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Pharmaceutical for treating of neurological and neuropsychiatric disorders

  • US 6,001,854 A
  • Filed: 05/30/1997
  • Issued: 12/14/1999
  • Est. Priority Date: 05/31/1996
  • Status: Expired due to Fees
First Claim
Patent Images

1. A compound of formula I or II:

  • ##STR57## or a pharmaceutically acceptable salt thereof, wherein;

    (1) X is nitrogen or carbon, and R2 is not present when X is nitrogen;

    (2) R2 (a) is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, cyano, (C2-C7) alkanoyl, aminocarbonyl, (C1-C6) alkylaminocarbonyl or dialkylaminocarbonyl wherein each alkyl is independently C1 to C6, (b) comprises (where R1 is not --O--R8 or --S--R8*) hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, (c) forms a double bond with an adjacent carbon or nitrogen from one of either R1, Rxb or Ryb, (d) is oxygen forming an oxa linkage with R1 or integrated into ring E (see, for example, Compound C6) or (e) is R2a linked by R2b to X;

    (2i) Rx is a ring-containing structure Rxa linked by Rxb to X;

    (2ii) Ry is a ring-containing structure Rya linked by Ryb to X;

    (2iii) Rxa, Rya and R2a, are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring having from 0 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein;

    (a) aryl is phenyl or naphthyl,(b) heteroaryl comprises a five-membered ring, a six-membered ring, a six-membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon,(c) each of Rxa, Rya and R2a can be independently substituted with one of Rq, Rr O-- or Rs S--, wherein Rq, Rr and Rs are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring as these structures are defined for Rxa, and(d) Rxa, Rya, R2a, Rq, Rr and Rs can be substituted or additionally substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, hydroxy, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, adamantyl, (C1-C12) alkyl, (C1-C12) alkenyl, amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl is independently C1 to C6, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, amidino that can independently substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl, wherein;

    (i) the substitutions of Rxa, Rya and R2a can be combined to form a second bridge between two of Rxa, Rya and R2a comprising (1) (C1-C2) alkyl or alkenyl, which can be independently substituted with one or more (C1-C6) alkyl, (2) sulfur, (3) oxygen, (4) amino, which can be substituted for hydrogen with one (C1-C6) alkyl, (5) carbonyl, (6) --CH2 C(═

    O)--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (7) --C(═

    O)--O--, (8) --CH2 --O--, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (9) --C(═

    O)--N(R24)--, wherein R24 is hydrogen or (C1-C6) alkyl, (10) --CH2 --NH--, which can be substituted for hydrogen with up to three (C1-C6) alkyl, or (11) --CH═

    N--, which can be substituted for hydrogen with (C1-C6) alkyl, or wherein two of Rxa, Rya and R2a can be directly linked by a single bond;

    (2iv) Rxb and R2b are independently a single bond or (C1-C2) alkylene;

    (2v) Ryb is a single bond, oxa, (C1-C2) alkylene, ethenylene or --CH═

    (where the double bond is with X), thia, methyleneoxy or methylenethio, or either --N(R6)-- or --CH2 --N(R6*)--, wherein R6 and R6* are hydrogen or (C1-C6) alkyl, wherein when X is nitrogen X is not bonded to another heteroatom;

    (3) R1 comprises;

    a single bond or double bond;

    a straight-chained (C1-C3) aliphatic group;

    or (where X is carbon and Ryb does not include a heteroatom attached to X) --O--R8 or --S--R8*, wherein either R8 or R8* is a single bond, (C1-C3) alkylene or (C2-C3) alkenylene and O or S is bonded to X;

    wherein R1 can be substituted with up to one hydroxy, up to one (C1-C6) alkoxy or up to one (C2-C7) alkanoyloxy, with up to two independent (C1-C6) alkyl, with up to one oxo, up to one (C2-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy, oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen, or (where R1 is --O--R8 and X is carbon) an oxa linkage to X forming a 1,3-dioxolane,wherein the alkyl or alkylidene substituents of R1 can be linked to form a 3 to 7-membered non-aromatic ring, andwherein if X is nitrogen, X is linked to R1 by a single bond and the terminal carbon of R1 that links R1 to N is saturated;

    (4) n is 0 or 1, and where if n is 1, R3* is either (C1-C6) alkyl (with the attached nitrogen having a positive charge) or oxygen (forming an N-oxide) and X is carbon;

    (5) wherein ring D is a 6-membered ring, a 6-membered ring substituted with a 3 to 6-membered spiro ring, or a 6-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens;

    wherein the carbon and nitrogen ring atoms of ring D can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl, (C1-C6) alkoxy, oxo, hydroxycarbonyl, aryl wherein the aryl is as defined for Ra or heteroaryl wherein the heteroaryl is as defined for Ra, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and

    wherein R1, R3 and G are such that at least two atoms separate X and the illustrated ring nitrogen;

    (6) wherein ring E is a 6-membered ring, a 6-membered ring substituted with a 3 to 6-membered spiro ring, or a 6-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated tertiary nitrogen can be aromatic, with the proviso that the ring atoms include no quaternary nitrogens;

    wherein the carbon and nitrogen ring atoms of ring E can be substituted with substituents selected from (C1-C6) alkyl, (C2-C6) alkenylene, cyano, nitro, trifluoromethyl, (C2-C7) alkyloxycarbonyl, (C1-C6) alkylidene, hydroxyl (C-C6) alkoxy, oxo, hydroxycarbonyl, (C1-C6) alkoxycarbonyl, aryl wherein the aryl is as defined for Ra, or heteroaryl wherein the heteroaryl is as defined for Ra, with the proviso that ring atoms substituted with alkylidene, hydroxycarbonyl or oxo are carbon, with the further proviso that ring atoms substituted with hydroxyl or alkoxy are separated from other ring heteroatoms by at least two intervening carbon atoms; and

    wherein G* and R18 are such that at least two atoms separate the illustrated ring nitrogen from the carbon linked to Rx and Ry ;

    (7) R19 (a) forms a double bond with R1, R3 or G, (b) is hydrogen (c) is (C1-C3) alkyl or alkylene, or (d) is incorporated into a fused ring;

    (8) R4 and R4* are independently hydrogen or (C1-C6) alkyl or one of R4 and R4* can be (C1-C6) hydroxyalkyl; and

    (9) R5 is (CO)NR13 R14, (CO)OR15, (CO)SR16, (SO2)NR17 R18, (PO)(OR19)(OR20), (CR22)(OR23)(OR24), CN or tetrazol-5-yl, wherein R13, R14, R15, R16, R17, R18, R19 and R20 are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R15 or the sulfur of R16 has no more than secondary branching and, (C2-C6) hydroxyalkyl, aminoalkyl where the alkyl is C2 to C6 and the amino can be substituted with up to two independent (C1-C6) alkyls, arylalkyl wherein the alkyl is C1-C6, heteroarylalkyl wherein the alkyl is C1 to C6, aryl or heteroaryl, R22 is hydrogen or OR25 and R23, R24 and R25 are (C1-C6) alkyl, phenyl, benzyl, acetyl or, where R22 is hydrogen, the alkyls of R23 and R24 can be combined to include 1,3-dioxylane or 1,3-dioxane;

    wherein the aryl is phenyl or naphthyl and the heteroaryl is a five-membered ring, a six-membered ring, a six-membered ring fused to a five-membered ring, a five-membered ring fused to a six-membered ring, or a six-membered ring fused to a six-membered ring, wherein the heteroaryl is aromatic and contains heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon;

    wherein the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of heteroarylalkyl can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, trifluoromethyl, amidosulfonyl which can have up to two independent (C1-C6) N-alkyl substitutions, (C1-C6) alkyl, (C2-C6) alkenyl, (C1-C6) alkylamine, dialkylamine wherein each alkyl is independently C1 to C6, amino, (C1-C6) alkoxy, (C2-C7) alkanoyl, (C2-C7) alkanoyloxy, trifluoromethoxy, hydroxycarbonyl, (C2-C7) alkyloxycarbonyl, aminocarbonyl that can be N-substituted with up to two independent (C1-C6) alkyl, (C1-C6) alkylsulfonyl, amidino that can substituted with up to three (C1-C6) alkyl, or methylenedioxy or ethylenedioxy with the two oxygens bonded to adjacent positions on the aryl or heteroaryl ring structure, which methylenedioxy or ethylenedioxy can be substituted with up to two independent (C1-C6) alkyl; and

    wherein R13 and R14 together with the nitrogen can form a 5 to 7-membered ring that can contain one additional heteroatom selected from oxygen and sulfur;

    wherein when (i) D is piperidine, (ii) R2 is OH, (iii) Rx is Rxa, and (iv) Ry is Rya, then Rxa and Rya are not phenyl, phenyl substituted with fluoro, chloro, bromo, hydroxy, trifluoromethyl, C1-C8 alkyl, C1-C6 alkoxy, or not pyridyl, and R5 is not (CO)NR13 R14 or (CO)OR15 when R13, R14, and R15 are independently hydrogen, C1-C8 alkyl, phenyl, or phenyl substituted with fluoro, chloro, bromo, C1-C6 alkyl or C1-C6 alkoxy; and

    wherein when (i) D is piperidine, (ii) X is carbon, (iii) R1 is OR8, (iv) R5 is (CO)OR15, (v) Rx is Rxa and (vi) Ry is Rya, then Rxa and Rya are not both phenyl or phenyl substituted with fluoro, chloro, bromo, C1-C4 alkyl or C1-C4 alkoxy and R15 is not hydrogen or C1-C4 alkoxy.

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