Erythromycin derivatives

Details Erythromycin derivatives Erythromycin derivatives

2000-10-16

2002-12-24

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06498146

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel tricyclic erythromycin derivatives. The compounds of this invention are useful as antibiotic agents in mammals, including man, as well as in fish and birds. The compounds of the present invention are broad-spectrum macrolide antibiotics that are effective against infections caused by certain gram-positive and gram-negative bacteria as well as protozoa. Various derivatives of erythromycin A, useful as antibiotic agents, are referred to in U.S. patent application Ser. No. 60/049,349, filed Jun. 11, 1997, and U.S. application Ser. No. 09/355092, filed Jul. 20, 1999, both of which are incorporated herein by reference in their entirety, and in U.S. patent application Ser. No. 60/063,676, entitled “9-Amino-3-Keto Erythromycin Derivatives”, (Yong-Jin Wu), filed Oct. 29, 1997, which is incorporated herein by reference thereto, in its entirety.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula I
and to pharmaceutically acceptable salts and prodrugs thereof, wherein:
R is C
1
-C
10
alkyl, C
3
-C
10
alkenyl, C
3
-C
10
alkynyl, or C
3
-C
10
cycloalkyl, wherein up to two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably one to four substituents), said substituents being selected from the group (hereinafter also referred to as “Group A”) consisting of:
(a) nitro;
(b) N
3
;
(c) CN;
(d) C
1
-C
10
alkoxy;
(e) C
1
-C
10
alkanoyl;
(f) C
1
-C
10
alkyl;
(g) C
2
-C
10
alkenyl;
(h) C
2
-C
10
alkynyl;
(i) C
3
-C
10
cycloalkyl;
(j) 4 to 10 membered heterocyclic;
(k) —C(O)R
10
;
(l) —C(O)OR
10
;
(m) —NR
10
R
11
;
(n) —NHC(O)R
10
;
(o) —NHC(O)NR
10
R
11
;
(p) —S(O)
n
, wherein n is 0,1, or 2;
(q) —SO
2
R
10
; and
(r) —SO
2
NR
10
R
11
;
each R
1
, R
2
, R
3
, and R
4
is independently selected from H, C
1
-C
12
C
3
-C
10
alkenyl, C
3
-C
10
alkynyl, and —(CR
8
R
9
)
m
Z, with m being an integer from 0 to 6; wherein up to two carbons of said alkyl, alkenyl, alkynyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by one or more substituents (preferably from one to four substituents), selected from Group A;
or R
2
and R
3
, together with the carbon to which they are attached, form a 3-10 membered ring; the ring carbons are optionally substituted by one or more heteroatoms selected from O, S and N;
R
5
is selected from C
1
-C
10
alkyl, C
3
-C
10
alkenyl, C
3
-C
10
alkynyl, —CH
2
—CH═CH—Z, and —(CR
9
R
10
)
m
Z; with m being an integer from 1 to 6; wherein the alkyl, alkenyl and alkynyl can be substituted with one or more substituents (preferably from one to four substituents) selected from Group A;
R
6
is H, —C(O)O(C
1
-C
18
) alkyl or —C(O)(C
1
-C
18
) alkyl, wherein one or more carbons of either of said alkyl may be replaced by a heteroatom selected from O, S and N;
each R
8
and R
9
is independently selected from H, halo, and C
1
-C
6
alkyl; or R
8
and R
9
, together with the carbon to which they are attached, can form a 3 to 10 membered cyclic or heterocyclic di-radical;
each R
10
and R
11
is independently H, C
1
-C
12
alkyl, aryl substituted C
1
-C
12
alkyl, or heteroaryl substituted C
1
-C
12
alkyl, wherein one or more carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N.
each Z is independently 4-10 membered heterocyclic or C
6
-C
10
aryl, wherein said heterocyclic and aryl groups are optionally substituted by one or more substituents (preferably one to four substituents) selected from Group A;
T is absent or selected from the group consisting of:
(a) —C(O)—,
(b) —C(O)—O—,
(c) —CH
2
—,
(d) —C(S)—S—,
(e) —C(O)—NR
10
—;
(f) —S(O)
n
—, where n is 0,1, or 2,
(g) —S(O)
n
—O—, wherein n is 0, 1, or 2,
(h) —P(O)(OR
10
)
n
—, wherein n is 0, 1, or 2, and
(i) —S(O)
2
—NR
10
—,
R
t
is selected from the group consisting of: C
1
-C
6
alkyl, C
3
-C
6
alkenyl, C
3
-C
12
cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups are optionally substituted by one or more substituents (preferably one to four substituents) selected from Group A.
The present invention also relates to compounds of formula 2:
and to pharmaceutically acceptable salts and prodrugs thereof, wherein:
each R
w
and R
x
is independently H, C
1
-C
10
alkyl, C
3
-C
10
alkenyl, C
3
-C
10
alkynyl, or C
3
-C
10
cycloalkyl, wherein up to two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably one to four substitutents) selected from Group A;
R
1
is as defined for formula 1, or R
1
and R
w
together with the nitrogen to which they are attached can form —N═C(R
1
)(R
2
), or form a 3-10 membered ring; the ring carbons are optionally substituted by one or more heteroatoms selected from O, S and N,
R
4
is as defined for formula 1, or R
4
and R
x
, together with the nitrogen to which they are attached, form —N═C(R
4
)(R
2
), or form a 3-10 membered ring; the ring carbons are optionally substituted by one or more heteroatoms selected from O, S and N,
R, R
5
, R
6
, R
t
and T are as defined for formula 1.
The present invention also relates to compounds of formula 3:
and to pharmaceutically acceptable salts and prodrugs thereof, wherein:
R
w
is H, C
1
-C
10
alkyl, C
3
-C
10
alkenyl, C
3
-C
10
alkynyl, C
3
-C
10
cycloalkyl, wherein one or two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably 1-4 substitutents) selected from Group A;
R
z
is H, C
1
-C
10
alkyl, C
3
-C
10
alkenyl, C
3
-C
10
alkynyl, C
3
-C
10
cycloalkyl, wherein one or two carbons of said alkyl, cycloalkyl, alkenyl, alkynyl are optionally replaced by one or more heteroatoms selected from O, S and N, and are optionally substituted by one or more substituents (preferably one to four substituents) selected from Group A;
R, R
1
, R
5
, R
6
, R
t
and T are as defined for formula 1.
A first embodiment of the invention is a compound having the formula 1, as described above, and a preferred embodiment is a compound of formula 1 wherein R=Et, R
2
=R
3
=R
4
=R
6
=H, R
5
=Me, and R
1
=—(CH
2
)
3
Z.
Representative compounds of the invention having formula 1 are those selected from the group consisting of:
Compounds of formula 1, wherein R=Et, R
1
=R
2
=R
3
=R
4
=R
6
=H, R
5
=—(CH
2
)—CH═CH—Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is absent, R
t
is H, acetyl, (4-methoxy)benzoyl, or methanesulfonyl,
Compounds of formula 1, wherein R=Et, R
1
=R
2
=R
3
=R
4
=R
6
=H, R
5
=—(CH
2
)—CH═CH—Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl , quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is —S(O)
2
, R
t
is —CH═CH
2
, —CH
2
CH
2
N(CH
3
)
2
, or —CH
2
CH
2
S-phenyl,
Compounds of formula 1, wherein R=Et, R
1
=R
2
=R
3
=R
4
=R
6
=H, R
5
=—(CH
2
)—CH═CH—Z, Z is quinolin-2-yl, quinolin-3-yl, quinolin-4-yl , quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl, T is —C(O)—NH, R
t
is (2-nitrophenyl), phenyl, allyl, —CH(CH
3
)
2
, or cyclohexyl,
Compounds of formula 1, wherein R=Et, R
1
=Me, R
2
=R
3
=R
4
=R
6
=H, R
5
=—(CH
2
)—CH═CH—Z, Z is quinol

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