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WO1993017682A1 - Antagonistes des recepteurs de l'angiotensine ii - Google Patents

Antagonistes des recepteurs de l'angiotensine ii Download PDF

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Publication number
WO1993017682A1
WO1993017682A1 PCT/US1993/001177 US9301177W WO9317682A1 WO 1993017682 A1 WO1993017682 A1 WO 1993017682A1 US 9301177 W US9301177 W US 9301177W WO 9317682 A1 WO9317682 A1 WO 9317682A1
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Prior art keywords
loweralkyl
hydrogen
substituted
halo
alkoxy
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PCT/US1993/001177
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English (en)
Inventor
Thomas M. Zydowsky
Biswanath De
Kazumi Shiosaki
Fatima Z. Basha
Martin Winn
John F. Debernardis
Thomas W. Von Geldern
Diane M. Yamamoto
Daniel J. Kerkman
Steven A. Boyd
Anthony K. L. Fung
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Abbott Laboratories
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Publication of WO1993017682A1 publication Critical patent/WO1993017682A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a 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
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4

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 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.
  • 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 11 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, saraiasin 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.
  • R 5 ' is hydrogen, halo, hydroxy, carboxy, alkoxy or thioalkoxy;
  • L, L', M and M' are independently selected from (i) hydrogen,
  • R 1 and R 1 ' are independently selected from (i) tetrazolyl,
  • 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,
  • 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 R 55 and R 57 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;
  • D is a bicyclic heterocycle comprising a 6-membered ring fused to another 6-membered ring, the bicyclic heterocycle comprising at least one
  • each of the 6-membered rings of the bicyclic heterocycle independently 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 each of the 6-membered rings of the bicyclic heterocycle comprising 0, 1 , 2 or 3 double bonds; the nitrogen atoms of the bicyclic heterocycle can be substituted with a substituent R 2 wherein at each occurrence R 2 is
  • R 10 is loweralkyl, halo- substituted loweralkyl, -PO 3 H 2 or -NR 11 R 12 wherein R 11 and R 12 are independently selected from hydrogen and loweralkyl and
  • azetidinyl pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridinyl or pyrimidinyl,
  • R 26b 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,
  • 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 23 is hydrogen or a carboxy-protecting group
  • R 28a alkoxy and -S(O) 2 R 28a 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
  • Preferred compounds of the invention are compounds wherein D is a substituted quinolinyl group, a substituted naphthyridinyl group, a substituted pteridinyl group, a substituted pyridopyrimidinyl group, a substituted quinazolinyl group, a substituted pyridopyrazinyl group, a substituted pyridotriazinyl group, a substituted pyrimidopyridazinyl group, a substituted pyridopyrazinyl group or a substituted pyrazinopyridazinyl 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, pentafiuoroethyl 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 carboxy methyl, carboxyethyl and the like.
  • alkoxycarbonyl refers to -C(O)OR 3 6 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.
  • alkanoyloxyalkyl 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
  • alkylaminocarbonylaminoalkyl 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.
  • heterocycliccarbonyloxyalkyl 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 in 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 quaternized; 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,
  • 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., dimethylaminoethy! 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 acetylaminomethyl 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
  • R 3 is bonded to either of the 6-membered rings and R 4 is bonded to either of the 6-membered rings.
  • 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.
  • substituents and/or variables are permissible only if such combinations result in stable compounds.
  • the compounds of this invention can be prepared by the processes illustrated in Schemes I through XXXI. 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. 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
  • 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.
  • 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.
  • Reaction Schemes IVA and IVB illustrate alternative methods of preparing compounds wherein -G-E- is -CH 2 -N(R 5 )- . According to Scheme
  • 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 olefin 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-XXX 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 pyridopyrimidine (in particular, 4- ⁇ N-propyl-N-[(2'-[1H- tetrazol-5-yl]biphenyl-4-yI)methyl]amino ⁇ -pyrido[3,2-d]pyrimidine-6-carboxylic acid).
  • a substituted pyridopyrimidine in particular, 4- ⁇ N-propyl-N-[(2'-[1H- tetrazol-5-yl]biphenyl-4-yI)methyl]amino ⁇ -pyrido[3,2-d]pyrimidine-6-carboxylic acid.
  • Broom in J. Org. Chem. 42, 993 (1977) describes chemistry relating to pyrido[3,2-d]pyrimidines.
  • Treatment of 5-aminouracil with dimethylacetylene dicarboxylate affords a Michael ad
  • Cyclization of compound 200 with Dowtherm A provides the trioxo compound of the Formula 201.
  • Exhaustive chlorination of compound 201 with phosphorus oxychloride affords a trichloride of the Formula 202.
  • Dechlorination of compound 204 by catalytic hydrogenation with 10% palladium on carbon and triethylamine in ethyl acetate provides a compound of the Formula 205.
  • Detritylation of compound 205 with acid followed by basic hydrolysis of the ester moiety affords a compound of the Formula 206.
  • Scheme XVII discloses the synthesis of a compound of the invention comprising a substituted pyridopyrimidine (in particular, 4- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -pyrido[3,2-d]pyrimidine-5-carboxyIic acid).
  • a substituted pyridopyrimidine in particular, 4- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -pyrido[3,2-d]pyrimidine-5-carboxyIic acid.
  • Broom in J. Org. Chem. 42, 993 (1977) describes chemistry relating to pyrido[3,2-d]pyrimidines.
  • Exhaustive chlorination of a compound of the Formula 210 prepared according to J. Am. Chem. Soc
  • Scheme XVIII discloses the synthesis of a compound of the invention comprising a substituted quinazoline (in particular, 4- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -quinazoline-5-carboxylic acid.
  • a substituted quinazoline in particular, 4- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -quinazoline-5-carboxylic acid.
  • Catalytic hydrogenation of a compound of the Formula 220 with palladium on carbon in methanol affords amino compound 221.
  • Treatment of compound 221 with potassium cyanate in refluxing acetic acid affords the known quinazoline 222, J. Het. Chem. 26, 1885 (1989).
  • Exhaustive chlorination of compound 222 with phosphorus oxychloride and N,N-diethylaniline affords dichloride 223.
  • Catalytic hydrogenation of compound 224 with palladium on carbon containing a base such as
  • Scheme XIX discloses the synthesis of a compound of the invention comprising a substituted naphthyridine (in particular, 4- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -1 ,5-naphthyridine-3-carboxylic acid).
  • Ethyl 4-chloro-1 ,5-naphthyridine-3-carboxylate 230 prepared by the method of Mendes et al., United States Patent No. 4,996,213, is reacted with amine 203, prepared as described in Example 2A, to give a compound of the Formula 231.
  • Compound 231 is deprotected with formic acid and hydrolyzed with sodium hydroxide to give a compound of the Formula 232.
  • Scheme XX discloses the synthesis of a compound of the invention comprising a substituted pyridopyrazine (in particular, 8- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ pyrido[2,3-b]pyrazine-7-carboxylic acid).
  • Hydroxy ester of the Formula 240 prepared as described by Tanaka and Narita, Yakugaku Zashi 95, 1092 (1975), is chlorinated using a procedure analogous to that described by Meades et al., United State Patent No.
  • Scheme XXI discloses the synthesis of a compound of the invention comprising a substituted pyridopyrimidine (in particular, 2,7-dimethyl-4- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ pyrido[4,5-d]pyrimidine).
  • the compound of the Formula 250 prepared by the method of Taylor, J. Am. Chem. Soc.82, 5711 (1960), is chlorinated by the method of Gupta et al., J. Het. Chem.12, 1311 (1975), to give a compound of the Formula 251.
  • Reaction of compound 251 with amine 203, prepared as described in Example 2A affords a compound of the Formula 252 which can be deprotected to give a compound of the Formula 253.
  • Scheme XXII discloses the synthesis of a compound of the invention comprising a substituted pyridotriazine (in particular, 3,7-dimethyl-5- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ pyrido[5,4-e]as-triazine).
  • the compound of the Formula 260 prepared as described by Biffin and Brown, Tetrahedron Lett. 2503 (1968), is reacted with amine 203, prepared as described in Example 2A, by the procedure desribed by Brown and Sugimoto, Austr. J. Chem. 24, 633 (1971 ), to give a compound of the Formula 261.
  • Formic acid deprotection gives a compound of the Formula 262.
  • Scheme XXIII discloses the synthesis of a compound of the invention comprising a substituted pyridopyrazine (in particular, 2,3-dimethyl-5- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ pyrido[3,4-b]pyrazine).
  • the chloro compound of the Formula 270 prepared by the method of Jam et al., Indian J. Chem. 4, 403 (1966), is reacted with amine 203, prepared as described in Example 2A, using the procedure of Temple et al., J. Het. Chem. 7, 1195 (1970).
  • Catalytic hydrogenation affords a diamine, which is reacted with butane-2,3-d ⁇ one to afford a pyrido[3,4-b]pyrazine of the Formula 272.
  • Scheme XXIV discloses the synthesis of a compound of the invention comprising a substituted pyrimidopyridazine (in particular, 8- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ pyrimido[5,4-c]pyridazine).
  • the mercapto compound of the Formula 280 prepared by the method of Nakagomi et al., J. Het. Chem.5, 523 (1968), is methylated with methyl iodide to give the methylthio compound 281.
  • Scheme XXV discloses the synthesis of a compound of the invention comprising a substituted pyrazinopyridazine (in particular, 5-amino-8- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ pyrazino[2,3-d]pyridazine).
  • the dichloro compound of the Formula 290 prepared by the method of Patel and Castle, J. Het. Chem. 3, 512 (1966), is reacted with secondary amine 203, prepared as described in Example 2A, to afford tertiary amine 291. Treatment of 291 with ammonia affords amino compound 292. Formic acid deprotection affords a compound of the Formula 293.
  • Scheme XXVI discloses the synthesis of a compound of the invention comprising a substituted naphthyridine (in particular, 2,8-diamino-4- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -1 ,5-naphthyridine).
  • the trichloro compound of the Formula 300 prepared by the method of Roch et al. German Patent 2926804, Chemical Abstracts 95:25109-s, is reacted with secondary amine 203, prepared as described in Example 2A, to give tertiary amine 301.
  • Treatment with ammonia affords diamino compound 302.
  • Formic acid deprotection affords a compound of the Formula 303.
  • Scheme XXVII discloses the synthesis of a compound of the invention comprising a substituted naphthyridine (in particular, 7- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -1,6-naphthyridine-8-carboxylic acid).
  • 2-Chloropyridine-3-carboxaldehyde ethylene acetal is treated with sodium hydride and diethylmalonate to give a compound of the Formula 311.
  • phosphorus oxychloride gives the 7-chloro compound which is treated with secondary amine 203, prepared as described in Example 2A, under basic conditions to afford tertiary amine 313.
  • Formic acid detritylation followed by sodium hydroxide ester hydrolysis affords a compound of the Formula 314.
  • Scheme XXVIII discloses the synthesis of a compound of the invention comprising a substituted pyridopyrimidine (in particular, 4- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -pyrido[3,2-d]pyrimidine-2-carboxylic acid).
  • 3-Aminopicolinic acid is treated with urea to give the dihydroxy compound 320.
  • Chlorination converts compound 320 to dichloro compound 321.
  • Treatment with cyanide anion give the 2-cyano compound 323.
  • Formic acid hydrolysis deprotects the compound and converts the nitrite to a carboxylic acid 324.
  • Scheme XXIX discloses the synthesis of a compound of the invention comprising a substituted naphthyridine (in particular, 8- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -[1 ,7]naphthyridine-6-carboxylic acid).
  • 3-Formylpicolinic acid prepared as described in Gazz. Chim. Ital. 86, 990 (1956) is converted into its ethyl ester 331.
  • ethyl cyanoacetate is prepared with sodium hydride and reacted with compound 331 to give the [1 ,7]-naphthyridine compound 332.
  • compound 332 is prepared from 2-cyano-3-iodopyridine which is reacted with ethyl 2-ethoxyacrylate with a palladium catalyst and the product thereof cyclized to give compound 332; the analogous reaction was carried out on the benzene analog as described in Heterocycles 27, 453 (1988). Chlorination of 332 with phosphorus oxychloride in analogy to the procedure described in J. Org. Chem. 44, 1887 (1979) for the analogous quinoline gives the chloro compound 333.
  • Treatment of compound 332 with phosphorus oxychloride in analogy to the procedure described in J. Org. Chem. 44, 1887 (1979) for the analogous quinoline gives the chloro compound 333.
  • Scheme XXXIV describes the synthesis of 6-isopropoxy-2-methyl-4- ⁇ N-propyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ -1 ,5-naphthyridine.
  • 2-Chloro-5-nitropyridine is treated with sodium isopropoxide in isopropanol followed by tin (II) chloride dihydrate to give the 5-amino-2-isopropoxy compound of the Formula 340.
  • Treatment of this compound with ethyl acetoacetate followed by acidification and then Dowtherm at 200 °C gives a compound of the Formula 341.
  • 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 (0.45 g, 2.1 mmol) was suspended in 2 mL of phosphorus oxychloride and heated at 90 °C for two hours. The solvents were removed in vacuo and the residue obtained was neutralized with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered through Celite and concentrated in vacuo. The crude product was combined with 3 mL of ethanol and 2 mL of n-propylamine and then heated at 80 °C overnight.
  • Example 1B To the compound resulting from Example 1B (185 mg , 0.72 mmol) dissolved in a mixture of tetrahydrofuran (0.72 mL) and 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) (0.72 mL) and cooled to 0 °C was added 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (1 mL) dropwise over 5 minutes.
  • DMPU ,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
  • Example 1C The compound resulting from Example 1C (240 mg, 0.33 mmol) was dissolved in a mixture of 3 mL of ethanol and 2 mL of tetrahydrofuran. p-Toluene sulfonic acid (167 mg) was added, and the resultant solution was stirred at ambient temperature for 8 hours. The reaction was concentrated under reduced pressure, and the residue was taken up in methanol (2 mL). Aqueous sodium hydroxide (2 mL of a 5 N. solution) was added. The reaction mixture was stirred overnight. The solvent were removed in vacuo; the residue was taken up in water and washed with ethyl acetate. The aqueous phase was acidified with 1 N.
  • the compound resulting from Example 2A (2.60 g, 4.86 mmol) and diisopropyl ethylamine (1.36 g, 10.54 mmol) were dissolved in 5 mL of acetonitrile and refluxed for 3 hours.
  • Example 2B The compound resulting from Example 2B (2.10 g) was dissolved in 17 mL of dichloromethane and 25 mL of 88% formic acid. After stirring for 2 hours at ambient temperature, the mixture was concentrated in vacuo. The residue was triturated with a solution (50 mL) of 1 :1 formic acid/water and the solid by-product obtained removed by filtration. The filtrate was concentrated under reduced pressure and chased with water. The pH was adjusted to 4.0 using sodium acetate, and the mixture was extracted with chloroform. The combined organic extracts were dried over sodium sulfate and concentrated under, reduced pressure. The residue obtained was triturated with ether to give 1.41 g of the title compound as a yellow powder.
  • Example 2 To the compound resulting from Example 2 (1.20 g, 2.43 mmol) was added 0.70 g of sodium hydroxide, 6.6 mL of water and 28 mL of ethanol. The mixture was refluxed for 105 minutes and then cooled in an ice bath. Acetic acid (1 mL) was added and then the solvent was removed under reduced pressure. To the cooled residue was added water, 1 mL of acetic acid and 0.5 mL of formic acid. The product was removed from solution by filtration and crystallized from acetonitrile to give 0.889 g of the title compound as a yellow solid.
  • the crude 8-chloro compound was suspended in 8 mL of ethanol and 4 mL of n-butylamine in a sealed tube.
  • the reaction mixture was heated at 110 °C for 5 hours, cooled to ambient temperature, concentrated under reduced pressure and then azeotroped with toluene.
  • the residue obtained was chromatographed on silica gel eluting with 4:1 hexane/ethyl acetate to afford 1.32 g (65%) of the title compound.
  • Lithium bis(trimethylsilyl)amide (3.0 mL of a 1.0M solution in tetrahydrofuran) was added dropwise. After stirring for 6 minutes at 0 °C, N-triphenylmethyl-5-[2-(4'-bromomethyl-biphenyl)]tetrazole, prepared as described in European Patent Application No. 291969, in 5 mL of tetrahydrofuran was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours and then stored at 0 °C overnight. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (400 mL) containing 25 mL of brine.
  • Example 4B The compound resulting from Example 4B (1.14 g, 1.68 mmol) in 25 mL of acetic acid, 2 mL of water and 25 mL of tetrahydrofuran was heated at 95 °C for 1 hour. The reaction mixture was concentrated in vacuo and chased with toluene (2 ⁇ ). The crude product was chromatographed on silica gel eluting with a gradient of ethanol in methylene chloride to afford 450 mg (60%) of the title compound.
  • Example 5A tetrahydrofuran at 0 °C under nitrogen was added the compound resulting from Example 5A (1.70 g, 3.1 mmol). After stirring for 3 hours at ambient temperature, the solution was concentrated in vacuo and the residue partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate (25 mL). The aqueous layer was extracted with additional ethyl acetate (2 ⁇ 25 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure.
  • Example 6A The compound resulting from Example 6A (0.9 g, 1.3 mmol) dissolved in 30 mL of 88% formic acid and 20 mL of methylene chloride was stirred at ambient temperature overnight. After removal of the solvent in vacuo, the residue was azeotroped with toluene and then chromatographed on silica gel eluting with 38:1 :1 ethyl acetate/water/formic acid. The product was
  • Example 7B The compound resulting from Example 7B (1.00 g, 1.3 mmol) was dissolved in tetrahydrofuran to which acetic acid and water had been added. The solution was refluxed for 2 hours and then concentrated under reduced pressure. The residue obtained was chromtographed on silica gel eluting with isopropanol in methylene chloride to provide the title compound as a colorless, amorphous solid (400 mg, 62%). MS (DCI/NH 3 ) m/e 494 (M+H) + .
  • Example 7C To the compound resulting from Example 7C (280 mg, 0.55 mmol) dissolved in methanol (10 mL) was added a solution of sodium hydroxide (111 mg, 2.8 mmol) in water (2 mL). After stirring for 16 hours at ambient
  • 6-Carbomethoxy-2,4,8-trichloropyrido[3,2-d]pyrimidine (1.47 g, 5 mmol), prepared by the procedure described in J. Org. Chem. 44, 433 (1979), was reacted with the compound resulting from Example 5A (5 mmol) by the procedure described in Example 7B. Flash chromatography on silica gel eluting with ethyl acetate/hexane/methylene chloride mixtures provided the title compound as an amorphous solid (2.55 g, 75%). MS (FAB) m/e 805 (M+H) + .
  • Example 9B The compound resulting from Example 9B (430 mg, 0.583 mmol) was deprotected by the procedure described in Example 7C and hydrolyzed by the procedure described in Example 8 to afford the title compound as an amorphous solid (150 mg, 54%).
  • Example 10A The compound resulting from Example 10A (610 mg, 0.86 mmol) was deprotected by the procedure described in Example 7C to afford the title compound as an amorphous solid (0.36 g, 90%).
  • Example 11A To the compound resulting from Example 11A (1.77 mmol) dissolved in tetrahydrofuran (15 mL) was added triethylamine (0.5 mL) and 4-chloro-6-methylquinazoiine (0.4 g, 2.24 mmol), prepared by the procedure described in J. Chem. Soc, 560 (1962). The reaction mixture was heated at 50 °C for 28 hours and then concentrated in vacuo. The work up followed the procedure described in Example.5B. Flash chromatography on silica gel eluting with ethyl acetate in hexane provided the title compound as an amorphous solid (0.5 g, 48%). MS (DCI/NH 3 ) m/e 706 (M+H) + .
  • Example 11B 4- ⁇ N-Pentyl-N-[(2'-[1 H-tetrazol-5-yl)biphenyl-4-yl)methyl]amino)-6-methyl- quinazoline
  • the compound resulting from Example 11B (0.49 g, 0.694 mmol) was deprotected by the procedure described in Example 7C. Purification by flash chromatography on silica gel eluting with ethanol in methylene chloride provided the title compound as an amorphous solid (90 mg, 28%) following recrystallization from methylene chloride and hexane.
  • Example 10A To the compound resulting from Example 10A (500 mg, 0.706 mmol) dissolved in 50 mL of methylene chloride and cooled to 0 °C was added boron tribromide (1 mL). The reaction mixture was stirred at 0 °C for 30 minutes and at ambient temperature for 30 minutes. The reaction was diluted with 150 mL of methylene chloride and the solution was washed with saturated aqueous ammonium chloride solution. The organic phase was dried over sodium sulfate and the filtered solution was concentrated under reduced pressure and then redissolved in 50 mL of tetrahydrofuran.
  • p-Toluene sulfonic acid 400 mg, 2.2 mmol was added and the reaction mixture was heated at 55 °C for 14 hours at which time potassium carbonate (500 mg) and 1 mL of water were added. The mixture was concentrated under reduced pressure and 100 mL of water was added. Solid sodium hydroxide was added to adjust the pH to 11 , and the mixture was extracted with diethyl ether (2 ⁇ 100 mL). The aqueous solution was acidified with formic acid and then extracted with ethyl acetate (2 ⁇ 100 mL). The combined organic extracts were concentrated under reduced pressure and final traces of formic acid were removed by azeotroping with toluene.
  • Ethyl 4-chloroquinoline-3-carboxylate prepared by the procedure described in J. Med. Chem.12, 1096 (1969), is reacted with the compound resulting from Example 5A by the procedure described in Example 7B to afford ethyl 4- ⁇ N-butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ quinoline-3-carboxylate.
  • 5-Methoxyquinazolin-4-one prepared by the method described in J. Org. Chem. 17. 141 (1952), is treated with phosphorus oxychloride according to the procedure described in Example 7A to afford 4-chloro-5-methoxyquinazoline.
  • Example 7B The above compound is reacted with the compound resulting from Example 5A by the procedure described in Example 7B to afford 5-methoxy-4- ⁇ N-butyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino ⁇ quinazoline.
  • Example 16B The compound resulting from Example 16B (3.72 g) was dechlorinated by the procedure described in Example 9B. Chromatography on silica gel eluting with ethyl acetate in hexane afforded the title compound as a yellow amorphous solid (1.89 g, 51%).
  • Example 16C The compound resulting from Example 16C is deblocked by the procedure described in Example 7C to afford the title compound.
  • 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
  • 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 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:
  • 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 buffer contained no cocaine, 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 concentration-contractile response curve for angiotensin II (A II: 1 ⁇ 10 -10 - 10 -8 M) was obtained. The tissue was washed several times until the baseline was reached.
  • 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. For single dose shift experiments 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.
  • 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 submultiples 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, intrastemal 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 injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • the 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 formulating art. They can optionally contain o pacifying 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.
  • 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 laurate; 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, emulsifiers 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, acetazolamide, amiioride, bumetanide, benzthiazide, ethacrynic acid, furosemide, ⁇ ndacrinone, metolazone, spironolactone, triamterene,
  • Representative adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranoiol, timolol, carteolol and the like or a pharmaceutically acceptable salt thereof.
  • vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside, flosequinan and the like or a pharmaceutically acceptable salt thereof.
  • Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof.
  • Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof.
  • Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof.
  • antiserotoninergic agents include ketanserin and the like or a pharmaceutically acceptable salt thereof.
  • renin inhibitiors include enalkiren, A-72517, PD-134672 or Ro 42-5892 and the like or a pharmaceutically acceptable salt thereof.
  • cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, guanabenz, reserpine and the like or a pharmaceutically acceptable salt thereof.
  • the compound of formula I and the other cardiovascular agent can be administered at the recommended maximum clinical dosage or at lower doses.
  • Dosage levels of the active compounds in the compositions of the invention can be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient.
  • the combination can be administered as separate compositions or as a single dosage form containing both agents.

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Abstract

Composés de la formule (I) qui sont des antagonistes des récepteurs de l'angiotensine II.
PCT/US1993/001177 1992-03-04 1993-02-09 Antagonistes des recepteurs de l'angiotensine ii WO1993017682A1 (fr)

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WO1994022838A1 (fr) 1993-04-07 1994-10-13 Nissan Chemical Industries, Ltd. Derive pyrazolique
US5602137A (en) * 1993-06-10 1997-02-11 Beiersdorf-Lilly Gmbh Pyrimidine compounds and their use as pharmaceuticals
US6043253A (en) * 1998-03-03 2000-03-28 Merck & Co., Inc. Fused piperidine substituted arylsulfonamides as β3-agonists
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
US6696566B2 (en) 2001-02-12 2004-02-24 Syntex (U.S.A.) Llc 6-substituted pyrido-pyrimidines
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
US6965030B2 (en) 2002-08-06 2005-11-15 Roche Palo Alto Llc 6-alkoxy-pyrido-pyridine
US7084147B2 (en) 1999-07-09 2006-08-01 Smithkline Beecham Corporation Anilinoquinazaolines as protein tyrosine kinase inhibitors
US7348331B2 (en) 2003-11-13 2008-03-25 Roche Palo Alto Llc Hydroxyalkyl substituted pyrido-7-pyrimidin-7-ones
US7534894B2 (en) 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
US7618975B2 (en) 2003-07-03 2009-11-17 Myriad Pharmaceuticals, Inc. 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US7625908B2 (en) 2003-11-13 2009-12-01 Astrazeneca Ab Quinazoline derivatives
EP2149565A1 (fr) 2008-07-24 2010-02-03 Bayer Schering Pharma AG Dérivés de chinazoline substitués par du sulfonamide en tant que modulateurs d'immunité pour le traitement de inflammations et allergies
US7659279B2 (en) 2003-04-30 2010-02-09 Astrazeneca Ab Quinazoline derivatives and their use in the treatment of cancer
US7820683B2 (en) 2005-09-20 2010-10-26 Astrazeneca Ab 4-(1H-indazol-5-yl-amino)-quinazoline compounds as erbB receptor tyrosine kinase inhibitors for the treatment of cancer
US7910731B2 (en) 2002-03-30 2011-03-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US7947676B2 (en) 2004-12-14 2011-05-24 Astrazeneca Ab Pyrazolo[3,4-d]pyrimidine compounds as antitumor agents
US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US7998949B2 (en) 2007-02-06 2011-08-16 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
EP2377532A1 (fr) * 2004-08-18 2011-10-19 Ace ApS Compositions cosmétiques et pharmaceutiques comportant des inhibiteurs ACE et/ou antagonistes de récepteur d'angiotensine II pour le traitement de troubles dermatologiques
US8088782B2 (en) 2008-05-13 2012-01-03 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A
US8101599B2 (en) 2002-05-17 2012-01-24 Novartis Ag Pharmaceutical composition containing anti-hypertensive agents
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
US8318752B2 (en) 2003-09-19 2012-11-27 Astrazeneca Ab 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoyl-methyl)piperidin-4-yl]oxy}quinazoline, its pharmaceutically acceptable salts, and pharmaceutical compositions comprising the same
US8399461B2 (en) 2006-11-10 2013-03-19 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for production of same
US8497369B2 (en) 2008-02-07 2013-07-30 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production
US8648191B2 (en) 2008-08-08 2014-02-11 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them
CZ304359B6 (cs) * 1998-07-10 2014-03-26 Novartis Ag Farmaceutická kombinační kompozice
US8735410B2 (en) 2005-02-26 2014-05-27 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors
CN104370890A (zh) * 2014-09-24 2015-02-25 重庆理工大学 一类喹唑啉类化合物及其作为免疫抑制剂的应用
US9296755B2 (en) 2013-01-25 2016-03-29 Glaxosmithkline Intellectual Property Development Limited 3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one compounds and their therapeutic applications
CN105646376A (zh) * 2016-03-01 2016-06-08 张宏业 一种治疗乙型肝炎的药物组合物
US10087181B2 (en) * 2012-06-15 2018-10-02 Curegenix, Inc. Compound as WNT signaling inhibitor, composition, and use thereof
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
US11780840B2 (en) 2020-07-02 2023-10-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11919908B2 (en) 2020-12-21 2024-03-05 Incyte Corporation Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors
US11958861B2 (en) 2021-02-25 2024-04-16 Incyte Corporation Spirocyclic lactams as JAK2 V617F inhibitors
US12037346B2 (en) 2021-04-13 2024-07-16 Nuvalent, Inc. Amino-substituted heteroaryls for treating cancers with EGFR mutations
US12084430B2 (en) 2022-03-17 2024-09-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors

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Cited By (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022838A1 (fr) 1993-04-07 1994-10-13 Nissan Chemical Industries, Ltd. Derive pyrazolique
US5721264A (en) * 1993-04-07 1998-02-24 Nissan Chemical Industries, Ltd. Pyrazole derivatives
US5817828A (en) * 1993-04-07 1998-10-06 Nissan Chemical Industries, Ltd. Pyrazole derivatives
US5840909A (en) * 1993-04-07 1998-11-24 Nissan Chemical Industries, Ltd. Pyrazole derivatives
US5846991A (en) * 1993-04-07 1998-12-08 Nissan Chemical Industries, Ltd. Pyrazole derivatives
US5602137A (en) * 1993-06-10 1997-02-11 Beiersdorf-Lilly Gmbh 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
US8912205B2 (en) 1998-01-12 2014-12-16 Glaxosmithkline Llc Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US6713485B2 (en) 1998-01-12 2004-03-30 Smithkline Beecham Corporation Heterocyclic compounds
US6727256B1 (en) 1998-01-12 2004-04-27 Smithkline Beecham Corporation Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US9199973B2 (en) 1998-01-12 2015-12-01 Novartis Ag 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
US6043253A (en) * 1998-03-03 2000-03-28 Merck & Co., Inc. Fused piperidine substituted arylsulfonamides as β3-agonists
CZ304359B6 (cs) * 1998-07-10 2014-03-26 Novartis Ag Farmaceutická kombinační kompozice
US7265123B2 (en) 1999-07-09 2007-09-04 Smithkline Beecham Corporation Heterocyclic compounds
US7084147B2 (en) 1999-07-09 2006-08-01 Smithkline Beecham Corporation Anilinoquinazaolines as protein tyrosine kinase inhibitors
US7189734B2 (en) 1999-07-09 2007-03-13 Smithkline Beecham Corporation Anilinoquinazaolines as protein tyrosine kianse inhibitors
US6933299B1 (en) 1999-07-09 2005-08-23 Smithkline Beecham Corporation Anilinoquinazolines as protein tyrosine kinase inhibitors
US7507741B2 (en) 1999-07-09 2009-03-24 Smithkline Beecham Corporation Heterocyclic compounds
US6586592B2 (en) 2000-06-20 2003-07-01 Pharmacia & Upjohn Company Bis-arylsulfones
US6579870B2 (en) 2000-06-20 2003-06-17 Pharmacia & Upjohn Company Bis-arylsulfones
US7169794B2 (en) 2001-02-12 2007-01-30 Roche Palo Alto Llc 6-substituted pyrido-pyrimidines
US6696566B2 (en) 2001-02-12 2004-02-24 Syntex (U.S.A.) Llc 6-substituted pyrido-pyrimidines
US7449581B2 (en) 2001-02-12 2008-11-11 Poche Palo Alto Llc 6-Substituted pyrido-pyrimidines
US8343982B2 (en) 2002-03-30 2013-01-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds pharmaceutical compositions containing these compounds, their use and process for preparing the same
US7910731B2 (en) 2002-03-30 2011-03-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US8101599B2 (en) 2002-05-17 2012-01-24 Novartis Ag Pharmaceutical composition containing anti-hypertensive agents
US7196097B2 (en) 2002-08-06 2007-03-27 Roche Palo Alto Llc 6-alkoxy-pyrido-pyrimidines
US7105525B2 (en) 2002-08-06 2006-09-12 Roche Palo Alto Llc 6-alkoxy-pyrido-pyrimidines
US6965030B2 (en) 2002-08-06 2005-11-15 Roche Palo Alto Llc 6-alkoxy-pyrido-pyridine
US7659279B2 (en) 2003-04-30 2010-02-09 Astrazeneca Ab Quinazoline derivatives and their use in the treatment of cancer
US7618975B2 (en) 2003-07-03 2009-11-17 Myriad Pharmaceuticals, Inc. 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US7989462B2 (en) 2003-07-03 2011-08-02 Myrexis, Inc. 4-arylamin-or-4-heteroarylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
US8318752B2 (en) 2003-09-19 2012-11-27 Astrazeneca Ab 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoyl-methyl)piperidin-4-yl]oxy}quinazoline, its pharmaceutically acceptable salts, and pharmaceutical compositions comprising the same
US7534894B2 (en) 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
US7750016B2 (en) 2003-11-13 2010-07-06 Roche Palo Alto Llc Hydroxyalkyl substituted pyrido-7-pyrimidin-7-ones
US7625908B2 (en) 2003-11-13 2009-12-01 Astrazeneca Ab Quinazoline derivatives
US7348331B2 (en) 2003-11-13 2008-03-25 Roche Palo Alto Llc Hydroxyalkyl substituted pyrido-7-pyrimidin-7-ones
EP2377532A1 (fr) * 2004-08-18 2011-10-19 Ace ApS Compositions cosmétiques et pharmaceutiques comportant des inhibiteurs ACE et/ou antagonistes de récepteur d'angiotensine II pour le traitement de troubles dermatologiques
US7947676B2 (en) 2004-12-14 2011-05-24 Astrazeneca Ab Pyrazolo[3,4-d]pyrimidine compounds as antitumor agents
US8258145B2 (en) 2005-01-03 2012-09-04 Myrexis, Inc. Method of treating brain cancer
US8735410B2 (en) 2005-02-26 2014-05-27 Astrazeneca Ab Quinazoline derivatives as tyrosine kinase inhibitors
US7820683B2 (en) 2005-09-20 2010-10-26 Astrazeneca Ab 4-(1H-indazol-5-yl-amino)-quinazoline compounds as erbB receptor tyrosine kinase inhibitors for the treatment of cancer
US8399461B2 (en) 2006-11-10 2013-03-19 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for production of same
US7998949B2 (en) 2007-02-06 2011-08-16 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
US8772298B2 (en) 2008-02-07 2014-07-08 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production
US8497369B2 (en) 2008-02-07 2013-07-30 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production
US8088782B2 (en) 2008-05-13 2012-01-03 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A
EP2149565A1 (fr) 2008-07-24 2010-02-03 Bayer Schering Pharma AG Dérivés de chinazoline substitués par du sulfonamide en tant que modulateurs d'immunité pour le traitement de inflammations et allergies
US8648191B2 (en) 2008-08-08 2014-02-11 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them
US10087181B2 (en) * 2012-06-15 2018-10-02 Curegenix, Inc. Compound as WNT signaling inhibitor, composition, and use thereof
US9296755B2 (en) 2013-01-25 2016-03-29 Glaxosmithkline Intellectual Property Development Limited 3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one compounds and their therapeutic applications
CN104370890A (zh) * 2014-09-24 2015-02-25 重庆理工大学 一类喹唑啉类化合物及其作为免疫抑制剂的应用
CN105646376A (zh) * 2016-03-01 2016-06-08 张宏业 一种治疗乙型肝炎的药物组合物
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
US11780840B2 (en) 2020-07-02 2023-10-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US12187725B2 (en) 2020-07-02 2025-01-07 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11919908B2 (en) 2020-12-21 2024-03-05 Incyte Corporation Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors
US11958861B2 (en) 2021-02-25 2024-04-16 Incyte Corporation Spirocyclic lactams as JAK2 V617F inhibitors
US12037346B2 (en) 2021-04-13 2024-07-16 Nuvalent, Inc. Amino-substituted heteroaryls for treating cancers with EGFR mutations
US12084430B2 (en) 2022-03-17 2024-09-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors

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