Pharmaceutical for treatment of neurological and neuropsychiatric disorders

Abstract

The invention provides a pharmaceutical for treatment of neurological and neuropsychiatric disorders comprising a compound of the formula: or a pharmaceutically acceptable salt thereof.

1 . A compound of the following formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof,  
     wherein: 
 (1) X is nitrogen or carbon, and R 2  is not present when X is nitrogen;  
 (2) R 2  (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 R 1  is not aminoethylene, —O—R 8  or —S—R 8 *) hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, (c) forms a double bond with an adjacent carbon or nitrogen from one of either R 1 , R xb  or R yb , or (d) is R 2a  linked by R 2b  to X;  
 (2 i ) R x  is R xa  linked by R xb  to X;  
 (2 ii ) R y  is R ya  linked by R yb  to X;  
 (2 iii ) R xa , R ya  and R 2a , are independently Ar 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) Ar is phenyl or naphthyl, or heteroaromatic that 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,  
 (b) each of R xa , R ya  and R 2a  can be independently substituted with one of R q , R r O— or R s S—, wherein each of R q , R r  and R s  are independently Ar aryl, heteroaryl, adamantyl or a 5 to 7-membered non-aromatic ring as these ring structures are defined for R xa , and  
 (c) R xa , R ya , R 2a , R q , R r  and R s  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, (C2-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 wherein the amidino can be 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 R xa , R ya  and R 2a  can be combined to form a second bridge between two of R xa , R ya  and R 2a  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) —CH 2 C(═O)—, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (7) —C(═O)—O—, (8) —CH 2 —O—, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (9) —C(═O)N(R 24 ), wherein R 24  is hydrogen or (C1-C6) alkyl, (10)—CH 2 —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 R xa , R ya  and R 2a  can be directly linked by a single bond;  
 
 
 (2 iv ) R xb  and R 2b  are independently a single bond or (C1-C2) alkylene;  
 (2 v ) R yb  is a single bond, oxo, (C1-C2) alkylene, ethenylene or —CH═ (where the double bond is with X), thio, methyleneoxy or methylenethio, or either —N(R 6 ) or —CH 2 —N(R 6 *)—, wherein R 6  and R 6 * are hydrogen or (C1-C6) alkyl, wherein when X is nitrogen X is not bonded to another heteroatom;  
 (3) R 1  comprises: a straight-chained (C2-C3) aliphatic group; where X is carbon, ═N—O-(ethylene), wherein the unmatched double bond is linked to X; —O—R 8  or —S—R 8 * wherein R 8  or R 8 *is a ethylene or ethenylene and O or S is bonded to X; aminoethylene where the amino is bonded to X: 
 wherein R 1  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 X, then R yb  does not contribute a heteroatom linked to X;  
 wherein the alkyl or alkylidene substituents of R 1  can be linked to form a 3 to 7-membered non-aromatic ring; and  
 wherein if X is nitrogen, X is linked to R 1  by a single bond and the terminal carbon of R 1  that links R 1  to N is saturated;  
 
 (4) R 3  (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 of R xa  (b) is —R 12 Z(R xx )(R yy )(R 11 ), wherein R 12  is bonded to N, Z is independently the same as X, R xx  is independently the same as R x , R yy  is independently the same as R y , R 11  is independently the same as R 2  and R 12  is independently the same as R 1 , or (c) forms, together with R 4 , a ring C, as follows:  
                     
 , wherein R 4 * is hydrogen when ring C is present;  
 (5) n is 0 or 1, and where if n is 1, R 3 * 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 R 5  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, Ar, 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) R 4  and R 4 * are independently hydrogen or (C1-C6) alkyl, or one of R 4  and R 4 * can be (C1-C6) hydroxyalkyl; and  
 (7) R 5  is (CO)NR 13 R 14 , (CO)OR 15 , (CO)SR 16 , (SO 2 )NR 17 R 18 , (PO)(OR 19 )(OR 20 ), (CR 22 )(OR 23 )(OR 24 ), CN or tetrazol-5-yl, wherein (a) R 13 , R 14 , R 15 , R 16 , R 17 , R 18  R 19  and R 20  are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R 15  or the sulfur of R 16  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) R 22  is hydrogen or OR 25  and R 23 , R 24  and R 25  are (C1-C6) alkyl, phenyl, benzyl, acetyl or the alkyls of R 23  and R 24  can be combined to include 1,3-dioxolane or 1,3-dioxane: 
 wherein the Ar of R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 , R 23  or R 24  is phenyl, naphthyl or heteroaryl that 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 Ar groups of R 13 , R 14 , R 15 , R 16  R 17 , R 18 , R 19 , R 20 , R 22 , R 23  or R 24  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, 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;  
 wherein R 13  and R 14  together with the nitrogen can form a 5 to 7-membered ring that can contain one additional heteroatom selected from oxygen and sulfur;  
 wherein if R 15  is hydrogen and R 1  is propylene, then at least one of the following applies (1) both R x  and R y  are not p-fluorophenyl, (2) one of R x  and R y  includes a heteroaryl, (3) R y  is Ar—(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio Ar-methylthio, Ar—N(R 6 )— or Ar—CH 2 —N(R 6 *)—, (4) R 2  is R xa  R xb —, (5) R 2  is not hydrogen, (6) R 3  is not hydrogen, (7) n is one, or (8) R 3  and R 4  form ring Q;  
 wherein if R 15  is hydrogen and R 1  is ethylene or X—R 1  is prop-1-enylene, then at least one of the following applies (1) an aryl of at least one of R x  and R y  is substituted with a radical different from hydrogen, (2) one of R x  and R y  comprises a heteroaryl, (3) R y  is Ar—(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—N(R 6 )— or Ar—CH 2 —N(R 6 *)—, (4) R 2  is R xa  R xb , (5) R 2  is not hydrogen, (6) R 3  is not hydrogen, (7) n is one, or (8) R 3  and R 4  form ring Q;  
 wherein if R 5  is C(O)NR 13 R 14  wherein R 13  and R 14  are hydrogen, (C1-C8) alkyl, phenyl or substituted phenyl, then at least one of the following applies (1) an aryl of at least one of R x  and R y  is substituted with a radical different from hydrogen, (2) one of R x  and R y  comprises a heteroaryl, (3) R y  is Ar—(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—N(R 6 )— or Ar—CH 2 —N(R 6 *)—, (4) R 2  is R xa  R xb —, (5) R 2 * is not hydrogen, (6) R 3  is not hydrogen, (7) n is one, (8) R 1  is not ethylene, or (9) R 3  and R 4  form ring Q;  
 wherein if R 13  is hydrogen and R 14  is (3,4-dihydro-2H-1-benzopyran-4-yl)methylene, then at least one of the following applies (1) an aryl of at least one of R x  and R y  is substituted with a radical different from hydrogen, (2) one of R x  and R y  comprises a heteroaryl, (3) R y  is Ar—(C1-C2)alkyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—N(R 6 )— or Ar—CH 2 —N(R 6 *)—, (4) R 2  is R xa  R xb —, (5) R 2  is not hydrogen, (6) R 3  is not ethyl, (7) n is one, or (8) R 3  and R 4  form ring Q; and  
 wherein if R 2  is phenyl, p-methylphenyl or p-methoxyphenyl, then at least one of the following applies (1) the aryls of R x  and R y  are not substituted with p-methylphenyl or p-methoxyphenyl, (2) an aryl of at least one of R x  and R y  is substituted with a radical different from hydrogen, (3) one of R x  and R y  comprises a heteroaryl, (4) R y  is Ar—(C1-C2)alklyl, Ar-oxy, Ar-methoxy, Ar-thio, Ar-methylthio, Ar—N(R 6 )— or Ar—CH 2 —N(R 6 *)—, (5) R 1  is not aminoethylene, OR 8  or SR 8 *, (6) n is one, or (7) R 3  and R 4  form ring Q.  
 
 
   
   
       2 . The compound of  claim 1 , the ring Q is a 4 to 8-membered ring that includes the illustrated ring nitrogen, with the remaining ring atoms being carbon.  
   
   
       3 . The compound of  claim 1 , wherein (A) at least one of R xa  R ya  and R 2a  is substituted with fluoro, chloro, bromo, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, (C3-C8) alkyl, R q , R r O—, R s S—, (B) R 3  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 R xa  or (C) the ring stuctures of R xa , R ya  and R 2a , including substituents thereto, otherwise include at least two aromatic ring structures that together include from 15 to 20 ring atoms.  
   
   
       4 . The compound of  claim 3 , wherein at least one of R xa , R ya  and R 2a  is substituted with fluoro, trifluoromethyl, trifluoromethoxy, nitro, cyano, or (C3-C8) alkyl.  
   
   
       5 . The compound of  claim 1 , wherein at least one of R xa , R ya  and R 2a  is substituted with R q , R r O—, or R s S—.  
   
   
       6 . The compound of  claim 1 , wherein an aryl or heteroaryl of at least one of R xa , R ya  and R 2a  is phenyl.  
   
   
       7 . The compound of  claim 1 , wherein R yb  is oxo, methyleneoxy, thio, methylenethio.  
   
   
       8 . The compound of claim, wherein R yb  is oxo or thio.  
   
   
       9 . The compound of  claim 1 , wherein R 5  is (CO)NR 13 R 14 , (CO)OR 15  or (CO)SR 16 .  
   
   
       10 . The compound of  claim 9 , wherein R 15  is (C2-C6) alkyl, (C2-C4) hydroxyalkyl, phenyl, phenylalkyl wherein the alkyl is C1-C3, or aminoalkyl where the alkyl is C2-C6 and the amino can be substituted with up to two independent (C1-C3) alkyls, wherein the phenyl or the phenyl of phenylalkyl can be substituted.  
   
   
       11 . The compound of  claim 9 , wherein R 15  is hydrogen.  
   
   
       12 . The compound of  claim 1 , wherein R 4  is hydrogen, methyl or hydroxymethyl and R 4 * is hydrogen.  
   
   
       13 . The compound of  claim 1 , wherein at least one of R xa , R ya  and R 2a  is a heteroaryl comprising diazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiolyl, diazinyl, triazinyl, benzoazolyl, benzodiazolyl, benzothiazolyl, benzoxazolyl, benzoxolyl, benzothiolyl, quinolyl, isoquinolyl, benzodiazinyl, benzotriazinyl, pyridyl, thienyl, furanyl, pyrrolyl, indolyl, isoindoyl or pyrimidyl.  
   
   
       14 . The compound of  claim 1 , wherein R 1  is -0-R 8  or —S—R 8 *.  
   
   
       15 . The compound of  claim 1 , wherein said second bridge between two of R xa , R ya  and R 2a  is L, and satisfies the following formula:  
     
       
         
         
             
             
         
       
     
     , wherein A and B are Ar groups of R xa  and R ya , respectively.  
   
   
       16 . The compound of  claim 14 , wherein R xa —R xb —, R ya —R yb — and X form:  
     
       
         
         
             
             
         
       
     
     wherein Y is a carbon bonded to R 1  by a single or double bond or a nitrogen that is bonded to R 1  and wherein R 21  either (i.) completes a single bond linking two aryl or heteroaryl rings of R x  and R y , (ii.) is (C1-C2) alkylene or alkenylene, (iii.) is sulfur or (iv.) is oxygen, and wherein R x  and R y  can be substituted as set forth above.  
   
   
       17 . The compound of  claim 16 , wherein R 21  is CH 2 CH 2  or CH═CH.  
   
   
       18 . The compound of  claim 1 , wherein the alkylenedioxy substitution of R xa , R ya  or R 2a  is as follows:  
     
       
         
         
             
             
         
       
     
     wherein the alkylenedioxy can be substituted with up to two independent (C1-C3) alkyl.  
   
   
       19 . The compound of  claim 1 , wherein R xa  and R ya  together can be substituted with up to six substituents, R 2a , R q  R r  and R s  can each be substituted with up to 3 substituents, and wherein the presence of each of R q , R r  or R s  is considered a substitution to the respective ring structure of R xa , R ya  and R 2a .  
   
   
       20 . The compound of  claim 1 , wherein a phenyl of R 3  is substituted with up to three substituents.  
   
   
       21 . The compound of  claim 1 , wherein the aryl, heteroaryl, aryl of arylalkyl or the heteroaryl of heteroarylalkyl of R 13 , R 14 , R 15 , R 16  R 17 , R 18 , R 19  or R 20  is substituted with up to three substituents.  
   
   
       22 . The compound of  claim 1 , wherein the compound is an optically pure enantiomer.  
   
   
       23 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient.  
   
   
       24 . The pharmaceutical composition of  claim 23 , wherein the compound of  claim 1  is present in an effective amount for: 
 (1) treating or preventing schizophrenia,    (2) enhancing treating or preventing dementia,    (3) treating or preventing epilepsy,    (4) treating or preventing spasticity,    (5) treating or preventing muscle spasm,    (6) treating or preventing pain,    (7) preventing neural cell death after stroke,    (8) preventing neural cell death in an animal suffering from a neurodegenerative disease,    (9) treating or preventing mood disorders,    (10) enhancing memory or learning, or    (11) treating or preventing learning disorders.    
   
   
       25 . 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 (11) treating or preventing learning disorders, comprising administering an amount effective for said treating, preventing or enhancing of a compound of formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, 
 (1) X is nitrogen or carbon, and R 2  is not present when X is nitrogen;  
 (2) R 2  (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 R 1  is not aminoethylene, —O—R 8  or —S—R 8 *) hydroxy, fluoro, chloro, bromo or (C2-C7) alkanoyloxy, (c) forms a double bond with an adjacent carbon or nitrogen from one of either R 1 , R xb  or R yb , or (d) is R 2a  linked by R 2b  to X;  
 (2 i ) R x  is R xa  linked by R xb  to X;  
 (2 ii ) R y  is R ya  linked by R yb  to X;  
 (2 iii ) R xa , R ya  and R 2a , are independently Ar, 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) Ar is phenyl or naphthyl, or heteroaromatic that 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,  
 (b) each of R xa , R ya  and R 2a  can be independently substituted with one of R q , R r O— or R s S—, wherein each of R q , R r  and R s  are independently Ar, adamantyl or a 5 to 7-membered non-aromatic ring as these ring structures are defined for R xa , and  
 (c) R xa , R ya , R 2a , R q , R r  and R s  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, (C2-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 wherein the amidino can be 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 R xa , R ya  and R 2a  can be combined to form a second bridge between two of R xa , R ya  and R 2a  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) —CH 2 C(═O)—, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (7) —C(═O)—O—, (8) —CH 2 —O—, which can be substituted for hydrogen with up to two independent (C1-C6) alkyl, (9) —C(═O)N(R 24 ), wherein R 24  is hydrogen or (C1-C6) alkyl, (10) —CH 2 —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 R xa , R ya  and R 2a  can be directly linked by a single bond;  
 
 
 (2 iv ) R xb  and R 2b  are independently a single bond or (C1-C2) alkylene;  
 (2 v ) R yb  is a single bond, oxo, (C1-C2) alkylene, ethenylene or —CH═ (where the double bond is with X), thio, methyleneoxy or methylenethio, or either —N(R 6 ) or —CH 2 —N(R 6 *)—, wherein R 6  and R 6 * are hydrogen or (C1-C6) alkyl, wherein when X is nitrogen X is not bonded to another heteroatom;  
 (3) R 1  comprises: a straight-chained (C2-C3) aliphatic group; where X is carbon, ═N—O-(ethylene), wherein the unmatched double bond is linked to X; —O—R 8  or —S—R 8 * wherein R 8  or R 8 *is a ethylene or ethenylene and O or S is bonded to X; aminoethylene where the amino is bonded to X: 
 wherein R 1  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 R 1  can be linked to form a 3 to 7-membered non-aromatic ring: and  
 wherein if X is nitrogen, X is linked to R 1  by a single bond and the terminal carbon of R 1  that links R 1  to N is saturated;  
 
 (4) R 3  (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 of R xa , (b) is —R 12 Z(R xx )(R yy )(R 11 ), wherein R 12  is bonded to N, Z is independently the same as X, R xx  is independently the same as R x , R yy  is independently the same as R y , R 11  is independently the same as R 2  and R 12  is independently the same as R 1 , or (c) forms, together with R 4 , a ring C, as follows:  
                     
 , wherein R 4 * is hydrogen when ring C is present;  
 (5) n is 0 or 1, and where if n is 1, R 3 * 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 R 5  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, Ar, 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) R 4  and R 4 * are independently hydrogen or (C1-C6) alkyl, or one of R 4  and R 4 * can be (C1-C6) hydroxyalkyl; and  
 (7) R 5  is (CO)NR 13 R 14 , (CO)OR 15 , (CO)SR 16 , (SO 2 )NR 17 R 18 , (PO)(OR 19 )(OR 20 ), (CR 22 )(OR 23 )(OR 24 ), CN or tetrazol-5-yl, wherein (a) R 13 , R 14 , R 15 , R 16 , R 17 , R 18  R 19  and R 20  are independently hydrogen, (C1-C8) alkyl which can include a (C3-C8) cycloalkyl, wherein the carbon linked to the oxygen of R 15  or the sulfur of R 16  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) R 22  is hydrogen or OR 25  and R 23 , R 24  and R 25  are (C1-C6) alkyl, phenyl, benzyl, acetyl or the alkyls of R 23  and R 24  can be combined to include 1,3-dioxolane or 1,3-dioxane: 
 wherein the Ar of R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 , R 23  or R 24  is phenyl, naphthyl or heteroaryl that 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 Ar groups of R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 22 , R 23  or R 24  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, 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 R 13  and R 14  together with the nitrogen can form a 5 to 7-membered ring that can contain one additional heteroatom selected from oxygen and sulfur.  
 
 
   
   
       26 . The method of  claim 25 , wherein the spasticity is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury or dystonia.  
   
   
       27 . The method of  claim 26 , wherein the neurodegenerative disease is Alzheimer's disease, multi-infarct dementia, AIDS dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis or stroke or head trauma.  
   
   
       28 - 42 . (canceled)