WO2010129467A1 - Compounds and methods for inhibition of renin, and indications therefor - Google Patents
Compounds and methods for inhibition of renin, and indications therefor Download PDFInfo
- Publication number
- WO2010129467A1 WO2010129467A1 PCT/US2010/033385 US2010033385W WO2010129467A1 WO 2010129467 A1 WO2010129467 A1 WO 2010129467A1 US 2010033385 W US2010033385 W US 2010033385W WO 2010129467 A1 WO2010129467 A1 WO 2010129467A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- lower alkyl
- ethyl
- dimethyl
- fluoro
- quinolin
- Prior art date
Links
- 0 CC(C)(CC1)c(cc(*=C)c(C(C)=O)c2)c2N1C(C(F)(F)F)=O Chemical compound CC(C)(CC1)c(cc(*=C)c(C(C)=O)c2)c2N1C(C(F)(F)F)=O 0.000 description 4
- VKMKOBCFJQIETA-UHFFFAOYSA-N CCc(c(C(C)NC(OC(C)(C)C)=O)c1)cc2c1NCCC2(C)C Chemical compound CCc(c(C(C)NC(OC(C)(C)C)=O)c1)cc2c1NCCC2(C)C VKMKOBCFJQIETA-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N BrCc1ccccc1 Chemical compound BrCc1ccccc1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- VLNBFIABCPDYQL-UHFFFAOYSA-N CC(C)(C1)c(cc(c(C(C)=O)c2)Br)c2NC1=O Chemical compound CC(C)(C1)c(cc(c(C(C)=O)c2)Br)c2NC1=O VLNBFIABCPDYQL-UHFFFAOYSA-N 0.000 description 1
- FNKAVSMEVXQRIV-UHFFFAOYSA-N CC(C)(C1)c2cc(OC)ccc2NC1=O Chemical compound CC(C)(C1)c2cc(OC)ccc2NC1=O FNKAVSMEVXQRIV-UHFFFAOYSA-N 0.000 description 1
- YXZPQEYSTGXZSY-TURZUDJPSA-N CC(C)(CC(N(Cc1ccccc1)c1c2)=O)c1cc(-c1ccc(C)cc1)c2/C(/C)=N/O Chemical compound CC(C)(CC(N(Cc1ccccc1)c1c2)=O)c1cc(-c1ccc(C)cc1)c2/C(/C)=N/O YXZPQEYSTGXZSY-TURZUDJPSA-N 0.000 description 1
- JTLBSYRYIZQBST-UHFFFAOYSA-N CC(C)(CC(N(Cc1ccccc1)c1c2)=O)c1cc(-c1ccc(C)cc1)c2C(C)=O Chemical compound CC(C)(CC(N(Cc1ccccc1)c1c2)=O)c1cc(-c1ccc(C)cc1)c2C(C)=O JTLBSYRYIZQBST-UHFFFAOYSA-N 0.000 description 1
- ZCPKOTKBQCMIAD-UHFFFAOYSA-N CC(C)(CC(N(Cc1ccccc1)c1c2)=O)c1cc(Br)c2C(C)=O Chemical compound CC(C)(CC(N(Cc1ccccc1)c1c2)=O)c1cc(Br)c2C(C)=O ZCPKOTKBQCMIAD-UHFFFAOYSA-N 0.000 description 1
- DFVKRLMPOVPJJA-UHFFFAOYSA-N CC(C)(CC1)c(cc(c(C(C)=O)c2)O)c2N1C(C(F)(F)F)=O Chemical compound CC(C)(CC1)c(cc(c(C(C)=O)c2)O)c2N1C(C(F)(F)F)=O DFVKRLMPOVPJJA-UHFFFAOYSA-N 0.000 description 1
- SJWLJYAMETUKAB-UHFFFAOYSA-N CC(C)(CC1)c2cc(OC)ccc2N1C(C(F)(F)F)=O Chemical compound CC(C)(CC1)c2cc(OC)ccc2N1C(C(F)(F)F)=O SJWLJYAMETUKAB-UHFFFAOYSA-N 0.000 description 1
- BDUBTLFQHNYXPC-UHFFFAOYSA-N CC(C)=CC(Cl)=O Chemical compound CC(C)=CC(Cl)=O BDUBTLFQHNYXPC-UHFFFAOYSA-N 0.000 description 1
- DTNQTWGDJIOYFP-UHFFFAOYSA-N CC(c(cc1N(Cc2cc(C)ncc2)CCC(C)(C)c1c1)c1-c1ccc(C)cc1)N Chemical compound CC(c(cc1N(Cc2cc(C)ncc2)CCC(C)(C)c1c1)c1-c1ccc(C)cc1)N DTNQTWGDJIOYFP-UHFFFAOYSA-N 0.000 description 1
- BQAAVOQNLPIOKX-UHFFFAOYSA-N CC(c1cc(N(Cc2ccccc2)C(CC2(C)C)=O)c2cc1-c1ccc(C)cc1)N Chemical compound CC(c1cc(N(Cc2ccccc2)C(CC2(C)C)=O)c2cc1-c1ccc(C)cc1)N BQAAVOQNLPIOKX-UHFFFAOYSA-N 0.000 description 1
- HWQXKRBJJHQVGT-KTKRTIGZSA-N CC/C(/C)=C\C(Nc(cc1)ccc1OC)=O Chemical compound CC/C(/C)=C\C(Nc(cc1)ccc1OC)=O HWQXKRBJJHQVGT-KTKRTIGZSA-N 0.000 description 1
- BYTLWWRUMSXZNL-UHFFFAOYSA-N CC1(C)c2cc(OC)ccc2NCC1 Chemical compound CC1(C)c2cc(OC)ccc2NCC1 BYTLWWRUMSXZNL-UHFFFAOYSA-N 0.000 description 1
- BWPBFXDEXNVTMV-UHFFFAOYSA-N CCc(c(C(C)=O)c1)cc(C(C)(C)CC2)c1N2N Chemical compound CCc(c(C(C)=O)c1)cc(C(C)(C)CC2)c1N2N BWPBFXDEXNVTMV-UHFFFAOYSA-N 0.000 description 1
- HNJGQNYKTQQBGG-UHFFFAOYSA-N CCc(c(C(C)N)c1)cc(C(C)(C)CC2)c1N2NC(NC)=O Chemical compound CCc(c(C(C)N)c1)cc(C(C)(C)CC2)c1N2NC(NC)=O HNJGQNYKTQQBGG-UHFFFAOYSA-N 0.000 description 1
- BKLZWXHBWJYJMT-UHFFFAOYSA-N CCc(c(C(C)N)c1)cc2c1N(CC1CCOCC1)CCC2(C)C Chemical compound CCc(c(C(C)N)c1)cc2c1N(CC1CCOCC1)CCC2(C)C BKLZWXHBWJYJMT-UHFFFAOYSA-N 0.000 description 1
- DGRRUUOJUVURSS-UHFFFAOYSA-N CCc(c(C(C)NC(OC(C)(C)C)=O)c1)cc2c1N(CC1CCOCC1)CCC2(C)C Chemical compound CCc(c(C(C)NC(OC(C)(C)C)=O)c1)cc2c1N(CC1CCOCC1)CCC2(C)C DGRRUUOJUVURSS-UHFFFAOYSA-N 0.000 description 1
- DAHFNKOGCSHXDC-UHFFFAOYSA-N CCc(cc1C(C)(C)CC2)c(C(C)N)cc1N2C(c1cnccc1)=O Chemical compound CCc(cc1C(C)(C)CC2)c(C(C)N)cc1N2C(c1cnccc1)=O DAHFNKOGCSHXDC-UHFFFAOYSA-N 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N COc(cc1)ccc1N Chemical compound COc(cc1)ccc1N BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- YPNIUIRSYZWQBO-UHFFFAOYSA-N Cc1ccc(BO)cc1 Chemical compound Cc1ccc(BO)cc1 YPNIUIRSYZWQBO-UHFFFAOYSA-N 0.000 description 1
- MQLFSPBSNWUXSO-UHFFFAOYSA-N ICC1CCOCC1 Chemical compound ICC1CCOCC1 MQLFSPBSNWUXSO-UHFFFAOYSA-N 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N OC(c1cnccc1)=O Chemical compound OC(c1cnccc1)=O PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- compounds are provided, as well as various salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof. Also contemplated in accordance with the present invention are methods for the use of the compounds in treating renin-mediated diseases and conditions.
- the use of compounds for therapeutic methods involving inhibition of renin are provided, hi certain embodiments, the compounds are used for therapeutic methods involving inhibition of renin activity, including treatment of a variety of indications, including, but not limited to, hypertension,
- compounds are of Formula I, Formula Ia or Formula Ib, as described below.
- R 1 is selected from the group consisting of lower alkyl, cycloalkyl. heterocycloalkyl, aryl and hetcroaryl, wherein lower alkyl is optionally substituted with one or more substituents R 25 , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents R 26 ;
- R 2 and R 3 arc independently hydrogen, lower alkyl, -R 16 , or -[C(R l7 R l s )] a -L 2 -[C(R 19 R 20 )] b -R 16 , wherein lower alkyl is optionally substituted with one or more substituents R 27 ; or
- R 2 and R " combine with the carbon to which they are bound to form a 3-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl. lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino. di-alkylamino, and cycloalkylamino; a is 1 , 2, or 3; b is O, 1 , 2, or 3;
- L is a bond, -O-, -S-, -N(R 13 )-, -C(O)-N(R 13 )-, -N(R 13 )-C(O), -C(S)-N(R 13 )-, -N(R 13 )-C(S)-, -S(O)-N(R 13 )-, -S(O) 2 -N(R 13 )-, -N(R I3 )-S(O), -N(R 13 )-S(O) 2 , -N(R 13 )-C(O)-N(R 13 )-, -N(R I3 )-C(S)-N(R 13 )-, or -N(R 13 )-S(O) 2 -N(R 13 )-;
- R 4 is -R 21 Or -L 3 -R 21 ;
- L 3 is -0-, -S-, or -N(R 13 )-;
- R 21 is -(CR 22 R 23 ) p -R 24 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents
- R 29 is 1 , 2, 3, 4, 5 or 6;
- R 5 , and R 6 are independently hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, phenyl, or benzyl, wherein the phenyl ring of phenyl or benzyl is optionally substituted with one or more substituents R' ⁇ ;
- R 7 and R 8 are independently hydrogen, fluoro, lower alkyl, fluoro substituted lower alkyl, phenyl, or benzyl, wherein the phenyl ring of phenyl or benzyl is optionally substituted with one or more substituents R 31 ; or
- R 7 and R 8 together form oxo
- R 10 , R 1 ', R 12 , and each R 22 and R 23 arc independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl; or
- R 9 and R 10 combine with the carbon to which they arc bound to form a 3-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic helerocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -Oil, -NII 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio. fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; each R 13 is independently hydrogen or lower alkyl;
- R 14 and R 15 are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl
- R 16 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R 28 ;
- R' 7 , R 1& , R 19 , and R 20 are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl; or any two R 17 and R 18 on the same carbon, or any two R 19 and R 20 on the same carbon, combine with the carbon to which they are bound to form a 3-7 membered cycloalkyl or a 5-7 mcmbcrcd monocyclic heterocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino
- R 24 is selected from the group consisting of hydrogen, fluoro, -O-R 32 , -S-R 34 , -N(R 32 )-R 33 , -C(O)-R 34 , -C(S)-R 34 , -S(O)-R 34 , -S(O) 2 -R 34 , -C(O)-O-R 32 , -C(O)-N(R 32 )-R 33 , -C(S)-N(R 32 )-R 33 , -S(O)-N(R 32 )-R 33 , -S(O) 2 -N(R 32 )-R 33 , -N(R 35 )-C(O)-R 34 , -N(R 35 )-C(S)-R 34 , -N(R 35 )-S(O)-R 34 , -N(R 35 )-S(O) 2 -R 34 , -
- lower alkylthio fluoro substituted lower alkylthio, mono-alkylammo, di-alkylamino. cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 26 , R 23 , R 29 , R 10 or R 31 , or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -CN, -NO 2 , -O-R 42 , -S-R 44 , -N(R 42 VR 43 , -N(R 15 VC(O)-R 44 , -N(R 35 VS(O) 2 -R 44 , -C(O)-R 44 , -S(O)-R 44 , -S(O) 2 -R 44 , -C(O)-O-R 42 .
- halogen lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; or any two R 26 , any two R 28 , any two R 29 , any two R 30 , or any two R 31 , on adjacent ring atoms, combine to form a fused ring selected from the group consisting of 3-7 membered cycloalkyl and 5-7 membered heterocycloalkyl, wherein the 3-7 membered cycloalkyl or 5-7 membered heterocycloalkyl are optionally substituted with one or more halogen, -OH, -NH 2 , oxo, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio,
- each R 32 , R 33 , R 39 and R 40 is independently selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy.
- R n , R" or R 40 , or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -CN, -NO 2 , -O-R 42 , -S-R 44 , -N(R 42 )-R 43 , -N(R 3 ⁇ -C(O)-R 44 , -N(R 35 )-S(O) 2 -R 44 , -C(O)-R 44 , -S(O)-R 44 , -S(O) 2 -R 44 , -C(O)-O-R 42 , -C(O)-O-R 42 , -C(O)-N(R 42 )-R 43 , -S(O) 2 -N(R 42 )-R 43 , oxo, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; each R
- each R 44 is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted low er alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkyl amino, and cycloalkylammo, and wherein heterocycloalkyl and heteroaryl are optionally substituted w ith one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy and each R 44 is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, flu
- L 1 is a bond, -C(R 9 R 10 )-, -C(O)-, -C(R 9 R 1 ⁇ -C(R 11 R 12 )-, -C(R 9 R 10 )-C(O)-, or -C(O)-C(R 1 1 R 12 ), preferably -C(R 9 R 10 )- or -C(R 9 R ⁇ )-C(R 1 1 R 12 )-, and R 1 is phenyl or monocyclic heteroaryl, wherein phenyl or monocyclic heteroaryl are optionally substituted with one or more substituents R 26
- Y is -C(R 14 R 15 )- and R 14 and R 15 are independently lower alkyl or fluoro substituted low er alkyl
- L 4 is a bond, -C(R 55 R 56 )-, -C(O)-, -C(R 55 R ifl )-C(R 57 R 58 )-, -C(R 55 R 56 )-C(O)-, or -C(O)-C(R 57 R 58 );
- R 43 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. wherein lower alkyl is optionally substituted with one or more substituents R' 0 , and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents R 7 ;
- R 46 and R 47 are independently hydrogen, lower alkyl, or -[C(R 59 R 60 )] c -R 61 , wherein lower alkyl is optionally substituted with one or more substituents R' 2 ; or
- R 46 and R 47 combine with the carbon to which they are bound to form a 3-7 membered cycloalkyl or a 5-7 membered monocyclic heterocycloalkyl, wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; c is O, 1 , 2, 3, 4, or 5;
- R 4 ⁇ is -R 62 or -L 5 -R 62 ;
- L 4 is -O-, -S-, or -N(R 63 )-; q is 1 , 2, 3, 4, 5 or 6;
- R 49 and R 50 arc independently lower alkyl or fluoro substituted lower alkyl
- R 51 and R 52 are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl
- R 53 and R 54 are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl; or
- R 53 and R 54 together form oxo
- R 55 , R 56 , R 57 , R 58 , and each R 59 , R 60 , R 64 and R 65 are independently hydrogen, fluoro, lower alkyl, or fluoro substituted lower alkyl; or
- R 61 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R 7j ;
- R 62 is -(CR 64 R 65 ) q -R 66 , cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R 74 ; each R 63 is independently hydrogen or lower alkyl;
- R 66 is independently selected from the group consisting of hydrogen, fluoro, -O-R 57 , -S-R M , -N(R 67 )-R 68 , -C(O)-R 69 , -C(S)-R 69 , -S(O)-R 69 , -S(O) 2 -R 69 , -C(O)-N(R 67 )-R 68 , -S(O) 2 -N(R 67 )-R 6S , -N(R 63 )-C(O)-R 69 , -N(R 63 )-S(O) 2 -R 69 , cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R' 4 ; each R' c and R 72
- lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 71 , R 73 or R 74 , or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -CN, -NO 2 , -0-R 8!
- each R 69 and R 80 is independently selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro. lower alkoxy.
- a compound or group of compounds includes salts of such compound(s) (including pharmaceutically acceptable salts), formulations of such compound(s) (including pharmaceutically acceptable formulations), conjugates thereof, derivatives thereof, forms thereof, prodrugs thereof, and all stereoisomers thereof.
- a compound of Formula I includes all sub-embodiments thereof (e.g. including Formula Ia, Formula Ib and all embodiments as described above).
- the compound is selected from the group consisting of l -[7-(l-Amino-cth>l)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-qumohn-l->lJ-2-methoxy-ethanone
- methods for treating or prophylaxis of a rerun-mediated disease or condition m an animal subject in need thereof wherein the method involves administering to the subject an effective amount of any one or more compound(s) of Formula I
- treat 'therapy,' and like terms refer to the administration of material, e g , one or more compound(s) of Formula I in an amount effective to prevent, alleviate, or ameliorate one or more symptoms ot a disease or condition, i e , indication, and/or to prolong the survival of the subject being treated
- renin-mediated disease or condition refers to a disease or condition in which the biological function of renin affects the development, course, and or symptoms of the disease or condition, and/or in which inhibition of the renin activity alters the development, course and ⁇ or symptoms of the disease or condition
- a renm-medutcd disease or condition includes a disease or condition for v, hich inhibition of renin provides a therapeutic
- methods for treating or prophylaxis of a renm-mediated disease or condition in an animal subject m need thereof, wherein the method involves administering to the subject an effective amount of a composition including any one or more compound(s) of Formula I
- the invention provides a kit that includes any one or more compound(s) of Formula I, or a composition thereof as described herein
- the composition is packaged, e g , m a vial, bottle, flask, which may be further packaged, e g , withm a box, envelope, or bag, the composition is approved by the U S Food and Drug Administration or similar regulatory agency for administration to a mammal, e g , a human, the composition is approved for administration to a mammal, e g , a human, for a renm-mediated disease or condition
- the invention kit includes written instructions for use and/or other indication that the composition is suitable or approved for administration to a mammal, e g , a human, for a renm-mediated disease or condition, and the composition is packaged m unit dose or single dose form, e g , single dose pills, capsules, or the like
- the invention provides methods for treating or prophylaxis of a renm- mediated disease or condition m an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more compound(s) of Formula I, or an effective amount of a composition including any one or more compound(s) of Formula I, wherein the disease or condition is. for example, without limitation
- Cardiovascular and cardiovascular-related diseases including, but not limited to, hypertension, essential hypertension, malignant hypertension, pulmonary hypertension, atherosclerosis, congestive heart failure, coronary artery disease myocardial infarction cardiac hypertrophy, cardiac fibrosis, ischemic or hemorrhagic stroke, stenosis of arteries, restenosis after angioplasty or other interventions, myocarditis, cardiomyopathy (e g diabetic cardiac myopath), post-mfarction cardiac myopathy), arrhythmia (e g supraventricular and ventiicular arrhvthmia atrial fibrillation and atrial flutter), myocardial ischemia, cardiac insufficiency, unstable coronary syndrome, det ⁇ mental vascular remodeling, angma (stable or unstable), diastolic dysfunction, left ventricular dysfunction, and abnormal vascular growth;
- cardiomyopathy e g diabetic cardiac myopath
- post-mfarction cardiac myopathy post-mfarction cardiac myopathy
- Pulmonary-i elated diseases including, but not limited to, chronic obstructive pulmonary disease, cor pulmonale, bronchiectasis, acute respiratory distress syndrome, acute lung injury, asthma, bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia, cystic fibrosis, idiopathic pulmonary fibrosis, connective tissue or autoimmune disease-related pulmonary fibrosis (e.g.
- scleroderma resulting from scleroderma, systemic lupus erythematosus, rheumatoid arthritis, or polymyositis
- hypersensitivity pneumonitis eosinophilic granuloma (Langerhan's cell histiocytosis), chronic eosinophilic pneumonia, Wegener's granulomatosis, idiopathic pulmonary hemosiderosis, lymphangioleiomyomatosis, silicosis, asbestosis, berylliosis, sarcoidosis, systemic sclerosis, atypical pneumonia, Pneumocystis pneumonia, Hamman-Rich syndrome, histiocytosis X, collagen vascular disease, granulomatous vasculitis, Goodpasture's syndrome, Hermansky-Pudlak syndrome, pulmonary alveolar proteinosis, lung cancer, and tuberculosis;
- Vasculitis and autoimmune disease and related tissue fibrosis including, but not limited to, fibrosis caused by sclerodactyly, scleroderma, amyloidosis, systemic scleiosis, dermatomyositis, dupytren's contracture, Peyronie's disease, polymyositis, amyloidosis, atrophoderma of Pasini and Pierini, Raynaud's phenomenon, Still's disease, eosinophilic fasciitis, Hutchmson-Gilfoid progeria syndrome, Lichen myxedematosus, mixed connective tissue disease, morphoea, porphyria cutanea tarda type 1 , scleredema adultorum, systemic sclerosis or lymphangitis carcinomatosis;
- Nephiopathies including, but not limited to, diabetic nephropathy, IgA nephropathy, Fabry nephropathy, renal fibrosis, nephritis, lupus nephritis, glomerulonephritis, glomerular sclerosis, renal vascular hypertension, hyperaldosteromsm, chronic kidney disease, renal insufficiency, renal ischemia, renal failure, and renal colic;
- Liver diseases including, but not limited to, hepatocellular carcinoma, liver fibrosis, liver cirrhosis, and hepatitis;
- Diabetes and complications resulting from diabetes including, but not limited to, nephropathy, vasculopathy, neuropathy, and diabetic retinopathy, and
- Other diseases including metabolic syndrome, obesity, thyroiditis, gast ⁇ tis, peptic ulcer, inflammatory bowel syndrome (e.g. ulcerative colitis, Crohn's disease), multiple sclerosis, rheumatoid arthritis, osteoarthritis, osteoporosis, endometriosis, preeclampsia, brain infarction, interstitial cystitis, pancreatitis, pancreatic cancer, erectile dysfunction, proteinuria, albuminuria, cognitive impairment, alzheimer's disease, dementia, anxiety states, cognitive di soi dei s, inci eased intraocular pressure, glaucoma, angiogenesis related disorders (e g.
- the invention provides methods for treating or prophylaxis of a renin- mediated disease or condition m an animal subject in need thereof, wherein the method involves administering to the subject an effective amount of any one or more compound(s) of Formula I, or an effective amount of a composition including any one or more compound(s) of Formula I, m combination with one or more other therapies for the disease or condition
- the one or more other therapies include, for example, without limitation angiotensin converting enz>me (ACE) inhibitors, including but not limited to, benazepril, cilazap ⁇ l, captop ⁇ l, delap ⁇ l, cnalap ⁇ l, iosinop ⁇ l, lndolap ⁇ l, lismop ⁇ l, meoxrpril, pe ⁇ ndop ⁇ l, pivop ⁇ l, quinapril, ramip ⁇ l, rescinnamine, spirap ⁇ l, trandola
- ACE angiotensin converting
- eplerenone ethacrvnic acid, furosemide, hydrochlorothiazide, mdacrmone mdapamide, mefruside, metolazone, spironolactone, torasemide, tricrynafen and triamterene
- sympatholytics including, but not limited to, clomdme, dobutamine, guanabenz, guanethidine, guanfacme, indoramin, lofexidine, mecamylamme, methyldopa, moxomdme, reserpme, ⁇ lmemdme, t ⁇ methaphan, and urapidil
- serotonin receptor antagonists including but not limited to ⁇ sce bclo ⁇ j, thromboxane-synthetase inhibitors, neutral endopeptidase inhibitors (NEP inhibitors), renin inhibitors, including, but not limited to
- agents suitable for treating inflammatory bowel syndrome including, but not limited to, corticosteroids, 6-mercaptopu ⁇ ne, mesalamme, and TNF anatogonists (including, but not limited to, adalimumab, etanercept, and infliximab), agents suitable for treating diabetes and complications associated with diabetes, including, but not limited to, benzafibrate, c ⁇ rofibratc, clofibrate, fenofibrate.
- agents suitable for treating cystic fibrosis including, but not limited to, alendronate, dornase alfa, denufosol, fluticasone, inhaled sodium bicarbonate, miglustat, and perfemdone
- agents suitable for treating pulmonary fibrosis including, but not limited to, azathiop ⁇ ne, budesomde, cyclophosphamide, dapsonc, dexamethasone, etanercept, lmatimb, interferon gamma- Ib, interferon alpha-2b minocycline, prednisone, methylpredmsolone, and thalidomide
- agents suitable tor treating COPD including, but not limited to, advair and llovcnt
- agents suitable for treating liver fibrosis including, but not limited to, adefo ⁇
- the invention provides a method of treating or prophylaxis of a disease or condition in an animal subject in need thereof, by administering to the subject a therapeutically effective amount of any one or more compound(s) of Formula I, a prodrug of such compound, a pharmaceutically acceptable salt of such compound or prodrug, or a pharmaceutically acceptable formulation of such compound or prodrug
- the compound can be alone or can be part of a composition
- the in ⁇ ention provides a method of treating or prophylaxis of a disease or condition in an animal subject in need thereof, by administering to the subject a therapeutically effective amount of any one or more compound(s) of Formula I, a prodrug of such compound a pharmaceutically acceptable salt of such compound or prodrug or a pharmaceutically acceptable formulation of such compound or prodrug m combination with one or more other suitable therapies for the disease or condition
- a compound of Formula I will have an IC 50 of less than 500 nm, less than I UO nM, less than 50 nM less than 20 nM less than 10 nM, less than 5 nM or less than 1 nM as determined in a generally accepted renin activity assay
- the compound selectn ely inhibits renin relative to other enzymes, including, but not limited to, selectivity of the compound relative to other proteases, whether a protease discussed herein, or other proteases
- the selectivity is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100- fold more active on renin than any other aspartyl protease, including, but not limited to, any of pepsin, cathepsm-D or BACF
- Selective inhibition of renin relative to another protease is such that the IC JO for the renin may be at least about 2-fold, also 5-fold, also 10-
- Halogen refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I)
- Lower alkyP alone or in combination means an alkane-de ⁇ ved radical containing fiom 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl
- the straight chain or branched lower alkyl group is chemically feasible and attached at any available point to provide a stable compound
- a lower alkyl is a straight or branched alkyl group containing from 1-6, 1-4, or 1 -2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like
- Lower alkyl that is ' optionally substituted denotes lower alkyl that is optionally independently substituted, unless indicated otherw ise, with one or more, preferably 1 2 1 4 or 5, also 1 2, or 3 -,ubstituents as indicated for example in the description of compounds ol Formula I
- possible substitutions include subsets of these substitution
- C>cloalkyl refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like
- Cycloalkyl that is "optionally substituted” denotes cycloalkyl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents as indicated, for example, m the description of compounds of Formula I It is understood that any substitutions are chemically feasible and attached at any available atom to provide a stable compound
- Heterocycloalkyl refers to a saturated or unsaturated non-aromatic cycloalkyl group having from 5 to 10 atoms m which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally fused w ith benzo or heteroaryl of 5-6 ring members Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, suit onyl and N-oxide of a tertiary ⁇ ng nitrogen Heterocycloalkyl is also intended to include compounds in which a ⁇ ng carbon may be oxo substituted, i e the ring carbon is a carbonyl group, for example as found in lactones and lactams The point of attachment of the heterocycloalkyl ring is chemically feasible, at a carbon or nitrogen atom, such that a stable compound is provided Examples of heterocycloalkyl groups include, but are not
- Aryl alone or in combination refers to a monocyclic or bicyclic ⁇ ng system containing aiomatic hydrocarbons such as phenyl or naphthyl, which may be optionally fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members ⁇ ryl that is “optionally substituted " denotes aryl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3. 4 or 5. also 1.
- Heteroaryl alone or in combination refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1 -3, even more preferably 1 -2, heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.
- heteroaryl groups include, but arc not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, t ⁇ a/olyi, furanyl, benzofuryl, and indolyl.
- Heteroaryl that is "optionally substituted” denotes heteroaryl that is optionally independently substituted, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents as indicated, for example, in the description of compounds of Formula I. It is understood that substitutions are chemically feasible and attached at any available atom to provide a stable compound.
- Lower alkoxy denotes the group -OR a , where R a is lower alkyl.
- Lower alkoxy that is “optionally substituted” denotes lower alkoxy in which R d is lower alkyl optionally independently substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I.
- substitution of lower alkoxy is with 1 , 2, 3, 4, or 5 substituents, also 1 , 2, or 3 substituents.
- fluoro substituted lower alkoxy denotes lower alkoxy in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkoxy is substituted with 1 , 2, 3, 4 or 5 fluoro atoms, also 1 , 2, or 3 fluoro atoms. It is understood that any substitutions on alkoxy are chemically feasible and attached at any available atom to provide a stable compound.
- Lower alkylthio denotes the group -SR , where R b is lower alkyl.
- Lower alkylthio that is “optionally substituted” denotes lower alkylthio in which R h is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I.
- substitution of lower alkylthio is with 1 , 2, 3, 4, or 5 substituents, also 1 , 2, or 3 substituents.
- fluoro substituted lower alkylthio denotes lower alkylthio in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkylthio is substituted with 1 , 2, 3, 4 or 5 fluoro atoms, also 1 , 2, or 3 fluoro atoms. It is understood that any substitutions on alkylthio are chemically feasible and attached at any available atom to provide a stable compound.
- Amino denotes the group -NH;.
- Mono-alkylamino denotes the group -NHR 0 where R c is lower alkyl.
- Di-alkylamino denotes the group -NR c R d , where R c and R d are independently lower alkyl,
- Cycloalkylamino denotes the group -NR 6 R', where R e and R f combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocycloalkyl may contain an additional heteroatom withm the nng, such as O, N, or S, and may also be further substituted with lower alkyl Examples of 5-7 membered heterocycloalkyl include, but are not limited to, pipe ⁇ dine, piperazmc, 4-methylpiperazme, morphohne, and thiomorphohne It is understood that when mono-alkylamino, di-alkylamino, or cyclo
- animal subject refers to human and non-human vertebrates, e g mammals, such as non-human primates sports and commercial animals, e g , equines, bovines, porcines, ovmes, rodents, and pets, e g , canines and felines
- solid form refers to a solid preparation (i e a preparation that is neither gas nor liquid) of a pharmaceutically active compound that is suitable for administration to an intended animal subject for therapeutic purposes
- the solid form includes any complex, such as a salt, co-crystal or an amorphous complex, as well as any polymorph of the compound l he solid form may be substantially crystalline, semi-crystallme or substantially amorphous
- the solid form may be administered directly or used in the preparation of a suitable composition having improved pharmaceutical properties
- the solid form may be used in a formulation comprising at least one pharmaceutically acceptable carrier or excipient
- substantially crystalline material embraces material which has greater than about 90% crystallmity, and "crystalline” material embraces material which has greater than about 98% crystallmity
- substantially amorphous material embraces material which has no more than about 10% crystallmity, and "amorphous” material embraces material which has no more than about 2% crystallmity
- a mixture of solid forms of a compound may be prepared, for example, a mixture of amorphous and crystalline solid foims, e g to provide a "semi-cry stalhne" solid form
- a ' semi-crystallme' solid form may be prepared by methods known in the art for example by mixing an amorphous solid form with a crystalline solid form in the desired ratio
- a compound mixed with acid or base forms an amorphous complex
- a semi-crystallme solid can be prepared employing an amount of compound component in excess of the stoichiomctry of the compound and acid or base in the amorphous complex
- the term "complex” refers to a combination of a pharmaceutically active compound and an additional molecular species that forms or produces a new chemical species m a solid form
- the complex may be a salt, i e where the additional molecular species provides an acid/base counter ion to an acid/base group of the compound resulting in an acid base interaction that forms a typical salt While such salt forms are typically substantially crystalline, they can also be partially cry stalline, substantially amorphous, or amorphous forms
- the additional molecular species, in combination with the pharmaceutically active compound forms a non-salt co-crystal, i e the compound and molecular species do not interact by way of a typical acid base interaction, but still form a substantially crystalline structure
- Co-crystals may also be formed from a salt of the compound and an additional molecular species
- the complex is a substantially amorphous complex, which may contain salt-like acid base interactions that do not form
- the term "stoichiometry" refers to the molar ratio of two or more reactants that combine to form a complex, for example, the molar ratio of acid or base to compound that form an amorphous complex
- a l l mixture of acid or base with compound (i e 1 mole acid or base per mole of compound) resulting in an amorphous solid form has a 1 1 stoichiometry
- composition refers to a pharmaceutical preparation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically active compound, including any solid form thereof
- the composition may include at least one pharmaceutically acceptable component to provide an improved formulation of the compound, such as a suitable earner or excipient
- pharmaceutically acceptable indicates that the indicated material does not have properties that would cause a reasonabl ⁇ prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration For example, it is commonly required that such a material be essentially sterile, e g , for injectibles
- the term "therapeutically effective” or “effective amount” indicates that the mate ⁇ als or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated
- the terms “synergistically effective” or “synergistic effect” indicate that two or more compounds that are therapeutically effective, when used in combination, provide improved therapeutic effects greater than the additive effect that would be expected based on the effect of each compound used by itself
- inhibitor is used to refer to a decrease the activity of a target biomolecule, e g , an enz>me such as a protease
- an inhibitor will be a small molecule, i e a compound with a molecular weight of 1500 daltons or less, or preferably 1000 daltons or less, 800 daltons or less, or 600 daltons or less
- a compound that inhibits renin a renin inhibitor
- renin will decrease the activity of renin, for example, the compound will reduce the conversion by renin of angiolensmogen to angiotensin 1
- Renin is an endopeptidase of approximately 40 kDa that is produced and secreted by the juxtaglomerular cells of the kidney, and circulates through the blood It is also produced locally m tissues, including, but not limited to brain, heart vasculature, adipose tissue, adrenal glands, pancreas, placenta and kidney, as well as m mast cells, and thus is active in a variety of tissues Renin specifically cleaves angiotensmogen, a naturally occurring plasma glycoprotein, to form angiotensin I Angiotensin-convertmg enzyme (ACE) acts m the lungs kidneys, or other tissues to cleave angiotensin T, forming angiotensin II Angiotensin II constricts blood and acts to release aldosterone from the adrenal gland, resulting in a significant increase in blood pressure I
- ACE Angiotensin-convertmg enzyme
- Renin inhibitors may also be used to treat fibrosis, for example fibrotic diseases in various tissues, including liver (e g cirrhosis, as caused, for example, by viral hepatitis, schistosomiasis or alcoholism), lung (e g interstitial lung diseases, such as idiopathic pulmonary disease, sarcoidosis, silicosis, drug reactions and infections, as well as collagen vascular diseases, such as rheumatoid arthritis and systemic sclerosis), kidney (e g diabetic nephropathy), heart and vascular (e g post myocardial infarction, hypertension, atherosclerosis and restenosis), eye (e g macular degeneration, retinal and vitreal retinopathy), skin (e g keloids, hypertrophic scars, and scleroderma), pancreas (e g pancreatitis), intestine (e g inflammatory bowel disease), and brain (e g Alzheimer'
- Renin inhibitors may be useful in treating cardiovascular and cardiovascular-related diseases, such as hypertension, essential hypertension, malignant hypertension, pulmonary hypertension, atherosclerosis, congestive heart failure, coronary artery disease, myocardial infarction, cardiac hypertrophy, cardiac fibrosis, ischemic or hemorrhagic stroke, stenosis ol arteries, restenosis after angioplasty or other interventions, myocarditis, cardiomyopathy (e g diabetic cardiac myopathy, postinfarction cardiac myopathy), arrhythmia (e g supraventricular and ventricular a ⁇ hythmia, atrial fibrillation and atrial flutter), myocardial ischemia, cardiac insufficiency, unstable coronary syndrome, detrimental vascular remodeling, angina (stable or unstable), diastolic dysfunction, left ventricular dysfunction, and abnormal vascular growth, pulmonary-related diseases, such as chronic obstructive pulmonary disease, cor pulmonale, bronchiectas
- scleroderma resulting from scleroderma, systemic lupus erythematosus, rheumatoid arthritis, or polymyositis
- hypersensitivity pneumonitis eosinophilic granuloma (Langerhan s cell histiocytosis), chronic eosinophilic pneumonia, Wegener's granulomatosis, idiopathic pulmonary hemosiderosis, lymphangioleiomyomatosis, silicosis, asbestosis, berylliosis sarcoidosis, systemic sclerosis, atypical pneumonia, Pneumocystis pneumonia, Hamman-Rich syndrome, histiocytosis X, collagen vascular disease, granulomatous vasculitis.
- Goodpasture's syndrome Hermansky-Pudlak syndrome, pulmonary alveolar proteinosis, lung cancer, and tuberculosis, vasculitis and autoimmune disease and related tissue fibrosis, such as fibrosis caused by sclerodactyly, scleroderma, amyloidosis, systemic sclerosis, dermatomyositis, dupytren's contracture, Peyronie's disease, polymyositis, amyloidosis, atrophoderma of Pasini and Pierim, Raynaud's phenomenon, Still's disease, eosinophilic fasciitis, Hutchmson-Gilford progeria syndrome, Lichen myxedematosus, mixed connective tissue disease, morphoea, porphyria cutanea tarda type 1.
- Nephropathies such as diabetic nephropathy, IgA nephropathy, Fabry nephropathy, renal fibrosis, nephritis, lupus nephritis, glomerulonephritis, glomerular sclerosis, renal vascular hypertension hyperaldosteromsm, chrome kidney disease, renal insufficiency, renal ischemia, renal failure, and renal colic, liver diseases, such as hepatocellular carcinoma, liver fibrosis, liver cirrhosis, and hepatitis, diabetes and complications resulting from diabetes, such as nephropathy, vasculopathy, neuropathy, and diabetic retinopathy, and other diseases, including metabolic syndrome, obesity, thyroiditis, gastntis, peptic ulcer, inflammatory bowel syndrome (e g ulcerative colitis, Crohn's disease) multiple sclerosis, rhe
- a number of different assays for renin activity can be utilized for assaying for the ability of a compound to inhibit renin
- Such assays can be formatted either in a fluorescence resonance energy transfer (FRET) format, or using an AlphaScreen (amplified /uminescent /roximit> ⁇ omogeneuus assay) format by varying the donor and acceptor reagents accordingly
- Similar assays may be utilized for assaying the activity against other aspartyl proteases, or other proteases, in order to assess the selectivity of the compound for inhibition of renin
- FRET fluorescence resonance energy transfer
- AlphaScreen amplified /uminescent /roximit> ⁇ omogeneuus assay
- invention compounds may exist in a number of different forms or derivatives, all within the scope of the present invention
- Alternative forms or dc ⁇ vatives include, for example, (a) prodrugs, and active metabolites (b) tautomers, isomers (including stereoisomers and regioisomers), and racemic mixtures (c) pharmaceutically acceptable salts and (d) solid forms, including different crystal forms, polymorphic or amorphous solids, including hydrates and sohates thereof and other forms (a) Prodrugs and Metabolites
- the invention also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and their pharmaceutically acceptable salts
- Prodrugs are compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when converted by soholysis, yield the desired active compound
- Piodrugs include, without limitation, esters, amides, carbamates, carbonates, ureides, solvates, or hydrates of the active compound
- the prodrug is inactive, or less active than the active compound, but may provide one or more advantageous handling, administration, and/or metabolic properties
- some prodrugs are esters of the active compound, during mctabolysis, the ester group is cleaved to yield the active drug
- Esters include, for example, esters of a carboxyhc acid group, or S-acyl or O-acyl derivatives of thiol, alcohol, ur phenol groups
- a common example is an alkyl ester of a carboxyhc acid
- Some prodrugs arc activated enzymatically to yield the active compound, or a compound may undergo further chemical reaction to yield the active compound Prodrugs may
- prodrugs can be conceptually divided into two non-exclusive catego ⁇ es, bioprecursor prodrugs and carrier prodrugs
- bioprccursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis Both the active drug form and any released metabolic products should have acceptably low toxicity
- the formation of active drug compound involves a metabolic process or reaction that is one of the following types
- Oxidative reactions are exemplified without limitation by reactions such as oxidation of alcohol, carbonyl, and acid functionalities, hydroxy lation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon- carbon double bonds, oxidation of nitrogen-contammg functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O- and S-dealkylation, oxidative deamination as well as other oxidative reactions [0054] Reductive reactions Reductive reactions are exemplified without limitation by reactions such as reduction of carbonyl functionalities, reduction of alcohol functionalities and carbon-carbon double bonds, reduction of mtrogen-containmg functional groups, and other reduction reactions
- Reactions without change in the oxidation state arc exemplified without limitation to reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, new atomic linkages resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen hahde molecule, and other such reactions
- Carrier prodrugs are drug compounds that contain a transport moiety, e g , that impro ⁇ es uptake and/or localized delivery to a site(s) of action
- the linkage between the drug moiety and the transport moiety is a covalent bond
- the prodrug is inactive or less active than the drug compound
- the prodrug and any release transport moiety are acceptably non-toxic
- the transport moiety is intended to enhance uptake
- the release of the transport moiety should be rapid
- it is desirable to utilize a moiety that provides slow release, e g , certain polymers or other moieties, such as cyclodext ⁇ ns See, e g , Cheng et al , U S Patent Publ No 20040077595, App No 10/656,838, incorporated herein by reference )
- Such earner prodrugs are often advantageous for orally administered drugs
- the transport moiety provides targeted delivery of the drug
- metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives i esultmg from metabolic processes in the body of a subject
- activ e metabolites are such pharmacologically active derivative compounds
- the prodrug compound is generally inactive or of lower activity than the metabolic product
- the parent compound may be either an active compound or may be an inactive prodrug
- one or more alkoxy groups can be metabolized to hydroxyl groups while retaining pharmacologic actn itv and/or carboxyl groups can be este ⁇ fied, e g , glucuronidation
- Metabolites of a compound may be identified using routine techniques known in the art, and their activities determined using tests such as those described herein. See, e.g., Bertolini et al., 1997, J, Med. Chem. , 40:2011 -2016; Shan et al., 1997, J Pharm Sci 86(7):756-757; Bagshawe, 1995, Drug Dev. Res., 34:220-230; Wermuth, supra.
- some of the compounds according to the present invention may exist as stereoisomers, i.e. having the same atomic connectivity of covalently bonded atoms yet differing in the spatial orientation of the atoms.
- compounds may be optical stereoisomers, which contain one or more chiral centers, and therefore, may exist in two or more stereoisomeric forms (e.g. enantiomers or diastereomers).
- stereoisomers i.e., essentially free of other stereoisomers
- racemates i.e., essentially free of other stereoisomers
- stereoisomers include geometric isomers, such as cis- or trans- orientation of substituents on adjacent carbons of a double bond. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention. Unless specified to the contrary, all such steroisomeric forms arc included within the formulae provided herein.
- a chiral compound of the present invention is in a form that contains at least 80% of a single isomer (60% enantiomeric excess ("e.c") or diastereomeric excess (“d.e.”)), or at least 85% (70% c.c. or d.e.), 90% (80% e.e. or d.e.), 95% (90% e.e. or d.e.). 97,5% (95% e.e. or d.e.), or 99% (98% e.e. or d.e,).
- an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomcrically pure), and an optically pure compound having more than one chiral center is one that is both diastereomerically pure and enantiomerically pure.
- the compound is present in optically pure form, such optically pure form being prepared and/or isolated by methods known in the art (e g by recrystalhzation techniques, chiral synthetic techniques (including synthesis from optically pure starting materials), and chromatographic separation using a chiral column
- compounds of Formula I can be in the form of pharmaceutically acceptable salts, or can be formulated as pharmaceutically acceptable salts
- Contemplated pharmaceutically acceptable salt forms include, without limitation, mono, bis, t ⁇ s tctrakis, and so on
- Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect
- Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate admmiste ⁇ ng higher concentrations of the drug
- a compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly can react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt
- Pharmaceutically acceptable salts include acid addition salts such as those containing chloride, bromide, iodide, hydrochloride, acetate, dichloroacetate, phenylacetate, acrylate, ascorbate, aspartate, benzoate, 2-phenoxybenzoate, 2-acetoxyben7oate dimtrobenzoate, hydroxybenzoatc, methoxybenzoate, methylbcnzoatc, bicarbonate, butyne-1 ,4 dioate, hexyne-l,6-dioate, caproate, caprylate, chlorobenzoate, cinnamate, citrate, decanoate, formate, fumarate, glycolate gluconate, glucarate, glucuronate, glucose-6-phosphate, glutamate, heptanoate, hexanoate, lsethionate, isobutyrate, gamma-hydroxybutyrate, phenylbutyrate,
- salts can be prepared by standard techniques For example, the free-base form of a compound can be dissolved m a suitable solvent, such as an aqueous or aqueous- alcohol solution containing the appropriate acid and then isolated by evaporating the solution In another example, a salt can be prepared by reacting the free base and acid in an organic solvent If the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid w ith an appropriate inorganic or organic base
- the pharmaceutically acceptable salt of the different compounds may be present as a complex
- ot complexes include 8-chlorotheophylhne complex (analogous to, e g , dimenhydrmate diphenhydramine 8-chlorotheophyllme (1 1) complex, Dramamine) and various cyclodext ⁇ n inclusion complexes
- the compounds and salts may exist in different crystal or polymorphic forms, or may be formulated as co- crystals, or may be in an amorphous form, or may be any combination thereof (e g partially crystalline, partially amorphous, or mixtures of polymorphs) all of which are intended to be within the scope of the present invention and specified formulae
- salts are formed by acid/base addition, i e a free base or free acid of the compound of interest forms an acid/base reaction with a corresponding addition base or addition acid, respectively resulting in an ionic charge interaction
- co- crvstals are a new chemical species that is formed between neutral compounds, resulting in the compound and an additional molecular species in the same crystal structure
- compounds of the invention are complexed with an acid or a base, including base addition salts such as ammonium, diethylamme, ethanolamme ethylenediamme, diethanolamme t-butylamme piperazme meglumine acid addition salts such as acetate, acetylsalicylate, besylate, camsylate, citrate, formate, rumarate, glutarate, hydrochlorate, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate and tosylate and amino acids such as alanine, argimne, asparagme, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidme, isoleuune, leucine, lysine methionine, phenylalanine, proline, serine, threonine, tryp
- the formulae are intended to cover hydrated or solvated as well as unhydrated or unsolvated forms of the identified structures
- the indicated compounds include both hydrated and non-hydrated forms
- Other examples of solvates include the structures in combination with a suitable solvent, such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamme
- the methods and compounds will typically be used in therapy for human subjects However, they may also be used to treat similar or identical indications in other animal subjects
- Compounds of Formula I can be administered by different routes, including injection (i c parenteral, including intravenous, intraperitoneal, subcutaneous, and intramuscular), oral, transdermal, transmucosal, rectal, or inhalant
- Such dosage forms should allow the compound to reach target ctlls
- Other factors are well known in the art, and include considerations such as toxicity and dosage forms that retard the compound or composition from exerting its effects
- Techniques and formulations generally may be lound in Remington The Science and Practice of Pharmacy, 2 ⁇ ⁇ edition, Lippmcott, Williams and Wilkins, Philadelphia, PA, 2005 (hereby incorporated by reference herein)
- compositions will comprise pharmaceutically acceptable earners or excipients, such as fillers binders, dismtegrants, ghdants, lubricants, complexmg agents, solubihzers, and surfactants, which may be chosen to facilitate administration of the compound by a particular route
- carriers include calcium carbonate, calcium phosphate, vanous sugars such as lactose glucose, or sucrose, types of starch, cellulose derivatives, gelatin, lipids, liposomes, nanoparticleb and the like
- Carriers also include physiologically compatible liquids as solvents or for suspensions, including, for example, sterile solutions of water for injection (WFI), saline solution, dextrose solution, Hank's solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like
- Excipients may also include, for example, colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium a
- oral administration may be used
- Pharmaceutical preparations for oral use can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops
- Compounds of Formula I may be combined with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e g aqueous, alcoholic, or oily solutions) and the like
- Suitable excipients are, in particular, fillers such as sugars including lactose glucose, sucrose, mannitol or sorbitol cellulose preparations for example, corn starch, wheat starch, rice starch, potato starch gelatin gum tragacanth, methyl cellulose, h>droxypropylmethyl-cellulose, sodium carbox>methylcellulose (CMC), and/or polyvinylpyrrolidone (PVP po
- compositions that can be used orally include push-fit capsules made of gelatin (“gelcaps”), as well as soft, scaled capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol
- the push-fit capsules can contain the active ingredients in admixture w ith filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stcaratc and, optionally, stabilizers
- the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols
- injection parenteral administration
- Compounds of Formula I for injection may be formulated m ste ⁇ le liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution Dispersions may also be prepared in non-aqueous solutions, such as glycerol, propylene glycol, cthanol, liquid polyethylene glycols, t ⁇ acetin, and vegetable oils Solutions may also contain a preservative, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like
- the compounds may be formulated m solid form, including, for example, lyophihzed forms, and redissolved or suspended pnor to use
- transmucosal, topical or transdermal administration may be used in such formulations of compounds of Formula I penetrants appropriate to the barrier to be permeated are used
- penetrants include, for example, for transmucosal administration, bile salts and fusidic acid derivatives Ln addition detergents may be used to facilitate permeation
- Transmucosal administration for example, may be through nasal sprays or suppositories (rectal or vaginal)
- Compositions of compounds of Formula I for topical administration may be formulated as oils, creams, lotions, ointments, and the like by choice of approp ⁇ ate carriers known in the art Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal tats and high molecular weight alcohol (greater than C u )
- carriers are selected such that the active ingredient is soluble Emulsifiers, stabilize
- compounds are administered as inhalants
- Compounds of Formula I may be formulated as dry powder or a suitable solution, suspension, or aerosol Powders and solutions may be formulated with suitable additives known in the art
- powders mav include a suitable powder base such as lactose or starch
- solutions may comprise propylene glycol, sterile water, ethanol sodium chlonde and other additives, such as acid, alkali and buffer salts
- Such solutions or suspensions may be administered by inhaling via spray, pump, atomizer, or nebulizer, and the like
- the compounds of Formula I may also be used in combination with other inhaled therapies, for example corticosteroids such as fluticasone prop ⁇ onate, beclomethasone dipropionate, triamcinolone acetonide, budesomde, and mometasone furoate, beta agonists such as albuterol, salmeterol, and formoterol, anticholinergic agents such as ipratroprium
- the amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound activity (in vitro, e g the compound IC 5 0 vs target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e g biological half-life or bioavailability), the age, size, and weight of the subject, and the disorder associated with the subject.
- factors such as the compound activity (in vitro, e g the compound IC 5 0 vs target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e g biological half-life or bioavailability), the age, size, and weight of the subject, and the disorder associated with the subject.
- a dose will be m the range of about 0 01 to 50 mg/kg, also about 0 1 to 20 mg/kg of the subject being treated Multiple doses may be used
- the compounds of Formula I may also be used in combination with other therapies for treating the same disease Such combination use includes administration of the compounds and one or more other therapeutics, at different times or co-administration of the compound and one or more other therapies
- dosage may be modified foi one or more of the compounds of the invention or other therapeutics used m combination, e g , reduction in the amount dosed relative to a compound or therapy used alone, by methods well known to those of ordinary skill in the art
- use in combination includes use with other therapies drugs, medical procedures e f c where the other therapy or procedure may be administered at different times (e g withm a short time, such as withm hours (e g 1, 2, 3 4-24 hours), or within a longer time (e g 1-2 days.
- the present invention provides for delivery of a compound of formula I and one or more other drug therapeutics delivered by a different route of administration or by the same route of administration
- the use in combination for any route of administration includes delivery of a compound of Formula I and one or more other drug therapeutics delivered by the same route of administration together in any formulation, including formulations where the two compounds are chemically linked in such a way that they maintain their therapeutic activity when administered
- the mass spectrometry result indicated foi a compound may have more than one value due to the isotope distribution of an atom m the molecule, such as a compound having a bromo or chloro substituent
- Example 1 Preparation of l-(6-ethyl-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-7-yl)-ethanone 9.
- Step 2 Preparation of6-ethvl-4,4-dimethyl-3,4-dihydr ⁇ -lH-qu ⁇ n ⁇ Hn-2- ⁇ ne (4): [0085] To a solution of 3-methyl-but-2-enoic acid (4-ethyl-phenyl)-amide (3, 164.4 g, 0.809 mol theoretical) in 1.6 L of 1 ,2-dichlorobenzene, aluminum trichloride (162 g, 1.21 mol) was added. The reaction mixture was stirred at 100 0 C for 2 hours, allowed to cool to room temperature and poured into 7 L of ice water.
- the aqueous layer was extracted with 1 L of ethyl acetate and the pooled organic layers were dried over sodium sulfate, filtered and the filtrate concentrated under vacuum.
- the resulting material was purified by silica gel column chromatography, eluting with a gradient of 0-50% ethyl acetate in heptane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a clear oil (5, 50 g, 77%).
- Step 4 Preparatoin oj l-(6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-l-yl)-2,2,2-trifluoro- ethanone (7):
- Step 5 Preparation of l-(7-acetyl-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-l-yl)-2,2,2- trifluoro-ethanone (8):
- Step 6 Preparation of 1 ' -(6-ethyl-4,4-dimethyl-l ,2,3 ,4-ietrahydr ⁇ -quinolin-7-yl)-ethanone (9): [0089] To a solution of 10% potassium hydroxide in 5 mL of methanol, l -(7-acetyl-6-ethyl-4,4- dimethyl-3,4-dihydro-2H-quinolin-l-yl)-2,2,2-trifluoro-ethanone (8, 107 mg, 0.327 mol) was added.
- Example 2 Alternative preparation of l-(6-ethyl-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-7- yl)-ethanone 9.
- l-(6-Ethyl-4,4-dimethyl-l ,2,3,4-tetrahydro-quinolin-7-yl)-ethanone 9 was prepared in five steps from l-(6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-l-yl)-2,2,2-trifluoro-ethanone 7 as shown in Scheme 2.
- Step 1 Preparation of ' 1 ' -( ' / '-brom ⁇ -6-ethyl-4 ⁇ 4-dimethyl-3 ,4-dihydro-2H-quinolin-l -yl)-2,2 ',2- trifluoroethanone (10):
- Step 2 Pt eparation of 7-bromo-6-ethyl-4 4-d ⁇ methvl-l 2 3 4-tet ⁇ ahydr oquinohne (11) 10092]
- Step 3 Piepatation of 7-bi omo-6-ethyl-4 4- ⁇ methyl-3 4 dihydro 2 H qumohne 1 carboxyhc acid tert-butyl ester (13)
- Step 5 Preparation of l-(6-ethyl-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (9): [0095] To a solution of 7-acetyl-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinoline-l -carboxylic acid tcrt-butyl ester (14, 1.40 g. 0.00422 mol) in 35 mL of dichloromethane, 8.0 mL of 4 M hydrogen chloride in 1,4-dioxane was added. The reaction mixture was stirred at room temperature for 0.5 hours, then concentrated under vacuum.
- Example 3 Preparation of [l-(6-ethyI-4,4-dimethyI-l,2,3,4-tetrahydro-quinoIin-7-yI)-ethyI]- carbamic acid tert-butyl ester 17.
- Step 1 Preparation of l-(6-ethyl-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-7-yl)-ethanone oxime (15):
- Step 3 Preparation of[l-(6-ethyl-4,4-dimethyI-l,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]-carbamic acid tert-butyl ester (17):
- Example 4 Preparation of l-[6-ethyl-l-(2-methoxy-ethyl)-4,4-dimethyl-l,2,3,4-tetrahydro- quinolin-7-yl]-ethylamine P-0002.
- Step 1 Preparation of l-[6-ethyl-l-(2-meth ⁇ y-ethyl)-4,4-dimethyl-l,2,3,4-te ⁇ rahydro-quinolin-7-yl]- ethanone (19)
- Step 2 Preparation of 1 -[6-cthyl- 1 -(2-methoxy-ethyl)-4, 4-dimethyl-l,2, 3, 4-tetrahydr ⁇ -quinolin-7-yl]- ethanone oxime (20):
- Step 3 Preparation of l-[6-ethyl-l-(2-mcthoxy-ethyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-7-ylJ- ethylamine (P-0002):
- Step 1 Preparation of [l-(6-ethyl-4,4-dimethyl-l-pyridin-3-ylmethyl-l,2,3,4-tetrahydroquinoHn- 7- yl) -ethyl] -carbamic acid tert-butyl ester (22):
- Step 2 Preparation of l-(6-ethyl-4,4-dimethyl ⁇ l-pyridin-3-ylmethyl-l,2, 3,4 ⁇ tetrahydroquinolin-7-vl)- ethylamine fP-0010):
- Step Ia Preparation of ⁇ l-[6-ethyl-4,4-dimethyI-]-(3-trifluoromethy!-bcn ⁇ yl)-l,2,3,4-tetrahydro- quinolin-7-yl]-ethyl ⁇ -carbam ⁇ c acid tert-butyl ester (22a):
- Step 2a Preparation of l-[6-ethyl-4,4-dimethyl-1 -(3-trifluoromethyl-benzyl)-l,2,3,4-tetrahydro- quinolin- 7 -yl] -ethyl amine (P-0026):
- Step Ih Preparation ⁇ f ⁇ l-[6-ethyl-4A-dimethyl-l-(2-methyl-pyridin-4-ylmethyl)-l,2,3,4-tctrahvdro quinolin-7-yl]-eth ⁇ i ⁇ -carbamic acid tert-butyl ester (22b):
- the vial was centrifuged to remove the silica, and the supernatant transferred to a new vial.
- the silica residue was washed with 500 ⁇ L of ethanol, centrifuged and the supernatants combined. The solvents were removed under vacuum and the residue used in the next step without further purification.
- Step 2b Preparation ofl-[6-ethvl-4,4-dimethyl-l-(2-methyl-pyridin-4-ylmethyl)-l,2,S,4-tetrahycln>- quinolin-7-yl] -ethylamine (P-0037):
- reaction conditions may have varied, for example, in terms of solvents used, time and temperature of the reaction, and in chromatography conditions for purification of the desired compounds, with the compound number in Column 1, the aryl-alkyl halidc or aryl-aldehyde used in Step 1/la/lb in Column 2, the resulting compound in
- Step 1 Preparation of l-(l-benzyl-6-ethyl-4,4-dimethyl-l,2,3,4-tetrahydro-quhwlin-7-y!-etha ⁇ o ⁇ e (24):
- the mixture was diluted with ethyl acetate, and the organic layer was washed with brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum.
- the crude material was purified by silica gel chromatography to provide the desired compound as a light yellow oil (24, 590 mg, 90%).
- Step 3 Preparation ofl-ben ⁇ yl-6-ethy1-7-(l ⁇ hydroxyimino-ethyl)-4,4-dimethyl-3,4-dihydro-lH- qmnolin-2-one (26):
- Step 4 Preparation of 7-(l-amino-ethyl)-l-benzyl-6-ethyl-4,4-dimethyl-3,4-dihydro-lIl-quinolin-2- one (P-0052):
- Example 7 Preparation of l-(l-benzyl-6-ethyl-4,4-dimethyI-l,2,3,4-tctrahydro-quinolin-7-yl)- propylamine P-0047.
- Step 1 Preparation of l-(l-benzyl-6-ethyl-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-7-yl)-propan-l- one (27):
- Step 2 Preparation of 1 -(I -benzyl-6-ethyl-4,4-dimethyl-l ,2,3,4-tetrahydro-quinolin-7-yI)-propan-l - one oxime (28):
- Step 3 Preparation of l-(l-ben ⁇ yl-6-ethyl-4,4-dimethyl-l, 2,3,4- -tetrahydro-quinolin-7-yl)- propylamine (P-0047):
- Example 8 Preparation of trifluoro-methanesulfonic acid 7-acetyl-4,4-dimethyl-l -(2,2,2- trifluoro-acetyl)-l,2,3,4-tetrahydro-quinolin-6-yl ester 35.
- Trifluoro-methanesulfonic acid 7-acetyl-4,4-dimcthyl-l -(2,2,2-trifluoro-acetyl)-l ,2,3,4- tetrahydro-quinolin-6-yl ester 35 was prepared in six steps from 4-methoxybenzenamine 29 as shown in Scheme 8.
- Step I Preparation of i-methyl-but-2-enoic acid (4-methoxy-phenyl)-amide (30): [0127] To a chilled (0 0 C) mixture of 4-methoxybenzenamine (29, 2.50 g, 20.3 mmol) and sodium hydroxide (2.0 g, 51 .0 mmol) in 20 mL of water and 30 mL of dichloromethane, 3,3-dimethylacryloyl chloride (2, 2.7 mL, 24,0 mmol) was added over a period of -5 minutes, The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution.
- the aqueous layer was washed 3x with ethyl acetate and the pooled organic layer was washed with ammonium chloride solution and brine, then dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under vacuum.
- the resulting brown oil was purified by silica gel column chromatography eluting with a gradient of 0-7% methanol in dichloromethane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound as a tan waxy solid (30, 3.78g, 91 %).
- Step 2 Preparation of6-methoxy-4,4-dimethyl-3, 4-dihydro-lH-qu ⁇ nolin-2-one (31): [0128] Aluminum trichloride (19.1 g, 143 mmol) was suspended in 300 mL of nitromethane and 3-methyl-but-2-enoic acid (4-mcthoxy-phenyl)-amide (30, 9.5 g, 46.0 mmol) was added dropwise over a period of ⁇ 5 minutes. The reaction mixture was stirred under an inert atmosphere overnight. Ice was added piece-by-peice to quench the reaction and the mixture was partitioned between ethyl acetate and water.
- Step 3 Preparation of 6-methoxy-4,4-dimethyl-l ,2,3,4-tetrahydro-quinoline (32): [0129] To a solution of 6-meth ⁇ xy-4,4-dimethyl-3,4-dihydro-l H-quinolin-2-one (31, 2.0 g, 9.7 mmol) in 150 mL of toluene, borane-dimethyl sulfide complex (1.7 mL, 19.0 mmol) was slowly added at 0 0 C. The reaction mixture was stirred at 0 0 C for 15 minutes and then stirred at 100 0 C for 2 hours. The reaction mixture was cooled to room temperature and poured into 150 mL of 10% sodium carbonate solution.
- the mixture was stirred at room temperature for 30 minutes.
- the organic layer was collected and the aqueous layer was extracted with 2 x 60 mL of ethyl acetate.
- the organic layers were combined and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum.
- the crude material was purified by silica gel chromatography to provide the desired compound as a light brown liquid (32, 1.2g, 64%).
- Step 5 Preparation of l-(7-acetyI ⁇ 6 ⁇ hydroxy-4,4-dimethyl-3,4-dihydro-2H-quinoHn-l-yl)-2,2,2- tnfluoro-ethanone (34):
- Step 6 Preparation oj tnfluoro-methane sulfonic acid 7-acetyl-4,4-d ⁇ methvl-l-(2,2,2-tr ⁇ uoro- acetylJ-1,2 3 4-tetrahydro-qu ⁇ nol ⁇ n-6-yl ester (35)
- Example 9 Preparation of l-[l-be ⁇ zyl-6-(4-fluoro-phenyl)-4,4-dimethyI-l,2,3,4-tetrahydro- quinolin-7-yI]-ethylainine P-0044.
- Step 1 Preparation of l-[7-acetyl-6-(4-fluoro-phenyl)-4,4-dimethyl-3,4-dihydro-2H-quinolin-l-yl]- 2,2,2-trifluoro-ethanone (37):
- reaction mixture was warmed to 70 0 C for 80 minutes via microware irradiation.
- the reaction mixture was diluted with ethyl acetate and the organic layer washed with brine, dried over magnesium sulfate, Filtered, and purified by silica gel chromatography to provide the desired compound (37, 46 mg, 70%).
- MS (ESI) [M ⁇ H 1 J * 393.95.
- Step 2 Preparation of l-[6-(4-fluoro-phenyI)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-7-yl]- ethanone (38):
- Step 3 Preparation of l-[l-benzyl-6-(4-fluoro-phenyl)-4,4-d ⁇ methyl-I,2,3,4-tetrahydro-quinolin-7- vl] -ethanone (39):
- Step 4 Preparation ⁇ f l-[l-benzyl-6-(4- ⁇ uoro-phenyI)-4,4-dime ⁇ hyl-l,2,3,4-tetrahydro-qninoIin-7- y!] -ethan ⁇ ne oxime (40):
- Step 5 Preparation of 1 -[I -benzyl-6-(4-fluoro-phenyl)-4,4-dimethyl-! ,2,3,4-tetrahydro-quinolin-7- ylj-ethy!amine (P-0044):
- Additional compounds may be prepared similarly to the protocol of Scheme 9, replacing 4- fluorophenylboronic acid 36 with an appropriate boronic acid or boronic acid ester in Step 1.
- Purification for the last step was alternatively done by HPLC, using Phenomenex Cl 8 column with 20-100% solvent B gradient over 40 minutes, with flow rate of 20 mL/minute, Solvent A was water with 0.1 % trifluoroacetic acid and solvent B was acetonitrile with 0.1 % trifluoroacetic acid.
- Step Ia Preparation of l-[6-(3-ethyJ-phenyl)-4,4-dimethyl- 1,2,3, 4-tetrahydr ⁇ -q ⁇ dnolin-7-yl]- ethano ⁇ e (38a):
- Example 10 Preparation of l-(l-Benzyl-6-benzyloxy-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin- 7-yl)-ethylamine P-0060.
- Step 2 Preparation of l-(6-benzyloxy-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (42): [0143] Into a 1-neck round-bottom flask, l -(7-acetyl-6-benzyloxy-4,4-dimethyl-3,4-dihydro-2II- quinolin-l -yl)-2,2,2-trifluoro-ethanone (41, 550 mg, 1.35 inmol) and 1 N potassium hydroxide (1.5 mL, 1.5 mmol), were mixed in 25 mL of methanol.
- Step 3 Preparation of 1 ' -(l-ben ⁇ yl-6-benzyl ⁇ xy-4 ,4-dimethyl-l ,2 ⁇ 3 ,4-tetrahydro-quinolin-/ " 7 -y0- ethanone (43):
- Step 4 Preparation of l-(l-benzyl-6-benzyloxy-4, 4-dimethyl-l,2,3,4-tetrahydro-quinolin-7-yl)- ethanone oxime (44):
- Step 5 Preparation of 1 '-(I -benzyl- ⁇ -benzyloxy-4 ',4-dimethyl- 1 ,2 ',3 ' ,4-tetrahydro-quinolin-/' '-yl)- ethylamine (P-0060):
- Step 1 Preparation of 2-methyl-isonicotinic acid pentafluorophenyl ester (47): [0148] To a suspension of 2-methyl-isonicotinic acid (45, 2,74 g, 20 mmol) and pcntafluorophenol (46, 3.7 g, 20 mmol) in 100 mL of anhydrous tetrahydrofuran, N,N'-diisopropylcarbodiimide (3, 1 niL, 20 mmol) was added. The mixture was stirred at room temperature overnight, then filtered through a pad of Celite. The filtrate was collected and used in the next step without further purification.
- Example 12 Preparation of l-[4,4-dimethyl-l-(2-methyl-pyridin-4-ylmethyl)-6-p-tolyl-l,2,3,4- tetrahydro-quinolin-7-yl]-ethylamine P-0062.
- Step 1 Preparation of I-(4,4-dimethyl-6-p-tolyl-l,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (50): [0152] Into a solution of trifluoromethanesulfonic acid 7-acetyl-4,4-dimethyl-l -(2,2,2-trifluoro- acety])-l ,2,3,4-tetrahydro-quinolin-6-yl ester (35, 100 mg, 0.20 mmol) in 3 mL of tetrahydrofuran in a microwave reaction vial, 4-toluene boronic acid (49, 61 mg, 0.45 mmol) and tetrakis(triphenylphosphine)palladium (0) ( ⁇ 2 mg, catalyst) were added.
- 4-toluene boronic acid 49, 61 mg, 0.45 mmol
- reaction mixture was warmed to 70 0 C for 20 minutes via microware irradiation.
- the reaction mixture was diluted with ethyl acetate and the organic layer washed with brine, dried over magnesium sulfate, filtered, and the filtrate purified by silica gel chromatography to provide the desired compound (50, 28 mg, 42%).
- MS (ESI) [M+HT - 294.3.
- Step 2 Preparation of l-[4,4-dimethyl-I-(2-methyl-pyridin-4-ylrnethylj-6-p-tolyl-1.2,3,4-tetrahydro- quinolin- 7-ylJ-ethun ⁇ ne (51):
- Step 4 Preparation of l-[4,4-dimethyl-l-(2-methyl- ⁇ yridin-4-ylmethyl)-6-p-tolyl-l,2,3,4-tetrahydro- quinolin- 7-ylJ-ethylamine (P-0062):
- Step 1 Preparation of l ⁇ (7-acetyl- ⁇ -ethyl-4,4-d ⁇ methyl-3,4-dihydro-2H-quinolin-I-yl)-2-methoxy ⁇ ethanone (54):
- Step 2 Preparation of l-(6-ethyl-7-(l-hydroxyimino-ethyl)-4,4-dimethyl-3,4-dihydro-2H-quinoHn-l- yl)-2-meth ⁇ xy-ethanone (55):
- Step 3 Preparation of l-[7-(l-amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-l-ylJ-2- methoxy-ethanone (P-OOOl):
- Example 14 Preparation of 7-(l-amino-ethyl)-l-(3-methoxy-propy])-4,4-di ⁇ iethyl-6-p-tolyl-3,4- dihydro-lII-quinolin-2-one P-0040 and l-[l-(3-methoxy-propyl)-4,4-diinethyl-6-p-tolyl-l,2,3,4- tetrahydro-quinolin-7-yl]-ethylamine P-0043.
- Step 1 Preparation of 3-methyl-but-2-enoic acid (3 -ethyl -phenyl) -amide (57): [0161] To a mixture of 3-ethylaniline (56, 20.00 g, 0.16 mol) and sodium hydroxide (16 g, 0.41 mol) in 160 mL of water and 100 mL of dichloromethane, a solution of 3,3-dimcthylacryloyl chloride (2, 22 mL, 0.20 mol) in 50 mL of dichloromethane was slowly added at __5 0 C. The reaction mixture was then stirred at room temperature for 16 hours, then poured into 400 mL of water and extracted with dichloromethane.
- Step 2 Preparation of " / '-ethyl-4 ' -,4-dimethyl-3 ',4-dihydro-l ' H-quinolin-2-onc (58): [0162] To a suspension of aluminum trichloride (13.1 g. 98,4 mmol) in 50 mL of 1 ,2- dichl ⁇ robenzene, a solution of 3-methyl-but-2-enoic acid (3-ethyl-phenyl)-amide (57, 10 g, 49.19 mmol) in chlorobenzcnc was added dropwisc at 0-10 0 C.
- Step 3 Preparation of6-bromo-7-ethyl-4,4-dimethyl-3,4-dihydro-lH-quino1m-2-one (59): [0163] To a solution of 7-ethyl-4,4-dimethyl-3,4-dihydro-l H-quinolin-2-one (58, 3.0 g, 15.0 mmol) in 100 ml of nitromethane, bromine (0.84 rnL, 16.0 mmol) was added dropwise, followed by aluminum trichloride (100 mg, 0.7 mmol).
- Step 4 Preparation of 7-acetyl-6-bromo-4,4-dimethyl-3,4-dihydro-lH-quinolin-2-one (60): [0164] To a mixture of 6-bromo-7-ethyl-4,4-dimethyl-3,4-dihydro-lH-quinolin-2-one (59, 1 g, 3 mmol) in 50 ml of dichloromethane, a premixed fine powder of potassium permanganate (4 g, 20.0 mmol) and copper(II) sulfate pentahydratc (6 g, 20.0 mmol) were added. The reaction mixture was gently refluxed for 72 hours, and then filtered through a Celite pad.
- Step 5 Preparation of 7-acetyl-6-bromo-l-(2-methoxy-ethyl)-4,4-dimethyl-3,4-dihydro-lH-quinolin- 2-one (62):
- Step 6 Preparation of 7-acetyl-l-(3-methoxy-propyl)-4,4-dimethyl-6-p-tolyl-3,4-dihvdro-lH- quinolin-2-one (63) -
- Step 7 Preparation of7- ⁇ l-[(E)-hydroxyimino]-ethyl ⁇ -l-(3-methoxy-propyl)-4,4 ⁇ dimethyl-6-p-tolyl- 3, 4-dihydro-lH-quinolin-2-one (64):
- Step 8a Preparation of7-(l-amino-ethyl)-l-(3-methoxy-pr ⁇ pyl)-4,4-dimethyl-6-p-tolyl-3,4-dihydro- lH-quinolin-2-one (P-0040):
- Step 8h Preparation of L (I buty!-4,4 ⁇ diniethy/-6-p-tofyI ⁇ l,2,3,4-tetrahydro-quinolin-7-yl)- ethylamine (P-0043):
- Step 1 Preparation f l-[6-ethyl-l-(3-methoxy-propyl)-4,4-d ⁇ methyl-l ,2,3, 4-tetrahydro-quinolin-7 - yl] -ethanone (65):
- Step 2 Preparation of 7-acetyl ⁇ 6 ⁇ ethyl ⁇ l ⁇ (3-methox) ⁇ -propy l)-4,4-dimethyl-3,4-dihydro-lH- quinolin-2-one (66):
- Step 3 Preparation of6-ethyl-7- ⁇ l-[(E)-hydroxyimino]-ethyl ⁇ -l-(3-methoxy-propyl)-4,4-dimethyl- 3, 4-dihydro-lH-quinolin-2-one (67):
- Example 16 Preparation of [7-(l-amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin- l-y]]-pyridi ⁇ -3-yl-methanone P-0018.
- Step I Preparation of ⁇ l-[6-ethyl-4,4-dim ⁇ thyl-l-(pyridine-3-carbonyl)-l,2, 3, 4-tetrahydro-quinolin- 7-yl]-ethyl ⁇ -carbamic acid tert-butyl ester (69):
- Step 2 Preparation of[7-(l-amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinolin-l- ⁇ I]- pyridin-3-yl-methanone (P-0018):
- Example 17 Preparation of l-[l-(2,2-difluoro-benzo[l,3]dioxol-5-ylmethyI)-6-ethyI-4,4- dimethyl-l,2,3,4-tetrahydro-quinolin-7-yl]-ethylamine P-0038.
- Step 1 Preparation of ⁇ l-[ l ⁇ (2,2-difluoro-benzo[ 1 ,3] dioxol-5-ylmethyl)-6-ethyi-4,4-dimethyl- l,2,3,4-tetrahydro-quinolin-7-yl]-ethyl ⁇ -carbamic acid tert-butyl ester (71):
- Step 2- Preparation of l-[l-(2,2-difluoro-benzo[l,3]diox ⁇ l-5-ylmethy1)-6-ethyl-4,4-dhnethyl-L2,3, 4- tetrahydro-quinolin- 7-yl] -ethylamine (P-0038).
- Example 18 Preparation of l-[6-ethyl-4,4-dimethyl-l-(tetrahydro-pyran-4-ylmethyl)-l,2,3,4- tetrahydro-qui ⁇ olin-7-yl]-ethylamine P-0058.
- Step 1 Preparation of ⁇ l-[6-ethyl-4,4-dimethyl-l-(tetrahydro-pyran-4-ylmethyl)-l,2,3,4-tetrahydro- quinolin-7-yl]-ethyl ⁇ -carbamic acid tert-hutyl ester (73):
- Step 2 Preparation of l-[6-ethyl-4,4-dimethyl-l-(tetrahydro-pyran-4-ylmethyl)-l,2,3,4-tetrahydro- quinolin- 7-yl] -ethylamine (P-0058):
- Example 19 Preparation of 7-(l-amino-ethyl)-6-ethyl-4,4-dimethyl-l-(2-methyl ⁇ pyridin-4- ylmethyl)-3,4-dihydro-lH-quinolin-2-one P-0061.
- Step 1 Preparation of ⁇ l-[6-ethyl-4,4-dimethyl-l -(2-methyl-pyridin-4-ylmethyl)-l ,2,3,4-tetrahydro- quir ⁇ oIin-7-ylJ-ethylj-carbamic acid tert-butyl ester (74):
- Step 2 Preparation ⁇ f ⁇ l-[6-ethyl-4,4-dimethyl-l-(2-methy l-pyridin-4-ylmethyl)-2-oxo- 1 ,2 ,3 ,4 - tetrahydro-quinolin-'/ 7 -yl] ' -ethyl ⁇ -carbamic acid tert-butyl eater (75):
- Step 3 Preparation of7-(l-amin ⁇ -ethyl)-6-ethyl-4,4-dimethyl-l-(2-methyl-pyridin-4-ylmethyl)-3,4- dihydro-lH-quinolin-2-one (P-0061):
- Step 4 Preparation of6-acetyl-7-ethyl-4H-benzo[l,4]oxazin-3-one (81): [0193] To aluminium chloride (229 mg; 1.7 mmol), cooled in an ice water bath, 52 ⁇ L of dimethylformamide was added dropwise. The mixture was stirred at 10 0 C for 1 hour, then heated to 50 0 C. To this mixture, 7-ethyl-4H-benzo[l ,4]oxazin-3-one (80, 50 mg, 0.28 mmol) was added, followed by 28 ⁇ L of acetyl chloride.
- the mixture was stirred at 50-70 0 C for 20 minutes, then cooled down to room temperature and the melt was taken up in 1 mL of toluene and quenched with 3 g of ice. The mixture was stirred for 30 minutes until all of the ice melted. The mixture was extracted 2 x 5 mL with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by flash silica gel column chromatography, eluting with dichloromethane and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a pale yellow solid (81, 6 mg, 10%)
- Step 5 Preparation of 6-acetyl-7-ethyl-4-(3-methoxy-propyl)-4H-benzo[ 1 ,4] ⁇ xazin-3-one (82) [0194] To 6-acetyl-7-ethyl-4H-benzo[l ,4]oxazin-3-one (81, 120 mg, 0.55 mmol) in 6 mL of acetonit ⁇ le, l -bromo-3-methoxy -propane (61, 210 mg, 1.37 mmol), potassium fluoride on alumina (412 mg, 2.84 mmol), and potassium iodide (5 mg, 0.03 mmol) were added.
- Step 6 Preparation of 7 -ethyl ⁇ 6- ⁇ l -[(E)-hy ⁇ roxyimin ⁇ ] -eihyl ⁇ -4-(3-methoxy-propyl)-4H- be ⁇ zofl, 4j 'oxazin-3-one (83):
- Step 7 Preparation of6-(l-amino-ethyl)-7-ethyl-4-(2-methoxy-ethyl)-4H-benzo[l,4]oxazin-3-one (P-OO 71):
- Example 21 Preparation of l-(6-ethyl-4,4-di ⁇ iethyH-phenyl-l,2,3,4-tetrahydro-quinolin-7-yl)- ethylamine P-0070.
- Step 1 Preparation of l-(6-ethyl-4, 4-dimethyl-l -phenyl- 1 ,2,3, 4-tetrahydro-q ⁇ inolin-7-yl)-ethanone
- Step 2 Preparation of l-(6-ethvl-4 4-dimethyl-l-phenyl-l l 2,3,4-tetrahydro-quinolin-7-vl)-ethanone oxime (86)
- Step 3 Preparation of I (6 ethyl-4,4-d ⁇ methyl-l-phenyl-l,2,3,4-tet>ahydro-qu ⁇ nol ⁇ n-7-yl)-ethylarmne (P-0070)
- Step 1 Preparation of 7-bromo-6-ethyl-l-(3-methoxy-propyl)-4 4-d ⁇ methyl- 1,2,3, 4-tetrahydro- quinoline (87)
- Step 2 Preparation of6-ethyl-l-(3-methoxy-propyl) ⁇ 4,4-d ⁇ methyl ⁇ l,2,3,4 ⁇ tetrahydro-qu ⁇ nol ⁇ ne-7- carbonitrile (88)
- Example 23 Preparation of 7-(l-amino-ethyl)-6-methoxy-l-(3-methoxy-propyl)-4,4-dimethyl- 3,4-dihydro-lH-quinolin-2-one P-0013.
- Step 1 Preparation of6-methoxy-4,4-dimethyl-3,4-dihydro-lH-quinolin-2-one (90) '
- Aluminum trichloride (10.4 g, 77.9 mmol) was suspended in 100 mL of 1 ,2-dichloroethane and 3-methyl-but-2-enoic acid (4-methoxy-phenyl)-amide (89, 5.16 g, 25.1 mmol) was added dropwise over a period of ⁇ 5 minutes.
- the reaction mixture was stirred under an inert atmosphere for 4 hours and partitioned between ethyl acetate and water.
- Step 2 Preparation of 7-acetyl-6-methoxy-4,4-dimethyl-3,4-dihydro-l H-quinolin-2-one (91): [0208] To a suspension of aluminum trichloride (2.9 g, 22.0 mmol) in 8 ml of nitromethane, chilled to 0 0 C, a solution of acetyl chloride (0.48 mL, 6.8 mmol) and 6-methoxy-4,4-dimethyl-3,4- dihydro-1 H-quinolin-2-one (90, 1 ,00 g, 4,87 mmol) in 10 mL of dichloromethane was added dropwise.
- Step 4 ' Preparation of 7- ⁇ l-[(E)-hydroxyimino]-ethyl ⁇ -6-methoxy-l-(3-methoxy-propyl)-4,4- dimethyl-3, 4-dihydro- 1 H-quinolin-2-one (93): j0210[ ⁇ solution of 7-acetyl-6-methoxy-l -(3-methoxy-propyl)-4,4-dimethyl-3,4-dihydro-lH- quinolin-2-one (92, 38 mg, 0.12 mmol), hydroxylamme hydrochloride (16.9 mg, 0.243 mmol), and pyridine (0.046 mL, 0.57 mmol) in 5 mL of ethanol was stirred at 80 U C for 2 hours.
- Step 5 Preparation of 7-(l-amino-ethyl)-6-methoxy-l-(3 ⁇ methoxy-propy!)-4,4-ditnethyl-3,4-dihydro ⁇ lH-quinolin-2-one (P-OOH):
- the reaction mixture was cooled down and poured into 150 mL of 10% aqueous sodium carbonate solution. The mixture was stirred at room temperature for 30 minutes. The organic layer was removed and the aqueous layer extracted with 2 x 60 mL of ethyl acetate. The organic layers were combined and dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (P-0013, 12 mg).
- Example 24 Preparation of l-[l-(3-methoxy-propyl)-4,4-dimethyl-6-phenyl-l,2,3,4-tetrahydro- quinolin-7-ylJ-ethylamine P-0021.
- Step I Preparation of l-(4,4-dimethyl-6-phenyl-l,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (94): [0213J Into a round bottom flask, trifluoro-methanesulfonic acid 7-acetyl-4,4-dimethyl-l -(2,2,2- trifluoro-acetyl)-1.2.3,4-tetrah ⁇ dr ⁇ -quin ⁇ lm-6-yl ester (34 ing, 0.076 mmol).
- Example 25 Preparation of l-(l-benzyl-4,4,6-trimethyl-l,2,3,4-tetrahydro-quinolin-7-yl)- ethylamine P-0076.
- Step 1 Preparation of4,4 l 6-Trime,thyl-3,4-dihydro-lH ⁇ q ⁇ nolin ⁇ 2- ⁇ ne (98).
- Aluminum trichloride (1 1 g, 84.0 mmol) was suspended in 30 mL of nitromcthane and 3- methyl-but-2-enoic acid p-tolylamide (97, 5.3 g, 28.0 mmol, prepared similarly to step 1 of Scheme 1 , substituting 4-ethylanilint; 1 with p-tolylamine) was added p ⁇ rtionwise over a period of ⁇ 5 minutes.
- the reaction mixture was stirred under an inert atmosphere at 80 0 C for 12 hours, then partitioned between ethyl acetate and water. The organic layer was collected and the aqueous layer was washed additional 3x with ethyl acetate. The organic fractions were pooled and washed with water, aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting yellow oil was purified by silica gel column chromatography eluting with ethyl acetate and hexane. The appropriate fractions were combined and solvents removed under vacuum to provide the desired compound as an off-white solid (98, 705 mg). 1 H NMR was consistent with the compound structure. Additional material was prepared similarly for the next step.
- Step 5 Preparation of ' 7-hromo-4,4,6-tr imethyl- 1 2 3 4-tetrahy ⁇ o-qu ⁇ nol ⁇ ne (102)
- Step 6 Preparation of l-benzyl-7-htomo-4,4 6-ti ⁇ methvl-l 2,3,4-tetrahyd ⁇ o-quinohne (103)
- Step 7 Preparation of l-(l-henzyl-4,4,6-tnmethyl-l,2,3,4-tetrahydro-q ⁇ nohn-7-yl)-ethanone (104)
- l-Benzyl-7-bromo-4,4,6-t ⁇ methyl-l , 2,3,4-tetrahydro-qumolme (103, 177 0 mg, 0 514 mmol)
- l,3-bis(diphenylphosphmo)propane 13 mg, 0 032 mmol
- potassium carbonate 73 2 mg, 0 530 mmol
- t ⁇ butyl-(l-ethoxy-vinyl)-stannane (0 61 mL, 1 8 mmol
- palladium acetate 3 0 mg, 0 013 mmol) in 1 0 mL of water and 3 0 ml of N,N-dimethylfo ⁇ iamide under nitrogen and heated at 80 0
- Step 8 Preparation of l-(l-benzyl-4,4, 6-tr ⁇ methyl-l ,2,3,4-tetrahydro-qu ⁇ nohn 7-yl) ethanone oxime
- Step 1 Preparation of7-acetyl-l-benzyl-6-bromo-4,4-dimethyl-3,4-dihydro-lH-quinolin-2-one (106):
- Step 2 Preparation of 7-acetyl-l-benzyl-4,4-dimethy ⁇ -6-p-tolyl-3,4-dihydro-lH-quinolin-2-one (108):
- Step 3 Preparation of l-benzyl-7- ⁇ l-[(E)-hydroxyimino]-ethyl ⁇ -4,4-dimethyl-6-p-tolyl-3,4-dihydro- 1 H-quinolin-2-one (109):
- Step 4 Preparation of 7-(l-amino-ethyl)-l-ben ⁇ yl-4,4-dimethyl-6-p-tolyl-3,4-dihydro-lH-quin ⁇ Iin-2- one (P-0078):
- Step 2 Preparation of 7-(l-amino-ethyl)-6-ethyl-4,4-dimethyl-3,4-dihydro-2H-quinoline-l- carboxylic acid tert-butyl ester (P-0069):
- Example 28 Synthesis of Compounds where L 1 is -S(O) 2 - or -S(O) 2 NH-.
- a mixture of sulfonyl chloride of Formula II (R is e.g. NHR 1 or R ! , where R 1 is as defined in paragraph [0003]), [l-(6-ethyl-4,4-dimethyl-l ,2,3,4-tetrahydro-quinolin-7-yl)-ethyl]-carbamic acid fert-butyl ester (17), and an appropriate base, such as triethyl amine in an appropriate solvent, such as dichloromethane is stirred at 20-80 0 C for 2-24 hours. The reaction is quenched with an aqueous work-up and purified by silica gel chromatography or crystallization to provide Compounds of Formula III.
- a compound of Formula III is stirred in a suitable solvent, such as dioxane, tetrahydrofuran or dichloromethane with a suitable acid, such as hydrochloric acid, trifluoroacetic acid, or tosic acid at 0-80 0 C for 0,25-24 hours.
- a suitable solvent such as dioxane, tetrahydrofuran or dichloromethane
- a suitable acid such as hydrochloric acid, trifluoroacetic acid, or tosic acid at 0-80 0 C for 0,25-24 hours.
- the reaction mixture is quenched with aqueous base and purified by silica gel chromatography or crystallization to provide a compound of Formula IV.
- Example 29 Synthesis of Compounds where L, is -NH-, -NHS(O) 2 - or -NHC(O)-.
- Compounds of Formula VIII having either -NHS(O) 2 - or -NHC(O)- linker at the 1 -position can be prepared, for example, in five steps from l -(6-ethyl-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin- 7-yl)-ethanone 9 as shown in Scheme B.
- Step 2 Preparation of l-(l-am ⁇ no-6-ethyl-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-7-yl)-ethanone (112):
- reaction mixture is stirred at room temperature or heated in an oil bath for 2 to 24 hours.
- the reaction mixture is poured into water and extracted with an appropriate solvent (such as dichloromethane or ethyl acetate).
- the organic layer is collected, washed with saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. After removal of drying agent and solvent, the residue can be purified by silica gel chromatography to provide the desired compound of Formula VI.
- a mixture of a compound of Formula VII, Raney nickel, and ammonium hydroxide in methanol is stirred under an atmosphere of hydrogen gas for 0.5-20 hours.
- the catalyst is removed by filtration and the filtrate concentrated under reduced pressure.
- the residue can be purified by silica gel chromatography to provide the desired compound of Formula VIII.
- Similar compounds with substituents other than ethyl at the 6 position, e.g. optionally substituted aryl, can be prepared similarly, for example, by replacing l -(6-ethyl-4,4-dimethyl-l ,2,3,4- tetrahydro-quinolin-7-yl)-ethanone 9 in step 1 with a suitable compound, including, but not limited to, l -[6-(4-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-7-yl]- ethanone 38 and similar compounds formed in the reaction Scheme 9 of Example 9; l-(6-benzyloxy-4,4-dimethyl-l , 2,3,4- tetrahydro-quinolin-7-yl)-ethanone 42 formed in the reaction Scheme 10 of Example 10; l-(4,4- dimethyl-6-p-tolyl-l ,2,3,4-tetrahydr
- Example 30 Synthesis of Compounds where L t is -NHC(O)NH-.
- a solution of a compound of Formula X, hydroxylammt hydrochloride, and pyridine in ethanol is stirred at 80-100 0 C for 2-24 hours
- the reaction mixture is concentrated and the residue dissolved in an appropriate solvent such as ethyl acetate, washed with water and brine, and dried over magnesium sulfate After removal of drying agent and solvent, the residue can be purified by silica gel chromatography to provide the desired compound of Formula XI
- Similar compounds with substituents other than ethyl at the 6 position, e g optionally substituted aryl, can be prepared similarly, for example, by replacing 1 -(I -amino-6-ethyl-4,4- dimethyl-l,2,3,4-tetrahydro-quinohn-7-yl)-ethanone 112 in step 1 with the product of step 1 of Scheme B made by replacing l-(6-ethyl-4,4-dimetliyl-l ,2,3,4-tetrahydro-quinohn-7-yl)-ethanone 9 with a suitable compound as descnbed in Example 30
- Step 1 Preparation of tnfluoro-methanesulfomc acid 7-acetyl-4,4-d ⁇ methyl-l,2,3,4-tetrahydro- qu ⁇ nol ⁇ n-6-yl ester (113)
- a mixture of a compound of Formula XIII, a terminal alkync or olefin, a suitable ligatcd palladium catalyst (CuI and an amine solvent such as triethylamme for alkyne) in a suitable solvent such or tetrahydrofuran is stirred at a temperature below 80 0 C for 1-36 hours
- the reaction mixture is concentrated under reduced pressure and partitioned between an organic solvent such as ethyl acetate and an aqueous solution
- the organic layer is dried over an anhydrous salt, filtered, concentrated and subjected to silica gel chromatography to provide the alkyne or olefin intermediate, which can be reduced to the corresponding saturated alkyl compound of Fo ⁇ nula XlV by treatment with a transition metal catalyst such as palladium, nickel or platinum under a hydrogen atmosphere
- a mixture of a compound of Fo ⁇ nula XIII an alkyl tin compound for Stille cross-coupling, or an alkyl boromc acid, ester or alkyl t ⁇ fluoroborate salt for Suzuki cross-couplmgs, and a suitable ligated palladium catalyst in a suitable solvent such or tetrahydrofuran is stirred at a temperature below 80 0 C for 1-36 hours
- the reaction mixture is concentrated under reduced pressure and partitioned between an organic solvent such as ethyl acetate and an aqueous solution
- the organic layer is dried over an anhydrous salt, filtered, concentrated and subjected to chromatography to provide the desired compound of Formula XIV
- vinyl tin and vm ⁇ l boronate reagents can also be employed to form olefin compounds
- These olefin products can be reduced to the corresponding saturated alkyl compound of Formula XIV by treatment with a transition metal catalyst such as palladium, nickel or platinum
- a solution of a compound of Formula XIV, hydroxylamine hydrochloride, and pyridine in ethanol is stirred at 80-100 °C for 2-24 hours.
- the reaction mixture is concentrated and the residue dissolved in an appropriate solvent such as ethyl acetate, washed with water and brine, and dried over magnesium sulfate. After removal of drying agent and solvent, the residue can be purified by silica gel chromatography to provide the desired compound of Formula XV.
- Renin protease activity is assessed in a FRET (Fluorescent resonance energy transfer) screen.
- the substrate peptide is linked to a Fluorescent probe (Hilytc Fluor 488) on one end and a quencher on the other end (QXL).
- protease such as renin will cleave the peptide and the fluorescence signal will increase.
- IC 50 values are determined with respect to inhibition of renin activity, where inhibition of cleavage of the peptide substrate is measured as a function of compound concentration. Compounds to be tested were dissolved in DMSO to a concentration of 20 mM.
- Substrate was 2 ⁇ M Hilyte Fluor 488 -Arg- Ile-IIis-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys (QXL-520)Arg-NH 2 (Anaspec, Inc.). Renin was at 4 ng per sample. The protease reaction was incubated for 210 minutes at 30 0 C, and the signal per well was read on a Tecan Saffire reader. The fluorescence signal was measured and the signal vs. compound concentration was used to determine the IC 50
- Porcine pepsin protease activity is assessed in a FRET screen similarly to that for renin.
- Substrate was 4 ⁇ M Hilyte Fluor 488 -Glu-Dap-Lys-Pro- Ile-Leu-Phe-Phe-Arg-Leu-Gly-Lys— GIu (QXL-520)Glu-NH 2 (Anaspec. Inc.). Porcine pepsin was at 0.5 ng per sample. The protease reaction was incubated for 30 minutes at 30 0 C and the signal per well was read on a Tecan Saffire reader. The fluorescence signal was measured and the signal vs. compound concentration was used to determine the IC 50 .
- CathcpsinD protease activity is assessed in a FRET screen similarly to that for renin.
- Compounds to be tested were dissolved in DMSO to a concentration of 20 mM. These were diluted 30 ⁇ L into 120 ⁇ L of DMSO (4 mM) and 1 ⁇ L was added to an assay plate. These were then serially diluted 1 :3 (50 ⁇ L to 100 ⁇ L DMSO) for a total of 8 points.
- each protease reaction is 20 ⁇ L in I x protease buffer (50 mM Sodium Acetate, pH 3.5, 150 mM Nacl, 0.01 %BSA, 0.01 % Tween-20), 5% DMSO.
- Substrate was 4 ⁇ M Hilyte Fluor 488 -Glu-Dap-Lys-Pro- Ile-Leu-Phe-Phe-Arg-Leu-Gly-Lys-Glu (QXL-520)Glu-NH 2 (Anaspec, Inc.).
- CathepsinD was at 0.15 ng per sample.
- the protease reaction was incubated for 60 minutes at 25 0 C and the signal per well was read on a Tecan Saffire reader. The fluorescence signal was measured and the signal vs. compound concentration was used to determine the IC 50 .
- BACE protease activity is assessed in a FRET screen similarly to that for renin.
- Compounds to be tested were dissolved in DMSO to a concentration of 20 mM. These were diluted 30 ⁇ L into 120 ⁇ L of DMSO (4 mM) and 1 ⁇ L was added to an assay plate. These were then serially diluted 1 :3 (50 ⁇ L to 100 ⁇ L DMSO) for a total of 8 points. Plates were prepared such that each protease reaction is 20 ⁇ L in Ix protease buffer (50 mM Sodium Acetate, pH 4.5, 150 mM Nacl, 0.01 %BS ⁇ , 0.01 % Tween-20), 5% DMSO.
- Ix protease buffer 50 mM Sodium Acetate, pH 4.5, 150 mM Nacl, 0.01 %BS ⁇ , 0.01 % Tween-20
- Substrate was 4 ⁇ M Hilyte Fluor 488 -Ser-Glu-Val-Asn-Leu-Asp- AIa-G Iu -Phc-Lys (QXL-520)Glu-NH 2 (Anaspec, Inc.).
- BACE was at 8 ng per sample. The protease reaction was incubated for 210 minutes at 30 0 C and the signal per well was read on a Tecan Saffire reader. The fluorescence signal was measured and the signal vs. compound concentration was used to determine the IC 50 .
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2011011735A MX2011011735A (en) | 2009-05-04 | 2010-05-03 | Compounds and methods for inhibition of renin, and indications therefor. |
CA2761009A CA2761009A1 (en) | 2009-05-04 | 2010-05-03 | Compounds and methods for inhibition of renin, and indications therefor |
SG2011081015A SG175877A1 (en) | 2009-05-04 | 2010-05-03 | Compounds and methods for inhibition of renin, and indications therefor |
IL216107A IL216107A0 (en) | 2009-05-04 | 2011-11-03 | Compounds and methods for inhibition of renin, and indications therefor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17541709P | 2009-05-04 | 2009-05-04 | |
US61/175,417 | 2009-05-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2010129467A1 true WO2010129467A1 (en) | 2010-11-11 |
WO2010129467A8 WO2010129467A8 (en) | 2010-12-16 |
Family
ID=42237224
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2010/033385 WO2010129467A1 (en) | 2009-05-04 | 2010-05-03 | Compounds and methods for inhibition of renin, and indications therefor |
Country Status (5)
Country | Link |
---|---|
CA (1) | CA2761009A1 (en) |
IL (1) | IL216107A0 (en) |
MX (1) | MX2011011735A (en) |
SG (1) | SG175877A1 (en) |
WO (1) | WO2010129467A1 (en) |
Cited By (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102993094A (en) * | 2011-09-08 | 2013-03-27 | 中国石油大学(北京) | Synthesizing method of tetrahydroquinoline derivative |
US8598156B2 (en) | 2010-03-25 | 2013-12-03 | Glaxosmithkline Llc | Chemical compounds |
US8835420B2 (en) | 2012-07-10 | 2014-09-16 | Takeda Pharmaceutical Company Limited | Azaindole derivatives |
US8969347B2 (en) | 2008-06-03 | 2015-03-03 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
US9018214B2 (en) | 2011-04-21 | 2015-04-28 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9181272B2 (en) | 2013-04-30 | 2015-11-10 | Boehringer Ingelheim International Gmbh | Aldosterone synthase inhibitors |
US9260437B2 (en) | 2008-05-19 | 2016-02-16 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9266883B2 (en) | 2013-10-25 | 2016-02-23 | Novartis Ag | Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors |
US9359379B2 (en) | 2012-10-02 | 2016-06-07 | Intermune, Inc. | Anti-fibrotic pyridinones |
US9358235B2 (en) | 2012-03-19 | 2016-06-07 | Plexxikon Inc. | Kinase modulation, and indications therefor |
US9371321B2 (en) | 2014-01-09 | 2016-06-21 | Astrazeneca Ab | Azaindole derivatives |
US9440969B2 (en) | 2009-12-23 | 2016-09-13 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9550768B2 (en) | 2011-05-17 | 2017-01-24 | Plexxikon Inc. | Kinase modulation and indications therefor |
US9617267B2 (en) | 2009-11-18 | 2017-04-11 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9617283B2 (en) | 2012-10-19 | 2017-04-11 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9617248B2 (en) | 2012-10-19 | 2017-04-11 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9624213B2 (en) | 2011-02-07 | 2017-04-18 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9663512B2 (en) | 2012-10-19 | 2017-05-30 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9676748B2 (en) | 2012-12-21 | 2017-06-13 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9682981B2 (en) | 2010-04-21 | 2017-06-20 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9718847B2 (en) | 2013-03-15 | 2017-08-01 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US9771363B2 (en) | 2015-09-21 | 2017-09-26 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US9771369B2 (en) | 2014-03-04 | 2017-09-26 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9783538B2 (en) | 2013-12-20 | 2017-10-10 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9802917B2 (en) | 2015-03-25 | 2017-10-31 | Novartis Ag | Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide |
US9822109B2 (en) | 2013-03-15 | 2017-11-21 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US9844539B2 (en) | 2007-07-17 | 2017-12-19 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9856259B2 (en) | 2014-09-15 | 2018-01-02 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US9873700B2 (en) | 2013-05-30 | 2018-01-23 | Plexxikon Inc. | Compounds for kinase modulation, and indications therefor |
US9938273B2 (en) | 2015-12-07 | 2018-04-10 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9980973B2 (en) | 2012-10-19 | 2018-05-29 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
CN108752272A (en) * | 2018-06-19 | 2018-11-06 | 西安交通大学 | 8- aminoquinolines amide derivatives, preparation method, the method for application and its fluorescence analysis |
US10160747B2 (en) | 2016-03-16 | 2018-12-25 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US10160755B2 (en) | 2015-04-08 | 2018-12-25 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US10227357B2 (en) | 2012-09-06 | 2019-03-12 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US10233195B2 (en) | 2014-04-02 | 2019-03-19 | Intermune, Inc. | Anti-fibrotic pyridinones |
US10428067B2 (en) | 2017-06-07 | 2019-10-01 | Plexxikon Inc. | Compounds and methods for kinase modulation |
US10435404B2 (en) | 2017-07-25 | 2019-10-08 | Plexxikon Inc. | Formulations of a compound modulating kinases |
US10463653B2 (en) | 2014-10-03 | 2019-11-05 | Novartis Ag | Use of ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors |
US10508085B2 (en) | 2016-09-22 | 2019-12-17 | Plexxikon Inc. | Compounds and methods for IDO and TDO modulation, and indications therefor |
US10577366B2 (en) | 2017-03-20 | 2020-03-03 | Plexxikon Inc. | Crystalline forms of a compound that inhibits bromodomain |
CN111053761A (en) * | 2020-01-16 | 2020-04-24 | 杭州旦承医药科技有限公司 | Bisphosphonic acid medicine for inhalation, preparation method thereof and application thereof in chronic obstructive pulmonary disease |
US10703757B2 (en) | 2016-12-23 | 2020-07-07 | Plexxikon Inc. | Compounds and methods for CDK8 modulation and indications therefor |
US10717735B2 (en) | 2017-10-13 | 2020-07-21 | Plexxikon Inc. | Solid forms of a compound for modulating kinases |
US10829484B2 (en) | 2015-07-28 | 2020-11-10 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US11103505B2 (en) | 2017-10-27 | 2021-08-31 | Plexxikon Inc. | Formulations of a compound modulating kinases |
US11149011B2 (en) | 2018-03-20 | 2021-10-19 | Plexxikon Inc. | Compounds and methods for IDO and TDO modulation, and indications therefor |
US11958818B2 (en) | 2020-04-29 | 2024-04-16 | Boehringer Ingelheim International Gmbh | (R)-(2-methyloxiran-2-yl)methyl 4-bromobenzenesulfonate |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008063888A2 (en) | 2006-11-22 | 2008-05-29 | Plexxikon, Inc. | Compounds modulating c-fms and/or c-kit activity and uses therefor |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000064887A1 (en) * | 1999-04-27 | 2000-11-02 | F. Hoffmann-La Roche Ag | Renin inhibitors |
WO2009005002A1 (en) * | 2007-06-29 | 2009-01-08 | Dainippon Sumitomo Pharma Co., Ltd. | Quinolone derivative |
-
2010
- 2010-05-03 MX MX2011011735A patent/MX2011011735A/en not_active Application Discontinuation
- 2010-05-03 CA CA2761009A patent/CA2761009A1/en active Pending
- 2010-05-03 SG SG2011081015A patent/SG175877A1/en unknown
- 2010-05-03 WO PCT/US2010/033385 patent/WO2010129467A1/en active Application Filing
-
2011
- 2011-11-03 IL IL216107A patent/IL216107A0/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000064887A1 (en) * | 1999-04-27 | 2000-11-02 | F. Hoffmann-La Roche Ag | Renin inhibitors |
WO2009005002A1 (en) * | 2007-06-29 | 2009-01-08 | Dainippon Sumitomo Pharma Co., Ltd. | Quinolone derivative |
Non-Patent Citations (20)
Title |
---|
BAGSHAWE, DRUG DEV. RES., vol. 34, 1995, pages 220 - 230 |
BERTOLINI ET AL., J. MED. CHERN., vol. 40, 1997, pages 2011 - 2016 |
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 46, no. 3, 2005, pages 1078 - 1084 |
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 46, no. 8, 2005, pages 2925 - 2931 |
KELLY ET AL., DIABETOLOGIA, vol. 50, 2007, pages 2398 - 2404 |
KISSELEVA ET AL., JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, vol. 22, no. 1, 2007, pages S73 - S78 |
KUBA ET AL., CURRENT OPINION IN PHARMACOLOGY, vol. 6, 2006, pages 271 - 276 |
KURIHARA ET AL., INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 47, no. 12, 2006, pages 5545 - 5552 |
MACKINNON ET AL., AMERICAN JOURNAL OF KIDNEY DISEASES, vol. 48, no. 1, 2006, pages 8 - 20 |
NAGAI ET AL., INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 48, no. 5, 2007, pages 2321 - 2326 |
REID ET AL., IMMUNOLOGICAL REVIEWS, vol. 217, 2007, pages 123 - 140 |
REMUZZI, ANNALS OF INTERNAL MEDICINE, vol. 136, no. 8, 2002, pages 604 - 615 |
RUSSO ET AL., AMERICAN JOURNAL OF KIDNEY DISEASES, vol. 38, no. 1, 2001, pages 18 - 25 |
SEGALL ET AL., NEPHROL DIAL TRANSPLANT, vol. 22, 2007, pages 2435 - 2439 |
SHAN ET AL., JPHARM SCI, vol. 86, no. 7, 1997, pages 756 - 757 |
T.A. WYNN, JOURNAL OF PATHOLOGY, vol. 214, 2008, pages 199 - 210 |
VEERAPPAN, PNAS, vol. 105, no. 4, 2008, pages 1315 - 1320 |
YAO ET AL., RCSPIRATION, vol. 73, 2006, pages 236 - 242 |
YOSHIJI ET AL., JOURNAL OF GASTROENTEROLOGY AND IIEPATOLOGY, vol. 22, no. 1, 2007, pages S93 - S95 |
ZHANG ET AL., CURRENT EYE RESEARCH, vol. 32, no. 10, 2007, pages 883 - 889 |
Cited By (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10426760B2 (en) | 2007-07-17 | 2019-10-01 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9844539B2 (en) | 2007-07-17 | 2017-12-19 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9260437B2 (en) | 2008-05-19 | 2016-02-16 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
USRE47142E1 (en) | 2008-06-03 | 2018-11-27 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
US8969347B2 (en) | 2008-06-03 | 2015-03-03 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
US9290450B2 (en) | 2008-06-03 | 2016-03-22 | Intermune, Inc. | Compounds and methods for treating inflammatory and fibrotic disorders |
US9617267B2 (en) | 2009-11-18 | 2017-04-11 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9440969B2 (en) | 2009-12-23 | 2016-09-13 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US8598156B2 (en) | 2010-03-25 | 2013-12-03 | Glaxosmithkline Llc | Chemical compounds |
US9682981B2 (en) | 2010-04-21 | 2017-06-20 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US11337976B2 (en) | 2011-02-07 | 2022-05-24 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9624213B2 (en) | 2011-02-07 | 2017-04-18 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US11866428B2 (en) | 2011-04-21 | 2024-01-09 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9018214B2 (en) | 2011-04-21 | 2015-04-28 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9676768B2 (en) | 2011-04-21 | 2017-06-13 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9550768B2 (en) | 2011-05-17 | 2017-01-24 | Plexxikon Inc. | Kinase modulation and indications therefor |
CN102993094B (en) * | 2011-09-08 | 2014-07-23 | 中国石油大学(北京) | Synthesizing method of tetrahydroquinoline derivative |
CN102993094A (en) * | 2011-09-08 | 2013-03-27 | 中国石油大学(北京) | Synthesizing method of tetrahydroquinoline derivative |
US9358235B2 (en) | 2012-03-19 | 2016-06-07 | Plexxikon Inc. | Kinase modulation, and indications therefor |
US10123998B2 (en) | 2012-03-19 | 2018-11-13 | Plexxikon Inc. | Kinase modulation, and indications therefor |
US9730918B2 (en) | 2012-03-19 | 2017-08-15 | Plexxikon Inc. | Kinase modulation, and indications therefor |
US8835420B2 (en) | 2012-07-10 | 2014-09-16 | Takeda Pharmaceutical Company Limited | Azaindole derivatives |
US10227357B2 (en) | 2012-09-06 | 2019-03-12 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9359379B2 (en) | 2012-10-02 | 2016-06-07 | Intermune, Inc. | Anti-fibrotic pyridinones |
US9675593B2 (en) | 2012-10-02 | 2017-06-13 | Intermune, Inc. | Anti-fibrotic pyridinones |
US10898474B2 (en) | 2012-10-02 | 2021-01-26 | Intermune, Inc. | Anti-fibrotic pyridinones |
US10376497B2 (en) | 2012-10-02 | 2019-08-13 | Intermune, Inc. | Anti-fibrotic pyridinones |
US9617283B2 (en) | 2012-10-19 | 2017-04-11 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9617248B2 (en) | 2012-10-19 | 2017-04-11 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9663512B2 (en) | 2012-10-19 | 2017-05-30 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9980973B2 (en) | 2012-10-19 | 2018-05-29 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9676748B2 (en) | 2012-12-21 | 2017-06-13 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US10301280B2 (en) | 2012-12-21 | 2019-05-28 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9822109B2 (en) | 2013-03-15 | 2017-11-21 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US9718847B2 (en) | 2013-03-15 | 2017-08-01 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US9181272B2 (en) | 2013-04-30 | 2015-11-10 | Boehringer Ingelheim International Gmbh | Aldosterone synthase inhibitors |
US9873700B2 (en) | 2013-05-30 | 2018-01-23 | Plexxikon Inc. | Compounds for kinase modulation, and indications therefor |
US10421761B2 (en) | 2013-05-30 | 2019-09-24 | Plexxikon Inc. | Compounds for kinase modulation, and indications therefor |
US9896449B2 (en) | 2013-10-25 | 2018-02-20 | Novartis Ag | Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors |
US9266883B2 (en) | 2013-10-25 | 2016-02-23 | Novartis Ag | Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors |
US9533988B2 (en) | 2013-10-25 | 2017-01-03 | Novartis Ag | Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors |
US10618895B2 (en) | 2013-12-20 | 2020-04-14 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US11225476B2 (en) | 2013-12-20 | 2022-01-18 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US11643410B2 (en) | 2013-12-20 | 2023-05-09 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9783538B2 (en) | 2013-12-20 | 2017-10-10 | Astex Therapeutics Limited | Bicyclic heterocycle compounds and their uses in therapy |
US9371321B2 (en) | 2014-01-09 | 2016-06-21 | Astrazeneca Ab | Azaindole derivatives |
US9771369B2 (en) | 2014-03-04 | 2017-09-26 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US10544161B2 (en) | 2014-04-02 | 2020-01-28 | Intermune, Inc. | Anti-fibrotic pyridinones |
US10233195B2 (en) | 2014-04-02 | 2019-03-19 | Intermune, Inc. | Anti-fibrotic pyridinones |
US9856259B2 (en) | 2014-09-15 | 2018-01-02 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US10507201B2 (en) | 2014-10-03 | 2019-12-17 | Novartis Ag | Use of ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors |
US10463653B2 (en) | 2014-10-03 | 2019-11-05 | Novartis Ag | Use of ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors |
US9802917B2 (en) | 2015-03-25 | 2017-10-31 | Novartis Ag | Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide |
US10160755B2 (en) | 2015-04-08 | 2018-12-25 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US10829484B2 (en) | 2015-07-28 | 2020-11-10 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US9975894B2 (en) | 2015-09-21 | 2018-05-22 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US10899761B2 (en) | 2015-09-21 | 2021-01-26 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US9771363B2 (en) | 2015-09-21 | 2017-09-26 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US10647716B2 (en) | 2015-09-21 | 2020-05-12 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US10370374B2 (en) | 2015-09-21 | 2019-08-06 | Plexxikon Inc. | Heterocyclic compounds and uses thereof |
US9938273B2 (en) | 2015-12-07 | 2018-04-10 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US10160747B2 (en) | 2016-03-16 | 2018-12-25 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
US10508085B2 (en) | 2016-09-22 | 2019-12-17 | Plexxikon Inc. | Compounds and methods for IDO and TDO modulation, and indications therefor |
US10703757B2 (en) | 2016-12-23 | 2020-07-07 | Plexxikon Inc. | Compounds and methods for CDK8 modulation and indications therefor |
US10577366B2 (en) | 2017-03-20 | 2020-03-03 | Plexxikon Inc. | Crystalline forms of a compound that inhibits bromodomain |
US10428067B2 (en) | 2017-06-07 | 2019-10-01 | Plexxikon Inc. | Compounds and methods for kinase modulation |
US10435404B2 (en) | 2017-07-25 | 2019-10-08 | Plexxikon Inc. | Formulations of a compound modulating kinases |
US10941142B2 (en) | 2017-07-25 | 2021-03-09 | Plexxikon Inc. | Formulations of a compound modulating kinases |
US10961240B2 (en) | 2017-07-25 | 2021-03-30 | Plexxikon Inc. | Formulations of a compound modulating kinases |
US10717735B2 (en) | 2017-10-13 | 2020-07-21 | Plexxikon Inc. | Solid forms of a compound for modulating kinases |
US11103505B2 (en) | 2017-10-27 | 2021-08-31 | Plexxikon Inc. | Formulations of a compound modulating kinases |
US11149011B2 (en) | 2018-03-20 | 2021-10-19 | Plexxikon Inc. | Compounds and methods for IDO and TDO modulation, and indications therefor |
CN108752272B (en) * | 2018-06-19 | 2021-02-19 | 西安交通大学 | 8-aminoquinoline amide derivative, preparation method, application and fluorescence analysis method thereof |
CN108752272A (en) * | 2018-06-19 | 2018-11-06 | 西安交通大学 | 8- aminoquinolines amide derivatives, preparation method, the method for application and its fluorescence analysis |
CN111053761A (en) * | 2020-01-16 | 2020-04-24 | 杭州旦承医药科技有限公司 | Bisphosphonic acid medicine for inhalation, preparation method thereof and application thereof in chronic obstructive pulmonary disease |
US11958818B2 (en) | 2020-04-29 | 2024-04-16 | Boehringer Ingelheim International Gmbh | (R)-(2-methyloxiran-2-yl)methyl 4-bromobenzenesulfonate |
Also Published As
Publication number | Publication date |
---|---|
CA2761009A1 (en) | 2010-11-11 |
MX2011011735A (en) | 2011-11-29 |
SG175877A1 (en) | 2011-12-29 |
IL216107A0 (en) | 2012-01-31 |
WO2010129467A8 (en) | 2010-12-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2010129467A1 (en) | Compounds and methods for inhibition of renin, and indications therefor | |
CN105492444B (en) | Tricyclic pyridine-carboxamides derivatives as ROCK inhibitor | |
CN105518005B (en) | Tricyclic pyridine-carboxamides derivatives as ROCK inhibitor | |
TWI473792B (en) | New quinoline compounds and their use | |
KR20190066604A (en) | Compounds and methods for coordinating IDO and TDO, and indications thereof | |
KR101111464B1 (en) | Novel pyridopyrazines and medicament as kinase modulators comprising the same | |
WO2019101086A1 (en) | Halo-allylamine ssao/vap-1 inhibitor and use thereof | |
JP2005521698A (en) | New tricyclic compounds | |
MX2007015678A (en) | Piperazine-piperidine antagonists and agonists of the 5-ht1a receptor. | |
WO2013013614A1 (en) | 4-(3-heteroarylarylamino)quinazoline and 1-(3-heteroarylarylamino)isoquinoline as hedgehog pathway inhibitor and use thereof | |
WO2007037543A1 (en) | Biarylamide derivative | |
JP2020506878A (en) | Activator of TREK (TWIK related K channel) channel | |
JP2021529746A (en) | Cardiac sarcomere inhibitor | |
KR20090114439A (en) | Acylguanidine derivative | |
KR20020073589A (en) | Fused Imidazolium Derivatives | |
WO2011148956A1 (en) | Fused imidazole derivative | |
AU2016353348A1 (en) | Heterocyclic compounds for the treatment of disease | |
JP2004269469A (en) | Pyrimidine derivative or salt thereof | |
US20160016933A1 (en) | Isoquinolines as potassium ion channel inhibitors | |
JP2020514399A (en) | Novel benzofuran, benzothiophene and indole analogs that inhibit the formation of tau oligomers and methods for their use | |
WO2007018168A1 (en) | Acylguanidine derivative or salt thereof | |
WO2016011940A1 (en) | Indole-amide derivative, preparation method therefor and application thereof in medicine | |
TW201406753A (en) | Benzofuran derivative, preparation method and medical use thereof | |
JP2008523155A (en) | Pyridyl-substituted spiro-hydantoin compounds and uses thereof | |
JP2018087173A (en) | Anti-malignant brain tumor therapeutic agent |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10717397 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012509872 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: CR2011-000570 Country of ref document: CR |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2761009 Country of ref document: CA Ref document number: 11150238 Country of ref document: CO Ref document number: 001901-2011 Country of ref document: PE Ref document number: MX/A/2011/011735 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: JP |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 10717397 Country of ref document: EP Kind code of ref document: A1 |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: PI1014458 Country of ref document: BR |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01E Ref document number: PI1014458 Country of ref document: BR Free format text: APRESENTAR, EM ATE 60 (SESSENTA) DIAS, EM LINGUA PORTUGUESA, AS FOLHAS DE RELATORIO DESCRITIVO E DESENHOS APRESENTADAS EM LINGUA ESTRANGEIRA NA PETICAO NO 020110112782 DE 03/11/2011, ADAPTADO A NORMA VIGENTE. |
|
ENPW | Started to enter national phase and was withdrawn or failed for other reasons |
Ref document number: PI1014458 Country of ref document: BR |