Beta lactam compounds and their use as inhibitors of tryptase

Details Beta lactam compounds and their use as inhibitors of tryptase Beta lactam compounds and their use as inhibitors of tryptase

1999-12-13

2002-01-01

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S210150, C540S200000, C540S354000, C540S355000, C540S359000, C540S362000

Reexamination Certificate

active

06335324

ABSTRACT:

BACKGROUND OF THE INVENTION
Han in U.S. Pat. Nos. 5,037,819, 5,110,812, 5,175,283, 5,250,677 and 5,326,863 discloses 3-guanidinoalkyl-2-azetidinones of the formula:
wherein:
U and W are independently selected from hydrogen and amino protecting groups;
n is an integer from 1 to 3;
X is hydrogen, trialkylsilyl, arylsulfonyl, amino substituted arylsulfonyl, alkylsulfonyl, arylaminocarbonyl, alkylcarbonyl or arylcarbonyl;
Y is hydrogen, arylalkenyl, arylalkyl, formyl, carboxy, alkoxycarbonyl, acyloxy, arylthio, arylsulfinyl, arylsulfonyl, alkythio, alkylsulfinyl, alkylsulfonyl, arylaminocarbonyl,
 R is hydrogen, alkyl, or arylalkyl;
m is an integer from 1 to 3; and
R′, is hydrogen or —CO
2
R″ wherein R″ is hydrogen, alkyl, or arylalkyl.
Han further discloses that the above compounds wherein:
U and W are hydrogen;
X is arylsulfonyl, amino substituted arylsulfonyl, alkylsulfonyl, arylaminocarbonyl, alkylcarbonyl, or arylcarbonyl; and
Y is hydrogen, arylalkyl, carboxy, alkoxycarbonyl, acyloxy, arylsulfonyl, alkylthio, alkylsulfonyl, arylaminocarbonyl,
 R is hydrogen, alkyl or arylalkyl;
R′, is hydrogen or —CO
2
R″;
R″, is hydrogen, alkyl, or arylalkyl and pharmaceutically acceptable salts thereof are inhibitors against serine proteases, particularly against thrombin and trypsin, and can be used to control blood coagulation or to treat pancreatitis.
Han defines “aryl” as a phenyl or naphthyl group which may be unsubstituted or substituted with one or more groups such as amino, nitro, or alkyl and defines “amino” as unsubstituted or substituted with one or two alkyl radicals.
SUMMARY OF THE INVENTION
This invention is directed to the novel beta lactam compounds of formulas I, II, III, IV, and V shown below and to the use of such compounds as inhibitors of various in vivo enzyme systems including tryptase, thrombin, trypsin, Factor Xa, Factor VIIa, and urokinase-type plasminogen activator. This invention is also directed to the use of the compounds of formula VI shown below as tryptase, Factor Xa, Factor VIIa, and urokinase-type plasminogen activator inhibitors.
Compounds of this invention include the formula:
wherein:
R
1
is hydrogen, carboxy, alkoxycarbonyl, A
2
-aryl,
or R
1
is alkyl provided that R
2
is alkyl and R
3
is hydrogen.
R
2
and R
3
are both hydrogen, or R
2
is alkyl provided that R
3
is hydrogen, or R
3
is alkyl provided that R
2
is hydrogen.
R
4
and R
5
are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, A
2
-cycloalkyl, A
2
-substituted cycloalkyl, aryl, substituted aryl, A
2
-aryl, A
2
-substituted aryl, heteroaryl, A
2
-heteroaryl, heterocycloalkyl, A
2
-heterocycloalkyl, aryl-A
3
-aryl, A
2
-aryl-A
3
-aryl, aryl-A
3
-cycloalkyl, A
2
-aryl-A
3
-cycloalkyl, aryl-A
3
-heteroaryl, A
2
-aryl-A
3
-heteroaryl, aryl-A
3
-heterocycloalkyl, A
2
-aryl-A
3
-heterocycloalkyl, aryl-A
3
-substituted aryl, A
2
-aryl-A
3
-substitued aryl, aryl-A
3
-substituted cycloalkyl, A
2
-aryl-A
3
-substituted cycloalkyl, cycloalkyl-A
3
-cycloalkyl, A
2
-cycloalkyl-A
3
-cycloalkyl, cycloalkyl-A
3
-aryl, A
2
-cycloalkyl-A
3
-aryl, cycloalkyl-A
3
-heteroaryl, A
2
-cycloalkyl-A
3
-heteroaryl, cycloalkyl-A
3
-heterocycloalkyl, A
2
-cycloalkyl-A
3
-heterocycloalkyl, cycloalkyl-A
3
-substituted cycloalkyl, A
2
-cycloalkyl-A
3
-substituted cycloalkyl, cycloalkyl-A
3
-substituted aryl, A
2
-cycloalkyl-A
3
-substituted aryl, substituted cycloalkyl-A
3
-cycloalkyl, A
2
-substituted cycloalkyl-A
3
-cycloalkyl, substituted cycloalkyl-A
3
-substituted cycloalkyl, A
2
-substituted cycloalkyl-A
3
-substituted cycloalkyl, substituted cycloalkyl-A
3
-aryl, A
2
-substituted cycloalkyl-A
3
-aryl, substituted cycloalkyl-A
3
-heteroaryl, A
2
-substituted cycloalkyl-A
3
-heteroaryl, substituted cycloalkyl-A
3
-heterocycloalkyl, A
2
-substituted cycloalkyl-A
3
-heterocycloalkyl, substituted cycloalkyl-A
3
-substituted aryl, A
2
-substituted cycloalkyl-A
3
-substituted aryl, heteroaryl-A
3
-heteroaryl, A
2
-heteroaryl-A
3
-heteroaryl, heteroaryl-A
3
-cycloalkyl, A
2
-heteroaryl-A
3
-cycloalkyl, heteroaryl-A
3
-substituted cycloalkyl, A
2
-heteroaryl-A
3
-substituted cycloalkyl, heteroaryl-A
3
-aryl, A
2
-heteroaryl-A
3
-aryl, heteroaryl-A
3
-heterocycloalkyl, A
2
-heteroaryl-A
3
-heterocycloalkyl, heteroaryl-A
3
-substituted aryl, A
2
-heteroaryl-A
3
-substituted aryl, heterocycloalkyl-A
3
-heterocycloalkyl, A
2
-heterocycloalkyl-A
3
-heterocycloalkyl, heterocycloalkyl-A
3
-cycloalkyl, A
2
-heterocycloalkyl-A
3
-cycloalkyl, heterocycloalkyl-A
3
-substituted cycloalkyl, A
2
-heterocycloalkyl-A
3
-substituted cycloalkyl, heterocycloalkyl-A
3
-aryl, A
2
-heterocycloalkyl-A
3
-aryl, heterocycloalkyl-A
3
-substituted aryl, A
2
-heterocycloalkyl-A
3
-substituted aryl, heterocycloalkyl-A
3
-heteroaryl, A
2
-heterocycloalkyl-A
3
-heteroaryl, substituted aryl-A
3
-substituted aryl, A
2
-substituted aryl-A
3
-substituted aryl, substituted aryl-A
3
-cycloalkyl, A
2
-substituted aryl-A
3
-cycloalkyl, substituted aryl-A
3
-substituted cycloalkyl, A
2
-substituted aryl-A
3
-substituted cycloalkyl, substituted aryl-A
3
-aryl, A
2
-substituted aryl-A
3
-aryl, substituted aryl-A
3
-heteroaryl, A
2
-substituted aryl-A
3
-heteroaryl, substituted aryl-A
3
-heterocycloalkyl, and A
2
-substituted aryl-A
3
-heterocycloalkyl.
R
6
is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, A
2
-cycloalkyl, A
2
-substituted cycloalkyl, aryl, substituted aryl, A
2
-aryl, A
2
-substituted aryl, aryl-A
3
-aryl, A
2
-aryl-A
3
-aryl, heteroaryl, A
2
-heteroaryl, heterocycloalkyl, A
2
-heterocycloalkyl, aryl-A
3
-cycloalkyl, A
2
-aryl-A
3
-cycloalkyl, aryl-A
3
-heteroaryl, A
2
-aryl-A
3
-heteroaryl, aryl-A
3
-heterocycloalkyl, A
2
-aryl-A
3
-heterocycloalkyl, carboxy, alkoxycarbonyl,
alkoxycarbonylamino, aryloxycarbonylamino, arylcarbonylamino, —N(alkyl)(alkoxycarbonyl), —N(alkyl)(aryloxycarbonyl), alkylcarbonylamino, —N(alkyl)(alkylcarbonyl), or —N(alkyl)(arylcarbonyl).
m is an integer from 1 to 5.
Y is O, S, N—R
4
, N—SO
2
—R
7
,
R
7
is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, A
2
-cycloalkyl, A
2
-substituted cycloalkyl, aryl, substituted aryl, A
2
-aryl, A
2
-substituted aryl, heteroaryl, A
2
-heteroaryl, heterocycloalkyl, A
2
-heterocycloalkyl, aryl-A
3
-aryl, A
2
-aryl-A
3
-aryl, aryl-A
3
-cycloalkyl, A
2
-aryl-A
3
-cycloalkyl, aryl-A
3
-heteroaryl, A
2
-aryl-A
3
-heteroaryl, aryl-A
3
-heterocycloalkyl, A
2
-aryl-A
3
-heterocycloalkyl, aryl-A
3
-substituted aryl, A
2
-aryl-A
3
-substitued aryl, aryl-A
3
-substituted cycloalkyl, A
2
-aryl-A
3
-substituted cycloalkyl, cycloalkyl-A
3
-cycloalkyl, A
2
-cycloalkyl-A
3
-cycloalkyl, cycloalkyl-A
3
-aryl, A
2
-cycloalkyl-A
3
-aryl, cycloalkyl-A
3
-heteroaryl, A
2
-cycloalkyl-A
3
-heteroaryl, cycloalkyl-A
3
-heterocycloalkyl, A
2
-cycloalkyl-A
3
-heterocycloalkyl, cycloalkyl-A
3
-substituted cycloalkyl, A
2
-cycloalkyl-A
3
-substituted cycloalkyl, cycloalkyl-A
3
-substituted aryl, A
2
-cycloalkyl-A
3
-substituted aryl, substituted cycloalkyl-A
3
-cycloalkyl, A
2
-substituted cycloalkyl-A
3
-cycloalkyl, substituted cycloalkyl-A
3
-substituted cycloalkyl, A
2
-substituted cycloalkyl-A
3
-substituted cycloalkyl, substituted cycloalkyl-A
3
-aryl, A
2
-substituted cycloalkyl-A
3
-aryl, substituted cycloalkyl-A
3
-heteroaryl, A
2
-substituted cycloalkyl-A
3
-heteroaryl, substituted cycloalkyl-A
3
-heterocycloalkyl, A
2
-substituted cycloalkyl-A
3
-heterocycloalkyl, substituted cycloalkyl-A
3
-substituted aryl, A
2
-substituted cycloalkyl-A
3
-substituted aryl, heteroaryl-A
3
-heteroaryl, A
2
-heteroaryl-A
3
-heteroaryl, heteroaryl-A
3
-cycloalkyl, A
2
-heteroaryl-A
3
-cycloalkyl, heteroaryl-A
3
-substituted cycloalkyl, A
2
-heteroaryl-A
3
-substituted cycloalkyl, heteroaryl-A
3
-aryl, A
2
-heteroaryl-A
3
-aryl, heteroaryl-A
3
-heterocycloalkyl, A
2
-heteroaryl-A
3
-heterocycloalkyl, heteroaryl-A
3
-substituted aryl, A
2
-heteroaryl-A
3
-substituted aryl, heterocycloalkyl-A
3
-heterocycloalkyl, A
2
-heterocycloalkyl-A
3
-heterocycloalkyl, heterocycloalkyl-A

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