US 7,622,452 B2Granted

C-9 alkenylidine bridged macrolides

AssigneeEnanta Pharmaceuticals, Inc.

InventorsLy Tam Phan, Yao-Ling Qiu, Yat Sun Or

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Abstract

The present invention discloses compounds of formulae (I), (II) or pharmaceutically acceptable salts, esters, or prodrugs thereof: which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.

Claims14

Dependent claims

Compounds represented by formula (I) or (II):

or the racemates, enantiomers, diastereomers, geometric isomers, tautomers, solvates, pharmaceutically acceptable salts and esters thereof,
wherein T is
(a) —R1—, where R1 is substituted or unsubstituted —C1-C8 alkylene-, —C2-C8 alkenylene or —C2-C8 alkynylene, containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(b) —R1—(C═O)—R2—, where R2 is independently selected from R1;
(c) —R1—(C═N—E—R3)—R2—, where E is absent, O, OC(O), NH, NHC(O), NHC(O)NH or NHSO2;
and R3 is independently selected from the group consisting of:
(1) hydrogen;
(2) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
and
(3) R4, where R4 is substituted or unsubstituted —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
and
(4) substituted or unsubstituted, saturated or unsaturated C3-C12 cycloalkyl;
(d) —R1—[C(OR5)(OR6)]—R2—, where R5 and R6 are selected from the group consisting of C1-C12 alkyl, aryl or substituted aryl;
or taken together is —(CRxRy)m—, where m is 2 or 3, Rx and Ry are independently selected from hydrogen and R4;
(e) —R1—[C(SR5)(SR6)]—R2—;
or
(f) —R1—(C═CH—R3)—R2—;
one of A and B is Ra and the other is ORa, wherein Ra is independently selected from:
(a) hydrogen;
and
(b) —R4;
alternatively, A and B taken together with the carbon atom to which they are attached to form ═CHCH(Rb)X1 or ═CHM1C(Rb)═N—ORc, wherein Rb is selected from the group consisting of:
(a) hydrogen;
(b) —R3;
(c) —C(O)—Rd, wherein Rd is independently selected from halogen and R3;
(d) —C(O)—O—Rd;
and
(e) —C(O)—NR8R9 wherein R8 and R9 are each independently selected R3;
alternatively, R8 and R9 taken together with the nitrogen atom to which they are connected form a 3- to 7-membered ring which may optionally contain one or more heterofunctions selected from the group consisting of:
—O—, —NH—, —N(R4)—, —N(R10)—, —S(O)n—, wherein n=0, 1 or 2, and R10 is selected from aryl;
substituted aryl;
heteroaryl;
and substituted heteroaryl;
Rc is selected from the group consisting of:
(a) hydrogen;
(b) —R4;
(c) —R10;
(d) —(CO)R3;
(e) —(CO)NHR3;
(f) —(CO)OR3;
(g) —C(O)—NR8R9;
and
(h) —C(O)—NR11NR12R13;
wherein R11 is hydrogen or alkyl, and R12 and R13 are independently selected from R4;
X1 is selected from the group consisting of:
(a) hydrogen;
(b) oxo;
(c) azido;
(d) cyano;
(e) —R4;
(f) —R10;
(g) —(CO)R3;
(h) —(CO)NHR3;
(i) —(CO)OR3;
(j) —C(O)—NR8R9;
(k) —OR14, where R14 is selected from the group consisting of N-phthalimido and Rc;
(l) —SR3;
(m) —NR8R9;
and
(n) —NR3R14;
M1 is absent or R1;
L is independently selected from R4;
W is selected from:
(a) hydrogen;
(b) —R4;
(c) —C(O)R3;
(d) —C(O)O—R3;
and
(e) —C(O)N(R8R9);
Q is:
(a) —R3;
(b) —(CO)R3;
(c) —(CO)NHR3;
(d) —(CO)OR3;
(e) —(SO)2R3;
(f) monosaccharide;
(g) disaccharide;
or
(h) trisaccharide;
Z is:
(a) hydrogen;
(b) —N3;
(c) —CN;
(d) —NO2;
(e) —CONH2;
(f) —COOH;
(g) —CHO;
(h) —R4;
(i) —COOR4;
(j) —C(O)R4;
or
(k) —C(O)NR8R9;
when U is hydrogen, V is selected from the group consisting of:
(a) hydrogen;
(b) —OR3;
(c) —OC(O)R3;
(d) —OC(O)NHR3;
(e) —OS(O)2R3;
(f) —O-monosaccharide;
and
(g) —O-disaccharide;
alternatively, U and V taken together with is oxo;
each of X and Y is independently:
a) hydrogen;
b) hydroxy;
c) halogen;
or
d) —R4;
G is selected from the group consisting of:
a) hydrogen;
b) hydroxy;
c) —O—R4;
d) —O—R10;
alternatively, G and W taken together to a form cyclic structure selected from:
where M is O or N—J—R20, and where J is absent, O, NH, NH(CO), or N═CH;
and R20 is selected from the group consisting of:
i. hydrogen;
ii. R4;
and
iii. R10.

120 more elements

Dependencies are inferred from the claim text.

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Abstract

Compounds represented by formula (I) or (II):

or the racemates, enantiomers, diastereomers, geometric isomers, tautomers, solvates, pharmaceutically acceptable salts and esters thereof,
wherein T is
(a) —R1—, where R1 is substituted or unsubstituted —C1-C8 alkylene-, —C2-C8 alkenylene or —C2-C8 alkynylene, containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(b) —R1—(C═O)—R2—, where R2 is independently selected from R1;
(c) —R1—(C═N—E—R3)—R2—, where E is absent, O, OC(O), NH, NHC(O), NHC(O)NH or NHSO2;
and R3 is independently selected from the group consisting of:
(1) hydrogen;
(2) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
and
(3) R4, where R4 is substituted or unsubstituted —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
and
(4) substituted or unsubstituted, saturated or unsaturated C3-C12 cycloalkyl;
(d) —R1—[C(OR5)(OR6)]—R2—, where R5 and R6 are selected from the group consisting of C1-C12 alkyl, aryl or substituted aryl;
or taken together is —(CRxRy)m—, where m is 2 or 3, Rx and Ry are independently selected from hydrogen and R4;
(e) —R1—[C(SR5)(SR6)]—R2—;
or
(f) —R1—(C═CH—R3)—R2—;
one of A and B is Ra and the other is ORa, wherein Ra is independently selected from:
(a) hydrogen;
and
(b) —R4;
alternatively, A and B taken together with the carbon atom to which they are attached to form ═CHCH(Rb)X1 or ═CHM1C(Rb)═N—ORc, wherein Rb is selected from the group consisting of:
(a) hydrogen;
(b) —R3;
(c) —C(O)—Rd, wherein Rd is independently selected from halogen and R3;
(d) —C(O)—O—Rd;
and
(e) —C(O)—NR8R9 wherein R8 and R9 are each independently selected R3;
alternatively, R8 and R9 taken together with the nitrogen atom to which they are connected form a 3- to 7-membered ring which may optionally contain one or more heterofunctions selected from the group consisting of:
—O—, —NH—, —N(R4)—, —N(R10)—, —S(O)n—, wherein n=0, 1 or 2, and R10 is selected from aryl;
substituted aryl;
heteroaryl;
and substituted heteroaryl;
Rc is selected from the group consisting of:
(a) hydrogen;
(b) —R4;
(c) —R10;
(d) —(CO)R3;
(e) —(CO)NHR3;
(f) —(CO)OR3;
(g) —C(O)—NR8R9;
and
(h) —C(O)—NR11NR12R13;
wherein R11 is hydrogen or alkyl, and R12 and R13 are independently selected from R4;
X1 is selected from the group consisting of:
(a) hydrogen;
(b) oxo;
(c) azido;
(d) cyano;
(e) —R4;
(f) —R10;
(g) —(CO)R3;
(h) —(CO)NHR3;
(i) —(CO)OR3;
(j) —C(O)—NR8R9;
(k) —OR14, where R14 is selected from the group consisting of N-phthalimido and Rc;
(l) —SR3;
(m) —NR8R9;
and
(n) —NR3R14;
M1 is absent or R1;
L is independently selected from R4;
W is selected from:
(a) hydrogen;
(b) —R4;
(c) —C(O)R3;
(d) —C(O)O—R3;
and
(e) —C(O)N(R8R9);
Q is:
(a) —R3;
(b) —(CO)R3;
(c) —(CO)NHR3;
(d) —(CO)OR3;
(e) —(SO)2R3;
(f) monosaccharide;
(g) disaccharide;
or
(h) trisaccharide;
Z is:
(a) hydrogen;
(b) —N3;
(c) —CN;
(d) —NO2;
(e) —CONH2;
(f) —COOH;
(g) —CHO;
(h) —R4;
(i) —COOR4;
(j) —C(O)R4;
or
(k) —C(O)NR8R9;
when U is hydrogen, V is selected from the group consisting of:
(a) hydrogen;
(b) —OR3;
(c) —OC(O)R3;
(d) —OC(O)NHR3;
(e) —OS(O)2R3;
(f) —O-monosaccharide;
and
(g) —O-disaccharide;
alternatively, U and V taken together with is oxo;
each of X and Y is independently:
a) hydrogen;
b) hydroxy;
c) halogen;
or
d) —R4;
G is selected from the group consisting of:
a) hydrogen;
b) hydroxy;
c) —O—R4;
d) —O—R10;
alternatively, G and W taken together to a form cyclic structure selected from:
where M is O or N—J—R20, and where J is absent, O, NH, NH(CO), or N═CH;
and R20 is selected from the group consisting of:
i. hydrogen;
ii. R4;
and
iii. R10.

120 more elements