US 2006/0142215 A1Published application

Tetracyclic bicyclolides

AssigneeEnanta Pharmaceuticals, Inc.

InventorsDatong Tang, Yonghua Gai, Ying Sun, Yat Or, Zhe Wang

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Abstract

The present invention discloses compounds of formula I, 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.

Claims23

Dependent claims

A compound represented by formula (I):

or the pharmaceutically acceptable salts, esters and prodrugs thereof,
wherein R1 is selected from the group consisting of:
a) hydrogen;
b) deuterium;
c) —CH2OH;
d) aryl;
e) substituted aryl;
f) heteroaryl;
g) substituted heteroaryl;
and
h) —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R2 is:
a) hydrogen;
b) hydroxy;
and
c) activated hydroxy;
when R1 is H, R2 is selected from the group consisting of:
a) hydrogen;
b) hydroxy;
c) activated hydroxy;
d) N3;
e) NH2;
f) CN;
g) protected hydroxy;
h) protected amino;
i) -A-R3, where A is O, S, S(O), SO2, NH, NCH3, NH(CO), NH(CO)NH or NHSO2;
and R3 is independently selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(vii) —C3-C12 cycloalkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
provided that when A=S(O) or SO2, R3 cannot be hydrogen;
and
(j) wherein G is absent, O, S, S(O), S(O)2, NR3, N(CO)R3, NSO2R3, or CHR3;
n=1, 2, or 3;
and m=2 or 3, where R3 is as previously defined;
or alternatively, R1 and R2 taken together with the carbon atom to which they are attached is selected from the group consisting of:
a) C═O;
b) C(OR4)(OR5), where R4 and R5 are selected from the group consisting of C1-C12 alkyl, aryl or substituted aryl;
or taken together are —(CH2)m, and where m is 2 or 3;
c) C(SR4)(SR5), where R4 and R5 are as previously defined above;
d) C═CHR3, where R3 is as previously defined;
e) C═CNH(amino protecting group);
and
f) C═N-Z-R3, where Z is absent, O, NH, NH(CO), NH(CO)NH or NHSO2;
and R3 is as previously defined;
Each of Ra, Rb, Rc and Rd is independently selected from the group consisting of:
a) hydrogen;
b) deuteurium;
c) hydroxy;
d) amino;
e) halogen;
and
f) -M-R3, where M is absent, O, NH, NCH3, NH(CO), NH(CO)NH or NHSO2;
and R3 is as previously defined;
alternatively, Ra and Rb or Rc and Rd taken together with the carbon atom to which they are attached is C═O;
r is 0, 1, or 2;
B is NR3OR40;
wherein R30 and R40 is independently selected from the group consisting of hydrogen, acyl, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, saturated or unsaturated heterocyclic group;
or can be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic or heteroaromatic ring;
V is selected from the group consisting of hydrogen, azido, cyano, nitro, aldehyde, carboxylic acid, amide, a substituted or unsubstituted, saturated or unsaturated aliphatic group;
Q is selected from the group consisting of:
(a) hydrogen;
(b) protected hydroxy;
(c) OR6, where R6 is a group consisting of:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
and
(vii) —C3-C12 cycloalkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
L is selected from the group consisting of:
(a) —CH2CH3;
(b) —CH(OH)CH3;
and
(c) —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
Rx is hydrogen, hydroxy protecting group or hydroxy prodrug group.

79 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound represented by formula (I):

or the pharmaceutically acceptable salts, esters and prodrugs thereof,
wherein R1 is selected from the group consisting of:
a) hydrogen;
b) deuterium;
c) —CH2OH;
d) aryl;
e) substituted aryl;
f) heteroaryl;
g) substituted heteroaryl;
and
h) —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R2 is:
a) hydrogen;
b) hydroxy;
and
c) activated hydroxy;
when R1 is H, R2 is selected from the group consisting of:
a) hydrogen;
b) hydroxy;
c) activated hydroxy;
d) N3;
e) NH2;
f) CN;
g) protected hydroxy;
h) protected amino;
i) -A-R3, where A is O, S, S(O), SO2, NH, NCH3, NH(CO), NH(CO)NH or NHSO2;
and R3 is independently selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(vii) —C3-C12 cycloalkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
provided that when A=S(O) or SO2, R3 cannot be hydrogen;
and
(j) wherein G is absent, O, S, S(O), S(O)2, NR3, N(CO)R3, NSO2R3, or CHR3;
n=1, 2, or 3;
and m=2 or 3, where R3 is as previously defined;
or alternatively, R1 and R2 taken together with the carbon atom to which they are attached is selected from the group consisting of:
a) C═O;
b) C(OR4)(OR5), where R4 and R5 are selected from the group consisting of C1-C12 alkyl, aryl or substituted aryl;
or taken together are —(CH2)m, and where m is 2 or 3;
c) C(SR4)(SR5), where R4 and R5 are as previously defined above;
d) C═CHR3, where R3 is as previously defined;
e) C═CNH(amino protecting group);
and
f) C═N-Z-R3, where Z is absent, O, NH, NH(CO), NH(CO)NH or NHSO2;
and R3 is as previously defined;
Each of Ra, Rb, Rc and Rd is independently selected from the group consisting of:
a) hydrogen;
b) deuteurium;
c) hydroxy;
d) amino;
e) halogen;
and
f) -M-R3, where M is absent, O, NH, NCH3, NH(CO), NH(CO)NH or NHSO2;
and R3 is as previously defined;
alternatively, Ra and Rb or Rc and Rd taken together with the carbon atom to which they are attached is C═O;
r is 0, 1, or 2;
B is NR3OR40;
wherein R30 and R40 is independently selected from the group consisting of hydrogen, acyl, a substituted or unsubstituted, saturated or unsaturated aliphatic group, a substituted or unsubstituted, saturated or unsaturated alicyclic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, saturated or unsaturated heterocyclic group;
or can be taken together with the nitrogen atom to which they are attached to form a substituted or unsubstituted heterocyclic or heteroaromatic ring;
V is selected from the group consisting of hydrogen, azido, cyano, nitro, aldehyde, carboxylic acid, amide, a substituted or unsubstituted, saturated or unsaturated aliphatic group;
Q is selected from the group consisting of:
(a) hydrogen;
(b) protected hydroxy;
(c) OR6, where R6 is a group consisting of:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
and
(vii) —C3-C12 cycloalkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
L is selected from the group consisting of:
(a) —CH2CH3;
(b) —CH(OH)CH3;
and
(c) —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
Rx is hydrogen, hydroxy protecting group or hydroxy prodrug group.

79 more elements