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US 2006/0217419 A1Published application
Piperidinyl substituted cyclohexane-1,4-diamines
AssigneeJanssen Pharmaceutica NV
InventorsGeorge Chiu, Shengjian Li, Peter Connolly, Virginia Pulito, Jingchun Liu, Steven Middleton
Life of this patent
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Abstract
The present invention relates to piperidine substituted cyclohexane-1,4-diamine compounds of Formula (I) and pharmaceutically acceptable forms thereof, as α1a/α1d adrenoreceptor modulators for the treatment of benign prostatic hypertrophy and lower urinary tract symptoms. The present invention also relates to pharmaceutical compositions comprising said new compounds, new processes to prepare these new compounds and new uses as a medicine as well as method of treatments.
Claims33
A compound of Formula (I)
- or a pharmaceutically acceptable form thereof, wherein
- R1 is selected from the group consisting of
- (1) aryl,
- (2) aryl-C1-8alkyl,
- (3) C3-8cycloalkyl,
- (4) C3-8cycloalkyl-C1-8alkyl,
- (5) heteroaryl,
- (6) heteroaryl-C1-8alkyl,
- (7) heterocyclyl, and
- (8) heterocyclyl-C1-8alkyl,
- wherein each aryl, C3-8cycloalkyl, heteroaryl and heterocyclyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of
- (i) C1-8alkyl,
- (ii) C1-8alkoxy,
- (iii) C1-8alkoxy-C1-8alkyl,
- (iv) halo-C1-8alkyl,
- (v) halo-C1-8alkoxy,
- (vi) hydroxy-C1-8alkyl,
- (vii) C1-8alkoxy-carbonyl,
- (viii) SO2 substituted with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (ix) amino optionally mono- or di-substituted with C1-8alkyl,
- (x) cyano,
- (xi) halogen,
- (xii) hydroxy,
- (xiii) nitro,
- (xiv) amino-C1-8alkyl optionally mono- or di-substituted on amino with C1-8alkyl,
- (xv) aryl-C1-8alkyl,
- (xvi) aryl-C1-8alkoxy,
- (xvii) heteroaryl-C1-8alkyl,
- (xviii) heterocyclyl-C1-8alkyl;
- (xix) C(O) substituted with a substituent selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xx) S(O) substituted with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxi) C(O)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxii) SO2N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxiii) NHSO2 substituted on sulfur with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxiv) NHC(O) substituted on carbonyl with a substituent selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxv) NHSO2N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxvi) NHC(O)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxvii) C3-8cycloalkyl,
- (xxviii) aryl,
- (xxix) heteroaryl, and
- (xxx) heterocyclyl;
- R2 is selected from the group consisting of hydrogen and C1-alkyl;
- R3 is one, two, three or four optionally present substituents independently selected from the group consisting of
- (1) C1-8alkyl,
- (2) C1-8alkoxy,
- (3) C1-8alkoxy-C1-8alkyl,
- (4) halo-C1-8alkyl,
- (5) halo-C1-8alkoxy,
- (6) hydroxy-C1-8alkyl,
- (7) C1-8alkoxy-carbonyl,
- (8) SO2 substituted with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (9) amino optionally mono- or di-substituted with C1-8alkyl,
- (10) cyano,
- (11) halogen,
- (12) hydroxy,
- (13) nitro,
- (14) amino-C1-8alkyl optionally mono- or di-substituted on amino with C1-8alkyl,
- (15) aryl,
- (16) aryl-C1-8alkyl,
- (17) aryl-C1-8alkoxy,
- (18) C3-8cycloalkyl,
- (19) C3-8cycloalkyl-C1-8alkyl,
- (20) C3-8cycloalkyl-C1-8alkoxy,
- (21) heteroaryl,
- (22) heteroaryl-C1-8alkyl,
- (23) heterocyclyl,
- (24) heterocyclyl-C1-8alkyl,
- (25) C(O) substituted with a substituent selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (26) S(O) substituted with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (27) SO2 substituted with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (28) C(O)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (29) SO2N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (30) NHSO2 substituted on sulfur with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (31) NHC(O) substituted on carbonyl with a substituent selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (32) NHSO2N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (33) NHC(O)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl, and
- (34) C3-8cycloalkoxy;
- wherein each aryl, C3-8cycloalkyl, heteroaryl and heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of
- (i) C1-8alkyl,
- (ii) C1-8alkoxy,
- (iii) C1-8alkoxy-C1-8alkyl,
- (iv) halo-C1-8alkyl,
- (v) halo-C1-8alkoxy,
- (vi) hydroxy-C1-8alkyl,
- (vii) C1-8alkoxy-carbonyl,
- (viii) C1-8alkyl-sulfonyl,
- (ix) amino optionally mono- or di-substituted with C1-8alkyl,
- (x) cyano,
- (xi) halogen,
- (xii) hydroxy,
- (xiii) nitro, and
- (xiv) amino-C1-8alkyl optionally mono- or di-substituted on amino with C1-8alkyl;
- and
- R4 and R5 is each selected from hydrogen or are one or two optionally present substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, amino, C1-8alkyl-amino, cyano, halogen, oxo and nitro.
91 more elements
A compound of Formula (I) or a pharmaceutically acceptable form thereof, wherein R1 is selected from the group consisting of
- (1) aryl, and
- (2) heterocyclyl,
- wherein each is optionally substituted with one, two, three or four substituents independently selected from the group consisting of
- (i) C1-8alkyl,
- (ii) C1-8alkoxy,
- (iii) halo-C1-8alkoxy, and
- (iv) halogen.
4 more elements
A compound of Formula (I) or a pharmaceutically acceptable form thereof, wherein R1 is selected from the group consisting of
- (1) aryl optionally substituted with one, two, three or four substituents independently selected from the group consisting of
- (i) C1-8alkyl,
- (ii) C1-8alkoxy,
- (iii) halo-C1-8alkoxy, and
- (iv) halogen, and
- (2) heterocyclyl.
3 more elements
A compound of Formula (I) or a pharmaceutically acceptable form thereof wherein R2 is hydrogen.
A compound of Formula (I) or a pharmaceutically acceptable form thereof wherein R3 is one, two, three or four optionally present substituents independently selected from the group consisting of
- (1) C1-8alkyl,
- (2) C1-8alkoxy,
- (3) halo-C1-8alkoxy, and
- (4) C3-8cycloalkyl-C1-8alkoxy.
1 more element
A compound of Formula (Ia):
- or a pharmaceutically acceptable form thereof, wherein
- R1 is selected from the group consisting of
- (1) aryl,
- (2) aryl-C1-8alkyl,
- (3) C3-8Cycloalkyl,
- (4) C3-8Cycloalkyl-C1-8alkyl,
- (5) heteroaryl,
- (6) heteroaryl-C1-8alkyl,
- (7) heterocyclyl, and
- (8) heterocyclyl-C1-8alkyl,
- wherein each aryl, C3-8cycloalkyl, heteroaryl and heterocyclyl is optionally substituted with one, two, three or four substituents independently selected from the group consisting of
- (i) C1-8alkyl,
- (ii) C1-8alkoxy,
- (iii) C1-8alkoxy-C1-8alkyl,
- (iv) halo-C1-8alkyl,
- (v) halo-C1-8alkoxy,
- (vi) hydroxy-C1-8alkyl,
- (vii) C1-8alkoxy-carbonyl,
- (viii) SO2 substituted with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (ix) amino optionally mono- or di-substituted with C1-8alkyl,
- (x) cyano,
- (xi) halogen,
- (xii) hydroxy,
- (xiii) nitro,
- (xiv) amino-C1-8alkyl optionally mono- or di-substituted on amino with C1-8alkyl,
- (xv) aryl-C1-8alkyl,
- (xvi) aryl-C1-8alkoxy,
- (xvii) heteroaryl-C1-8alkyl,
- (xviii) heterocyclyl-C1-8alkyl;
- (xix) C(O) substituted with a substituent selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xx) S(O) substituted with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxi) C(O)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxii) SO2N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxiii) NHSO2 substituted on sulfur with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxiv) NHC(O) substituted on carbonyl with a substituent selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxv) NHSO2N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxvi) NHC(O)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (xxvii) C3-8cycloalkyl,
- (xxviii) aryl,
- (xxix) heteroaryl, and
- (xxx) heterocyclyl;
- R2 is selected from the group consisting of hydrogen and C1-8alkyl;
- and
- R3 is one, two, three or four optionally present substituents independently selected from the group consisting of
- (1) C1-8alkyl,
- (2) C1-8alkoxy,
- (3) C1-8alkoxy-C1-8alkyl,
- (4) halo-C1-8alkyl,
- (5) halo-C1-8alkoxy,
- (6) hydroxy-C1-8alkyl,
- (7) C1-8alkoxy-carbonyl,
- (8) SO2 substituted with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (9) amino optionally mono- or di-substituted with C1-8alkyl,
- (10) cyano,
- (11) halogen,
- (12) hydroxy,
- (13) nitro,
- (14) amino-C1-8alkyl optionally mono- or di-substituted on amino with C1-8alkyl,
- (15) aryl,
- (16) aryl-C1-8alkyl,
- (17) aryl-C1-8alkoxy,
- (18) C3-8cycloalkyl,
- (19) C3-8cycloalkyl-C1-8alkyl,
- (20) C3-8cycloalkyl-C1-8alkoxy,
- (21) heteroaryl,
- (22) heteroaryl-C1-8alkyl,
- (23) heterocyclyl,
- (24) heterocyclyl-C1-8alkyl,
- (25) C(O) substituted with a substituent selected from the group consisting of hydrogen, C1-8alkyl, C3-cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (26) S(O) substituted with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (27) SO2 substituted with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (28) C(O)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (29) SO2N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (30) NHSO2 substituted on sulfur with a substituent selected from the group consisting of C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (31) NHC(O) substituted on carbonyl with a substituent selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (32) NHSO2N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl,
- (33) NHC(O)N substituted on nitrogen with two substituents selected from the group consisting of hydrogen, C1-8alkyl, C3-8cycloalkyl, aryl, heteroaryl, and heterocyclyl, and
- (34) C3-8cycloalkoxy;
- wherein each aryl, C3-8cycloalkyl, heteroaryl and heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of
- (i) C1-8alkyl,
- (ii) C1-8alkoxy,
- (iii) C1-8alkoxy-C1-8alkyl,
- (iv) halo-C1-8alkyl,
- (v) halo-C1-8alkoxy,
- (vi) hydroxy-C1-8alkyl,
- (vii) C1-8alkoxy-carbonyl,
- (viii) C1-8alkyl-sulfonyl,
- (ix) amino optionally mono- or di-substituted with C1-8alkyl,
- (x) cyano,
- (xi) halogen,
- (xii) hydroxy,
- (xiii) nitro, and
- (xiv) amino-C1-8alkyl optionally mono- or di-substituted on amino with C1-8alkyl.
90 more elements
A compound of formula of Formula (Ia) and pharmaceutically acceptable forms thereof, wherein R1 is selected from the group consisting of
- (1) aryl, and
- (2) heterocyclyl,
- wherein each is optionally substituted with one, two, three or four substituents independently selected from the group consisting of
- (i) C1-8alkyl,
- (ii) C1-8alkoxy,
- (iii) halo-C1-8alkoxy, and
- (iv) halogen.
4 more elements
A compound a compound of Formula (Ia) and pharmaceutically acceptable forms thereof, wherein R1 is selected from the group consisting of
- (1) aryl optionally substituted with one, two, three or four substituents independently selected from the group consisting of
- (i) C1-8alkyl,
- (ii) C1-8alkoxy,
- (iii) halo-C1-8alkoxy, and
- (iv) halogen, and
- (2) heterocyclyl.
3 more elements
A compound of Formula (Ia) or pharmaceutically acceptable form thereof, wherein R2 is hydrogen.
A compound of Formula (Ia) or a pharmaceutically acceptable form thereof, wherein R3 is one, two, three or four optionally present substituents independently selected from the group consisting of
- (1) C1-8alkyl,
- (2) C1-8alkoxy,
- (3) halo-C1-8alkoxy, and
- (4) C3-8cycloalkyl-C1-8alkoxy.
1 more element
A compound of Formula (Ib):
- or a pharmaceutically acceptable form thereof, wherein
- R1 is selected from 3,4-(OCH3)2-phenyl, 3,4-F2-phenyl, 5-Cl-2-OCH3-phenyl, 5-Cl-2-F-phenyl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,4-Cl2-phenyl, benzo[1,3]dioxol-5-yl, 3-OCHF2-phenyl and 4-OCHF2-phenyl;
- and
- R3 is selected from 2-OCH(CH3)2, 2-OCH2CF3, 2-cyclopropoxy, 2-O(CH2)3F, 2-OCH2CH(F2), 4-F-2-OCH(CH3)2 and 5-F-2-OCH(CH3)2.
1 more element
A compound of Formula (Ic):
- or a pharmaceutically acceptable form thereof, wherein
- R1 is selected from 3,4-(OCH3)2-phenyl, 3,4-F2-phenyl, 5-Cl-2-OCH3-phenyl, 5-Cl-2-F-phenyl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,4-Cl2-phenyl, benzo[1,3]dioxol-5-yl, 3-OCHF2-phenyl and 4-OCHF2-phenyl;
- and
- R3 is selected from 2-OCH(CH3)2, 2-OCH2CF3, 2-cyclopropoxy, 2-O(CH2)3F, 2-OCH2CH(F2), 4-F-2-OCH(CH3)2 and 5-F-2-OCH(CH3)2.
1 more element
Dependencies are inferred from the claim text.