Carbamate and carbazate ketolide antibiotics

Details Carbamate and carbazate ketolide antibiotics Carbamate and carbazate ketolide antibiotics

1999-09-20

2002-07-16

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007400

Reexamination Certificate

active

06420343

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to novel 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 pharmaceutical compositions containing the novel compounds and to methods of treating bacterial and protozoal infections in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment.
Macrolide antibiotics are known to be useful in the treatment of a broad spectrum of bacterial and protozoal infections in mammals, fish and birds. Such antibiotics include various derivatives of erythromycin A such as azithromycin which is commercially available and is referred to in U.S. Pat. Nos. 4,474,768 and 4,517,359, both of which are incorporated herein by reference in their entirety. Other macrolide antibiotics are disclosed and claimed in PCT international application number PCT/IB98/00741, filed May 15, 1998 (Attorney docket number PC 9726A), which designates the United States, and U.S. Pat. No. 5,527,780, issued Jun. 18, 1996. U.S. Pat. No. 5,527,780 and PCT international application number PCT/IB98/00741 are incorporated herein by reference in their entirety. Like azithromycin and other macrolide antibiotics, the novel macrolide compounds of the present invention possess activity against various bacterial and protozoal infections as described below.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula
and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein:
X
1
is —CH
2
— or —NR
4
—;
X
2
is ═O or ═NOR
1
;
Z is H, C
1
-C
14
alkyl, (C
6
-C
10
aryl)(C
1
-C
10
alkyl)- or (4-10 membered heterocyclic)(C
1
-C
10
alkyl)-, wherein one or two carbon atoms of the foregoing alkyl moieties are optionally replaced by a heteroatom selected from O, S and —N(R
4
), and the foregoing groups, except H, are optionally substituted with 1 to 3 substituents independently selected from halo, hydroxy, C
1
-C
14
alkoxy, C
1
-C
14
alkyl, (C
6
-C
10
aryl)(C
1
-C
10
alkoxy)- and (4-10 membered heterocyclic)(C
1
-C
10
alkoxy)-;
R
1
is H, methyl or ethyl;
R
2
is a group of the formula
wherein n is an integer from 1 to 4;
R
3
is C
6
-C
10
aryl or 4-10 membered heterocyclic, wherein said R
3
is optionally substituted by I to 3 substituents independently selected from the group consisting of C
1
-C
6
alkoxy, trifluoromethyl, trifluoromethoxy, halo, and —NR
4
R
5
;
each R
4
and R
5
is independently selected from H and C
1
-C
6
alkyl;
R
6
is H; and,
R
7
and R
8
are each independently selected from H and C
1
-C
6
alkyl except that at least one of R
7
and R
8
is C
1
-C
6
alkyl.
Preferred compounds of formula 1 include those wherein Z is H, X
1
is —NH— or —CH
2
—, n is 2, R
7
is C
1
-C
3
alkyl, R
8
is H or C
1
-C
3
alkyl, X
2
is O, ═NOCH
3
or ═NOCH
2
CH
3
, and R
3
is 5 or 6-membered aromatic heterocyclic containing 1 or 2 nitrogen atoms in said heterocyclic ring. More preferred are the foregoing compounds wherein n is 2, R
7
is methyl or ethyl, R
8
is H, methyl or ethyl, and R
3
is pyridyl.
Specific preferred compounds of formula 1 include those having the structure of formula 33
and pharmaceutically acceptable salts, prodrugs and solvates thereof; wherein X
1
is NH or —CH
2
—; X
2
is ═O or ═NOR
1
; and R
1
is H, methyl or ethyl. More preferred compounds are those compounds of formula 33 wherein x
2
is O, ═NOCH
3
or ═NOCH
2
CH
3
.
Other specific preferred compounds of formula 1 include those having the structure of formula 32
and pharmaceutically acceptable salts, prodrugs and solvates thereof; wherein X
1
is NH or —CH
2
—; X
2
is ═O or ═NOR
1
; and R
1
is H, methyl or ethyl. More preferred compounds are those compounds of formula 32 wherein X
2
is O, ═NOCH
3
or ═NOCH
2
CH
3
.
The present invention also relates to the preparation of compounds of formula 30
which comprises treating a compound of formula 19 with a compound of formula 29
wherein X
2
, R
7
, R
3
and R
8
are as defined above, in a solvent, preferably toluene.
The present invention also relates to intermediates of the formula 29
wherein R
3
, R
7
and R
8
are as defined above.
The invention also relates to a pharmaceutical composition for the treatment of a bacterial infection or a protozoa infection, or a disorder related to a bacterial or protozoal infection, in a mammal, fish, or bird, which comprises a therapeutically effective amount of a compound of formula 1, 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, or a disorder related to a bacterial or protozoal 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 1 or a pharmaceutically acceptable salt, prodrug or solvate thereof.
The invention also relates to a method of treating cancer or atherosclerosis in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt, prodrug or solvate thereof.
The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, refers to the act of treating, as “treating” is defined immediately above.
As used herein, unless otherwise indicated, the terms or phrases “bacterial infection(s)”, “protozoal infection(s)”, and “disorders related to bacterial infections or protozoal infections” include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by
Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus faecalls, E. faecium, E. casselflavus, S. epidermidis, S. haemolyticus
, or Peptostreptococcus spp.; pharyngitis, rheumatic fever, and glomewulonephritis related to infection by
Streptococcus pyogenes
, Groups C and G streptococci,
Corynebacterium diphtheriae
, or
Actinobacillus haemolyticum
; respiratory tract infections related to infection by
Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae
, or
Chlamydia pneumoniae
; blood and tissue infections, including endocarditis and osteomyelitis, caused by
S. aureus, S. haemolyticus, E faecalis, E faecium, E. durans
, including strains resistant to known antibacterials such as, but not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracylines and macrolides; uncomplicated skin and soft tissue infections and abscesses, and puerperal fever related to infection by
Staphylococcus aureus
, coagulase-negative staphylococci (i.e.,
S. epidermidis, S. hemolyticus
, etc.),
Streptococcus pyogenes, Streptococcus agalacfiae
, Streptococcal groups C-F (minute-colony streptococci), viridans streptococci,
Corynebactetium minutissimum
, Clostridium spp., or
Bartonella henselae
; uncomplicated acute urinary tract infections related to infection by
Staphylococcus aureus
, coagulase-negative staphylococcal species, or Enterococcus spp.; urethritis and cervicitis; 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 related to infection by
Chlamydia trachomati

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