogen;
and
D is
(i) a bicyclic heterocycle comprising a 6-membered ring fused to a
5-membered ring, the bicyclic heterocycle comprising at least one
heteroatom selected from N, O and S; 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 1 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 R2 wherein at each occurrence R2 is independently selected from hydrogen, loweralkyl, carboxy-substituted loweralkyl or alkoxycarbonyl-substituted loweralkyl; the nitrogen atoms of the bicyclic heterocycle can be oxidized; one or two carbon atoms of the bicyclic heterocycle can be substituted with an oxo (=O) substituent and the sulfur atoms of the bicyclic heterocycle can be substituted with one or two oxo (=O) substituents; the bicyclic heterocycle can be substituted with one, two or three substituents independently selected from R3 and R4, R3 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle and R4 being bonded to a carbon atom or a nitrogen atom of the bicyclic heterocycle, wherein
R3 is
(i) hydrogen,
(ii) loweralkyl,
(iii) halo,
(iv) halo-substituted loweralkyl,
(v) thioalkoxy,
(vi) alkoxy-substituted loweralkyl,
(vii) thioalkoxy-substituted loweralkyl,
(viii) aryl,
(ix) arylalkyl,
(x) -NO2, (xi) -COOR8 wherein R8 is hydrogen or a carboxy-protecting group, (xii) -OR9 wherein R9 is hydrogen, loweralkyl, halo-substituted
Ioweralkyl, aryl, arylalkyl, heterocyclic-substituted ioweralkyl or
-C(O)R10 wherein R10 is loweralkyl, halo- substituted loweralkyl, -PO3H2 or -NR11R12 wherein R11 and R12 are independently selected from hydrogen and loweralkyl and
(xiii) -NR13R14 or -CH2NR13R14 wherein R13 and R14 are
independently selected from (1 ) hydrogen, (2) lower
alkyl, (3) arylalkyl, (4) -C(O)R15, (5) -S(O)2R15 wherein R15 is
loweralkyl or halo- substituted loweralkyl and
(6) -R16-R17 wherein R16 is alkylene and R17 is
(a) -NR18R19 wherein R18 and R19 are independently
selected from hydrogen and ioweralkyl or
(b) unsubstituted or loweralkyl substituted aziridinyl,
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
morphoiinyl, thiomorpholinyl, pyridinyl or pyrimidinyl,
or R13 and R14 taken together with the nitrogen atom to
which they are attached form a 5- to 7-membered aliphatic
heterocycle and
(i) hydrogen,
(ii) loweralkyl,
(iii) halo-substituted loweralkyl,
(iv) -CN,
(v) -NO2,
(vi) -NH2,
(vii) -NH-C(=N(R25a))(R26a) wherein R25a is hydrogen, -CN or-NO2 and
R26a is hydrogen, loweralkyl, alkylamino, dialkylamino, alkoxy or thioalkoxy,
(viii) -NH(R26b) wherein R26b is a 5-membered aromatic 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 substitutent selected from amino, alkylamino, dialkylamino, hydroxy, alkoxy, thioalkoxy, halo, loweralkyl and halo-substituted loweralkyl, (ix) -CHO or -CH(=N-OH),
(x) tetrazolyl,
(xi) -NHS(O)2R20 or -CH2NHS(O)2R20 or -NHC(O)R21 or
-N(OH)C(O)R21 or-CH2NHC(O)R21 or -CH2N(OH)C(O)R21 wherein R20 is ioweralkyl, halo- substituted loweralkyl or -NR27aR27b wherein R27a and R27b are independently selected from hydrogen, -OH and loweralkyl and R21 is loweralkyl, halo-substituted loweralkyl, amino, alkylamino, dialkylamino or -COOH,
(xii) -CH(OH)R22 or -C(O)R22 wherein R22 is loweralkyl, halo- substituted loweralkyl, -CF2COOR23 or -CH2COOR23
wherein R23 is hydrogen or a carboxy-protecting group,
(xiii) -COOR24 or -CH2COOR24 wherein R24 is hydrogen or a
carboxy-protecting group,
(xiv) -C(O)NR25R26 or -CH2C(O)NR25R26 or-NHC(O)NR25R26
or -CH2NHC(O)NR25R26 or -NHC(S)NR25R26
or -CH2NHC(S)NR25R26 wherein R25 and R26 are
independently selected from hydrogen, loweralkyl,
hydroxy, alkoxy, hydroxy-substituted loweralkyl,
alkoxy-substituted loweralkyl, alkoxy-substituted
alkoxy and -S(O)2R28a wherein R28a is loweralkyl or aryl, or R25 and R26 taken together with the nitrogen atom to which they are attached form a 5- to 7- membered aliphatic heterocycle;
(xv) -CH2OR27 wherein R27 is selected from hydrogen,
loweralkyl and -C(O)R28 wherein R28 is hydrogen,
loweralkyl or aryl;
(xvi) -CH2NR29R30 wherein R29 is selected from hydrogen,
loweralkyl, -C(O)R31 , -C(O)NR31 R32 and -S(O)2R33 wherein R31 is selected from hydrogen, ioweralkyl and aryl and R33 is selected from ioweralkyl and halo- substituted loweralkyl and wherein R30 and R32 are
independently selected from hydrogen, loweralkyl,
hydroxy and alkoxy;
(xvii) -SO3H, -OSO3H or -CH2SO3H,
(xviii) -OPO3H, -PO3H2 or -CH2PO3H2.
(xix) -SO2NR25R26 or -CH2SO2NR25R26 wherein R25 and R26
are defined as above and
(xx) -C(O)NHSO2R59, -C(O)NHC(O)R59 or -C(O)NHNHSO2R59
wherein R59 is loweralkyl, halo-substituted loweralkyl or
aryl;
or D is
or
Figure imgf000100_0001
Figure imgf000100_0002
wherein R3 and R4 are defined as above;
or a pharmaceutically acceptable salt or prodrug thereof.
4. The compound of Claim 3 wherein A is a covalent bond, L, L', M, M' and R1' are hydrogen, -G-E- is -CH2-N(R5)- and D is a substituted purinyl group.
5. A compound of the formula:
Figure imgf000101_0001
wherein
A is
(i) a covalent bond,
(ii) -O-,
(iii) -C(O)-,
(iv) -CH2-.
(v) -S-, -S(O)- or -S(O)2-;
E-G is
(i) -N(R5)-,
(ii) -O-,
(iii) -S-,
(iv) -N(R5)-CH(R5)-,
(v) -O-CH(R5)-,
(vi) -S-CH(R5)-, (vii) -C(R5')(R5)-CH(R5)-,
(viii) -CH(R5)-C(R5')(R5)-,
(ix) -CH(R5)-N(R5)-,
(x) -CH(R5)-O-,
(xi) -CH(R5)-S-,
(xii) -N(R5)-N(R5)-,
(xiii) -C(R5)=C(R5)- or
(xiv) -CH(R5)-C(R5')(R5)-N(R5)- wherein at each occurrence R5 is
independently selected from hydrogen, loweralkyl, alkoxy-substituted loweralkyl, halo-substituted loweralkyl, carboxy-substituted loweralkyl, heterocyclic-substituted loweralkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl and R5' is hydrogen, halo, hydroxy, carboxy, alkoxy or thioalkoxy; and M' are independently selected from
(i) hydrogen,
(ii) loweralkyl.
(iii) halo-substituted loweralkyl,
(iv) halo,
(v) -CN,
(vi) -NO2,
(vii) -OH,
(viii) hydroxy-substituted loweralkyl,
(ix) alkoxy-substituted loweralkyl,
(x) -NH2,
(xi) alkylamino,
(xii) dialkylamino,
(xiii) -SH,
(xiv) alkoxy and
(xv) thioalkoxy; R1' are independently selected from (i) tetrazolyl,
Figure imgf000103_0001
or
Figure imgf000103_0002
,
,
Figure imgf000103_0003
(iv) -NH-C(=N(R50a))(R51a) wherein R50a is hydrogen, -CN or -NO2 and R51a is hydrogen, loweralkyl, alkylamino, dialkylamino, alkoxy or thioalkoxy,
(v) -NH(R51b) wherein R51b is a 5-membered aromatic 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,
(vi) -COOR6 or -CH2COOR6 wherein R6 is hydrogen or a carboxy- protecting group or
(vii) -NHS(O)2R7 or -CH2NHS(O)2R7 or -NHC(O)R7a or
-CH2NHC(O)R7a wherein R7 is loweralkyl, halo-substituted
loweralkyl or -NR7bR7c wherein R7b and R7c are independently selected from hydrogen and loweralkyl and R7a is loweralkyl, halo- substituted loweralkyl, amino, alkylamino, dialkylamino or -COOH; (viii) -C(O)NR50R51 or -CH2C(O)NR50R51 or -NHC(O)NR50R51 or -CH2NHC(O)NR50R51 or -NHC(S)NR50R51 or
-CH2NHC(S)NR50R51 wherein R50 and R51 are independently selected from hydrogen, loweralkyl, hydroxy, alkoxy, hydroxy- substituted loweralkyl, alkoxy-substituted ioweralkyl, alkoxysubstituted alkoxy and -S(O)2R50a wherein R50a is loweralkyl or aryl, or R50 and R51 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered aliphatic heterocycle; (ix) -CH2OR52 wherein R52 is selected from hydrogen, loweralkyl and
-C(O)R53 wherein R53 is hydrogen, loweralkyl or aryl;
(x) -CH(OH)R52a or -C(O)R52a wherein R52a is loweralkyl, halo- substituted loweralkyl, -CF2COOR53a or -CH2COOR53a
wherein R53a is hydrogen or a carboxy-protecting group,
(xii) -CH2NR54R55 wherein R54 is selected from hydrogen, loweralkyl, -C(O)R56, -C(O)NR56R57 and -S(O)2R58 wherein R56 is selected from hydrogen, loweralkyl and aryl and R58 is selected from lower alkyl and halo-substituted loweralkyl and wherein R55 and R57 are independently selected from hydrogen, loweralkyl, hydroxy and alkoxy;
(xiii) -SO3H, -OSO3H or -CH2SO3H,
(xiv) -OPO3H2, -PO3H2 or-CH2PO3H2,
(xv) -SO2NR50R51 or -CH2SO2NR50R51 wherein R50 and R51
are defined as above and
(xvi) -C(O)NHSO2R60, -C(O)NHC(O)R60 or -C(O)NHNHSO2R60 wherein R60 is loweralkyl, halo-substituted loweralkyl or aryl;
with the proviso that one of R1 and R1' is hydrogen, but R1 and R1 ' are not both hydrogen;
and
D is
Figure imgf000105_0001
wherein R2 is selected from hydrogen, loweralkyl, carboxy-substituted loweralkyl or alkoxycarbonyl-substituted loweralkyl,
R3 is
(i) hydrogen,
(ii) loweralkyl,
(iii) halo,
(iv) halo-substituted loweralkyl,
(v) thioalkoxy,
(vi) alkoxy-substituted loweralkyl,
(vii) thioalkoxy-substituted loweralkyl,
(viii) aryl,
(ix) arylalkyl,
(x) -NO2,
(xi) -COOR8 wherein R8 is hydrogen or a carboxy-protecting group,
(xii) -OR9 wherein R9 is hydrogen, loweralkyl, halo-substituted
loweralkyl, aryl, arylalkyl, heterocyclic-substituted loweralkyl or -C(O)R10 wherein R10 is loweralkyl, halo- substituted ioweralkyl, -PO3H2 or -NR11R12 wherein R11 and R12 are independently selected from hydrogen and loweralkyl and (xiii) -NR13R14 or -CH2NR13R14 wherein R13 and R14 are
independently selected from (1) hydrogen, (2) lower
alkyl, (3) arylalkyl, (4) -C(O)R15, (5) -S(O)2R15 wherein R15 is ioweralkyl or halo- substituted ioweralkyl and
(6) -R16-R17 wherein R16 is alkylene and R17 is
(a) -NR18R19 wherein R18 and R19 are independently
selected from hydrogen and loweralkyl or
(b) unsubstituted or loweralkyl substituted aziridinyl,
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, pyridinyl or pyrimidinyl,
or R13 and R14 taken together with the nitrogen atom to
which they are attached form a 5- to 7-membered aliphatic
heterocycle and R4 is
(i) hydrogen,
(ii) loweralkyl,
(iii) halo-substituted loweralkyl,
(iv) -CN,
(v) -NO2.
(vi) -NH2,
(vii) -NH-C(=N(R25a))(R26a) wherein R25a is hydrogen, -CN or -NO2 and R26a is hydrogen, loweralkyl, alkylamino, dialkylamino, alkoxy or thioalkoxy,
(viii) -NH(R26b) wherein R26b is a 5-membered aromatic 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 substitutent selected from amino, alkylamino, dialkylamino, hydroxy, alkoxy, thioalkoxy, halo, loweralkyl and halo-substituted loweralkyl,
(ix) -CHO or-CH(=N-OH), (x) tetrazolyl,
(xi) -NHS(O)2R20 or -CH2NHS(O)2R20 or -NHC(O)R21 or
-N(OH)C(O)R21 or -CH2NHC(O)R21 or -CH2N(OH)C(O)R21 wherein R20 is loweralkyl, halo- substituted loweralkyl or -NR27aR27b wherein R27a and R27b are independently selected from hydrogen, -OH and loweralkyl and R21 is loweralkyl, halo-substituted loweralkyl, amino, alkylamino, dialkylamino or -COOH,
(xii) -CH(OH)R22 or -C(O)R22 wherein R22 is loweralkyl, halo- substituted loweralkyl, -CF2COOR23 or -CH2COOR23
wherein R23 is hydrogen or a carboxy-protecting group,
(xiii) -COOR24 or -CH2COOR24 wherein R24 is hydrogen or a
carboxy-protecting group,
(xiv) -C(O)NR25R26 or -CH2C(O)NR25R26 or -NHC(O)NR25R26
or -CH2NHC(O)NR25R26 or-NHC(S)NR25R26
or -CH2NHC(S)NR25R26 wherein R25 and R26 are
independently selected from hydrogen, loweralkyl,
hydroxy, alkoxy, hydroxy-substituted loweralkyl,
alkoxy-substituted loweralkyl, alkoxy-substituted
alkoxy and -S(O)2R28a wherein R28a is loweralkyl or aryl, or R25 and R26 taken together with the nitrogen atom to which they are attached form a 5- to 7- membered aliphatic heterocycle;
(xv) -CH2OR27 wherein R27 is selected from hydrogen,
loweralkyl and -C(O)R28 wherein R28 is hydrogen,
loweralkyl or aryl;
(xvi) -CH2NR29R30 wherein R29 is selected from hydrogen,
loweralkyl, -C(O)R31 , -C(O)NR31 R32 and -S(O)2R33
wherein R31 is selected from hydrogen, loweralkyl and
aryl and R33 is selected from loweralkyl and halosubstituted loweralkyl and wherein R30 and R32 are
independently selected from hydrogen, loweralkyl,
hydroxy and alkoxy;
(xvii) -SO3H, -OSO3H or -CH2SO3H, (xviii) -OPO3H, -PO3H2 or -CH2PO3H2,
(xix) -SO2NR25R26 or -CH2SO2NR25R26 wherein R25 and R26
are defined as above and
(xx) -C(O)NHSO2R59, -C(O)NHC(O)R59 or -C(O)NHNHSO2R59
wherein R59 is loweralkyl, halo-substituted loweralkyl or
aryl;
or a pharmaceutically acceptable salt or prodrug thereof.
6. The compound of Claim 5 wherein A is a covalent bond, L, L', M, M' and R1' are hydrogen and -G-E- is -CH2-N(R5)-.
7. A pharmaceutical composition for blocking the interaction of angiotensin II with angiotensin II receptors comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1.
8. A pharmaceutical composition for treating hypertension or
congestive heart failure comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1.
9. A method of blocking the interaction of angiotensin II with angiotensin II receptors comprising administering to a human or other mammal in need a therapeutically effective amount of a compound of Claim 1.
10. A method of treating hypertension or heart failure comprising administering to a human or other mammal in need a therapeutically effective amount of a compound of Claim 1.
PCT/US1993/001105 1992-03-04 1993-02-04 Angiotensin ii receptor antagonists WO1993018035A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5571813A (en) * 1993-06-10 1996-11-05 Beiersdorf-Lilly Gmbh Fused pyrimidine compounds and their use as pharmaceuticals
US6169091B1 (en) 1995-10-11 2001-01-02 Glaxo Wellcome Inc. Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US6579870B2 (en) 2000-06-20 2003-06-17 Pharmacia & Upjohn Company Bis-arylsulfones
US6586592B2 (en) 2000-06-20 2003-07-01 Pharmacia & Upjohn Company Bis-arylsulfones
US6713485B2 (en) 1998-01-12 2004-03-30 Smithkline Beecham Corporation Heterocyclic compounds
US6933299B1 (en) 1999-07-09 2005-08-23 Smithkline Beecham Corporation Anilinoquinazolines as protein tyrosine kinase inhibitors
US7084147B2 (en) 1999-07-09 2006-08-01 Smithkline Beecham Corporation Anilinoquinazaolines as protein tyrosine kinase inhibitors
WO2007018248A1 (en) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Pyridone compound
US7534894B2 (en) 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
US8193182B2 (en) 2008-01-04 2012-06-05 Intellikine, Inc. Substituted isoquinolin-1(2H)-ones, and methods of use thereof
US8476282B2 (en) 2008-11-03 2013-07-02 Intellikine Llc Benzoxazole kinase inhibitors and methods of use
US8604032B2 (en) 2010-05-21 2013-12-10 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
US8637542B2 (en) 2008-03-14 2014-01-28 Intellikine, Inc. Kinase inhibitors and methods of use
US8642604B2 (en) 2006-04-04 2014-02-04 The Regents Of The University Of California Substituted pyrazolo[3,2-d]pyrimidines as anti-cancer agents
US8697709B2 (en) 2008-10-16 2014-04-15 The Regents Of The University Of California Fused ring heteroaryl kinase inhibitors
US8703778B2 (en) 2008-09-26 2014-04-22 Intellikine Llc Heterocyclic kinase inhibitors
US8703777B2 (en) 2008-01-04 2014-04-22 Intellikine Llc Certain chemical entities, compositions and methods
US8785470B2 (en) 2011-08-29 2014-07-22 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8785454B2 (en) 2009-05-07 2014-07-22 Intellikine Llc Heterocyclic compounds and uses thereof
US8809349B2 (en) 2011-01-10 2014-08-19 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US8901133B2 (en) 2010-11-10 2014-12-02 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8969363B2 (en) 2011-07-19 2015-03-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8980899B2 (en) 2009-10-16 2015-03-17 The Regents Of The University Of California Methods of inhibiting Ire1
US8993580B2 (en) 2008-03-14 2015-03-31 Intellikine Llc Benzothiazole kinase inhibitors and methods of use
FR3011240A1 (en) * 2013-10-01 2015-04-03 Centre Nat Rech Scient 5'-NUCLEOTIDASE INHIBITORS AND THERAPEUTIC USES THEREOF
US9056877B2 (en) 2011-07-19 2015-06-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9096611B2 (en) 2008-07-08 2015-08-04 Intellikine Llc Kinase inhibitors and methods of use
US9295673B2 (en) 2011-02-23 2016-03-29 Intellikine Llc Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
US9321772B2 (en) 2011-09-02 2016-04-26 The Regents Of The University Of California Substituted pyrazolo[3,4-D]pyrimidines and uses thereof
US9359365B2 (en) 2013-10-04 2016-06-07 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9359349B2 (en) 2007-10-04 2016-06-07 Intellikine Llc Substituted quinazolines as kinase inhibitors
US9481667B2 (en) 2013-03-15 2016-11-01 Infinity Pharmaceuticals, Inc. Salts and solid forms of isoquinolinones and composition comprising and methods of using the same
US9512125B2 (en) 2004-11-19 2016-12-06 The Regents Of The University Of California Substituted pyrazolo[3.4-D] pyrimidines as anti-inflammatory agents
US9629843B2 (en) 2008-07-08 2017-04-25 The Regents Of The University Of California MTOR modulators and uses thereof
US9708330B2 (en) 2013-01-25 2017-07-18 Glaxosmithkline Intellectual Property Development Limited 2,3-dihydroimidazol[1,2-C]pyrimidin-5(1-H)-one based ipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitors
US9708348B2 (en) 2014-10-03 2017-07-18 Infinity Pharmaceuticals, Inc. Trisubstituted bicyclic heterocyclic compounds with kinase activities and uses thereof
US9751888B2 (en) 2013-10-04 2017-09-05 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9775844B2 (en) 2014-03-19 2017-10-03 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US10131668B2 (en) 2012-09-26 2018-11-20 The Regents Of The University Of California Substituted imidazo[1,5-a]pYRAZINES for modulation of IRE1
US10160761B2 (en) 2015-09-14 2018-12-25 Infinity Pharmaceuticals, Inc. Solid forms of isoquinolinones, and process of making, composition comprising, and methods of using the same
CN110156761A (en) * 2019-06-18 2019-08-23 郑州大学 Containing cumarin-biphenyl backbone compound, preparation method and applications
US10759806B2 (en) 2016-03-17 2020-09-01 Infinity Pharmaceuticals, Inc. Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as PI3K kinase inhibitors
US10919914B2 (en) 2016-06-08 2021-02-16 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US11110096B2 (en) 2014-04-16 2021-09-07 Infinity Pharmaceuticals, Inc. Combination therapies
US11147818B2 (en) 2016-06-24 2021-10-19 Infinity Pharmaceuticals, Inc. Combination therapies

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0415886A2 (en) * 1989-08-30 1991-03-06 Ciba-Geigy Ag Aza compounds
EP0430300A2 (en) * 1989-12-01 1991-06-05 Takeda Chemical Industries, Ltd. Xanthine derivatives, their production and use
GB2239240A (en) * 1989-12-21 1991-06-26 American Home Prod Imidazo[4,5-c] pyridine antiosteoporotic agents
WO1991019715A1 (en) * 1990-06-15 1991-12-26 G.D. Searle & Co. 1H-SUBSTITUTED-IMIDAZO[4,5-d]PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS
US5102880A (en) * 1989-05-30 1992-04-07 Merck & Co., Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
US5124335A (en) * 1991-01-30 1992-06-23 Merck & Co., Inc. Substituted pyrollo-fused 6 membered heterocycles as angiotensin ii antagonists

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5102880A (en) * 1989-05-30 1992-04-07 Merck & Co., Inc. Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists
EP0415886A2 (en) * 1989-08-30 1991-03-06 Ciba-Geigy Ag Aza compounds
EP0430300A2 (en) * 1989-12-01 1991-06-05 Takeda Chemical Industries, Ltd. Xanthine derivatives, their production and use
GB2239240A (en) * 1989-12-21 1991-06-26 American Home Prod Imidazo[4,5-c] pyridine antiosteoporotic agents
WO1991019715A1 (en) * 1990-06-15 1991-12-26 G.D. Searle & Co. 1H-SUBSTITUTED-IMIDAZO[4,5-d]PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS
US5124335A (en) * 1991-01-30 1992-06-23 Merck & Co., Inc. Substituted pyrollo-fused 6 membered heterocycles as angiotensin ii antagonists

Cited By (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5602137A (en) * 1993-06-10 1997-02-11 Beiersdorf-Lilly Gmbh Pyrimidine compounds and their use as pharmaceuticals
US5602136A (en) * 1993-06-10 1997-02-11 Beiersdorf-Lilly Gmbh Pyrimidine compounds and their use as pharmaceuticals
US5571813A (en) * 1993-06-10 1996-11-05 Beiersdorf-Lilly Gmbh Fused pyrimidine compounds and their use as pharmaceuticals
US6169091B1 (en) 1995-10-11 2001-01-02 Glaxo Wellcome Inc. Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US7109333B2 (en) 1998-01-12 2006-09-19 Smithkline Beecham Corporation Heterocyclic compounds
US6713485B2 (en) 1998-01-12 2004-03-30 Smithkline Beecham Corporation Heterocyclic compounds
US9199973B2 (en) 1998-01-12 2015-12-01 Novartis Ag Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US6727256B1 (en) 1998-01-12 2004-04-27 Smithkline Beecham Corporation Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US8912205B2 (en) 1998-01-12 2014-12-16 Glaxosmithkline Llc Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US8513262B2 (en) 1998-01-12 2013-08-20 Glaxosmithkline Llc Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US7265123B2 (en) 1999-07-09 2007-09-04 Smithkline Beecham Corporation Heterocyclic compounds
US7189734B2 (en) 1999-07-09 2007-03-13 Smithkline Beecham Corporation Anilinoquinazaolines as protein tyrosine kianse inhibitors
US7507741B2 (en) 1999-07-09 2009-03-24 Smithkline Beecham Corporation Heterocyclic compounds
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US8476282B2 (en) 2008-11-03 2013-07-02 Intellikine Llc Benzoxazole kinase inhibitors and methods of use
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US8980899B2 (en) 2009-10-16 2015-03-17 The Regents Of The University Of California Methods of inhibiting Ire1
US9738644B2 (en) 2010-05-21 2017-08-22 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
US9181221B2 (en) 2010-05-21 2015-11-10 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
US8604032B2 (en) 2010-05-21 2013-12-10 Infinity Pharmaceuticals, Inc. Chemical compounds, compositions and methods for kinase modulation
US8901133B2 (en) 2010-11-10 2014-12-02 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US9388183B2 (en) 2010-11-10 2016-07-12 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
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US8809349B2 (en) 2011-01-10 2014-08-19 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
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US11312718B2 (en) 2011-01-10 2022-04-26 Infinity Pharmaceuticals, Inc. Formulations of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one
USRE46621E1 (en) 2011-01-10 2017-12-05 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
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