Antithrombotic diamines

Details Antithrombotic diamines Antithrombotic diamines

1999-08-05

2001-07-24

Huang, Evelyn Mei (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C540S602000, C540S597000, C540S596000, C544S058100, C544S146000, C544S153000, C548S243000, C548S518000, C548S523000, C546S202000, C546S194000, C549S052000, C549S058000

Reexamination Certificate

active

06265575

ABSTRACT:

This invention relates to thrombin inhibitors which are useful anticoagulants in mammals. In particular it relates to diamine derivatives having high anticoagulant activity, and antithrombotic activity. Thus, this invention relates to new inhibitors of thrombin, 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 diamine derivatives 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.
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. See, for example Robert M. Scarborough,
Annual Reports in Medicinal Chemistry,
(1995), 30, 71-80.
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 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 thrombin inhibitors that may have high bioavailability following oral administration.
According to the invention there is provided a method of inhibiting thrombin comprising using an effective amount of a thrombin inhibiting compound of formula I (or a pharmaceutically acceptable salt thereof)
wherein
A is O, S, —CH═CH— or —CH
2
—CH
2
—;
A
2
is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6-relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-)relationship and which divalent radical may bear a hydroxymethyl, benzyloxymethyl, (1-3C)alkyl, (1-2C)alkoxy, hydroxy or halo substituent;
A
3
is an aromatic or heteroaromatic divalent radical selected from para-phenylene, a 6-membered ring heteroaromatic divalent radical containing 1 or 2 ring nitrogens in which the valences are in the 1,4- or 2,5- or 3,6-relationship, and a 5-membered ring heteroaromatic divalent radical containing one oxygen or sulfur ring atom and 0, 1 or 2 ring nitrogens in which the valences are in the 2,5- (or 3,5-)relationship and which divalent radical may bear one or two substituents independently selected from dimethylamino, (1-4C)alkyl, halo, trifluoromethyl, (1-2C)alkoxy, hydroxy, cyano, aminomethyl, nitro, —NHCH
2
R
f
, —NHC(O)R
f
or —NHS(O)
2
R
g
in which R
f
is hydrogen or (1-2C)alkyl and R
g
is (1-2C)alkyl or phenyl;
R
1
denotes 0, 1 or 2 substituents on the benz-ring independently selected from halo, methyl, ethyl, hydroxy, methoxy, carbamoyl, aminomethyl and hydroxymethyl;
X
1
is O, S, methylene, carbonyl or ethene-1,1-diyl;
(a) X
2
is imino, a direct bond, methylene, O or S; j is 0; k is 0; m is 5, 1, 2, 3 or 4; provided that when m is 1, then X
2
is a direct bond; and R
a
and R
b
are independently hydrogen or (1-3C)alkyl or the group NR
a
R
b
is 1-imidazolyl, 1-pyrazolyl, N-(1,2,4-triazolyl), neopentylamino, (cyclohexylmethyl)amino, benzylamino, (3-pyridylmethyl)amino, (2,3-dihydroxypropyl)amino, (1-iminoethyl)amino, 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, 2-methyl-1-piperidinyl, morpholino or hexamethyleneimino; or
(b) X
2
is imino, O or S; j is 1; k is 1; m is 1; R
2
is hydroxy; and R
a
and R
b
are independently hydrogen or (1-3C)alkyl or the group NR
a
R
b
is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or
(c) X
2
is imino, O or S; j is 1; k is 1; m is 0; R
2
is methyl, carboxy, hydroxymethyl or methoxycarbonyl; and R
a
and R
b
are independently hydrogen or (1-3C)alkyl; or
(d) X
2
is imino, O or S; j is 0, 1, 2 or 3; k is 1; m is 0 or 1; provided that j and m are not both 0; R
2
and R
a
together form a diradical —(CH
2
)
n
— in which n is 2, 3 or 4 and the sum of m and n is 3 or 4; and R
b
is hydrogen or (1-3C)alkyl; or
(e) X
2
is —NH—C(O)—; j is 0; k is 0; m is 1; and R
a
and R
b
are independently hydrogen or (1-3C)alkyl or the group NR
a
R
b
is 1,1-dioxothiomorpholin-4-yl, pyrrolidino, piperidino, morpholino or hexamethyleneimino; and
(1) X
3
is a direct bond, methylene, imino, O or S; q is 0, 1 or 2; and r is 0 or 1; provided that q and r are not both zero, and provided that when q is 1 and r is 0, then X
3
is a direct bond; each R
3
is hydrogen or the two R
3
groups together form a divalent radical —(CH
2
)
s
— in which s is 3 or 4; or q and r are each 1 and the group —(CHR
3
—CHR
3
)— is propane-2,2-diyl; and R
c
and R
d
are independently hydrogen or (1-4C)alkyl or the group NR
c
R
d
is 1-pyrazolyl, 2-(hydroxymethyl)-1-pyrrolidinyl, 2-(methoxymethyl)-1-pyrrolidinyl, pyrrolidino, piperidino, morpholino, hexamethyleneimino, 1-imidazolyl or 4,5-dihydro-1-imidazolyl; or
(2) X
3
is imino, O or S; q is 0; r is 1; one R
3
group is (1-5C)alkyl and the other R
3
group is independently hydrogen or (1-5C)alkyl; and R
c
and R
d
are independently hydrogen or (1-3C)alkyl or the group NR
c
R
d
is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or
(3) X
3
is imino, O or S; q is 0, 1 or 2; r is 1; one R
3
group is hydrogen and the other R
3
group together with the group R
c
forms a divalent radical —(CH
2
)
t
— in which t is 2, 3 or 4 such that the resulting ring is a pyrrolidine or piperidine; and R
d
is hydrogen or (1-3C)alkyl; or
(4) X
3
is —N(R
h
)—; q is 0; r is 1; the R
3
group on the carbon bonded to X
3
and the group R
h
together form a diradical —(CH
2
)
3
—; the other R
3
group is hydrogen; and R
c
and R
d
are independently (1-3C)alkyl or the group NR
c
R
d
is pyrrolidino, piperidino, morpholino or hexamethyleneimino; or
(5) X
3
is ethene-1,2-diyl or ethyne-1,2-diyl; q is 1; r is 0; and R
c
and R
d
are independen

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