Patent ID: 6391872
Filing Date: 2002-05-21
Classification: A61P,C07D

Abstract:
A compound useful for treating a disease or condition mediated by or associated with adrenergic &agr;1-antagonist or &bgr;1-agonist activity consisting of Formula (I1) or (I2): or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, wherein:RC is a member independently selected from the group consisting of hydrogen; hydroxy; â€”Oâ€”(C1-C4)alkyl; and phenyl substituted by 0 to 2 substituents Rs where Rs is a member independently selected from the group consisting of Br, Cl, or F; (C1-C4) alkoxy; and CF3 RA is a member independently selected from the group consisting of hydrogen; (C1-C9) alkyl; â€”(CH2)n(C3-C10) cycloalkyl wherein n is 0 to 2; â€”(C1-C6) alkyl(C1-C6) alkoxy; (C2-C6) alkenyl; â€”(CH2)n(C3-C9) heterocyclyl wherein n is 0 to 2; and â€”(Zâ€²)b(Zâ€³)c(C6-C10) aryl wherein b and c are each independently 0 or 1, Zâ€² is (C1-C6) alkylene or (C2-C6) alkenylene, and Zâ€³ is â€”Oâ€”, â€”Sâ€”, â€”SO2â€”, or â€”N(R9)â€”, and wherein said alkyl, alkenyl, alkoxyalkyl, heterocyclyl, and aryl moieties of said RA (groups are substituted by 0 to 3 substituents independently selected from halo; hydroxy; (C1-C5) alkyl; (C2-C5) alkenyl; (C1-C5) alkoxy; (C3-C6) cycloalkoxy; trifluoromethyl; nitro; â€”C(&boxH;O)OR9; â€”C(&boxH;O)NR9R10, â€”NR9R10, and â€”S(&boxH;O)2NR9R10; where said aryl moiety consists of a member selected from the group consisting of phenyl; naphthyl; indenyl (from 2,3-dihydro-1H-indene); indanyl; and fluorenyl (from 9-H-fluorene); where said heterocyclyl moiety consists of a member independently selected from the group consisting of acridinyl; benzimidazolyl; benzodioxolane; 1,3-benzodioxol-5-yl; benzo[b]furanyl; benzo[b]thiophenyl; benzoxazolyl; benzthiazolyl; carbazolyl; cinnolinyl; 2,3-dihydrobenzofuranyl; 1,3-dioxane; 1,3-dioxolane; 1,3-dithiane; 1,3-dithiolane; furanyl; imidazolidinyl; imidazolinyl imidazolyl; 1H-indazolyl; indolinyl; indolyl; 3H-indolyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; morpholinyl; 1,8-naphthyridinyl; oxadiazolyl; 1,3-oxathiolane; oxazolidinyl; oxazolyl; oxiranyl; parathiazinyl; phenazinyl; phenothiazinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; pteridinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolo[1,5-c]triazinyl; pyrazolyl; pyridazinyl; pyridyl; pyrimidinyl; pyrimidyl; pyrrolyl; pyrrolidinyl; purinyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; tetrazolidinyl; tetrazolyl; thiadiazolyl; thiazolidinyl; thiazolyl; thienyl; thiomorpholinyl; triazinyl; and triazolyl; and R9 and R10 are independently selected from the group consisting of hydrogen and (C1-C4) alkyl substituted by 0 to 3 fluorine atoms; RB is a member independently selected from the group consisting of hydrogen; (C1-C9) alkyl; (C2-C3) alkenyl; phenyl; (C3-C7) cycloalkyl; and â€”(C1-C2) alkyl(C3-C7) cycloalkyl; wherein said alkyl, alkenyl and phenyl RB groups are substituted with 0 to 3 substituents independently selected from the group consisting of methyl;ethyl; trifluoromethyl; and halo; and Ra and Rb are each individually and independently a member selected from the group consisting of hydrogen and a substituent defined under (II) below, provided that both of Ra and Rb cannot be hydrogen at the same time; (II) wherein said compound of Formula (I1) or (I2) having adrenergic &agr;1-antagonist or &bgr;1-agonist activity consists of a compound of Formulas (6.22) or (6.23): whereinRC2 and RA2 and RB2 have the same meaning as RA, RB, and RC recited above, to which they correspond, but are selected on an independent basis therefrom; and R2a and R2b are each individually and independently a member selected from the group consisting of hydrogen and the substituents defined by partial Formulas (6.24), (6.26), (6.41), (6.43), (6.48), and (6.50) below, provided that both of R2a and R2b cannot be hydrogen at the same time: (II-A) wherein the dashed line represents an optional double bond; R23 is a member selected from the group consisting of hydrogen; (C1-C4) alkyl, (C2-C4) alkenyl, and phenyl(C1-C4) alkyl-, where said alkyl, alkenyl, and phenyl or alkyl group attached thereto are substituted by 0 to 3 substituents R5, where the substituent R5 is as defined herein, but independently selected therefrom; and R24 is a member selected from the group consisting of hydrogen and (C1-C4) alkoxy; (II-B) R2a and R2b are taken together to form the moiety of partial Formula (6.26): wherein E represents N, resulting in a pyrimidinyl moiety and overall a quinazoline series of compounds; or represents CH, resulting in a pyridyl moiety and overall a quinoline series of compounds; R25 and R26 are each a member independently selected from the group consisting of hydrogen; (C1-C6) alkyl; (C2-C6) alkenyl; (C3-C8) cycloalkyl; hydroxy(C1-C6) alkyl; phenyl; benzyl; phenylethyl; and 2-furfuryl; and R27 is independently selected from the group consisting of: (a)(b)(6.27)(6.28)(c)(d)Morpholino; 1-Azacycloheptyl; 1-Azacyclooctyl; Pyrrolidino; Piperidino(6.29)(e)(f)(6.30)(6.31)(g)(h)(6.32)(6.33)wherein &diam;&diam; R28 is a member selected from the group consisting of hydrogen; acetyl;; (C1-C6) alkyl; and (C2-C6) alkenyl; &diam;&diam; R29 is a member selected from the group consisting of; hydrogen; (C1-C6) alkyl; hydroxy(C1-C6) alkyl; allyl; propargyl; 2-methylallyl; phenyl unsubstituted or substituted by bromo or chloro; benzyl unsubstituted or substituted by bromo or chloro; trifluoromethyl; methoxyphenyl; methylphenyl; carboxylic acid (C1-C6) alkyl ester; carboxylic acid (C2-C6) alkenyl ester; and â€”C(&boxH;O)â€”R30, where &diam;&diam; R30 is a member independently selected from the group consisting of (C1-C6) alkyl; â€”Oâ€”(C1-C6) alkyl; hydroxy(C1-C6) alkyl-Oâ€”; â€”Oâ€”(C2-C6) alkenyl; phenyl unsubstituted or substituted by bromo, chloro, methyl, 3,4,5-trimethoxy, or trifluoromethyl; naphthyl; furyl; benzofuryl; thienyl; pyridyl; tetrahydrofuryl; and tetrahydropyran; &diam;&diam; R31 is a member independently selected from the group consisting of hydrogen; (C1-C6) alkyl; (C1-C4) alkoxy; hydroxy; hydroxy(C1-C3) alkyl; phenyl; benzyl; and 4-phenyl-4-carboxylic acid (C1-C6) alkyl ester; &diam;&diam; R33 and R34 are each independently a member selected from the group consisting of hydrogen; (C1-C6) alkyl; (C1-C6) alkoxy; bromo, chloro and fluoro; â€”C(&boxH;O)(C1-C6)alkyl; â€”O(&boxH;O)â€”Oâ€”(C1-C6) alkyl; and â€”C(&boxH;O)NR36R37 and â€”S(&boxH;O)2NR36R37, where &diam;&diam; R36 and R37 are each independently hydrogen or (C1-C6) alkyl; &diam;&diam; R35 is independently hydrogen or (C1-C6) alkyl; &diam;&diam; X is â€”CHR35â€” or â€”CH2CH2â€” where R35 is as defined above; &diam;&diam; L is absent or represents (i) a heterocyclic group of partial Formula (6.32.1): where N is attached to the 2-position of the quinoline or quinazoline ring; &diam;&diam; Aa is absent or represents C(&boxH;O) or S(&boxH;O)2; &diam;&diam; Za represents CH or N; &diam;&diam; m is an integer selected from 1 and 2, as; well as from 0 when Za represents CH; and &diam;&diam; n is an integer selected from 1, 2, and 3; provided that the sum of m and n is an integer selected from 2, 3, 4, and 5; or (ii) a moiety of partial Formula (6.32.2): where N is attached to the 2-position of the quinoline or quinazoline ring; &diam;&diam; Ab and Zb have the same definition as Aa and Za above; &diam;&diam; Rt and Ru are each a member independently selected from the group consisting of hydrogen and (C1-C4) alkyl; and &diam;&diam; p is an integer selected from 1, 2, and 3, provided that when Zb is CH, p may also be selected from 0; &diam;&diam; R39 is a member independently selected from the group consisting of 4-, 5-, and 6-membered heterocyclic rings containing 1 or 2 heteroatoms selected from N, O, and S, said ring optionally being fused to a benzene ring or to a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, said ring system comprising R39 being substituted by 0 to 2 members selected from the group consisting of OH; (C1-C4) alkyl; (C1-C4) alkoxy; Br, Cl, or F; S(&boxH;O)2NRtRu; and NHS(&boxH;O)2(C1-C4) alkyl; and when said ring heteroatom is S, it may be substituted by 0 to 2 oxygen atoms; and Rt and Ru are as defined above, but independently selected therefrom; (C1-C6) alkyl; benzyl unsubstituted or substituted by fluoro, bromo, chloro, or methoxy; and where Aa is absent, â€”C(&boxH;O)â€”R40, where &diam;&diam; R40 is a member independently selected from the group consisting of (C1-C6) alkyl; phenyl unsubstituted of substituted by fluoro, bromo, chloro, methoxy, or methanesulfonyl; styryl unsubstituted or ring substituted by fluoro, bromo, chloro, methoxy, or 3,4-methylenedioxy; 4-morpholino; and 2-furyl; including particularly wherein R27 is a 1,4-diazepan of partial Formula (6.32.3): where &diam;&diam; Ra39 has the same definition as R39 but is independently selected therefrom; provided that â€”Lâ€”R39 of partial Formula (6.32) may not be piperidine or piperazine; &diam;&diam; R43 and R44 are each a member independently selected from the group consisting of hydrogen; (C1-C4)alkyl; and benzyl; &diam;&diam; n is an integer selected from 2, 3, and 4; and &diam;&diam; R45 is (C3-C6) cycloalkyl or a radical selected from the group consisting of: where &diam;&diam; m is an integer independently selected from 0, 1 and 2; and &diam;&diam; p is an integer independently selected from 0, 1 and 2; (II-C) wherein m is an integer independently selected from 2 and 3 in each instance of its occurrence; n is an integer selected from 2, 3, and 4; p is an integer selected from 2 and 3; and n and p together represent a total which is an integer selected from 5, 6, and 7; (II-D) wherein R47 is a member independently selected from the group consisting of: (a) (C1-C4) alkyl unsubstituted or substituted by 1 or 2 hydroxyl groups; phenyl(C1-C4) alkyl- unsubstituted or substituted on the phenyl portion thereof by 1 or 2 hydroxyl groups; and cinnamyl; (b) â€”CH2C(&boxH;O)NHR48 where R48 is a member independently selected from the group consisting of (C1-C4) alkyl; and phenyl unsubstituted or substituted by (C1-C4) alkoxy, trifluoromethyl, fluoro, bromo, or chloro; (c) â€”CH2C(&boxH;O)NHR49R50 where R49 and R50 are each defined the same as R48; but are selected on an independent basis therefrom; (d) a radical of partial Formula (6.44): â€ƒwherein the nitrogen atom forms part of a heterocyclic radical selected from the group consisting of morpholino; hexamethylene-imino; and pyrrolidino; and (e) â€”CH2C(&boxH;O)OR51 where R51 is hydrogen or (C1-C4) alkyl; (II-E) wherein RC2 is a member independently selected from the group consisting of hydrogen; hydroxy; and â€”Oâ€”(C1-C4) alkyl, in accordance with whether an inclusionary or exclusionary bioisostere is intended; and R54a and R54b are independently selected from the group consisting of CnH2n+1 where n is an integer selected from 1, 2, 3, and 4; and (II-F) whereinR57 is a member independently selected from the group consisting of hydrogen; (C1-C2) alkyl; and hydroxy; R58 is a member independently selected from the group consisting of hydrogen; and (C1-C2) alkyl; W is â€”C(R64)(R65)â€”; â€”CH(R64)CH(R65)â€”; or â€”CH(R64)CH(R65)CH2â€”; where R64 is a member independently selected from the group consisting of hydrogen and methyl; and R65 is a member independently selected from the group consisting of hydrogen, methyl, and hydroxy; R59 is a member selected independently from the group consisting of hydrogen; methyl; phenyl; and benzoyl; where said phenyl and benzoyl groups are unsubstituted or substituted by a member independently selected from the group consisting of m-hydroxy; p-hydroxy; m- and p-dihydroxy; m-(C1-C2)alkyl; (C1-C3)alkoxy; fluoro; chloro; cyano; hydroxymethyl; acetyl; and o-allyl; and R60 is a member independently selected from the group consisting of hydrogen; and methyl.