Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-02
2001-10-02
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S212080, C540S524000, C540S527000
Reexamination Certificate
active
06297233
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to lactam inhibitors of the enzyme Factor Xa which are useful as anticoagulants in the treatment of cardiovascular diseases associated with thromboses.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, novel lactam derivatives are provided which are inhibitors of the enzyme Factor Xa and have the structure I
including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrugs thereof, wherein
n is an integer from 1 to 5;
Y is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, cycloalkyl, heteroaryl, cycloheteroalkyl, cyano, nitro, hydroxy, amino, —ORa, —SRa,
R
1
, R
2
, R
4
, R
6
, R
8
, and R
9
are the same or different and are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl cycloheteroalkyl, cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, substituted alkylcarbonyl, cycloheteroalkylcarbonyl and heteroarylcarbonyl;
R
3
is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, cyano, nitro, hydroxy, —ORa, —SRa,
R
5
, R
5a
, and R
7
are the same or different and are independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroaryl, cycloalkyl, aryl, cycloheteroalkyl,
R
10
is selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloalkylcarbonyl, substituted alkyl-carbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl,
or when R
9
is hydrogen and R
8
and R
10
are on adjacent carbons they join to complete a cycloalkyl or phenyl ring;
R
a
and R
b
are the same or different and are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, substituted alkyl-carbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl;
R
c
is hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, cycloheteroaryl,
and wherein R
1
and R
2
, and/or R
3
and R
4
and/or R
a
and R
b
can be taken together with the nitrogen to which they are attached, i.e.
to form a cycloheteroalkyl ring or a heteroaryl ring;
R
3
and Y can be taken together to form a heteroaryl ring;
R
3
or R
4
or Y can form a ring with R
6
which can be a cycloheteroalkyl or a heteroaryl ring;
R
5
and R
5a
can be taken together to the carbon to which they are attached to form a cycloalkyl ring, a heteroaryl ring or a cycloheteroalkyl ring; and
where one or more of R
3
R
4
or R
6
are H, then double bond isomers are possible which are included in the present invention.
In addition, in accordance with the present invention, a method for preventing, inhibiting or treating cardiovascular diseases associated with thromboses is provided, wherein a compound of formula I is administered in a therapeutically effective amount which inhibits Factor Xa.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
The term “alkyl” or “alk” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons containing 1 to 20 carbons, preferably 1 to 12 carbons, more preferably 1 to 8 carbons in the normal chain. Examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the various additional branched chain isomers thereof. The term “lower alkyl” includes both straight and branched chain hydrocarbons containing 1 to 4 carbons.
The term “alkenyl” as employed herein alone or as part of another group includes both straight and branched hydrocarbons having one or more double bonds, preferably one or two, and being of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain. Examples include
The term “alkynyl” as employed herein alone or as part of another group includes both straight and branched hydrocarbons having one or more triple bonds, preferably one or two, and being of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain. Examples include
The terms “substituted alkyl”, “substituted lower alkyl”, “substituted alkenyl” and “substituted alkynyl” refer to such groups as defined above having one, two, or three substituents selected from halo, alkoxy, haloalkoxy, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, arylcycloalkyl, aryloxy, arylalkoxy, heteroaryloxo, hydroxy, —N
3
, nitro, cyano, (R
20
)(R
21
)N—, carboxy, thio, alkylthio, arylthio, arylalkylthio, heteroarylthio, alkyl-C(O)—, alkoxycarbonyl, (R
20
)(R
21
)N—C(O)—, arylcarbonyloxy, alkyl-C(O)—NH—, alkyl-C(O)—N(alkyl)—, aryl-C(O)—NH—, aryl-C(O)—N(alkyl)—, aryl-C(O)—, arylalkoxycarbonyl, alkoxycarbonyl-NH—, alkoxycarbonyl-N(alkyl)—, cycloalkyl-C(O)—, cycloheteroalkyl-C(O)—, heteroaryl-C(O)—, cycloalkyl-C(O)—NH—, cycloalkyl-C(O)—N(alkyl), cycloheteroalkyl-C(O)—NH—, cycloheteroalkyl-C(O)—N(alkyl)—, heteroaryl-C(O)—NH—, heteroaryl-C(O)—N(alkyl)—, arylsulfinyl, alkylsulfinyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl, heteroarylsulfinyl, arylsulfonyl, alkylsulfonyl, cycloalkylsulfinyl, cycloheteroalkylsulfinyl, heteroarylsulfinyl, (R
20
)(R
21
)N-sulfinyl, (R
20
) (R
21
) N-sulfonyl, alkyl-SO
2
—NH—, alkyl-SO
2
-N(alkyl)—, aryl-SO
2
—NH—, aryl-SO
2
—N(alkyl)—, cycloalkyl-SO
2
—NH—, cycloalkyl-SO
2
-N(alkyl)—, cycloheteroalkyl-SO
2
—NH—, cycloheteroalkyl-SO
2
—N(alkyl)—, heteroaryl-SO
2
—NH—, heteroaryl-SO
2
—N(alkyl)—, (R
20
) (R
21
)N—C(O)—NH—, (R
20
) (R
21
)N—C(O)—N(alkyl)—, hydroxy-NH—C(O)—, hydroxy-N(alkyl)—C(O)—,
The term “halo” refers to chloro, bromo, fluoro and iodo.
The term “cycloalkyl” as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds and/or 1 or 2 triple bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 4 to 12 carbons forming the rings. Also included within the definition of “cycloalkyl” are such rings fused to an aryl, cycloheteroalkyl, or heteroaryl ring and bridged multicyclic rings containing 5 to 20 carbons, preferably 6 to 12 carbons, and 1 or 2 bridges. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, cyclopentynyl, cyclohexynyl, cycloheptynyl, cyclooctynyl, etc. Also included within the definition of “cycloalkyl” are such groups having one, two or three substituents selected from alkyl, substituted alkyl, halo, hydroxy, (R
20
) (R
21
) N—, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylthio, heteroaryl and cycloheteroalkyl.
The term “aryl” as employed herein alone or as part of another group refers to phenyl, 1-naphthyl, and 2-naphthyl as well as such rings fused to a cycloalkyl, aryl, cycloheteroalkyl, or heteroaryl ring. Examples include
The term “aryl” also includes such ring systems wherein the phenyl, 1-naphthyl, or 2-naphthyl has one two, or three substitutents selected from halo, hydroxy, alkyl, alkenyl, alkoxy, haloalkoxy, carboxy, cyano, nitro, substituted alkyl, substituted alkenyl, alkylcarbonyl, (substituted alkyl) —C(O)—, aryloxy, arylalkoxy, arylthio, arylalkylthio, cycloheteroalkyl, heteroaryl, —N(R
20
) (R
21
), alkyl-SO
2
—, (substituted
Bisacchi Gregory S.
Li Chi
O'Connor Stephen P.
Shi Yan
Stein Philip D.
Bristol--Myers Squibb Company
Kifle Bruck
Rodney Burton
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