Benzo thiadiazine matrix metalloproteinase inhibitors

Details Benzo thiadiazine matrix metalloproteinase inhibitors Benzo thiadiazine matrix metalloproteinase inhibitors

2002-02-13

2003-12-02

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S222800, C514S219000, C514S211150, C514S211080, C514S212080, C544S012000, C544S013000, C540S599000

Reexamination Certificate

active

06656932

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a group of benzo thiadiazine derivatives which inhibit matrix metalloproteinase enzymes, and thus are useful for treating diseases resulting from tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (sometimes referred to as MMPs) are naturally occurring enzymes found in most mammals. Over-expression and activation of MMPs or an imbalance between MMPs and inhibitors of MMPs have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues.
Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP) family. Other members include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3 (MMP-13), TNF-alpha converting enzyme (TACE), and other newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M.,
Nature,
1994;370:61-65). These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis. A method for preventing and treating these and other diseases is now recognized to be by inhibiting metalloproteinase enzymes, thereby curtailing and/or eliminating the breakdown of connective tissues that results in the disease states.
The catalytic zinc in matrix metalloproteinases is typically the focal point for inhibitor design. The modification of substrates by introducing zinc chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIMPs) have been used successfully to treat animal models of cancer and inflammation. MMP inhibitors have also been used to prevent and treat congestive heart failure and other cardiovascular diseases, U.S. Pat. No. 5,948,780.
A major limitation on the use of currently known MMP inhibitors is their lack of specificity for any particular enzyme. Recent data has established that specific MMP enzymes are associated with some diseases, with no effect on others. The MMPs are generally categorized based on their substrate specificity, and indeed the collagenase subfamily of MMP-1, MMP-8, and MMP-13 selectively cleave native interstitial collagens, and thus are associated only with diseases linked to such interstitial collagen tissue. This is evidenced by the recent discovery that MMP-13 alone is over expressed in breast carcinoma, while MMP-1 alone is over expressed in papillary carcinoma (see Chen et al.,
J. Am. Chem. Soc.,
2000;122:9648-9654).
There appears to be few selective inhibitors of MMP-13 reported. A compound named WAY-170523 has been reported by Chen et al., supra., 2000, and a few other compounds are reported in PCT international application publication number WO 01/63244 A1, as allegedly selective inhibitors of MMP-13. Further, U.S. Pat. No. 6,008,243 discloses inhibitors of MMP-13. However, no selective or nonselective inhibitor of MMP-13 has been approved and marketed for the treatment of any disease in any mammal. Accordingly, the need continues to find new low molecular weight compounds that are potent and selective MMP inhibitors, and that have an acceptable therapeutic index of toxicity/potency to make them amenable for use clinically in the prevention and treatment of the associated disease states. An object of this invention is to provide a group of selective MMP-13 inhibitor compounds characterized as being benzo thiadiazines.
SUMMARY OF THE INVENTION
This invention provides a group of benzo thiadiazine compounds that are inhibitors of matrix metalloproteinase enzymes, and especially MMP-13. The invention is more particularly directed to compounds defined by Formula I
or a pharmaceutically acceptable salt thereof, wherein:
n is 0, 1,or 2;
X is O or NH;
R
2
is H, C
1
-C
6
alkyl, or C
1
-C
6
substituted alkyl;
R
1
and R
3
independently are H, acyl, substituted acyl, C
1
-C
6
alkyl, C
1
-C
6
substituted alkyl, C
2
-C
6
alkenyl, C
2
-C
6
substituted alkenyl, C
2
-C
6
alkynyl, C
1
C
6
substituted alkynyl, (CH
2
)
m
aryl, (CH
2
)
m
substituted aryl, (CH
2
)
m
heteroaryl, (CH
2
)
m
substituted heteroaryl, (CH
2
)
m
cycloalkyl, or (CH
2
)
m
substituted cycloalkyl; and
each m independently is an integer of from 0 to 6,
with the proviso that R
3
is not (CH
2
)
m
biphenyl or (CH
2
)
m
substituted biphenyl.
Another invention embodiment are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R
1
and R
3
are not both selected from H or C
1
-C
6
alkyl.
Another invention embodiment are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein R
3
is not acyl or substituted acyl when X is O.
Another invention embodiment are compounds of Formula I, or a pharmaceutically acceptable salt thereof, wherein each m is 1.
Another invention embodiment are compounds of Formula II
or a pharmaceutically acceptable salt thereof, wherein R
1
, R
2
, R
3
, and X are as defined above.
Another invention embodiment are compounds of Formulas I or II, or a pharmaceutically acceptable salt thereof, wherein R
2
is H, alkyl or substituted alkyl, and R
1
and R
3
independently are (CH
2
)
m
phenyl, (CH
2
)
m
heteroaryl, (CH
2
)
m
cycloalkyl, C
2
-C
6
alkenyl, or C
2
-C
6
substituted alkenyl, wherein phenyl, heteroaryl, and cycloalkyl may be unsubstituted or substituted.
Another invention embodiment are compounds of Formulas I or II, or a pharmaceutically acceptable salt thereof, wherein R
2
is hydrogen or C
1
-C
6
alkyl, and R
1
and R
3
independently are C
1
-C
6
substituted alkyl, wherein at least one substituent is an aryl group such as phenyl or substituted phenyl.
Another invention embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, selected from:
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l
6
-benzo[1,2,4]thiadiazine-7-carboxylic acid benzyl ester;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l
6
-b enzo[1,2,4]thiadiazine-7-carboxylic acid benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l
6
-benzo[1,2,3,4]thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l
6
-benzo[1,2,4]thiadiazine-7-carboxylic acid (1H-indol-5-ylmethyl)-amide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l
6
-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l
6
-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-(2-tert-butylsulfamoyl-ethyl)-benzylamide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l
6
-benzo[1,2,4]thiadiazine-7-carboxylic acid (1H-indol-2-ylmethyl)-amide;
2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l
6
-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-(2-sulfamoyl-ethyl)-benzylamide;
2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l
6
-benzo[1,2,3,4]thiadiazine-7-carboxylic acid benzylamide;
4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l
6
-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester;
4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l
6
-benzo[1,2,4]thiadiazin-2-ylmethyl)-benzoic acid;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l
6
-benzo[1,2,3,4]thiadiazin-2-ylmethyl]-benzoic acid tert-butyl ester;
4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l
6
-benzo&l

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