In one aspect, this invention discloses quinoxalinones which display inhibitory effects on serine proteases such as factor Xa, thrombin and/or factor VIIa. The invention also discloses pharmaceutically acceptable salts and prodrugs of the compounds, pharmaceutically acceptable compositions comprising the compounds, their salts or prodrugs, and methods of using them as therapeutic agents for treating or preventing disease states in mammals characterized by abnormal thrombosis.
In economically developed countries, cardiovascular disease still represents a major cause of mortality. In particular, abnormal coagulation and inappropriate thrombus formation within blood vessels precipitates many acute cardiovascular disease states. While it has long been recognized that a variety of plasma proteins such as fibrinogen, serine proteases, and cellular receptors are involved in hemostasis, it is the abnormal regulation that has emerged as important contributing factors to cardiovascular disease. Thrombin can be considered the key or principal regulatory enzyme in the coagulation cascade; it serves a pluralistic role as both a positive and negative feedback regulator in normal hemostasis. However, in some pathologic conditions, the former is amplified through catalytic activation of cofactors required for thrombin generation such as factor Xa. Factor Xa, as part of the prothrombinase complex composed of non-enzymatic cofactor Va, calcium ions, and a phospholipid membrane surface regulates the generation of thrombin from its zymogen prothrombin. Furthermore, the location of the prothrombinase complex at the convergence of both the intrinsic and extrinsic coagulation pathways suggests that inhibition of factor Xa, and hence thrombin generation, may be a viable approach to limiting the procoagulant activity of thrombin.
Indeed, ample evidence exists for the role of factor Xa inhibitors as anticoagulants. Antistasin, a potent inhibitor of blood coagulation factor Xa from the Mexican leech: Haementeria officinalis, displays antithrombotic activity in various models of arterial and venous thrombosis (Lapatto et al., Embo. J., 1997:5151-5161). Other protein or polypeptide factor Xa inhibitors include recombinant tick anticoagulant peptide (rTAP), which is known to accelerate the recombinant tissue plasminogen activator mediated clot lysis and prevent acute reocclusion in the dog, hence indicating factor Xa inhibitors may be useful as an adjunct to thrombolytic therapy (Mellott et al., Fibrinolysis, 1993:195-202). Furthermore, in a canine coronary artery electrolytic lesion model, rTAP was demonstrated to reduce thrombus mass and time to occlusion in the absence of dramatic hemodynamic or hemostatic changes indicating the primary role for factor Xa in the process of arterial thrombosis (Lynch et al., Thromb. Haemostasis, 1995:640-645; Schaffer et al., Circulation, 1991:1741-1748). On the venous side, rTAP was also demonstrated to reduce fibrin deposition in a rabbit model of venous thrombosis while having little affect on systemic hemostatic parameters (Fioravanti et al., Thromb. Res., 1993:317-324). In addition to these relatively high molecular weight proteins that are not suitable as oral antithrombotic agents, there also exist examples of low molecular weight factor Xa inhibitors. In particular DX9065a, a low molecular weight synthetic factor Xa inhibitor, has also shown antithrombotic potential in various experimental thrombosis rat models. In both arteriovenous shunt and venous stasis models, inhibition of thrombus formation was achieved at doses that had little effect on APTT, indicating that DX9065a is effective in preventing thrombosis and hence has therapeutic antithrombotic potential (Wong et al., Thromb. Res., 1996:117-126).
The majority of factor Xa inhibitors known to date have been previously summarized in two reviews (Edmunds et al., Annual Reports in Medicinal Chemistry, 1996:51 and Kunitada and Nagahara, Curr. Pharm. Des., 1996:531-542). However, it is readily apparent that there still exists a need for more effective agents that regulate factor Xa proteolytic activity.
Some quinoxalinones have been reported, and these compounds have displayed marked pharmacological activity: Japanese Application: JP 88-99097 880421; Japanese Application: JP 89-254348 890929; CAN 116: 83686; World Publication 9707116; Otomasu et al., Yakugaku Zasshi, 1970;90(11):1391-1395; Seth M et al., Indian J. Chem., 1974;12(2):124-1288; Japanese Patent 63145272; Sparatore et al., Farmaco, 1989;44(10):945-950; and F. Hahn et al., Arch. Int. Pharmacodyn. Ther., 1992:108.
None of the above articles set forth above disclose or suggest compounds of Formula I that are inhibitors of serine proteases involved in the blood coagulation cascade.
One object of the present invention is to provide serine protease inhibitors that display inhibitory activity towards enzymes involved in the coagulation cascade and principally the target enzymes, factor Xa, thrombin, and factor VIIa.
A further object of the present invention is to provide serine protease inhibitors that display inhibitory activity towards the target enzyme factor Xa and are provided for in a pharmacologically acceptable state.
Still, a further object of the present invention is to provide for the use of these factor Xa inhibitors and formulations thereof as anticoagulant and factor Xa inhibitory agents.
Yet, a further object of the present invention is to provide for the use of these factor Xa inhibitors and formulations thereof for therapeutic treatment of various thrombotic maladies.
A further object of the present invention is a process for the synthesis of these low molecular weight thrombin inhibitors. The enzyme inhibitors of the present invention are encompassed by the structure of general Formula I set forth below.
The present invention meets these objectives and provides for novel compounds that display antithrombotic activity. More specifically, the present invention provides for novel compounds that display antithrombotic activity via the inhibition of factor Xa as reflected in Formula I, or pharmaceutically acceptable salts or prodrug forms thereof. The present invention also provides pharmaceutically acceptable compositions comprising the novel compounds or their salts or prodrug forms, and methods of using them as therapeutic agents for treating or preventing disease states in mammals characterized by abnormal thrombosis.
Thus in a first embodiment, the present invention provides novel compounds of Formula I: 
or stereoisomers or pharmaceutically acceptable salts, esters, amides or prodrugs thereof, wherein:
A is selected from N, Nalkyl, NCH2, N(alkyl)CH2, CH2N, CH2N(alkyl), NO;
B is selected from H, (C3-20)alkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, each optionally substituted with R1 and R2;
D is selected from H, (C3-20)alkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heteroalkylalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, each optionally substituted with R1 and R2;
E is absent or selected from O, S, NH;
F is selected from N, NCH2, CH2N;
G is absent or selected from alkyl, alkyl interrupted by one or more heteroatoms, cycloalkyl, cycloalkyl interrupted by one or more heteroatoms;
J is absent or selected from aryl or heterocycle each optionally substituted with R1 and R2;
K is absent or selected from an alkyl, alkyl interrupted by one or more heteroatoms, cycloalkyl interrupted by one or more heteroatoms, cycloalkylalkyl interrupted by one or more heteroatoms, each optionally substituted with R1 and R2;
L is selected from H, chlorine, fluorine, bromine, iodine, OH, O(alkyl), amine, alkyl, fluoroalkyl, amide, NO2, SH, S(O)n(alkyl), SO3H, SO3alkyl, aldehyde, ketone, acid, ester, urea, Oalkylamide, Oalkylester, Oalkylacid, Nalkylacid, alkylamine, alkylamide, alkylketone, alkylacid, alkylester, alkylurea, Nalkylamide, Nalkylester, NC(xe2x95x90O)alkyl, NC(xe2x95x90O)aryl, nitrile, NC(xe2x95x90O)cycloalkyl, NC(xe2x95x90O)cycloalkylalkyl, NC(xe2x95x90O) alkylaryl, R1, R2;
R1 is selected from H, amine, alkylamine, amide, C(xe2x95x90NH)NHNH2, alkylC(xe2x95x90NH)NHNH2, C(xe2x95x90NH)NHOH, alkylC(xe2x95x90NH)NHOH, NHC(xe2x95x90NH)NH2, alkylNHC(xe2x95x90NH)NH2, C(xe2x95x90S)NH2, alkylC(xe2x95x90S)NH2, C(xe2x95x90NH)alkyl, alkylC(xe2x95x90NH)alkyl, C(xe2x95x90NR3)N(R4)(R5), alkylC(xe2x95x90NR3)N(R4)(R5);
R2 is selected from H, chlorine, fluorine, bromine, iodine, OH, Oalkyl, amine, alkylaldehyde, alkylamide, alkylester, alkylketone, alkylacid, Oalkylamide, Oalkylacid, Oalkylester, aninealkylacid, aminealkylamide, aminealkylester, NC(xe2x95x90O)alkyl, NC(xe2x95x90O)aryl, NC(xe2x95x90O)cycloalkyl, NC(xe2x95x90O)alkylaryl, alkylamine, amide, aldehyde, ester, ketone, NO, SH, S(O)n(C1-10alkyl), SO3H, SO3alkyl, CHO, acid, alkyl, C(xe2x95x90NH)alkyl, C(xe2x95x90NH)NHNH2, alkylC(xe2x95x90NH)NHNH2, C(xe2x95x90NH)NHOH, alkylC(xe2x95x90NH)NHOH, NHC(xe2x95x90NH)NH2, alkylNHC(xe2x95x90NH)NH2, C(xe2x95x90S)NH2, alkylC(xe2x95x90S)NH2, alkylC(xe2x95x90NH)alkyl, C(xe2x95x90NR3)N(R4)(R5), alkylC(xe2x95x90NR3)N(R4)(R5);
R3, R4, and R5 are a hydrogen atom, alkyl group having 1 to 4 carbon atoms optionally interrupted by a heteroatom, or R4 and R5 are bonded to form xe2x80x94(CH2)pxe2x80x94Wxe2x80x94(CH2)qxe2x80x94, wherein p and q are an integer of 2 or 3, a certain position on the methylene chain is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms, W is a direct bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R6)xe2x80x94, or xe2x80x94S(O)rxe2x80x94 wherein R6 is H or alkyl, and r is 0 or 1 or 2;
n is selected from 0, 1, 2;
X1 is C or N;
X2 is C or N;
X3 is C or N;
X4 is C or N; and
represents an optional additional bond when A is N.
Preferred compounds according to this invention have the Formula II: 
or stereoisomers or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein A, B, E, G, J, K, and L are as defined above.
Another preferred group of compounds have the Formula III: 
or stereoisomers or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein A is N or Nalkyl, and B, G, J, K, L, and - - - are as defined above.
Even more preferred compounds have the Formula IV: 
or stereoisomers or pharmaceutically acceptable salts, esters, amides, or prodruqs thereof, wherein G, J, K, L, R1, and - - - are as defined above.
The most preferred compounds provided by this invention are compounds of Formula V: 
or stereoisomers or pharmaceutically acceptable salts, esters, amides, or prodrugs thereof, wherein X, Y, R7, R8, and - - - are as follows:
X is selected from (CH2)5,
(CH2))4,
(CH2)6,
CH2C(xe2x95x90O)NHCH2CH2,
CH2CH2NHC(xe2x95x90O)CH2,
(CH2)2NH(CH2)2,
(CH2)2O (CH2)2,
C6H4,
CH2C6H4,
C6H4CH2,
C6H 10,
CH2CH 6H10,
C6H10CH2,
C5H8,
CH2C5H8,
C5H8CH2, and
CH2CHxe2x95x90CHCH2CH2;
Y is selected from 2,6-dimethylpiperidinyl,
piperidinyl,
2, 6,6-tetramethyl-piperidinyl-4-one,
(2-carboxy)piperidinyl,
(3-carboxy)piperidinyl,
(4-carboxy)piperidinyl,
3,5-dimethylpiperidinyl,
(4-hydroxy)piperidinyl,
(2-imino)piperidinyl,
piperidin-4-one-yl,
(2-dimethylaminomethyl)-piperidinyl,
(4-dimethylamino)-piperidinyl,
(4-sulphonyloxy)-piperidinyl,
(2-phenyl)piperidinyl,
2,5-dimethylpyrrolidinyl,
pyrrolidinyl,
(2-carboxy)pyrrolidinyl,
(3-N-acetyl-N-methyl)pyrrolidinyl,
(3-amino)pyrrolidinyl,
(2,5-bis-methoxymethyl)-pyrrolidinyl,
2-hydroxymethyl-pyrrolidinyl,
2-hydroxymethyl-5-methyl-pyrrolidinyl,
diisopropylamino,
dimethylamino,
diethylamino,
methyl amino,
1-methyl-4,5-dihydro-1H-imidazol-2-yl,
2,5-dimethyl-1H-1-imidazolyl,
morpholinyl,
2,6-dimethylmorpholinyl,
piperazinyl,
2,6-dimethylpiperazinyl,
1H-pyrazolyl,
tetrahydro-1H-pyrazolyl, and
2,5-dimethyltetrahydro-1H-1-pyrazolyl;
R7 is selected from (3-amidino)phenyl,
(3-hydroxy)phenyl,
[3-hydroxylamino(imino)methyl]-phenyl,
[3-hydrazino(imino)methyl]-phenyl,
(3-aminomethyl)phenyl,
(3-amino)phenyl,
(3-methylamino)phenyl,
(3-dimethylamino)phenyl,
(5-amidino-2-hydroxy)phenyl
(1-amidino)piperid-3-yl,
(1-amidino)pyrrolid-3-yl,
(5-amidino)thien-2-yl,
(5-amidino)furan-2-yl,
(5-amidino)-1,3-oxazol-2-yl,
(2-amidino)-1,3-oxazol-5-yl,
1H-pyrazol-5-yl,
tetrahydro-1H-pyrazol-3-yl,
(1-amidino)tetrahydro-1H-pyrazol-3-yl,
(2-amidino)-1H-imidazol-4-yl,
(2-amino)-1H-imidazol-4-yl,
(5-amidino)-1H-imidazol-2-yl,
(5-amino)-1H-imidazol-2-yl,
pyridin-3-yl,
(4-amino)pyridin-3-yl,
(4-dimethylamino)pyridin-3-yl,
(6-amino)pyridin-2-yl,
(6-amidino)pyridin-2-yl,
(2-amino)pyridin-4-yl,
(2-amidino)pyridin-4-yl,
(2-amidino)pyrimid-4-yl,
(2-amino)pyrimidin-4-yl.
(4-amidino)pyrimid-2-yl,
(4-amino)pyrimidin-2-yl,
(6-amidino)pyrazin-2-yl,
(6-amino)pyrazin-2-yl,
(4-amidino)-1,3,5-triazin-2-yl,
(4-amino)-1,3,5-triazin-2-yl,
(3-amidino)-1,2,4-triazin-5-yl,
(3-amino)-1,2,4-triazin-5-yl,
(3-amidino)benzyl,
(3-amino)benzyl,
(3-aminomethyl)benzyl,
(1-amidino)piperid-3-ylmethyl,
(1-amidino)pyrrolid-3-ylmethyl,
(5-amidino)thien-2-ylmethyl,
(5-amidino)furan-2-ylmethyl,
(5-amidino)oxazol-2-ylmethyl,
(2-amidino)imidazol-5-ylmethyl,
(5-amidino)imidazol-2-ylmethyl,
(6-amidino)pyridin-2-ylmethyl,
(6-amino)pyridin-2-ylmethyl,
(2-amidino)pyrimidin-4-ylmethyl,
(2-amino)pyrimidin-4-ylmethyl,
(4-amidino)pyrimidin-2-ylmethyl,
(4-amino)pyrimidin-2-ylmethyl,
(6-amidino)pyrazin-2-ylmethyl,
(6-amino)pyrazin-2-ylmethyl,
3-aminocyclohexyl,
3-amidinocyclohexyl,
3-aminocyclohexylmethyl,
3-amidinocyclohexylmethyl,
3-aminocyclopentyl,
3-amidinocyclopentyl,
3-aminocyclopentylmethyl, and
3-amidinocyclopentylmethyl; and
R8 is selected from H,
Cl,
F,
SH,
SMe,
CF3,
CH3,
CO2H,
CO2Me,
CN,
C(xe2x95x90NH)NH,
C(xe2x95x90NH)NHOH,
C(xe2x95x90NH)NHNH2,
C(xe2x95x90O)NH2,
CH2OH,
CH2NH2,
NO2,
OH,
OMe,
OCH2Ph,
OCH2CO2)H,
O(CH2)2CO2H,
O(CH2)3CO2H,
NHCH2CO2H,
NH(CH2)2CO2H,
NH(CH2)3CO2H,
OCH2CH2OH,
OCH2(1H-tetrazol-5-yl),
NH2,
NHButyl,
NMe2,
NHPh,
NHCH2Ph,
NHC(xe2x95x90O)Me
NHC(xe2x95x90O)c-Hexyl,
NHC(xe2x95x90O)CH2c-Hexyl,
NHC(xe2x95x90O)Ph,
NHC(xe2x95x90O)CH2Ph,
NHC(xe2x95x90O)2Me,
NHS(xe2x95x90O)2c-Hexyl,
NHS(xe2x95x90O)2CH2c-Hexyl,
NHS(xe2x95x90O)2Ph, and
NHS(xe2x95x90O)2CH2Ph
In one embodiment of Formula V, Y, R7 and R8 are as defined above and X is (CH2)5. In another embodiment of Formula V, X, R7 and R8 are as defined above and Y is 2,6-dimethylpiperidinyl. In another embodiment of Formula V, X, Y, and R8 are as defined above and R7 is (5-amidino-2-hydroxy) phenyl. In another embodiment of Formula V X, Y and R7 are as defined above and R8 is H. In yet another embodiment of Formula V, R7 is as defined above and X is (CH2)5, Y is 2,6-dimethylpiperidinyl and R8 is H. In yet another embodiment of Formula V, R7 is as defined above and X is (CH2)5, Y is 2,5-dimethylpyrrolidinyl and R8 is H.
Representative compounds of the present invention include:
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-(3-hydroxyphenyl)-2(1H)-quinoxalinone;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-N-hydroxybenzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidohydrazide;
3-[3-(Aminomethyl)phenyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
3-(3-Aminophenyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1,(2H)-pyridinyl]pentyl-3-[3-(methylamino)phenyl]-2(1H)-quinoxalinone;
3-[3-(Dimethylamino)phenyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-4-hydroxybenzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)tetrahydro-1(2H)-pyridinecarboximidamide;
3-(4-5-[(2R6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-1-pyrrolidinecarboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-2-thiophenecarboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-2-furancarboximidamide;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-1,3-oxazole-5-carboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-1,3-oxazole-2-carboximidamide;
1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-(1H-pyrazol-3-yl)-2(1H)-quinoxalinone;
1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-tetrahydro-1H-pyrazol-3-yl-2(1H)-quinoxalinone;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-1-pyrazolidinecarboximidamide;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-1H-imidazole-2-carboximidamide;
3-(2-Amino-1H-imidazol-5-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1H (2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-1H-imidazole-5-carboximidamide;
3-(5-Amino-1H-imidazol-2-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
1-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-(3-pyridinyl)-2(1H)-quinoxalinone;
3-(6-Amino-3-pyridinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
3-[6-(Dimethylamino)-3-pyridinyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
3-(6-Amino-2-pyridinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-2-pyridinecarboximidamide;
3-(2-Amino-4-pyridinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone,
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-2-pyridinecarboximidamide;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-2-pyrimidinecarboximidamide;
3-(2-Amino-4-pyrimidinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
2-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-4-pyrimidinecarboximidamide;
3-(4-Amino-2-pyrimidinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
6-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-2-pyrazinecarboximidamide;
3-(6-Amino-2-pyrazinyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
4-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(21)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-1,3,5-triazine-2-carboximidamide;
3-(4-Amino-1,3,5-triazin-2-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
5-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-1,2,4-triazine-3-carboximidamide;
3-(3-Amino-1,2,4-triazin-5-yl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)methyl]benzenecarboximidamide;
3-(3-Aminobenzyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
3-[3-(Aminomethyl)benzyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone,
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)methyl]tetrahydro-1(2H)-pyridinecarboximidamide;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)methyl]-1-pyrrolidinecarboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)methyl]-2-thiophenecarboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)methyl]-2-furancarboximidamide;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3 4-dihydro-2-quinoxalinyl)methyl]-1,3-oxazole-5-carboximidamide;
5-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)methyl]-1H-imidazole-2-carboximidamide;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)methyl]-1H-imidazole-5-carboximidamide;
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)methyl]-2-pyridinecarboximidamide,
3-[(6-Amino-2-pyridinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-7 (1H-quinoxalinone;
4-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)methyl]-2-pyrimidinecarboximidamide;
3-[(2-Amino-4-pyrimidinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
2-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo -3,4-dihydro-2-quinoxalinyl)methyl]-4-pyrimidinecarboximidamide;
3-[(4-Amino-2-pyrimidinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
6-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo -3,4-dihydro-2-quinoxalinyl)methyl]-2-pyrazinecarboximidamide;
3-[(6-Amino-2-pyrazinyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
3-(3-Aminocyclohexyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2,H)-pyridinyl]pentyl-3-oxo -3,4-dihydro-2-quinoxalinyl)cyclohexanecarboximidamide;
3-[(3-Aminocyclohexyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo -3,4-dihydro-2-quinoxalinyl)methyl]cyclohexanecarboximidamide;
3-(3-Aminocyclopentyl)-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)cyclopentanecarboximidamide;
3-[(3-Aminocyclopentyl)methyl]-1-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-2(1H)-quinoxalinone;
3-[(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)methyl]cyclopentanecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2,H)-pyridinyl]butyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(4-6-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]hexyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide,
2-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinoxalinyl]-N-2-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]ethylacetamide;
3-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinoxalinyl]-N-[(2R,6S)-2,6-dimethyltetrahydro-1(2H )-pyridinyl]methylpropanamide;
3-4-[2-(2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethylamino)ethyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-[4-(2-2-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]ethoxyethyl)-3-oxo-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-(4-4-[(2R,65)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]phenyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]benzyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylphenyl)-3-oxo-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-(4-4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclohexylmethyl)-3-oxo-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-[4-(4-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclohexyl)-3-oxo-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-(4-3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]cyclopentylmethyl)-3-oxo-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-[4-(3-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]methylcyclopentyl)-3-oxo-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide,
3-(4-(E)-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]-2-pentenyl -3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-[3-Oxo-4-(5-piperidinopenty)-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-3-Oxo-4-[5-(2,2,6,6-tetramethylpiperidino)pentyl]-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinoxalinyl]pentyl-2-piperidinecarboxylic acid:
1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinoxalinyl]pentyl-3-piperidinecarboxylic acid;
1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinoxalinyl]pentyl-4-piperidinecarboxylic acid;
3-4-[5-(3,5-Dimethylpiperidino)pentyl] -3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-4-[5-(4-Hydroxypiperidino)pentyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-4-[5-(2-Iminopiperidino)pentyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-3-Oxo-4-[5-(4-oxopiperidino)pentyl]-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-[4-(5-2-[(Dimethylamino)methyl]piperidinopentyl)-3-oxo-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-(4-5-[4-(Dimethylamino)piperidino]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinoxalinyl]pentyl -4-piperidinesulfonic acid;
3-3-Oxo-4-[5-(2-phenylpiperidino)pentyl]-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-4-[5-(2,5-Dimethyl-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-3-Oxo-4-[5-(1-pyrrolidinyl)pentyl]-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinoxalinyl]pentyl-2-pyrrolidinecarboxylic acid;
N-(1-5-[3-3-[Amino(imino)methyl]phenyl-2-oxo-1(2H)-quinoxalinyl]pentyltetrahydro-1H-pyrrol-3-yl)-N-methylacetamide;
3-4-[5-(3-Amino-1-pyrrolidinyl)pentyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-(4-5-[2,5-bis(Methoxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(4-5-[2-(Hydroxymethyl)-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(4-5-[2-(Hydroxymethyl)-5-methyl-1-pyrrolidinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-4-[5-(Diisopropylamino)pentyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-4-[5-(Diethylamino)pentyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-4-[5-(Methylamino)pentyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-4-[5-(1-Methyl-1H-imidazol-2-yl)pentyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-4-[5-(2,5-Dimethyl-1H-imidazol-1-yl)pentyl]-3-oxo-3 4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-[4-(5-Morpholinopentyl)-3-oxo-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-4-[5-(3,5-Dimethylmorpholino)pentyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-[3-Oxo-4-(5-piperazinopentyl)-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-4-[5-(2,6-Dimethylpiperazino)pentyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-3-Oxo-4-[5-(1H-pyrazol-1-yl)pentyl]-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide,
3-[3-Oxo-4-(5-tetrahydro-1H-pyrazol-1-ylpentyl)-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-4-[5-(2,5-Dimethyltetrahydro-1H-pyrazol-1-yl)pentyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide,
3-(6-Chloro-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-fluoro-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-sulfanyl-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-[4-5-[(2R,6S)-,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(methylsulfanyl)-3-oxo-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-(trifluoromethyl)-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2M)-pyridinyl]pentyl-6-methyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinecarboxylic acid;
Methyl 2-3-[amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinecarboxylate;
3-(6-Cyano-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3)4-dihydro-6-quinoxalinecarboximidamide;
?-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H1)-pyridinyl]pentyl-N-hydroxy-3-oxo-3 4-dihydro-6-quinoxalinecarboximidamide;
3-4-5-[(2R,6S)-2 6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[hydrazino(imino)methyl]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
2 2-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-(hydroxymethyl)-3-oxo-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-(6-(Aminomethyl)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-nitro-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-hydroxy-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-methoxy-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(6-(Benzyloxy)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinyl)oxy]acetic acid;
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinyl)oxy]propanoic acid;
4-[(2-3-[Amino(imino)m ethyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinyl)oxy]butanoic acid;
2-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinyl)aminoacetic acid;
3-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-5 dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinyl)amino]propanoic acid;
4-[(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3)4-dihydro-6-quinoxalinyl)amino]butanoic acid;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H1)-pyridinyl]pentyl-6-(2-hydroxyethoxy)-3-oxo-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-[4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-6-(1H-1,2,3,4-tetraazol-5-ylmethoxy)-3,4-dihydro-2-quinoxalinyl]benzenecarboximidamide;
3-(6-Amino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(6-(Butylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(6-(Dimethylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(6-Anilino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(6-(Benzylamino)-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinyl)acetamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinyl)cyclohexanecarboxamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinyl)-2-cyclohexylacetamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinyl)benzenecarboxamide;
N-(2-3-[Amino(imino)methyl]phenyl-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-6-quinoxalinyl)-2-phenylacetamide;
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2H)-pyridinyl]pentyl-6-[(methylsulfonyl)amino]-3-oxo-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide;
3-(6-[(Cyclohexylsulfonyl)amino]-4-5-[(2R,6S)-,6-dimethyltetrahydro -1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
3-(6-[(Cyclohexylmethyl)sulfonyl]amino-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)benzenecarboximidamide;
7-Chloro-1-(3-dimethylamino-propyl)-3-phenyl-1H-quinoxalin-2-one;
7-Chloro-1-(3-dimethylamino-propyl)-3-phenyl-1H-quinoxalin-2-one;
3-(4-Chloro-phenyl)-7-methoxy-1-(4-methoxy-phenyl)-1H-quinoxalin-2-one;
2(1H)-Quinoxalinone, 7-methoxy-3-bis(p-methoxyphenyl);
3-(3-Chloro-phenyl)-7-methoxy-1-(4-methoxy-phenyl)-1H-quinoxalin-2-one;
3-(4-Fluoro-phenyl)-7-methoxy-1-(4-methoxy-phenyl)-1H-quinoxalin-2-one;
3-(3,4-Dichloro-phenyl)-7-methoxy-1-(4-methoxy-phenyl)-1H-quinoxalin -2-one;
1-(2-Diethylamino-ethyl)-4-oxy-3-phenyl-1 1-quinoxalin-2-one;
1-(2-Diethylamino-ethyl)-4-oxy-3-phenyl-1H-quinoxalin-2-one;
3-(2-Chloro-phenyl)-7-methoxy-1-(4-methoxy-phenyl)-1H-quinoxalin-2-one;
3-(4-Bromo-phenyl)-7-methoxy-1-(4-methoxy-phenyl)-1H-quinoxalin-2-one;
2(1H)-Quinoxalinone, 7-methoxy-1-(p-methoxyphenyl)-3-phenyl;
7-Methoxy-1-(4-methoxy-phenyl)-3-(4-trifluoromethyl-phenyl)-1H-quinoxalin-2-one;
2(1H)-Quinoxalinone, 1-methyl-3-phenyl-, 4-oxide;
7-Methoxy-1-(4-methoxy-phenyl)-3-(3-trifluoromethyl-phenyl)-1H-quinoxalin-2-one;
7-Methoxy-1-(4-methoxy-phenyl)-3-p-tolyl-1H-quinoxalin-2-one;
3-(2-Fluoro-phenyl)-7-methoxy-1-(4-methoxy-phenyl)-1H-quinoxalin-2-one;
1-(3-Diethylamino-propyl)-3-phenyl-1H-quinoxalin-2-one;
7-Hydroxy-1-(4-hydroxy-phenyl)-3-phenyl-1H-quinoxalin-2-one;
3-(4-Chloro-phenyl)-1-phenyl-1H-quinoxalin-2-one;
2(1H)-Quinoxalinone, 1,3-diphenyl,
1-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-phenyl-1H-quinoxalin-2-one,
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-1-methyl-3-oxo-1,2,3,4-tetrahydro-quinoxalin-2-yl}-N-hydroxy-benzamidine,
3-{4-[5-(2,6-Dimethyl-piperidin-1-yl)-pentyl]-3-oxo-3,4-dihydro-quinoxalin-2-yl}-N-hydroxy-benzamide;
3-(3-Amino-1H-indazol-5-yl)-1-[5-(2,6-dimethyl-piperidin-1-yl)-pentyl]-1H-quinoxalin-2-one;
2(1H/)-Quinoxalinone, 1-[2-(diethylamino)ethyl]-3-[[4-(methoxy)phenyl]methyl];
3-4-5-[(2R,6S)-2,6-Dimethyltetrahydro-1(2,1)-pyridinyl]pentyl-3-oxo-6-[(phenylsulfonyl)amino]-3,4-dihydro-2-quinoxalinylbenzenecarboximidamide; and
3-(6-[(Benzylsulfonyl)amino]-4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-,4-dihydro-2-quinoxalinyl)benzenecarboximidamide.
The term xe2x80x9calkylxe2x80x9d means a straight, branched, saturated or unsaturated carbon chain having from 1 to 20 carbon atoms. Typical alkyl groups include methyl, isobutyl, pentyl, 2-methyl-pentyl, pent-1,4-dienyl, but-1-enyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated or unsaturated carbon chain which forms a ring having from 3 to 20 carbon atoms. Typical examples include cyclopropyl, cyclohexyl and the like.
The term xe2x80x9ccycloalkylalkylxe2x80x9d means a cycloalkyl group attached to an alkyl group wherein xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9calkylxe2x80x9d are as defined above and includes, for example, cyclopropylmethyl, cyclopentylethyl and the like.
The term xe2x80x9cheteroalkylxe2x80x9d means a straight, branched, saturated or unsaturated carbon chain having from 1 to 20 carbon atoms wherein one or more carbon atoms is replaced by a heteroatom selected from oxygen, nitrogen, sulfur, sulphoxide, or sulphone. Typical xe2x80x9cheteroalkylxe2x80x9d groups include methoxymethyl, 3-thiomethylpropyl, and 2-thiomethoxyethoxymethyl and the like.
The term xe2x80x9carylxe2x80x9d represents an unsaturated carbocyclic ring(s) of 6 to 16 carbon atoms which is optionally substituted with, OH, O(alkyl), SH, S(alkyl), amine, halogen, acid, ester, amide, alkyl ketone, aldehyde, nitrite, fluoroalkyl, nitro, sulphone, sulfoxide, or (C1-6)alkyl. Typical rings include phenyl, naphthyl, phenanthryl, and anthracenyl. Preferred aryl rings are phenyl, substituted phenyl, and naphthyl.
The term xe2x80x9carylalkylxe2x80x9d means an aromatic radical attached to an alkyl radical wherein xe2x80x9carylxe2x80x9d and xe2x80x9calkylxe2x80x9d are as defined above and includes, for example, benzyl and naphthylmethyl.
The term xe2x80x9cheterocyclexe2x80x9d means a saturated or unsaturated mono- or polycyclic (i.e., bicyclic) ring incorporating one or more (i.e., 1-4) heteroatoms selected from N, O, and S. It is understood that a heterocycle is optionally substituted with OH, O(alkyl), SH, S(alkyl), amine, halogen, acid, ester, amide, alkyl ketone, aldehyde, nitrite, fluoroalkyl, nitro, sulphone, sulfoxide, or C1-6 alkyl. Examples of suitable monocyclic heterocycles include, but are not limited to, substituted or unsubstituted thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, pyrrolidinyl, piperazinyl, azetidinyl, aziridinyl, morpholinyl, thietanyl, oyetanyl. Preferred monoydicheterocycles include, but are not limited to, 2- or 3-thienyl, 2- or 3-furanyl, 1-, 2-, or 3-pyrrolyl; 1-, 2-, 4-, or 5-imidazolyl; 1-, 3-, 4-, or 5-pyrazolyl; -4-, or 5-thiazolyl; 3-, 4-, or 5-isothiazolyl; 2-, 4-, or 5-oxazolyl 3-, 4-, or 5-isoxazolyl; 1,3-, or 5-triazolyl; 1-, 2-, or 3-tetrazolyl; 3- or 4-pyridinyl; 2-pyrazinyl; 2-, 4-, or 5-pyrimidinyl; 1-, 2-, 3-, or 4- piperidinyl; 1-, 2-, or 3-pyrrolidinyl; 1- or 2-piperazinyl; 1-, 2-, or 3-azetidinyl;, 1- or 2-aziridinyl; 2-, 3-, or 4-morpholinyl; 2- or 3- thietanyl; 2- or 3-oxetanyl. Examples of suitable bicyclic heterocycles include, but are not limited to, indolizinyl, isoindolyl, benzothienyl, benzoxazolyl. benzimidazolyl, quinolinyl, isoquinolinyl, and preferably 1-, 2-, 4-, 5-, 6-, or 7-indolyl; 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 2-, 3-, 4-,5-, 6-, or 7-isoindolyl; 2-, 3-, 4-, 5-, 6-, or 7-benzothienyl; 2-, 4-, 5-, 6-, or 7-benzoxazolyl; 1-,2-, 4-, 5-, 6-, or 7-benzimidazolyl; 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl; 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl.
The term xe2x80x9cheteroatomxe2x80x9d as used herein represents oxygen, nitrogen, or sulfur (O, N, or S) as well as sulfoxyl or sulfonyl (SO or SO2) unless otherwise indicated. It is understood that alkyl chains interrupted by one or more heteroatoms means that a carbon atom of the chain is replaced with a heteroatom having the appropriate valency. Preferably, an alkyl chain is interrupted by 1 to 4 heteroatoms and that two adjacent carbon atoms are not both replaced. Examples of such groups include methoxymethyl, 3-thiomethylpropyl, and 2-thiomethoxyethoxymethyl.
The term xe2x80x9caminexe2x80x9d refers to a group such as NH2, NHalkyl, NH(cycloalkyl), NH(cycloalkylalkyl), NH(aryl), NH(arylalkyl), NH(heteroaryl), NH(heteroarylalkyl), N(alkyl)(alkyl), N(alkyl)(cycloalkyl), N(alkyl)(cycloalkylalkyl), N(alkyl)(aryl), N(alkyl)(arylalkyl), N(alkyl)(heteroaryl), N(alkyl)(heteroarylalkyl), N(cycloalkyl)(cycloalkyl), N(cycloalkyl)(cycloalkylalkyl), N(cycloalkyl)(aryl), N(cycloalkyl)(arylalkyl), N(cycloalkyl)(heteroaryl), N(cycloalkyl)(heteroarylalkyl), N(cycloalkylalkyl)(cycloalkylalkyl), N(cycloalkylalkyl)(aryl), N (cycloalkylalkyl)(arylalkyl), N(cycloalkylalkyl)(heteroaryl), N(cycloalkylalkyl)(heteroarylalkyl), N(aryl)(cycloalkylalkyl), N(aryl)(aryl), N(aryl)(arylalkyl), N(aryl)(heteroaryl), N(aryl)(heteroarylalkyl), N(arylalkyl)(arylalkyl),N(arylalkyl)(heteroaryl), N(arylalkyl)(heteroarylalkyl), N(heteroaryl)(heteroaryl), N(heteroaryl)(heteroarylalkyl), N(heteroarylalkyl)(heteroarylalkyl).
The term xe2x80x9cacidxe2x80x9d refers to C(xe2x95x90O)OH.
The term xe2x80x9cketonexe2x80x9d refers to C(xe2x95x90O)alkyl, C(xe2x95x90O)cycloalkyl, C(xe2x95x90O)cycloalkylalkyl, C(xe2x95x90O)aryl, C(xe2x95x90O)arylalkyl, C(xe2x95x90O)heteroaryl, C(xe2x95x90O)heteroarylalkyl.
The term xe2x80x9cesterxe2x80x9d refers to a group such as C(xe2x95x90O)Oalkyl, C(xe2x95x90O)Ocycloalkyl, C(xe2x95x90O)Ocycioalkylalkyl, C(xe2x95x90O)Oaryl, C(xe2x95x90O)Oarylalkyl, C(xe2x95x90O)Oheteroaryl, C(xe2x95x90O)Oheteroarylalkyl.
The term xe2x80x9camidexe2x80x9d refers to a group such as C(xe2x95x90O)NH2, C(xe2x95x90O)NHalkyl, C(xe2x95x90O)NH(cycloalkyl), C(xe2x95x90O)NH(cycloalkylalkyl), C(xe2x95x90O)NH(aryl), C(xe2x95x90O)NH(arylalkyl), C(xe2x95x90O)NH(heteroaryl), C(xe2x95x90O)NH(heteroarylalkyl), C(xe2x95x90O)N(alkyl)(alkyl), C(xe2x95x90O)N(alkyl)(cycloalkyl), C(xe2x95x90O)N(alkyl)(cycloalkylalkyl), C(xe2x95x90O)N(alkyl)(aryl), C(xe2x95x90O)N(alkyl)(arylalkyl), C(xe2x95x90O)N(alkyl)(heteroaryl), C(xe2x95x90O)N(alkyl)(heteroarylalkyl), C(xe2x95x90O)N(cycloalkyl)(cycloalkyl), C(xe2x95x90O)N(cycloalkyl)(cycloalkylalkyl), C(xe2x95x90O)N(cycloalkyl)(aryl), C(xe2x95x90O)N(cycloalkyl)(arylalkyl), C(xe2x95x90O)N(cycloalkyl)(heteroaryl), C(xe2x95x90O)N(cycloalkyl)(heteroarylalkyl), C(xe2x95x90O)N(cycloalkylalkyl)(cycloalkylalkyl), C(xe2x95x90O)N(cycloalkylalkyl)(aryl), C(xe2x95x90O)N(cycloalkylalkyl)(arylalkyl), C(xe2x95x90O)N(cycloalkylalkyl)(heteroaryl), C(xe2x95x90O)N(cycloalkylalkyl)(heteroarylalkyl), C(xe2x95x90O)N(aryl)(cycloalkylalkyl), C(xe2x95x90O)N(aryl)(aryl), C(xe2x95x90O)N(aryl)(arylalkyl), C(xe2x95x90O)N(aryl)(heteroaryl), C(xe2x95x90O)N(aryl)(heteroarylalkyl), C(xe2x95x90O)N(arylalkyl)(arylalkyl), C(xe2x95x90O)N(arylalkyl)(heteroaryl), C(xe2x95x90O)N(arylalkyl)(heteroarylalkyl), C(xe2x95x90O)N(heteroaryl)(heteroaryl), C(xe2x95x90O)N(heteroaryl)(heteroarylalkyl), C(xe2x95x90O)N(heteroarylalkyl)(heteroarylalkyl).
The term xe2x80x9cureaxe2x80x9d refers to a (group such as NHC(xe2x95x90O)N(alkyl)(alkyl) NHC(xe2x95x90O)N(alkyl)(cycloalkyl), NHC(xe2x95x90O)N(alkyl)(cycloalkylalkyl), NHC(xe2x95x90O)N(alkyl)(aryl), NHC(xe2x95x90O)N(alkyl)(arylalkyl), NHC(xe2x95x90O)N(alkyl)(heteroaryl), NHC(xe2x95x90O)N(alkyl)(heteroarylalkyl), NHC(xe2x95x90O)N(cycloalkyl)(cycloalkyl), NHC(xe2x95x90O)N (cycloalkyl)(cycloalkylalkyl), NHC(xe2x95x90O)N(cycloalkyl)(aryl), NHC(xe2x95x90O)N(cycloalkyl)(arylalkyl), NHC(xe2x95x90O)N(cycloalkyl)(heteroaryl), NHC(xe2x95x90O)N(cycloalkyl)(heteroarylalkyl) NHC(xe2x95x90O)N(cycloalkylalkyl)(cycloalkylalkyl), NHC(xe2x95x90O)N(cycloalkylalkyl)(aryl), NHC(xe2x95x90O)N(cycloalkylalkyl)(arylalkyl), NHC(xe2x95x90O)N(cycloalkylalkyl)(heteroaryl), NHC(xe2x95x90O)N(cycloalkylalkyl)(heteroarylalkyl), NHC(xe2x95x90O)N(aryl)(cycloalkylalkyl), NHC(xe2x95x90O)N(aryl)(aryl), NHC(xe2x95x90O)N(aryl)(arylalkyl), NHC(xe2x95x90O)N(aryl)(heteroaryl), NHC(xe2x95x90O)N(aryl)(heteroarylalkyl), NHC(xe2x95x90O)N(arylalkyl)(arylalkyl), NHC(xe2x95x90O)N(arylalkyl)(heteroaryl), NHC(xe2x95x90O)N(arylalkyl)(heteroarylalkyl), NHC(xe2x95x90O)N(heteroaryl)(heteroaryl), NHC(xe2x95x90O)N(heteroaryl)(heteroarylalkyl), NHC(xe2x95x90O)N(heteroarylalkyl)(heteroarylalkyl).
The term xe2x80x9chalogenxe2x80x9d refers to chlorine, fluorine, bromine and iodine.
The wedge or hash is only one representation of a stereochemical descriptor. All stereoisomers, including enantiomers and diastereomers, are included within Formulas I to V and are provided by this invention. When specific isomers are drawn, they are the preferred isomers.
In some situations, compounds may exist as tautomers. All tautomers are included within Formulas I to V and are provided by this invention.
When compounds are administered, some metabolism may occur. All metabolites are included within Formulas I to V and are provided by this invention.
When a bond to a substituent is shown to cross the bond connecting 2 atoms in a ring, then such substituent may be bonded to any atom in the ring, provided the atom will accept the substituent without violating its valency. When there appears to be several atoms of the substituent that may bond to the ring atom, then it is the first atom of the listed substituent that is attached to the ring.
When a bond is represented by a line such as xe2x80x9c- - - ,xe2x80x9d this is meant to represent that the bond may be absent or present provided that the resultant compound is stable and of satisfactory valency.
Compounds of the present invention are capable of forming acid addition salts (see, for example. Berge S. M. et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d Journal of Pharmaceutical Science, 1977:1-10) with inorganic acids such as, for example, hydrochloric acid, sulfuric acid and the like, as well as salts derived from organic acids such as, for example, aliphatic mono- and dicarboxylic acids or aliphatic and aromatic sulphonic acids. The acid addition salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt. The free base form may be regenerated by contacting the salt form with a base. While the free base more may differ from the salt form in terms of physical properties such as solubility, the salts are equivalent to their respective free bases for the purposes of the present invention.
Certain compounds of the present invention can exist in unsolvated form as well as solvated form including hydrated form. In general, the solvated form including hydrated form is equivalent to unsolvated form and is intended to be encompassed within the scope of the present invention.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carrier which releases the active parent drug according to Formulas I to V in vivo. Examples of prodrugs include acetates, formates benzoate derivatives of alcohols and amines present in compounds of Formulas I to V. They also include derivatives of the amidine or guanine functionality and would include C(xe2x95x90NR3)NH2 where R3 is selected from OH, NH2, C1-4 alkoxy C6-10 aryloxy, C1-10 alkoxycarbonyl, C6-10 aryloxycarbonyl. Preferred derivatives include examples wherein R3 is OH, NH2, methoxy, and ethoxycarbonyl.
The following table provides a list of abbreviations and definitions thereof used in the present invention.
Also provided by this invention is a method for preventing and treating acute, subacute, and chronic thrombotic disorder in a mammal comprising administering to such mammal an effective amount of a compound of Formulas I to V. The compounds are useful as anticoagulants for the treatment and prophylaxis of disorders such as venous and arterial thrombosis, pulmonary embolism, and ischemic events such as myocardial infarction or cerebral infarction. These compounds also have therapeutic utility for the prevention and treatment of complications of indwelling vascular access ports and arteriovenous shunts and coagulpathies associated with cardiopulmonary bypass or other extra corporeal systems. These compounds are useful for preventing or treating unstable angina, intermittent claudication refractory angina, disseminated intravascular coagulation and ocular buildup of fibrin. Since thrombin and serine proteases have also been demonstrated to activate a number of different cell types, these compounds are useful for the treatment or prophylaxis of septic shock and other inflammatory responses such as acute or chronic atherosclerosis. The compounds also have utility in treating neoplasia/metastasis and neurodegenerative diseases such as Alzheimer""s and Parkinson""s disease. In a preferred method, the thrombotic disorder is selected from venous thrombosis, arterial thrombosis, pulmonary embolism, myocardial infarction, cerebral infarction, angina, cancer, and diabetes. A further embodiment of this invention is a pharmaceutical formulation comprising a compound of Formulas I to V administered with a diluent, excipient, or carrier thereof.
The compounds of Formulas I to V can be prepared by any of various methods known to those skilled in the art of organic chemistry. The following general schemes represent preferred routes to provide the compounds of this disclosure. The reactions are typically performed in solvents appropriate to the reagents and substrates employed. It is understood that functionality present in the molecule must be compatible with the reagents and reaction conditions proposed. Not all compounds of Formulas I to V falling into a given class may be compatible with some of the reaction conditions described. Such restrictions are readily apparent to those skilled in the art of organic synthesis, and alternative methods must then be used.
Compounds of the present invention may be prepared by a number of synthetic sequences. One such preferred route is outlined in Scheme 1. 
Step a
Ortho-phenylenediamine is treated with a suitably substituted bromoacetic acid derivative, such as 2-bromo-2-(3-bromophenyl)acetic acid, in basic medium, such as aqueous sodium hydroxide, which upon warming to 60xc2x0 C. and then maintaining at this temperature for 30 minutes, affords the product 3-(3-bromophenyl)-1,2,3,4-tetrahydro-2-quinoxalinone as a precipitate.
Step b
Simply treating the tetrahydroisoquinoline with an oxidant, such as dichloro dicyanobenzoquinone (DDQ), or lead tetraacetate, and warming in toluene, affords the product 3-(3-bromophenyl)-1,2-dihydro-2-quinoxalinone, which may be purified by, for example, recrystallisation.
Step c
The aryl bromide is converted to the corresponding nitrile by, for example, treatment with copper cyanide in a solvent such as DMF. Typically, the reaction mixture is warmed to 160xc2x0 C. and maintained at this temperature for several hours, typically 12, to afford the required product. Alternatively, the bromide, or iodide, or triflate is converted to the nitrile by treatment with a transition metal, such as palladium tetrakis triphenylphosphine and zinc cyanide. The mixture is then warmed in a solvent such as DMF, typically to a temperature of 80xc2x0 C. for several hours or until the reaction is judged complete, by for example TLC.
Step d
Alkylation is typically achieved by treatment with an appropriate electrophile and by the addition of a base in a dipolar aprotic solvent. Typical conditions include, for example, use of a bis-electrophilic substrate such as 1,5-dibromopentane in a dipolar aprotic solvent such as DMF or DMSO and addition of a base, such as sodium hydride. Alternatively, alkylation can be achieved by the addition of a phase transfer reagent such as an alkylammonium salt, such as benzyltriethylammonium chloride, and employing a base such as sodium ethoxide. Reaction rates are typically improved by the application of heat, and hence, reactions are run at from 0xc2x0 C. to 70xc2x0 C.
Step e
Treatment with an amine, such as cis-2,6-dimethylpiperidine at an elevated temperature such as 50xc2x0 C. affords the expected N-alkylated piperidine. The amine may be used as solvent, or alternatively, the amine may be added in stoichiometric proportions and the reaction mixture refluxed in a solvent such as ethanol, acetonitrile, or toluene. The product, as the appropriate acid addition salt, is then neutralized by the addition of base such as aqueous potassium hydroxide, and isolated by extraction with an organic solvent such as ethylacetate.
Step f
Conversion of the nitrile to the hydroxyamidine is achieved by allowing the nitrile to react with hydroxylamine in methanol at room temperature. Typically, hydroxylamine hydrochloride is added to the nitrile containing substrate at room temperature, and the reaction is initiated by the addition of base such as potassium carbonate or diisopropylethylamine.
Step g
The amidoxime may be reduced directly, but is typically activated by the addition of acetic anhydride of trifluoroacetic anhydride to afford the O-acylated, or O-trifluoroacetyl, intermediate, which may be isolated or alternatively used directly in the subsequent reduction step. Steps g and h may be combined; i.e., the reduction with Pd/C is performed in acetic anhydride/acetic acid, or trifluoroacetic anhydride/trifluoroacetic acid.
Step h
The substrate is dissolved in methanol, or acetic acid, or trifluoroacetic acid, and treated with a transition metal catalyst such as Palladium dispersed on carbon and is then hydrogenated briefly, typically for 1 to 12 hours, at 50 psi, in a solvent such as methanol or ethanol. The product is then isolated, typically by crystallization or via chromatography such as reverse phase HPLC.
An alternative procedure for the preparation of compounds of Formula I involves that shown in Scheme 2, similar to the procedure of M. C. Alamanni Farmaco, Ed. Sci., 1981;36(5):359 and Ahmad A. R., Tetrahedron 1995;51(47): 12899-12910. 
Step a
Treatment of [N-5-(2,6-dimethylpiperidyl)pentyl]-ortho-phenylenediamine with methyl 2-(3-cyanophenyl)-2-oxoacetate in, for example, ethanol affords the expected quinoxalinone.
Steps b and c
Similar to the procedure discussed in Scheme 1 the nitrile is converted to the corresponding amidine.
An alternative procedure to prepare compounds of Formula I is outlined in Scheme 3. 
Step a
Treatment of (2-aminophenyl)methylamine with 2-bromo-2-(3-cyanophenyl)acetic acid, by way of specific example, affords the quinoxalinone. Typically, the reaction is performed in the presence of aqueous base with the application of external heating such that the reaction mixture is maintained at a temperature of about 60xc2x0 C. for several hours, typically two. In favorable situations, the product precipitates directly from the reaction mixture. The product may also be isolated by extraction of the reaction mixture with ethylacetate, and the required regioisomer is isolated by crystallization or chromatography on silica gel. The predominant regioisomer is that drawn.
Step b
The intermediate is then alkylated with, for example, 1-(5-bromopentyl)-2,6-dimethylpiperidine by treatment of the quinoxalinone with sodium hydride in a solvent such as DMF at from 0xc2x0 C. to 50xc2x0 C. Accordingly, the N versus O regioisomers are separated by chromatography. Alternatively, 1,5-dibromopentane may be used in excess and the required N-alkyl-bromide isolated by chromatography. A separate step is then required to convert the bromide to, for example, 2,6-dimethylpiperidine. This transformation is achieved by heating the bromide in neat 2,6-dimethylpiperidine, typically around 80xc2x0 C.
Step c
The final step involves conversion of the nitrile to the amidine, and hence may be accomplished by the procedure outlined above, by way of an amidoxime intermediate, or by treatment of the nitrile with anhydrous hydrogen chloride in an alcoholic solvent, such as methanol to afford the intermediate imino ether. This intermediate is then treated with a source of ammonia, such as ammonium acetate to afford the required amidine.
The substituted alpha-bromo phenylacetates used in these reactions are prepared by a number of standard procedures, such as, for example, that shown in Scheme 4. 
Step a
Acetic acid derivatives are prepared by conversion of the substituted benzoic acid to the corresponding acid chloride with, for example, oxalyl chloride and catalytic DMF and is then treated with ethereal diazomethane.
Step b
Rearrangement with silver oxide in an alcoholic solvent, such as methanol, affords the homologated acetic acid methyl ester.
Step c
Functionalization of the alpha position is then achieved by refluxing a solution of the ester in carbon tetrachloride with N-bromosuccinimide in the presence of a radical initiator such as AIBN.
An alternative procedure involves treatment of acetic acid derivatives with bromine in the presence of phosphorus tribromide will afford the alphabromo phenyl acetate in a manner typical of the Hell-Volhard-Zelinskii reaction.
Alternatively, the intermediate alpha bromo ester may be prepared by the procedure shown in Scheme 5. 
Step a
In this situation the aldehyde, such as 3-bromobenzaldehyde as a representative example, is reacted with malonitrile in the presence of catalytic piperidine in a solvent such as dioxane to afford the 2-[(3-bromophenyl)methylene]malononitrile.
Step b
Epoxide formation proceeds readily with commercial bleach at a pH of 5 to 6.
Step c
Treatment with hydrobromic acid in methanol then affords the required methyl 2-bromo-2-(3-bromophenyl)acetate; alternatively, use of hydrobromic acid in the absence of an alcoholic solvent then affords the corresponding acid derivatives.
Alternative procedures for the conversion of nitriles to amidines are also available. Treatment of the nitrile with hydrogen chloride in an alcoholic solvent affords the corresponding iminoether hydrochloride. These intermediates are then treated with source of ammonia, for example, ammonia in methanol, or ammonium chloride, or ammonium acetate, and the mixture is stirred and warmed, if necessary, to afford the amidine. The nitriles, in turn, are available by, for example, a palladium catalyzed cross-coupling reaction with Zn(CN)2.
Scheme 6 demonstrates yet another method that may be employed to prepare compounds of this invention and is similar to that reported by Holley et al. J. Amer. Chem. Soc., 1952, 74, 5445-5448 and Kirk et al. J. Org. Chem., 1969, 34, 395. 
Step a
In this situation a natural or unnatural amino acid, such as L-phenylalanine, or 2-amino-2-[2-(benzyloxy)-5-cyanophenyl]acetic acid is combined with an ortho fluoronitrobenzene in a solvent such as ethanol with additional base such as sodium bicarbonate and the mixture heated. Advantageously the nitro benzene substrate is substituted para to the fluoro substituent, with for example a carbomethoxy substituent such that the addition reaction with an amino acid (or peptide derivative) may proceed at a lower temperature.
Step b
Reduction of the nitro substituent to afford an intermediate aniline may proceed by way of hydrogenation over a transition metal catalyst such as palladium on carbon in a solvent such as water and base (sodium bicarbonate for example). Rapid intramolecular cyclization then proceeds, upon neutralization, to afford the required intermediate 3,4-dihydro-quinoxalinone.
Step c
Treatment of the dihydroquinoxalinone with an oxidant such as DDQ affords the intermediate quinoxalinone, which may then be elaborated as described in scheme 1 to afford for example, the desired factor Xa inhibitors such as 3-(4-5-[(2R,6S)-2,6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl-3-oxo-3,4-dihydro-2-quinoxalinyl)-4-hydroxybenzenecarboximidamide.
Compounds of the present invention are further characterized by their ability to inhibit the catalytic activity of factor Xa, which is demonstrated in the assay as follows. Compounds of the present invention may be prepared for assay by dissolving them in buffer to give solutions ranging in concentrations from 1 to 100 xcexcM. In an assay to determine the inhibitory dissociation constant, Ki, for a given compound, a chromogenic or fluorogenic substrate of factor Xa would be added to a solution containing a test compound and factor Xa; the resulting catalytic activity of the enzyme is spectrophotometrically determined. This assay is well-known to those skilled in the art and is commonly used to determine antithrombotic activity.
The compounds of the present invention may be used as anti-coagulants in vitro or ex vivo as in the case of contact activation with foreign thrombogenic surfaces, such as is found in tubing used in extracorporeal shunts. The compounds of the invention may also be used to coat the surface of such thrombogenic conduits. To this end, the compounds of the invention can be prepared as lyophilized powders, redissolved in isotonic saline or similar diluent, and added in an amount sufficient to maintain blood in an anticoagulated state.
The therapeutic agents of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers. The proportion of each carrier is determined by the solubility and chemical nature of the compound, the route of administration, and standard pharmaceutical practice. For example, the compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously. For parenteral administration, the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic. The compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may also be administered sublingually in the form of troches or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form. The compounds may be administered orally in the form of solutions which may contain coloring and/or flavoring agents. Typical formulations will contain from about 5 to 95 percent by weight of an invention compound.
The amount of invention compound to be utilized to prevent and treat thrombotic disorders is that amount which is effective to prevent or treat the condition without causing unacceptable side effects. Such effective amounts will be from about 0.01 mg/kg to about 500 mg/Kg, preferably from about 1 mg/kg to about 100 mg/kg. Physicians will determine the precise dosage of the present therapeutic agents which will be most suitable. Dosages may vary with the mode of administration and the particular compound chosen. In addition, the dosage may vary with the particular patient under treatment.
When the composition is administered orally, a larger quantity of the active agent will typically be required to produce the same effect as caused with a smaller quantity given parenterally.
To further assist in understanding the present invention, the following non-limiting examples of such factor Xa inhibitory compounds are provided. The following examples, of course, should not be construed as specifically limiting the present invention, variations presently known or later developed, which would be within the purview of one skilled in the art and considered to fall within the scope of the present invention as described herein. The preferred compounds as of the present invention are synthesized using conventional preparative steps and recovery methods known to those skilled in the art of organic and bio-organic synthesis, while providing a new and unique combination for the overall synthesis of each compound. Preferred synthetic routes for intermediates involved in the synthesis, as well as the resulting anti-thrombotic compounds of the present invention, follow.
USPTO Backgrounds
USPTO Backgrounds