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Pharmaceutical for treatment of neurological and neuropsychiatric disorders

  • US 6,191,165 B1
  • Filed: 05/30/1997
  • Issued: 02/20/2001
  • Est. Priority Date: 05/31/1996
  • Status: Expired due to Fees
First Claim
Patent Images

1. A compound of the following formula:

  • or a pharmaceutically acceptable salt thereof,wherein;

    (1) C* is a substituted carbon;

    (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 aminoethylene, —

    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 R2a linked by R2b to C*, or (e) is ethylene forming a third bridging structure as set forth in (2iii)(b)(i);

    (2i) Rx is Rxa linked by Rxb to C*;

    (2ii) Ry is Rya linked by Ryb to C*;

    (2iii) Rxa, Rya and R2a, are independently Ar, which is phenyl or naphthyl, or a 5 to 7-membered non-aromatic ring having 0 heteroatoms wherein;

    (a) each of Rxa and Rya can be independently substituted with one of Rq, RrO—

    or RsS—

    , wherein each of Rq, Rr and Rs are independently Ar or adamantyl, and (b) Rxa, Rya, R2a, Rq, Rr and Rs can be substituted or additionally substituted with one or more 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, (C1-C12) alkyl, (C2-C12) alkenyl, amino, (C1-C6) alkylamino, dialkylamino wherein each alkyl of dialkylamino 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, or amidino wherein the amidino can be independently substituted with up to three (C1-C6) alkyl groups, wherein;

    (i.) the substitutions of Rxa and Rya can be combined to form a second bridge between Rxa and Rya comprising (1) methylene or ethylene, which methylene or ethylene can be substituted by an R2 when R2 is ethylene to form the third bridging structure, or (2) —

    CH═

    CH—

    or wherein Rxa and Rya 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, oxy, (C1-C2) alkylene, ethenylene or —

    CH═

    (where the double bond is with C*), thio, methyleneoxy or methylenethio, or either —

    N(R6) or —

    CH2

    N(R6*)—

    , wherein R6 and R6* are hydrogen or (C1-C6) alkyl;

    (3) R1 comprises;

    a straight-chained (C2-C3) aliphatic group;



    N—

    O-(ethylene), wherein the unmatched double bond is linked to C*;



    O—

    R8 or —

    S—

    R8* wherein R8 or R8* is a ethylene or ethenylene and O or S is bonded to C*;

    aminoethylene where the amino is bonded to C*;

    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 (C1-C6) alkylidene, with the proviso that the hydroxy, alkoxy, alkanoyloxy or oxo substituents are not bonded to a carbon that is bonded to a nitrogen or oxygen;

    wherein if R1 contributes a heteroatom linked to C*, then Ryb does not contribute a heteroatom linked to C*; and

    wherein the alkyl or alkylidene substituents of R1 can be linked to form a 3 to 7-membered non-aromatic ring;

    (4) R3 (a) is hydrogen, (C1-C6) alkyl, or phenyl or phenylalkyl wherein the alkyl is C1 to C6 and the phenyl or phenyl of phenylalkyl can be substituted with the same substituents defined above for the phenyl of Rxa, (b) is —

    R12C(Rxx)(Ryy)(R11), wherein R12 is bonded to N, Rxx is independently the same as Rx, Ryy is independently the same as Ry, R11 is independently the same as R2 and R12 is independently the same as R1;

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

    (6) R5 is (CO)NR13R14, (CO)OR15, (CO)SR16, (SO2)NR17R18, (PO)(OR19)(OR20), (CR22)(OR23)(OR24), CN or tetrazol-5-yl, wherein (a) 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, Ar-alkyl wherein the alkyl is C1-C6, or Ar, and (b) R22 is hydrogen or OR25 and R23, R24 and R25 are independently (C1-C6) alkyl, phenyl, benzyl or acetyl or, the alkyls of R23 and R24 can be combined to include 1,3-dioxolane or 1,3-dioxane;

    wherein the phenyl or naphthyl groups of R13, R14, R15, R16, R17, R18, R19, R20, R22, R23 or R24 can be substituted with substituents selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, hydroxy, 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, or amidino that can substituted with up to three (C1-C6) alkyl;

    wherein R13 and R14 together with the attached nitrogen can form a 5 to 7-membered ring;

    and wherein further the following provisos apply;

    if R15 is hydrogen and R1 is propylene, then at least one of the following applies (1) both Rxa and Rya are not fluorophenyl, (2) Ry is Ar—

    (C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—

    N(R6)—

    or Ar—

    CH2

    N(R6*)—

    , (3) R2 is R2a R2b

    , (4) R2 is not hydrogen, or (5) R3 is not hydrogen;

    if R15 is hydrogen and R1 is ethylene or C*R1 is prop-1-enylene, then at least one of the following applies (1) an Ar of at least one of Rxa and Rya is substituted with a radical different from hydrogen, (2) Ry is Ar—

    (C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—

    N(R6)—

    or Ar—

    CH2

    N(R6*)—

    , (3) R2 is R2a R2b

    , (4) R2 is not hydrogen, or (5) R3 is not hydrogen;

    if R5 is C(O)NR13R14 wherein R13 and R14 are hydrogen, (C1-C8) alkyl, phenyl or substituted phenyl, then at least one of the following applies (1) an Ar of at least one of Rx and Ry is substituted with a radical different from hydrogen, fluoro, chloro, or bromo (2) Ry is Ar—

    (C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—

    N(R6)—

    or Ar—

    CH2

    N(R6*)—

    , (3) R2 is R2a R2b

    , (4) R2 is not hydrogen, (5) R3 is not hydrogen, or (6) R1 is not ethylene;

    if R2 is phenyl or p-methylphenyl, then at least one of the following applies (1) the Ar of Rx and Ry are not substituted with p-methylphenyl or p-methoxyphenyl, (2) an Ar of at least one of Rx and Ry is substituted with a radical different from hydrogen, (3) Ry is Ar—

    (C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—

    N(R6)—

    or Ar—

    CH2—

    N(R6*)—

    , or (4) R1 is not aminoethylene, OR8 or SR8*;

    if R2 is p-methoxyphenyl, then at least one of the following applies (1) an Ar of at least one of Rx and Ry is substituted with a radical different from hydrogen, (2) Ry is Ar—

    (C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—

    N(R6)—

    or Ar—

    CH2

    N(R6*)—

    , or (3) R1 is not OR8 or —

    SR8*, and the compound is not N-(1,1-diphenylpropyl)-glycinamide or N-(1,1-diphenylpropyl)-glycinamide having one or more halo substitutions on one or more of the phenyls and differs therefrom by at least two of the following;

    (a) substitutions or (b) differences in Rx, Ry, R1, R3, R4, R4* or R5.

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