US 6,686,484 B2 · Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade

Abstract

The invention relates to polycyclic aryl and heteroaryl substituted 1,4-quinone compounds useful as inhibitors of serine proteases of the coagulation cascade and compounds, compositions and methods for anticoagulant therapy for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular diseases.

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Claims8

Dependent claims

A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein;
B is phenyl or a heteroaryl of 5 to 6 ring members, wherein (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachement is optionally substituted by R32, (b) a ring carbon is a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R36, (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R32, is optionally substituted by R33, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R36, is optionally substituted by R35, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an aplha position relative to each of the ring atoms optionally substituted by R33 and R35, respectively, is optionally substituted by R34,
R32, R33, R34, R35, and R36 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanisino, alkoxy, hydroxy, amino, alkoxyamino, alkulamino, alkulthio, amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyaloalkyl, carboalkoxy, carboxy, carboxamido, cyano, and Qb;
A id a bond or (CH(R15))pa wherein pa is an integer selected from 0 through 3,
R15 is selected from the group consisting of hydrido, halo, alkyl, and haloalkyl;
Xo is selected from the group consisting of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and halo;
R2 is Z0-Q;
Z0 is selected from the group consisting of a bond, CH2, CH2CH2, W0-(CH(R42))p wherein p is 0 to 1 and W0 is selected from the group consisting of O, S, and N(R41);
R41 and R42 are independently hydrido and alkyl;
Q id phenyl or a heteroaryl of 5 or 6 ring members, wherein (a) a ring carbon in a first alpha position relative to the ring carbon at the point of attachment is optionally substituted by R9, (b) a ring carbon in a second alpha position relative to the ring carbon at the point of attachment is optionally substituted by R13m (c) a ring carbon, in a first beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R9, is optionally substituted by R10, (d) a ring carbon, in a second beta position relative to the ring carbon at the point of attachment and in an alpha position relative to the ring atom optionally substituted by R13, is optionally substituted by R12, and (e) a ring carbon, if present, in the gamma position relative to the ring carbon at the point of attachment and in an alpha position relative to each of the ring atoms optionally substituted by R10 and R12, respectively, is optionally substituted by R11;
R9, R11, and R13 are independently selected from the group consisting of hydrido, hydroxy, amino, amidino, guanidino, alkylamino, alkylthio, alkylsulfonamido, alkylsulfiflyl, alkylsulfonyl, amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyhaloalkyl, carboxy, carboxamido, and cyano;
R10 and R12 are independently selected from the group consisting of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl, alkoxy, cycloalkoxy, cycloal kylalkoxy, aralkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, heterocyclylalkoxy, hydroxy, amino, alkoxyamino, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroaralkylamino, heterocyclylamino, heterocyclylalkylamino, alkylsulfonamido, amidosulfonyl, arylsulfinyl, aralkylsulfinyl, cycloalkylsulfinyl, heteroarylsulfinyl, arylsulfonyl, aralkylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl, hydroxyalkyl, hydroxyhaloalkyl, aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, halo, haloalkyl, and cyano;
Y0 is the formula
wherein J5, J6, D5, D6 and the ring carbon atoms to which they are attached define a phenyl or 5- or 6-membered heteroaryl ring, T, wherein one of J5 and J6 is absent when T is a 5-membered heteroaryl ring, J6 is optionally substituted by R17 when J5 is a carbon atom, J6 is optionally substituted by R18 when J5 is a carbon atom, D5 is optionally substituted by R16 when D5 is a carbon atom and D6 is optionally substituted by R19 when D6 is a carbon atom;
R16, R17, R18, and R19 are independently selected from the group consisting of hydrido, amidido, guanidino, carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
Qb is selected from the group consisting of NR20R21, hydrido, and C(NR25)NR23R24, with the proviso that no more than one of R20 and R21 is hydroxy and no more than one of R23 and R24 is hydroxy;
R20, R21, R23, R24, and R25 are independently selected from the group consisting of hydrido, alkyl, and hydroxy;
and QS is selected from the group consisting of a bond, CH2, and CH2CH2.

15 more elements

Dependencies are inferred from the claim text.

Description45,911 words

Summary39,889 words

#This invention is in the field of anticoagulant therapy, and specifically relates to compounds, compositions and methods for preventing and treating thrombotic conditions such as coronary artery and cerebrovascular disease. More particularly, the invention relates to polycyclic aryl and heteroaryl substituted 1,4-quinone compounds that inhibit serine proteases of the coagulation cascade.

#Physiological systems control the fluidity of blood in mammals [Majerus, P. W. et al: Anticoagulant, Thrombolytic, and Antiplatelet Drugs. In Hardman, J. G. and Limbird, L. E., editors: Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th edition. New York, McGraw-Hill Book Co., 1996, pp. 1341-1343]. Blood must remain fluid within the vascular systems and yet be able to undergo hemostasis, cessation of blood loss from a damaged vessel, quickly. Hemostasis or clotting begins when platelets first adhere to macromolecules in subendothelian regions of an injured and/or damaged vessels. These platelets aggregate to form the primary hemostatic plug and stimulate local activation of plasma coagulation factors leading to generation of a fibrin clot that reinforces the aggregated platelets.

#Plasma coagulation factors include factors II, V, VII, VIII, IX, X, XI, and XII; these are also called protease zymogens. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called “coagulation cascade” or chain reaction [Handin, R. I.: Bleeding and Thrombosis. In Wilson, J., et al. editors: Harrison's Principles of Internal Medicine. 12th Edition, New York, McGraw-Hill Book Co., 1991, p.350]. Coagulation or clotting occurs in two ways through different pathways. An intrinsic or contact pathway leads from XII to XIIa to XIa to IXa and to the conversion of X to Xa. Xa with factor Va converts prothrombin (II) to thrombin (IIa) leading to conversion of fibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot. An extrinsic pathway is initiated by the conversion of coagulation factor VII to VIIa by Xa. The presence of Tissue Factor and VIIa accelerates formation of Xa in the presence of calcium ion and phospholipids. Formation of Xa leads to thrombin, fibrin, and a fibrin clot as described above. The presence of one or more of these many different coagulation factors and two distinct pathways of clotting could enable the efficacious, selective control and better understanding of parts of the coagulation or clotting process.

Detailed description6,022 words

#The 1,4-quinone compounds of the present invention can be synthesized, for example, according to the following procedures and Schemes given below.

#Schemes 1, 2, 3, 4, 5, and 6 above summarize generic procedures that permit the preparation of a wide variety of the compounds of the present invention through the ability to introduce numerous R2 substituents represented by Zo-Q wherein Zo is a single bond, a wide variety of amino substituting groups represented by B—, B—CH2, B—CO, and B—SO2, and a large number of amide forming Y groups at the carboxylic acid group in which Eo is C(O)NH. Examples 1, 2, and 3 below shows the preparation of a compound wherein Xo is hydrido although other substituents can be present at this position.

#Triethylamine (3.46 mL, 24.8 mmol) was added to a solution of the appropriate phenol (5.0 g, 20.7 mmol) and triflic anhydride (4.1 mL, 24.8 mmol) in dichloromethane at −10° C. After stirring at room temperature for 3 hours, the solution was acidified with 2N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and filtered. The solvent was removed by evaporation to afford the crude product. The product was purified by column chromatography (15% ethyl acetatehexane) to afford 5.53 g (72%) of a clear oil of product EX-1A; 1H NMR ppm: 3.78 (s, 3H), 3.87 (d, 2H), 3.96 (s, 3H), 7.27 (d, 1H, J=9.2 Hz), 7.95 (d, 1H, J=9.2 Hz); 19F NMR ppm: −73.89 (s, 3F); HPLC purity (retention time): >99% (3.62 min); HRMS calcd for C11H10O8N1F3 (M++NH4) 391.0423, found 391.0396.

Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade

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Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade

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Abstract

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Claims8

Description45,911 words

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Description45,911 words

Classification17 codes

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