Azalides and methods of making same

Details Azalides and methods of making same Azalides and methods of making same

2000-01-26

2001-08-07

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Conjugate or complex of monoclonal or polyclonal antibody,...

Conjugated via claimed linking group, bond, chelating agent,...

C549S271000, C549S263000

Reexamination Certificate

active

06270768

ABSTRACT:

FIELD OF INVENTION
This invention relates to novel azalides that are useful as anticancer agents, antibacterial agents, and antiprotozoa agents, and to methods of making same.
BACKGROUND OF THE INVENTION
Macrolide antibiotics are useful in the treatment of a broad spectrum of bacterial infections and protozoa infections in mammals, fish and birds. These antibiotics include derivatives of erythromycin A, some of which have been formed by the addition of naturally occurring intermediates of erythromycin biogenesis to the fermentation media of
Streptomyces antibioticus
ATCC 31771. Spagnoli, R., et al.,
J. Antibiotics,
34(4):365-375 (1983); U.S. Pat. No. 4,439,426. The resulting oleandrose derivatives are more stable than erythromycin A under acidic conditions.
Other derivatives of erythromycin A include azalides such as azithromycin, the synthesis of which is described by U.S. Pat. Nos. 4,474,768 and 4,517,359. The azalide aglycone contains a nitrogen atom and is structurally, conformationally and electronically distinct from naturally occurring macrolide aglycones. Prior to the invention, it was believed that biological cultures would not glycosilate this unnatural macrolide aglycone.
SUMMARY OF THE INVENTION
The invention is directed to compounds of Formula 1:
and to pharmaceutically acceptable salts and solvates thereof, wherein:
X is —CH
2
N(R
1
)—, —N(R
a
)CH
2
—, or —C(O)— wherein the first dash of each of the foregoing X groups is attached to the C-10 carbon of the compound of Formula 1 and the last dash of each group is attached to the C-8 carbon of the compound of Formula 1, and R
a
is H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4;
R
1
is straight-chain or alpha-branched C
1
-C
8
alkyl, alkenyl, alkynyl, alkoxyalkyl or alkylthioalkyl group any of which may be substituted by one or more hydroxyl groups; a C
3
-C
8
cycloalkyl or C
5
-C
8
cycloalkenyl group, either of which may optionally be substituted by methyl or one or more hydroxyl or one or more C
1
-C
4
alkyl groups or halo atoms; or a 3 to 6 membered oxygen or sulphur containing heterocyclic ring which may be saturated, or fully or partially unsaturated, and which may be substituted by one or more C
1
-C
4
alkyl groups or halo atoms or a group of the formula SR
b
, wherein R
b
is C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
2
-C
8
alkynyl, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, phenyl or substituted phenyl wherein the substituent is C
1
-C
4
alkyl, C
1
-C
4
alkoxy or halo or a 3 to 6 membered oxygen or sulfur containing heterocyclic ring which may be saturated, or fully or partially unsaturated and which may be substituted by one or more C
1
-C
4
alkyl groups or halo atoms;
or R
1
is phenyl which may be substituted with at least one substituent selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy and C
1
-C
4
alkylthio groups, halogen atoms, hydroxyl groups, trifluoromethyl, and cyano;
or R
1
is of the formula
wherein Z
1
is O, S or —CH
2
—, and a, b, c, and d is each independently an integer ranging from 0 to 2 and a+b+c+d#5;
R
2
is H or OH;
R
3
is —C(O)NR
c
R
d
, wherein each of R
c
and R
d
is independently H, C
1
-C
10
alkyl, C
2
-C
20
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
(C
6
-C
10
aryl), or —(CH
2
)
m
(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein each of the foregoing R
c
and R
d
groups, except H, may be substituted by 1 to 3 Q groups; or wherein R
c
and R
d
may be taken together to form a 4-7 membered saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings may include 1 or 2 heteroatoms selected from O, S and N, in addition to the nitrogen to which R
c
and R
d
are attached, and said saturated ring may include 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings may be substituted by 1 to 3 Q groups;
or R
2
and R
3
taken together form a carbonate ring;
R
4
is H, OH, O(C
1
-C
10
alkyl);
R
5
is H, —C(O)R
e
, —C(O)OR
e
, —C(O)NR
e
R
f
, or a hydroxy protecting group, and R
e
and R
f
is each independently H or C
1
-C
6
alkyl;
R
6
is H or OH;
R
7
is H or OH;
R
8
is C
1
-C
10
alkyl, C
2
-C
20
alkenyl, C
2
-C
10
alkynyl, cyano, —CH
2
S(O)
n
R
g
wherein n is an integer ranging from 0 to 2, —CH
2
OR
g
, —CH
2
N(OR
h
)R
g
, —CH
2
NR
g
R
i
, —(CH
2
)
m
(C
6
-C
12
aryl), or —(CH
2
)
m
(5-10 membered heteroalkyl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R
8
groups may be substituted by 1 to 3 Q groups;
each R
g
is independently H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
q
CR
g(1)
R
g(2)
(CH
2
)
r
NR
g(3)
R
g(4)
wherein q and r is each independently an integer ranging from 0 to 3 except q and r are not both 0, —(CH
2
)
m
(C
6
-C
10
aryl), or —(CH
2
)
m
(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R
g
groups, except H, may be substituted by 1 to 3 Q groups;
each of R
g(1)
, R
g(2)
, R
g(3)
and R
g(4)
is independently selected from H, C
1
-C
10
alkyl, —(CH
2
)
m
(C
6-
C
10
aryl), or —(CH
2
)
m
(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing R
g(1)
, R
g(2)
, R
g(3)
and R
g(4)
groups, except H, may be substituted by 1 to 3 Q groups;
or R
g(1)
and R
g(3)
are taken together to form —(CH
2
)
p
— wherein p is an integer ranging from 0 to 3 such that a 4-7 membered saturated ring is formed that may include 1 or 2 carbon-carbon double or triple bonds;
or R
g(3)
and R
g(4)
are taken together to form a 4-10 membered monocyclic or polycyclic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings may include 1 or 2 heteroatoms selected from O, S and N, in addition to the nitrogen to which R
g(3)
and R
g(4)
are attached, said saturated ring may include 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings may be substituted by 1 to 3 Q groups;
R
h
is H or C
1
-C
6
alkyl;
R
i
is H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, or C
2
-C
10
alkynyl, wherein the foregoing R
i
group may be substituted by 1 to 3 substituents independently selected from halo, OH, and O(C
1
-C
6
alkyl);
and if R
8
is —CH
2
NR
g
R
i
, then R
g
and R
i
may be taken together to form a 4-10 membered saturated monocyclic or polycycic saturated ring or a 5-10 membered heteroaryl ring, wherein said saturated and heteroaryl rings optionally include 1 or 2 heteroatoms selected from O, S and N, in addition to the nitrogen to which R
g
and R
i
are attached, said saturated ring may include 1 or 2 carbon-carbon double or triple bonds, and said saturated and heteroaryl rings may be substituted by 1 to 3 Q groups;
or R
7
and R
8
are taken together to form an oxazolyl ring as shown below
wherein Z
2
is —SR
g
, —(CH
2
)
n
C(O)R
g
wherein n is 0 or 1, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
(C
6
-C
10
aryl), or —(CH
2
)
m
(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein the foregoing Z
2
groups may be substituted by 1 to 3 Q groups;
each Q is independently selected from halo, cyano, nitro, trifluoromethyl, azido, —C(O)Q
1
, —OC(O)Q
1
, —C(O)OQ
1
, —OC(O)OQ
1
, —NQ
2
C(O)Q
3
, —C(O)NQ
2
Q
3
, —NQ
2
Q
3
, hydoxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(5-10 membered heteroaryl), wherein m is an integer ranging from 0 to 4, and wherein said aryl and heteroaryl substituents may be substituted by 1 or 2 substituents independently selected from halo, cyano, nitro, trifluoromethyl, azide, —C(O)Q
1
, —C(O)OQ
1
, —OC(O)OQ
1
, —NQ
2
C(O)Q
3
, —C(O)NQ
2
Q
3
, —NQ
2
Q
3
, hydroxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
each Q
1
, Q
2
and Q
3
is independently selected from H, OH, C
1
-C
10
alkyl, C
1
-C
6
alkoxy, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CH
2
)
m
(C
6
-C
10
aryl), and —(CH
2
)
m
(5-10 membered heteroaryl),

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