Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-08
2003-10-21
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S314000, C514S332000, C514S333000, C514S352000, C514S340000, C514S343000, C514S275000, C514S252030, C514S253010, C514S235500, C514S237200, C544S238000, C544S331000, C544S364000, C544S361000, C544S130000, C546S194000, C546S175000, C546S262000, C546S256000, C546S309000, C546S268100, C546S278400
Reexamination Certificate
active
06635657
ABSTRACT:
This invention relates to antithrombotic aromatic amides which demonstrate activity as inhibitors of factor Xa and, accordingly, which are useful anticoagulants in mammals. In particular it relates to aromatic amides having high anticoagulant activity, and antithrombotic activity. Thus, this invention relates to new amides which are inhibitors of factor Xa, pharmaceutical compositions containing the amides as active ingredients, and the use of the amides as anticoagulants for prophylaxis and treatment of thromboembolic disorders such as venous thrombosis, pulmonary embolism, arterial thrombosis, in particular myocardial ischemia, myocardial infarction and cerebral thrombosis, general hypercoagulable states and local hypercoagulable states, such as following angioplasty and coronary bypass operations, and generalized tissue injury as it relates to the inflammatory process. In addition, the antithrombotic agents are useful as anticoagulants in in vitro applications.
The process of blood coagulation, thrombosis, is triggered by a complex proteolytic cascade leading to the formation of thrombin. Thrombin proteolytically removes activation peptides from the A&agr;-chains and the B&bgr;-chains of fibrinogen, which is soluble in blood plasma, initiating insoluble fibrin formation. The formation of thrombin from prothrombin is catalyzed by factor Xa.
Anticoagulation currently is achieved by the administration of heparins and coumarins. Parenteral pharmacological control of coagulation and thrombosis is based on inhibition of thrombin through the use of heparins. Heparins act indirectly on thrombin by accelerating the inhibitory effect of endogenous antithrombin III (the main physiological inhibitor of thrombin). Because antithrombin III levels vary in plasma and because clot-bound thrombin seems resistant to this indirect mechanism, heparins can be an ineffective treatment. Because coagulation assays are believed to be associated with efficacy and with safety, heparin levels must be monitored with coagulation assays (particularly the activated partial thromboplastin time (APTT) assay). Coumarins impede the generation of thrombin by blocking the posttranslational gamma-carboxylation in the synthesis of prothrombin and other proteins of this type. Because of their mechanism of action, the effect of coumarins can only develop slowly, 6-24 hours after administration. Further, they are not selective anticoagulants. Coumarins also require monitoring with coagulation assays (particularly the prothrombin time (PT) assay).
Recently, interest has grown in small synthetic molecules which demonstrate potent direct inhibition of thrombin and factor Xa. See, Joseph P. Vacca (Annette M. Doherty Section Editor),
Annual Reports in Medicinal Chemistry
, (1998), 33, 81-90.
Although the heparins and coumarins are effective anticoagulants, there still exists a need for anticoagulants which act selectively on factor Xa or thrombin, and which, independent of antithrombin III, exert inhibitory action shortly after administration, preferably by an oral route, and do not interfere with lysis of blood clots, as required to maintain hemostasis.
The present invention is directed to the discovery that the amides of the present invention, as defined below, are potent inhibitors of factor Xa which may have high bioavailability following oral administration.
According to the invention there is provided a compound of formula I
(or a pharmaceutically acceptable salt thereof) wherein:
A
3
, A
4
, A
5
and A
6
, together with the two carbons to which they are attached, complete a substituted benzene in which A
3
is CR
3
, A
4
is CR
4
, A
5
is CR
5
, and A
6
is CR
6
wherein
R
3
is hydrogen, methyl, methoxy, fluoro, chloro or carboxy;
one of R
4
and R
5
is hydrogen, (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, R
f
O—, R
f
O
2
CCH
2
O—, HO(CH
2
)
a
— (in which a is 2, 3 or 4), R
f
O
2
C—, R
f
O
2
CCH
2
—, R
g
NH—, R
h
SO
2
—, hydroxymethyl, formyl, cyano, acetyl, 1-hydroxyethyl, 1-(hydroxyimino)ethyl, 1-(methoxyimino)ethyl, methylthio or R
f
O
2
C(CH
2
)
2
—;
the other of R
4
and R
5
is hydrogen; and
R
6
is hydrogen, methyl, fluoro, chloro or methoxy;
in which R
f
is hydrogen, (1-4C)alkyl or benzyl; R
g
is hydrogen or R
h
SO
2
—; and R
h
is (1-4C)alkyl or dimethylamino;
or each of R
3
, R
4
and R
6
is hydrogen; and R
5
is vinyl, 2-cyanovinyl, 2-({(1-2C)alkoxy}carbonyl)vinyl or R
a
in which R
a
is phenyl (which is unsubstituted or bears one or more substituents independently selected from halo, methyl, methoxy and hydroxy) or heteroaryl (which heteroaryl is a 5-membered aromatic ring which includes one to four heteroatoms selected from sulfur, oxygen and nitrogen or is a 6-membered aromatic ring which includes one to three nitrogen atoms, wherein the heteroaryl is attached at carbon and may bear one or more methyl substituents on carbon or nitrogen);
L
1
is —CO—NH— such that —L
1
—Q
1
is —CO—NH—Q
1
;
Q
1
is 2-pyridinyl (which bears a methyl, methoxy, methylthio, fluoro or chloro substituent at the 5-position), 3-pyridinyl (which bears a methyl, fluoro or chloro substituent at the 6-position), 2-pyrimidinyl (which may bear a methyl, fluoro or chloro substituent at the 5-position) or 3-pyridazinyl (which may bear a methyl, fluoro or chloro substituent at the 6-position);
R
2
is —L
2
—Q
2
in which —L
2
— is —NH—CO—, —NH—CO—X—, —NH—CO—O—X—, —NH—CO—NH—X—, —NH—CH
2
—, —NH—C(CH
3
)—, —N(CH
3
)—CH
2
— or —O—CH
2
—; and Q
2
is Q
2A
, Q
2B
, Q
2C
, Q
2D
, Q
2E
or Q
2F
wherein X is a single bond or methylene and the values of L
2
and Q
2
are together selected from —NH—CO—X—Q
2A
, —NH—CO—O—X—Q
2A
, —NH—CO—NH—X—Q
2A
, —NH—CH
2
—Q
2A
, —NH—C(CH
3
)H—Q
2A
, —N(CH
3
)—CH
2
—Q
2A
, —O—CH
2
—Q
2A
, —NH—CO—X—Q
2B
, —NH—CO—Q
2C
, —NH—CO—Q
2D
, —NH—CO—Q
2E
and —NH—CO—Q
2F
in which:
Q
2A
(showing the L
2
to which it is attached) is
in which
each of m and n independently is 0 or 1, or m is 2 and n is 1, and
R
2A
is hydrogen, t-butyl, methylsulfonyl, —CHR
y
R
z
, —CHR
w
R
x
, or 4-pyridinyl (which is unsubstituted or bears a substituent R
v
at the 2- or 3-position) wherein
R
v
is methyl, hydroxymethyl, {(1-2C)alkoxy}carbonyl; cyano, carbamoyl, thiocarbamoyl, or N-hydroxyamidino;
each of R
w
and R
x
independently is hydrogen or (1-3C)normal alkyl; or —CHR
w
R
x
is 2-indanyl or (showing the nitrogen to which it is attached) is
in which T is a single bond or methylene and U is methylene, ethylene, oxy, —S(O)
q
— (wherein q is 0, 1 or 2) or imino (which may bear a methyl substituent), or T is ethan-1,1-diyl and U is a single bond or methylene;
R
y
is hydrogen or methyl; and
R
z
is isopropyl, t-butyl, (3-6C)cycloalkyl, phenyl (which is unsubstituted or bears one or more substituents independently selected from halo, methyl, methoxy and hydroxy), 4-quinolinyl or heteroaryl (which heteroaryl is a 5-membered aromatic ring which includes one to four heteroatoms selected from sulfur, oxygen and nitrogen or is a 6-membered aromatic ring which includes one to three nitrogen atoms, wherein the heteroaryl is attached at carbon and may bear one or more methyl substituents on carbon or nitrogen);
or R
2A
is —L
b
—CH
2
—R
b
in which —L
b
— is a direct bond, —CH
2
—, —C(CH
3
)H— or —CH
2
—CH
2
—; and R
b
is carboxy, {(1-2C) alkoxy}carbonyl, cyano, carbamoyl or trifluoromethyl;
or R
2A
is —CO—R
c
in which R
c
is hydrogen, (1-3C)alkyl, {(1-2C)alkoxy}carbonyl-(CH
2
)
c
— (in which c is 1 or 2), phenyl (which is unsubstituted or bears one or more substituents independently selected from halo, methyl, methoxy and hydroxy), heteroaryl (which heteroaryl is a 5-membered aromatic ring which includes one to four heteroatoms selected from sulfur, oxygen and nitrogen or is a 6-membered aromatic ring which includes one to three nitrogen atoms, wherein the heteroaryl is attached at carbon and may bear one or more methyl substituents on carbon or nitrogen) or —NR
d
R
e
in which each of R
d
and R
e
is independently hydrogen, methyl or ethyl, or —NR
d
R
e
is pyrrolidino, pi
Beight Douglas Wade
Craft Trelia Joyce
Denny Carl Penman
Franciskovich Jeffry Bernard
Goodson Theodore
Eli Lilly and Company
Huang Evelyn Mei
Jackson Thomas E.
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