US 10,292,960 B2 · Anticancer agent comprising aminoacetonitrile compound as active ingredient

Abstract

The present invention relates to an anticancer agent having a high safety and a superior anticancer activity, and an anticancer agent containing, as an active ingredient, an aminoacetonitrile compound represented by the formula (I) wherein R1 is a hydrogen atom, an alkyl group and the like, R2, R3, and R4 are the same or different and each is a hydrogen atom, an alkyl group and the like, R5 and R6 are the same or different and each is a hydrogen atom, a halogen atom and the like, m is 0 or 1, R is a halogen atom, a cyano group, a nitro group, a phenyl group optionally substituted by an alkyl group and the like, an alkyl group and the like, Ar1 is a phenyl group, a naphthyl group, a pyridyl group, a pyrazolyl group, or the like, each of which is optionally substituted by a halogen atom, a cyano group, a nitro group, alkyl group and the like, and W is —O—, —S—, —SO2—, or —N(R7)— wherein R7 is a hydrogen atom, a (C1-C6) alkyl group and the like, or a pharmacologically acceptable salt thereof.

A compound represented by formula (I)

wherein
R1 is
(a1) a hydrogen atom,
(a2) a (C1-C6)alkyl group,
(a3) a (C2-C6)alkenyl group,
(a4) a (C2-C6)alkynyl group, or
(a5) a (C3-C6)cycloalkyl group;
R2, R3, and R4 are the same or different and each is
(b1) a hydrogen atom,
(b2) a (C1-C6)alkyl group, or
(b3) a (C3-C6)cycloalkyl group, or
(b4) R2 and R3 are optionally bonded to form a (C1-C6)alkylene group wherein the (C1-C6)alkylene group optionally has the same or different one or more substituents selected from a halogen atom, a (C1-C6)alkyl group, and a (C1-C6)alkoxy group on the chain;
R5 and R6 are the same or different and each is
(c1) a hydrogen atom,
(c2) a halogen atom,
(c3) a (C1-C6)alkyl group,
(c4) a (C3-C6)cycloalkyl group, or
(c5) a (C1-C6)alkoxy group, or
(c6) R5 and R6 are optionally bonded to form a (C1-C6)alkylene group;
m is 0 or 1;
R is
(d1) a phenyl group,
(d2) a phenyl group having, on the ring, the same or different 1 to 5 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a (C1-C6)alkyl group,
(e) a halo(C1-C6)alkyl group,
(f) a (C2-C6)alkenyl group,
(g) a (C2-C6)alkynyl group,
(h) a (C1-C6)alkoxy group,
(i) a halo(C1-C6)alkoxy group,
(j) a halo(C2-C6)alkenyloxy group,
(k) a halo(C2-C6)alkynyloxy group,
(l) a (C1-C6)alkylthio group,
(l1) a (C1-C6)alkylsulfinyl group,
(m) a (C1-C6)alkylsulfonyl group,
(n) a halo(C1-C6)alkylthio group,
(n1) a halo(C1-C6)alkylsulfinyl group,
(n2) a halo(C1-C6)alkylsulfonyl group,
(o) a phenyl(C2-C6)alkynyl group,
(o1) a phenyl group,
(o2) a phenyl group having, on the ring, the same or different 1 to 5 substituents selected from
(i) a halogen atom,
(ii) a cyano group,
(iii) a nitro group,
(iv) a (C1-C6)alkyl group, and
(v) a halo(C1-C6)alkyl group;
(p) a phenoxy group,
(q) a pyridyloxy group having, on the ring, the same or different 1 to 4 substituents selected from
(i) a halogen atom, and
(ii) a halo(C1-C6)alkyl group;
(r) a pyridyl(C2-C6)alkynyl group,
(s) a (C1-C6)alkylcarbonyl group,
(t) a (C1-C6)alkoxycarbonyl group,
(u) an aminocarbonyl group,
(v) a (C1-C6)alkylcarbonylamino group,
(w) a (C1-C6)alkoxycarbonylamino group,
(x) a di(C1-C6)alkylamino group (the alkyl groups are the same or different), and
(y) a (C1-C6)alkylaminocarbonylamino group,
(d3) a naphthyl group,
(d4) a naphthyl group having, on the ring, the same or different 1 to 7 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a (C1-C6)alkyl group, and
(e) a halo(C1-C6)alkyl group,
(d5) a (C1-C12)alkyl group,
(d6) a pyridyl group,
(d7) a pyridyl group having, on the ring, the same or different 1 to 4 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a (C1-C6)alkyl group, and
(e) a halo(C1-C6)alkyl group,
(d8) a pyrazinyl group,
(d9) a pyrazinyl group having, on the ring, the same or different 1 to 3 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a (C1-C6)alkyl group, and
(e) a halo(C1-C6)alkyl group,
(d10) a thiazolyl group,
(d11) a thiazolyl group having, on the ring, the same or different 1 to 2 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a (C1-C6)alkyl group, and
(e) a halo(C1-C6)alkyl group,
(d12) a pyrazolyl group, or
(d13) a pyrazolyl group having, on the ring, the same or different 1 to 3 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a (C1-C6)alkyl group, and
(e) a halo(C1-C6)alkyl group;
Ar1 is
e1) a phenyl group,
(e2) a phenyl group having, on the ring, the same or different 1 to 5 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a (C1-C6)alkyl group,
(e) a halo(C1-C6)alkyl group,
(f) a (C2-C6)alkenyl group,
(g) a (C2-C6)alkynyl group,
(h) a (C1-C6)alkoxy group,
(i) a halo(C1-C6)alkoxy group,
(j) a halo(C2-C6)alkenyloxy group,
(k) a halo(C2-C6)alkynyloxy group,
(l) a (C1-C6)alkylthio group,
(m) a (C1-C6)alkylsulfonyl group that is optionally substituted by one or more halogen atoms,
(n) a halo(C1-C6)alkylthio group,
(o) a phenyl(C2-C6)alkynyl group,
(p) a phenoxy group,
(q) a pyridyloxy group having, on the ring, the same or different 1 to 4 substituents selected from
(i) a halogen atom, and
(ii) a halo(C1-C6)alkyl group,
(r) a hydroxyl group,
(s) a phenyl group, and
(t) a halo(C1-C6)alkylsulfonylamino group,
(e3) a naphthyl group,
(e4) a naphthyl group having, on the ring, the same or different 1 to 7 substituents selected from
(a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a (C1-C6)alkyl group, and
(e) a halo(C1-C6)alkyl group,
(e5) a pyridyl group,
(e6) a pyridyl group having, on the ring, the same or different 1 to 4 substituents selected from
(a) a halogen atom,
(b) a (C1-C6)alkyl group,
(c) a halo(C1-C6)alkyl group,
(d) a (C1-C6)alkylthio group,
(e) a (C1-C6)alkylsulfonyl group,
(f) a halo(C1-C6)alkylthio group, and
(g) a (C1-C6)alkoxy group,
(e7) a pyrazolyl group, or
(e8) a pyrazolyl group having, on the ring, the same or different 1 to 3 substituents selected from
(a) a halogen atom,
(b) a (C1-C6)alkyl group,
(c) a halo(C1-C6)alkyl group,
(d) a (C1-C6)alkylthio group,
(e) a (C1-C6)alkylsulfonyl group,
(f) a (C1-C6)alkoxycarbonyl group,
(g) a (C1-C6)alkoxy group,
(h) a halo(C1-C6)alkoxy group,
(i) a (C1-C6)alkoxy(C1-C6)alkoxy group,
(j) a cyclo(C3-C6)alkyl group,
(k) a phenoxy group, and
(l) a phenyl group, or
(e9) a heterocyclic group selected from following Q-1 to Q-17,
wherein X and Y are the same or different and each is
(a) a halogen atom,
(b) a cyano group,
(c) a nitro group,
(d) a (C1-C6)alkyl group,
(e) a cyclo(C3-C6)alkyl group,
(f) a halo(C1-C6)alkyl group,
(g) a (C1-C6)alkoxy group,
(h) a halo(C1-C6)alkoxy group,
(i) a (C1-C6)alkylthio group,
(j) a phenyl group,
(m) a phenyl group having, on the ring, the same or different 1 to 4 substituents selected from
(i) a halogen atom,
(ii) a (C1-C6)alkyl group,
(iii) a halo(C1-C6)alkyl group, and
(iv) a (C1-C6)alkoxy group,
(n) a pyridyl group,
(o) a (C1-C6)alkylcarbonyl group,
(p) a (C1-C6)alkoxycarbonyl group,
(q) a mono(C1-C6)alkylamino group,
(r) a (C1-C6)alkoxy(C1-C6)alkylamino group,
(s) a di(C1-C6)alkylamino group (the alkyl groups are the same or different),
(t) a (C1-C6)alkoxycarbonylamino group,
(u) a monophenylamino group,
(v) a morpholino group, or
(w) a piperidino group,
• is a binding position,
n is an integer of 0 to 3;
and
W is —O—, —S—, —SO2—, or —N(R7) — wherein R7 is a hydrogen atom, a (C1-C6)alkyl group or a (C3-C6)cycloalkyl group;
wherein
(i) Ar1 is a phenyl group substituted with a single substituent selected from halo(C1-C6)alkylthio and halo(C1-C6)alkylsulfonyl, except that when Ar1 is a phenyl group substituted with a single halo(C1-C6)alkylthio group, R is not a phenyl group substituted with one or more (d2)(a) or (d2)(e) groups;
or
(ii) R is a phenyl group substituted with a single substituent selected from halo(C1-C6)alkylthio group, halo(C1-C6)alkylsulfinyl group, and halo(C1-C6)alkylsulfonyl group;
excluding
N-[(1S)-1-cyano-2-(5-cyano-2-trifluoromethylphenoxy)-1-methyl-ethyl]-4-trifluoromethylsulfanylbenzamide,
N-[(1R)-1-cyano-2-(5-cyano-2-trifluoromethylphenoxy)-1-methy-ethyl]-4-trifluoromethylsulfanylbenzamide,
N-[1-cyano-2-(5 -cyano-2-trifluoromethylphenoxy)- 1-methyl-ethyl]-4-trifluoromethylsulfanylbenzamide,
N-[2-(2-chlorophenoxy)-1-cyano-1-methyl-ethyl]-4-trifluoromethylbenzamide,
N-[1-cyano-2-(2-trifluoromethylphenoxy)-1-methy-ethyl]-4-trifluoromethylbenzamide,
N-[1-cyano-2-(2-trifluoromethylphenoxy)-1-methyl-ethyl]-4-trifluoromethoxybenzamide,
N-[1-cyano-2-(2,5-dichlorophenoxy)-1-methyl-ethyl]-4-trifluoromethoxybenzamide,
N-[2-(2-chloro-5-fluorophenoxy)-1-cyano-1-methyl-ethyl]-4-trifluoromethoxybenzamide,
N-[2-(2-chloro-4-fluorophenoxy)-1-cyano-1-methyl-ethyl]-4-trifluoromethoxybenzamide,
N-[2-(2-bromo-4,5-difluorophenoxy)-1-cyano-1-methyl-ethyl]-4-trifluoromethoxybenzamide, and
N-[1-cyano-2-(4,5-difluoro-2-trifluoromethylphenoxy)-1-methyl-ethyl]-4-trifluoromethoxybenzamide,
or a pharmacologically acceptable salt thereof.

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Anticancer agent comprising aminoacetonitrile compound as active ingredient

Life of this patent

Anticancer agent comprising aminoacetonitrile compound as active ingredient

Life of this patent

Abstract

Claims15