EP0960102A1 - AMIDINOINDOLES, AMIDINOAZOLES ET LEURS ANALOGUES AGISSANT EN TANT QU'INHIBITEURS DU FACTEUR Xa ET DE LA THROMBINE - Google Patents

AMIDINOINDOLES, AMIDINOAZOLES ET LEURS ANALOGUES AGISSANT EN TANT QU'INHIBITEURS DU FACTEUR Xa ET DE LA THROMBINE

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Publication number
EP0960102A1
EP0960102A1 EP97933214A EP97933214A EP0960102A1 EP 0960102 A1 EP0960102 A1 EP 0960102A1 EP 97933214 A EP97933214 A EP 97933214A EP 97933214 A EP97933214 A EP 97933214A EP 0960102 A1 EP0960102 A1 EP 0960102A1
Authority
EP
European Patent Office
Prior art keywords
methyl
substituted
phenyl
alkyl
amidinoindole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97933214A
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German (de)
English (en)
Inventor
Celia Dominguez
Qi Han
Daniel Emmett Duffy
Jeongsook Maria Park
Mimi Lifen Quan
Karen Anita Rossi
Ruth Richmond Wexler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bristol Myers Squibb Pharma Co
Original Assignee
DuPont Merck Pharmaceutical Co
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Publication date
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Publication of EP0960102A1 publication Critical patent/EP0960102A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D463/00—Heterocyclic compounds containing 1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D463/02—Preparation
    • C07D463/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates generally to amidinoindoles, amidinoazoles, and analogs which are inhibitors of trypsin- like serine protease enzymes, especially thrombin and factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.
  • A is an alkylene linker optionally substituted by hydroxyalkyl , carboxyl, alkoxycarbonyl , alkoxycarbonylalkyl, or carboxyalkyl
  • X is a bond, O, S, or carbonyl
  • n is 0-4
  • Y is an optionally substituted carbocycle or heterocycle.
  • the present invention does not involve compounds containing the above noted combination of A, X, n, and Y.
  • factor Xa inhibitory activity of a series of aromatic mono- and di-amidines describe factor Xa inhibitory activity of a series of aromatic mono- and di-amidines.
  • the a idino aromatic moieties are include indole, indoline, benzofuran and benzimidazole.
  • R 1 and R 2 wherein one of R 1 and R 2 is amidine, X may be methyl or ethyl when Y and Z are H, Y may be C(0)CH 2 CH 3 when X and Z are H, and Z may be CHO, COCH , COCF 3 , or C ⁇ 0)Ph when X and Y are H. Thrombin inhibition constants are given for these compounds.
  • core ring is a heterocycle
  • B is a basic group
  • A is an acidic group
  • Ri is an optional substituent
  • R 2 is an optional substituent
  • L a and ⁇ are linkers which may optionally be substituted.
  • the present invention does not contain the L a -A group.
  • alkylene alkenylene, phenylene or phenylenedimethylene linker.
  • the DNA binding capabilities of these compounds were studied and reported, but inhibition of trypsin-like enzymes was not discussed.
  • WO 95/08540 depicts bis (amidinobenzi idazolyl) alkanes of the formula :
  • Z is an amidine derivative and R and R 1 are selected from a variety of substituents including hydroxyl, amino, and alkoxy. These compounds are said to be useful in the treatment of viruses, specifically HIV. No mention is made of Xa or thrombin inhibition.
  • Trypsin-like enzymes are a group of proteases which hydrolyzed peptide bonds at basic residues liberating either a C-terminal arginyl or lysyl residue.
  • enzymes of the blood coagulation and fibrinolytic system required for hemostasis They are Factors II, X, VII, IX, XII, kallikrein, tissue plasminogen activators, urokinase-like plasminogen activator, and plasmin. Elevated levels of proteolysis by these proteases can result in disease states.
  • consumptive coagulopathy a condition marked by a decrease in the blood levels of enzymes of both the coagulation system, the fibrinolytic system and accompanying protease inhibitors is often atal. More specifically, proteolysis by thrombin is required for blood clotting. Inhibition of thrombin results in an effective inhibitor of blood clotting.
  • conventional anticoagulants such as heparin (and its complex with the protein inhibitor, antithrombin III) are ineffective in blocking arterial thrombosis associated with myocardial infarctions and other clotting disorders.
  • thrombin inhibitor containing a different functionality, was effective in blocking arterial thrombosis (Hanson and Harker, Proc . Na tl . Acad. Sci . U. S.A . 85, 3184 (1988) .
  • Activated factor Xa whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation.
  • thrombin the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca ⁇ + and phospholipid) . Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K. : Optimization of condi tions for the ca talytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation . Thro b. Res . 1979, 15, 617-629) , inhibition of factor Xa may be more efficient that inactivation of thrombin in interrupting the blood coagulation system.
  • one object of the present invention is to provide novel amidinoindoles and analogs thereof which are useful as factor Xa or thrombin inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
  • It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
  • It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of suc treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
  • I or pharmaceutically acceptable salt or prodrug forms thereof wherein D, D a , J, J a , J b , W, W 1 , W 2 , and W 3 , are defined below, are effective factor Xa or thrombin inhibitors.
  • the present invention provides a novel compound of formula I :
  • W and W 3 are selected from CH and N;
  • W 1 and W 2 are selected from C, CH, and N;
  • W 1 , W 2 , and W 3 are N;
  • one of D and D a is selected from H, C 1 -. 4 alkoxy, CN,
  • J a and J b are substituted by - (CH 2 ) n -Z-A-B;
  • J, J a , and J b combine to form an aromatic heterocyclic system containing from 1-2 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 1 , provided that J b can only be C or N;
  • J, J a , and J b can, alternatively, combine to form a heterocyclic ring wherein J b is N and J and J a are CH 2 substituted with 0-1 R 1 ;
  • J, J a , and J b can, alternatively, combine to form a heterocyclic ring wherein J b is CH, J is NR 1 and J a is CH 2 substituted with 0-1 R 1 ;
  • R 2 is selected from H, OR 3 , C 1 -4 alkyl, NR 3 R 3 ' , CF 3 , and C 3 -. 10 carbocyclic residue substituted with 0-2 R 6 ;
  • R 3 and R 3 ' are independently selected from H, C ⁇ _ 4 alkyl, and C 3 - 10 carbocyclic residue substituted with 0-2 R 6 ;
  • R 4 is selected from C1-.4 alkyl, NR 3 R 3 ' , and C - 10 carbocyclic residue substituted with 0-2 R 6 ⁇
  • Q is selected from a bond, O, NR 3 , C(O), C(0)NR 3 , NR 3 C(0), S0 2 , NR 3 S0 2 , and S0 2 NR 3 ;
  • Q' is selected from a bond, C(O), C(0)NR 3 , S0 2 , and S0 2 NR 3 ;
  • R 5 is selected from H, C 1 - 4 alkyl, C 3 -. 10 carbocyclic residue substituted with 0-2 R 6 , and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 6 , provided that when Q is S0 2 or R 3 SU 2 , R 5 is other than H and when Q' is S0 2 , R 5 is other than H;
  • R 5a is selected from NHR 5 , OR 5 , and R 5 ;
  • B is selected from:
  • a and B can, alternatively, combine to form a C 9 -. 10 carbocyclic residue substituted with 0-2 R 6 or a 9-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 6 ;
  • X is selected from C ⁇ _ 4 alkylene, -C(O)-, -C (0) CR 3 R 3 ' - , -CR 3 R 3 'C(0), -S(0) p -, -S(0) p CR 3 R 3 '-, -CR 3 R 3 ' S (O) p - , -S(0) 2 NR 3 -, -NR 3 S(0) 2 -, -C(0)NR 3 -, -NR 3 C(0)-, -NR 3 - -NR 3 CR 3 R 3 '-, -CR 3 R 3 'NR 3 -, O, -CR 3 R 3 ' ⁇ -, and -OCR 3 R 3 '
  • Y is selected from:
  • R 7 is selected from H, OH, C ⁇ -6 alkyl, C ⁇ _ 6 alkylcarbonyl, Ci-g alkoxy, C1-4 alkoxycarbonyl, Cg_ 10 aryloxy, C 6 - 10 aryloxycarbonyl , C6-1 0 arylmethylcarbonyl , C 1 -. 4 alkylcarbonyloxy C 1 - 4 alkoxycarbonyl, C 6 _ ⁇ 0 arylcarbonyloxy C 1 - 4 alkoxycarbonyl, C ⁇ _ 6 alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C 1 - 4 alkoxycarbonyl ;
  • R 8 is selected from H, C ⁇ _ 6 alkyl and (CH ) n -phenyl ;
  • R 9 is selected from H, C - ⁇ , alkyl and (CH 2 ) n -phenyl ,-
  • n is selected from 0, 1, 2, 3, and 4 ;
  • n 0, 1, and 2;
  • p is selected from 0, 1, and 2 ;
  • q is selected from 1 and 2;
  • r is selected from 0, 1, 2, 3, and 4;
  • (a) Z is other than CH ; and, (b) if Z is CH( (CH 2 )r n Q(CH 2 ) m R 5 ) or CH ( (CH 2 ) m C (O) (CH 2 ) m R 5a ) , then B is other than X-Y, a C3-10 carbocyclic residue or a 5-10 membered heterocyclic system.
  • the present invention provides compounds of formula II :
  • R 2 is selected from H, OR 3 , C 1 -. 4 alkyl, NR 3 R 3 ' , and CF 3 ,-
  • R 3 and R 3 ' are independently selected from H, C 1 -. 4 alkyl, and phenyl;
  • R 4 is selected from C 1 - 4 alkyl, phenyl and NR 3 R 3 ' ;
  • B is selected from:
  • a and B can, alternatively, combine to form a Cg-io carbocyclic residue substituted with 0-2 R 6 or a 9-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 6 ; and,
  • R 6 is selected from H, OH, (CH 2 ) n 0R 3 , halo, C ⁇ _ alkyl, CN, N0 2 , (CH 2 ) r NR 3 R 3' , (CH 2 ) r C(0)R 3 , NR 3 C(0)R 3 ', NR 3 C (O) NRR 3 ' , S0 2 NR 3 R 3 ', C0NHS0 2 R 4 , NR 3 S0 2 NR 3 R ' , NR 3 S0 2 -C ⁇ _ 4 alkyl and (C 1 -. 4 alkyl) -tetrazolyl.
  • the present invention provides compounds of formula II, wherein:
  • J, J a , and J b combine to form an aromatic heterocyclic system containing from 1-2 nitrogen atoms, substituted with 0-1 R 1 ;
  • J, J a , and J b can, alternatively, combine to form a heterocyclic ring wherein J b is N and J and J a are CH 2 substituted with 0-1 R 1 ;
  • J, J a , and J b can, alternatively, combine to form a heterocyclic ring wherein J b is CH, J is NR 1 and J a is CH 2 substituted with 0-1 R 1 ,-
  • Z is selected from CH ( (CH 2 ) m Q (CH 2 )mR 5 ) .
  • A is selected from: benzyl substituted with 0-2 R 6 ,
  • B is selected from: X-Y, C 3 - 6 alkyl, benzyl substituted with 0-2 R 6 , C5-6 carbocyclic residue substituted with 0-2 R 6 , and 5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 6 ;
  • X is selected from -C(O)-, -C (0) CR 3 R 3 ' - , -S(0) 2 -, -S (0) p CR 3 R 3 ' - , -S(0) 2 NR 3 -, -C(0)NR 3 -, -NR 3 -, -NR 3 CR 3 R 3 ' - , and O;
  • Y is selected from: C 5 -6 carbocyclic residue substituted with 0-2 R 6 , and 5-6 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R 6 ;
  • R 6 is selected from H, OH, (CH 2 ) n OR 3 , halo, C 1 - 4 alkyl, CN, N0 2 , (CH 2 ) r NR 3 R 3 ' , (CH 2 ) r C(0)R 3 , NR 3 C(0)R 3 ', NR 3 C (O) NR 3 R 3 ' , S0 2 NR 3 R 3' , CONHS0 2 R 4 , NR 3 S0 2 NR 3 R 3 ' , NR S0 2 -Ci- alkyl and ⁇ C 1 -. 4 alkyl) -tetrazolyl;
  • n is selected from 0, 1, and 2;
  • r is selected from 0, 1, and 2.
  • the present invention provides compounds of formula II:
  • J and J b combine to form an aromatic heterocyclic system containing from 1-2 nitrogen atoms, substituted with 0-1 R 1 ;
  • J and J b can, alternatively, form a heterocyclic ring nerem J b is N and J is CH substituted with 0-1 R 1 ;
  • J and J b can, alternatively, form a heterocyclic ring wherein J b is CH and J is NR 1 ;
  • Z is selected from C (0) N(Q' R 5a ) , C(O), C(0)NR 3 , NR 3 C(0), and S0 2 NR 3 ;
  • Q' is selected from C(0) and C(0)NR 3 ;
  • R 5 is selected from H and C 1 - 4 alkyl
  • R 5a is selected from NHR 5 , OR 5 , and R 5 ,
  • A is selected from: benzyl substituted with 0-1 R 6 , phenyl substituted w th 0-1 R 6 , pipe ⁇ dinyl substituted with 0-1 R 6 , piperazmyl substituted with 0-1 R 6 , and pyridyl substituted with 0-1 R 6 ;
  • B is selected from: X-Y, benzyl substituted with 0-1 R 6 , phenyl substituted with 0-2 R 6 , cyclohexyl substituted with 0-1 R 6 , and pyridyl substituted with 0-1 R 6 ;
  • X is selected from: -C(O)-, -S(0) 2 -, SO?CH 2 , -S(0) 2 NR 3 -, -NR 3 - and -C(0)NR 3 -;
  • Y is selected from: phenyl substituted with 0-2 R 6 , and pyridyl substituted with 0-1 R 6 ;
  • R 6 is selected from H, OH, (CH 2 ) n OR 3 , halo, C 1 - 4 alkyl, CN, N0 2 , (CH 2 ) r NR 3 R 3' , (CH 2 ) r C(0)R 3 , NR 3 C(0)R 3 ', NR 3 C (0) NR 3 R 3 ' , S0 2 NR 3 R 3' , CONHS0 2 R 4 , NR 3 S0 2 NR 3 R 3 ' , NR 3 S0 2 -C ⁇ _ 4 alkyl and (C ⁇ - 4 alkyl) -tetrazolyl;
  • n is selected from 0, 1, and 2.
  • the present invention provides compounds selected from:
  • the present invention provides compounds of formula IVa :
  • the present invention provides compounds selected from:
  • the present invention provides compounds selected from:
  • D, D a , Z, A, and B are as defined above.
  • the present invention provides compounds selected from:
  • R and R a are - (CH 2 ) n -Z-A-B and the other H;
  • W, W 2 , and W 3 are selected from CH and N, provided that at most one of W, W , and W 3 can be N;
  • J is selected from N and C-R 1 ;
  • R 2 is selected from H, OR 3 , C 1 -. 4 alkyl, NR 3 R 3 ' , CF 3 , and C 3 _ 10 carbocyclic residue substituted with 0-2 R 6 ;
  • R 3 and R 3 ' are independently selected from H, C ⁇ _ 4 alkyl, and C 3 - 10 carbocyclic residue substituted with 0-2 R 6 ,-
  • R 4 is selected from OR 3 , C 1 - 4 alkyl, NR 3 R 3 ' , and C 3 - 10 carbocyclic residue substituted with 0-2 R 6 ;
  • Q is selected from a bond, 0, NR 3 , C(O), C(0)NR 3 , NR 3 C(0), S 02 NR 3 S0 2 , and S0 2 NR 3 ;
  • Q' is selected from a bond, C(0), C(0)NR 3 , SO 2 , and SO 2 NR 3 ;
  • R 5 is selected from H, C ⁇ _ alkyl, C 3 - 8 carbocyclic residue substituted with 0-2 R 6 , and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 6 , provided that when Q is SO2 or NR 3 S0 2 , R 5 is other than H and when ' is S0 2 , R 5 is other than H;
  • R 5a is selected from NHR 5 , OR 5 , and R 5 ;
  • A is selected from: benzyl substituted with 0-2 R 6 ,
  • B is selected from:
  • X is selected from C 1 - 4 alkylene, -C(O)-, -C (0) CR 3 R 3 '-, -CR 3 R 3' C(0), -S(0) p -, -S(0) p CR 3 R 3 '-, -CR 3 R 3 'S (0) p -, -S(0) 2 NR 3 -, -NR 3 S(0) 2 ⁇ , -C(0)NR 3 -, -NR 3 C(0)-, -NR 3 -, -NR 3 CR 3 R 3 '-, -CR 3 R 3 'NR 3 -, 0, -CR 3 R 3 ' ⁇ -, and -0CR 3 R 3 ' - ;
  • Y is selected from:
  • n is selected from 0, 1, 2, 3, and 4 ;
  • n 0, 1, and 2;
  • p is selected from 0, 1, and 2;
  • q is selected from 1 and 2;
  • r is selected from 0, 1, 2, 3, and 4.
  • W and W 2 are selected from CH and N, provided that at most one of W and W 2 can be N;
  • J is selected from N and C-R 1 ;
  • R 2 is selected from H, OR 3 , C 1 -. 4 alkyl, NR R 3 ', and CF 3 ;
  • R 3 and R 3 ' are independently selected from H, C ⁇ _ 4 alkyl, and phenyl ;
  • R 4 is selected from OR 3 , C ⁇ _ alkyl, NR 3 R 3 ' , and phenyl;
  • Z is selected from C(O), C(0)CH 2 , C(0)NR 3 , NR 3 C(0), S(0) 2 , S0 2 CH 2 , S0 2 NR 3 , NR 3 S0 2 , and NR 3 S0 2 NR 3 ;
  • A is selected from:
  • B is selected from:
  • X is selected from -C(O)-, -C (0)CR 3 R 3 ' -, -CRR 3 'C(0), -S(0) p -, -S(0) p CR 3 R 3 '-, -CR 3 R 3 'S(0) p -, -S(0) 2 NR 3 -, -NR 3 S(0) 2 -, -C(0)NR 3 -, -NR 3 -, -NR 3 CR 3 R 3 '-, and -CR 3 R 3 'NR 3 -;
  • Y is selected from: 3 - 10 carbocyclic residue substituted with 0-2 R 6 , and 5-10 membered heterocyclic system containing from 1-3 heteroatoms selected from the group consisting of N, 0, and S substituted with 0-2 R 6 ;
  • p is selected from 0, 1, and 2;
  • r is selected from 0, 1, 2, 3, and 4.
  • the present invention provides compounds of formula VII :
  • W and 2 are selected from CH and N, provided that at most one of W and W 2 can be N;
  • R 2 is selected from H, OR 3 , C ⁇ - 4 alkyl, NR 3 R 3 ', and CF 3 ;
  • R 3 and R 3 ' are independently selected from H, C ⁇ _ 4 alkyl, and phenyl ;
  • R 4 is selected from OR 3 , C 1 - 4 alkyl, NR 3 R 3 ' , and phenyl;
  • Z is selected from C(O), C(0)CH 2 , C(0)NR 3 , S(0) , S0 2 CH , S0 2 NR 3 , and NR 3 S0 2 NR 3 ;
  • A is selected from:
  • B is selected from:
  • X is selected from -S(0) p -, -S (0) p CR 3 R 3 ' - , -CR 3 R 3 'S (0) p - , -S(0) 2 NR 3 -, -NR 3 S(0) 2 -, and -C(0)NR 3 -;
  • Y is selected from:
  • n is selected from 0, 1, 2, 3, and 4;
  • p is selected from 0, 1, and 2;
  • r is selected from 0, 1, 2, 3, and 4.
  • the present invention provides compounds selected from:
  • the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.
  • the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug form thereof.
  • the compounds herein described may have asymmetric centers.
  • C 1 - 4 alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl;
  • Alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.
  • Halo or "halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • carrier or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl , ; [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane (decalin) , [2.2.2] bicyclooctane, phenyl, naphthyl , indanyl , adamantyl, or tetrahydronaphthyl (tetralin) .
  • heterocycle or “heterocyclic system” is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic) , and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another.
  • aromatic heterocyclic system is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, 0 and S. It is preferred that the total number of S and 0 atoms in the aromatic heterocycle is not more than 1.
  • heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5 , 2-dithiazinyl , 2H- pyrrolyl, 3H-indolyl, 4-piperidonyl , 4aH-carbazole, 4H- quinolizinyl, 6H-1, 2 , 5-thiadiazinyl , acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl , benzimidazalonyl, carbazolyl , 4ai ⁇ -carbazolyl , ⁇ -carbolinyl , chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H- 1,
  • oxazolyl oxazolidinylperimidinyl, phenanthridinyl , phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl , phenoxazinyl , phthalazinyl, piperazinyl, piperidinyl, pteridinyl , 4-piperidonyl , pteridinyl , purinyl, pyranyl, pyrazinyl, pyrazolidinyl , pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl , pyridyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrroly
  • Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl , or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfa ic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pa oic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfa ic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington ' s Pharmaceu tical
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Prodrugs are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of formula (I) wherein a hydroxy, a ino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and a ine functional groups in the compounds of formula (I), and the like.
  • More preferred prodrugs are where R 7 is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl .
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent .
  • SYNTHESIS Compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those methods described below.
  • Each of the references cited below are hereby incorporated herein by reference. All the temperatures are reported herein in degrees Celsius.
  • the compounds of Formula I can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the trans ormations being effected.
  • Scheme 2 shows palladium (0) catalyzed coupling of 3- amino-4-nitrophenyl halides with zinc cyanide in DMF under reflux can provide compound 6 (see Lawton et al J. Org. Chem. 1959, 24, 26) .
  • Acylation of 6 with an acyl chloride or anhydride in the presence of base, followed by hydrogenation can form compound 7.
  • Alkylation of 7 with a halide in the presence of a base, such as Cs 2 C ⁇ 3 can provide compound 8.
  • Reductive amination of an aldehyde with 7 using borane- pyridine in acetic acid can afford N-alkylated product 9.
  • Compounds 8 and 9 can be converted to either their 6-amidinobenzimidazole or 5-amidino-benzimidazole derivatives, respectively via the Pinner reaction.
  • Scheme 5 details the synthesis of 2-substituted-amidino- benzimidazoles from 3 , 4-diamino-benzonitrile and 3-amino-4- hydroxybenzonitrile 13 which are obtained by hydrogenation of 4-amino-3-nitro-benzonitrile or 4-hydroxy-3-nitrobenzonitrile.
  • Treatment of 13 with an acyl chloride or an acid in the presence of PPA can form compound 14 (see Walker et al Synthesis 1981, 303) .
  • Compound 14 can be converted to its amidino derivative via the Pinner reaction.
  • alkylation of 14 with a halide in the presence of a base, such as K 2 C0 3 can afford a mixture of two regioisomers 15 and 16, which can, after being separated, be subjected to the Pinner reaction to give 2-substituted-6- amidino-benzimidazoles and 2-substituted-5-amidino- benzimidazole derivatives, respectively.
  • Scheme 8 shows 3-substituted-amidino-indoles and -indazoles are also derivable from 5-cyanoindole.
  • Compound 26 may be obtained by substitution of R 1 on 24 to form 25 and acylation of 25 in the presence of oxalyl chloride at r.t. under nitrogen atmosphere.
  • the compound can be subjected to selective ketone reduction with triethylsilane in trifluoroacetic acid for 3h and then coupled with H-A-B.
  • piperazine phenylsulfonamide, 31, and various other sulfonamide analogues can be prepared from commercially available BOC-piperazine via sulfonation with phenylsulfonyl chloride in CH2CI2 and triethylamine as indicated in Scheme 9.
  • Biphenyl compounds may be prepared by procedures known to those of skill in the art. For example, Scheme 10 shows how to obtain substituted biphenyls via a Suzuki coupling with BOC protected 4-bromoaniline (or l-bromo-4-nitrobenzene) to afford compound 35.
  • Scheme 12 shows how intermediates 43-45 may be obtained via the same intermediate 39.
  • Acylation with oxalyl chloride followed by addition of methanol should yield ketoester 40 and selective reduction with triethyl silane may afford methyl acetate 42.
  • Reduction with sodium borohydride can give the alcohol which then can be converted to 45 with R ⁇ .
  • Intermediate 43 may be obtained via formylation with POCI3 in DMF to yield aldehyde 41 which could then subjected to a Wittig olefination to afford compound 43.
  • Sulfonyl chloride 49 may be obtained via aldehyde 47.
  • the aldehyde can be reduced with sodium borohydride, sulfonated with methane sulfonyl chloride, and displaced with sodium sulfite in ethanol .
  • Sulfonyl chloride 49 should then be obtained via chlorination with sulfonyl chloride as detailed in Scheme 13.
  • Scheme 13 Addition of R 1 to l-protected indoles or indazoles
  • P is a protecting group e . g . MEM-group .
  • Scheme 14 details how substitution at the 2-position of the indole may be acomplished via lithiation with s-BuLi at -78 'C followed by addition of R x to yield compound 51.
  • Compound 51 can then converted to compound 52 by the previously mentioned methodology.
  • Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis.
  • the required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis.
  • the tables that follow the chemistry required to effect the coupling of A to B is outlined.
  • A-C(0)C1 a secondary NH as A-C(0)-Y part of a ring or chain
  • the chemistry of Table 1 can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20 C to the reflux point of the solvent and with or without a trialkylamine base.
  • aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene
  • the coupling chemistry of Table 2 can be carried out by a variety of methods.
  • the Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0 C to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temeprature (- 20 " c or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide'dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof.
  • the ether and thioether linkages of Table 3 can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.
  • a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide
  • a base such as potassium carbonate, sodium hydride or potassium t-butoxide
  • the thioethers of Table 3 serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table 4.
  • a combination of wet alumina and oxone provides a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone.
  • Examples 1-15 were prepared by Michael addition of 5- cyano-benzimidazole to the ⁇ , ⁇ -unsaturated esters by using K 2 CO 3 (2 mmol) as a base in DMF (10 mL) at 90-110°C for 16-24 hours, followed by the Pinner reaction.
  • a mixture of meta- and para-isomers was obtained by purification on TLC plates with 10-20% MeOH in CH2CI 2 . The pure eta - or para-isomer was separated by HPLC .
  • Example 2 The mixture was further separated by HPLC on chiral OJ column with C0 2 /MeOH/TEA (80/20/0.1) to give Example 2, ethyl 2- (3-amidinophenyl) ethyl-3 - (5- amidinobenzimidazole) propionate, and Example 3, ethyl 2- (3- amidinophenyl ) ethyl-3- ( 6-amidinobenzimidazole) propionate .
  • Example 4 was made using the same method as described for Example 1, except ethyl 2- (4-cyanophenyl) ethacrylate (2 mmol) was used (100 g, 13% for two steps): mp 230°C (Dec); ESMS: 407 (M+H) + ; HRMS : 407.2200 (obs.), 407.2195 (calcd. ) for C 22 H 26 N 6 O 2 .
  • Example 4 was further separated to give Examples 5 and 6.
  • Examples 51-63 were prepared by Method A, B, or C. All compounds were finally purified by HPLC (CH 3 CN/H 2 /O .05% TFA) .
  • Examples 51-59 were made by Suzuki coupling reactions of [ (4-bromophenyl) carbonyl]methyl-6- cyanobenzimidazole or [ (4-bromophenyl) carbonyl]methyl-5- cyanobenzimidazole with a variety of boronic acids by using Na 2 C0 3 (2-4 equivalents) and Pd(PPh 3 ) 4 (5-10% mmol -1 ) as catalyst in THF (80% in H 2 0, 10 mL/mmol), followed by Pinner reactions .
  • Method B Examples 60, 61 and 62 were made by alkylation of 5-cyanobenzimidazole with [4- (2- tert- butylaminosulfonylphenyl ) phenylaminocarbonyl ] methylene chloride, or (4-benzylpiperidinecarbonyl)methylene chloride, followed by Pinner reactions.
  • (4-Benzylpiperidinecarbonyl) methylene chloride was prepared by acylation of 4-benzyIpiperidine (100 mmol) with a- chloroacetyl chloride (100 mmol) in THF (250 mL) and K 2 CO 3 (100 mL.
  • Example 63 was made by Ulmann coupling reaction of 4-chloro-3-nitrobenzenitrile with (4- benzylpiperidinecarbonyl)methylamine, followed by reduction of
  • (4-Benzylpiperidinecarbonyl)methylamine was made by treatment of (4-benzylpiperidinecarbonyl)methylene chloride with Na 3 in aqueous acetone, followed by hydrogenation with 5% Pd/C. Reaction of (4-benzylpiperidinecarbonyl )methylamine (8.6 mmol) with 4-chloro-3-nitro-benzonitrile (10 mmol) in DMF (10 mL) in the presence of NaHCO> 3 (10 mmol) at 100°C for 16 hours gave 4- [ ( -benzylpiperidinecarbonyl)methyl]amino-3- nitrobenzonitrile (1.6 g, 49.2% of yield), which was then hydrogenated in MeOH in the presence of 5% of Pd/C (10% w/w) to produce 1- (4-benzylpiperidinecarbonyl)methyl-6- cyanobenzimidazole (1.3 g, 90% of yield). l-(4-
  • N-ethylmalonyl-4 ' -__minobiphenyl-2-tert-butylsulfonamide N-ethylmalonyl-4 ' -__minobiphenyl-2-tert-butylsulfonamide .
  • N-ethylmalonyl-4 , -aminobiphenyl-2-tert-butylsulfonamide N-ethylmalonyl-4 , -aminobiphenyl-2-tert-butylsulfonamide.
  • Example 66 A solution of Example 66 (26 mg) in TFA (0.5 mL) was heated for 16 hours. Removed all of the solvent and purified by HPLC with H2O-CH3CN-TFA to give the title compound (13 mg) .
  • N-l- Acetyl-1-N' -piperidinyl-4-benzyl-5-cyanoindole 500mg
  • Example 103 was prepared via the same method as example 101.
  • HRMS FAB glycerol matrix for C23H26N FO (M+H)+ calc. 393.209065, found 393.208858.
  • Example 109 Preparation of 1- (4-benzoylpiperidinecarbonyl)methyl-5- amidinoindole 1- (4-B ⁇ nzoylpiperidin ⁇ carbonyl)methyl-5-cyanoindole. Prepared as in example 108 except using 4-benzoylpiperidine. HRMS NH3- CI (M+H) + for C23H21N3O2 calc.372.171702, found 372.171620.
  • Methyl ⁇ -ketoacetate (4.90g) was dissolved in 50 mL trifluoro acetic acid at 0°C and triethyl silane (5.0g) was slowly added via a drop funnel (20 min.) . It was then stirred at 0°C for 3h. The resulting yellow solution was concentrated in vacuo, neutralized with sodium bicarbonate, extracted with diethyl acetate, dried with magnesium sulfate filtered and concentrated in vacuo. Purification was accomplished via silica gel chromatography using 1% Me0H/CH2Cl2 as the eluant to afford 2.48g of product. LRMS (M+H) + 232. 3-(5-Cyanoindole) acetic acid.
  • This product was treated with trifluoroacetic acid at 55°C for 2 h for deprotection of sulfonamide.
  • the reaction mixture was evaporated and purified by HPLC on a C-18 column eluted with solvent mixture A (water: TFA 99.95:0.05) and solvent mixture B (acetonitrile :TFA 99.95:0.05) using a gradient starting with A at 80 % and changing to B at 100 % over 60 min. to give 10.0 mg of pure product (3 %, poor yield due to poor solubility); HRMS (M+H) + calc. 449.164738, found 449.165207.
  • Example 224 The titled compound was prepared as in Example 203. HRMS for C 23 H 21 IN 5 O 3 S (M+H) + calc. 574.040989; found 574.042800.
  • Example 224
  • 'Ex. 65 contains the CH 2 -Z-A-B group at the 2-position
  • thromboembolic disorders as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms.
  • the anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.
  • the effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate.
  • the rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, OH) was measured both in the absence and presence of compounds of the present invention.
  • Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM.
  • a decrease in the rate of absorbance change at 405 run in the presence of inhibitor is indicative of enzyme inhibition.
  • the results of this assay are expressed as inhibitory constant, Ki .
  • Ki Ki values were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, IN) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate Ki values:
  • Ki is the dissociation constant of the enzyme : inhibitor complex; S is the concentration of substrate ,- Km is the Michaelis constant.
  • the antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model.
  • AV arterio-venous
  • rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used.
  • a saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae.
  • the AV shunt device consists of a piece of 6-cm tygon tubing which contains a piece of silk thread. Blood will flow from the femoral artery via the AV- shunt into the femoral vein.
  • the exposure of flowing blood to a silk thread will induce the formation of a significant thrombus.
  • the shunt is disconnected and the silk thread covered with thrombus is weighed.
  • Test agents or vehicle will be given (i.v., i.p., s.c, or orally) prior to the opening of the AV shunt.
  • the percentage inhibition of thrombus formation is determined for each treatment group.
  • the ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.
  • the compounds of formula (I) are also considered to be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.
  • Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system.
  • In vitro inhibition constants were determined by the method described by Kettner et al . in J. Biol . Chem . 265, 18289-18297 (1990), herein incorporated by reference.
  • thrombin- mediated hydrolysis of the chromogenic substrate S2238 Helena Laboratories, Beaumont, TX
  • Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition.
  • Human thrombin (Enzyme Research Laboratories, Inc., South Bend, IN) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5 , 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a Kj of less than 5 ⁇ , thereby confirming the utility of the compounds of the invention as effective thrombin inhibitors.
  • the compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents.
  • additional therapeutic agents include other anticoagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.
  • the compounds are administered to a mammal in a therapeutically effective amount.
  • therapeutically effective amount it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.
  • administered in combination or “combination therapy” it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated.
  • each component may be administered at the same time or sequentially in any order at different points in time.
  • each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
  • Other anticoagulant agents or coagulation inhibitory agents
  • warfarin and heparin as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.
  • anti-platelet agents denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets.
  • agents include, but are not limited to, the various known non-steroidal anti- inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof.
  • NSAIDS non-steroidal anti- inflammatory drugs
  • aspirin acetylsalicyclic acid or ASA
  • piroxicam are preferred.
  • Suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof .
  • Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use.
  • Still other suitable platelet inhibitory agents include Ilb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
  • thrombin inhibitors or anti-thrombin agents
  • thrombin-mediated processes such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted.
  • thrombin inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof.
  • Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof .
  • the term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin.
  • Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Patent No.
  • thrombolytics or fibrinolytic agents (or thrombolytics or fibrinolytics) , as used herein, denotes agents that lyse blood clots (thrombi) .
  • Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof.
  • tissue plasminogen activator anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein.
  • urokinase as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase .
  • Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each.
  • a lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
  • the compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa .
  • Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa.
  • a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound.
  • compounds according to the present invention could be used to test their effectiveness.
  • the compounds of the present invention may also be used in diagnostic assays involving factor Xa.
  • the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but no compound of the present invention, then one would conclude factor Xa was present.
  • the compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations) , pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal , subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.
  • a physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.
  • the daily oral dosage of each active ingredient when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day.
  • the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
  • Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
  • Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen .
  • the compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol , waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines .
  • Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol , polyhydroxyethylaspartamidephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans , polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans , polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
  • Dosage forms suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours . Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours . Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol .
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences. Mack Publishing Company, a standard reference text in this field.
  • a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • a mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried. Tablets
  • a large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.
  • Appropriate coatings may be applied to increase palatability or delay absorption. Iniectable
  • a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized. Suspension
  • An aqueous suspension is prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 mL of vanillin.
  • a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight.
  • the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.
  • a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight .
  • a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.
  • the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
  • one active ingredient may be enteric coated.
  • enteric coating one of the active ingredients it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines.
  • One of the active ingredients may also be coated with a material which effects a sustained- release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients.
  • the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine.
  • Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components.
  • HPMC hydroxypropyl methylcellulose
  • the polymer coating serves to form an additional barrier to interaction with the other component.

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Abstract

La présente demande concerne des amidinoindoles, des amidinoazoles et leurs analogues répondant à la formule (I), où W, W?1, W2 et W3¿ sont choisis parmi CH et N, à condition que l'un des éléments W1 et W2 soit C(C(=NH)NH¿2?), que deux au plus des éléments W, W?1, W2 et W3¿ soient N, et que l'un des éléments Ja et Jb soit substitué par -(CH¿2?)n-Z-A-B, et pouvant être utiles en tant qu'inhibiteurs du facteur Xa ou de la thrombine.
EP97933214A 1996-07-08 1997-06-30 AMIDINOINDOLES, AMIDINOAZOLES ET LEURS ANALOGUES AGISSANT EN TANT QU'INHIBITEURS DU FACTEUR Xa ET DE LA THROMBINE Withdrawn EP0960102A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US67676696A 1996-07-08 1996-07-08
US676766 1996-07-08
US4951997P 1997-06-13 1997-06-13
US49519P 1997-06-13
PCT/US1997/011325 WO1998001428A1 (fr) 1996-07-08 1997-06-30 AMIDINOINDOLES, AMIDINOAZOLES ET LEURS ANALOGUES AGISSANT EN TANT QU'INHIBITEURS DU FACTEUR Xa ET DE LA THROMBINE

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EP0960102A1 true EP0960102A1 (fr) 1999-12-01

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EP (1) EP0960102A1 (fr)
JP (1) JP2002514162A (fr)
AU (1) AU3645697A (fr)
CA (1) CA2259573A1 (fr)
IL (1) IL127873A0 (fr)
NZ (1) NZ333696A (fr)
WO (1) WO1998001428A1 (fr)

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AU3645697A (en) 1998-02-02
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CA2259573A1 (fr) 1998-01-15
WO1998001428A1 (fr) 1998-01-15
JP2002514162A (ja) 2002-05-14

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