Triazole derivative
The invention relates to a triazole derivative with an activity inhibiting glycine transporter and for use as a pharmaceutical drug, and a novel triazole derivative. The inventive triazole derivative has an excellent activity inhibiting glycine transporter and is useful as a therapeutic agent of dementia, schizophrenia, cognitive disorders, or cognitive disorders involved in various diseases such as Alzheimer disease, Parkinson's disease, or Huntington disease or the like, or spasm involved in diseases such as nerve degenerative diseases and cerebrovascular disorders, or the like. Particularly, the pharmaceutical drug is useful for the amelioration of learning disability of dementia and the like.
1. A pharmaceutical composition for glycine transporter inhibitor which comprises a triazole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as the effective ingredient:
(in the formula, the symbols represent the following meanings;
Ring A:
(3) a 5-membered hetero ring which may be substituted and contain one or two nitrogen atoms as the hetero atoms composing the ring and may contain one oxygen atom or sulfur atom as a hetero atom other than the nitrogen atoms and may be condensed with benzene ring or
Ring B or D may be the same or different and each represents aromatic carbon ring which may be substituted, an aliphatic carbon atom which may be substituted, or a hetero ring which may be substituted.
R: H, halogeno-lower alkyl, aryl which may be substituted, hetero ring which may be substituted, cycloalkyl which may be substituted, or -[Alk1]m-X-[Alk2]n-Y—R 1
wherein R 1 : H, OH, cyano, aryl which may be substituted, hetero ring which may be substituted, cycloalkyl which may be substituted, or lower alkoxyl;
X: bond, oxygen atom, S(O)q, or —N(R 2 )—;
Y: bond, —C(O)—, —C(O)—N(R 3 )—, -Z 1 -Alk3-, or —N(R 3 )-Alk3-C(O)—, with the proviso that R 1 represent other than OH and lower alkoxy, when Y is bond;
Alk1 or Alk2 may be the same or different and each represents lower alkylene, lower alkenylene or lower alkynylene; and
m or n may be the same or different and each represents 0 or 1 or m+n=1, provided that X represents bond;
Z 1 : S(O)q, —N(R 3 )—, —C(O)— or —C(O)—N(R 3 )—;
Alk3: lower alkylene;
R 2 or R 3 : the same or different from each other and each represents H or lower alkyl;
q may be 0, 1, or 2.
2. A pharmaceutical composition for ameliorating learning disability according to claim 1 .
3. A triazole derivative represented by the following general formula (Ia) or a salt thereof:
(in the formula, the symbols represent the following meanings;
Ring A′:
the formula:
(4) a 5-membered hetero ring which may be substituted with one or two substituents selected from the group represented by Rf and contain one or two nitrogen atoms as the hetero atoms composing the ring and may contain one oxygen atom or sulfur atom as a hetero atom other than the nitrogen atoms and may be condensed with benzene ring; or
Ring B′: benzene or nitrogen-containing monocyclic hetero ring; or
Ring D′: benzene or hetero ring, provided that ring A′, B′ and D′ never simultaneously represents benzene ring;
Ra: a halogeno-lower alkyl, a hetero ring which may be substituted, cycloalkyl which may be substituted, or -[Alk1]m-X-[Alk2]n-Y—R 1
wherein
R 1 : H, OH, cyano, aryl which may be substituted, hetero ring which may be substituted, cycloalkyl which may be substituted, or lower alkoxyl;
X: bond, oxygen atom, S(O)q, or —N(R 2 )—;
Y: bond, —C(O)—, —C(O)—N(R 3 )—, -Z 1 -Alk3-, or —N(R 3 )-Alk3-C(O)—, with the proviso that R1 represent other than OH and lower alkoxy, when Y is bond;
Alk1 or Alk2 may be the same or different and each represents lower alkylene, lower alkenylene, or lower alkynylene;
m or n may be the same or different and each represents 0 or 1 or m+n=1, provided that X represents bond;
Z 1 : S(O)q, —N(R 3 )—, —C(O)— or —C(O)—N(R 3 )—;
Alk3: lower alkynylene;
R 2 or R 3 : the same or different from each other and each represents H, or lower alkyl;
Rb: halogen atom, lower alkyl which may be substituted with the following substituents, lower alkynyl, halogeno-lower alkyl, hetero ring, hetero ring-O—, cyano, nitro, halogeno-lower alkyl-O—, lower alkoxyl, —O-lower alkylene-N(R 3 )-lower alkylene-C(O)O—R 6 , Z 2 -R 6 , or Z 3 -R 7 , the substituents of the lower alkyl: OH, cyano, lower alkoxyl, amino which may be substituted with lower alkyl;
Z 2 : S(O)q, —N(R 3 )—, —C(O)—, —C(O)—N(R 3 )—, —N(R 3 )—C(O)—, —C(O)—S(O)q-, —N(R 3 )—S(O)q-, or —C(O)O—;
Z 3 : —N(R 3 )—, or —N(R 3 )—C(O)—;
R 6 : H, lower alkyl or aryl;
R 7 : OH, or lower alkoxyl;
p: 0 or 1;
q: 0, 1 or 2;
Rc: lower alkyl, or halogen atom;
Rd or Re: the same or different from each other and each represents H, halogen atom, lower alkyl, lower alkoxyl, OH, lower alkyl, halogeno-lower alkyl, phenyl, halogeno-lower alkyl-O—, amino which may be substituted with lower alkyl or —N R 8 C(O)—R 9 ;
R 8 or R 9 : the same or different from each other and each represents H, or lower alkyl;
Rf: a group represented by Rb, oxo group, or aryl, with the proviso that Rd represents other than H, when the ring A′ represents benzene substituted with lower alkoxyl and the ring B′ represents benzene.