US 9,512,139 B2 · Conformationally constrained, fully synthetic macrocyclic compounds

Abstract

Conformationally restricted, spatially defined 12-30 membered macrocyclic ring systems of formulae Ia and Ib are constituted by three distinct molecular parts: Template A, conformation Modulator B and Bridge C. These macrocycles Ia and Ib are readily manufactured by parallel synthesis or combinatorial chemistry in solution or on solid phase. They are designed to interact with a variety of specific biological target classes, examples being the agonistic or antagonistic activity on G-protein coupled receptors (GPCRs), ion channels and signal transduction pathways. In particular, these macrocycles act as antagonists of the motilin receptor, the FP receptor and the purinergic receptors P2Y1, as modulators of the serotonin receptor of subtype 5-HT2B, as blockers of the voltage-gated potassium channel Kv1.3 and as inhibitors of the β-catenin-dependent “canonical” Wnt pathway. Thus they are showing great potential as medicaments for a variety of diseases.

Compounds consisting of a cyclic arrangement of the building blocks A, B and C and represented by the general formula Ia

wherein
building block A (“Template”) is represented by
building block B (“Modulator”) is represented by
building block C (“Bridge”) is represented by
wherein
is further represented by respectively
and wherein
M represents a divalent or trivalent radical selected from the group of
forming an integral part of the
M-L connectivity which in turn represents a divalent radical selected from the group of
U represents a divalent radical selected from the group of
X represents a divalent radical selected from the group of
V and W are independently representing a divalent radical selected from the group of
and wherein
said building block A is a bivalent radical selected from the group consisting of
building block B is a bivalent radical selected from the group of
building block C is a bivalent radical selected from the group of
and wherein further
R1 is H;
F;
Cl;
Br;
CH3;
OCH3;
OH;
or aryl;
R2 is H;
CH3;
heterocycloalkyl;
aryl;
benzyl;
heteroaryl;
—OR20;
—NR4R11;
—NR4COOR21;
—NR4COR22;
—NR4CONR4R11;
or —NR4SO2R23;
R3 is H;
R4 is H;
acetyl;
lower alkyl;
lower alkenyl;
or a suitable N-protecting group;
R5, R7 and R9 are independently defined as H;
CF3;
lower alkyl;
lower alkenyl;
lower cycloalkyl;
lower heteroarylalkyl;
aryl;
heteroaryl;
lower arylalkyl;
lower heteroarylalkyl;
—OR20;
—NR4R11;
—NR4COR22;
—NR4CONR4R11;
—NR4SO2R23;
—COOR21;
—COOR21;
—CONR4R11;
or —COR22;
R6, R8 and R10 are defined as H;
R11 is H;
alkyl;
aryl;
heteroaryl;
lower arylalkyl;
lower heteroarylalkyl;
—(CR18R19)rOR20;
—(CR18R19)rNR4R27;
—(CR18R19)qCOOR21;
—COR22;
—(CR18R19)qR24;
or —(CR18R19)qR31;
R12 and R13 are defined as H;
R14 and R16 are independently defined as H;
lower alkyl;
or lower arylalkyl;
R15 and R17 are defined as H;
R18 and R19 are defined as H;
R20 is H;
aryl;
heteroaryl;
lower arylalkyl;
lower heteroarylalkyl;
or —(CR29R30)qR24;
R21 is H;
lower alkyl;
lower arylalkyl;
or a suitable O-protecting group;
R22 is lower alykyl;
lower alkenyl;
aryl;
heteroaryl;
lower arylalkyl;
lower heteroarylalkyl;
—(CR29R30)sOR31;
—(CR29R30)sNR28R31;
—(CR29R30)sCOOR21;
—(CR29R30)tR24;
or —(CR29R30)tR31;
R23 is H;
lower alkyl;
aryl;
heteroaryl;
or —R24;
R24 is aryl;
heteroaryl;
or —C6H2R34R35R31;
R27 is H;
acetyl;
CH3;
or —(CH2)qR24;
R28 is H;
—(CR23R33)sOR21;
or —(CR32R33)sNR43R42;
R29 is H;
lower alkyl;
aryl;
or heteroaryl;
R30, R32 and R33 are independently defined as H;
CF3;
or CH3;
R31 is H;
alkyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
or heteroarylalkyl;
R34 and R35 are independently defined as H;
heterocycloalkyl;
—OR31;
or —NR28R31;
R36 is H;
alkyl;
alkenyl;
alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
or —NR28R31;
R38 is H;
—NR28R31;
—NR28COR31;
or —NR28COOR31;
R42 and R43 are independently defined as H;
CH3;
or benzyl;
R51 is H;
F;
Cl;
CF3;
OCF3;
or lower alkyl;
R52 is H;
F;
Cl;
CF3;
OCF3;
OCHF3;
NO2;
CN;
lower alkyl;
lower alkenyl;
lower alkynyl;
lower cycloalkyl;
lower heterocycloalkyl;
aryl;
heteroaryl;
lower arylalkyl;
or lower heteroarylalkyl;
Z is O;
S;
S(═O);
S(═O)2;
or NR28;
Y is O;
S;
or NR4;
Q is O;
S;
or NR28;
q is an integer of 0-4;
r is an integer of 2-4;
s is an integer of 1-4;
t is an integer of 0-2;
and all possible stereoisomers of such compounds;
or salts, solvates, clathrates, N-oxides, isotopically enriched or enantiomerically enriched versions thereof.

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Conformationally constrained, fully synthetic macrocyclic compounds

Life of this patent

Conformationally constrained, fully synthetic macrocyclic compounds

Life of this patent

Abstract

Claims11