Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-08
2004-02-10
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C546S193000, C514S318000, C514S275000, C514S255050, C514S255060, C544S238000, C544S331000, C544S405000
Reexamination Certificate
active
06689780
ABSTRACT:
This invention relates to antithrombotic heteroaromatic amides which demonstrate activity as inhibitors of factor Xa and, accordingly, which are useful anticoagulants in mammals. In particular it relates to heteroaromatic 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 heteroaromatic amides 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 heteroaromatic ring in which
(a) one of A
3
, A
4
, A
5
and A
6
is N, and each of the others is CR
3
, CR
4
, CR
5
or CR
6
, respectively; or
(b) two non-adjacent residues of A
3
, A
4
, A
5
and A
6
are each N, and each of the others is CR
3
, CR
4
, CR
5
or CR
6
, respectively; wherein
each of R
3
, R
4
, R
5
and R
6
is independently hydrogen or methyl, or one of R
3
, R
4
, R
5
and R
6
attached to a carbon which is not bonded to an N-atom is chloro and the others are hydrogen;
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), 3-pyridazinyl (which may bear a methyl, fluoro or chloro substituent at the 6-position) or 2-benzothiazolyl (which may bear a methyl, fluoro, chloro or bromo 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— or —NH—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—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, 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);
Q
2B
is 1-piperazinyl which bears at the 4-position the group R
2A
(defined as above);
Q
2C
is 3,4-didehydropiperidin-4-yl which bears at the 1-position the group R
2A
(defined as above);
Q
2D
is cyclohexyl which bears at the 4-position the group —NR
s
R
t
in which each of R
s
and R
t
independently is hydrogen or methyl or R
s
and R
t
together are trimethylene or tetramethylene;
Q
2E
is 1-piperidinyl which bears at the 4-position the group —NR
s
R
t
(defined as above); and
Q
2F
(showing the L
2
to which it is attached) is
in which R
o
is hydrogen, halo, (1-6C)alkyl, hydroxy, (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, oxy, —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.
As used herein, the expression a compound of formula I or the expression a compound of the invention includes the compound and any conventional prodrug thereof, as well as a pharmaceutically acceptable salt of said compound or prodrug.
A pharmaceutically acceptable salt of an antithrombotic agent of the instant invention includes one which is an acid-addition salt made from a basic compound of formula I and an acid which provides a pharmaceutically acceptable anion, as well as a salt which is made from an acidic compound of formula I and a base which provides a pharmaceutically acceptable cation. Thus, a salt of a novel compound of formula I as provided herein made with an acid or base which affords a pharmaceutically acceptable counterion provides a particular
Beight Douglas Wade
Craft Trelia Joyce
Franciskovich Jeffry Bernard
Goodson Jr. Theodore
Hall Steven Edward
Eli Lilly and Company
Jackson Thomas E.
Liu Hong
Shah Mukund J.
LandOfFree
Heteroroaromatic amides as inhibitor of factor Xa does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Heteroroaromatic amides as inhibitor of factor Xa, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Heteroroaromatic amides as inhibitor of factor Xa will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3329778