Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-22
2002-11-05
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S425000, C514S417000
Reexamination Certificate
active
06476053
ABSTRACT:
This application is a 371 of PCT/SE99/00732 filed May 3, 1999.
The present invention relates to compounds for use in the treatment of mycobacterial diseases, particularly those diseases caused by pathogenic mycobacteria such as
Mycobacterium tuberculosis, M. bovis, M. avium and M. marinum.
Tuberculosis is still a major public health problem affecting nearly all parts of the world. Based on skin test reactivity it has been estimated that about one-third of the world's population, i.e., 1.7 billion people, are infected with
Mycobacterium tuberculosis
. Despite the availability of effective chemotherapies, it is responsible for three million deaths and from eight to ten million new cases annually and thus remains the leading cause of death world-wide due to a single infectious agent: 26% of all preventable deaths, 7% of all deaths. According to the World Health Organisation, 450,000 deaths per year due to tuberculosis in developing countries occur in children under fifteen years of age, and the disease mostly affects the younger, more productive adults.
There are five front-line drugs known to be highly effective against
M. tuberculosis
and five second-line drugs that can be used when resistance to one or more of the front-line drugs is detected. The preferred mode of treatment for tuberculosis is the short course chemotherapy in which there are two phases. The first phase consists of a daily regimen for two months with isoniazid (300 mg), rifampicin (600 mg), pyrazinamide (3 g) and ethambutol (1.5 g). The second phase or the continuation phase consists of a daily regimen for the next four months with isoniazid and rifampicin. Although infection with drug-sensitive strains of
M. tuberculosis
can be effectively cured with the short course chemotherapy, the cure rate is very poor in most countries due to poor compliance which is reflective of the long duration of therapy.
The situation is further complicated by the rapid emergence of multi-drug resistant tuberculosis (MDR-TB) strains. For example, in certain populations, the incidence of resistance to isoniazid is as high as 26% and the resistance to rifampicin is about 15%. Prior to 1984, about 10% of tubercle bacilli isolated from patients in the United States were resistant to at least one single mycobacterial drug. By 1984, this figure had risen to 52%, of which over half (32%) were resistant to more than one drug (MDR-TB). Ten percent of the recorded MDR-TB cases have occurred in previously healthy people whose mortality rate—70 to 90%—has been nearly the same as that of immunosuppressed individuals with MDR-TB. The number of cases of MDR-TB has doubled since 1984 and in many of them the tubercle bacilli are resistant to both isoniazid and rifampicin. The median interval between diagnosis of MDR-TB and death is only four weeks and therefore MDR-TB demands a shorter response time between diagnosis and appropriate commencement of treatment. However, MDR-TB is difficult to treat as such since most patients do not respond very well to the second-line drugs and the cost of alternate treatment procedures, including hospitalisation and possibly surgery, increases the cost to as much as ten times the cost of traditional treatment.
Thus, there is an urgent medical need to identify new drugs with significant therapeutic activity against single- or multiple-drug resistant strains of
M. tuberculosis
and with pharmacokinetic properties that permit reduced dosing which will in turn encourage better compliance.
In accordance with the present invention, there is therefore provided the use of a compound of general formula
wherein x is 0 or 1;
R
1
represents a hydrogen atom, or a C
1
-C
20
alkyl or myrtanyl group, or a phenyl or benzyl group optionally substituted in the aromatic ring by one or more substituents selected from amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl, or a group (CH
2
)
y
CONH—R
5
where y is an integer from 1 to 6 and R
5
represents a phenyl group optionally substituted by one or more substituents selected from amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl; and either
R
2
represents a hydrogen atom or a C
1
-C
6
alkyl group, or R
2
together with R
3
represents a carbon-carbon single bond provided that x is 0, or R
2
together with R
4
represents a group ═CH
2
,
R
3
represents a hydrogen atom or is linked to R
2
as defined above, and
R
4
represents a hydrogen atom or a C
1
-C
6
alkyl group; or a C
1
-C
10
alkylamino group optionally substituted by a di(C
1
-C
6
alkyl)amino substituent group; or an anilino group optionally substituted in the aromatic ring by one or more substituents selected from amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl, C
1
-C
6
alkyl, C
1
-C
6
alkoxy,
C
1
-C
6
alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl; or a group —SCH
2
CH
2
OH, —SCH
2
CH
2
NH
2
, —SCH
2
CH
2
(NH
2
)CO
2
H or —SCH
2
CH
2
NHCO—R
6
where R
6
represents a
C
1
-C
10
alkyl or C
3
-C
6
cycloalkyl group, or a phenyl group optionally substituted by one or more substituents selected from amino, nitro, hydroxyl, carboxyl, halogen, trifluoromethyl,
C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
alkoxycarbonyl, piperidyl, piperazinyl and morpholinyl;
or R
4
is linked to R
2
as defined above;
or
R
2
, R
3
and R
4
together represent a phenyl group;
with the provisos that:
(i) R
1
, R
2
, R
3
and R
4
do not each simultaneously represent a hydrogen atom,
(ii) when x is 0, R
1
represents a 4-fluorophenyl group and R
4
represents a hydrogen atom, then R
2
and R
3
do not together represent a carbon-carbon single bond, and
(iii) when x is 0, R
1
represents a 4-fluorophenyl group and R
2
and R
3
both represent a hydrogen atom, then R
4
does not represent an anilino, 4-chloroanilino, 2,6-dichloroanilino, 3,4-dichloroanilino, 2,5-dichloroanilino, 3-chloro-4-fluoroanilino or 4-fluoroanilino group;
or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in the treatment of a mycobacterial disease, in particular tuberculosis.
In the context of the present specification, unless otherwise stated, an alkyl (substituent) group or an alkyl moiety in an alkoxy or alkoxycarbonyl substituent group may be linear or branched.
Preferably R
1
in formula (I) represents a hydrogen atom, or a C
1
-C
15
, more preferably C
1
-C
10
, alkyl or myrtanyl group, or a phenyl or benzyl group optionally substituted in the aromatic ring by one to four, particularly one or two, substituents selected from amino, nitro, hydroxyl, carboxyl, halogen (e.g. fluorine, chlorine or bromine), trifluoromethyl, C
1
-C
4
alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl), C
1
-C
4
alkoxy (e.g. methoxy, ethoxy, propoxy, or butoxy), C
1
-C
4
alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), piperidyl, piperazinyl and morpholinyl, or a group (CH
2
)
y
CONH—R
5
where y is an integer 1, 2, 3 or 4 and R
5
represents a phenyl group optionally substituted by one to four, particularly one or two, substituents selected from amino, nitro, hydroxyl, carboxyl, halogen (e.g. fluorine, chlorine or bromine), trifluoromethyl, C
1
-C
4
alkyl (e.g. methyl, ethyl, propyl, isopropyl or butyl), C
1
-C
4
alkoxy (e.g. methoxy, ethoxy, propoxy, or butoxy), C
1
-C
4
alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), piperidyl, piperazinyl and morpholinyl.
The group R
1
especially represents a hydrogen atom, or a C
4
-C
10
alkyl (e.g. butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl) or myrtanyl group, or a phenyl group substituted by a piperidyl substituent group, or a group (CH
2
)
y
CONH—R
5
where y is 1 or 2 and R
5
represents a phenyl group substituted by a piperidyl substituent group.
Preferably R
2
represents a hydrogen atom or a C
1
-C
4
alkyl, particularly methyl, group,
Balganesh Meenakshi
Ethirajulu Kantharaj
Ganguly Babita Singh
Janakiraman Ramachandran
Kajipalya Rangarao
McKane Joseph K.
Saeed Kamal
White & Case LLP
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