http://rdf.ncbi.nlm.nih.gov/pubchem/patent/AR-058400-A1
Outgoing Links
| Predicate | Object |
|---|---|
| assignee | http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_a7f82940e47ba7a1188f8e2ffca55e0f |
| classificationCPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P35-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P19-10 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P19-02 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P17-06 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K31-424 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P9-08 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P9-06 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P9-12 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P3-10 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P9-10 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D498-04 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P17-02 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P9-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P9-04 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P9-02 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P29-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P3-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P7-02 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P27-06 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P7-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P13-12 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P13-10 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P27-02 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P25-28 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P11-06 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P1-16 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P11-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P43-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P1-02 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D471-04 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P25-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07D487-04 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P37-02 |
| filingDate | 2006-12-20-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationDate | 2008-01-30-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | AR-058400-A1 |
| titleOfInvention | OXAZOLOISOQUINOLINE DERIVATIVES AS ANTHOGONISTS OF THE THROMBIN RECEPTOR |
| abstract | Oxazoloisoquinoline derivatives are described, as well as pharmaceutical compositions containing them and a method for treating diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, and cancer by administering said compounds. A combination therapy with other cardiovascular agents is also claimed. Claim 1: A compound represented by formula (1), or a pharmaceutically acceptable salt, solvate, or ester of said compound, wherein the dotted line represents a double or single bond, as allowed by the valence requirement; with the proviso that R10 or R11 are absent when the carbon to which R10 or R11 is attached is part of a double bond; B is - (CH2) n3-, - (CH2) -O-, - (CH2) S-, - (CH2) -NR6-, -C (O) NR6-. -NR6C (O) -, cyclopropylene, - (CH2) n4CR12 = CR12a (CH2) n5 or - (CH2) n4CsC (CH2) n5- where n3 is 0-5, n4 and n5 are independently 0-2, and R12 and R12a are independently selected from the group consisting of hydrogen, C1-6 alkyl and halogen; A, G, J, M and U are independently selected from the group consisting of -N (R54) -, - (CR1R2) -, -O-,> C = O, -S-, -S (O) -, - S (O) 2- Y> N = R1; with the proviso that the selection of A, G, U, J, and M does not result in adjacent oxygen or sulfur atoms and that at least one carbon atom appears between any oxygen, nitrogen or sulfur atom; each n is independently 0, 1 or 2 with the proviso that all variables n cannot be simultaneously 0 and that the total of variables n cannot be greater than 7; K is selected from the group consisting of,> C =, -CR1-, and -N-; Het is a mono-, bi- or tricyclic heteroaromatic group of 5 to 14 atoms composed of 1 to 13 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, with the proviso that there is no adjacent oxygen or sulfur atoms present in the heteroaromatic group, where a ring nitrogen can form an N-oxide or quaternary group with an alkyl group, where Het is attached to B by a ring member of the carbon atom, and where the Het group is substituted by 1 to 4 portions, W, where each W is independently selected from the group consisting of hydrogen, alkyl, fluoralkyl, difluoralkyl, trifluoralkyl, haloalkyl, dihaloalkyl, trihaloalkyl, cycloalkyl, cycloalkyl substituted with alkyl, alkenyl, or alkynyl, heterocycloalkyl, heterocycloalkyl substituted with alkyl, alkenyl, or alkynyl, R21-arylalkyl, R21-aryl-alkenyl, heteroaryl, heteroarylalkyl, heteroarylalkyl, hydroxyalkyl lo, dihydroxyalkyl, aminoalkyl, alkylaminoalkyl, di- (alkyl) -aminoalkyl, thioalkyl, alkoxy, alkenyloxy, halogen, -NR4R5, -SH, -CN, -OH, -C (O) OR17, -COR16, -OS (O2 ) CF3, -CH2OCH2CF3, alkylthio, -C (O) NR4R5, -OCHR6-phenyl, phenoxyalkyl, -NHCOR16, -NHSO2R16, biphenyl, - OC (R6) 2COOR7, -OC (R6) 2C (O) NR4R5, substituted alkoxy with alkyl, amino or -NHC (O) OR17, aryl, aryl substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, halogen, alkoxy, methylenedioxy, carboxylic acid, carboxamide, amine, urea, amide, sulfonamide, -CN , -CF3, -OCF3, -OH, alkylamino-, di- (alkyl) amino-, -NR25R26-alkyl-, hydroxyalkyl-, -C (O) OR17, -COR17, -NHCOR16, -NHS (O) 2R16, -NHS (O) 2CH2CF3, -C (O) NR25R26, NR25-C (O) -NR25R26, -S (O) R13, -S (O) 2R13 and - SR13, or alkyl optionally substituted with -NR1R2, -NR1COR2 , -NR1CONR1R2, -NR1C (O) OR2, -NR1S (O) 2R2, -NR1S (O) 2NR1R2, -C (O) OH, -C (O) OR1, -CONR1R2-heteroaryl, hydroxyalkyl, alkyl, -S (O) 2-alkyl, -C (O) NR4R5 or heteroary ilo; where adjacent carbons in the Het ring can optionally form a ring with a methylenedioxy group; R1 and R2 are independently selected from the group consisting of hydrogen, halogen, alkyl, fluoralkyl, difluoralkyl, trifluoralkyl, cycloalkyl, alkenyl, alkoxy, arylalkyl, arylalkyl, heteroarylalkyl, heteroarylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkyl, amino, alkoxy, aryloxy, alkyl, amino CN, and thioalkyl; or R1 and R2 when bound to nitrogen, taken together, form a monocyclic heterocyclic ring of 4 to 10 atoms, with 1-3 heteroatoms selected from -O-, -N-, -S-, -S ( O) -, -S (O) 2- and> C = O, with the proviso that atoms of the S and O ring are not adjacent to each other, where said heterocyclic ring is unsubstituted or substituted with one or more independently selected groups between alkyl, halogen, hydroxy, alkoxy, aryloxy and arylalkoxy; R6 is hydrogen, alkyl or phenyl; R7 is hydrogen or alkyl; R16 and R16a are independently selected from the group consisting of hydrogen, alkyl, phenyl and benzyl; R16b is hydrogen, alkoxy, alkyl, alkoxyalkyl-, R22-OC (O) -alkyl-, cycloalkyl, R21-aryl, R21-arylalkyl, haloalkyl, alkenyl, substituted halo alkenyl, alkynyl, substituted halo alkynyl, R21-heteroaryl, ( R21-heteroaryl) -alkyl-, (R21-heterocycloalkyl) -alkyl-, R28R29N-alkyl-, R28R29N-C (O) -alkyl-, R28R29N-C (O) O-alkyl-, R28OC (O) N (R29 ) -alkyl-, R28S (O) 2N (R29) -alkyl-, R28R29N-C (O) - N (R29) -alkyl-, R28R29N-S (O) 2N (R29) -alkyl-, R28-C ( O) N (R29) -alkyl-, R28R29N-S (O) 2-alkyl-, HOS (O) 2-alkyl-, (OH) 2P (O) 2-alkyl-, R28-S-alkyl-, R28 -S (O) 2-alkyl-, or hydroxyalkyl; R17 is selected from the group consisting of hydrogen, alkyl, phenyl and benzyl; R18 and R19 are hydrogen, alkyl, aryl, R21-aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, arylalkoxyalkyl, heteroaryloxyalkyl, (heterocyclyl) alkyloxyalkyl, alkoxyalkyl-2-alkyl (NH) ) NR1R2 or alkyl substituted with one or two portions independently selected from the group consisting of cycloalkyl, halogen, hydroxy, -NR1R2, -NR1C (O) R2, -NR1C (O) NR1R2, -NR1C (O) OR2, NR1S (O) 2R2, -NR1S (O) 2NR1R2, -C (O) OH, - C (O) OR1 and -C (O) NR1R2; or R18 and R19 together with the nitrogen to which they are attached, form a mono or bicyclic heterocyclic ring of 4 to 10 atoms, with 1-3 ring heteroatoms selected from the group consisting of -O-, -N-, -S- , -S (O) -, -S (O) 2-. and> C = O, with the proviso that the atoms of S and O are not adjacent to each other, the ring being unsubstituted or substituted with one or more groups independently selected from alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, -NR1R2, - NR1COR2, -NR1C (O) NR1R2, -NR1C (O) OR2, -NR1S (O) 2R2, -NR1S (O2) NR1R2, -C (O) OR1, -CONR1R2 and alkyl substituted with -NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C (O) OR2, -NR1S (O) 2R2, -NR1S (O) 2NR1R2, -C (O) OR1 or -CONR1R2; R21 is 1 to 3 portions and each R21 is independently selected from the group consisting of hydrogen, -CN, -CF3, -OCF3, halogen, -NO2, alkyl, -OH, alkoxy, alkylamino-, di- (alkyl) amino-, -NR25R26-alkyl-, hydroxyalkyl-, -C (O) OR17, -COR17, -NHCOR16, -NHS (O) 2R16, -C (NH) -NH2, - NHS (O) 2CH2CF3, -C (O) NR25R26 , -NR25-C (O) -NR25R26, -S (O) R16, -S (O) 2R16, -SR16, -SO2NR4R5 and -CONR4R5; or two adjacent R21 portions may form a methylenedioxy group; R22 is hydrogen, alkyl, phenyl, benzyl, -COR16, CONR18R19, -COR23, -S (O) R31, -S (O) 2R31, -S (O2) NR24R25 or -C (O) OR27; R23 is -C (NH2) R35R36, where R35 and R36 are independently selected from the group consisting of hydrogen, alkyl, and R37-substituted alkyl, where R37 is selected from the group consisting of HO-, HS-, CH2S -, - NH2, phenyl, p-hydroxyphenyl and indolyl; or R23 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkyl substituted with 1 to 3 substituents independently selected from the group consisting of alkoxyalkyl, alkyl, halogen, hydroxy, alkoxy, aryloxy, arylalkoxy, -NR1R2, -NR1C ( O) R2, -NR1C (O) NR1R2, -NR1C (O) OR2, -NR1S (O) 2R2, -NR1S (O) 2NR1R2, -C (O) OH, -C (O) OR1 and -CONR1R2, aryl , aralkyl, heteroaryl, heterocycloalkyl, or alkyl substituted with -NR1R2, -NR1COR2, -NR1CONR1R2, -NR1C (O) OR2, -NR1S (O2) R2, -NR1S (O2) NR1R2, -C (O) OH, -C (O) OR1, -CONR1R2 or -SO3H; R24, R25 and R26 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, hydroxy and alkoxy; R27 is 1 to 3 portions and each R27 is independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, where when R27 is alkyl or cycloalkyl, R27 is optionally substituted with -OH, -C (O) OH, halogen or alkoxy; R28 and R29 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, heterocyclyl, heterocyclylalkyl, and haloalkyl; or R28 and R29 taken together form a spirocyclic ring or a heteroespirocyclic ring having 3-6 ring atoms; R32 and R33 are independently selected from the group consisting of hydrogen, R34-alkyl, R34-alkenyl, R34-alkynyl, R40-heterocycloalkyl, R38-aryl, R38-aralkyl, R42-cycloalkyl, R42-cycloalkenyl, -OH, -OC ( O) R43, -C (O) OR43, -C (O) R43, -C (O) NR43R44, -NR43R44, -NR43C (O) R44, - NR43C (O) NR44R45, -NHS (O) 2R43, - OC (O) NR43R44, R37-alkoxy, R37-alkenyloxy, R37-alkynyloxy, R40-heterocycloalkyloxy, R42-cycloalkyloxy, R42-cyclo-alkenyloxy, R42-cycloalkyl-NH-, -NHSO2NHR16 and -CH (= NOR17); or R32 and R10 together with the carbon to which they are attached, or R33 and R11 together with the carbon to which they are attached, independently form an R42-substituted carbocyclic ring of 3-10 atoms; or an R42-substituted heterocyclic ring of 4-10 atoms where 1-3 ring members are independently selected from the group consisting of -O-, -NH- and -SO0-2-, provided that R32 and R10 form a ring, or R33 and R11 form a ring the optional double bond is absent; R42 is 1 to 3 substituents independently selected from the group consisting of hydrogen, -OH, C1-6 alkyl, C1-6 alkoxy, NH2, and halogen; or R32 and R33 combine to form a Q ring structure represented by formula (2), where R9 is hydrogen |
| priorityDate | 2005-12-22-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
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