Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-08-22
2002-07-16
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S372000, C514S456000, C514S457000, C514S382000, C514S381000, C514S345000, C549S250000, C549S252000, C549S289000
Reexamination Certificate
active
06420401
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to peptidomimetics which are substituted derivatives of 1,2,5 thiadiazolidin-3-one-1,1-dioxide.
Degenerative diseases associated with serine proteases such as human leukocyte elastase include cystic fibrosis, chronic obstructive pulmonary disease (e.g., emphysema and asthma), adult respiratory distress syndrome (ARDS), inflammatory bowel disease, chronic bronchitis, psoriasis, rheumatoid arthritis, pancreatitis, periodontal disease, and other inflammatory diseases.
Diseases associated with cysteine proteases include cancer metastasis, osteoporosis and osteoarthritis (McGrath et al. (1997)
Nature: Structural Biology
4(2):105-109), bone resorption, muscular dystrophy, parasitic diseases (leishmaniasis, malaria) (Li et al. (1996)
Bioorg. Med. Chem.
4(9):1421-1427; Rosenthal et al. (1993)
J. Clin. Invest.
91:1052-1056), inflammation, common cold (Webber et al. (1996)
J. Med. Chem.
39:5072-5082), and hepatitis A (Malcolm et al. (1996)
Biochemistry
34:8172-8179).
SUMMARY OF THE INVENTION
The invention features a compound having the formula (I)
Each of R
1
and R
3
, is independently selected from H, alkyl, aryl, aralkyl, alkaryl, and substituted aryl. R
5
is selected from the values for R
1
and halo. R
2
is selected from H, alkyl, aralkyl, alkylthioalkyl, hydroxyalkyl, and R
xxi
(amino acids). R
4
is H, alkyl, aryl, aralkyl, an amino acid side chain, —PO(OR
A
)
2
, —N═C═O, —(NHCHR
i
CO)OR
C
, —NHCOOR
C
, —NHCONR
X
R
Y
, —(C═O)—Q, —CH(R
i
)NHW, —[CHR
i(r)
NH(C═O)]
r
R
C
, —[CHR
i(r)
(C═O)NH]
r
R
C
or —NHG. Q is —OR
C
, —OJ, NR
Y
R
Z
, a halogen, —[NHCHR
i(q)
(C═O)]
q
OR
C
, —[NHCHR
i(q)
(C═O)]
q
NR
C
R
E
, —OPn, or —NHPn. Pn is a polymer; each of W and W
1
is H, G, or —(C═O)NHCHR
i
COOR
C
. Each of q and r is an integer between 1 and 10. R
6
is selected from H, alkyl, aryl, aralkyl, —N═C═O, —(C═O)R
B
, —(C═O)Q′, —(NHCHR
xi
(C═O))OR
D
, —NH
2
, —NHG, —NHCOOR
D
, —NH(C═O)NR
K
R
L
, —O(C═O)CH
2
—(OCH
2
CH
2
)
2
—OR, and —O—X. R is alkyl. Q′ is —OR
D
, —OJ, —NR
K
R
L
, —[NHCHR
xi(z)
(C═O)]
z
—OR
D
, or a halogen. X is —(C═O)R
B
, —[(C═O)CH(R
xi(z)
)—NH]
z
X
p
, —CH(R
xi
)NHY, —CHR
xi
(NH(C═O)CHR
xi(p)
)
p
—NHW
1
, —[(C═O)NHCHR
xi(z)]
z
—(C═O)OR
D
, —(C═O)OR
D
, —S(O)
n
R
B
, or —N(SO
2
R
Q
)—[(C═O)K]. X
p
is H or G, G being an amino protecting group. J is a carboxyl protecting group. Y is H, R
B
, —(C═O)R
B
, or G; z is between 1 and 10, n is from 0 to 2. K is R
B
, —OR
B
, —NHR
B
, —OCHR
xi
NHV, —[NHCHR
xi(m)
(C═O)]
m
OR
B
, or —[NHCHR
xi(m)
(C═O)]
m
NR
C
R
F
. V is G, H, or —(C═O)CHR
xi
NHZ. Z is G or H; m is from 1 to 2. In addition, R
5
and R
6
can be taken together to form a lactone. Each of R
i
through R
xxi
is independently selected from an amino acid side chain. Each of R
A
and R
B
is independently selected from alkyl, aryl, aralkyl, alkaryl, and heterocyclic radical. Each of R
C
and R
D
is independently selected from H and the values for R
A
. Each of R
E
and R
F
is independently selected from (heterocyclic radical) alkyl. Each of R
Y
and R
Z
, and each of R
K
and R
L
, is independently selected from the values for R
C
. Furthermore, each pair (R
Y
and R
Z
, or R
K
and R
L
) can be taken together to form a bivalent moiety selected from alkylene, heterocyclic diradical, alkenylene, arylene, or alkylarylene. R
Q
is selected from the values of R
A
and NHR
r
. R
r
is alkyl, aryl, or aralkyl, provided that where one of R
5
and R
6
is H and the other is benzyl, and one of R
3
and R
4
is H, the other of R
3
aand R
4
is not alkyl; and provided that where one R
3
and R
4
is H, and the other is alkyl, and one of R
5
and R
6
is H, the other R
5
and R
6
is not —O(C═O)-aryl. The invention also features oligomers and polymers containing one or more of the disclosed inhibitor compounds.
The invention also features oligomers and polymers containing one or more of the disclosed inhibitor compounds. One embodiment is a peptidomimetic composition including between 1 and 20 monomers of a compound of formula (II); and between 0 and 19 amino acid residues. The monomers and amino acid residues are linked to each other by amide linkages, and the terminal monomers or amino acid residues are terminated by hydroxyl, amino, —OJ, or —NHG to form carboxyl, primary amide, or protected amino or carboxyl groups. For example, a terminal monomer may have a HO—[(C═O)— or a H[NH— terminus, where the bracket is the bracket in formula II. Formula II is shown below.
In formula II, A
4
is selected from —[NHCH(R
i
)—, —[(C═O)—, and —[NH—. B
6
is selected from —CH(R
i
)NH]—, —NH]— and —(C═O)]—. Each of R
1
and R
3
is independently selected from the H, alkyl, aryl, aralkyl, alkaryl, and substituted aryl. R
5
is selected from the values for R
1
and halo. R
2
is selected from H, alkyl, aralkyl, alkylthioalkyl, hydroxyalkyl, and an amino acid side chain. G is an amino protecting group. J is a carboxyl protecting group. Each R
i
is independently selected from an amino acid side chain. In some embodiments, the sum of the number of monomers and the number of amino acid residues is between 4 and 10, or between 2 and 6. In other embodiments, the number of monomer units is preferably between 2 and 8; the number of amino acid residues is 0, or between 0 and 6; at least two of the monomer units are the same; at least two of the monomer units are different; two of the monomer units have different R
1
groups; or combinations thereof.
Another aspect of the invention features a method for synthesizing a peptidomimetic product. The method includes covalently linking a compound of formula I to an amino acid residue or a peptidomimetic reactant having an isocyanate, chloroformate, hydroxyl, or preferably amino, activated amino, carboxyl, or activated carboxyl functional group. The resulting linking moiety is selected from urea, urethane, ester, and preferably amide linkages.
The invention also features a method of N-chloromethylating a cyclic N-acylated sulfamide, or the sulfonamide analog, including reacting a compound of formula III:
with at least 2 equivalents of a bisulfite adduct of formaldhyde in thionyl chloride at a temperature between 50° C.-120° C. for a reaction time between 2-30 hours. In formula III each of R
1
and R
3
is independently selected from H, alkyl, aryl, aralkyl, alkaryl, and substituted aryl. R
2
is selected from H, alkyl, aralkyl, alkylthioalkyl, hydroxyalkyl, and R
xxi
. R
4
is H, alkyl, aryl, aralkyl, an amino acid side chain, —PO(OR
A
)
2
, —N═C═O, —(NHCHR
i
CO)OR
C
, —NHCOOR
C
, —NHCONR
X
R
Y
, —(C═O)—Q, —CH(R
i
)NHW, —[CHR
i(r)
NH(C═O)]
r
R
C
, —[CHR
i(r)
(C═O)NH]
r
R
C
, or —NHG. Q is —OR
C
, —OJ, —NR
Y
R
Z
, a halogen, —[NHCHR
i(q)
(C═O)]
q
OR
C
, —[NHCHR
i(q)
(C═O)]
q
NR
C
R
E
, —OPn, or —NHPn. Pn is a polymer, each of W and W
1
is H, G, or —(C═O)NHCHR
i
COOR
C
, and each of q and r is an integer between 1 and 10. Each of R
i
through Rxxi is independently selected from an amino acid side chain. R
A
, R
C
, R
E
, R
Y
and R
Z
are as in formula I. In some embodiments, the amount of bisulfite adduct is at least 3 equivalents, between 5 and 10 equivalents, or between 4 and 8 equivalents. In another embodiment, R
4
and R
6
of formula III are not selected from reactive functional groups such as carboxyl, primary and secondary amines, amino, aldehyde, and primary amides. For example, R
4
is H, alkyl, aryl, aralkyl, an amino acid side chain, —PO(OR
A
)
2
, —(NHCHR
i
CO)OR
C
, —NHCOOR
C
, —NHCONR
X
R
Y
, —(C═O)—Q, —CH(R
i
)NHW, —[CHR
i(r)
NH(C═O)]
r
R
C
, —[CHR
i(r)
(C═O)NH]
r
R
C
, or —NHG, where Q is —OR
C
, —OJ, —NR
Y
R
Z
, a halogen, —[NHCHR
i(q)
(C═O)]
q
OR
C
, —
Groutas William C.
Kuang Rongze
Goodrich & Rosati
Higel Floyd D.
Sackey Ebenezer
Sonsini Wilson
Weitz David J.
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