Tricyclic erythromycin derivatives

Details Tricyclic erythromycin derivatives Tricyclic erythromycin derivatives

1999-07-15

2001-09-18

Peselev, Elli (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C514S029000, C536S018500

Reexamination Certificate

active

06291656

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. 60/046,150, filed May 9, 1997, both of which are incorporated herein by reference in their entirety, and in U.S. patent application Ser. No. 60/063676, entitled “9-Amino-3-Keto Erythromycin Derivatives”, (Yong-Jin Wu), filed Oct. 29, 1997, which is incorporated herein by reference in its entirety.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula I
and pharmaceutically acceptable salts thereof, wherein:
each R
1
and R
2
is independently selected from H and C
1
-C
2
alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of —C(O)OR
6
, —OR
6
, C
1
-C
10
alkanoyl, halo, nitro, cyano, R
6
, R
8
, —NR
6
R
7
, —SR
6
, —SOR
6
, —SO
2
R
6
and —SO
2
NR
6
R
7
.
R
3
is H, R
7
, C(O)R
7
, C(O)R
8
, C(O)OR
7
, C(O)OR
8
, or (CR
6
R
7
)
m
R
8
, wherein m is an integer ranging from 0 to 6;
R
4
is H or C
1
-C
12
alkyl, wherein one or two carbons of said alkyl are optionally replaced by a heteroatom selected from O, S and N, and are optionally substituted by 1 to 3 substituents selected from the group consisting of —C(O)OR
6
, —OR
6
, C
1
-C
10
alkanoyl, halo, nitro, cyano, R
6
, R
8
, —NR
6
R
7
, —SR
6
, —SOR
6
, —SO
2
R
6
and —SO
2
NR
6
R
7
;
R
5
is H, —C(O)R
8
or C
1
-C
18
alkanoyl, wherein in the alkyl portion of said alkanoyl one or two carbons optionally may be replaced by a heteroatom selected from O, S and N;
each R
6
and R
7
is independently selected from H and C
1
-C
12
alkyl; and
each R
8
is independently a 4-10 membered heterocyclic or C
6
-C
10
aryl, wherein said heterocycyclic and aryl groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of 4-10 membered heterocyclic, C
6
-C
10
aryl, —NHC(O)R
6
, —NHC(O)NR
6
R
7
, —C(O)OR
6
, —OR
6
, —C(O)R
6
, halo, nitro, cyano, R
6
, —NR
6
R
7
, —SR
6
, —S(O)R
6
, —SO
2
R
6
and —SO
2
NR
6
R
7
.
More specific embodiments of the invention include compounds of claim
1
wherein R
5
is H.
More specific embodiments of the invention include compounds of claim
1
wherein R
1
is H.
More specific embodiments of the invention include compounds of claim
1
wherein each of R
1
and R
2
is H.
More specific embodiments of the invention include compounds of claim
1
wherein each of R
1
and R
2
is H and wherein R
4
is H, methyl, ethyl, isopropyl, propyl, or cyclopropyl.
More specific embodiments of the invention include compounds of claim
1
wherein R
3
is (CH
2
)
m
R
8
, m is an integer ranging from 0 to 6 and R
8
is as defined in formula I.
More specific embodiments of the invention include compounds of claim
1
wherein R
3
is (CH
2
)
3
R
8
.
Specific embodiments of R
8
include quinolin-4-yl, 4-phenyl-1-imidazol-1-yl, imidazo(4,5-b)pyridin-3-yl, or 4-pyridin-3-yl-imidazol-1-yl.
Examples of preferred compounds of the present invention include a compound of formula I selected from the group consisting of:
the compound of formula I wherein each of R
1
, R
2
, R
4
and R
5
is H and R
3
is 3-quinolin-4-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is methyl and R
3
is 3-quinolin-4-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is ethyl and R
3
is 3-quinolin-4-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is propyl and R
3
is 3-quinolin-4-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is isopropyl and R
3
is 3-quinolin-4-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is cyclopropyl and R
3
is 3-quinolin-4-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
, R
4
and R
5
is H and R
3
is 3-(7-methoxy-quinolin-4-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is methyl and R
3
is 3-(7-methoxy-quinolin-4-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is ethyl and R
3
is 3-(7-methoxy-quinolin-4-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is propyl and R
3
is 3-(7-methoxy-quinolin-4-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is isopropyl and R
3
is 3-(7-methoxy-quinolin-4-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is cyclopropyl and R
3
is 3-(7-methoxy-quinolin-4-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
, R
4
and R
5
is H and R
3
is 3-(4-phenyl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is CH
3
and R
3
is 3-(4-phenyl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is ethyl and R
3
is 3-(4-phenyl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is propyl and R
3
is 3-(4-phenyl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is isopropyl and R
3
is 3-(4-phenyl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is cyclopropyl and R
3
is 3-(4-phenyl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
, R
4
and R
5
is H and R
3
is 3-(4-pyridin-3-yl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is CH
3
and R
3
is 3-(4-pyridin-3-yl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is ethyl and R
3
is 3-(4-pyridin-3-yl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is propyl and R
3
is 3-(4-pyridin-3-yl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is isopropyl and R
3
is 3-(4-pyridin-3-yl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is cyclopropyl and R
3
is 3(4-pyridin-3-yl-imidazol-1-yl)-propyl;
the compound of formula I wherein each of R
1
, R
2
, R
4
and R
5
is H and R
3
is 3-imidazo(4,5-b)pyridin-3-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is CH
3
and R
3
is 3-imidazo(4,5-b)pyridin-3-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is ethyl and R
3
is 3-imidazo(4,5-b)pyridin-3-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is propyl and R
3
is 3-imidazo(4,5-b)pyridin-3-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is isopropyl and R
3
is 3-imidazo(4,5-b)pyridin-3-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is cyclopropyl and R
3
is 3-imidazo(4,5-b)pyridin-3-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
, R
4
and R
5
is H and R
3
is 3-pyridin-4-yl-propyl;
the compound of formula I wherein each of R, R
2
and R
5
is H, R
4
is CH
3
and R
3
is 3-pyridin-4-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is ethyl and R
3
is 3-pyridin-4-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is propyl and R
3
is 3-pyridin-4-yl-propyl;
the compound of formula I wherein each of R
1
, R
2
and R
5
is H, R
4
is isopropyl and R
3
is 3-pyridin-4-yl-propyl;
the compound of formula I wherein each of R

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