US 9,695,191 B2 · Conformationally constrained, fully synthetic macrocyclic compounds

Abstract

Conformationally restricted, spatially defined 12-30 membered macrocyclic ring systems of type (I) are constituted by three distinct building blocks: an aromatic template a, a conformation modulator b and a spacer moiety c as detailed in the description and the claims. Macrocycles of type (I) are readily manufactured by parallel synthesis or combinatorial chemistry. They are designed to interact with specific biological targets. In particular, they show agonistic or antagonistic activity on the motilin receptor (MR receptor), on the serotonin receptor of subtype 5-HT2B (5-HT2B receptor), and on the prostaglandin F2•receptor (FP receptor). They are thus potentially useful for the treatment of hypomotility disorders of the gastrointestinal tract such as diabetic gastroparesis and constipation type irritable bowl syndrome; of CNS related diseases like migraine, schizophrenia, psychosis or depression; of ocular hypertension such as associated with glaucoma and preterm labour.

Compounds of the general formula I incorporating the building blocks A, B and C

wherein the encircled moiteties a, b and c in building blocks A, B and C are selected from Tables 1, 2 and 3, respectively, and are appropriately and independently substituted as defined below:
TABLE 1
a1
a2
a3
a4
a5
a6
a7
a8
a9
a10
a11
a12
a13
a14
a15
a16
a17
a18
a19
a20
a21
a22
a23
a24
a25
TABLE 2
B1 (b1)
B2 (b2)
B3 (b2)
B4 (b3)
B5 (b3)
B6 (b3)
B7 (b3)
B8 (b3)
B9 (b3)
B10 (b3)
B11 (b4 )
B12 (b4)
B13 (b4)
B14 (b4)
B15 (b4)
B16 (b4)
B17 (b5)
B18 (b8)
B19 (b10)
B20 (b11)
B21 (b11)
the encircled parts of the bridge subunits c1-c3 representing optionally substitued groups, definitions of c1-c3 being depicted in Table 3, below, each reading from the N-terminus to the C-terminus of the linker C, said linker C being, in the simplest case, constituted by one subunit c1, i.e. c1-1 to c1-6, and for the embodiments consisting of two or three subunits all possible combinations of the subunits c1-c3 and the connectivities U, V and W being possible;
TABLE 3
Scope of Subunits of c1-c3 of the Linker Group C
C
U =
V, W =
c1-1
c1-2
c1-3
c1-4
c1-5
c1-6
c2-1
c2-2
c2-3
c2-4
c2-5
c2-6
c3-1
c3-2
c3-3
the substituents directly attached to building blocks A, B and C, i.e. R1-R17, being defined as follows:
R1 is H;
F;
Cl;
Br;
I;
CF3;
OCF3;
OCHF2;
NO2;
CN;
alkyl;
alkenyl;
alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR18R19)qOR20;
—(CR18R19)qSR20;
—(CR18R19)qNR4R11;
—(CR18R19)qOCONR4R11;
—(CR18R19)qOCOOR21;
—(CR18R19)qNR4COOR21;
—(CR18R19)qNR4COR22;
—(CR18R19)qNR4CONR4R11;
—(CR18R19)qNR4SO2R23;
—(CR18R19)qNR4SO2NR4R11;
—(CR18R19)qCOOR21;
—(CR18R19)qCONR4R11;
—(CR18R19)qSO2NR4R11;
—(CR18R19)qPO(OR21)2;
—(CR18R19)qOPO(OR21)2;
—(CR18R19)qCOR22;
—(CR18R19)qSO2R23;
—(CR18R19)qOSO3R21;
—(CR18R19)qR24;
—(CR18R19)qR25;
or —(CR18R19)qR26;
R2 is H;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR18R19)qOR20;
—(CR18R19)qSR20;
—(CR18R19)qNR4R11;
—(CR18R19)qOCONR4R11;
—(CR18R19)qOCOOR21;
—(CR18R19)qNR4COOR21;
—(CR18R19)qNR4COR22;
—(CR18R19)qNR4CONR4R11;
—(CR18R19)qNR4SO2R23;
—(CR18R19)qNR4SO2NR4R11;
—(CR18R19)qCOOR21;
—(CR18R19)qCONR4R11;
—(CR18R19)qSO2NR4R11;
—(CR18R19)qR24;
—(CR18R19)qR25;
or —(CR18R19)qR26;
R3 is H;
CF3;
alkyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
R4 is H;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
or heteroarylalkyl;
R5, R7 and R9 are independently defined as H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR18R19)sOR20;
—(CR18R19)sSR20;
—(CR18R19)sNR4R11;
—(CR18R19)sOCONR4R11;
—(CR18R19)sOCOOR21;
—(CR18R19)sNR4COOR21;
—(CR18R19)sNR4COR22;
—(CR18R19)sNR4CONR4R11;
—(CR18R19)sNR4SO2R23;
—(CR18R19)sNR4SO2NR4R11;
—(CR18R19)qCOOR21;
—(CR18R19)qCONR4R11;
—(CR18R19)qSO2NR4R11;
—(CR18R19)qPO(OR21)2;
—(CR18R19)qCOR22;
—(CR18R19)qSO2R23;
—(CR18R19)qR24;
—(CR18R19)qR25;
or —(CR18R19)qR26;
R6, R8 and R10 are independently defined as H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
or heteroarylalkyl;
R11 is H;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR18R19)rOR20;
—(CR18R19)rSR20;
—(CR18R19)rNR4R27;
—(CR18R19)rOCONR4R27;
—(CR18R19)rOCOOR21;
—(CR18R19)rNR4COOR21;
—(CR18R19)rNR4CONR4R27;
—(CR18R19)rNR4SO2R23;
—(CR18R19)rNR4SO2NR4R27;
—(CR18R19)qCOOR21;
—(CR18R19)qCONR4R27;
—(CR18R19)qCOR22;
—(CR18R19)qSO2R23;
—(CR18R19)qSO2NR4R27;
—(CR18R19)qR24;
—(CR18R19)sR25;
or —(CR18R19)qR26;
R12 and R13 are independently defined as H;
or alkyl;
R14 and R16 are independently defined as H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR18R19)sOR20;
—(CR18R19)sNR4R11;
—(CR18R19)sNR4COOR21;
—(CR18R19)sNR4COR22;
—(CR18R19)sNR4CONR4R11;
—(CR18R19)sNR4SO2R23;
—(CR18R19)sNR4SO2NR4R11;
—(CR18R19)qCOOR21;
—(CR18R19)qCONR4R11;
—(CR18R19)qSO2NR4R11;
or —(CR18R19)qCOR22;
R15 and R17 are independently defined as H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
or heteroarylalkyl;
substituents introduced in the sub-definitions of the radical R1-R17 being defined as follows:
R18 is H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR29R30)sOR31;
—(CR29R30)sSR31;
—(CR29R30)sNR28R31;
—(CR29R30)sOCONR28R31;
—(CR29R30)sOCOOR21;
—(CR29R30)sNR28COOR21;
—(CR29R30)sNR28COR31;
—(CR29R30)sNR28CONR28R31;
—(CR29R30)sNR28SO2R23;
—(CR29R30)sNR28SO2NR28R31;
—(CR29R30)qCOOR21;
—(CR29R30)qCONR28R31;
—(CR29R30)qSO2NR28R31;
—(CR29R30)qPO(OR21)2;
—(CR29R30)qCOR31;
—(CR29R30)qSO2R23;
—(CR29R30)qR24;
—(CR29R30)qR25;
or —(CR29R30)qR26;
R19 is H;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
R20 is H;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR29R30)rOR31;
—(CR29R30)rSR31;
—(CR29R30)rNR28R31;
—(CR29R30)rOCONR28R31;
—(CR29R30)rNR28COOR21;
—(CR29R30)rNR28COR31;
—(CR29R30)rNR28CONR28R31;
—(CR29R30)rNR28SO2R23;
—(CR29R30)rNR28SO2NR28R31;
—(CR29R30)qCOOR21;
—(CR29R30)qCONR28R31;
—(CR29R30)qSO2NR28R31;
—(CR29R30)qCOR31;
—(CR29R30)qSO2R23;
—(CR29R30)qR24;
—(CR29R30)qR25;
or —(CR29R30)qR26;
R21 is alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
or heteroarylalkyl;
R22 is alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR29R30)sOR31;
—(CR29R30)sSR31;
—(CR29R30)sNR28R31;
—(CR29R30)sOCONR28R31;
—(CR29R30)sNR28COOR21;
—(CR29R30)sNR28COR31;
—(CR29R30)sNR28CONR28R31;
—(CR29R30)sNR28SO2R23;
—(CR29R30)sNR28SO2NR28R31;
—(CR29R30)sCOOR21;
—(CR29R30)sCONR28R31;
—(CR29R30)sSO2NR28R31;
—(CR29R30)tCOR31;
—(CR29R30)sSO2R23;
—(CR29R30)tR24;
—(CR29R30)tR25;
or —(CR29R30)tR26;
R23 is H;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
or —(CR32R33)tR24;
R24 is aryl, an optionally substituted phenyl group of type C6H2R34R35R31;
or a heteroaryl group, one of the groups of formulae H1-H34 (Table 4), below;
TABLE 4
Groups of Formulae H1-H34
H1
H2
H3
H4
H5
H6
H7
H8
H9
H10
H11
H12
H13
H14
H15
H16
H17
H18
H19
H20
H21
H22
H23
H24
H25
H26
H27
H28
H29
H30
H31
H32
H33
H34
R25 is one of the groups of formulae H35-H41 as shown in Table 5, below;
TABLE 5
Radicals of formulae H35-H41
H35
H36
H37
H38
H39
H40
H41
R26 is one of the groups of formulae H42-H50 as shown in Table 6, below;
TABLE 6
Groups of Formulae H43-H50
H42
H43
H44
H45
H46
H47
H48
H49
H50
R27 is H;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
or
—(CR29R30)R24;
R28 is H;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR32R33)sOR21;
—(CR32R33)sNR43R42;
—(CR32R33)sNR42CONR43R42;
—(CR32R33)sNR42COR21;
—(CR32R33)sNR42SO2NR21;
—(CR32R33)qCOOR21;
—(CR32R33)qCOR23;
—(CR32R33)qSO2R21;
R29 is H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR32R33)sOR31;
—(CR32R33)sSR31;
—(CR32R33)sNR28R31;
—(CR32R33)sOCONR28R31;
—(CR32R33)sOCOOR21;
—(CR32R33)sNR28COOR21;
—(CR32R33)sNR28COR31;
—(CR32R33)sNR28CONR28R31;
—(CR32R33)sNR28SO2R23;
—(CR32R33)sNR28SO2NR28R31;
—(CR32R33)qCOOR21;
—(CR32R33)qCONR28R31;
—(CR32R33)qSO2NR28R31;
—(CR32R33)2PO(OR21)2;
—(CR32R33)qCOR31;
—(CR32R33)qSO2R23;
—(CR32R33)qR31;
R30 is H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
R31 is H;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
or one of the groups of formulae H51-H55 as shown in Table 7 below;
TABLE 7
Groups of Formulae H51-H55
H51
H52
H53
H54
H55
R32 and R33 are independently defined as H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
R34 and R35 are independently defined as H;
F;
Cl;
CF3;
OCF3;
OCHF2;
NO2;
CN;
alkyl;
alkenyl;
alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
——(CR29R30)qOR31;
—(CR29R30)qSR31;
—(CR29R30)qNR28R31;
—(CR29R30)qOCONR28R31;
—(CR29R30)qNR28COOR21;
—(CR29R30)qNR28COR31;
—(CR29R30)qNR28CONR28R31;
—(CR29R30)qNR28SO2R23;
—(CR29R30)qNR28SO2NR28R31;
—(CR29R30)qCOOR21;
—(CR29R30)qCONR28R31;
—(CR29R30)qSO2NR28R31;
—(CR29R30)qCOR31;
—(CR29R30)qSO2R23;
or —(CR29R30)qR31;
R36 H;
alkyl;
alkenyl;
alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
or —NR28R31;
R37 is H;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR29R30)rOR31;
—(CR29R30)rSR31;
—(CR29R30)rNR28R31;
—(CR29R30)rOCONR28R31;
—(CR29R30)rNR28COOR21;
—(CR29R30)rNR28COR31;
—(CR29R30)rNR28CONR28R31;
—(CR29R30)rNR28SO2R23;
—(CR29R30)rNR28SO2NR28R31;
—(CR29R30)qCOOR21;
—(CR29R30)qCONR28R31;
—(CR29R30)rSO2NR28R31;
—(CR29R30)qCOR31;
—(CR29R30)qSO2R23;
or —(CR29R30)qR31;
R38 is H;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR29R30)qOR31;
—(CR29R30)qSR31;
—(CR29R30)qNR28R31;
—(CR29R30)qNR28COOR21;
—(CR29R30)qNR28COR31;
—(CR29R30)qNR28CONR28R31;
—(CR29R30)qCOOR21;
—(CR29R30)qCONR28R31;
—(CR29R30)qCOR31;
or
—(CR29R30)qR31;
R39 is H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR32R33)uOR21;
—(CR32R33)uNR28R43;
—(CR32R33)tCOOR21;
or —(CR32R33)tCONR28R43;
R40 is H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR32R33)uOR21;
—(CR32R33)uNR28R43;
—(CR32R33)tCOOR21;
or —(CR32R33)tCONR28R43;
R41 is H;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—OR21;
—NR28R43;
—NR28COR23;
—NR28COOR21;
—NR28SO2R23;
—NR28CONR28R43;
—COOR21;
—CONR28R43;
—C(═NR43)NR28N43;
—NR28C(═NR43)NR28N43;
or one of the groups of formulae H56-H110 as shown in Table 8 below;
TABLE 8
Groups of Formulae H56-H110
H56
H57
H58
H59
H60
H61
H62
H63
H64
H65
H66
H67
H68
H69
H70
H71
H72
H73
H74
H75
H76
H77
H78
H79
H80
H81
H82
H83
H84
H85
H86
H87
H88
H89
H90
H91
H92
H93
H94
H95
H96
H97
H98
H99
H100
H101
H102
H103
H104
H105
H106
H106
H108
H109
H110
R42 is H;
alkyl;
alkenyl;
cycloalkyl;
cycloheteroalkyl;
aryl;
heteroaryl;
—(CR23R33)sOR21;
—(CR23R33)sNR28R43;
—(CR23R33)qCOOR21;
or —(CR23R33)qCONR21R43;
R43 is H;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
or heteroarylalkyl;
R44, R45 and R46 are independently defined as H;
F;
CF3;
OCF3;
OCHF2;
NO2;
CN;
alkyl;
alkenyl;
alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—OR23;
—NR28R43;
—NR28COR23;
—NR28SO2R23;
—NR28CONR28R43;
—COR23;
—SO2R23;
R47 is H;
CF3;
alkyl;
alkenyl;
alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—COOR21;
or —CONR28R43;
R48 is H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
cycloheteroalkyl;
aryl;
heteroaryl;
—(CR23R33)tOR21;
—(CR23R33)tNR28R43;
—(CR23R33)tCOOR21;
—(CR23R33)tCONR21R43;
R49 and R50 are independently defined as H;
F;
CF3;
alkyl;
alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
arylalkyl;
heteroarylalkyl;
—(CR32R33)qOR21;
—(CR32R33)qNR28R43;
—(CR32R33)qCOOR21;
or
—(CR32R33)qCONR28R43;
taken together the following pairs of said substituents can define cyclic structural elements:
(R4 and R11);
(R4 and R27);
(R5 and R6);
(R5 and R7);
(R5 and R9);
(R5 and R14);
(R5 and R16);
(R7 and R8);
(R7 and R9);
(R7 and R16);
(R9 and R10);
(R14 and R15);
(R16 and R17);
(R18 and R19);
(R27 and R28);
(R28 and R31);
(R28 and R43);
(R29 and R30);
(R32 and R33);
(R34 and R35);
(R37 and R38);
(R39 and R40);
(R39 and R41);
(R39 and R49);
(R42 and R43);
(R44 and R45);
or (R44 and R46) can form optionally substituted cycloalkyl or heterocycloalkyl moieties;
in addition, the structural elements —NR4R11;
—NR27R28;
—NR28R31 or —NR28R43 can form one of the groups of formulae H111-H118 as shown in Table 9, below;
TABLE 9
Heterocyclic Groups Defined by Linking the Residues of the
Disubstituted Amino Groups —NR4R11;
—NR27R28;
—NR28R31 or
—NR28R43.
H111
H112
H113
H114
H115
H116
H117
H118
varibale heteroatoms and connector groups in the aforementioned structures being as follows:
Z:
O;
S;
S(═O);
S(═O)2;
or NR28;
Y:
O;
S;
or NR37;
X:
O;
S;
S(═O);
or S(═O)2;
Q:
O;
S;
or NR28;
U, V and W:
as defined in Table 3, above;
T:
CR46 or N;
in case T occurs several times in the same ring structure each T being defined independently of the other;
and
the indices being defined as follows:
q=0-4;
r=2-4;
s=1-4;
t=0-2;
and u=1-2;
all possible stereoismers and pharmaceutical acceptable salts thereof.

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Conformationally constrained, fully synthetic macrocyclic compounds

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Conformationally constrained, fully synthetic macrocyclic compounds

Life of this patent

Abstract

Claims13