US 2006/0148731 A1Published application

11,12-Lactone bicyclolides

AssigneeEnanta Pharmaceuticals, Inc.

InventorsDatong Tang, Yonghua Gai, Ying Sun, Zhigang Chen, 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 W is selected from the group consisting of:
a) hydrogen;
b) CN;
c) -E-R3, where E is S, SO, SO2, NH, NCH3, CH2O, CH2NH, CH2NCH3 or CO;
and R3 is independently selected from the group consisting of:
(i) —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
and
(ii) —C1-C6 substituted alkyl, —C2-C6 substituted alkenyl, or —C2-C6 substituted alkynyl;
provided that when A=S(O) or SO2, R3 cannot be hydrogen;
and
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;
or
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-R4, where A is O, S, S(O), SO2, NH, NCH3, NH(CO), NH(CO)NH or NHSO2;
and R4 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, R4 cannot be hydrogen;
and
wherein G is absent, O, S, S(O), S(O)2, NR4, N(CO)R4, NSO2R4, or CHR4;
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(OR5)(OR6), where R5 and R6 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(SR5)(SR6), where R5 and R6 are as previously defined above;
d) C═CHR4, where R4 is as previously defined;
e) C═CNH;
and
f) C═N-Z-R4, where Z is absent, O, NH, NH(CO), NH(CO)NH or NHSO2;
and R3 is as previously defined;
and
X and Y are:
(a) when one of X and Y is a hydrogen, the other is selected from the group consisting of:
(i) hydrogen;
(ii) deuterium;
(iii) hydroxy;
(iv) protected hydroxy;
(v) amino;
(vi) protected amino;
and
wherein G is absent, O, S, S(O), S(O)2, NR4, N(CO)R4, NSO2R4, or CHR4;
n=1, 2, or 3;
and m=2 or 3, where R4 is as previously defined;
or
b) X and Y taken together with the carbon atom to which they are attached is:
(i) C═O;
(ii) C═N—OR7, wherein R7 is selected from the group consisting of:
1. hydrogen;
2. —CH2O(CH2)2OCH3;
3. —CH2O(CH2O)nCH3, wherein n is as previously defined;
4. —C1-C12 alkyl, containing 0, 1, 2, or 3 heteroatoms, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
5. C3-C12 cycloalkyl;
6. C(O)—C1-C12 alkyl;
7. C(O)—(C3-C12 cycloalkyl);
8. C(O)—R4, wherein R4 is as previously defined;
and
9. —Si(Ra)(Rb)(Rc), wherein Ra, Rb and Rc are each independently selected from the group consisting of C1-C12 alkyl, aryl and substituted aryl;
or
(iii) C═N—O—C(R8)(R9)—O—R10, wherein R8 and R9 taken together with the carbon atom to which they are attached form a C3 to C12 cycloalkyl group or each independently is selected from the group consisting of:
hydrogen and C1-C12 alkyl;
and R10 is selected from the group consisting of:
1. —C1-C12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
2. —C3-C12 cycloalkyl;
and
3. —Si(Ra)(Rb)(Rc), wherein Ra, Rb and Rc are as previously defined;
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;
and
(c) OR11, where R11 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 or —C3-C12 substituted 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;
and
Rx is hydrogen, hydroxylprotecting group or hydroxylprodrug group.

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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 W is selected from the group consisting of:
a) hydrogen;
b) CN;
c) -E-R3, where E is S, SO, SO2, NH, NCH3, CH2O, CH2NH, CH2NCH3 or CO;
and R3 is independently selected from the group consisting of:
(i) —C1-C6 alkyl, —C2-C6 alkenyl, or —C2-C6 alkynyl;
and
(ii) —C1-C6 substituted alkyl, —C2-C6 substituted alkenyl, or —C2-C6 substituted alkynyl;
provided that when A=S(O) or SO2, R3 cannot be hydrogen;
and
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;
or
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-R4, where A is O, S, S(O), SO2, NH, NCH3, NH(CO), NH(CO)NH or NHSO2;
and R4 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, R4 cannot be hydrogen;
and
wherein G is absent, O, S, S(O), S(O)2, NR4, N(CO)R4, NSO2R4, or CHR4;
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(OR5)(OR6), where R5 and R6 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(SR5)(SR6), where R5 and R6 are as previously defined above;
d) C═CHR4, where R4 is as previously defined;
e) C═CNH;
and
f) C═N-Z-R4, where Z is absent, O, NH, NH(CO), NH(CO)NH or NHSO2;
and R3 is as previously defined;
and
X and Y are:
(a) when one of X and Y is a hydrogen, the other is selected from the group consisting of:
(i) hydrogen;
(ii) deuterium;
(iii) hydroxy;
(iv) protected hydroxy;
(v) amino;
(vi) protected amino;
and
wherein G is absent, O, S, S(O), S(O)2, NR4, N(CO)R4, NSO2R4, or CHR4;
n=1, 2, or 3;
and m=2 or 3, where R4 is as previously defined;
or
b) X and Y taken together with the carbon atom to which they are attached is:
(i) C═O;
(ii) C═N—OR7, wherein R7 is selected from the group consisting of:
1. hydrogen;
2. —CH2O(CH2)2OCH3;
3. —CH2O(CH2O)nCH3, wherein n is as previously defined;
4. —C1-C12 alkyl, containing 0, 1, 2, or 3 heteroatoms, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
5. C3-C12 cycloalkyl;
6. C(O)—C1-C12 alkyl;
7. C(O)—(C3-C12 cycloalkyl);
8. C(O)—R4, wherein R4 is as previously defined;
and
9. —Si(Ra)(Rb)(Rc), wherein Ra, Rb and Rc are each independently selected from the group consisting of C1-C12 alkyl, aryl and substituted aryl;
or
(iii) C═N—O—C(R8)(R9)—O—R10, wherein R8 and R9 taken together with the carbon atom to which they are attached form a C3 to C12 cycloalkyl group or each independently is selected from the group consisting of:
hydrogen and C1-C12 alkyl;
and R10 is selected from the group consisting of:
1. —C1-C12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
2. —C3-C12 cycloalkyl;
and
3. —Si(Ra)(Rb)(Rc), wherein Ra, Rb and Rc are as previously defined;
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;
and
(c) OR11, where R11 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 or —C3-C12 substituted 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;
and
Rx is hydrogen, hydroxylprotecting group or hydroxylprodrug group.

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