(a) Field of the Invention
The invention relates to 2-heterocyclyloxymethyl and 2-heterocyclylthiomethyL-1,2,5-thiadiazolidin-3-one 1,1-dioxides to pharmaceutical compositions containing the same and to the method of use thereof in the treatment of degenerative diseases.
(b) Information Disclosure Statement
The inhibition of proteolytic enzymes by nontoxic reagents is useful in the treatment of degenerative disorders, such as emphysema, rheumatoid arthritis and pancreatitis, in which proteolysis is a substantive element.
Protease inhibitors are widely utilized in biomedical research. Serine proteases are the most widely distributed class of proteolytic enzymes. Some serine proteases are characterized as chymotrypsin-like or elastase-like based upon their substrate specificity.
Chymotrypsin and chymotrypsin-like enzymes normally cleave peptide bonds in proteins at a site at which the amino acid residue on the carboxyl side is typically Trp, Tyr, Phe, Met, Leu or another amino acid residue which contains aromatic or large alkyl side chains.
Elastase and elastase-like enzymes normally cleave peptide bonds at a site at which the amino acid residue on the carboxyl side of the bond is typically Ala, Val, Ser, Leu or other similar, smaller amino acids.
Both chymotrypsin-like and elastase-like enzymes are found in leukocytes, mast cells and pancreatic juice in higher organisms, and are secreted by many types of bacteria, yeast and parasites.
Cha, Biochem. Pharmacol., 1975, 24, 2177-2185, discusses kinetic approaches to the study of the binding of inhibitors to macromolecules, such as enzymes, and methods for the determination of such parameters as the inhibition constants, reaction rates and bound and unbound enzyme concentrations.
Groutas et al., Biochemical and Biophysical Research Communications 1994, 198 (1), 341-349 disclose compounds of the formula: ##STR1## wherein R.sub.1 is H, methyl, benzyl, CH.sub.2 COOt-Bu or CH.sub.2 COOBzl and their in vitro inhibitory activity towards human leukocyte elastase.
Muller and DuBois, J. Org. Chem. 1989, 54, 4471-4473 disclose compounds of the formula: ##STR2## wherein R is H, CH.sub.3, benzyl or (CH.sub.2).sub.2 SCH.sub.3. The compounds were tested for sweet taste activity and were found to be not sweet or to have sweetness potencies of less than 10 times sucrose.
Lee et al., J. Org. Chem. 1989, 54, 3077-3083 disclose the synthesis of compounds of the formula: ##STR3## wherein R is phenethyl, phenyl or 1-naphthyl. No utility is disclosed for these compounds.
Lee and Kohn, Journal of Pharmaceutical Sciences 1990, (8), 716-718 disclose compounds of the formula: ##STR4## wherein R.sup.4 is phenethyl, phenyl or 1-naphthyl and R.sup.4 ' is hydrogen, or R.sup.4 and R.sup.4 ' are both phenyl. The compounds were tested for anticonvulsant activity and three of the four compounds were found to be devoid of anticonvulsant activity.
Hanewacker et al., Arch. Pharm. 1993, 326, 497-498 disclose the synthesis of compounds of the formula: ##STR5## wherein R is CH.sub.2 CH (CH.sub.3).sub.2, cyclopropylmethyl, CH.sub.2 Ph, (CH.sub.2).sub.2 Ph, 2-furanylmethyl, 1-naphthylmethyl, or 3-indolylethyl.
Unterhalt and Hanewacker, Arch. Pharm. 1988, 321, 375-376 disclose the synthesis of compounds of the formula: ##STR6## wherein R is hydrogen, methyl, isopropyl, CH.sub.2 CH(CH.sub.3).sub.2 or benzyl without an indication of utility.
Unterhalt and Hanewacker, Arch. Pharm. 1988, 321, 749-751 disclose the synthesis of compounds of the formula: ##STR7## wherein R=CH.sub.3, R.sup.1 =H and R.sup.2 =3-indolylmethyl; R=CH.sub.3, R.sup.1 =H, and R.sup.2 =phenyl; R=C.sub.2 H.sub.5, R.sup.1 =H, and R.sup.2 =phenyl; R=isopropyl, R.sup.1 =H, and R.sup.2 =phenyl; R=methyl, R.sup.1 =CH.sub.3 O(O)CCH.sub.2, and R.sub.2 =H; R=CH.sub.3,
R.sup.1 =HO(O)CCH.sub.2 and R.sup.2 =H; R=CH.sub.3, R.sup.1 =C.sub.2 H.sub.5 and R.sup.2 =phenyl; R=R.sup.1 =R.sup.2 =CH.sub.3 ; and R=C.sub.2 H.sub.5, R.sup.1 =R.sup.2 =CH.sub.3. PA1 R.sup.3 is hydrogen, or lower-alkyl; or R.sup.2 and R.sup.3 together are --(CH.sub.2).sub.n --wherein n is 3 or 4; PA1 X is O or S; and R.sup.4 is a heterocycle selected from the group consisting of tetrazolyl, pyrazolyl, imidazolyl, thiadiazolyl, thiazolyl, and triazolyl which is attached through any available carbon atom thereof to the --X-- group (or said heterocycle substituted on any available carbon atom thereof by lower-alkyl, or trihalomethyl; and/or on any available nitrogen atom thereof by lower-alkyl, or phenyl); or a pharmaceutically acceptable acid-addition salt thereof; or where applicable, an enantiomer or a racemic mixture thereof.
Aouf et al., Tetrahedron Letters 1991, 32(45), 6545-6546 disclose the synthesis of 4-phenylmethyl-l,2,5-thiadiazolidin-3-one 1,1-dioxide.
Dewynter et al., Tetrahedron 1993, 49(1), 65-76 disclose the synthesis of compounds of the formula: ##STR8## wherein R is CH.sub.2 Ph or CH.sub.2 CH(CH.sub.3)(C.sub.2 H.sub.5).
Dunlap et al., U.S. Pat. No. 5,236,917, issued Aug. 17, 1993 disclose a series of 2-substituted saccharin derivatives, such as 4- (1-methylethyl) -2- [(3-oxo-1, 2,5-thiadiazolidin-2-yl)methyl-1,2-benzisothiazol-3 (2H)-one S,S,1,1-tetraoxide, 2-(1-methyl-1H-tetrazol-5-yl-thiomethyl) saccharin and various 2-halomethyl saccharin derivatives, which are stated to be useful in the treatment of degenerative diseases.
Strasser et al. , German Patent Application DE 4141218, published Jun. 17, 1993, disclose a series of thiadiazolidin-3-one 1,1-dioxide derivatives as intermediates in the synthesis of various 1,1-dioxo- [1,2,6] thiadiazinecarboxamides which are stated to be potentially useful as analgesics, antipyretics and inflammation inhibitors.