Pharmaceutical for treatment of neurological and neuropsychiatric disorders

A method (1) of treating or preventing schizophrenia comprising administering a schizophrenia treating or preventing effective amount of a compound, (2) of treating or preventing dementia comprising administering a dementia treating or preventing effective amount of a compound, (3) of treating or preventing epilepsy comprising administering an epilepsy treating or preventing effective amount of a compound, (4) of treating or preventing spasticity comprising administering a spasticity treating or preventing effective amount of a compound, (5) of treating or preventing muscle spasm comprising administering a muscle spasm treating or preventing effective amount of a compound, (6) of treating or preventing pain comprising administering a pain treating or preventing effective amount of a compound, (7) of preventing neural cell death after stroke comprising administering a neural cell death preventing effective amount of a compound, (8) of preventing neural cell death in an animal suffering from a neurodegenerative disease, (9) treating or preventing mood disorders. (10) enhancing memory or learning, or (I 1) treating or preventing learning disorders, comprising administering an amount effective for said treating, preventing or enhancing of a compound of formula:

• 48
• or a pharmaceutically acceptable salt thereof,
• (1) X is nitrogen or carbon, and R2 is not present when X is nitrogen;
• (2) R2 (a) is hydrogen, (C1-6) alkyl, (C1-6) 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, or (d) is R2a linked by R2b to X;
• (2i) Rx is Rxa linked by Rxb to X;
• (2ii) Ry is Rya linked by Ryb to X;
• (2ii) 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, RrO— or RsS—, wherein each of Rq, Rr and Rs are independently aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring as these ring structures are defined for Rxa, and
• (d) Rxa, Rya, R2a, Rq, Rr and Rs can be 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, adamantyl, (C1-C12) alkyl, (C1-C12) alkenyl, amino, (C1-6) 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) —CH2C(═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 (I 1)—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 straight-chained (C2-C3) aliphatic group;
• where X is carbon ═N—O—(ethylene), wherein the unmatched double bond is linked to X;
• (where X is carbon and Ryb does not include a heteroatom attached to X), —O—R8or —S—R8* wherein R8 or R8* is a ethylene or ethenylene and O or S is bonded to X;
• (where X is carbon and Ryb does not include a heteroatom attached to X), aminoethylene where the amino 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 (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 the alkyl or alkylidene substituents of R1 can be linked to form a 3 to 7-membered non-aromatic ring:
• and
• wherein 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) R3 (a) is hydrogen, (C1-C6) alkyl, or phenyl or phenylalkyl wherein the alkyl is C1 to C6 and either such phenyl can be substituted with the same substituents defined above for the aryl or heteroaryl of Rxa, (b) is —R12Z(Rxx)(Ryy)(R11), wherein R12 is bonded to N, Z is independently the same as X, Rxx is independently the same as Rx, Ryy is independently the same as Ry, R1 1 is independently the same as R2 and R12 is independently the same as R1, or (c) forms, together with R4, a ring C, as follows:
• 49
• , wherein R4* is hydrogen when ring C is present;
• (5) 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′) Q together with the illustrated ring nitrogen and ring carbon bearing R5 form ring C, wherein ring C is a 3 to 8-membered ring, a 3 to 8-membered ring substituted with a 3 to 6-membered spiro ring, or a 3 to 8-membered ring fused with a 5 to 6-membered ring, wherein the fused ring lacking the illustrated ring nitrogen can be aromatic or heteroaromatic, wherein for each component ring of ring C there are up to two heteroatoms selected from oxygen, sulfur or nitrogen, including the illustrated nitrogen, and the rest carbon, with the proviso that the ring atoms include no quaternary nitrogens other than the illustrated nitrogen, with the proviso that, in saturated rings, ring nitrogen atoms are separated from other ring heteroatoms by at least two intervening carbon atoms:
• wherein the carbon and nitrogen ring atoms of ring C 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 Rxa or heteroaryl wherein the heteroaryl is as defined for Rxa, 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;
• (6) R4 and R4* are independently hydrogen or (C1-C6) alkyl, or one of R4 and R4* can be (C1-C6) hydroxyalkyl;
• and
• (7) R5 is (CO)NR13R14, (CO)OR15, (CO)SR16, (SO2)NR17R18, (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 C1-6, heteroarylalks 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-dioxolane 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 or arylalkyl or the heteroaryl of heteroarylalkyl 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 CI 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 (C1-6) 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.

A compound of the following formula:

• 82
• 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 and Rya, are independently Ar, which is phenyl or naphthyl, heteroaryl, or 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, and R2a, when present, is Ar, and wherein:
• (a) heteroaryl comprises thienyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, or one of the foregoing fused to phenyl, or methylenedioxyphenyl,
• (b) 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, 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, and
• (c) 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 (3) sulfur, or (4) oxygen, or wherein Rxa and Rya can be directly linked by a single bond,
• (d) wherein at least one of Rxa, Rya, Rq, Rr or Rs is heteroaryl, or a second bridge between Rxa and Ryacomprises sulfur or oxygen as set forth below, or Ar substituted with a methylenedioxy;
• (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, (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, (C1-6) 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.