2-substituted 1,2,5,-thiadiazolidin-3-one 1,1-dioxides and compositions and method of use thereof

2-Substituted 1,2,5-thiadiazolidin-3-one 1,1-dioxides, pharmaceutical compositions containing them and methods for the treatment of degenerative diseases utilizing them.

BACKGROUND OF THE INVENTION 
(a) Field of The Invention 
The invention relates to 2-substituted 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, 79(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.dbd.CH.sub.3, R.sup.1 .dbd.H and R.sup.2 .dbd.3-indolylmethyl; 
R.dbd.CH.sub.3, R.sup.1 .dbd.H, and R.sup.2 .dbd.phenyl; R.dbd.C.sub.2 
H.sub.5, R.sup.1 .dbd.H, and R.sup.2 .dbd.phenyl; R.dbd.isopropyl, R.sup.1 
.dbd.H, and R.sup.2 .dbd.phenyl; R.dbd.methyl, R.sup.1 .dbd.CH.sub.3 
O(O)CCH.sub.2, and R.sup.2 .dbd.H; R.dbd.CH.sub.3, R.sup.1 
.dbd.HO(O)CCH.sub.2 and R.sup.2 .dbd.H; R.dbd.CH.sub.3, R.sup.1 
.dbd.C.sub.2 H.sub.5 and R.sup.2 .dbd.phenyl; R.dbd.R.sup.1 .dbd.R.sup.2 
.dbd.CH.sub.3 ; and R.dbd.C.sub.2 H.sub.5, R.sup.1 .dbd.R.sup.2 
.dbd.CH.sub.3. 
Aouf et al., Tetrahedron Letters 1991, 32(45), 6545-6546 disclose the 
synthesis of 4-phenylmethyl-1,2,5-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-benzisot 
hiazol-3(2H)-one S,S,1,1-tetraoxide, 
2-(1-methyl-1H-tetrazol-5-yl-thiomethyl)saccharin, and various substituted 
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. 
Hlasta et al., European Patent Application No. 547708, published Jun. 23, 
1993, disclose various 2-substituted saccharin derivatives which are 
stated to be useful in the treatment of degenerative diseases. 
SUMMARY OF THE INVENTION 
The invention relates to compounds of the Formula I: 
##STR9## 
wherein R.sup.1 is hydrogen, lower-alkyl, or phenyl-lower-alkyl; R.sup.2 
is hydrogen, lower-alkyl, or phenyl-lower-alkyl; R.sup.3 is hydrogen, or 
lower-alkyl; and -Z is a group of the formula: 
##STR10## 
wherein X is hydrogen, halogen, lower-alkoxycarbonyl, lower-alkyl, phenyl, 
phenyl-lower-alkyl, phenylcarbonyl, lower-alkanoyl, 1-piperidinyl, 
4-morpholinyl-lower-alkyl, or phenoxy; and --Y-- is the remaining atoms of 
a monocyclic or bicyclic substituted or unsubstituted heterocyclic ring 
system; or a pharmaceutically acceptable acid-addition salt thereof; or 
where applicable, an enantiomer or a racemic mixture thereof. 
The compounds of the present invention inhibit the activity of serine 
proteases, specifically human leukocyte elastase, and are thus useful in 
the treatment of degenerative disease conditions such as emphysema, 
rheumatoid arthritis, pancreatitis, cystic fibrosis, chronic bronchitis, 
adult respiratory distress syndrome, inflammatory bowel disease, 
psoriasis, bullous pemphigoid, periodontal disease, and 
alpha-1-antitrypsin deficiency. 
Preferred compounds of the Formula I above are those wherein R.sup.1, 
R.sup.2, R.sup.3 and X are as defined above; and --Y-- is 
--(CH.sub.2).sub.m --O--, --CHR--O--, --C(R).sub.2 --O--, 
--(CH.sub.2).sub.m --N(R')--, --CHR-N(R')--, --C(R).sub.2 --N(R')--, 
--C(R').dbd.C(R')--O--, --C(R').dbd.C(R')--N(R')--, 
--C(.dbd.O)--C(R").dbd.C(R")--, --C(Z').dbd.C(Z')--O--, 
--C(Z').dbd.C(Z')--N(R')--, --N(Z")--C(Z").dbd.N-- or 
--N.dbd.C(Z")--N(Z")-- wherein m is 1, 2, 3, or 4, R is the same or 
different lower-alkyl, phenyl or phenyl-lower-alkyl, R' is H or R, R" is H 
or R or the R" groups taken together with the carbon atoms to which they 
are bonded are furano, the Z' groups taken together with the carbon atoms 
to which they are bonded are benzo, furano, pyrido, pyrimidino or 
pyridazino, and the Z" groups taken together with the carbon or nitrogen 
atoms to which they are bonded are pyrido, pyrimidino or pyridazino. 
A preferred species of the Formula I above is the compound wherein R.sup.1 
is hydrogen; R.sup.2 is 3-methylbutyl; R.sup.3 is methyl; and Z is 
##STR11## 
or a pharmaceutically acceptable acid-addition salt thereof; or an 
enantiomer or a racemic mixture thereof. 
The invention further relates to a pharmaceutical composition for the 
treatment of degenerative diseases which comprises a pharmaceutically 
acceptable carrier, adjuvant, diluent or vehicle together with an 
effective proteolytic enzyme inhibiting amount of a compound of the 
Formula I. 
The invention further relates to a method for the treatment of degenerative 
diseases which comprises administering to a patient in need of such 
treatment an effective proteolytic enzyme inhibiting amount of a compound 
of the Formula I. 
DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS 
The term lower-alkyl as used herein means linear or branched hydrocarbon 
chains having one to about five carbon atoms and thus includes methyl, 
ethyl, propyl, isopropyl, n-butyl, sec-butyl, 3-methylbutyl; n-pentyl, and 
the like. 
The term halogen or halide as used herein means chlorine, bromine, iodine, 
and fluorine. 
The term lower-alkoxy as used herein means linear or branched alkyloxy 
substituents having from one to about four carbon atoms and thus includes 
methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and the like. 
The term lower-alkanoyl as used herein means linear or branched hydrocarbon 
chains having two to about four carbon atoms and thus includes acetyl, 
propionyl, isobutyryl, and the like. 
The numbering system used throughout this specification is shown in the 
ring system which is illustrated below. This ring 
##STR12## 
system is named in the chemical literature as a 1,2,5-thiadiazolidin-3-one 
1,1-dioxide. 
The synthesis of the compounds of the invention may be outlined as shown in 
Scheme A: 
##STR13## 
A suitably substituted 2-halomethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide 
derivative of the formula II, wherein X is a halogen, preferably chlorine, 
in a suitable organic solvent, such as dimethylformamide, is treated with 
an excess of an alcohol of the formula III or a dione of the formula IV, 
in the presence of an excess of a base, such as potassium carbonate, at a 
temperature in the range of about room temperature up to the boiling point 
of the solvent used, preferably at a temperature of about room 
temperature, to afford the compounds of the formula I, 
##STR14## 
wherein Z is 
It will be appreciated that the compounds of the formula I possess an 
asymmetric carbon at position C-4 of the 1,2,5-thiadiazolidin-3-one 
1,1-dioxide ring and are thus capable of existing as enantiomers. Unless 
otherwise specified herein, the invention is intended to extend to each of 
the enantiomeric forms including the racemates. In some cases there may be 
advantages, i.e. greater potency, to using a particular enantiomer when 
compared to the other enantiomer or the racemate in the treatment of 
degenerative diseases and such advantages can be readily determined by 
those skilled in the art. The separate enantiomers may be synthesized from 
chiral starting materials or the racemates may be resolved by conventional 
procedures which are well known in the art of chemistry such as chiral 
chromatography, fractional crystallization of diastereomeric salts and the 
like. 
The compounds of Formula I are useful both in the free base form and in the 
form of acid-addition salts, and, both forms are within the purview of the 
invention. The acid-addition salts are often a more convenient form for 
use; and in practice, use of the salt form inherently amounts to use of 
the base form. The acids which can be used to prepare the acid-addition 
salts include preferably those which produce, when combined with the free 
base, pharmaceutically-acceptable salts, that is, salts whose anions are 
relatively innocuous to the animal organism in pharmaceutical doses of the 
salts, so that the beneficial properties inherent in the free base are not 
vitiated by side effects ascribable to the anions. In practicing the 
present invention it is convenient to use the free base form or the 
hydrochloride, fumarate, toluenesulfonate, methanesulfonate or maleate 
salts. However, other appropriate pharmaceutically acceptable salts within 
the scope of the invention are those derived from other mineral acids and 
organic acids. The acid-addition salts of the basic compounds are prepared 
by standard procedures well known in the art which include, but are not 
limited thereto, dissolving the free base in an aqueous alcohol solution 
containing the appropriate acid and isolating the salt by evaporating the 
solution, or by reacting the free base and an acid in an organic solvent, 
in which case the salt separates directly, or is precipitated with a 
second organic solvent, or can be obtained by concentration of the 
solution. Although medicinally acceptable salts of the basic compounds are 
preferred, all acid-addition salts are within the scope of the present 
invention. All acid-addition salts are useful as sources of the free base 
form even if the particular salt per se is desired only as an intermediate 
product, as, for example, when the salt is formed for purposes of 
purification or identification, or when it is used as an intermediate in 
preparing a medicinally acceptable salt by, for example, ion exchange 
procedures. 
The suitably substituted 2-halomethyl-1,2,5-thiadiazolidin-3-one 
1,1-dioxides of the formula II, which are required for the synthesis of 
the compounds of the formula I, can be prepared as shown in scheme B: 
##STR15## 
The cesium salt of a suitably substituted 1,2,5-thiadiazolidin-3-one 
1,1-dioxide of the formula V, (prepared by the treatment of a compound of 
the formula V in a lower-alkanol solvent, i.e. methanol, with cesium 
carbonate at a temperature of about room temperature), in a suitable 
organic solvent, such as dimethylformamide, is treated with an excess of a 
halomethyl phenyl sulfide, wherein X' is a halogen, preferably chlorine, 
at a temperature in the range of about room temperature up to the boiling 
point of the solvent used, preferably at the boiling point of the solvent 
used, to afford the compounds of the formula VII. The compound of the 
formula VII can then be treated with an excess of a sulfuryl halide of the 
formula SO.sub.2 X.sub.2 ', wherein X' is a halogen, preferably chlorine, 
in a suitable organic solvent, such as methylene chloride, at a 
temperature of about room temperature, to afford the compounds of the 
formula II. 
The suitably substituted 1,2,5-thiadiazolidin-3-one 1,1-dioxides of the 
formula V can be prepared as shown in Scheme C: 
##STR16## 
A suitably substituted compound of the formula VIII wherein R is 
lower-alkyl, in an appropriate lower-alkanol solvent, such as methanol, is 
treated with an excess of an alkali metal lower-alkoxide; i.e. sodium 
methoxide, at a temperature in the range of about room temperature up to 
the boiling point of the solvent used, preferably at a temperature of 
about room temperature, followed by treatment with a proton source, such 
as BIO-RAD.RTM. 50 W.times.8 H.sup.+ ion exchange resin, to afford the 
compounds of the formula V. 
The compounds of the formula VIII, which are required for the synthesis of 
the compounds of the formula V, can be prepared as illustrated in Scheme 
D: 
##STR17## 
A halosulfonyl isocyanate of the formula IX, wherein X' is a halogen, 
preferably chlorine, is treated with an excess of an .alpha.-amino acid 
ester of the formula X, wherein R is lower-alkyl and X'.sup.- is a 
halogen, preferably chlorine, and an excess of benzyl alcohol, in the 
presence of an excess of a base, such as triethylamine, in an appropriate 
organic solvent, such as methylene chloride, at a temperature in the range 
of about -10.degree. C. up to about room temperature, to afford a compound 
of the formula XI (Note, if desired, the .alpha.-amino acid ester can be 
used as the limiting reagent rather than the halosulfonyl isocyanate). The 
compound of the formula XI can then be hydrogenated at a hydrogen pressure 
of about 50 psi, in a lower-alkanol solvent, such as methanol, in the 
presence of a catalyst, preferably palladium on carbon, to produce the 
compounds of the formula VIII. 
The compounds of the formulas III and IV are either commercially available, 
or they can be prepared by procedures known in the art (see, for example, 
allowed U.S. patent application Ser. No. 08/066,805 which is incorporated 
herein by reference). The halomethyl phenyl sulfides of the formula VI, 
the halosulfonyl isocyanates of the formula IX, and the .alpha.-amino acid 
esters of the formula X are either commercially available, or they can be 
prepared by procedures known in the art, or by the procedures described 
hereinbelow in the examples. 
The structures of the compound of the invention were established by the 
mode of synthesis, and by one or more of elemental analysis, and infrared, 
nuclear magnetic resonance and mass spectroscopy. The course of the 
reactions and the identity and homogeneity of the products were assessed 
by one or more of thin layer chromatography (TLC), high pressure liquid 
chromatography (HPLC), or gas-liquid chromatography (GLC). 
The following examples will further illustrate the invention without, 
however, limiting it thereto. All melting points (m.p.) are given in 
degrees centigrade (.degree.C.) and are uncorrected.

EXAMPLE 1 
(a) 
To a solution of N-t-butoxycarbonyl-sarcosine (50 g; 0.264 mol) in 700 ml 
of benzene was added 1,8-diazabicyclo 5.4.0!-undec-7-ene (DBU; 40.19 g, 
0.264 mol) in one portion. To the above clear solution added 74.94 g 
(0.528 mol) of methyl iodide in one portion and the resulting clear 
solution was allowed to reflux for 7 hours. After adding additional methyl 
iodide (16 ml), the reaction mixture was refluxed with stirring and then 
cooled to room temperature, and stirred overnight. The reaction mixture 
was filtered, the residue washed with ether, and the combined filtrate was 
washed with water, a saturated sodium bicarbonate solution, and then 
brine. The resulting organic layer was dried over sodium sulfate, 
filtered, and concentrated in vacuo to afford 46.38 g (86.4%) of 
N-t-butoxycarbonyl-sarcosine methyl ester as a yellow oil. 
(b) 
A 2M solution of LDA (70.32 ml, 0.14 mol) was added (via syringe) to a 
solution of N-t-butoxycarbonyl-sarcosine methyl ester (26 g, 0.1279 mol) 
in 40 ml of dry THF at -78.degree. C. under nitrogen and the mixture was 
stirred at this temperature for 30 minutes. To the above mixture was added 
4-bromo-2-methyl-2-butene (20 g, 0.134 mol) with stirring continuing at 
-78.degree. C., and the resulting mixture was allowed to warm to room 
temperature. The reaction mixture was quenched with 6 ml of saturated 
ammonium chloride solution at -78.degree. C., 20 ml of water was added, 
and the resulting reaction mixture was extracted with ethyl acetate. The 
organic layer was washed with water and brine, dried over sodium sulfate, 
and concentrated in vacuo to yield a yellow oil, which was purified by 
silica gel column chromatography (20% ethyl acetate in hexane) to afford 
22.1 g (63.7%) of N-t-butoxycarbonyl-2-(3-methyl-2-butenyl)-sarcosine 
methyl ester as an oil. 
(c) 
A solution of N-t-butoxycarbonyl-2-(3-methyl-2-butenyl)-sarcosine methyl 
ester (22.1 g, 81.44 mmol) in 400 ml of methanol under nitrogen was cooled 
to 0.degree. C. and 1.5 g of 10% Pd/C was added. The mixture was placed 
into a Parr Apparatus and hydrogenated at 50 psi for 6 hours. The catalyst 
was removed on a pad of CELITE.RTM. and the filtrate was concentrated in 
vacuo to afford 22.04 g (99%) of 
N-t-butoxycarbonyl-2-(3-methylbutyl)-sarcosine methyl ester as an oil. 
(d) 
A mixture of N-t-butoxycarbonyl-2-(3-methylbutyl)-sarcosine methyl ester 
(22.04 g, 80.62 mmol) in 360 ml of ethereal HCl was stirred at room 
temperature for 3 days. The resulting mixture was cooled in an ice/bath 
and the solvent was concentrated in vacuo to afford, after drying, 13.17 g 
(78%) of 2-(3-methylbutyl)-sarcosine methyl ester hydrochloride (Formula 
X: R.dbd.CH.sub.3 ; R.sup.2 .dbd.(CH.sub.2).sub.2 CH(CH.sub.3).sub.2 ; 
R.sup.3 .dbd.CH.sub.3 ; X.sup.- .dbd.Cl.sup.-) which was recrystallized 
from methanol/ether, m.p. 110.degree.-111.degree. C. 
(e) 
To a stirred solution of 5.77 ml (66.78 mmol) of chlorosulfonyl isocyanate 
in methylene chloride was added, under nitrogen, benzyl alcohol (6.89 ml, 
66.57 mmol) at 0.degree.-5.degree. C. After stirring the above solution 
for 1 hour, a solution of 13.166 g (62.78 mmol) of 
2-(3-methylbutyl)-sarcosine methyl ester hydrochloride in methylene 
chloride containing triethylamine (27.33 ml, 194.62 mmol) was added at 
0.degree.-5.degree. C. and the resulting mixture was stirred overnight 
allowing the mixture to warm to room temperature. The reaction mixture was 
poured into 600 ml of a 10% aq. HCl solution, saturated with sodium 
chloride, and the organic layer was separated. The aqueous layer was 
extracted with methylene chloride and the combined organic layer was 
washed with brine, dried over magnesium sulfate and concentrated in vacuo 
to yield 21.22 g (87.2%) of 
N-(carbobenzyloxyaminosulfonyl)-2-(3-methylbutyl)-sarcosine methyl ester 
(Formula XI: R.dbd.CH.sub.3 ; R.sup.1 .dbd.H; R.sup.2 
.dbd.(CH.sub.2).sub.2 CH(CH.sub.3).sub.2 ; R.sup.3 .dbd.CH.sub.3) which 
was purified by silica column chromatography (20% ethyl acetate in hexane) 
to afford an oil. 
(f) 
A solution of N-(carbobenylzoxyaminosulfonyl)-2-(3-methylbutyl)-sarcosine 
methyl ester (20.6 g, 53.17 mmol) in 200 ml of methanol under nitrogen was 
cooled to 0.degree. C. and 1.5 g of 10% Pd/C was added. The mixture was 
placed into a Parr Apparatus and hydrogenated for 3.5 hours at 50 psi. The 
catalyst was removed on a pad of CELITE.RTM. and the filtrate was 
concentrated in vacuo to afford 13.24 g (98.6%) of 
N-(aminosulfonyl)-2-(3-methylbutyl)-sarcosine methyl ester (Formula VIII: 
R.dbd.CH.sub.3 ; R.sup.1 .dbd.H; R.sup.2 .dbd.(CH.sub.2).sub.2 
CH(CH.sub.3).sub.2 ; R.sup.3 .dbd.CH.sub.3) as an oil. 
(g) 
A solution of N-(aminosulfonyl)-2-(3-methylbutyl)-sarcosine methyl ester 
(12.28 g, 48.67 mmol) in methanol (150 ml) was added under nitrogen to a 
solution of sodium methoxide (Na=2.1 g, 95.71 mmol) in 150 ml of ice-cold 
methanol. The resulting reaction mixture was stirred at room temperature 
under nitrogen for 1.5 hours, and the mixture was treated with 25 g of 
ion-exchange resin (BIO RAD.RTM. 50W.times.8H.sup.+ ; 200-400 mesh) for 40 
minutes and filtered. The filtrate was concentrated in vacuo to afford 
10.7 g (99.8%) of 4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin3-one 
1,1-dioxide (Formula V: R.sup.1 .dbd.H; R.sup.2 .dbd.(CH.sub.2).sub.2 
CH(CH.sub.3).sub.2 ; R.sup.3 .dbd.CH.sub.3) as a solid, m.p. 
212.degree.-214.degree. C. 
(h) 
A mixture of 4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 
1,1-dioxide cesium salt (prepared by reacting 7.7 g (34.95 mmol) of 
4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide in 
methanol with 5.13 g of CS.sub.2 CO.sub.3 followed by removal of the 
solvent and drying under high vacuum) and phenylthiomethyl chloride (6.65 
g, 41.94 mmol) suspended in DMF was heated at 85.degree. C. for 17 hours. 
The mixture was cooled, and poured into 300 ml of ice/water. The reaction 
mixture was extracted with ethyl acetate (3.times.) and the organic layer 
was washed with water and brine, and dried over sodium sulfate. The 
organic layer was concentrated in vacuo and the residue was purified by 
silica column chromatography (10% ethyl acetate in hexane) to afford 8.15 
g (70.6%) of 
2-phenylthiomethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 
1,1-dioxide (Formula VII: R.sup.1 .dbd.H; R.sup.2 
.dbd.(CH.sub.2)2CH(CH.sub.3).sub.2 ; R.sup.3 .dbd.CH.sub.3) as an oil. 
(i) 
To a solution of 
2-phenylthiomethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 
1,1-dioxide (8.15 g, 24.66 mmol) in 200 ml of methylene chloride was added 
in one portion under nitrogen sulfuryl chloride (2.36 ml, 29.6 mmol) and 
the mixture was stirred for 3.5 hours at room temperature. The mixture was 
concentrated in vacuo and the residue was triturated in hexane to afford 
4.64 g (70%) of 
2-chloromethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 
1,1-dioxide (Formula II: R.sup.1 .dbd.H; R.sup.2 .dbd.(CH.sub.2).sub.2 
CH(CH.sub.3).sub.2 ; R.sup.3 .dbd.CH.sub.3 ; X'.dbd.Cl) as a solid, m.p. 
59.degree.-60.degree. C. 
(j) 
A mixture of 
2-chloromethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 
1,1-dioxide (1 g; 3.72 mmol), 2,4-dioxo-4-H-pyrido 1,2-a!pyrimidine 
(Formula IV: X.dbd.H; Y.dbd. 
##STR18## 
(0.72 g; 4.44 mmol), and potassium carbonate (0.67 g; 4.84 mmol) in 35 ml 
of DMF was stirred at room temperature for 24 hours. The mixture was 
poured into ice/water, extracted with ethyl acetate, and the organic layer 
was washed with water, brine, and dried. The solvent was concentrated in 
vacuo and the residue purified by silica gel flash chromatography (70% 
hexane/ethyl acetate, 5% methanol/ethyl acetate) to afford 0.29 g of 
2-(4-oxo-4-H-pyrido 1,2-a!pyrimidin-2-yl-oxymethyl)-4-(3-methylbutyl)-5-me 
thyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R.sup.1 .dbd.H; 
R.sup.2 .dbd.(CH.sub.2).sub.2 CH(CH.sub.3); R.sup.3 .dbd.CH.sub.3 ; 
##STR19## 
Example 1J) as a solid, m.p. 106.5.degree.-107.5.degree. C., and 0.34 g of 
2-(4-oxo-4-H-2-hydroxypyrido 1,2-a!pyrimidin-3-yl-methyl)-4-(3-methylbutyl 
)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide as a solid, m.p. 
165.degree.-170.degree. C. 
EXAMPLE 2 
(a) 
Following a procedure similar to that described in example 1(b), but 
substituting 2.1 equivalents of methyl iodide for 
4-bromo-2-methyl-2-butene and utilizing 2.2 equivalents of lithium 
diisopropyl amide (LDA) it is contemplated that there can be prepared a 
compound of the formula: (CH.sub.3).sub.2 C(CO.sub.2 
CH.sub.3)N(CH.sub.3)(CO.sub.2 tBu). 
(b) 
Following a procedure similar to that described in example 1(d), but 
substituting the compound example 2(a) for the compound of example 1(c), 
it is contemplated that there can be prepared a compound of the formula 
(CH.sub.3).sub.2 C(CO.sub.2 CH.sub.3)NH(CH.sub.3).HCl. 
Following procedures similar to those described in Examples 1(e)-(g), but 
substituting an appropriate .alpha.-amino acid ester of the formula X for 
the compound of example 1(d), it is contemplated that there can be 
prepared the following compounds of the formula V illustrated in Table I. 
TABLE I 
______________________________________ 
##STR20## 
Example 
No. R.sup.1 R.sup.2 
R.sup.3 
Ester Used 
______________________________________ 
3 CH.sub.3 
CH.sub.3 
CH.sub.3 
(CH.sub.3).sub.2 C(NHCH.sub.3)CO.sub.2 
CH.sub.3.HCl 
4 CH.sub.2 Ph 
H H C.sub.6 H.sub.5 CH.sub.2 CH(NH.sub.2)CO.sub.2 
CH.sub.3.HCl 
______________________________________ 
Following a procedure similar to that described in example 1(h) but 
substituting an appropriate compound of the Formula V for 
4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide it is 
contemplated that there can be prepared the following compounds of the 
formula VII illustrated in Table II: 
TABLE II 
______________________________________ 
##STR21## 
Example No. R.sup.1 R.sup.2 
R.sup.3 
______________________________________ 
5 CH.sub.3 CH.sub.3 
CH.sub.3 
6 CH.sub.2 Ph H H 
______________________________________ 
Following a procedure similar to that described in example 1(i), but 
substituting an appropriate compound of the formula VII for 
2-phenylthiomethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 
1,1-dioxide it is contemplated that there can be prepared the following 
compounds of the formula II illustrated in Table III: 
TABLE III 
______________________________________ 
##STR22## 
Example No. R.sup.1 R.sup.2 R.sup.3 
X' 
______________________________________ 
7 CH.sub.3 
CH.sub.3 CH.sub.3 
Cl 
8 CH.sub.2 Ph 
H H Cl 
______________________________________ 
Following a procedure similar to that described in example 1(j), but 
utilizing an appropriate compound of the formula III or IV and, if 
applicable, substituting an appropriate compound of the formula II for 
2-chloromethyl-4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 
1,1-dioxide, it is contemplated that there can be prepared the following 
compounds of the formula I illustrated in table IV. 
TABLE IV 
__________________________________________________________________________ 
##STR23## 
Example 
No. R.sup.1 
R.sup.2 R.sup.3 
z 
__________________________________________________________________________ 
9 CH.sub.3 
CH.sub.3 CH.sub.3 
##STR24## 
10 CH.sub.2 Ph 
H H 
##STR25## 
11 H (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 
CH.sub.3 
##STR26## 
12 CH.sub.3 
CH.sub.3 CH.sub.3 
##STR27## 
13 CH.sub.2 Ph 
H H 
##STR28## 
14 H (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 
CH.sub.3 
##STR29## 
15 CH.sub.3 
CH.sub.3 CH.sub.3 
##STR30## 
16 CH.sub.2 Ph 
H H 
##STR31## 
17 H (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 
CH.sub.3 
##STR32## 
18 CH.sub.3 
CH.sub.3 CH.sub.3 
##STR33## 
19 CH.sub.2 Ph 
H H 
##STR34## 
20 H (CH.sub.2)CH(CH.sub.3).sub.2 
CH.sub.3 
##STR35## 
21 CH.sub.3 
CH.sub.3 CH.sub.3 
##STR36## 
22 CH.sub.2 Ph 
H H 
##STR37## 
23 H (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 
CH.sub.3 
##STR38## 
24 CH.sub.3 
CH.sub.3 CH.sub.3 
##STR39## 
25 CH.sub.2 Ph 
H H 
##STR40## 
26 H (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 
CH.sub.3 
##STR41## 
27 CH.sub.3 
CH.sub.3 CH.sub.3 
##STR42## 
28 CH.sub.2 Ph 
H H 
##STR43## 
29 H (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 
CH.sub.3 
##STR44## 
30 CH.sub.3 
CH.sub.3 CH.sub.3 
##STR45## 
31 CH.sub.2 Ph 
H H 
##STR46## 
32 H (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 
CH.sub.3 
##STR47## 
33 CH.sub.2 
CH.sub.3 CH.sub.3 
##STR48## 
34 CH.sub.2 Ph 
H H 
##STR49## 
35 H (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 
CH.sub.3 
##STR50## 
36 CH.sub.3 
CH.sub.3 CH.sub.3 
##STR51## 
37 CH.sub.2 Ph 
H H 
##STR52## 
38 H (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 
CH.sub.3 
##STR53## 
39 CH.sub.3 
CH.sub.3 CH.sub.3 
##STR54## 
__________________________________________________________________________ 
Biological Test Results 
Representative examples of the compounds of the invention have been found 
to possess valuable pharmacological properties. In particular, they have 
been found to inhibit the activity of serine proteases, specifically human 
leukocyte elastase, and are thus useful in the treatment of degenerative 
disease conditions such as emphysema, rheumatoid arthritis, pancreatitis, 
cystic fibrosis, chronic bronchitis, adult respiratory distress syndrome, 
inflammatory bowel disease, psoriasis, bullous pemphigoid, periodontal 
disease, and alpha-1-antitrypsin deficiency. 
The pharmacological properties of representative examples of the compounds 
of the invention were demonstrated by the following conventional in vitro 
biological test procedure. 
The test compound (inhibitor) is dissolved in DMSO in a vial to produce an 
inhibitor stock solution which has a concentration in the range of 
200-1000 .mu.M. The inhibitor stock solution is diluted (1:4, 1:16 and 
1:64) into assay vials (vials 1, 2 and 3 respectively) containing 2.4 mL 
of buffer solution (50 mM 
N- 2-hydroxyethyl!piperazine-N'- 2-ethanesulfonic acid!/NaOH, 500 mM NaCl, 
pH 7.8 at 25.degree. C.) and DMSO is added so that the total volume in 
each vial is 3.2 mL. 70 .mu.L, 50 .mu.L, 35 .mu.L and 25 .mu.L of 
inhibitor from assay vial 1 is placed into the first four wells of a 
96-well microtiter plate and each well is made up to 90 .mu.L total volume 
with the addition of a 25% DMSO/buffer solution. The inhibitor from assay 
vials 2 and 3 is processed in a similar manner and placed in wells 5-12 
respectively to afford a total of 12 different inhibitor concentrations. 
Four wells (wells 13-16) containing 90 .mu.L of the 25% DMSO/buffer 
solution but no inhibitor are also run simultaneously with the inhibited 
wells as a control. 150 .mu.L of substrate solution (prepared by the 
addition of 500 .mu.L of the human leukocyte elastase (HLE) substrate 
MeOSuc-Ala-Ala-Pro-Val-pNA (18.7 mM in DMSO) to 19.5 mL of buffer 
solution) is then added simultaneously into each of the 16 wells and the 
solution in each well was thoroughly mixed. 
The 96-well microtiter plate is placed into a Microplate Reader #89815A 
spectrophotometer and 110 BL of the enzyme solution (prepared as follows: 
a mixture of 20 mL of buffer solution and 20 mg of bovine serum albumen is 
gently vortexed in a scintillation vial and 5 BL HLE stock solution (1 
mg/mL dissolved in deionized water) is added) is added simultaneously to 
each of the 16 wells. Each of the solutions in the wells is throughly 
mixed and then the time-dependent absorbance data is collected at an 
absorbance of 410 nM until the assay is complete. It should be noted that 
although this assay method can be done manually, it is preferred to 
perform the assay robotically using a Hewlett Packard MicroAssay System 
Robot. 
A plot of the absorbance versus time data thus obtained affords progress 
curves the final slope of which is equal to the final steady-state 
velocities (VF). Using the program ENZFITTER (Elsevier software), the 
progress curves for the four control assays ( I!=0) are fit by linear 
regression to yield the enzyme reaction velocity values in the absences of 
inhibit or (V.sub.o) which are averaged to produce a single fixed value. 
The inhibition constant K.sub.i (nM) is then obtained from a plot of 
##EQU1## 
which affords a linear plot wherein: 
##EQU2## 
and S! is the concentration of the substrate and K.sub.m is the Michaelis 
constant. 
A representative compound of the invention, Example 1(j), was tested for 
human leukocyte elastase inhibitory activity according to the 
above-described procedure and had a K.sub.i of 0.79 nM. 
The compounds of the invention can be prepared for pharmaceutical use by 
conventional pharmaceutical procedures that are well known in the art; 
that is, by formulating a pharmaceutical composition which comprises 
compounds of the invention or their pharmaceutically acceptable salts 
together with one or more physiologically acceptable carriers, adjuvants, 
diluents or vehicles, for oral administration in solid or liquid form, 
parenteral administration, topical administration or aerosol inhalation 
administration, and the like. 
Solid compositions for oral administration include compressed tablets, 
pills, powders and granules. In such solid compositions, the active 
compound is admixed with at least one inert diluent such as starch, 
calcium carbonate, sucrose or lactose. These compositions may also contain 
additional substances other than inert diluents, e.g., lubricating agents, 
such as magnesium stearate, talc and the like. 
Liquid compositions for oral administration include pharmaceutically 
acceptable emulsions, solutions, suspensions, syrups and elixirs 
containing inert diluents commonly used in the art, such as water and 
liquid paraffin. Besides inert diluents such compositions may also contain 
adjuvants, such as wetting and suspending agents, and sweetening, 
flavoring, perfuming and preserving agents. According to the invention, 
the compounds for oral administration also include capsules of absorbable 
material, such as gelatin, containing said active component with or 
without the addition of diluents or excipients. 
Preparations according to the invention for parenteral administration 
include sterile aqueous, aqueous-organic, and organic solutions, 
suspensions and emulsions. Examples of organic solvents or suspending 
media are propylene glycol, polyethylene glycol, vegetable oils such as 
olive oil and injectable organic esters such as ethyl oleate. These 
compositions can also contain adjuvants such as stabilizing, preserving, 
wetting, emulsifying and dispersing agents. 
Preparations according to the invention for topical administration or 
aerosol inhalation administration include dissolving or suspending a 
compound of the invention in a pharmaceutically acceptable vehicle such as 
water, aqueous alcohol, glycol, oil solution or oil-water emulsion, and 
the like. 
If desired, the compounds of the invention can further be incorporated into 
slow release or targeted delivery systems such as polymer matrices, 
liposomes, and microspheres. 
The percentage of active component in such compositions may be varied so 
that a suitable dosage is obtained. The dosage administered to a 
particular patient is variable depending upon the clinician's judgment 
using as criteria: The route of administration, the duration of treatment, 
the size and physical condition of the patient, the potency of the active 
component and the patient's response thereto. An effective dosage amount 
of the active component can thus readily be determined by the clinician 
after a consideration of all criteria and using his best judgment on the 
patient's behalf.