Method for treating COPD

Details Method for treating COPD Method for treating COPD

2000-06-28

2002-04-09

Spivack, Phyllis G. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C514S363000, C514S364000, C514S381000, C514S530000, C514S531000, C514S538000, C514S615000, C514S619000, C514S646000

Reexamination Certificate

active

06369108

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the use of certain compounds for treating chronic obstructive pulmonary disease (COPD).
BACKGROUND OF THE INVENTION
Chronic obstructive pulmonary disease (COPD) is an umbrella term frequently used to describe two conditions of fixed airways disease, chronic bronchitis and emphysema. Chronic bronchitis and emphysema are most commonly caused by smoking; approximately 90% of patients with COPD are or were smokers. Although approximately 50% of smokers develop chronic bronchitis, only 15% of smokers develop disabling airflow obstruction. Certain animals, particularly horses, suffer from COPD as well.
The airflow obstruction associated with COPD is progressive, may be accompanied by airway hyperreactivity, and may be partially reversible. Non-specific airway hyper-responsiveness may also play a role in the development of COPD and may be predictive of an accelerated rate of decline in lung function in smokers.
COPD is a significant cause of death and disability. It is currently the fourth leading cause of death in the United States and Europe. Treatment guidelines advocate early detection and implementation of smoking cessation programs to help reduce morbidity and mortality due to the disease. However, early detection and diagnosis has been difficult for a number of reasons.
COPD takes years to develop and smokers often deny any ill effects from smoking, attributing the early warning signs of increased breathlessness as a sign of age. Similarly, acute episodes of bronchitis often are not recognized by the general practitioner as early signs of COPD. Many patients exhibit features of more than one disease (e.g. chronic bronchitis or asthmatic bronchitis) making precise diagnosis a challenge, particularly in early disease. Also, many patients do not seek medical help until they are experiencing more severe symptoms associated with reduced lung function, such as dyspnea, persistent cough, and sputum production. As a consequence, the vast majority of patients are not diagnosed or treated until they are in a more advanced stage of disease.
There is a need for a new approach to treating COPD. This invention provides one such approach.
SUMMARY OF THE INVENTION
This invention covers a method for the prophylaxis or treatment of COPD in a mammal by administering to a mammal in need thereor an effective amount of a compound of Formula (I) alone or in admixture with a pharmaceutically acceptable excipient wherein Formula (I) comprises:
wherein:
R
1
is —(CR
4
R
5
)
n
C(O)O(CR
4
R
5
)
m
R
6
, —(CR
4
R
5
)
n
C(O)NR
4
(CR
4
R
5
)
m
R
6
, —(CR
4
R
5
)
n
O(CR
4
R
5
)
m
R
6
, or —(CR
4
R
5
)
r
R
6
wherein the alkyl moieties may be optionally substituted with one or more halogens;
m is 0 to 2;
n is 1 to 4;
r is 0 to 6;
R
4
and R
5
are independently selected from hydrogen or a C
1-2
alkyl;
R
6
is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC
1-3
alkyl, halo substituted aryloxyC
1-3
alkyl, indanyl, indenyl, C
7-11
polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C
3-6
cycloalkyl, or a C
4-6
cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by OH, 1 to 3 methyl groups or one ethyl group;
provided that:
a) when R
6
is hydroxyl, then m is 2; or
b) when R
6
is hydroxyl, then r is 2 to 6; or
c) when R
6
is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or
d) when R
6
is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;
e) when n is 1 and m is 0, then R
6
is other than H in —(CR
4
R
5
)
n
O(CR
4
R
5
)
m
R
6
;
X is YR
2
, halogen, nitro, NR
4
R
5
, or formyl amine;
Y is O or S(O)
m
′;
m′ is 0, 1, or 2;
X
2
is O or NR
8
;
X
3
is hydrogen or X;
X
4
is
X
5
is H, R
9
, OR
8
, CN, C(O)R
8
, C(O)OR
8
, C(O)NR
8
R
8
, or NR
8
R
8
;
R
2
is independently selected from the group consisting of —CH
3
and —CH
2
CH
3
optionally substituted by 1 or more halogens;
s is 0 to 4;
R
3
is hydrogen, halogen, C
1-4
alkyl, CH
2
NHC(O)C(O)NH
2
, halo-substituted C
1-4
alkyl, —CH═CR
8′
R
8′
, cyclopropyl optionally substituted by R
8′
, CN, OR
8
, CH
2
OR
8
, NR
8
R
10
, CH
2
NR
8
R
10
, C(Z′)H, C(O)OR
8
, C(O)NR
8
R
10
, or C≡CR
8′
,
Z′ is O, NR
9
, NOR
8
, NCN, C(—CN)
2
, CR
8
CN, CR
8
NO
2
, CR
8
C(O)OR
8
, CR
8
C(O)NR
8
R
8
, C(—CN)NO
2
, C(—CN)C(O)OR
9
, or C(—CN)C(O)NR
8
R
8
;
Z is C(Y′)R
14
, C(O)OR
14
, C(Y′)NR
10
R
14
, C(NR
10
)NR
10
R
14
, CN, C(NOR
8
)R
14
, C(O)NR
8
NR
8
C(O)R
8
, C(O)NR
8
NR
10
R
14
, C(NOR
14
)R
8
, C(NR
8
)NR
10
R
14
, C(NR
14
)NR
8
R
8
, C(NCN)NR
10
R
14
, C(NCN)SR
9
, (2-, 4- or 5-imidazolyl), (3-, 4- or 5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]), (5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or 5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]), (2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or 5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of the heterocylic ring systems may be optionally substituted one or more times by R
14
;
the dotted line in formula (a) represents a single or double bond;
Y′ is O or S;
R
7
is —(CR
4
R
5
)
q
R
12
or C
1-6
alkyl wherein the R
12
or C
1-6
alkyl group is optionally substituted one or more times by C
1-2
alkyl optionally substituted by one to three fluorines, —F, —Br, —Cl, —NO
2
, —NR
10
R
11
, —C(O)R
8
, —C(O)OR
8
, —OR
8
, —CN, —C(O)NR
10
R
11
, —OC(O)NR
10
R
11
, —OC(O)R
8
, —NR
10
C(O)NR
10
R
11
, —NR
10
C(O)R
11
, —NR
10
C(O)OR
9
, —NR
10
C(O)R
13
, —C(NR
10
)NR
10
R
11
, —C(NCN)NR
10
R
11
, —C(NCN)SR
9
, —NR
10
C(NCN)SR
9
, —NR
10
C(NCN)NR
10
R
11
, —NR
10
S(O)
2
R
9
, —S(O)
m′
R
9
, —NR
10
C(O)C(O)NR
10
R
11
, —NR
10
C(O)C(O)R
10
, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;
q is 0, 1, or 2;
R
12
is C
3-7
cycloalkyl, (2-, 3- or 4-pyridyl), pyrirnidyl, pyrazolyl, (1- or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or 5-thiazolyl), quinolinyl, naphthyl, or phenyl;
R
8
is independently selected from hydrogen or R
9
;
R
8
′ is R
8
or fluorine;
R
9
is C
1-4
alkyl optionally substituted by one to three fluorines;
R
10
is OR
8
or R
11
;
R
11
is hydrogen, or C
1-4
alkyl optionally substituted by one to three fluorines; or when R
10
and R
11
are as NR
10
R
11
they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O, N, or S;
R
13
is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C
1-2
alkyl groups;
R
14
is hydrogen or R
7
; or when R
10
and R
14
are as NR
10
R
14
they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;
provided that:
f) when R
12
is N-pyrazolyl, N-imnidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or
g) when X
2
R
1
is OCF
2
H or OCF
3
, X is OCF
2
H or OCF
3
, X
3
is H, s is zero, X
5
is H, Z is C(O)OR
14
and R
14
is C
1-7
unsubstituted alkyl, then R
3
is other than H;
or the pharmaceutically acceptable salts thereof.
In a second aspect, this invention relates to the use of a compound of Formula (II) for treating COPD in a mammal, particularly a human, wherein Formula (II) is defined as follows:
wherein:
R
1
is —(CR
4
R
5
)
n
C(O)O(CR
4
R
5
)
m
R
6
, —(CR
4
R
5
)
n
C(O)NR
4
(CR
4
R
5
)
m
R
6
, —(CR
4
R
5
)
n
O(CR
4
R
5
)
m
R
6
, or —(CR
4
R
5

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