Macrolide antibiotics

Details Macrolide antibiotics Macrolide antibiotics

2001-06-26

2004-10-26

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06809080

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to macrolide compounds that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to methods of preparing the compounds, intermediates useful in preparation of the compounds, and pharmaceutical compositions containing the compounds. In addition, the present invention includes methods of treating bacterial and protozoal infections through the administration of the compounds to mammals, fish and birds requiring such treatment.
Derivatives of erythromycin A that are useful as antibiotic agents are referred to in International patent applications WO 98/56800, published Dec. 17, 1998; WO 98/51696, published Nov. 19, 1998; WO 99/21866, published May 6, 1999; WO 99/62920, published Dec. 9, 1999; WO 99/21865, published May 6, 1999; PCT/IB99/01701, filed Oct. 18, 1999; European patent application EP 895999, published Feb. 10, 1999; U.S. patent application Ser. No. 60/117,342, filed Jan. 27, 1999; U.S. patent application Ser. No. 60/130,809, filed Apr. 23, 1999; U.S. patent application Ser. No. 60/130,912, filed Apr. 23, 1999; and U.S. patent application Ser. No. 60/130,913, filed Apr. 23, 1999. Derivatives of erythromycin A are also referred to in U.S. Pat. Nos. 4,474,768 and 4,517,359, relating to the commercially available antibiotic azithromycin. These patents and patent applications are incorporated by reference herein in their entireties.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
X is C, Br, I, or F;
Y is ═O, or ═NOR
5
or Y means both —H and —OR
5
; or both —H and —NR
5
R
10
(i.e. Y is double bonded to the macrolide ring where it is ═O or ═NOR
5
, or refers to two single bonded groups where it is both —H and —OR
5
; or both —H and —NR
5
R
10
);
R
1
, R
2
, and R
3
are independently selected from H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, (4- to 10-membered heterocyclic) C
1
-C
6
alkyl, (4- to 10-membered heterocyclic) C
2
-C
6
alkenyl, (4- to 10-membered heterocyclic) C
2
-C
6
alkynyl, (C
6
-C
10
aryl) C
1
-C
6
alkyl, (C
6
-C
10
aryl) C
2
-C
6
alkenyl, and (C
6
-C
10
aryl) C
2
-C
6
alkynyl wherein said alkyl moieties of the foregoing groups are optionally substituted by halo or C
1
-C
6
alkyl, and wherein said heterocyclic moieties are optionally substituted by 4- to 10-membered heterocyclic, (4- to 10-membered heterocyclic) C
1
-C
6
alkyl, or (C
6
-C
10
aryl) C
1
-C
6
alkyl, and further wherein the aryl and heterocyclic moieties of each of the foregoing groups and optional substituents is optionally substituted by 1 to 4 R
7
groups;
R
4
is selected from H, C
1
-C
10
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, (C
1
-C
6
alkoxy) C
1
-C
6
alkyl, (C
1
-C
6
alkylthio) C
1
-C
6
alkyl, (C
5
-C
8
cycloalkyl) C
2
-C
5
alpha branched alkyl, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, 3 to 6 membered O or S containing heterocyclic group, or phenyl, wherein each R
4
group may be substituted with from 1 to 3 substituents independently selected from hydroxy, halo, (C
6
-C
10
aryl) C
2
-C
6
alkenyl, and C
1
-C
4
alkyl;
R
5
and R
10
are independently selected from H, C
1
-C
6
alkyl, C
6
-C
10
aryl, 4- to 10-membered heterocyclic, (4- to 10-membered heterocyclic) C
1
-C
6
alkyl and (C
6
-C
10
aryl) C
1
-C
6
alkyl, wherein said aryl and heterocyclic groups are optionally substituted by 1 to 4 R
7
groups;
R
6
is H, —C(O)C
1
-C
6
alkyl, benzyl, benzyloxycarbonyl, or (C
1
-C
6
alkyl)
3
silyl;
R
7
is independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R
8
, —C(O)OR
8
, —OC(O)R
8
, —NR
8
C(O)R
9
, —C(O)NR
8
R
9
, —NR
8
R
9
, hydroxy, C
1
-C
6
alkyl, C
2
-C
5
alkenyl, C
2
-C
6
alkynyl, C
6
-C
10
aryl, 4- to 10-membered heterocyclic, and C
1
-C
6
alkoxy; and
each R
8
and R
9
is independently selected from H, C
1
-C
6
alkyl, C
6
-C
10
aryl, and 4- to 10-membered heterocyclic.
In one embodiment of the invention, Y is ═O or ═NOR
5
, R
1
is (4- to 10-membered heterocyclic) C
1
-C
6
alkyl substituted by 4- to 10-membered heterocyclic, R
2
is C
1
-C
10
alkyl or C
2
-C
10
alkenyl, R
3
is C
1
-C
6
alkyl, R
4
is ethyl, R
5
is C
1
-C
6
alkyl, and R
6
is H.
In another embodiment, the compound of the invention has the following formula:
In one embodiment of the compound of formula la, Y is ═O or ═NOR
5
, R
2
is C
1
-C
10
alkyl or C
2
-C
10
alkenyl, and R
6
is H, —C(O)C
1
-C
6
alkyl, benzyl, benzyloxycarbonyl, or (C
1
-C
6
alkyl)
3
silyl. In one aspect of this embodiment, Y is ═O and R
6
is H. In another aspect of this embodiment, Y is ═NOR
5
and R
6
is H. Preferably, in this embodiment, R
2
is CH
3
, CH
2
CH
3
, CH
2
CH═CH
2
, trans-CH
2
CH═CHCH
3
, trans-CH
2
CH═CHCH
2
CH
3
, or trans-CH
2
—CH═C(CH
3
)CH
2
CH
2
CH═(CH
3
)CH
3
.
The invention also relates to a pharmaceutical composition for the treatment of a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, and a pharmaceutically acceptable carrier.
The invention also relates to a method of treating a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, prodrug, or solvate thereof.
The term “treatment”, as used herein, unless otherwise indicated, includes the treatment or prevention of a bacterial infection or protozoa infection as provided in the method of the present invention.
As used herein, unless otherwise indicated, the terms “bacterial infection(s)” and “protozoa infection(s)” include bacterial infections and protozoa infections that occur in mammals, fish and birds as well as disorders related to bacterial infections and protozoa infections that may be treated or prevented by administering antibiotics such as the compounds of the present invention. Such bacterial infections and protozoa infections, and disorders related to such infections, include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by
Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus,
or Peptostreptococcus spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by
Streptococcus pyogenes,
Groups C and G streptococci,
Clostridium diptheriae,
or
Actinobacillus haemolyticum;
respiratory tract infections related to infection by
Mycoplasma pneumoniae, Legionelia pneumophila, Streptococcus pneumoniae, Haemophilus influenzae,
or
Chiamydia pneumoniae;
uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by
Staphylococcus aureus,
coagulase-positive staphylococci (i.e.,
S. epidermidis, S. hemolyticus,
etc.),
Streptococcus pyogenes, Streptococcus agalactiae,
Streptococcal groups C-F (minute-colony streptococci), vindans streptococci,
Corynebacterium minutissimum,
Clostridium spp., or
Bartonella henselae;
uncomplicated acute urinary tract infections related to infection by
Staphylococcus saprophyticus
or Enterococcus spp.; urethritis and cervicitis; and sexually transmitted diseases related to infection by
Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum,
or
Neiserria gonorrheae;
toxin diseases related to infection by
S. aureus
(food poisoning and Toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by
Helicobacter pylori;
systemic febrile syndromes related to infection by
Borrelia recurrentis;
Lyme disease related to infection by
Borrelia burgdorferi;
conjunctivitis, keratitis, and dacrocystitis relat

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