US 2011/0212919 A1 · PROTEIN CROSS-LINKING INHIBITOR

Abstract

The present invention provides a protein cross-linking inhibitor containing a compound represented by any of the following formulas (1)-(13), or a pharmaceutically acceptable salt thereof: R3—[—X—B(ZR1)—Y—B(ZR2)—W—]n—R4, (1) R3—[—X—B(ZR1)—Y—]n—R4, (2) R3—[—B(ZR1)—Y—B(ZR2)—W—]n—R4, (3) R3—[—X—B(ZR1)—]n—R4, (4) R3—[—B(ZR2)—W—]n—R4, (5) R3—X—B(ZR1)-T[B(ZR2)—W—R4]2, (6) R3—B(OH)2, (7) R3—B(ZR1)—X—B(ZR2)—R4, (8) R3—B(R1)—O—B(R2)—R4, (9) R3—[—X—B(ZR1)—Y—B(ZR2)—]n—R4, (10) R3—[—X—B(ZR1)—Y—B(ZR2)—W-Q-]n—R4, (11) R3—[—P—X—B(ZR1)—Y—B(ZR2)—W—]n—R4, (12) [R3—X—B(ZR1)—Y]2B(ZR2), (13) wherein each symbol is as defined in the DESCRIPTION.

A compound represented by any of the following formulas (1)-(13) or a pharmaceutically acceptable salt thereof;

R3—[—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (1)
R3—[—X—B(ZR1)—Y—]n—R4 (2)
R3—[—B(ZR1)—Y—B(ZR2)—W—]n—R4 (3)
R3—[—X—B(ZR1)—]n—R4 (4)
R3—[—B(ZR2)—W—]n—R4 (5)
R3—X—B(ZR1)-T[B(ZR2)—W—R4]2 (6)
R3—B(OH)2 (7)
R3—B(ZR1)—X—B(ZR2)—R4 (8)
R3—B(R1)—O—B(R2)—R4 (9)
R3—[—X—B(ZR1)—Y—B(ZR2)—]n—R4 (10)
R3—[—X—B(ZR1)—Y—B(ZR2)—W-Q-]n—R4 (11)
R3—[—O—X—B(ZR1)—Y—B(ZR2)—W—]n—R4 (12)
[R3—X—B(ZR1)—Y]2B(ZR2) (13)
wherein B is a boron atom,
Z is O or S,
R1 and R2 are independently a group selected from H, —(CH2)m—NR5R6, —CO—(CH2)m—NR7R8, —COCH(NH2)—R9, —CH2CH(NH2)—R10, —CHR11R12, —COCH(—NR13R14)—R15, —COCH(NH2)—(CH2)mNHCR18NH2, —COCH(NH2)—(CH2)m—COR19, —COR20, —(CH2)m—R22, —O(CH2)mNH2, —COCH(NH2)—(CH2)m—R23, —(CH2CH2NH)2—R23,
and heterocyclylalkyl, or when R1 and R2 are present in plurality, R1 may be bonded to R1, R2 may be bonded to R2, or R1 may be bonded to R2,
R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R19, R20 and R22 are independently H, or each is a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclyl, amino, aminoalkylcarbonyl, hydroxy, aromatic group or heterocyclylalkyl,
R18 is oxo or ═NH,
Q is a group represented by —R16—O—R17—, —R21—O—, —O— (wherein R16, R17 and R21 mean a single bond or lower alkylene),
R23 is a fluorescence group,
m is an integer of 1 to 5,
R3 and R4 are H, OH, CH2OH, CH2OCH2OCH3, cyano or aryloxy, or each is a substituted or unsubstituted alkyl or aryl,
T is a substituted or unsubstituted aryl,
X, Y and W are independently groups containing aromatic series or fatty series, and
n is an integer of 1 to 100,
excluding a compound represented by the following formula (Ia)
wherein
B is a boron atom,
V is an oxygen or sulfur atom,
J1 and J3 are each independently a monocyclic aromatic group, a polycyclic aromatic group, or a heterocyclic group containing at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom,
J2 is a hydrogen atom;
—(CH2)D—NJ4J5 wherein D is an integer of 1-4, J4 and J5 are independently a hydrogen atom, or C1-4 alkyl substituted or unsubstituted by an amino group, a mono or di-C1-4 alkylamino group or a phenyl group, or J4 and J5 form, together with the nitrogen atom bonded thereto, a 5- or 6-membered cyclo ring);
—CO—(CH2)D—NJ4J5 wherein D, J4 and J5 are as defined above;
—COCH(NH2)J6 wherein J6 is an amino acid residue, or —(CH2)D′NH2 wherein D′ is an integer of 1 to 3;
—CHJ7J8 wherein J7 and J8 are independently an amino group, C1-4 alkyl substituted or unsubstituted by a mono or di(C1-4 alkyl substituted or unsubstituted by an amino group)amino group or phenyl group, or phenyl substituted by pyridyl or a C1-3 alkoxy group;
—CH2CH(NH2)-J9 wherein J9 is phenyl, or C1-4 alkyl substituted by phenyl;
quinolyl or isoquinolyl substituted by a C1-4 alkyl group;
or C1-4 alkyl substituted by a pyridyl group, a piperidino group or a pyrrolidinyl group, and
U is a monocyclic aromatic group, a polycyclic aromatic group or a heterocyclic group, which is the same as or different from J1 and J3, or a bifunctional group having a monocyclic aromatic group, a polycyclic aromatic group or a heterocyclic group bonded to both sides thereof via a group selected from the group consisting of a single bond, O, CH2, S, SO2, CH2OCH2, OCH2, OCH2CH2OCH2, OCH2OCH2CH2 and CH2OCH2CH2, and a compound represented by the following formula (Ib)
wherein J10 is
(1) a hydrogen atom,
(2) —(CH2)D″—NJ11J12 wherein D″ is an integer of 1 to 3, J11 and J12 are each independently a hydrogen atom, C1-4 alkyl, C5-6 monocyclic carbocycle, C1-4 alkyl substituted by C5-6 monocyclic carbocycle, or 5- or 6-membered monocyclic heterocycle,
the carbon atom in —(CH2)D″— is optionally substituted by 1 or 2 J13, and further, said carbocycle and heterocycle are optionally substituted by 1 or 2 J16,
J13 is (a) C1-8 alkyl, (b) carboxyl, (c) C1-4 alkoxycarbonyl, (d) keto, (e) C5-6 monocyclic carbocycle, (f) guanidino(C1-2)alkyl, (g) C1-6 alkyl substituted by C5-6 monocyclic carbocycle, (h) C1-2 alkyl substituted by 4-chlorophenoxy, or (i) C1-4 alkyl substituted by di(C1-4 alkyl)amino,
(3) C1-6 alkyl or C2-6 alkenyl substituted by C5-6 monocyclic carbocycle, wherein said carbocycle is optionally substituted by 1 to 5 J16, and further, said C1-6 alkyl or C2-6 alkenyl is optionally substituted by 1 or 2 J19,
(4) C1-6 alkyl or C2-6 alkenyl substituted by 5- or 6-membered monocyclic heterocycle, wherein said heterocycle is optionally substituted by 1 to 5 J16, and further, said C1-6 alkyl or C2-6 alkenyl is optionally substituted by 1 or 2 J19, and
J19 is C1-4 alkyl or C2-4 alkenyl,
(5) a —CHJ14J15 group wherein J14 and J15 are each independently
(i) C5-6 monocyclic carbocycle,
(ii) 5- or 6-membered monocyclic heterocycle, C1-6 alkyl or C2-6 alkenyl substituted by C5-6 monocyclic carbocycle, or
(iv) C1-6 alkyl or C2-6 alkenyl substituted by 5- or 6-membered monocyclic heterocycle, wherein said carbocycle and heterocycle are optionally substituted by 1 to 5 J16, or
(6) 5,6,7,8-tetrahydroquinolin-8-yl,
J16 is (a) C1-4 alkyl, (b) C1-4 alkoxy, (c) a halogen atom, (d) —CF3, (e) nitro, (f) C5-6 monocyclic carbocycle, (g) C1-4 alkyl substituted by C5-6 monocyclic carbocycle, (h) amino, (i) —NHCO(C1-4 alkyl), or (j) C1-4 alkoxycarbonyl,
G is Cyc1 or hydroxy, Cyc1 is C5-10 monocyclic or bicyclic carbocycle, or 5- to 10-membered monocyclic or bicyclic heterocycle, wherein said carbocycle and heterocycle are optionally substituted by 1 to 5 J17,
Cyc2 is C5-10 monocyclic or bicyclic heterocycle or 5- to 10-membered monocyclic or bicyclic heterocycle, wherein said carbocycle and heterocycle are optionally substituted by 1 to 5 J18, J17 and J18 are each independently
(a) C1-4 alkyl,
(b) C2-4 alkenyl,
(c) C1-4 alkoxy,
(d) a halogen atom,
(e) —CF3,
(f) C1-4 alkylthio,
(g) amino,
(h) (C1-4 alkyl)amino,
(i) di(C1-4 alkyl)amino,
(j) formyl,
(k) phenyl,
(l) phenoxy,
(m) hydroxy(C1-2)alkyl,
(n) (C5-10 monocyclic or bicyclic carbocycle)-O—(C1-2)alkyl,
(o)C1-4 alkoxycarbonylvinyl,
(p) C1-2 alkyl substituted by a group selected from —O—(C1-2 alkylene)-phenyl (said phenyl is optionally substituted by 1 to 3 C1-4 alkoxy), —O—CONH-phenyl (said phenyl is optionally substituted by 1 to 3 C1-4 alkyl, nitro or C1-4 alkoxycarbonyl), or —O—CONH—(C1-4)alkyl (said alkyl is optionally substituted by 1 to 3 C1-4 alkyl, carboxyl or C1-4 alkoxycarbonyl),
(q) phenylthio,
(r) —CON(C1-4 alkyl)2,
(s) —SO2N(C1-4 alkyl)2,
(t) C1-4 alkoxy(C1-2)alkyl,
(u) C1-4 alkoxycarbonyloxy(C1-2)alkyl,
carbocycle, phenyl, Cyc1 and Cyc2 in J17 and J18 are optionally substituted by 1 or 2 J16, or J17 and J18 in combination optionally show —O—, and J18 and J19 in combination optionally show a single bond,
d′1 is an integer of 1 to 4,
d′2 is an integer of 1 to 4,
d′3 is an integer of 1 to 4, and
E is a single bond or C1-4 alkylene substituted or unsubstituted by C5-6 monocyclic carbocycle.

79 more elements

Protein cross-linking inhibitor

Life of this patent

Protein cross-linking inhibitor

Life of this patent

Abstract

Claims22