Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-21
2003-08-12
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...
C514S330000, C514S318000, C514S327000, C514S326000, C514S417000, C514S411000, C514S357000, C514S370000, C514S237500, C514S343000, C514S443000, C514S469000, C514S616000, C514S603000, C514S465000, C546S308000, C546S194000, C546S221000, C546S234000, C546S213000, C546S214000, C546S209000, C548S473000, C548S450000, C548S451000, C548S332100, C548S195000, C548S194000, C544S165000, C549S439000, C549S058000, C549S467000, C564S155000, C564S157000, C564S086000
Reexamination Certificate
active
06605626
ABSTRACT:
This invention relates to antithrombotic aromatic compounds which demonstrate activity as inhibitors of factor Xa and, accordingly, which are useful anticoagulants in mammals. In particular it relates to aromatic compounds having high anticoagulant activity, and antithrombotic activity. Thus, this invention relates to new inhibitors of factor Xa, pharmaceutical compositions containing the compounds as active ingredients, and the use of the compounds 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, Jeremy J. Edmunds and Stephen T. Rapundalo (Annette M. Doherty Section Editor),
Annual Reports in Medicinal Chemistry
, (1996), 31, 51-60.
Although the heparins and coumarins are effective anticoagulants, no commercial drug has yet emerged from the small synthetic molecules; and despite the continuing promise for this class of compounds, 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 compounds 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 method of inhibiting factor Xa comprising using an effective amount of a factor Xa inhibiting compound of formula I
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, hydroxy, [(1-2C)alkyl]carbonyloxy (which may bear an &ohgr;-carboxy substituent), benzoyloxy (which may bear one or more halo, hydroxy, methoxy or methyl substituents), methyl or methoxy;
one of R
4
and R
5
is hydrogen, methyl, halo, trifluoromethyl, nitro, amino(imino)methyl, amino(hydroxyimino)-methyl, R
f
O—, R
f
O
2
C—, R
f
O
2
C—CH
2
—, R
f
O
2
C—CH
2
—O—, 3-methoxycarbonyl-1-oxopropyl, R
g
NH— or bis(methylsulfonyl)amino;
the other of R
4
and R
5
is hydrogen, halo or methyl; and
R
6
is hydrogen, fluoro, hydroxy, [(1-2C)alkyl]-carbonyloxy (which may bear an &ohgr;-carboxy substituent), benzoyloxy (which may bear one or more halo, hydroxy, methoxy or methyl substituents), methyl or methoxy;
in which R
f
is hydrogen, (1-4C)alkyl or benzyl; R
g
is hydrogen, [(1-4C)alkyl]carbonyl, acetyl, trifluoroacetyl, methoxyacetyl, dimethylaminoacetyl, phenylalanyl, 2-(t-butoxycarbonylamino)-4-methylsulfinyl-1-oxobutyl, 3-[[(1-2C)alkoxy]carbonyl]-1-oxopropyl or R
h
SO
h
— (wherein h is 1 or 2); and R
h
is (1-4C)alkyl, trifluoromethyl, phenyl, 3,5-dimethylisoxazol-4-yl or dimethylamino; or
two adjacent residues selected from R
3
, R
4
, R
5
and R
6
together form a benz ring; and the other two are each hydrogen;
L
1
is —NH—CO—, —O—CO— or —CO—NH— such that —L
1
—Q
1
is —NH—CO—Q
1
, —O—CO—Q
1
or —CO—NH—Q
1
;
Q
1
is phenyl, 2-furanyl, 2-thienyl, 4-thiazolyl, 2-pyridyl, 2-naphthyl, 1,2-dihydrobenzofuran-5-yl, 1,2-dihydrobenzofuran-6-yl or 1,2-benzisoxazol-6-yl in which the phenyl may bear one, two or three substituents at the 3-, 4- or 5-position(s) independently selected from halo, cyano, carbamoyl, aminomethyl, methyl, methoxy, difluoromethoxy, hydroxymethyl, formyl, vinyl, amino, hydroxy and 3,4-methylenedioxy, and in addition the phenyl may bear a 2-chloro or 2-fluoro substituent, the 2-furanyl or 2-thienyl may bear a chloro or methyl substituent at the 5-position, the 4-thiazolyl may bear an amino substituent at the 2-position, the 2-pyridyl may bear an amino substituent at the 6-position, and the 1,2-benzisoxazol-6-yl may bear a chloro or methyl substituent at the 3-position; or —CO—Q
1
is cyclopentenylcarbonyl or cyclohexenylcarbonyl;
R
2
is —L
2A
—Q
2A
, —L
2B
—Q
2B
, —L
2C
—Q
2C
, —L
2D
—Q
2D
or —L
2E
—Q
2E
wherein
L
2A
is a direct bond; and
Q
2A
is
in which D is carbonyl or —CHR
k
— in which R
k
is hydrogen, hydroxy, (1-6C)alkoxy, or —CH
2
—R
j
in which R
j
is carboxy, [(1-4C)alkoxy]carbonyl or carbamoyl which may bear one or two (1-2C)alkyl substituents on the nitrogen; and one of R
m
and R
n
is hydrogen and the other is amino, bromo, (1-4C)alkyl or (1-4C)alkoxy, or R
m
and R
n
together form a benz ring;
L
2B
is —NH—CO—, —O—CO—, —CH
2
—O— or —O—CH
2
— such that —L
2B
—Q
2B
is —NH—CO—Q
2B
, —O—CO—Q
2B
, —CH
2
—O—Q
2B
or —O—CH
2
—Q
2B
; and
Q
2B
is
in which R
o
is hydrogen, halo, (1-6C)alkyl, (1-4C)alkoxy, benzyloxy or (1-4C)alkylthio; and R
p
is 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, 4-piperidinyl, 4-pyridinyl, dimethylaminosulfonyl or —J—R
q
in which J is a single bond, methylene, carbonyl, oxo, —S(O)
q
— (wherein q is 0, 1 or 2), or —NR
r
— (wherein R
r
is hydrogen or methyl); and R
q
is (1-6C)alkyl, phenyl, 3-pyridyl or 4-pyridyl;
L
2C
is —NR
v
—CO—X—, —NR
v
—CS—Y—, —CH
2
—CO—NR
w
—CH
2
—, —O—CO—, —O—CH
2
—, —S—CH
2
— or —CH
2
—NR
x
—CH
2
— such that —L
2C
—Q
2C
is —NR
v
—CO—X—Q
2C
, —NR
v
—CS—Y—Q
2C
, —CH
2
—CO—NR
w
—CH
2
—Q
2C
, —O—CO—Q
2C
, —O—CH
2
—Q
2C
, —S—CH
2
—Q
2C
or —CH
2
—NR
x
—CH
2
—Q
2C
in which X is —(CH
2
)
x
— (wherein x is 0, 1 or 2), —NR
w
—, —NR
w
—CH
2
—, —O—, —O—CH
2
— or —S—CH
2
—; Y is —NR
w
—CH
2
— or —O—CH
2
—; each of R
v
and R
w
is independently hydrogen, benzyl or (1-6C)alkyl which is not branched at the &agr;-position; and R
x
is hydrogen, benzyloxycarbonyl or [(1-4C)alkoxy]carbonyl; and
Q
2C
is 1-(4-pyridyl)piperidin-4-yl, 1-(4-pyridyl)piperidin-3-yl or 1-(4-pyridyl)pyrrolidin-3-yl in which the pyridyl may bear a substituent at its 2-position selected from cyano, aminomethyl, carboxy, hydroxymethyl and (1-2C)alkyl;
L
2D
is —NH—CO— such that —L
2D
Beight Douglas Wade
Craft Trelia Joyce
Franciskovich Jeffry Bernard
Goodson Jr. Theodore
Hall Steven Edward
Eli Lilly and Company
Huang Evelyn Mei
Jackson Thomas E.
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