US 2006/0142214 A1Published application

3,6-bicyclolides

AssigneeEnanta Pharmaceuticals, Inc.

InventorsYat Or, Datong Tang, Ying Sun, Yonghua Gai, Guoyou Xu, 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.

Claims47

Dependent claims

Compounds 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 selected from the group consisting of:
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;
provided that when A=S(O) or SO2, R3 cannot be hydrogen;
and
wherein E 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:
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;
or
f) C═N-Z-R3, where Z is absent, O, NH, NH(CO), NH(CO)NH or NHSO2;
and R3 is as previously defined;
X and Y are:
a) when one of X and Y is a hydrogen, the other is selected from:
(i) hydrogen;
(ii) deuterium;
(iii) hydroxy;
(iv) protected hydroxy;
(v) amino;
(vi) protected amino;
or
wherein E 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;
b) X and Y taken together with the carbon atom to which they are attached is:
(i) C═O;
(ii) C═N—OR6, wherein R6 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)—R3, wherein R3 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(R7)(R8)—O—R9, wherein R7 and R8 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 R9 is selected from the group consisting of:
1. —C1-C2 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;
W is selected from the group consisting of:
a) hydrogen;
b) methyl;
c) allyl;
and
d) —OCH2SCH3
G is selected from the group consisting of:
a) hydroxy;
b) —O-aryl;
—O-substituted aryl;
—O-heteroaryl;
—O-substituted heteroaryl;
and
c) —OC1-C6 alkyl, —OC2-C6 alkenyl, or —OC2-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;
U is hydrogen;
when U and G are taken together to form a bond, W is selected from the group consisting of:
a) hydrogen;
and
b) —C(O)LGp, where LGp is a leaving group, such as but not limited to, Cl, imidazole, triazole, cyano, p-nitrobenzene and the like;
or alternatively, structure
of formula (I) taken together is:
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. aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
and
iii. —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;
B is NR30R40;
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) OR21, where R21 is selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
(iii) —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
(iv) —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;
and
Rx is hydrogen, hydroxy protecting group or hydroxy prodrug group.

132 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/295,736Filed 6 Dec 2005
Priority: 7 Dec 2004
Published: 29 Jun 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07H 17/08
Heterocyclic radicals containing only oxygen as ring hetero atoms: hetero rings containing eight or more ring members, e.g. erythromycins
A61P 11/00
Drugs for disorders of the respiratory system
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents

Family

Application11/008,581Continuation in part · filed 7 Dec 2004
Application11/295,736Continuation in part · filed 6 Dec 2005
US 2006/0122128 A1Published application
US 7,229,972 B2Related patent
US 7,419,962 B2Related patent
US 2006/0142214 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Compounds 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 selected from the group consisting of:
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;
provided that when A=S(O) or SO2, R3 cannot be hydrogen;
and
wherein E 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:
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;
or
f) C═N-Z-R3, where Z is absent, O, NH, NH(CO), NH(CO)NH or NHSO2;
and R3 is as previously defined;
X and Y are:
a) when one of X and Y is a hydrogen, the other is selected from:
(i) hydrogen;
(ii) deuterium;
(iii) hydroxy;
(iv) protected hydroxy;
(v) amino;
(vi) protected amino;
or
wherein E 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;
b) X and Y taken together with the carbon atom to which they are attached is:
(i) C═O;
(ii) C═N—OR6, wherein R6 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)—R3, wherein R3 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(R7)(R8)—O—R9, wherein R7 and R8 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 R9 is selected from the group consisting of:
1. —C1-C2 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;
W is selected from the group consisting of:
a) hydrogen;
b) methyl;
c) allyl;
and
d) —OCH2SCH3
G is selected from the group consisting of:
a) hydroxy;
b) —O-aryl;
—O-substituted aryl;
—O-heteroaryl;
—O-substituted heteroaryl;
and
c) —OC1-C6 alkyl, —OC2-C6 alkenyl, or —OC2-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;
U is hydrogen;
when U and G are taken together to form a bond, W is selected from the group consisting of:
a) hydrogen;
and
b) —C(O)LGp, where LGp is a leaving group, such as but not limited to, Cl, imidazole, triazole, cyano, p-nitrobenzene and the like;
or alternatively, structure
of formula (I) taken together is:
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. aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
and
iii. —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;
B is NR30R40;
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) OR21, where R21 is selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
(iii) —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
(iv) —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;
and
Rx is hydrogen, hydroxy protecting group or hydroxy prodrug group.

132 more elements

Facts

Application

11/295,736Filed 6 Dec 2005

Priority

7 Dec 2004

Published

29 Jun 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07H 17/08
Heterocyclic radicals containing only oxygen as ring hetero atoms: hetero rings containing eight or more ring members, e.g. erythromycins
A61P 11/00
Drugs for disorders of the respiratory system
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents

Family

Application11/008,581Continuation in part · filed 7 Dec 2004

Application11/295,736Continuation in part · filed 6 Dec 2005

US 2006/0122128 A1Published application

US 7,229,972 B2Related patent

US 7,419,962 B2Related patent

US 2006/0142214 A1This patent

From the US filing history. Foreign family members aren’t listed.