US 7,459,459 B2 · Tri-heterocyclic compounds and a pharmaceutical comprising them as an active ingredient

Abstract

Tri-heterocyclic compound of formula (I) wherein each of W, X and Y is carbon or nitrogen; each of U and Z is CR2, NR13, nitrogen, oxygen, sulfur etc.; A ring is carbocyclic ring, heterocyclic ring; R1 is alkyl, alkenyl, alkynyl, NR4R5, OR6 etc.; R3 is carbocyclic ring, heterocyclic ring; and a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical comprising them as an active ingredient. A compound of formula (I) is useful, in order to possess corticotropin releasing factor receptor antagonistic activity, for the prevention and/or treatment of depression, anxiety, eating disorder, posttraumatic stress disorder, peptic ulcer, irritable bowl syndrome, Alzheimer's disease, drug addiction or alcohol dependence syndrome etc.

A compound of formula (I)

wherein X is carbon;
Y is nitrogen;
W is carbon or nitrogen;
U and Z each independently, is CR2, NR13, nitrogen, oxygen, sulfur, C═O or C═S;
R2 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) C2-8 alkynyl,
(v) halogen atom,
(vi) CF3,
(vii) cyano,
(viii) nitro,
(ix) NR9R10 in which R9 and R10 each independently,
(i) hydrogen,
(ii) C1-4 alkyl,
(iii) C3-10 mono- or bi-carbocyclic ring,
(iv) 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) or
(v) C1-4 alkyl substituted by C3-10 mono- or bi-carbocyclic ring or 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s),
(x) OR11 in which R11 is
(i) hydrogen,
(ii) C1-4 alkyl,
(iii) C5-6 carbocyclic ring,
(iv) 5 or 6 membered heterocyclic ring containing 1-2 of nitrogen(s), 1 of oxygen and/or 1 of sulfur or
(v) C1-4 alkyl substituted by C5-6 carbocyclic ring or 5 or 6 membered heterocyclic ring containing 1-2 of nitrogen(s), 1 of oxygen and/or 1 of sulfur,
(xi) SH,
(xii) S(O)nR12 in which n is 0, 1 or 2, R12 is
(i) C1-4 alkyl,
(ii) C5-6 carbocyclic ring,
(iii) 5 or 6 membered heterocyclic ring containing 1-2 of nitrogen(s), 1 of oxygen and/or 1 of sulfur or
(iv) C1-4 alkyl substituted by C5-6 carbocyclic ring or 5 or 6 membered heterocyclic ring containing 1-2 of nitrogen(s), 1 of oxygen and/or 1 of sulfur,
(xiii) COR11,
(xiv) COOR11,
(xv) CONR9R10,
(xvi) C3-10 mono-or bi-carbocyclic ring,
(xvii) 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) or
(xviii) C1-4 alkyl substituted by 1-2 of substitutes selected from halogen atom, CF3, OCF3, cyano, nitro, NR9R10, OR11, ═N—OR11, SH, S(O)nR12, COR11, COOR11, CONR9R10, C3-10mono- or bi- carbocyclic ring and 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s),
R13 is
(i) hydrogen,
(ii) C1-4 alkyl,
(iii) C2-4 alkenyl,
(iv) C2-4 alkynyl,
(v) C3-10 mono- or bi-carbocyclic ring,
(vi) 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) or
(vii) C1-4 alkyl substituted by C3-10 mono- or bi-carbocyclic ring or 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s),
is a single bond or a double bond,
is C4-6 carbocyclic ring which is unsubstituted or substituted by 1-3 of substitutes selected from C1-4 alkyl, C1-4 alkoxy, halogen atom and CF3,
R1 is
(i) C1-8 alkyl which is unsubstituted or substituted by 1-5 of R14,
(ii) C2-8 alkenyl which is unsubstituted or substituted by 1-5 of R14,
(iii) C2-8 alkynyl which is unsubstituted or substituted by 1-5 of R14,
(iv) NR4R5 in which R4 and R5 each independently,
(i) hydrogen,
(ii) C1-15 alkyl which is unsubstituted or substituted by 1-5 of R17,
(iii) C2-15 alkenyl which is unsubstituted or substituted by 1-5 of R17,
(iv) C2-15 alkynyl which is unsubstituted or substituted by 1-5 of R17,
(v) C3-15 mono- or bi-carbocyclic ring which is unsubstituted or substituted by 1-5 of R18,
(vi) 3-15 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R18,
(v) OR6 in which R6 is
(i) hydrogen,
(ii) C 1-10 alkyl,
(iii) C2-10 alkenyl,
(iv) C2-10 alkynyl,
(v) C3-15 mono- or bi-carbocyclic ring which is unsubstituted or substituted by 1-5 of R18,
(vi) 3-15 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R18,
(vii) C1-4 alkyl substituted by 1-2 of substitutes selected from halogen atom, CF3, OCF3, cyano, nitro, NR9R10, OR11, ═N—OR11, SH, S(O)nR12, COR11, COOR11, CONR9R10, C3-10 mono- or bi-carbocyclic ring which is unsubstituted or substituted by 1-5 of R18, and 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R18,
(vi) SH,
(vii) S(O)nR7 in which n is as hereinbefore defined, R7 is
(i) C1-8 alkyl,
(ii) C3-10 mono- or bi-carbocyclic ring which is unsubstituted or substituted by 1-5 of R18,
(iii) 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R18,
(iv) C1-4 alkyl substituted by C3-10 mono- or bi-carbocyclic ring, which is unsubstituted or substituted by 1-5 of R18 or 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R18,
(viii) COR6,
(ix) COOR6,
(x) CONR4R5,
(xi) NR8COR6a in which R6a is
(i) hydrogen,
(ii) C1-10 alkyl,
(iii) C2-10 alkenyl,
(iv) C2-10 alkynyl or
(v) C1-4 alkyl substituted by 1-2 of substitutes selected from halogen atom, CF3, OCF3, cyano, nitro, NR9R10, OR11a, ═N—R11, SH, S(O)nR12, COR11, COOR11 and CONR9R10,
(xii) NR8COOR6 in which R6 is as hereinbefore defined, R8 is
(i) hydrogen,
(ii) C1-8 alkyl,
(iii) C2-8 alkenyl,
(iv) C2-8 alkynyl,
(v) C3-10 mono- or bi-carbocycic ring which is unsubstituted or substituted by 1-5 of R18,
(vi) 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R18 or
(vii) C1-4 alkyl substituted by 1-2 of substitutes selected from halogen atom, CF3, OCF3, cyano, nitro, NR9R10,═N—OR11, SH, S(O)nR12, COR11,COOR11, CONR9R10, C3-10 mono- or bi-carbocyclic ring which is unsubstituted or substituted by 1-5 of R18, and 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R18,
(xiii) NR8CONR4R5,
(xiv) C3-15 mono- or bi-carbocyclic ring which is unsubstituted or substituted by 1-5 of R15 or
(xv) 3-15 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R15,
R11a is (i) hydrogen, (ii) C1-4 alkyl or (iii) C1-4 alkyl substituted by C5-6 carbocyclic ring or 5 or 6 membered heterocyclic ring containing 1-2 of nitrogen(s), 1 of oxygen and/or 1 of sulfur,
R14 is (a) halogen atom, (b) CF3, (c) OCF3, (d) cyano, (e) nitro, (f) NR4R5, (g) OR6, (h) ═N—OR6, (j) SH, (k) S(O)nR7, (l) COR6, (m) COOR6, (n) CONR45, (o) NR8COR6, (p) NR8COOR6, (q) NR8CONR4R5, (r) C3-15 mono- or bi-carbocyclic ring which is unsubstituted or substituted by 1-5 of R15 or (s) 3-15 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R15,
R15 is (a) C1-8 alkyl, (b) C2-8 alkenyl, (c) C2-8 alkynyl, (d) C1-4 alkoxy(C1-4)alkyl, (e) halogen atom, (f) CF3, (g) OCF3, (h) cyano, (j) nitro, (k) NR4R5, (l) OR6, (m) SH, (n) S(O)nR7, (o) COR6, (p) COOR6, (q) CONR4R5, (r) NR8COR6, (s) NR8COOR6, (t) NR8CONR4R5, (u) C3-10 mono- or bi-carbocyclic ring which is unsubstituted or substituted by 1-5 of R20, (v) 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R20 or (w) C1-4 alkyl substituted by 1-2 of substitutes selected from halogen atom, CF3, OCF3, cyano, nitro, NR4R5, OR6, ═N—OR6, SH, S(O)nR7, COR6,COOR6, CONR4R5,NR8COR6,NR8COOR6, NR8CONR4R5, C3-10 mono- or bi-carbocyclic ring which is unsubstituted or substituted by 1-5 of R20, and 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R20,
R17 is (a) halogen atom, (b) CF3, (c) OCF3, (d) cyano, (e) nitro, (f) NR9R10, (g) OR11a, (h) ═N—OR11, (j) SH, (k) S(O)nR12, (l) COR11, (m) COOR11, (n) CONR9R10, (o) NR8COR11, (p) NR8COOR11, (q) NR8CONR9R10, (r) C3-15 mono- or bi-carbocyclic ring which is unsubstituted or substituted by 1-5 of R18a or (s) 3-15 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) which is unsubstituted or substituted by 1-5 of R18a,
R18 is (a) C1-4 alkyl, (b) C2-4 alkenyl, (c) C2-4 alkynyl, (d) halogen atom, (e) CF3, (f) OCF3, (g) cyano, (h) nitro, (j) SH, (k) S(O)nR12, (l) NR9R10, (m) OR11, (n) COR11, (o) COOR11, (p) CONR9R10, (q) C5-6 carbocyclic ring, (r) 5 or 6 membered heterocyclic ring containing 1-2 of nitrogen(s), 1 of oxygen and/or 1 of sulfur or (s) C1-4 alkyl substituted by C5-6 carbocyclic ring or 5 or 6 membered heterocyclic ring containing 1-2 of nitrogen(s), 1 of oxygen and/or 1 of sulfur,
R18a is (a) C1-4 alkyl, (b) C2-4 alkenyl, (c) C2-4 alkynyl, (d) halogen atom, (e) CF3, (f) OCF3, (g) cyano, (h) nitro, (j) SH, (k) S(O)nR12, (l) NR9R10, (m) OR11a, (n) COR11, (o) COOR11 or (p) CONR9R10,
R19 is C1-4 alkyl, C1-4 alkoxy, halogen atom, CF3, OCF3, cyano, nitro, amino, NH(C1-4 alkyl) or N(C1-4 alkyl)2,
R3 is (i) C5-10 mono- or bi-carbocyclic ring substituted by 1-5 of R16 or
(ii) 5-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s) substituted by 1-5 of R16,
R16 is(a)C1-8 alkyl,
(b) C2-8 alkenyl,
(c) C2-8 alkynyl,
(d) halogen atom,
(e) CF3,
(f) OCF3,
(g) cyano,
(h) nitro,
(j) NR9R10,
(k) OR11,
(l) SH,
(m) S(O) nR12,
(n) COR11,
(o) COOR11,
(p) CONR9R10,
(q) NR8COR11,
(r) NR8COOR11,
(s) NR8CONR9R10,
(t) C3-10 mono- or bi-carbocyclic ring,
(u) 3-10 membered mono- or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s)
(v) C1-4 alkyl substituted by 1-2 of substitutes selected from halogen atom, CF3, OCF3, cyano, nitro, NR9R10, OR11, ═N-OR11, SH, S(O) nR12, COR11, COOR11, CONR9R10, NR8COR11, NR8COOR11, NR8CONR9R10, C3-10 mono- or bi-carbocyclic ring, and 3-10 membered mono-or bi-heterocyclic ring containing 1-4 of nitrogen(s), 1-2 of oxygen(s) and/or 1-2 of sulfur(s),
with the proviso that (1) when each of X and W is carbon, each of Y and Z is nitrogen, U is CR2 and R1 is OR6, then R3 is not phenyl substituted by 1 of halogen atom, phenyl substituted by 1 of trifluoromethyl and phenyl substituted by trifluoromethyl and nitro, (2) when each of X and Z is carbon and each of U and W is nitrogen, then R3 is C5-10 mono- or bi-carbocyclic ring substituted by 1-5 of R16;
and (3) when R16 is S(O)nR12 and R12 is (iii), R12 is a 5 or 6 membered heterocyclic ring containing 1-2 nitrogen, a 5 or 6 membered heterocyclic ring containing 1 of oxygen and/or a 5 membered heterocyclic ring containing 1 of sulfur;
a pharmaceutically acceptable salt thereof or a hydrate thereof.

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Tri-heterocyclic compounds and a pharmaceutical comprising them as an active ingredient

Life of this patent

Tri-heterocyclic compounds and a pharmaceutical comprising them as an active ingredient

Life of this patent

Abstract

Claims12