US 7,491,748 B2 · Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient

Abstract

A carboxylic acid derivative of formula (I): wherein R1 is —COOH, —COOR6, etc.; A is a single bond, alkylene, etc.; R2 is alkyl, alkoxy, etc.; B is a carbocyclic ring or a heterocyclic ring; Q is alkylnene-Cyc2, etc.; D is a linking chain; and R3 is alkyl, a carbocyclic ring or a heterocyclic ring, or a non-toxic salt thereof. The compound of formula (I) binds to PGE2 receptor, especially subtypes EP3 and/or EP4 and show the antagonizing activity, are useful for the prevention and/or treatment of diseases induced pain, itch, urticaria, allergy, urinary frequency, urinary disturbance, Alzheimer's disease, cancer, dysmenorrhea, endometriosis, etc.

A carboxylic acid compound of formula (I):

wherein R1 is —COOH, —COOR4,
R4 is C1-6 alkyl or —(C1-4 alkylene)—R11,
R11 is hydroxy, C1-4 alkoxy, —COOH, C1-4 alkoxycarbonyl or —CONR7R8,
R7 and R8 each independently, is
(i) hydrogen,
(ii) C1-6 alkyl,
(iii) hydroxy,
(iv) —COR17,
(v) a C3-15 mono-, bi- or tri-carbocyclic ring or a 3- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R12 or unsubstituted, or
(vi) C1-4 alkyl substituted with a C3-15 mono-, bi- or tri-carbocyclic ring or a 3- to 15-membered mono-, bi- or tri-heterocyclic ring which is substituted with 1-5 of R12 or unsubstituted,
R12 is (a) C1-6 alkyl, (b) C1-6 alkoxy, (c) C1-6 alkylthio, (d) halogen, (e) CF3, (f) cyano, (g) nitro, (h) hydroxy, (i) —COOR13, (j) —NHCOR13, (k) —SO2R14, (1) —NR15R16, (m) a C3-7 mono-carbocyclic ring which is substituted with C1-4 alkyl or oxo or unsubstituted, (n) a 3- to 7-membered mono-heterocyclic ring which is substituted with C1-4 alkyl or oxo or unsubstituted, or (o) C1-4 alkyl substituted with hydroxy, —COOR13, —NHCOR13, SO2R14 or —NR15R16,
R13 is hydrogen, C1-4 alkyl, phenyl, or phenyl-(C1-4) alkyl,
R14 is C1-4 alkyl,
R15 and R16 each independently, is hydrogen, C1-4 alkyl, phenyl, or phenyl-(C1-4) alkyl,
R17 is C1-4 alkyl or phenyl,
A is
(i) C1-6 alkylene,
(ii) C2-6 alkenylene,
the alkylene and alkenylene in A may be substituted with 1-6 of the following substituents of (a)-(i):
(a) C1-6 alkyl, (b) C1-6 alkoxy, (c) halogen, (d) CHF2, (e) CF3, (f) OCHF2, (g) OCF3, (h) hydroxy, (i) hydroxyl-(C1-4) alkyl,
B ring is a benzene
R2 is C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, halogen, CHF2, CF3, nitro, cyano, phenyl or oxo,
m is 0, 1 or 2,
n is 1
Q is
(1) (i) —(C1-4 alkylene)-Z-Cyc3,
(i) hydroxyl(C1-4) alkyl,
(ii) C1-4 alkoxy(C1-4) alkyl, or
(iii) —(C1-4 alkylene)-O-benzyl,
R23 is hydrogen, C1-4 alkyl, phenyl or phenyl(C1-4) alkyl,
R30 is C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio, halogen, CF3, OCF3, SCF3, CHF2, SCHF2, hydroxy, cyano, nitro, —NR31R32, —CONR31R32, formyl, C2-5 acyl, hydroxy(C1-4) alkyl, C1-4 alkoxy(C1-4) alkyl, C1-4 alkylthio(C1-4) alkyl, —(C1-4 alkylene)—CONR31R32, —SO2(C1-4) alkyl, —NR23CO—(C1-4) alkyl, —NR23SO2—(C1-4) alkyl, benzoyl, oxo, a C3-7 mono-carbocyclic ring, a 3- to 7-membered mono-heterocyclic ring, —(C1-4 alkylene)—NR31R32, —M—(C3-7 mono-carbocyclic ring), or —M—(3- to 7-membered mono-heterocyclic ring),
the C3-7 mono-carbocyclic ring and 3- to 7-membered mono-heterocyclic ring in R30 may be substituted with 1-5 of the following substituents (a)-(1):
(a) C1-6 alkyl, (b) C2-6 alkenyl, (c) C2-6 alkyl, (d) c1-6 alkoxy, (e) C1-6 alkylthio, (f) halogen, (g) CHF2, (h) CF3, (I) nitro, (j) cyano, (k) hydroxy, (l) amino;
M is —O—, —S—, C1-4 alkylene, —O—(C1-4 alkylene)-, —S—(C1-4 alkylene)-, —(C1-4 alkylene)-O— or —(C1-4 alkylene)-S—,
R31 and R32 each independently, is hydrogen or C1-4 alkyl,
Z is —O—,
p is 0, 1 or 2,
Cyc3 is a benzene which is substituted with 1-5 of R30 or unsubstituted,
D is —CONH—CH2—, —CONH—CHR40—, —CONH—C(R40)2—, —CONH—(CH2)2—, —CONH—CH2—CHR40—,
R40 is (a) C1-8 alkyl, (b) C2-8 alkenyl, (c) C2-8 alkynyl, (d) oxo, (e) halogen, (f) CF3, (g) hydroxy, (h) C1-6 alkoxy, (i) C2-6 alkenyloxy, (j) C2-6 alkynyloxy, (k) OCF3, (l) —S(O)p—(C1-6) alkyl, (m) —S(O)p—(C2-6) alkenyl, (n) —S(O)p—(C2-6) alkynyl, (o) C2-5 acyl, (p) Cyc9, (q) C1-4 alkoxy(C1-4) alkoxy, or (r) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with 1 or 2 of substituents selected from halogen, CF3, OCF3, hydroxy, cyano, C1-4 alkoxy, —S(O)p—(C1-6) alkyl, Cyc9 and C1-4 alkoxy(C1-4) alkoxy or
two R40's taken together with the atom of a linking chain to which they bind, may form
Cyc9 is a phenyl,
R3 is a benzene or naphthalene which is substituted with 1-5 of R42 or unsubstituted,
R42 is (a) C1-6 alkyl, (b) C1-6 alkoxy, (c) C1-6 alkylthio, (d) halogen, (e) cyano, (f) CF3, (g) CHF2, (h) OCF3, (i) OCHF2, (j) SCF3, (k) —NR43R44, (l) —SO2R45, (m) —NR46COR47, (n) hydroxy, (o) oxo, (p) C1-4 alkoxy(C1-4) alkyl, (q) Cyc10, (r) C1-6 alkylene-Cyc10, (s) —CO-Cyc10, (t) —W-Cyc10, (u) —(C1-6 alkylene)—W-Cyc10, (v) —W—(C1-6 alkylene)-Cyc10 or (w) —(C1-6 alkylene)—W—(C1-6 alkylene)-Cyc10,
R43 and R44 each independently, is hydrogen or C1-4 alkyl,
R45 is C1-4 alkyl,
R46 is hydrogen or C1-4 alkyl,
R47 is hydrogen or C1-4 alkyl,
Cyc10 is a C3-12 mono- or bi-carbocyclic ring or a 3- to 12-membered mono- or bi-heterocyclic ring which is substituted with 1-5 of substitutes of the following (a)-(j) or unsubstituted,
(a) C1-4 alkyl, (b) C2-5 acyl, (c) 1-4 alkoxy, (d) halogen, (e) hydroxy, (f) nitro, (g) cyano, (h) amine, (i) CF3, (j) OCF3,
W is —O—, —S(O)p— or —NR48—,
R48 is hydrogen or C1-4 alkyl;
or a non-toxic salt thereof.

50 more elements

Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient

Life of this patent

Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient

Life of this patent

Abstract

Claims5