US 8,173,642 B2 · Aminodihydrothiazine derivatives

Abstract

A composition having BACE 1 inhibitory activity containing a compound represented by the general formula (I): wherein ring A is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; E is lower alkylene; X is S, O, or NR1; R1 is a hydrogen atom or lower alkyl; R2a, R2b, R3a, R3b, R4a and R4b is each independently a hydrogen atom, halogen, or hydroxy etc.; n and m are each independently an integer of 0 to 3; n+m is an integer of 0 to 3; R5 is a hydrogen atom or substituted lower alkyl; its pharmaceutically acceptable salt, or a solvate thereof.

A compound represented by the formula (I):

wherein E is bond and ring A is phenyl, phenyl being substituted optionally with at least one selected from the group consisting of
(A) the substituent α, the substituent α being at least one selected from the group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group;
(B) lower alkyl optionally substituted with one or more substituents selected from the group of substituent α;
(C) amino lower alkyl substituted with one or more substituents selected from the group of substituent α;
(D) hydroxyimino lower alkyl;
(E) lower alkoxyimino lower alkyl;
(F) lower alkenyl optionally substituted with one or more substituents selected from the group of substituent α;
(G) lower alkynyl optionally substituted with one or more substituents selected from the group of substituent α;
(H) lower alkoxy optionally substituted with one or more substituents selected from the group of substituent α;
(I) lower alkylthio optionally substituted with one or more substituents selected from the group of substituent α;
(J) lower alkylamino substituted with one or more substituents selected from the group of substituent α;
(K) lower alkylsulfonyl optionally substituted with one or more substituents selected from the group of substituent α;
(L) aryl lower alkoxycarbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(M) acyl substituted with one or more substituents selected from the group of substituent α;
(N) cycloalkyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(O) lower alkylsulfinyl optionally substituted with one or more substituents selected from the group of substituent α;
(P) sulfamoyl;
(Q) aryl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(R) heterocyclic group optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(S) aryloxy optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(T) heterocyclicoxy optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(U) arylthio optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(V) heterocyclic thio optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(W) arylamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(X) heterocyclicamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(Y) aryl lower alkylamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(Z) heterocyclic lower alkylamino optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AA) lower alkyl sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α;
(AB) aryl sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AC) heterocyclic sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AD) arylsulfonyl substituted optionally with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AE) heterocyclic sulfonyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AF) aryl carbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AG) heterocyclic carbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AH) aryl lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AI) heterocyclic lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alky;
(AJ) aryloxycarbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AK) heterocyclicoxycarbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido, and lower alkyl;
(AL) lower alkylenedioxy substituted optionally with halogen;
(AM) oxo;
(AN) azido;
and
(AO) one of the following formulae:
wherein Q1, Q2 and Q3 are each independently a bond, lower alkylene or lower alkenylene, lower alkylene and lower alkenylene being substituted optionally with a substituent α, the substituent α being at least one selected from the group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group;
Q4 is lower alkylene or lower alkenylene, lower alkylene and lower alkenylene being substituted optionally with a substituent α, the substituent α being at least one selected from the group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group;
W1 and W2 are each independently O or S;
W3 is 0, S or NR12;
R12 is a hydrogen atom, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic group lower alkyl or acyl;
R14 is a hydrogen atom or lower alkyl;
ring B is a carbocyclic group or a heterocyclic group,
the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the group consisting of
(a) a substituent α, the substituent α being at least one selected from the group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group;
(b) lower alkyl optionally substituted with the substituent α;
(c) amino lower alky substituted with the substituent α;
(d) hydroxyimino lower alkyl;
(e) lower alkoxyimino lower alkyl;
(f) lower alkenyl optionally substituted with the substituent α;
(g) lower alkynyl optionally substituted with the substituent α;
(h) lower alkoxy optionally substituted with the substituent α;
(i) lower alkylthio optionally substituted with the substituent α;
(j) lower alkylamino substituted with the substituent α;
(k) lower alkylsulfonyl optionally substituted with the substituent α;
(l) aryl lower alkoxycarbonyl optionally substituted with one or more substituents selected from the group of substituent α and lower alkyl;
(m) acyl substituted with the substituent α;
(n) lower alkylsulfonyl optionally substituted with the substituent α;
(o) sulfamoyl;
(p) lower alkyl sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α;
(q) cycloalkyl optionally substituted with one or more substituents selected from the group of substituent α azido and lower alkyl;
(r) aryl optionally substituted with one or more substituents selected from the group of substituent α azido and lower alkyl;
(s) heterocyclic group optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(t) aryloxy optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(u) heterocyclicoxy optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(v) arylthio optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(w) heterocyclic thio optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(x) arylamino optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(y) heterocyclic amino optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(z) aryl lower alkylamino optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(aa) heterocyclic lower alkylamino optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ab) arylsulfamoyl optionally substituted with one or more substituents selected from the group of substituent α azido and lower alkyl;
(ac) heterocyclic sulfamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ad) arylsulfonyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ae) heterocyclic sulfonyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(af) arylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ag) heterocyclic carbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ah) aryl lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ai) heterocyclic lower alkylcarbamoyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(aj) aryloxy carbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(ak) heterocyclicoxycarbonyl optionally substituted with one or more substituents selected from the group of substituent α, azido and lower alkyl;
(al) lower alkylenedioxy substituted optionally with halogen;
and
(am) oxo;
Alk2 is lower alkyl, lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α;
and
p is an integer of 1 or 2;
X is S;
R2a and R2b are each independently a hydrogen atom, hydroxy, lower alkyl, lower alkenyl, amino, amidino, acyl, carbamoyl, carbamoylcarbonyl, lower alkylsulfonyl, arylsulfonyl, or a heterocyclic group,
lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α, the substituent α being at least one selected from the group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group, lower alkenyl being substituted optionally with the substituent α,
amino being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
amidino being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
acyl includes aliphatic acyl of a carbon number of 1 to 10, carbocyclic carbonyl and heterocyclic carbonyl;
and
acyl being substituted optionally with the substituent α;
and the ring part of the “carbocyclic carbonyl” and the “heterocyclic carbonyl” is substituted optionally with at least one selected from the group of “lower alkyl”;
the “substituent group α”;
and “lower alkyl substituted with at least one selected from the group of the substituent α”,
carbamoyl being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
carbamoylcarbonyl being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
lower alkylsulfonyl being substituted optionally with the substituent α, the arylsulfonyl being substituted optionally with at least one selected from the group consisting of the substituent α and a lower alkyl, and
carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the group consisting of the substituent α and a lower alkyl;
R3a, R3b, R4a, and R4b are each independently a hydrogen atom, halogen, hydroxy, lower alkyl, lower alkenyl, acyl, carboxy, lower alkoxycarbonyl, amino, carbamoyl, a carbocyclic group, or a heterocyclic group,
lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α, the substituent α being at least one selected from the group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group,
lower alkenyl being substituted optionally with the substituent α,
acyl includes aliphatic acyl of a carbon number of 1 to 10, carbocyclic carbonyl and heterocyclic carbonyl;
and
acyl being substituted optionally with the substituent α;
and the ring part of the “carbocyclic carbonyl” and the “heterocyclic carbonyl” is substituted optionally with at least one selected from the group of “lower alkyl”;
the “substituent group a”;
and “lower alkyl substituted with at least one selected from the group of the substituent α”,
lower alkoxycarbonyl being substituted optionally with the substituent α, amino being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group,
carbamoyl being substituted optionally with at least one selected from the group consisting of lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, a carbocyclic group and a heterocyclic group, and
the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the group consisting of the substituent α and a lower alkyl;
n=2 and m=0;
each R3a, each R3b, each R4a, and each R4b may be independently different;
R5 is a hydrogen atom, lower alkyl, lower alkenyl, lower alkynyl, a carbocyclic group, or a heterocyclic group,
lower alkyl being substituted optionally with at least one selected from the group consisting of a substituent α, the substituent α being at least one selected from the group consisting of halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano, nitro, aryl, and heterocyclic group, lower alkenyl being substituted optionally with the substituent α,
lower alkynyl being substituted optionally with the substituent α, and
the carbocyclic group and the heterocyclic group being substituted optionally with at least one selected from the group consisting of the substituent α and lower alkyl;
with the proviso that the compounds;
i) wherein R5 is a hydrogen atom, and ring A is non-substituted phenyl;
ii) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 is methyl, and ring A is phenyl or 4-methoxyphenyl;
iii) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 is ethyl, and ring A is 3,4-dimethoxyphenyl;
iv) wherein n is 2, m is 0, R2a is a hydrogen atom, R2b is a hydrogen atom or acetyl, R5 and ring
A is phenyl;
v) and wherein R5 is a hydrogen atom,
ring A is phenyl which has only one or two substituent(s) selected from the group consisting of hydroxy, halogen, lower alkyl, lower alkoxy, nitro, amino, lower alkylcarbonylamino, mercapto, lower alkylthio, and carbamoyl,
non-substituted phenyl,
or non-substituted naphthyl;
are excluded,
a pharmaceutically acceptable salt thereof or a hydrate thereof.

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Aminodihydrothiazine derivatives

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Aminodihydrothiazine derivatives

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Abstract

Claims13