Method of treating gout with certain indole compounds

Details Method of treating gout with certain indole compounds Method of treating gout with certain indole compounds

2000-03-06

2001-10-16

Jarvis, William R. A. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S316000, C514S323000, C514S415000

Reexamination Certificate

active

06303610

ABSTRACT:

This invention relates to the use of tryptophan derivatives as inhibitors of neutrophil mediated oxidant production and their use in treating neutrophil associated diseases and disorders.
Neutrophils play a vital role in the resistance of a host to infection. Key characteristics of neutrophils in this role include their ability to adhere initially to the endothelium, to migrate into tissue, and to kill engulfed microbes with oxidants and proteolytic enzymes. Unfortunately, in certain disease states, neutrophils secrete these oxidants and proteolytic enzymes extracellularly resulting in inflammatory diseases and conditions.
The compounds of the present invention have been shown to effectively inhibit adhesion-dependent oxidant production. Accordingly, this invention provides methods of treating disease and conditions associated with excess neutrophil mediated oxidant production, including the following inflammatory diseases and other conditions: smoking, chronic bronchitis, emphysema, asthma, cystic fibrosis, cancer, adult respiratory distress syndrome, Wegener's granulomatosis, idiopathic pulmonary fibrosis, collagen vascular disorders, interstitial lung disease, hypersensitivity pneumonitis, sarcoidosis, bronchiolitis obliterans with organizing pneumonia, Crohn's Disease, Secondary Sjörgren's Syndrome, rheumatoid arthritis, progressive systemic sclerosis, dermatopolymyositis, mixed connective tissue disease, familial idiopathic pulmonary fibrosis, systemic lupus erythematosus, progressive systemic sclerosis, autoimmune thyroid disease, inflammatory bowel disease, juvenile periodontitis, myocardial infarction, hemorrhagic shock, septic shock, ischemic shock, cerebral ischemia, stroke, hypertension, unstable angina, diabetes complications, thrombotic stroke, fibrosing alveolitis, bronchiectasis, periodontal disease, glomerulonephritis, alcoholic hepatitis, Kawasaki Disease, gingivitis, chronic obstructive pulmonary disease, pulmonary infections (staphylococcal or klebsiella pneumonia), ulcerative colitis, psoriasis, artherosclerosis, gout, gastroesophageal reflux disease, carditis, Barrett's Esophagus, Behcet's Disease, iritis, acute glomerulonephritis, periarteritis nodosa, unstable angina, coronary artery disease, coronary angioplasty, immune complex disease, cryoglobulinemic glomerulonephritis, anti-gbm glomerulonephritis, Goodpasture's Syndrome, myositis, and acute pancreatitis.
The invention provides a method for inhibiting neutrophil mediated oxidant production, comprising administering to a mammal in need thereof, a pharmaceutically effective amount of a compound of the formula I:
wherein
m is 0, 1, 2, or 3;
n is 0 or 1;
o is 0, 1, or 2;
p is 0 or 1;
R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl;
which groups may be substituted with one or two halo, C
1
-C
3
alkoxy, trifluoromethyl, C
1
-C
4
alkyl, phenyl-C
1
-C
3
alkoxy, or C
1
-C
4
alkanoyl groups;
R
1
is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C
1
-C
4
alkyl)-, phenyl-(C
1
-C
4
alkoxy)quinolinyl-(C
1
-C
4
alkyl)-, isoquinolinyl-(C
1
-C
4
alkyl)-, reduced quinolinyl-(C
1
-C
4
alkyl)-, reduced isoquinolinyl-(C
1
-C
4
alkyl)-, benzoyl-(C
1
-C
3
alkyl)-, C
1
-C
4
alkyl, or —NH—CH
2
—R
5
;
any one of which R
1
groups may be substituted with halo, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, trifluoromethyl, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, or C
2
-C
4
alkanoylamino;
or any one of which R
1
groups may be substituted with phenyl, piperazinyl, C
3
-C
8
cycloalkyl, benzyl, C
1
-C
4
alkyl, piperidinyl, pyridinyl, pyrimidinyl, C
2
-C
6
alkanoylamino, pyrrolidinyl, C
2
-C
6
alkanoyl, or C
1
-C
4
alkoxycarbonyl;
any one of which groups may be substituted with halo, C
1
-C
4
alkyl, C
1
-C
4
alkoxy, trifluoromethyl, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, or C
2
-C
4
alkanoylamino;
or R
1
is amino, a leaving group, hydrogen, C
1
-C
4
alkylamino, or di(C
1
-C
4
alkyl)amino;
R
5
is pyridyl, anilino-(C
1
-C
3
alkyl)-, or anilinocarbonyl;
R
2
is hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkylsulfonyl, carboxy-(C
1
-C
3
alkyl)-, C
1
-C
3
alkoxycarbonyl-(C
1
-C
3
alkyl)-, or —CO—R
6;
R
6
is hydrogen, C
1
-C
4
alkyl, C
1
-C
3
haloalkyl, phenyl, C
1
-C
3
alkoxy, C
1
-C
3
hydroxyalkyl, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, or —(CH
2
)
q
—R
7
;
q is 0 to 3;
R
7
is carboxy, C
1
-C
4
alkoxycarbonyl, C
1
-C
4
alkylcarbonyloxy, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, C
1
-C
6
alkoxycarbonylamino, or
phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C
1
-C
4
alkyl)-, quinolinyl-(C
1
-C
4
alkyl)-, isoquinolinyl-(C
1
-C
4
alkyl)-, reduced quinolinyl-(C
1
-C
4
alkyl)-, reduced isoquinolinyl-(C
1
-C
4
alkyl)-, benzoyl-C
1
-C
3
alkyl;
any one of which R
7
groups may be substituted with halo, trifluoromethyl, C
1
-C
4
alkoxy, C
1
-C
4
alkyl, amino, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, or C
2
-C
4
alkanoylamino;
or any one of which R
7
groups may be substituted with phenyl, piperazinyl, C
3
-C
8
cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C
2
-C
6
alkanoyl, or C
1
-C
4
alkoxycarbonyl;
any of which groups may be substituted with halo, trifluoromethyl, amino, C
1
-C
4
alkoxy, C
1
-C
4
alkyl, C
1
-C
4
alkylamino, di(C
1
-C
4
alkyl)amino, or C
2
-C
4
alkanoylamino;
R
8
is hydrogen or C
1
-C
6
alkyl;
R
3
is phenyl, phenyl-(C
1
-C
6
alkyl)-, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, C
1
-C
8
alkyl, naphthyl, C
2
-C
8
alkenyl, or hydrogen;
any one of which groups except hydrogen may be substituted with one or two halo, C
1
-C
3
alkoxy, C
1
-C
3
alkylthio, nitro, trifluoromethyl, or C
1
-C
3
alkyl groups; and
R
4
is hydrogen or C
1
-C
3
alkyl;
with the proviso that if R
1
is hydrogen or halo, R
3
is phenyl, phenyl-(C
1
-C
6
alkyl)-, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, or naphthyl;
with the proviso that if R
1
is hydrogen or halo, R
3
is phenyl, phenyl-(C
1
-C
6
alkyl)-, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, or naphthyl;
or pharmaceutically acceptable salts, solvates, or prodrugs thereof.
All temperatures stated herein are in degrees Celsius (° C.). All units of measurement employed herein are in weight units except for liquids which are in volume units.
As used herein, the term “C
1
-C
8
alkyl” refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 8 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl and the like. The term “C
1
-C
8
alkyl” includes within its definition the terms “C
1
-C
6
alkyl” and “C
1
-C
4
alkyl”.
“Divalent(C
1
-C
4
) alkyl” represents a straight or branched divalent saturated aliphatic chain having from one to four carbon atoms. Typical divalent(C
1
-C
4
) alkyl groups include methylene, ethylene, propylene, 2-methylpropylene, butylene and the like.
“Halo” represents chloro, fluoro, bromo or iodo.
“Halo(C
1
-C
4
)alkyl” represents a straight or branched alkyl chain having from one to four carbon atoms with 1, 2 or 3 halogen atoms attached to it. Typical halo(C
1
-C
4
)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like.
“Hydroxy(C
1
-C
4
)alkyl” represents a straight or branched alkyl chain having from one to four carbon atoms with hydroxy group attached to it. Typical hydroxy(C
1
-C
4
)alkyl groups include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyisopropyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxyisobutyl, hydroxy-t-butyl and the like.
“C
1
-C
6
alkylthio” represents a straight o

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