WO2003093242A2 - Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade - Google Patents

Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade Download PDF

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Publication number
WO2003093242A2
WO2003093242A2 PCT/US2002/031770 US0231770W WO03093242A2 WO 2003093242 A2 WO2003093242 A2 WO 2003093242A2 US 0231770 W US0231770 W US 0231770W WO 03093242 A2 WO03093242 A2 WO 03093242A2
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group
compound
ring
hydroxy
hydrocarbyl
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PCT/US2002/031770
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WO2003093242A3 (en
Inventor
Michael S. South
Ronald K. Webber
Horng-Chih Huang
Mihaly V. Toth
Alan E. Moormann
Jeffrey S. Snyder
Jeffrey A. Scholten
Danny J. Garland
Melvin L. Rueppel
William L. Neumann
Scott Long
Huang Wei
John Trujillo
John J. Parlow
Darin E. Jones
Brenda Case
Michael J. Hayes
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Pharmacia LLC
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Pharmacia LLC
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Priority to CA002462645A priority Critical patent/CA2462645A1/en
Priority to MXPA04003170A priority patent/MXPA04003170A/en
Priority to EP02807360A priority patent/EP1432687A2/en
Priority to JP2004501381A priority patent/JP2005525413A/en
Priority to BR0213099-8A priority patent/BR0213099A/en
Priority to AU2002367752A priority patent/AU2002367752A1/en
Publication of WO2003093242A2 publication Critical patent/WO2003093242A2/en
Anticipated expiration legal-status Critical
Publication of WO2003093242A3 publication Critical patent/WO2003093242A3/en
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Definitions

  • the present invention relates to compounds, compositions and methods for preventing and treating thrombotic conditions such as coronary artery and cerebrovascular disease. More particularly, the invention relates to 5-membered polycyclic compounds, and prodrugs thereof that inhibit serine proteases of the coagulation cascade.
  • Hemorrhage, intravascular thrombosis, and embolism are common clinical manifestations of many diseases (see R. I. Handin in Harrison's Principles of Internal Medicine (J.D. Wilson, et al . eds., 12th ed. 1991) New York, McGraw-Hill Book Co., pp. 348-351).
  • the normal hemostatic system limits blood loss by precisely regulated interactions between components of the vessel wall, circulating blood platelets, and plasma proteins. Unregulated activation of the of the hemostatic system, however, may cause thrombosis, which can reduce blood flow to critical organs like the brain and myocardium.
  • Physiological systems control the fluidity of blood in mammals (see P.W. Majerus, et al . in Goodman & Gilman's The Pharmacological Basis of Therapeutics (J.G. Hardman & L.E. imbird, eds., 9th ed. 1996) New York, McGraw-Hill Book Co., pp. 1341-1343). Blood must remain fluid within the vascular systems and yet quickly be able to undergo hemostasis. Hemostasis, or clotting, begins when platelets first adhere to macromolecules in subendothelian regions of injured and/or damaged blood vessels.
  • Plasma coagulation factors also referred to as protease zymogens, include factors II, V, VII, VIII, IX, X, XI, and XII. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called "coagulation cascade" or chain reaction.
  • Coagulation or clotting occurs in two ways through different pathways.
  • An intrinsic or contact pathway leads from XII to Xlla to XIa to IXa and to the conversion of X to Xa .
  • Xa with factor Va converts prothrombin (II) to thrombin (Ila) leading to conversion of fibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot.
  • An extrinsic pathway is initiated by the conversion of coagulation factor VII to Vila by Xa.
  • Factor Vila a plasma protease, is exposed to, and combines with its essential cofactor tissue factor (TF) which resides constitutively beneath the endothelium. The resulting factor VIIa/TF complex proteolytically activates its substrates , factors IX and X, triggering a cascade of reactions that leads to the generation of thrombin and a fibrin clot as described above.
  • thrombosis results when platelet aggregation and/or a fibrin clot blocks (i.e., occludes) a blood vessel.
  • Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery.
  • a myocardial infarction or heart attack can result.
  • a thrombosis occurring in a vein may cause tissues drained by the vein to become edematous and inflamed.
  • Thrombosis of a deep vein may be complicated by a pulmonary embolism.
  • Preventing or treating clots in a blood vessel may be therapeutically useful by inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, inhibiting embolus formation, and for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels.
  • this polar functional group is a nitrogen atom of, for example, a guanidine, alkyl-amidine or aryl-amidine group. Because these functionalities are highly basic, they remain protonated at physiologically relevant pH's. The ionic nature of such protonated species hinders their permeability across lipophilic membranes, which can reduce bioavailability when the pharmaceutical agent is administered orally.
  • the derivatization In order to circumvent such a problem, it is often advantageous to perform a derivatization or chemical modification of the polar functionality such that the pharmaceutical agent becomes neutrally charged and more lipophilic, thereby facilitating absorption of the drug.
  • the derivatization must be bioconvertable at the target site or sites of desired pharmacological activity and cleaved under normal physiological conditions to yield the biologically active drug.
  • prodrug has been used to denote such a chemically modified intermediate.
  • prodrug compounds useful for selective inhibition of certain enzymes that act upon the coagulation cascade thereby preventing and treating thrombotic conditions in mammals.
  • these prodrug compounds undergo hydrolysis, oxidation, reduction or elimination at a derivatized amidine group to yield the active compound.
  • the present invention is directed to the compound, per se, to the prodrug of the compound, to pharmaceutical compositions comprising the compound or prodrug and a pharmaceutically acceptable carrier, and to methods of use.
  • the invention embraces compounds having formula (I) :
  • X comprises a 5-membered heterocyclic or carbocyclic ring, the ring atoms being X x , X 2 , X 3 , X 4 , and X 5 , wherein X 1# X 3 , and X 4 , are independently carbon or nitrogen and X 2 and X 5 are independently carbon, nitrogen, oxygen or sulfur;
  • L x , L 3 and L 4 are linkages through which Z ⁇ ⁇ Z 3 , and Z 4 , respectively, are covalently bonded to different ring atoms of the 5-membered heterocyclic or carbocyclic ring of X, wherein Z x is covalently bonded to X 1# Z 3 is covalently bonded to X 3 , and Z 4 is covalently bonded to X 4 , each of L 1; L 3 and L 4 independently being a covalent bond or comprising one or more atoms through which Z l t Z 3 , and Z 4 are covalently bonded to X 1# X 3 and X 4 , respectively;
  • Z x is hydrocarbyl or substituted hydrocarbyl .
  • Z 3 comprises a 5- or 6-membered heterocyclic or aromatic ring substituted with an amidine group, the ring atoms of the 5- or 6-membered heterocyclic or aromatic ring of Z 3 being carbon, sulfur, nitrogen, or oxygen, wherein the 5- or 6-membered ring is optionally substituted at any position with halogen, alkyl or hydroxy; and
  • Z 4 comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of the 5- or 6-membered heterocyclic or carbocyclic ring of Z 4 being carbon, nitrogen, oxygen, or sulfur.
  • Another aspect of the invention provides compounds corresponding to formula (II)
  • X 2 and X 5 are as defined for compounds having formula ( I ) ;
  • X x , X 3 and X 4 are independently carbon or nitrogen;
  • X 9 is a direct bond or -(CH 2 ) m - where m is 1 or 2; and Z l t Z 3 and Z 4 are as defined for compounds having formula (I) .
  • reaction is generally meant to encompass any one or more of the following reactions: (1) a reaction that results in a compound fragmenting into two or more compounds; and (2) a reaction that results in one or more groups being removed from a compound without being replaced by other groups .
  • oxidation is generally meant to encompass any one or more of the following reactions: (1) a reaction that results in an increase in the oxidation number of an atom in a compound, whether the atom is uncharged or charged and whether free or covalently bound; (2) a reaction that results in the loss of hydrogen from a compound; (3) a reaction that results in the loss or removal of one or more electrons from a compound, with or without concomitant loss or removal of a proton or protons;
  • reaction is generally meant to encompass any one or more of the following reactions: (1) any reaction which results in a decrease in the oxidation number of an atom in a compound; and (2) any reaction that results in oxygen being withdrawn from, hydrogen being added to, or an electron being added to (with or without the addition of a proton) a compound.
  • hydrolysis is generally meant to encompass any one or more of the following reactions: (1) any reaction which results in the addition of a nucleophile to a compound to form a new bond with concurrent loss of a group from the compound; (2) any reaction which results in the addition of water to a compound; and (3) any reaction that results in the rupture of one or more chemical bonds by reaction with, and involving the addition of, the elements of water.
  • physiological conditions are those conditions characteristic to an organism's (to a human beings) healthy or normal functioning.
  • hydrocarbon and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl . Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
  • substituted hydrocarbyl moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a heteroatom such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur, or a halogen atom.
  • Exemplary substituted hydrocarbyl moieties include, heterocyclo, alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl , aryloxyalkyl, hydroxyalkyl, protected hydroxyalkyl , keto, acyl , nitroalkyl, aminoalkyl, cyano, alkylthioalkyl , arylthioalkyl, ketals, acetals, amides, acids, esters and the like.
  • heteroatom shall mean atoms other than carbon and hydrogen.
  • the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms . They may be straight or branched chain or cyclic and include methyl, ethyl, propyl , isopropyl, butyl, hexyl and the like.
  • the alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl , isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
  • alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl , butynyl , isobutynyl, hexynyl, and the like.
  • aryl or “ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl , biphenyl, naphthyl , substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl .
  • halogen or “halo” as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
  • heterocyclo or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
  • the heterocyclo group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom.
  • heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl , oxazolyl, pyrrolyl , indolyl , quinolinyl, or isoquinolinyl and the like.
  • substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • heteroaromatic as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
  • the heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom.
  • Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.
  • substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • acyl denotes the moiety formed by removal of the hydroxyl group from the group -COOH of an organic carboxylic acid, e.g., RC(O)-, wherein R is hydrogen, R 1 , R ⁇ -, R 1 RN-, or R ⁇ -, R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R 2 is hydrogen, hydrocarbyl or substituted hydrocarbyl.
  • acyloxy denotes an acyl group as described above bonded through an oxygen linkage (-0-), e.g., RC(0)0- wherein R is as defined in connection with the term "acyl.”
  • acetamidyl as used herein describes a chemical moiety represented by the formula NR 1 C(0)R 2 .
  • alkoxycarbonyl as used herein describes a chemical moiety represented by the formula C(0)OR.
  • sulfonamido as used herein describes a chemical moiety represented by the formula S0 2 NR 1 R 2 .
  • alkylsulfonyl as used herein describes a chemical moiety represented by the formula S0 2 R.
  • sulfonamidyl as used herein describes a chemical moiety represented by the formula NRS0 2 R.
  • R, R ⁇ and R 2 are independently hydrogen, alkyl, aryl, and arylakyl, optionally substituted with halogen, hydroxy or alkoxy.
  • One aspect of the invention embraces compounds that correspond to formula (I)
  • X comprises a 5-membered heterocyclic or carbocyclic ring, the ring atoms being X-, X 2 , X 3 , X 4 , and X 5 , wherein X 1; X 3 , and X 4 , are independently carbon or nitrogen and X 2 and X 5 are independently carbon, nitrogen, oxygen or sulfur;
  • L l7 3 and L 4 are linkages through which Z-, Z 3 , and Z 4 , respectively, are covalently bonded to different ring atoms of the 5-membered heterocyclic or carbocyclic ring of X, wherein Z x is covalently bonded to X 1# Z 3 is covalently bonded to X 3 , and Z 4 is covalently bonded to X 4 , each of L x , 3 and L 4 independently being a covalent bond or comprising one or more atoms through which Z l t Z 3 , and Z 4 are covalently bonded to X 17 X 3 and X 4 , respectively;
  • Z- is hydrocarbyl or substituted hydrocarbyl;
  • Z 3 comprises a 5- or 6-membered heterocyclic or aromatic ring substituted with an amidine group, the ring atoms of the 5- or 6-membered heterocyclic or aromatic ring of Z 3 being carbon, sulfur, nitrogen, or oxygen, wherein the 5- or 6-membere
  • Z 4 comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of the 5- or 6-membered heterocyclic or carbocyclic ring of Z 4 being carbon, nitrogen, oxygen, or sulfur.
  • each of X-, X 2 , X 3 , X 4 , and X 5 are as defined in the embodiment above;
  • L x is -X 9 NH- wherein X 9 is covalently bonded directly to Z and X 9 is a direct bond or -(CH 2 ) m - wherein m is 1 to 5;
  • L 3 is a glycine derivative
  • L 4 is a direct bond
  • Z x is selected from the group consisting of C.-C B alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen;
  • Z 3 comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy;
  • Z 4 comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of Z 4 being Z 40 , Z 41 , Z 42 , Z 44 and Z 45 when Z 4 is a 5-membered ring and Z 40 , Z 41 , Z 42 , Z 43 , Z 44 and Z 45 when Z 4 is a 6-membered ring, Z 40 , Z 41 , Z 42 , Z 43 , Z 44 and Z 45 , being carbon, nitrogen, oxygen or sulfur, Z 40 being the ring atom through which Z 4 is attached to the heterocyclic ring, Z 41 and Z 45 each being in an alpha position relative to Z 40 , Z 42 and Z 44 each being in a beta position relative to Z 40 , Z 43 being in the gamma position relative to Z 40 when Z 4 is a 6-membered ring, Z 4 having a substituent R 42 covalently attached to Z 42 , and a second substituent bonded to one of Z 41 , Z 43 , Z 44 ,
  • R 42 is amino
  • R 4 ⁇ , R 43 , R 44 and R 45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R 41 , R 43 , R 44 or R 45 is other than hydrogen.
  • Still a further embodiment provides compounds having formula (I) , where L- is -X 9 NH- wherein X 9 is covalently bonded directly to Z x and X 9 is a direct bond; L 3 is -CH 2 CONHCH 2 - and Z 3 is covalently bonded to the methylene bonded to the amine nitrogen of L 3 ;
  • Z is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl ;
  • Z 3 comprises a phenyl ring, the phenyl ring being optionally further substituted with fluorine or hydroxy;
  • Z 4 comprises a phenyl or thienyl ring having two substituents, R 42 and R 44 , and two ring atoms each of which is in the beta position relative to the ring atom of Z 4 through which Z 4 is covalently bonded to X, wherein one of R 42 and R 44 is covalently bonded to one of the beta positions and the other of R 42 and R 44 is covalently bonded to the other of the beta positions;
  • R 42 is amino
  • R 44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, and an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus.
  • the Li linkage is -X 9 NH- where X 9 is covalently bonded directly to Z. and is a direct bond or an alkylene chain having the formula (CH 2 ) m wherein m is 0 to 5. In an alternative embodiment, m is 0 to 2. In another embodiment, the L. linkage is a bond.
  • the L 3 linkage is a glycine derivative, an alanine derivative, an amino derivative, or a sulfonyl derivative.
  • the L 3 linkage is a glycine derivative.
  • the L 3 linkage is -CH 2 CONHCH 2 - where Z 3 is covalently bonded to the methylene bonded to the amine nitrogen of 3 .
  • the L 4 linkage is a direct bond, methylene, ethylene or an optionally substituted heteroatom selected from the group nitrogen, oxygen, sulfur or phosphorus. In another embodiment, the 4 linkage is a direct bond.
  • Z x is a C.-C 3 alkyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy or alkoxycarbonyl .
  • the Ci-C 3 alkyl is a cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl.
  • the C x - C 5 alkyl is isopropyl or cyclobutyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl.
  • Z x is trifluoroethyl or carboxymethyl .
  • Z 3 is a 5- or 6-membered heterocyclic or aromatic ring substituted with an amidine group and may be optionally substituted at any substitutable position with halogen, hydroxy, haloalkyl, alkyl, carboxy, alkoxycarbonyl, or hydrocarbyloxy, or any combination thereof.
  • a preferred halogen is fluorine.
  • Z 3 is a 6-membered carbocyclic aromatic ring substituted with an amidine group.
  • Z 3 comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with an amidine group, and optionally further substituted at any substitutable position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy .
  • Z 3 corresponds to formula (a)
  • R 304 and R 306 are independently selected from the group consisting of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy and alkoxycarbonyl ;
  • R 305 and R 307 are independently selected from the group consisting of hydrogen, fluorine, methoxy, hydroxy and carboxy .
  • Z 3 is selected from the group consisting of benzamidine-4-yl, 3-hydroxybenzamidine-4-yl , 3 , 5-dihydroxybenzamidine-4-yl,
  • R 3 03 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur, provided at least one of R 301 , R 302 / R 303 is other than hydrogen.
  • R 3 03 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur, provided at
  • R 300 is a 6-membered carbocyclic aromatic ring, and at least two of R 30 ⁇ , R302.
  • R 303 are ring atoms of a heterocyclic ring.
  • R 300 is a 6-membered carbocyclic aromatic ring, and at least one of R 301 , R 302 .
  • R 303 are ring atoms of a heterocyclic ring fused to R 300 -
  • Yet another embodiment encompasses prodrug compounds having formula (I) where Z 3 is a benzamidine derivatized with one or more groups selected from carbonyl , thiocarbonyl, imino, enamino, phosphorus, and sulfur, where the benzamidine derivative hydrolyzes under physiological conditions to form benzamidine.
  • Z 3 is a benzamidine derivatized with one or more groups selected from optionally substituted hydrocarbyl, provided that the carbon atom directly bonded to the amidine is sp 3 hybridized and aryl, where the benzamidine derivative is oxidized under physiological conditions to form benzamidine.
  • Z 3 is a benzamidine derivatized with one or more heteroatoms selected from oxygen, nitrogen in its most reduced state, and sulfur in its most reduced state, where the benzamidine derivative is reduced under physiological conditions to form benzamidine.
  • Z 3 is a benzamidine derivatized with one or more substituents selected from a hydrocarbyl substituted at the beta carbon with carbonyl, sulfonyl, sulfinyl, cyano, nitro and an alkyl, aryl, or heterocyclic group substituted with oxygen, nitrogen, or sulfur at the carbon directly bonded to the amidine group, where the benzamidine derivative undergoes elimination at physiological conditions to form benzamidine.
  • Z 3 corresponds to formula (b)
  • R a is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, and heterocylo, provided, however, that the carbon atom of R 30 ⁇ , R 302 . and R 303 directly bonded to the amidine is sp 2 hybridized when R 301 , R 302 . an ⁇ 3 R 303 is alkenyl,
  • R 304 is selected from the group consisting of halogen, hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio;
  • R 305 is selected from the group consisting of oxygen, sulfur, halogen, hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio,-
  • R 306 is selected from the group consisting of halogen, hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio;
  • R 307 is selected from the group consisting of oxygen, sulfur, halogen, hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio.
  • the benzamidine derivative is hydrolyzed under physiological conditions to form benzamidine when Z 3 is a benzamidine derivative having formula (b) and R 30 ⁇ , 302 .
  • the benzamidine derivative is oxidized under physiological conditions to form benzamidine when Z 3 is a benzamidine derivative having formula (b) and R 30 ⁇ , R 3o2 .
  • an ⁇ R 303 are independently selected from hydrogen, optionally substituted hydrocarbyl and aryl, provided, however, the carbon atom of R 30 ⁇ , R 302 .
  • an ⁇ 3 R 303 directly bonded to the amidine is sp 3 hybridized when R 30 ⁇ , R 302 . and R 303 is optionally substituted hydrocarbyl.
  • the benzamidine derivative is reduced under physiological conditions to form benzamidine when Z 3 is a benzamidine derivative having formula (b) and R 301/ R 302 and R 303 are independently selected from hydrogen, -OR,b-
  • each R b is independently optionally substituted hydrocarbyl, and heterocylo.
  • the benzamidine derivative undergoes elimination at physiological conditions to form benzamidine when Z 3 is a benzamidine derivative having formula (b) and R 3o ⁇ R 302 an d R 303 are independently selected from hydrogen, substituted hydrocarbyl wherein the carbon bonded to the amidine group is substituted with -OR c , -SR C , -NR C , or -N(R C ) 2 , wherein each R c is independently -C(0)R d , -C(0)NR d , -C(0)0R d -C(0)N(R d ) 2 and each R d is independently hydrocarbyl, substituted hydrocarbyl or heterocyclo, and substituted alkyl with the carbon atom beta to the point of attachment to the amidine group being an unsaturated electron withdrawing group.
  • a further embodiment embraces compounds having formula (I) where Z 4 is a substituted, 6-membered carbocyclic aromatic ring.
  • Z 4 corresponds to formula (c)
  • R 42 is amino;
  • R 44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, halogen and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and
  • R 41 , R 43 and R 45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • R 44 is selected from hydrocarbyl, substituted hydrocarbyl, acetamido, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, carboalkoxy, carboxy, carboxamidoalkyl , and carboxamidoalkylaryl .
  • R 44 is selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, heterocyclo, halogen, acetamido, guanidino, hydroxy, nitro, amino, amidosulfonyl, acylamido, hydrocarbyloxy, substituted hydrocarbyloxy, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylsulfonyl , and substituted hydrocarbylsulfonyl .
  • R 44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl, carboxamidobenzyl , carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3- aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, m-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl -2 -methylbutylamide , isobutylacylamine , isobutylsulfoxyl, 2-cyclohe
  • R 41 , R 43 and R 45 are independently selected from the group consisting of hydrogen, halogen, alkoxy, or hydroxy and R 44 is as defined in any of the alternative embodiments above.
  • R 41 , R 43 and R 45 are independently selected from the group consisting of hydrogen and halogen and R 44 is as defined in any of the alternative embodiments above.
  • R 45 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, carboxy, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine.
  • R 45 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl , haloalkoxy, haloalkythio, alkoxycarbonyl, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine.
  • R 45 is selected from the group consisting of hydroxy, carboxy, carboxamido, alkoxy, alkylsulfonyl , sulfonamido, and alkoxycarbonyl.
  • R 45 is selected from the group consisting of sec-butylamide, carboxy, ethoxycarbonyl , isopropoxycarbonyl , butoxycarbonyl , isopropylamide and hydroxy.
  • R 41 , R 43 and R 44 are independently selected from the group consisting of hydrogen, halogen, alkoxy, or hydroxy and R 45 is as defined in any of the alternative embodiments above.
  • R 41/ R 43 and R 44 are independently selected from the group consisting of hydrogen and halogen and R 45 is as defined in any of the alternative embodiments above.
  • R 43 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, carboxy, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine.
  • R 43 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine.
  • R 43 is selected from the group consisting of hydroxy, carboxy, carboxamido, alkoxy, alkylsulfonyl , sulfonamido, and alkoxycarbonyl.
  • R 43 is selected from the group consisting of sec-butylamide, carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropylamide and hydroxy.
  • R 41 , R 44 and R 45 are independently selected from the group consisting of hydrogen, halogen, alkoxy, or hydroxy and R 43 is as defined in any of the alternative embodiments above.
  • R 41 , R 44 and R 45 are independently selected from the group consisting of hydrogen and halogen and R 43 is as defined in any of the alternative embodiments above.
  • R 41 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, carboxy, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine.
  • R 41 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine.
  • R 41 is selected from the group consisting of hydroxy, carboxy, carboxamido, alkoxy, alkylsulfonyl , sulfonamido, and alkoxycarbonyl .
  • R 41 is selected from the group consisting of sec-butylamide, carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropylamide and hydroxy.
  • R 43 , R 44 and R 45 are independently selected from the group consisting of hydrogen, halogen, alkoxy, or hydroxy and R 41 is as defined in any of the alternative embodiments above.
  • R 43 , R 44 and R 45 are independently selected from the group consisting of hydrogen and halogen and R 41 is as defined in any of the alternative embodiments above.
  • Z 4 is a five-membered ring having formula (d)
  • Z 40 , Z 41 , Z 42 , Z 44 , and Z 45 are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;
  • R 42 is amino
  • R 44 is selected from the group consisting of is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, halogen and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur;
  • R 41 and R 45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • R 44 is selected from hydrocarbyl, substituted hydrocarbyl, acetamido, alkoxy, hydroxy, amino, alkylsulfonyl , haloalkyl, haloalkoxy, haloalkylthio, carboalkoxy, carboxy, carboxamidoalkyl , and carboxamidoalkylaryl .
  • R 44 is selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, heterocyclo, halogen, acetamido, guanidino, hydroxy, nitro, amino, amidosulfonyl , acylamido, hydrocarbyloxy, substituted hydrocarbyloxy, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylsulfonyl , and substituted hydrocarbylsulfonyl .
  • R 44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl, carboxamidobenzyl , carboxamidobutyl-2-yl , isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3- aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, m-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl -2 -methylbutylamide , isobutylacylamine , isobutylsulfoxyl, 2-cyclo
  • R 41 and R 4S are independently selected from the group consisting of hydrogen, halogen, alkoxy, or hydroxy and R 44 is as defined in any of the alternative embodiments above.
  • R 41 and R 45 are independently selected from the group consisting of hydrogen and halogen and R 44 is as defined in any of the alternative embodiments above.
  • Still another embodiment provides compounds having formula (I) where X 2 or X 5 are hydrogen bond acceptors. In another embodiment, both X 2 and X 5 are hydrogen bond acceptors. Generally speaking, the phrase "hydrogen bond acceptor" encompasses heteroatoms having a lone pair of electrons available for hydrogen bonding.
  • Suitable hydrogen bond acceptors when taken with the carbon to which Z 2 is attached, are typically selected from the group consisting of C (O) , C(S), C(C1), C(Br), C(F), C (OH) , COCH 3/ COR, C(SH), CSR, and CNR-R;, wherein R, R x and R 2 are independently hydrogen, alkyl, aryl, and arylakyl, optionally substituted with halogen, hydroxy or alkoxy.
  • Suitable X 2 groups include carbon substituted with hydrogen, fluorine, oxygen, or sulfur, nitrogen optionally substituted with hydrogen or oxygen, oxygen, or sulfur.
  • Suitable X 5 groups include oxygen, sulfur, nitrogen, carbonyl and carbon substituted with a halogen selected from fluorine, chlorine and bromine.
  • X 17 X 2 , X 3 , X 4 , and X 5 are carbon or nitrogen.
  • X 1 X 2 and X 5 are carbon, and X 3 and X 4 are nitrogen.
  • X 1# X 3 , X 4 and X 5 are carbon and X 2 is nitrogen.
  • X lf X 2 , X 3 , X 4 and X 5 are all carbon.
  • X l t X 4 and X 5 are carbon and X 2 and X 3 are nitrogen.
  • X l7 X 2 , X 3 , X 4 , and X 5 form a 5-membered heterocyclic or carbocyclic ring selected from pyrazolinone, pyrrole, thiophene, pyrazole-N-oxide, 1-amino-pyrazole, 1,3,4- triazole, 2-amino-4-aryl-thiazole, 2-amino-5-aryl-thiazole, pyrrolidine, 2-amino-5-aryl-oxazole, 3-amino-pyrazole, 2- amio-4-aryl-oxazole, tetrahydrofuran, cyclopentadienone, and N-hydroxypyrrolidine .
  • X 1 X 2 , X 3 , X 4 , and X 5 form a pyrazolinone, thiophene, pyrazole-N-oxide, 2-amino-5-aryl-thiazole, tetrahydrofuran, cyclopentadienone, or a N- hydroxypyrrolidine ring.
  • the ring is a pyrazolinone, pyrazole-N-oxide, cyclopentadienone, or a N-hydroxypyrrolidine.
  • the ring is a pyrazolinone.
  • Another aspect of the invention embraces compounds that correspond to formula (II)
  • X 2 and X 5 are as defined for compounds having formula
  • X x , X 3 and X 4 are independently carbon or nitrogen;
  • X 9 is a direct bond or -(CH 2 ) m - where m is 1 or 2; and Z lf Z 3 and Z 4 are as defined for compounds having formula (I) .
  • each of X lf X 2 , X 3 , X 4 , and X 5 is carbon or nitrogen;
  • X 9 is selected from the group consisting of a direct bond, methylene, and ethylene;
  • Z is selected from the group consisting of alkyl, C 2 -C 8 alkenyl, and C 2 -C 8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen;
  • Z 3 comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy;
  • Z 4 comprises a phenyl or thienyl ring having two substituents, R 42 and R 44 , and two ring atoms each of which is in the beta position relative to the ring atom of Z 4 through which Z 4 is covalently bonded to X, wherein one of R 42 and R 44 is covalently bonded to one of said beta positions and the other of R 42 and R 44 is covalently bonded to the other of said beta positions; R 42 is amino; and
  • R 44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, and an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus.
  • each of X 1# X 2 , X 3 , X 4 , and X 5 is carbon or nitrogen;
  • X 9 is a direct bond;
  • Z x is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl;
  • Z 3 is a phenyl ring, the phenyl ring being optionally further substituted with fluorine or hydroxy;
  • Z 4 is a substituted phenyl ring as described in other embodiments for compounds having formula (II) ;
  • R 44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl , carboxamidobenzyl , carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2 -methylbutylamide, isobutylacylamine, isobutylsulfoxyl , 2-cyclohexylamide, meth
  • a further embodiment provides compounds having formula (II) that are represented by formula (Ila)
  • Z x is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl;
  • R 302 R 303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur; and
  • Z 4 is a phenyl ring having formula (c) wherein: R 42 is amino; R 44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl, carboxamidobenzyl, carboxamidobutyl-2-yl , isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2-methylbutylamide, isobutylacylamine, iso
  • R 41 , R 43 and R 45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • a further embodiment provides compounds having formula (II) that are represented by formula (lib)
  • Z x is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl ;
  • R 302 R 303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur; and
  • Z 4 is a phenyl ring having formula (c) wherein: R 42 is amino;
  • R 44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl , carboxamidobenzyl , carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2-methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy,
  • R 41 , R 43 and R 45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Z x is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl ;
  • Z 3 is wherein R 300 is a phenyl ring, R 3o ⁇ .
  • R 302 R 303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur; and
  • Z 4 is a phenyl ring having formula (c) wherein: R 42 is amino;
  • R 44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl, carboxamidobenzyl , carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2 -methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy,
  • R 41 , R 43 and R 45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Still a further embodiment provides compounds having formula (II) that are represented by formula (lid)
  • Z is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl;
  • Z 4 is a phenyl ring having formula (c) wherein: R 42 is amino;
  • R 44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl, carboxamidobenzyl, carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl -2 -methylbutylamide , isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy,
  • R 41 , R 43 and R 45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • a further aspect of the invention embraces compounds having formula (III)
  • each of X l f X 2 , X 3 , X 4 , and X 5 form any of the 5- membered heterocyclic or carbocyclic rings indicated in Table 1 below and are selected from pyrazolinone, pyrrole, thiophene, pyrazole-N-oxide, 1-amino-pyrazole, 1,3,4- triazole, 2-amino-4-aryl-thiazole, 2-amino-5-aryl-thiazole, pyrrolidine, 2-amino-5-aryl-oxazole, 3-amino-pyrazole, 2- amio-4-aryl-oxazole, tetrahydrofuran, cyclopentadienone, and N-hydroxypyrrolidine; and
  • Z- and R 44 are any of the groups detailed in Table 1 below.
  • each ring formed by X 17 X 2 , X 3 , X 4 , and X 5 identified in Table 1 is shown below Additionally, the structure for each R 44 group identified in Table 1 is shown below.
  • Another aspect of the invention embraces compounds that correspond to formula (IV)
  • R 44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl , carboxamidobenzyl, carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, m- f.luorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2 -methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide,
  • a further embodiment provides compounds having formula (IV) that are represented by formula (IVa)
  • Z x is isopropyl, cyclopropyl, cyclobutyl or cycylopentyl optionally substituted by fluorine, hydroxy, carboxy, or alkoxycarbonyl;
  • R 44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl , carboxamidobenzyl, carboxamidobutyl-2 -yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3 -aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, m-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-
  • R 310 and R 311 are independently selected from the group consisting of hydrogen, fluorine, hydroxy, alkoxy, and carboxy, provided at least one of R 310 and R 311 is other than fluorine and hydrogen.
  • Z x is isopropyl, cyclopropyl, cyclobutyl or cycylopentyl optionally substituted by fluorine, hydroxy, carboxy, or alkoxycarbonyl;
  • R Room is Ci-Cg alkyl, aryl, aralkyl, carboxy, hydroxy or carboxyalkyl, wherein the alkyl, aryl, aralkyl, carboxy, hydroxy or carboxyalkyl is optionally further substituted by fluorine .
  • Still another embodiment provides compounds having formula (IV) that are represented by formula (IVc)
  • Z x is isopropyl, cyclopropyl, cyclobutyl or cycylopentyl optionally substituted by fluorine, hydroxy, carboxy, or alkoxycarbonyl;
  • Z 3 corresponds to formula (a) detailed above ;
  • R 440 is Ci-Cg alkyl, aryl, aralkyl, carboxy, or carboxyalkyl, wherein the alkyl, aryl, aralkyl, carboxy, or carboxyalkyl is optionally further substituted by fluorine.
  • a further aspect of the invention embraces compounds having formula (V)
  • Z 1; Z 3 , Z 4 , L 3 , X 2 , X 3 , and X 4 are as defined for any of formulas (I) - (IV) ;
  • X x and X s are independently carbon and nitrogen;
  • X 7 and X 8 are independently a covalent bond, carbon, nitrogen, oxygen or sulfur;
  • X 9 is carbon substituted with a methylene group or carbon substituted with an ethylene group wherein said methylene or ethylene group covalently links X 9 and Z x ; Z 2 , when present, is a hydrogen bond acceptor covalently or datively bonded to X 2 ; n is 0 to 2; and
  • R 70 and R 80 are independently selected from the group consisting of hydrogen, halogen, amino, hydrocarbyl, substituted hydrocarbyl, aryl, wherein aryl is phenyl either unsubstituted or substituted with hydroxy, amino, C--C 6 alkyl, C 3 -C 8 cycloalkyl, or halogen provided that R 70 is not present when X 7 is a bond and R 80 is not present when X 8 is a bond; or R 70 and R 80 , along with the ring atoms to which each is attached, form a 5 or 6 membered saturated ring.
  • Yet another aspect of the invention provides compounds that are intermediates in the synthesis of compounds having formulas (I) - (V) . These intermediate compounds correspond to formula (VI)
  • X 17 X 2 , X 3 , and X 5 are members of a heterocyclic or carbocyclic ring; X 1; X 2 , and X 3 are independently carbon or nitrogen;
  • T 3 is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, and substituted amino;
  • T 4 is selected from the group consisting of -Cl, -Br, -I, -S(CH 3 ), and -OS0 2 (CF 3 ) ;
  • Z x is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; and Z 2 , when present, is a hydrogen bond acceptor covalently or datively bonded to X 2 .
  • Yet another aspect of the invention provides compounds that are intermediates in the synthesis of compounds having formulas (I) - (V) . These intermediate compounds correspond to formula (VII)
  • X ⁇ ⁇ X 2 , X 3 , and X 5 are members of a heterocyclic or aromatic core ring;
  • X lf X 2 , and X 3 are independently carbon or nitrogen;
  • Z x is hydrocarbyl, or substituted hydrocarbyl
  • Z 2 when present, is a hydrogen bond acceptor covalently or datively bonded to X 2 ;
  • Z 4 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of the 5- or 6-membered heterocyclic or carbocyclic ring of Z 4 being carbon, nitrogen, oxygen, or sulfur.
  • any compound corresponding to any of formulas (I) - (V) having one or more prodrug moieties as part of the molecule, can be converted under physiological conditions to the biologically active drug by a number of chemical and biological mechanisms.
  • these prodrug conversion mechanisms are hydrolysis, reduction, oxidation, and elimination.
  • conversion of the prodrug to the biologically active drug can be accomplished by hydrolysis of the prodrug moiety provided the prodrug moiety is chemically or enzymatically hydrolyzable with water.
  • the reaction with water typically results in removal of the prodrug moiety and liberation of the biologically active drug.
  • a hydrolyzable prodrug derivative at the amidine group may be a carbonyl derivative such as N- acyl. Hydrolysis results in freeing the amidine group of the drug by removal of the acyl as carbon acid.
  • suitable hydrolyzable prodrug derivatives include carbonyl, thiocarbonyl, imine, enamine, and oxygenated sulfur.
  • Yet another aspect of the invention provides conversion of the prodrug to the biologically active drug by reduction of the prodrug moiety.
  • the prodrug moiety is reducible under physiological conditions in the presence of a reducing enzymatic process.
  • the reduction preferably results in removal of the prodrug moiety and liberation of the biologically active drug.
  • An example of a reducible prodrug derivative at the amidine group is an oxygen containing group in which an oxygen is directly attached to the amidine. Reduction results in freeing the amidine group of the drug by removal of oxygen as water or an alcohol.
  • other suitable reducible prodrug derivatives include a nitrogen containing group, and a sulfur containing group, provided both nitrogen and sulfur are each preferably in their most reduced state.
  • conversion of the prodrug to the biologically active drug can also be accomplished by oxidation of the prodrug moiety.
  • the prodrug moiety is oxidizable under physiological conditions in the presence of an oxidative enzymatic process. The oxidation preferably results in removal of the prodrug moiety and liberation of the biologically active drug.
  • An example of an oxidizable prodrug derivative at the amidine group is a hydrocarbyl containing unsaturation in the carbon beta to the carbon directly connected to the amidine group. Oxidation results in forming an oxygenated intermediate that breaks down, thereby freeing the amidine group of the drug with concurrent hydrolysis of the oxygenated hydrocarbyl residue.
  • Suitable oxidizable prodrug derivatives of the amidine include saturated hydrocarbyl, unsaturated substituted hydrocarbyl , aryl , and aralkyl .
  • a further aspect of the invention encompasses conversion of the prodrug to the biologically active drug by elimination of the prodrug moiety. Generally speaking, in this embodiment the prodrug moiety is removed under physiological conditions with a chemical or biological reaction. The elimination results in removal of the prodrug moiety and liberation of the biologically active drug.
  • an eliminateable prodrug derivative at the amidine group is a hydrocarbyl containing an unsaturated electron withdrawing group bonded to the carbon beta to the carbon directly connected to the amidine.
  • the hydrocarbyl group could have a cyano group beta to the carbon directly bonded to the amidino group. Elimination results in the freeing of the amidine group of the drug with concurrent removal of the unsaturated hydrocarbyl residue derived from the prodrug moiety.
  • Other suitable eliminateable prodrug derivatives of the amidine include a hydrocarbyl substituted at the beta carbon with carbonyl, alkoxycarbonyl, amidocarbonyl , nitro, or sulfonyl or an alkyl group substituted with oxygen, nitrogen or sulfur at the carbon directly bonded to the amidine group.
  • Any compound of the present invention corresponding to formulas (I) - (V) may undergo any combination of the above detailed mechanisms to convert the prodrug to the biologically active compound.
  • a particular compound may undergo hydrolysis, oxidation, elimination, and reduction to convert the prodrug to the biologically active compound.
  • a particular compound may undergo only one of these mechanisms to convert the prodrug to the biologically active compound.
  • the compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of compounds having any of formulas (I) - (V) .
  • Pharmaceutically acceptable salts of such tautomeric, geometric or stereoisomeric forms are also included within the invention.
  • cis and trans denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond ("sis") or on opposite sides of the double bond ("trans").
  • Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or “E” and “Z” geometric forms.
  • some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures or R and S forms for each stereocenter present .
  • pharmaceutically-acceptable salts are also included in the family of compounds having any of formulas (I) - (V).
  • pharmaceutically-acceptable salt embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically- acceptable acid addition salts of the compounds may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic) , methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, and galacturonic acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic,
  • Suitable pharmaceutically-acceptable base addition salts of the compounds include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'- dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the selected compound of any of formulas (I) - (V) .
  • the present invention also comprises a pharmaceutical composition comprising a therapeutically-effective amount of the compound of the invention in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
  • compositions of the present invention can comprise the active compounds of formulas (I) - (V) in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier” materials) and, if desired, other active ingredients.
  • carrier non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants
  • the active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, oculary, or topically.
  • the compounds may be administered intraocularly or topically as well as orally or parenterally.
  • the compounds can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient.
  • the active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramusculary as depot injections or implants.
  • Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, silastic, silicone rubber or other silicon containing polymers.
  • the compounds 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 .
  • the compounds may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol , polyhydroxyethyl-aspartamide-phenol, or ployethyleneoxide- polylysine substituted with palmitoyl residues.
  • the compounds 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 , polycyanoacrylates and cross linked or amphitpathic 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 , polycyanoacrylates and cross linked or amphitpathic block copolymers of hydrogels.
  • the pharmaceutical composition may be in the form of, for example, tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, liquids including syrups, and emulsions.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient . Examples of such dosage units are tablets or capsules.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
  • the amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely.
  • the pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg.
  • a daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate.
  • the daily dose can be administered in one to four doses per day.
  • the compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w.
  • the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1, 3-diol , mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof.
  • the topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
  • the compounds of this invention can also be administered by a transdermal device.
  • topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.
  • the encapsulating agent may also function as the membrane.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others .
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should preferably be a non-greasy, non- staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • the active compounds of the present invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art .
  • compounds having formula (I) - (V) or a pharmaceutically-acceptable salt thereof comprise a treatment and prophylaxis for thrombotic events resulting from coronary artery disease, cerebrovascular disease and other coagulation cascade related disorders in a subject.
  • the treatment comprises administering to the subject having such disorder a therapeutically-effective amount of compounds having formulas (I)-(V) or a pharmaceutically- acceptable salt thereof.
  • the compounds or a pharmaceutically-acceptable salt thereof can also be used whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage.
  • coagulation inhibitors of the present invention can be added to or contacted with stored whole blood and any medium containing or suspected of containing plasma coagulation factors and in which it is desired that blood coagulation be inhibited, e.g. when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prothesis, cardiac prosthesis, and extracorporeal circulation systems.
  • Compounds of Formula (I) - (V) are capable of inhibiting activity of serine proteases related to the coagulation cascade.
  • these compounds could be used in the manufacture of a medicament as a method for the prophylactic or therapeutic treatment of diseases mediated by coagulation cascade serine proteases, such as inhibiting the formation of blood platelet aggregates, inhibiting the formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, in blood, in blood products, and in mammalian organs.
  • the compounds also can be used for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels in a mammal.
  • the compounds also can be used to study the mechanism of action of coagulation cascade serine proteases to enable the design of better inhibitors and development of better assay methods.
  • the compounds would be also useful in prevention of cerebral vascular accident (CVA) or stroke.
  • CVA cerebral vascular accident
  • the compounds and pharmaceutical compositions are administered alone or in combination with one another, or in combination with other therapeutics or in vivo diagnostic agents.
  • the compounds can also be co- administered with suitable anti-platelet aggregation agents, including, but not limited to aspirin, ticlopidine, or clopidrogel, fibrinogen receptor antagonists (e.g.
  • anti-coagulants such as aspirin, warfarin or heparins, thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various pathologies
  • lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as mevastatin, lovastatin, simvastatin, pravastatin, and fluvastatin, HMG CoA synthatase inhibitors, etc.), anti-diabetic drugs, or other cardiovascular agents (e.g.
  • loop diuretics e.g. spironolactone and epoxymexlerenone
  • aldosterone antagonistics e.g. spironolactone and epoxymexlerenone
  • angiotensin converting enzyme e.g. ACE
  • angiotensin II receptor antagonists e.g. beta-blockers
  • antiarrythmics e.g. anti- hypertension agents
  • calcium channel blockers e.g., calcium channel blockers to treat or prevent atheriosclerosis .
  • fibrinogen receptor antagonists and coagulation cascade inhibitors of the present invention would benefit from coadministration of fibrinogen receptor antagonists and coagulation cascade inhibitors of the present invention.
  • coagulation cascade inhibitors could enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion.
  • Typical doses of compounds of the present invention with other suitable anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents may be the same as those doses of coagulation cascade inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, or may be substantially less than those doses of coagulation cascade inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, depending on a patient's therapeutic needs.
  • the present methods preferably employ prodrug compounds that when converted to the biologically active compound selectively inhibit human TF-VIIA over the inhibition of both human Thrombin II and human factor Xa.
  • the compounds have a human TF-VIIA IC 50 of less than 0.5 mM and also have a selectivity ratio of TF-VIIA inhibition over both human Thrombin II and human factor Xa inhibition of at least 10, and more preferably at least 100.
  • the compounds have a human TF-VIIA IC 50 of less than 0.1 mM and also have a selectivity ratio of TF-VIIA inhibition over both human Thrombin II and human factor Xa inhibition of at least 1000, and most preferably at least 10,000.
  • R303' ⁇ 304 ' 305/ R 306 , R 307 , R 308 R 309 R 310 - R 3i ⁇ / and X 7 encompasses every group described for each particular variable for each embodiment of compounds having formulas (I)-(V) as detailed herein.
  • a specific synthetic process, useful in the preparation of many of the heterocyclic compounds of the present invention, is the arylation or heteroarylation of an intermediate compound characterized by having a suitable leaving group on a sp 2 hybridized carbon of a heterocyclic ring.
  • the leaving group is replace by an aryl group or a heteroaryl group.
  • Suitable leaving groups for the reaction include chloro, bromo, iodo, methylthio, and triflates.
  • the heterocyclic ring with the leaving group will preferably have an acetic acid group or a derivative thereof bonded to a ring atom alpha to the bromo and a substituted or unsubstituted amino group bonded to a ring atom that is both beta to the carbon having the acetic acid group and gamma to the bromo substituted ring carbon.
  • the aryl group that is reacted at the sp 2 hybridized carbon is generally an aryl boronic acid or an ester of the aryl boronic acid; similarly, heteroaryl boronic acids or esters of these boronic acids can be used in the same manner as aryl boronates .
  • the aryl and heteroaryl boronates may be substituted or unsubstituted.
  • the aryl or heteroaryl becomes bonded to the sp 2 hybridized carbon at the point at which the boron was attached to the aryl or heteroaryl ring.
  • Aryl and heteroaryl organoSn compounds can also be used instead of the corresponding boronates.
  • Suitable reaction conditions for carrying out this transformation include:
  • Pd[P (phenyl) 3 ] note, 2M Na 2 C0 3 , 60-75°C, dimethoxyethane (DME) , H 2 0, N 2 ; 2. Pd[P (phenyl) 3 ] 4 , Cs 2 C0 3 , dioxane, 100°C;
  • the organo palladium (Pd [P (phenyl) 3 ] 4 ) compound is used catalytically in a ratio of 1 to 40 mole %.
  • the carbonate base is normally used in an excess of 1.2 to 2 molar equivalents.
  • Suitable solvents include dimethoxyethane (DME) , dioxane, 1-propanol, and tetrahydrofuran.
  • the temperature of the reaction is normally in the range of from about 50 to 100°C.
  • Cu (I) -2-thiophenecarboxylate (Cu(I)-TC) is normally used in a mole % of 110-150.
  • Scheme G shows a specific application of this specific synthetic process.
  • Procedures for preparing the intermediate heterocyclic or cycloalkenyl ring compounds having a suitable leaving group on sp 2 hybridized carbon and useful as suitable intermediates in this specific synthetic process are given in the schemes and examples listed above.
  • Scheme J illustrates a general synthetic process for substitution at a nitrogen of the heterocyclic ring. The synthetic process applies whether the ring is 5- or 6- membered.
  • TBTU Z benzyloxycarbonyl

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Abstract

The present invention relates to substituted 5-membered polycyclic compounds and prodrugs thereof, compositions and methods useful for preventing and treating thrombotic conditions in mammals. The compounds of the present invention, and prodrugs thereof, selectively inhibit certain proteases of the coagulation cascade.

Description

Substituted 5-membered Polycyclic Compounds Useful for Selective Inhibition of the Coagulation Cascade
Field of the Invention
The present invention relates to compounds, compositions and methods for preventing and treating thrombotic conditions such as coronary artery and cerebrovascular disease. More particularly, the invention relates to 5-membered polycyclic compounds, and prodrugs thereof that inhibit serine proteases of the coagulation cascade.
Background of the Invention
Hemorrhage, intravascular thrombosis, and embolism are common clinical manifestations of many diseases (see R. I. Handin in Harrison's Principles of Internal Medicine (J.D. Wilson, et al . eds., 12th ed. 1991) New York, McGraw-Hill Book Co., pp. 348-351). The normal hemostatic system limits blood loss by precisely regulated interactions between components of the vessel wall, circulating blood platelets, and plasma proteins. Unregulated activation of the of the hemostatic system, however, may cause thrombosis, which can reduce blood flow to critical organs like the brain and myocardium.
Physiological systems control the fluidity of blood in mammals (see P.W. Majerus, et al . in Goodman & Gilman's The Pharmacological Basis of Therapeutics (J.G. Hardman & L.E. imbird, eds., 9th ed. 1996) New York, McGraw-Hill Book Co., pp. 1341-1343). Blood must remain fluid within the vascular systems and yet quickly be able to undergo hemostasis. Hemostasis, or clotting, begins when platelets first adhere to macromolecules in subendothelian regions of injured and/or damaged blood vessels. These platelets aggregate to form the primary hemostatic plug and stimulate local activation of plasma coagulation factors leading to generation of a fibrin clot that reinforces the aggregated platelets . Plasma coagulation factors, also referred to as protease zymogens, include factors II, V, VII, VIII, IX, X, XI, and XII. These coagulation factors or protease zymogens are activated by serine proteases leading to coagulation in a so called "coagulation cascade" or chain reaction.
Coagulation or clotting occurs in two ways through different pathways. An intrinsic or contact pathway leads from XII to Xlla to XIa to IXa and to the conversion of X to Xa . Xa with factor Va converts prothrombin (II) to thrombin (Ila) leading to conversion of fibrinogen to fibrin. Polymerization of fibrin leads to a fibrin clot. An extrinsic pathway is initiated by the conversion of coagulation factor VII to Vila by Xa. Factor Vila, a plasma protease, is exposed to, and combines with its essential cofactor tissue factor (TF) which resides constitutively beneath the endothelium. The resulting factor VIIa/TF complex proteolytically activates its substrates , factors IX and X, triggering a cascade of reactions that leads to the generation of thrombin and a fibrin clot as described above.
While clotting as a result of an injury to a blood vessel is a critical physiological process for mammals, clotting can also lead to disease states. A pathological process called thrombosis results when platelet aggregation and/or a fibrin clot blocks (i.e., occludes) a blood vessel. Arterial thrombosis may result in ischemic necrosis of the tissue supplied by the artery. When the thrombosis occurs in a coronary artery, a myocardial infarction or heart attack can result. A thrombosis occurring in a vein may cause tissues drained by the vein to become edematous and inflamed. Thrombosis of a deep vein may be complicated by a pulmonary embolism. Preventing or treating clots in a blood vessel may be therapeutically useful by inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, inhibiting embolus formation, and for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels.
In order to treat such conditions, researchers have sought to discover chemical compounds that efficaciously and selectively control the clotting process. In addition, such compounds may provide a better understanding of the pathways involved in the coagulation process.
Thus far, the compounds that have been discovered often possess a polar or basic functional group which is integrally responsible for the desired biological activity. Frequently, this polar functional group is a nitrogen atom of, for example, a guanidine, alkyl-amidine or aryl-amidine group. Because these functionalities are highly basic, they remain protonated at physiologically relevant pH's. The ionic nature of such protonated species hinders their permeability across lipophilic membranes, which can reduce bioavailability when the pharmaceutical agent is administered orally.
In order to circumvent such a problem, it is often advantageous to perform a derivatization or chemical modification of the polar functionality such that the pharmaceutical agent becomes neutrally charged and more lipophilic, thereby facilitating absorption of the drug. However, for the derivatization to be useful, the derivatization must be bioconvertable at the target site or sites of desired pharmacological activity and cleaved under normal physiological conditions to yield the biologically active drug. The term "prodrug" has been used to denote such a chemically modified intermediate.
Summary of the Invention
Among the several aspects of the present invention, therefore, is the provision of compounds useful for selective inhibition of certain enzymes that act upon the coagulation cascade thereby preventing and treating thrombotic conditions in mammals.
Another aspect of the present invention is the provision of prodrug compounds useful for selective inhibition of certain enzymes that act upon the coagulation cascade thereby preventing and treating thrombotic conditions in mammals. In general, these prodrug compounds undergo hydrolysis, oxidation, reduction or elimination at a derivatized amidine group to yield the active compound. Briefly, therefore, the present invention is directed to the compound, per se, to the prodrug of the compound, to pharmaceutical compositions comprising the compound or prodrug and a pharmaceutically acceptable carrier, and to methods of use. In one embodiment, the invention embraces compounds having formula (I) :
Figure imgf000005_0001
( I ) wherein :
X comprises a 5-membered heterocyclic or carbocyclic ring, the ring atoms being Xx, X2, X3, X4, and X5, wherein X1# X3, and X4, are independently carbon or nitrogen and X2 and X5 are independently carbon, nitrogen, oxygen or sulfur;
Lx , L3 and L4 are linkages through which Zχ ι Z3, and Z4, respectively, are covalently bonded to different ring atoms of the 5-membered heterocyclic or carbocyclic ring of X, wherein Zx is covalently bonded to X1# Z3 is covalently bonded to X3, and Z4 is covalently bonded to X4, each of L1; L3 and L4 independently being a covalent bond or comprising one or more atoms through which Zl t Z3, and Z4 are covalently bonded to X1# X3 and X4, respectively;
Zx is hydrocarbyl or substituted hydrocarbyl .
Z3 comprises a 5- or 6-membered heterocyclic or aromatic ring substituted with an amidine group, the ring atoms of the 5- or 6-membered heterocyclic or aromatic ring of Z3 being carbon, sulfur, nitrogen, or oxygen, wherein the 5- or 6-membered ring is optionally substituted at any position with halogen, alkyl or hydroxy; and
Z4 comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of the 5- or 6-membered heterocyclic or carbocyclic ring of Z4 being carbon, nitrogen, oxygen, or sulfur.
Another aspect of the invention provides compounds corresponding to formula (II)
Figure imgf000006_0001
(ID wherein:
X2 and X5 are as defined for compounds having formula (I);
Xx, X3 and X4 are independently carbon or nitrogen;
X9 is a direct bond or -(CH2)m- where m is 1 or 2; and Zl t Z3 and Z4 are as defined for compounds having formula (I) .
Other aspects and features of this invention will be in part apparent and in part pointed out hereafter.
Abbreviations and Definitions
The term "elimination" is generally meant to encompass any one or more of the following reactions: (1) a reaction that results in a compound fragmenting into two or more compounds; and (2) a reaction that results in one or more groups being removed from a compound without being replaced by other groups .
The term "oxidation" is generally meant to encompass any one or more of the following reactions: (1) a reaction that results in an increase in the oxidation number of an atom in a compound, whether the atom is uncharged or charged and whether free or covalently bound; (2) a reaction that results in the loss of hydrogen from a compound; (3) a reaction that results in the loss or removal of one or more electrons from a compound, with or without concomitant loss or removal of a proton or protons;
(4) the action or process of reacting a compound with oxygen; and (5) a reaction that results in the addition of one or more oxygen atoms to a compound.
The term "reduction" is generally meant to encompass any one or more of the following reactions: (1) any reaction which results in a decrease in the oxidation number of an atom in a compound; and (2) any reaction that results in oxygen being withdrawn from, hydrogen being added to, or an electron being added to (with or without the addition of a proton) a compound.
The term "hydrolysis" is generally meant to encompass any one or more of the following reactions: (1) any reaction which results in the addition of a nucleophile to a compound to form a new bond with concurrent loss of a group from the compound; (2) any reaction which results in the addition of water to a compound; and (3) any reaction that results in the rupture of one or more chemical bonds by reaction with, and involving the addition of, the elements of water. The term "physiological conditions" are those conditions characteristic to an organism's (to a human beings) healthy or normal functioning.
The terms "hydrocarbon" and "hydrocarbyl" as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl . Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
The "substituted hydrocarbyl" moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a heteroatom such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur, or a halogen atom. Exemplary substituted hydrocarbyl moieties include, heterocyclo, alkoxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl , aryloxyalkyl, hydroxyalkyl, protected hydroxyalkyl , keto, acyl , nitroalkyl, aminoalkyl, cyano, alkylthioalkyl , arylthioalkyl, ketals, acetals, amides, acids, esters and the like.
The term "heteroatom" shall mean atoms other than carbon and hydrogen.
Unless otherwise indicated, the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms . They may be straight or branched chain or cyclic and include methyl, ethyl, propyl , isopropyl, butyl, hexyl and the like. Unless otherwise indicated, the alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl , isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
Unless otherwise indicated, the alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl , butynyl , isobutynyl, hexynyl, and the like.
The terms "aryl" or "ar" as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl , biphenyl, naphthyl , substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl . The terms "halogen" or "halo" as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
The terms "heterocyclo" or "heterocyclic" as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl , oxazolyl, pyrrolyl , indolyl , quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
The term "heteroaromatic" as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
The term "acyl," as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group -COOH of an organic carboxylic acid, e.g., RC(O)-, wherein R is hydrogen, R1, R^-, R1RN-, or R^-, R1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R2 is hydrogen, hydrocarbyl or substituted hydrocarbyl.
The term "acyloxy, " as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (-0-), e.g., RC(0)0- wherein R is as defined in connection with the term "acyl." The term "acetamidyl" as used herein describes a chemical moiety represented by the formula NR1C(0)R2.
The term "carboxamido" as used herein, describes a chemical moiety represented by the formula C(0)NR1R2.
The. term "alkoxycarbonyl" as used herein describes a chemical moiety represented by the formula C(0)OR. The term "sulfonamido" as used herein describes a chemical moiety represented by the formula S02NR1R2.
The term "alkylsulfonyl" as used herein describes a chemical moiety represented by the formula S02R. The term "sulfonamidyl" as used herein describes a chemical moiety represented by the formula NRS02R.
As described herein for the terms "acetamidyl" , " carboxamido" , "alkocycarbonyl " , "sulfonamido" , " alkylsulfonyl " , and "sulfonamidyl", R, Rλ and R2 are independently hydrogen, alkyl, aryl, and arylakyl, optionally substituted with halogen, hydroxy or alkoxy.
Description of the Preferred Embodiment
One aspect of the invention embraces compounds that correspond to formula (I)
Figure imgf000011_0001
(I) wherein:
X comprises a 5-membered heterocyclic or carbocyclic ring, the ring atoms being X-, X2, X3, X4, and X5, wherein X1; X3, and X4, are independently carbon or nitrogen and X2 and X5 are independently carbon, nitrogen, oxygen or sulfur;
Ll7 3 and L4 are linkages through which Z-, Z3, and Z4, respectively, are covalently bonded to different ring atoms of the 5-membered heterocyclic or carbocyclic ring of X, wherein Zx is covalently bonded to X1# Z3 is covalently bonded to X3, and Z4 is covalently bonded to X4, each of Lx, 3 and L4 independently being a covalent bond or comprising one or more atoms through which Zl t Z3, and Z4 are covalently bonded to X17 X3 and X4, respectively; Z- is hydrocarbyl or substituted hydrocarbyl; Z3 comprises a 5- or 6-membered heterocyclic or aromatic ring substituted with an amidine group, the ring atoms of the 5- or 6-membered heterocyclic or aromatic ring of Z3 being carbon, sulfur, nitrogen, or oxygen, wherein the 5- or 6-membered ring is optionally substituted at any position with halogen, alkyl or hydroxy; and
Z4 comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of the 5- or 6-membered heterocyclic or carbocyclic ring of Z4 being carbon, nitrogen, oxygen, or sulfur.
In another embodiment for compounds having formula (I) , each of X-, X2, X3, X4, and X5 are as defined in the embodiment above;
Lx is -X9NH- wherein X9 is covalently bonded directly to Z and X9 is a direct bond or -(CH2)m- wherein m is 1 to 5;
L3 is a glycine derivative;
L4 is a direct bond;
Zx is selected from the group consisting of C.-CB alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen;
Z3 comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy;
Z4 comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of Z4 being Z40, Z41, Z42, Z44 and Z45 when Z4 is a 5-membered ring and Z40, Z41, Z42, Z43, Z44 and Z45 when Z4 is a 6-membered ring, Z40, Z41, Z42, Z43, Z44 and Z45, being carbon, nitrogen, oxygen or sulfur, Z40 being the ring atom through which Z4 is attached to the heterocyclic ring, Z41 and Z45 each being in an alpha position relative to Z40, Z42 and Z44 each being in a beta position relative to Z40, Z43 being in the gamma position relative to Z40 when Z4 is a 6-membered ring, Z4 having a substituent R42 covalently attached to Z42, and a second substituent bonded to one of Z41, Z43, Z44, or Z45, the substituent being R41 when bonded to Z41, the substituent being R43 when bonded to Z43, the substituent being R44 when bonded to Z44, and the substituent being R45 when bonded to Z45;
R42 is amino; and
R4ι, R43, R44 and R45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R41, R43, R44 or R45 is other than hydrogen.
Still a further embodiment provides compounds having formula (I) , where L- is -X9NH- wherein X9 is covalently bonded directly to Zx and X9 is a direct bond; L3 is -CH2CONHCH2- and Z3 is covalently bonded to the methylene bonded to the amine nitrogen of L3;
Z is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl ;
Z3 comprises a phenyl ring, the phenyl ring being optionally further substituted with fluorine or hydroxy;
Z4 comprises a phenyl or thienyl ring having two substituents, R42 and R44, and two ring atoms each of which is in the beta position relative to the ring atom of Z4 through which Z4 is covalently bonded to X, wherein one of R42 and R44 is covalently bonded to one of the beta positions and the other of R42 and R44 is covalently bonded to the other of the beta positions;
R42 is amino; and
R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, and an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus. In one embodiment for compounds having formula (I) , the Li linkage is -X9NH- where X9 is covalently bonded directly to Z. and is a direct bond or an alkylene chain having the formula (CH2)m wherein m is 0 to 5. In an alternative embodiment, m is 0 to 2. In another embodiment, the L. linkage is a bond.
In another embodiment for compounds having formula (I) , the L3 linkage is a glycine derivative, an alanine derivative, an amino derivative, or a sulfonyl derivative. In an alternative embodiment, the L3 linkage is a glycine derivative. In still another embodiment, the L3 linkage is -CH2CONHCH2- where Z3 is covalently bonded to the methylene bonded to the amine nitrogen of 3.
In a further embodiment for compounds having formula (I) , the L4 linkage is a direct bond, methylene, ethylene or an optionally substituted heteroatom selected from the group nitrogen, oxygen, sulfur or phosphorus. In another embodiment, the 4 linkage is a direct bond.
In yet another embodiment for compounds having formula (I) , Zx is a C.-C3 alkyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy or alkoxycarbonyl . Generally speaking, the Ci-C3 alkyl is a cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl. In another embodiment, the Cx- C5 alkyl is isopropyl or cyclobutyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl. In yet another alternative of this embodiment, Zx is trifluoroethyl or carboxymethyl . In one embodiment of compounds corresponding to formula (I) , Z3 is a 5- or 6-membered heterocyclic or aromatic ring substituted with an amidine group and may be optionally substituted at any substitutable position with halogen, hydroxy, haloalkyl, alkyl, carboxy, alkoxycarbonyl, or hydrocarbyloxy, or any combination thereof. A preferred halogen is fluorine. In another alternative of this embodiment, Z3 is a 6-membered carbocyclic aromatic ring substituted with an amidine group. In yet another embodiment, Z3 comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with an amidine group, and optionally further substituted at any substitutable position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy . In yet another alternative of this embodiment, Z3 corresponds to formula (a)
Figure imgf000015_0001
(a) wherein:
R304 and R306 are independently selected from the group consisting of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy and alkoxycarbonyl ; and
R305 and R307 are independently selected from the group consisting of hydrogen, fluorine, methoxy, hydroxy and carboxy . In one alternative of compounds wherein Z3 corresponds to formula (a) , Z3 is selected from the group consisting of benzamidine-4-yl, 3-hydroxybenzamidine-4-yl , 3 , 5-dihydroxybenzamidine-4-yl,
2,5, 6-trifluoro-3-hydroxybenzamidine-4-yl, 2-hydroxybenzamid ine-4-yl and
3,5, 6-trifluoro-2-hydroxybenzamidine-4-yl .
A further embodiment embraces prodrug compounds having formula (I) where Z3 is -R300C (=NR301)NR302R303, wherein R300 is a 6-membered carbocyclic aromatic ring, R30ι/ R302. R 303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur, provided at least one of R301, R302/ R303 is other than hydrogen. In yet another embodiment, Z3 is
-R3oo c (=NR301)NR302R303, wherein R300 is a 6-membered carbocyclic aromatic ring, and at least two of R30ι, R302. R 303 are ring atoms of a heterocyclic ring. In an alternative embodiment, Z3 is -R300C (=NR301) NR302R303, R300 is a 6-membered carbocyclic aromatic ring, and at least one of R301, R302. R 303 are ring atoms of a heterocyclic ring fused to R300-
Yet another embodiment encompasses prodrug compounds having formula (I) where Z3 is a benzamidine derivatized with one or more groups selected from carbonyl , thiocarbonyl, imino, enamino, phosphorus, and sulfur, where the benzamidine derivative hydrolyzes under physiological conditions to form benzamidine. In an alternative to this embodiment, Z3 is a benzamidine derivatized with one or more groups selected from optionally substituted hydrocarbyl, provided that the carbon atom directly bonded to the amidine is sp3 hybridized and aryl, where the benzamidine derivative is oxidized under physiological conditions to form benzamidine. In yet another alternative for this embodiment, Z3 is a benzamidine derivatized with one or more heteroatoms selected from oxygen, nitrogen in its most reduced state, and sulfur in its most reduced state, where the benzamidine derivative is reduced under physiological conditions to form benzamidine. In still another alternative for this embodiment, Z3 is a benzamidine derivatized with one or more substituents selected from a hydrocarbyl substituted at the beta carbon with carbonyl, sulfonyl, sulfinyl, cyano, nitro and an alkyl, aryl, or heterocyclic group substituted with oxygen, nitrogen, or sulfur at the carbon directly bonded to the amidine group, where the benzamidine derivative undergoes elimination at physiological conditions to form benzamidine.
In a further embodiment for prodrug compounds having formula (I) , Z3 corresponds to formula (b)
Figure imgf000017_0001
(b) wherein:
R 3oι. R 02. and 303 are independently selected from the group consisting of: (i) hydrogen, -C(=0)Ra, -C(=0)ORa, -S(=0)ORa,
-S(=0)SRa, -S(=0)2ORa, -S(=0)2SRa and alkenyl, wherein Ra is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, and heterocylo, provided, however, that the carbon atom of R30ι, R302. and R303 directly bonded to the amidine is sp2 hybridized when R301, R302. an<3 R303 is alkenyl,
(ii) hydrogen, optionally substituted hydrocarbyl and aryl, provided, however, the carbon atom of R30ι, R302. and R303 directly bonded to the amidine is sp3 hybridized when R301. R 302 an< R 303 is optionally substituted hydrocarbyl,
(iii) hydrogen, -ORb, -SRb, -NRb, or -N(Rb)2, wherein each Rb is independently optionally substituted hydrocarbyl, and heterocylo, and
(iv) hydrogen, substituted hydrocarbyl wherein the carbon bonded to the amidine group is substituted with -0RC, -SRC, -NRC, or -N(RC)2, wherein each Rc is independently -C(0)Rd, -C(0)NRd, -C(0)ORd, -C(0)N(Rd)2 and each Rd is independently hydrocarbyl, substituted hydrocarbyl or heterocyclo, and substituted alkyl with the carbon atom beta to the point of attachment to the amidine group being an unsaturated electron withdrawing group, provided, however, at least one of R301, R302/ and R303 i-s other than hydrogen; R304 is selected from the group consisting of halogen, hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio;
R305 is selected from the group consisting of oxygen, sulfur, halogen, hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio,-
R306 is selected from the group consisting of halogen, hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio; and
R307 is selected from the group consisting of oxygen, sulfur, halogen, hydrogen, hydroxyl, alkyl, sulfhydryl, alkoxy, and alkylthio.
In one embodiment for prodrug compounds having formula (I) , the benzamidine derivative is hydrolyzed under physiological conditions to form benzamidine when Z3 is a benzamidine derivative having formula (b) and R30ι, 302. and
R303 are independently selected from hydrogen, -C(=0)Ra, -C(=0)ORa, -S(=0)0Ra, -S(=0)SRa, -S(=0)2ORa, -S (=0) 2SRa and alkenyl, wherein Ra is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, and heterocylo, provided, however, that the carbon atom of R301, R302. an< R 303 directly bonded to the amidine is sp2 hybridized when R30ι, R302, and R303 is alkenyl.
In a further embodiment for prodrug compounds having formula (I) , the benzamidine derivative is oxidized under physiological conditions to form benzamidine when Z3 is a benzamidine derivative having formula (b) and R30ι, R 3o2. an< R303 are independently selected from hydrogen, optionally substituted hydrocarbyl and aryl, provided, however, the carbon atom of R30ι, R302. an<3 R303 directly bonded to the amidine is sp3 hybridized when R30ι, R302. and R303 is optionally substituted hydrocarbyl. In still another embodiment for prodrug compounds having formula (I) , the benzamidine derivative is reduced under physiological conditions to form benzamidine when Z3 is a benzamidine derivative having formula (b) and R 301/ R 302 and R303 are independently selected from hydrogen, -OR,b-
-SRb, -NRb, or -N(Rb)2, wherein each Rb is independently optionally substituted hydrocarbyl, and heterocylo.
In an alternative embodiment for prodrug compounds having formula (I) , the benzamidine derivative undergoes elimination at physiological conditions to form benzamidine when Z3 is a benzamidine derivative having formula (b) and R 3oι R 302 and R 303 are independently selected from hydrogen, substituted hydrocarbyl wherein the carbon bonded to the amidine group is substituted with -ORc, -SRC, -NRC, or -N(RC)2, wherein each Rc is independently -C(0)Rd, -C(0)NRd, -C(0)0Rd -C(0)N(Rd)2 and each Rd is independently hydrocarbyl, substituted hydrocarbyl or heterocyclo, and substituted alkyl with the carbon atom beta to the point of attachment to the amidine group being an unsaturated electron withdrawing group.
A further embodiment embraces compounds having formula (I) where Z4 is a substituted, 6-membered carbocyclic aromatic ring. In an alternative of this embodiment, Z4 corresponds to formula (c)
Figure imgf000019_0001
(c) wherein:
R42 is amino; R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, halogen and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and R41, R43 and R45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur. In another embodiment of compounds wherein Z4 corresponds to formula (c) and R42 is amino, R44 is selected from hydrocarbyl, substituted hydrocarbyl, acetamido, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, carboalkoxy, carboxy, carboxamidoalkyl , and carboxamidoalkylaryl . In an alternative of this embodiment, R44 is selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, heterocyclo, halogen, acetamido, guanidino, hydroxy, nitro, amino, amidosulfonyl, acylamido, hydrocarbyloxy, substituted hydrocarbyloxy, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylsulfonyl , and substituted hydrocarbylsulfonyl . In yet another alternative of this embodiment, R44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl, carboxamidobenzyl , carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3- aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, m-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl -2 -methylbutylamide , isobutylacylamine , isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy. In still another alternative of this embodiment, R41, R43 and R45 are independently selected from the group consisting of hydrogen, halogen, alkoxy, or hydroxy and R44 is as defined in any of the alternative embodiments above. In yet another alternative of this embodiment, R41, R43 and R45 are independently selected from the group consisting of hydrogen and halogen and R44 is as defined in any of the alternative embodiments above.
In another embodiment for compounds wherein Z4 corresponds to formula (c) and R42 is amino, R45 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, carboxy, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine. In another alternative of this embodiment (i.e., when Z4 corresponds to formula (c) and R42 is amino) , R45 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl , haloalkoxy, haloalkythio, alkoxycarbonyl, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine. In still another alternative of this embodiment, R45 is selected from the group consisting of hydroxy, carboxy, carboxamido, alkoxy, alkylsulfonyl , sulfonamido, and alkoxycarbonyl. In yet another alternative of this embodiment, R45 is selected from the group consisting of sec-butylamide, carboxy, ethoxycarbonyl , isopropoxycarbonyl , butoxycarbonyl , isopropylamide and hydroxy. In still another alternative of this embodiment, R41, R43 and R44 are independently selected from the group consisting of hydrogen, halogen, alkoxy, or hydroxy and R45 is as defined in any of the alternative embodiments above. In yet another alternative of this embodiment, R41/ R43 and R44 are independently selected from the group consisting of hydrogen and halogen and R45 is as defined in any of the alternative embodiments above. In yet another embodiment for compounds wherein Z4 corresponds to formula (c) and R42 is amino, R43 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, carboxy, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine. In another alternative of this embodiment (i.e., when Z4 corresponds to formula (c) and R42 is amino) , R43 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine. In still another alternative of this embodiment, R43 is selected from the group consisting of hydroxy, carboxy, carboxamido, alkoxy, alkylsulfonyl , sulfonamido, and alkoxycarbonyl. In yet another alternative of this embodiment, R43 is selected from the group consisting of sec-butylamide, carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropylamide and hydroxy. In still another alternative of this embodiment, R41, R44 and R45 are independently selected from the group consisting of hydrogen, halogen, alkoxy, or hydroxy and R43 is as defined in any of the alternative embodiments above. In yet another alternative of this embodiment, R41, R44 and R45 are independently selected from the group consisting of hydrogen and halogen and R43 is as defined in any of the alternative embodiments above.
In still another embodiment for compounds wherein Z4 corresponds to formula (c) and R42 is amino, R41 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, carboxy, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine. In another alternative of this embodiment (i.e., when Z4 corresponds to formula (c) and R42 is amino) , R41 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamidyl, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkoxy, haloalkythio, alkoxycarbonyl, sulfonamido, carboxamido and sulfonamidyl, optionally substituted with fluorine. In still another alternative of this embodiment, R41 is selected from the group consisting of hydroxy, carboxy, carboxamido, alkoxy, alkylsulfonyl , sulfonamido, and alkoxycarbonyl . In yet another alternative of this embodiment, R41 is selected from the group consisting of sec-butylamide, carboxy, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isopropylamide and hydroxy. In still another alternative of this embodiment, R43, R44 and R45 are independently selected from the group consisting of hydrogen, halogen, alkoxy, or hydroxy and R41 is as defined in any of the alternative embodiments above. In yet another alternative of this embodiment, R43, R44 and R45 are independently selected from the group consisting of hydrogen and halogen and R41 is as defined in any of the alternative embodiments above.
In yet another embodiment, Z4 is a five-membered ring having formula (d)
Figure imgf000023_0001
(d) wherein :
Z40, Z41, Z42, Z44, and Z45 are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;
R42 is amino;
R44 is selected from the group consisting of is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, halogen and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and
R41 and R45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
In another embodiment of compounds wherein Z4 corresponds to formula (d) and R42 is amino, R44 is selected from hydrocarbyl, substituted hydrocarbyl, acetamido, alkoxy, hydroxy, amino, alkylsulfonyl , haloalkyl, haloalkoxy, haloalkylthio, carboalkoxy, carboxy, carboxamidoalkyl , and carboxamidoalkylaryl . In an alternative of this embodiment, R44 is selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, heterocyclo, halogen, acetamido, guanidino, hydroxy, nitro, amino, amidosulfonyl , acylamido, hydrocarbyloxy, substituted hydrocarbyloxy, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylsulfonyl , and substituted hydrocarbylsulfonyl . In yet another alternative of this embodiment, R44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl, carboxamidobenzyl , carboxamidobutyl-2-yl , isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3- aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, m-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl -2 -methylbutylamide , isobutylacylamine , isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy. In still another alternative of this embodiment, R41 and R4S are independently selected from the group consisting of hydrogen, halogen, alkoxy, or hydroxy and R44 is as defined in any of the alternative embodiments above. In yet another alternative of this embodiment, R41 and R45 are independently selected from the group consisting of hydrogen and halogen and R44 is as defined in any of the alternative embodiments above.
Still another embodiment provides compounds having formula (I) where X2 or X5 are hydrogen bond acceptors. In another embodiment, both X2 and X5 are hydrogen bond acceptors. Generally speaking, the phrase "hydrogen bond acceptor" encompasses heteroatoms having a lone pair of electrons available for hydrogen bonding. Suitable hydrogen bond acceptors, when taken with the carbon to which Z2 is attached, are typically selected from the group consisting of C (O) , C(S), C(C1), C(Br), C(F), C (OH) , COCH3/ COR, C(SH), CSR, and CNR-R;, wherein R, Rx and R2 are independently hydrogen, alkyl, aryl, and arylakyl, optionally substituted with halogen, hydroxy or alkoxy. Suitable X2 groups include carbon substituted with hydrogen, fluorine, oxygen, or sulfur, nitrogen optionally substituted with hydrogen or oxygen, oxygen, or sulfur. Suitable X5 groups include oxygen, sulfur, nitrogen, carbonyl and carbon substituted with a halogen selected from fluorine, chlorine and bromine.
In one embodiment for compounds having formula (I) , X17 X2, X3, X4, and X5 are carbon or nitrogen. In an alternative of this embodiment, X1 X2 and X5 are carbon, and X3 and X4 are nitrogen. In another alternative of this embodiment, X1# X3, X4 and X5 are carbon and X2 is nitrogen. In yet another alternative of this embodiment, Xlf X2, X3, X4 and X5 are all carbon. In still a further alternative of this embodiment, Xl t X4 and X5 are carbon and X2 and X3 are nitrogen.
In another embodiment for compounds having formula (I) , Xl7 X2, X3, X4, and X5 form a 5-membered heterocyclic or carbocyclic ring selected from pyrazolinone, pyrrole, thiophene, pyrazole-N-oxide, 1-amino-pyrazole, 1,3,4- triazole, 2-amino-4-aryl-thiazole, 2-amino-5-aryl-thiazole, pyrrolidine, 2-amino-5-aryl-oxazole, 3-amino-pyrazole, 2- amio-4-aryl-oxazole, tetrahydrofuran, cyclopentadienone, and N-hydroxypyrrolidine . In an alternative of this embodiment, X1 X2, X3, X4, and X5 form a pyrazolinone, thiophene, pyrazole-N-oxide, 2-amino-5-aryl-thiazole, tetrahydrofuran, cyclopentadienone, or a N- hydroxypyrrolidine ring. In yet another embodiment, the ring is a pyrazolinone, pyrazole-N-oxide, cyclopentadienone, or a N-hydroxypyrrolidine. In still another embodiment, the ring is a pyrazolinone.
Another aspect of the invention embraces compounds that correspond to formula (II)
Figure imgf000026_0001
(ID wherein:
X2 and X5 are as defined for compounds having formula
(I);
Xx , X3 and X4 are independently carbon or nitrogen;
X9 is a direct bond or -(CH2)m- where m is 1 or 2; and Zlf Z3 and Z4 are as defined for compounds having formula (I) .
In yet another embodiment for compounds having formula (II) , each of Xlf X2, X3, X4, and X5 is carbon or nitrogen;
X9 is selected from the group consisting of a direct bond, methylene, and ethylene;
Z is selected from the group consisting of
Figure imgf000026_0002
alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen; Z3 comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy;
Z4 comprises a phenyl or thienyl ring having two substituents, R42 and R44, and two ring atoms each of which is in the beta position relative to the ring atom of Z4 through which Z4 is covalently bonded to X, wherein one of R42 and R44 is covalently bonded to one of said beta positions and the other of R42 and R44 is covalently bonded to the other of said beta positions; R42 is amino; and
R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, and an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus.
In yet another embodiment for compounds having formula (II) , each of X1# X2, X3, X4, and X5 is carbon or nitrogen; X9 is a direct bond; Zx is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl;
Z3 is a phenyl ring, the phenyl ring being optionally further substituted with fluorine or hydroxy;
Z4 is a substituted phenyl ring as described in other embodiments for compounds having formula (II) ; and
R44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl , carboxamidobenzyl , carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2 -methylbutylamide, isobutylacylamine, isobutylsulfoxyl , 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl , and carbmethoxy .
A further embodiment provides compounds having formula (II) that are represented by formula (Ila)
Figure imgf000028_0001
(Ha) wherein: each of Zχ ι Z3, and Z4 are as defined for compounds having formulas (I) and (II) .
In another embodiment for compounds having formula (Ila) , Zx is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl;
Z3 is -R300C (=NR301)NR302R303, wherein R300 is a phenyl ring, R 3oι. R 302 R 303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur; and
Z4 is a phenyl ring having formula (c) wherein: R42 is amino; R44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl, carboxamidobenzyl, carboxamidobutyl-2-yl , isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2-methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy; and
R41, R43 and R45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
A further embodiment provides compounds having formula (II) that are represented by formula (lib)
Figure imgf000029_0001
(lib) wherein: each of Z 3 ' and Z4 are as defined for compounds having formulas (I) and (II) .
In an alternative for compounds having formula (lib) , Zx is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl ;
Z3 is -R300C(=NR301)NR302R303, wherein R300 is a phenyl ring, R 3oι. R 302 R 303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur; and Z4 is a phenyl ring having formula (c) wherein: R42 is amino;
R44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl , carboxamidobenzyl , carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2-methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy; and
R41, R43 and R45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
Yet a further embodiment provides compounds having formula (II) that are represented by formula (lie)
Figure imgf000030_0001
(He) wherein: each of Z1; Z3, and Z4 are as defined for compounds having formulas (I) and (II) .
In an alternative for compounds having formula (lie) , Zx is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl ;
Z3 is
Figure imgf000031_0001
wherein R300 is a phenyl ring, R 3oι. R 302 R 303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur; and
Z4 is a phenyl ring having formula (c) wherein: R42 is amino;
R44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl, carboxamidobenzyl , carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2 -methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy; and
R41, R43 and R45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
Still a further embodiment provides compounds having formula (II) that are represented by formula (lid)
Figure imgf000031_0002
(lid) wherein: each of Z1; Z3, and Z4 are as defined for compounds having formulas (I) and (II) . In an alternative for compounds having formula (lid) ,
Z is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl;
Z3 is -R300C (=NR301)NR302R303, wherein R300 is a phenyl ring, R 3oι R 302 R 303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur; and
Z4 is a phenyl ring having formula (c) wherein: R42 is amino;
R44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl, carboxamidobenzyl, carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl -2 -methylbutylamide , isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy; and
R41, R43 and R45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur. A further aspect of the invention embraces compounds having formula (III)
Figure imgf000033_0001
(III) wherein: each of Xl f X2, X3, X4, and X5 form any of the 5- membered heterocyclic or carbocyclic rings indicated in Table 1 below and are selected from pyrazolinone, pyrrole, thiophene, pyrazole-N-oxide, 1-amino-pyrazole, 1,3,4- triazole, 2-amino-4-aryl-thiazole, 2-amino-5-aryl-thiazole, pyrrolidine, 2-amino-5-aryl-oxazole, 3-amino-pyrazole, 2- amio-4-aryl-oxazole, tetrahydrofuran, cyclopentadienone, and N-hydroxypyrrolidine; and
Z- and R44 are any of the groups detailed in Table 1 below.
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
The structure for each ring formed by X17 X2, X3, X4, and X5 identified in Table 1 is shown below Additionally, the structure for each R44 group identified in Table 1 is shown below.
Figure imgf000049_0001
PYRAZOLINONE PYRROLE THIOPHENE
Figure imgf000049_0002
PYRAZOLE-N-OXIDE 1-AMINO-PYRAZOLE 1 ,3,4-TRIAZOLE
Figure imgf000049_0003
2-AMINO-4-ARYL-THIAZOLE 2-AMINO-5-ARYL-THIAZOLE PYRROLIDINE
Figure imgf000049_0004
2-AMINO-5-ARYL-OXAZOLE 3-AMINO-PYRAZOLE 2-AMINO-4-ARYL-OXAZOLE
Figure imgf000049_0005
TETRAHYDROFURAN CYCLOPENTADIENONE N-HYDROXYPYRROLIDINE
Figure imgf000050_0001
hydroxy isobutylsulfonyl trifluoromethyl
Figure imgf000050_0002
isobutoxy carboethoxy carboxyl
Figure imgf000050_0003
carboxamidobenzyl carboxamidobutyl-2-yl isobutyramido
Figure imgf000050_0004
phenethylamine isobutylamine methoxyethylamide
Figure imgf000050_0005
ammo 3 -aminomethyl hiophene benzylamine
Figure imgf000051_0001
1-carboxylbenzylamide p-f luorobenzylamide cyclobutylamide R or S ISOMERS
Figure imgf000051_0002
benzylacylamine isobutylamide sec -pentylamine
Figure imgf000051_0003
m- f luorobenzylamide 1 -methylbenzylamide sec-butylamide RACEMIC or R or S R or S ISOMERS
Figure imgf000051_0004
isobutylsulfoxyl 2-cyclohexylamide methoxyl R or S ISOMERS
Figure imgf000052_0001
cyclopentylacylamine 1-carboxyl-2 -methylbutylamide isobutylacylamine
Figure imgf000052_0002
sulfonamide isobutylsulfonamide aminoacyltrifluoromethyl
Figure imgf000052_0003
carbmethoxy
Another aspect of the invention embraces compounds that correspond to formula (IV)
Figure imgf000052_0004
(IV) wherein:
Z is isopropyl, cyclopropyl, cyclobutyl or cycylopentyl optionally substituted by fluorine, hydroxy, carboxy, or alkoxycarbonyl; is -R300C(=NR301)NR302R303, wherein R 300 is a 6-membered carbocyclic aromatic ring, R301, R3 02' are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur; and
R44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl , carboxamidobenzyl, carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, m- f.luorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2 -methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl , and carbmethoxy.
A further embodiment provides compounds having formula (IV) that are represented by formula (IVa)
Figure imgf000053_0001
(IVa) wherein:
Zx is isopropyl, cyclopropyl, cyclobutyl or cycylopentyl optionally substituted by fluorine, hydroxy, carboxy, or alkoxycarbonyl; R44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl , carboxamidobenzyl, carboxamidobutyl-2 -yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3 -aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, m-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2 -methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl , and carbmethoxy; and
R310 and R311 are independently selected from the group consisting of hydrogen, fluorine, hydroxy, alkoxy, and carboxy, provided at least one of R310 and R311 is other than fluorine and hydrogen.
Yet another embodiment provides compounds having formula (IV) that are represented by formula (IVb)
Figure imgf000054_0001
(IVb) wherein:
Zx is isopropyl, cyclopropyl, cyclobutyl or cycylopentyl optionally substituted by fluorine, hydroxy, carboxy, or alkoxycarbonyl;
Z3 corresponds to formula (a) detailed above; and
R„ is Ci-Cg alkyl, aryl, aralkyl, carboxy, hydroxy or carboxyalkyl, wherein the alkyl, aryl, aralkyl, carboxy, hydroxy or carboxyalkyl is optionally further substituted by fluorine .
Still another embodiment provides compounds having formula (IV) that are represented by formula (IVc)
Figure imgf000055_0001
(IVc) wherein:
Zx is isopropyl, cyclopropyl, cyclobutyl or cycylopentyl optionally substituted by fluorine, hydroxy, carboxy, or alkoxycarbonyl;
Z3 corresponds to formula (a) detailed above ; and
R 440 is Ci-Cg alkyl, aryl, aralkyl, carboxy, or carboxyalkyl, wherein the alkyl, aryl, aralkyl, carboxy, or carboxyalkyl is optionally further substituted by fluorine.
A further aspect of the invention embraces compounds having formula (V)
Figure imgf000056_0001
(V) wherein:
Z1; Z3, Z4, L3, X2, X3, and X4 are as defined for any of formulas (I) - (IV) ; Xx and Xs are independently carbon and nitrogen;
X7 and X8 are independently a covalent bond, carbon, nitrogen, oxygen or sulfur;
X9 is carbon substituted with a methylene group or carbon substituted with an ethylene group wherein said methylene or ethylene group covalently links X9 and Zx ; Z2, when present, is a hydrogen bond acceptor covalently or datively bonded to X2; n is 0 to 2; and
R70 and R80 are independently selected from the group consisting of hydrogen, halogen, amino, hydrocarbyl, substituted hydrocarbyl, aryl, wherein aryl is phenyl either unsubstituted or substituted with hydroxy, amino, C--C6 alkyl, C3-C8 cycloalkyl, or halogen provided that R70 is not present when X7 is a bond and R80 is not present when X8 is a bond; or R70 and R80, along with the ring atoms to which each is attached, form a 5 or 6 membered saturated ring.
Yet another aspect of the invention provides compounds that are intermediates in the synthesis of compounds having formulas (I) - (V) . These intermediate compounds correspond to formula (VI)
Figure imgf000057_0001
(VI) wherein:
X17 X2, X3, and X5 are members of a heterocyclic or carbocyclic ring; X1; X2, and X3 are independently carbon or nitrogen;
X5 is selected from the group consisting of carbon, nitrogen, oxygen, and sulfur, provided that when X5 is carbon, it is -CH=, -C(F)=, or -C(Br)=;
T3 is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, and substituted amino;
T4 is selected from the group consisting of -Cl, -Br, -I, -S(CH3), and -OS02 (CF3) ;
Zx is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; and Z2, when present, is a hydrogen bond acceptor covalently or datively bonded to X2.
Yet another aspect of the invention provides compounds that are intermediates in the synthesis of compounds having formulas (I) - (V) . These intermediate compounds correspond to formula (VII)
Figure imgf000057_0002
(VII) wherein:
Xχ ι X2, X3, and X5 are members of a heterocyclic or aromatic core ring;
Xlf X2, and X3 are independently carbon or nitrogen;
X5 is selected from the group consisting of carbon, nitrogen, oxygen, and sulfur, provided that when X5 is carbon, it is -CH=, -C(F)=, or -C(Br)=;
Zx is hydrocarbyl, or substituted hydrocarbyl;
Z2, when present, is a hydrogen bond acceptor covalently or datively bonded to X2; and
Z4 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of the 5- or 6-membered heterocyclic or carbocyclic ring of Z4 being carbon, nitrogen, oxygen, or sulfur.
In yet a further embodiment, compounds having any of formulas (I) - (IV) are selected from the compounds in Table below.
TABLE 2
Compound No, Compound
Figure imgf000058_0001
TABLE 2
Compound No. Compound
Figure imgf000059_0001
TABLE 2
Compound No . Compound
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000060_0003
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Any compound corresponding to any of formulas (I) - (V) , having one or more prodrug moieties as part of the molecule, can be converted under physiological conditions to the biologically active drug by a number of chemical and biological mechanisms. In general terms, these prodrug conversion mechanisms are hydrolysis, reduction, oxidation, and elimination. For illustrative purposes, the following paragraphs detail prodrugs in which the prodrug moiety is covalently bonded to the amidine group on Z3 as depicted embodiments for each of formulas (I) - (V) above.
In one embodiment, conversion of the prodrug to the biologically active drug can be accomplished by hydrolysis of the prodrug moiety provided the prodrug moiety is chemically or enzymatically hydrolyzable with water. The reaction with water typically results in removal of the prodrug moiety and liberation of the biologically active drug. By way of example, a hydrolyzable prodrug derivative at the amidine group may be a carbonyl derivative such as N- acyl. Hydrolysis results in freeing the amidine group of the drug by removal of the acyl as carbon acid. Other suitable hydrolyzable prodrug derivatives include carbonyl, thiocarbonyl, imine, enamine, and oxygenated sulfur.
Yet another aspect of the invention provides conversion of the prodrug to the biologically active drug by reduction of the prodrug moiety. Typically in this embodiment, the prodrug moiety is reducible under physiological conditions in the presence of a reducing enzymatic process. The reduction preferably results in removal of the prodrug moiety and liberation of the biologically active drug. An example of a reducible prodrug derivative at the amidine group is an oxygen containing group in which an oxygen is directly attached to the amidine. Reduction results in freeing the amidine group of the drug by removal of oxygen as water or an alcohol. Generally speaking, other suitable reducible prodrug derivatives include a nitrogen containing group, and a sulfur containing group, provided both nitrogen and sulfur are each preferably in their most reduced state.
In another embodiment, conversion of the prodrug to the biologically active drug can also be accomplished by oxidation of the prodrug moiety. Typically in this embodiment, the prodrug moiety is oxidizable under physiological conditions in the presence of an oxidative enzymatic process. The oxidation preferably results in removal of the prodrug moiety and liberation of the biologically active drug. An example of an oxidizable prodrug derivative at the amidine group is a hydrocarbyl containing unsaturation in the carbon beta to the carbon directly connected to the amidine group. Oxidation results in forming an oxygenated intermediate that breaks down, thereby freeing the amidine group of the drug with concurrent hydrolysis of the oxygenated hydrocarbyl residue. Other suitable oxidizable prodrug derivatives of the amidine include saturated hydrocarbyl, unsaturated substituted hydrocarbyl , aryl , and aralkyl . A further aspect of the invention encompasses conversion of the prodrug to the biologically active drug by elimination of the prodrug moiety. Generally speaking, in this embodiment the prodrug moiety is removed under physiological conditions with a chemical or biological reaction. The elimination results in removal of the prodrug moiety and liberation of the biologically active drug. By way of example, an eliminateable prodrug derivative at the amidine group is a hydrocarbyl containing an unsaturated electron withdrawing group bonded to the carbon beta to the carbon directly connected to the amidine. More specifically, for illustration purposes and exemplification, the hydrocarbyl group could have a cyano group beta to the carbon directly bonded to the amidino group. Elimination results in the freeing of the amidine group of the drug with concurrent removal of the unsaturated hydrocarbyl residue derived from the prodrug moiety. Other suitable eliminateable prodrug derivatives of the amidine include a hydrocarbyl substituted at the beta carbon with carbonyl, alkoxycarbonyl, amidocarbonyl , nitro, or sulfonyl or an alkyl group substituted with oxygen, nitrogen or sulfur at the carbon directly bonded to the amidine group. Any compound of the present invention corresponding to formulas (I) - (V) may undergo any combination of the above detailed mechanisms to convert the prodrug to the biologically active compound. For example, a particular compound may undergo hydrolysis, oxidation, elimination, and reduction to convert the prodrug to the biologically active compound. Equally, a particular compound may undergo only one of these mechanisms to convert the prodrug to the biologically active compound.
The compounds of the present invention can exist in tautomeric, geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of compounds having any of formulas (I) - (V) . Pharmaceutically acceptable salts of such tautomeric, geometric or stereoisomeric forms are also included within the invention. The terms "cis" and "trans", as used herein, denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond ("sis") or on opposite sides of the double bond ("trans"). Some of the compounds described contain alkenyl groups, and are meant to include both cis and trans or "E" and "Z" geometric forms. Furthermore, some of the compounds described contain one or more stereocenters and are meant to include R, S, and mixtures or R and S forms for each stereocenter present .
Also included in the family of compounds having any of formulas (I) - (V) are the pharmaceutically-acceptable salts thereof. The term "pharmaceutically-acceptable salt" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically- acceptable acid addition salts of the compounds may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic) , methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of the compounds include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'- dibenzylethyleneldiamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the selected compound of any of formulas (I) - (V) . The present invention also comprises a pharmaceutical composition comprising a therapeutically-effective amount of the compound of the invention in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent. Pharmaceutical compositions of the present invention can comprise the active compounds of formulas (I) - (V) in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly, oculary, or topically. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.
The compounds can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramusculary as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, silastic, silicone rubber or other silicon containing polymers.
Moreover, the compounds 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 .
The compounds may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol , polyhydroxyethyl-aspartamide-phenol, or ployethyleneoxide- polylysine substituted with palmitoyl residues. Furthermore, the compounds 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 , polycyanoacrylates and cross linked or amphitpathic block copolymers of hydrogels.
For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, liquids including syrups, and emulsions. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient . Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely. The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1, 3-diol , mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without stabilizer (s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others .
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non- staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. For therapeutic purposes, the active compounds of the present invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os , the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art .
As a further embodiment, compounds having formula (I) - (V) or a pharmaceutically-acceptable salt thereof comprise a treatment and prophylaxis for thrombotic events resulting from coronary artery disease, cerebrovascular disease and other coagulation cascade related disorders in a subject. The treatment comprises administering to the subject having such disorder a therapeutically-effective amount of compounds having formulas (I)-(V) or a pharmaceutically- acceptable salt thereof.
In another aspect of the invention, the compounds or a pharmaceutically-acceptable salt thereof can also be used whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus coagulation inhibitors of the present invention can be added to or contacted with stored whole blood and any medium containing or suspected of containing plasma coagulation factors and in which it is desired that blood coagulation be inhibited, e.g. when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prothesis, cardiac prosthesis, and extracorporeal circulation systems. Compounds of Formula (I) - (V) are capable of inhibiting activity of serine proteases related to the coagulation cascade. Thus, these compounds could be used in the manufacture of a medicament as a method for the prophylactic or therapeutic treatment of diseases mediated by coagulation cascade serine proteases, such as inhibiting the formation of blood platelet aggregates, inhibiting the formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, in blood, in blood products, and in mammalian organs. The compounds also can be used for treating or preventing unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels in a mammal. Moreover, the compounds also can be used to study the mechanism of action of coagulation cascade serine proteases to enable the design of better inhibitors and development of better assay methods. The compounds would be also useful in prevention of cerebral vascular accident (CVA) or stroke.
In practicing the methods of the present invention for the treatment and prevention of a variety of thrombotic conditions including coronary artery and cerebrovascular disease, the compounds and pharmaceutical compositions are administered alone or in combination with one another, or in combination with other therapeutics or in vivo diagnostic agents. In another aspect, the compounds can also be co- administered with suitable anti-platelet aggregation agents, including, but not limited to aspirin, ticlopidine, or clopidrogel, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocculsion after angioplasty and restenosis) , anti-coagulants such as aspirin, warfarin or heparins, thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various pathologies, lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as mevastatin, lovastatin, simvastatin, pravastatin, and fluvastatin, HMG CoA synthatase inhibitors, etc.), anti-diabetic drugs, or other cardiovascular agents (e.g. loop diuretics, thiazide type diuretics, nitrates, aldosterone antagonistics (e.g. spironolactone and epoxymexlerenone) , angiotensin converting enzyme (e.g. ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, antiarrythmics, anti- hypertension agents, and calcium channel blockers to treat or prevent atheriosclerosis . By way of example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and coagulation cascade inhibitors of the present invention. Also, coagulation cascade inhibitors could enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion. Typical doses of compounds of the present invention with other suitable anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents may be the same as those doses of coagulation cascade inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, or may be substantially less than those doses of coagulation cascade inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, cardiovascular therapeutic agents, or thrombolytic agents, depending on a patient's therapeutic needs.
The present methods preferably employ prodrug compounds that when converted to the biologically active compound selectively inhibit human TF-VIIA over the inhibition of both human Thrombin II and human factor Xa. Preferably, the compounds have a human TF-VIIA IC50 of less than 0.5 mM and also have a selectivity ratio of TF-VIIA inhibition over both human Thrombin II and human factor Xa inhibition of at least 10, and more preferably at least 100. Even more preferably, the compounds have a human TF-VIIA IC50 of less than 0.1 mM and also have a selectivity ratio of TF-VIIA inhibition over both human Thrombin II and human factor Xa inhibition of at least 1000, and most preferably at least 10,000.
All mentioned references are incorporated by reference as if here written. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. The following examples are provided to illustrate the present invention and are not intended to limit the scope thereof. Without further elaboration, it is believed that one skilled in the art can, using the preceding descriptions, utilize the present invention to its fullest extent. Therefore, the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. Compounds containing multiple variations of the structural modifications illustrated in the schemes or the following Examples are also contemplated. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds .
One skilled in the art may use these generic methods to prepare the following specific examples, which have been or may be properly characterized by XH NMR, mass spectrometry, elemental composition, and similar procedures. These compounds also may be formed in vivo. The following examples contain detailed descriptions of the methods of preparation of compounds having each of formulas (I) - (V) . These detailed descriptions fall within the scope and are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are Degrees centigrade unless otherwise indicated.
GENERAL SYNTHETIC PROCEDURES AND SPECIFIC EXAMPLES The compounds of the present invention can be synthesized, for example, according to the following procedures and Schemes given below.
Abbreviations used in the schemes and tables include : "AA" represents amino acids, "AcCN" represents acetonitrile, "AcOH" represents acetic acid, "BINAP" represents 2,2'- bis (diphenylphosphino) -1, 1' -binaphthyl, "BnOH" represents benzyl alcohol, "BnCHO" represents 2-phenylethanal , "BnS02Cl" represents benzylsulfonyl chloride, "Boc" represents tert-butyloxycarbonyl , "BOP" represents benzotriazol-1-yl-oxy-tris- (dimethylamino) , "bu" represents butyl, "dba" represents dibenzylidene-acetone, "DCC" represents 1, 3-dicyclohexylcarbodiimide, "DCM" represents dichloromethane or methylene chloride, "DIBAH" or "DIBAL" represents diisobutylaluminum hydride, "DMF" represents dimethylformamide, "DMSO" represents dimethylsulfoxide, "DPPA" represents diphenylphosphoryl azide" , "EDC" represents 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, "Ex. No." represents Example Number, "Fmoc" represents 9-fluorenylmethoxycarbonyl , "HOBt" represents hydroxybenzoltriazole" , "LDA" represents lithium diisopropylamide, "MW" represents molecular weight, "NMM" represents N-methylmorpholine, "Ph" represents phenyl or aryl, "PHTH" represents a phthaloyl group, "pnZ" represents 4 -nitrobenzyloxy-carbonyl, "PTC" represents a phase transfer catalyst , "py" represents pyridine, "R" represents a hydrocarbyl or a substituted hydrocarbyl, " RNH2" represents a primary organic amine, "SEM" represents 2- (trimethylsilyl) ethoxy-methyl chloride, "p-TsOH" represents paratoluenesulfonic acid, "TBAF" represents tetrabutylammonium fluoride, "TBTU" represents 2- (1H- benzotriozole-1-yl) -1, 1, 3 , 3-tetramethyl uronium tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents trifluoroacetic acid, "THF" represents tetrahydrofuran, "TMS" represents trimethylsilyl, "TMSCN" represents trimethylsilyl cyanide, and "Cbz" or "Z" represents benzyloxycarbonyl "X" represents a halogen and typically is a bromine or chlorine. As used in the schemes and examples, Zx , Z3, Z4, R44, 8o R301' R302. R303' ^304 ' 305/ R306, R307, R308 R309 R310- R3iι/ and X7, along with any other variable depicted, encompasses every group described for each particular variable for each embodiment of compounds having formulas (I)-(V) as detailed herein. A specific synthetic process, useful in the preparation of many of the heterocyclic compounds of the present invention, is the arylation or heteroarylation of an intermediate compound characterized by having a suitable leaving group on a sp2 hybridized carbon of a heterocyclic ring. In the product of the reaction, the leaving group is replace by an aryl group or a heteroaryl group. Suitable leaving groups for the reaction include chloro, bromo, iodo, methylthio, and triflates. The heterocyclic ring with the leaving group will preferably have an acetic acid group or a derivative thereof bonded to a ring atom alpha to the bromo and a substituted or unsubstituted amino group bonded to a ring atom that is both beta to the carbon having the acetic acid group and gamma to the bromo substituted ring carbon. The aryl group that is reacted at the sp2 hybridized carbon is generally an aryl boronic acid or an ester of the aryl boronic acid; similarly, heteroaryl boronic acids or esters of these boronic acids can be used in the same manner as aryl boronates . The aryl and heteroaryl boronates may be substituted or unsubstituted. The aryl or heteroaryl becomes bonded to the sp2 hybridized carbon at the point at which the boron was attached to the aryl or heteroaryl ring. Aryl and heteroaryl organoSn compounds can also be used instead of the corresponding boronates.
Suitable reaction conditions for carrying out this transformation include:
1. Pd[P (phenyl) 3]„, 2M Na2C03, 60-75°C, dimethoxyethane (DME) , H20, N2; 2. Pd[P (phenyl) 3]4, Cs2C03, dioxane, 100°C;
3. Pd [P (phenyl) 3]4, Cu (I) -2-thiophenecarboxylate, 70-75°C, anhydrous THF, argon; and
4. Z4-Sn(n-butyl) 3] , Pd [P (phenyl) 3] 4, LiCl, anhydrous dioxane, 85 °C, argon or N2.
The organo palladium (Pd [P (phenyl) 3] 4) compound is used catalytically in a ratio of 1 to 40 mole %. The carbonate base is normally used in an excess of 1.2 to 2 molar equivalents. Suitable solvents include dimethoxyethane (DME) , dioxane, 1-propanol, and tetrahydrofuran. The temperature of the reaction is normally in the range of from about 50 to 100°C. Cu (I) -2-thiophenecarboxylate (Cu(I)-TC) is normally used in a mole % of 110-150.
Scheme G shows a specific application of this specific synthetic process. Procedures for preparing the intermediate heterocyclic or cycloalkenyl ring compounds having a suitable leaving group on sp2 hybridized carbon and useful as suitable intermediates in this specific synthetic process are given in the schemes and examples listed above. Scheme J illustrates a general synthetic process for substitution at a nitrogen of the heterocyclic ring. The synthetic process applies whether the ring is 5- or 6- membered.
Scheme A:
Figure imgf000078_0001
Deprotection: H2, Pd/C orLiOH,H2O,MeOH
Figure imgf000078_0002
Figure imgf000078_0003
Z = benzyloxycarbonyl
Figure imgf000078_0004
Figure imgf000078_0005
Scheme A: (continued from page 77)
Figure imgf000079_0001
Scheme B :
Figure imgf000080_0001
Figure imgf000080_0002
Scheme B: (continued from page 79)
Figure imgf000081_0001
Scheme C :
Figure imgf000082_0001
Z = benzyloxycarbonyl
Figure imgf000082_0002
Scheme C: (continued from page 81)
Figure imgf000083_0001
Scheme D;
Figure imgf000084_0001
Figure imgf000084_0002
Figure imgf000084_0003
Figure imgf000084_0004
Figure imgf000084_0005
Scheme D: (continued from page 83)
Figure imgf000085_0001
Z = benzyloxycarbonyl
Figure imgf000085_0002
Figure imgf000085_0003
Scheme E
Figure imgf000086_0001
Figure imgf000086_0002
Figure imgf000086_0003
Figure imgf000086_0004
Figure imgf000086_0005
Figure imgf000086_0006
Scheme E: (continued from page 85)
Figure imgf000087_0001
Z = benzyloxycarbonyl
Figure imgf000087_0002
Figure imgf000087_0003
Scheme F :
Figure imgf000088_0001
Chloranil t-butanol/pyridine
Figure imgf000088_0002
Figure imgf000088_0003
Figure imgf000088_0004
heat
Figure imgf000088_0005
Figure imgf000088_0006
See Page 88 Scheme F: (continued from page 87)
Figure imgf000089_0001
Z = benzyloxycarbonyl
Figure imgf000089_0002
Figure imgf000089_0003
Scheme G:
.PBΓJL
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000090_0003
Lewis Acid, Br2
Figure imgf000090_0004
Figure imgf000090_0005
Figure imgf000090_0006
Figure imgf000091_0001
Z = benzyloxycarbonyl
Figure imgf000091_0002
Figure imgf000091_0003
Figure imgf000091_0004
Scheme H :
Figure imgf000092_0001
Figure imgf000092_0002
Figure imgf000092_0003
Figure imgf000092_0004
TBTU Z = benzyloxycarbonyl
See Page 92 DMF
DIEA Scheme H: (continued from page 91)
Figure imgf000093_0001
Figure imgf000093_0002
Scheme I
Figure imgf000094_0001
Figure imgf000094_0002
H
Figure imgf000094_0003
Figure imgf000094_0004
Scheme I: (continued from page 93)
Figure imgf000095_0001
Z = benzyloxycarbonyl
TBTU
DMF
DIEA
Figure imgf000095_0002
Figure imgf000095_0003

Claims

ClaimsWHAT IS CLAIMED IS:
1. A compound having the structure
Figure imgf000096_0001
wherein:
X comprises a 5-membered heterocyclic or carbocyclic ring, the ring atoms being Xlr X2, X3, X4, and X5, wherein X17 X3, and X4, are independently carbon or nitrogen and X2 and X5 are independently carbon, nitrogen, oxygen or sulfur;
Llf L3 and L4 are linkages through which Z1# Z3, and Z4, respectively, are covalently bonded to different ring atoms of the 5-membered heterocyclic or carbocyclic ring of X, wherein Zx is covalently bonded to Xχ ι Z3 is covalently bonded to X3, and Z4 is covalently bonded to X4, each of L1# L3 and L4 independently being a covalent bond or comprising one or more atoms through which Zχ ι Z3, and Z4 are covalently bonded to Xx , X3 and X4, respectively; Zx is hydrocarbyl or substituted hydrocarbyl;
Z3 comprises a 5- or 6-membered heterocyclic or aromatic ring substituted with an amidine group, the ring atoms of the 5- or 6-membered heterocyclic or aromatic ring of Z3 being carbon, sulfur, nitrogen, or oxygen, wherein the 5- or 6-membered ring is optionally substituted at any position with halogen, alkyl or hydroxy; and
Z4 comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of the 5- or 6-membered heterocyclic or carbocyclic ring of Z4 being carbon, nitrogen, oxygen, or sulfur.
2. The compound of claim 1 wherein: each of X17 X2, X3, X4, and X5 are as defined in claim 1;
Li is -X9NH- wherein X9 is covalently bonded directly to Zx and X9 is a direct bond or -(CH2)m- wherein m is 1 to 5; L3is a glycine derivative;
L4 is a direct bond;
Zx is selected from the group consisting of C -Q. alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen;
Z3 comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy;
Z4 comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of Z4 being Z40, Z41, Z42, Z44 and Z4S when Z4 is a 5-membered ring and Z40, Z41, Z42, Z43, Z44 and Z45 when Z4 is a 6-membered ring, Z40, Z41, Z42, Z43, Z44 and Z45, being carbon, nitrogen, oxygen or sulfur, Z40 being the ring atom through which Z4 is attached to the heterocyclic ring, Z41 and Z45 each being in an alpha position relative to Z40, Z42 and Z44 each being in a beta position relative to Z40, Z43 being in the gamma position relative to Z40 when Z4 is a 6-membered ring, Z4 having a substituent R42 covalently attached to Z42, and a second substituent bonded to one of Z41, Z43, Z44, or Z45, the substituent being R41 when bonded to Z41, the substituent being R43 when bonded to Z43, the substituent being R44 when bonded to Z44, and the substituent being R45 when bonded to Z45;
R42 is amino; and
R41, R43, R44 and R45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R41, R43, R44 or R45 is other than hydrogen.
3. The compound of claim 2 wherein:
X9 is a direct bond;
L3 is -CH2CONHCH2- and Z3 is covalently bonded to the methylene bonded to the amine nitrogen of L3; Z is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl ; Z3 comprises a phenyl ring, the phenyl ring being optionally further substituted with fluorine or hydroxy;
Z4 comprises a phenyl or thienyl ring having two substituents, R42 and R44, and two ring atoms each of which is in the beta position relative to the ring atom of Z4 through which Z4 is covalently bonded to X, wherein one of
R42 and R44 is covalently bonded to one of the beta positions and the other of R42 and R44 is covalently bonded to the other of the beta positions;
R42 is amino; and R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, and an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus.
4. The compound of claim 1 wherein Lx is -X9NH- wherein X9 is covalently bonded directly to Zx and X9 is a direct bond or -(CH2)m- wherein m is 1 to 5.
5. The compound of claim 1 wherein L3 is selected from the group consisting of a glycine derivative, an alanine derivative, an amino derivative, and a sulfonyl derivative .
6. The compound of claim 5 wherein L3 is a glycine derivative .
7. The compound of claim 6 wherein L3 is -CH2CONHCH2- and Z3 is covalently bonded to the methylene bonded to the amine nitrogen of L3.
8. The compound of claim 1 wherein L4 is selected from the group consisting of a direct bond, methylene, ethylene and an optionally substituted heteroatom selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus .
The compound of claim 8 wherein L4 is a direct bond.
10. The compound of claim 1 having the structure
Figure imgf000099_0001
wherein:
X2 and X5 are as defined in claim 1 ;
Xx , X3 and X4 are independently carbon or nitrogen;
X9 is a direct bond or -(CH2)ra- where m is 1 or 2; and
Z- , Z, and ZΛ are as defined in claim 1.
11. The compound of claim 10 wherein:
X9 is selected from the group consisting of a direct bond, methylene, and ethylene;
Zx is selected from the group consisting of Ci-Cg alkyl, C2-C8 alkenyl, and C2-C3 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen;
Z3 comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy;
Z4 comprises a phenyl or thienyl ring having two substituents, R42 and R44, and two ring atoms each of which is in the beta position relative to the ring atom of Z4 through which Z4 is covalently bonded to X, wherein one of R42 and R44 is covalently bonded to one of said beta positions and the other of R42 and R44 is covalently bonded to the other of said beta positions; R42 is amino; and
R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, and an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus.
12. The compound of claim 11 wherein:
X9 is a direct bond;
Zx is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl ;
Z3 is a phenyl ring, the phenyl ring being optionally further substituted with fluorine or hydroxy; Z4 is a substituted phenyl ring; and
R44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl , carboxamidobenzyl, carboxamidobutyl-2 -yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2 -methylbutylamide , isobutylacylamine , isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy.
13. The compound of claim 1 or 10 wherein: Xχ ι X2 and X5 are carbon; and
X3 and X4 are nitrogen.
14. The compound of claim 1 or 10 wherein: Xx , X3, X4 and X5 are carbon; and
X2 is nitrogen.
15. The compound of claim 1 or 10 wherein: X17 X2, X3, X4 and X5 are carbon.
16. The compound of claim 1 or 10 wherein: X17 X4 and X5 are carbon; and
X2 and X3 are nitrogen.
17. The compound of claim 1 or 10 wherein Xχ ι X2, X3, X4, and X5 are selected to provide a heterocyclic or carbocyclic ring selected from the group consisting of pyrazolinone, pyrrole, thiophene, pyrazole-N-oxide, 1-amino, pyrazole, 1 , 3 , 4-triazole, 2-amino-4-aryl-thiazole, 2-amino- 5-aryl-thiazole, pyrrolidine, 2-amino-5-aryl-oxazole, 3- amino-pyrazole, 2-amio-4-aryl-oxazole, tetrahydrofuran, cyclopentadienone, and N-hydroxypyrrolidine.
18. The compound of 17 wherein the heterocyclic or carbocyclic ring is selected from the group consisting of cyclopentadienone, pyrazole-N-oxide, pyrazolinone and N- hydroxypyrrolidine .
19. The compound of claim 18 wherein the heterocyclic ring is pyrazolinone.
20. The compound of claim 2 or 10 wherein X9 is a direct bond.
21. The compound of claim 2 or 10 wherein X9 is methylene or ethylene .
22. The compound of claim 1 or 10 wherein Zx is selected from the group consisting of C.-Cg alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen.
23. The compound of claim 22 wherein Zx is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl.
24. The compound of claim 23 wherein Zx is selected from the group consisting of cyclopropyl, isopropyl, cyclobutyl, isobutyl, and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl .
25. The compound of claim 24 wherein Zx is isopropyl or cyclobutyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl.
26. The compound of claim 1 or 10 wherein Z3 comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy.
27. The compound of claim 26 wherein Z3 is -R300C (=NH)NH2, wherein R300 is a 6-membered carbocyclic aromatic ring, the 6-membered ring being optionally substituted at any substitutable position with a halogen or hydroxy .
28. The compound of claim 27 wherein Z3 is
Figure imgf000103_0001
wherein :
R304 and R306 are independently selected from the group consisting of hydrogen, fluorine, hydroxy, carboxy, hydrocarbyloxy, and alkoxycarbonyl; and
R305 and R307 are independently selected from the group consisting of hydrogen, fluorine, methoxy, hydroxy, and carboxy.
29. The compound of claim 1 or 10 wherein Z3 is -R300C (=NR301) NR302R303, wherein R300 is a 6-membered carbocyclic aromatic ring, R30ι, R302. R303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur, provided at least one of R3oι. R 302. R 303 is other than hydrogen.
30. The compound of claim 29 wherein Z3 is a benzamidine derivative, which upon hydrolysis, oxidation, reduction or elimination forms a benzamidine.
31. The compound of claim 1 or 10 wherein Z4 comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of Z4 being Z40, Z41, Z42, Z44 and Z45 when Z4 is a 5-membered ring and Z40, Z41, Z42, Z43, Z44 and Z45 when Z4 is a 6-membered ring, Z40, Z41, Z42, Z43, Z44 and Z45, being carbon, nitrogen, oxygen or sulfur, Z40 being the ring atom through which Z4 is attached to the heterocyclic ring, Z41 and Z45 each being in an alpha position relative to Z40, Z42 and Z44 each being in a beta position relative to Z40 Z43 being in the gamma position relative to Z40 when Z4 is a 6-membered ring, Z4 having a substituent R42 covalently attached to Z42, and a second substituent bonded to one of Z41, Z43, Z44, or Z45, the substituent being R41 when bonded to Z41, the substituent being R43 when bonded to Z43, the substituent being R44 when bonded to Z44, and the substituent being R45 when bonded to Z45;
R42 is amino; and
R41, R43, R44 and R45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or a substituted or unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R41, R43, R44 or R45 is other than hydrogen.
32. The compound of claim 31 wherein Z4 is a substituted, 6-membered, carbocyclic aromatic ring.
33. The compound of claim 32 wherein Z4 has the structure
Figure imgf000104_0001
wherein
R42 is amino;
R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, halogen and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and
R41, R43 and R45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
34. The compound of claim 33 wherein R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamido, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, carboalkoxy, carboxy, carboxamidoalkyl , and carboxamidoalkylaryl .
35. The compound of claim 33 wherein R44 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, heterocyclo, halogen, acetamido, guanidino, hydroxy, nitro, amino, amidosulfonyl , acylamido, hydrocarbyloxy, substituted hydrocarbyloxy, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylsulfonyl, and substituted hydrocarbylsulfonyl .
36. The compound of claim 33 wherein R44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl, carboxamidobenzyl, carboxamidobutyl -2 -yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3- aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, zn-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl -2 -methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl , and carbmethoxy.
37. The compound of claim 33 wherein each of R41, R43 and R45 is hydrogen.
38. The compound of claim 31 wherein Z4 has the structure
Figure imgf000106_0001
wherein :
Z40, Z41, Z42, Z44, and Z45 are independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur; R42 is amino;
R44 is selected from the group consisting of is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, halogen and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; and
R41 and R45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
39. The compound of claim 38 wherein R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamido, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, carboalkoxy, carboxy, carboxamidoalkyl , and carboxamidoalkylaryl .
40. The compound of claim 38 wherein R44 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, heterocyclo, halogen, acetamido, guanidino, hydroxy, nitro, amino, amidosulfonyl, acylamido, hydrocarbyloxy, substituted hydrocarbyloxy, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylsulfonyl, and substituted hydrocarbylsulfonyl .
41. The compound of claim 38 wherein R44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl, carboxamidobenzyl, carboxamidobutyl -2 -yl , isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3- aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, m-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl -2 -methylbutylamide , isobutylacylamine , isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy .
42. The compound of claim 38 wherein each of R41, R42 and R45 is hydrogen.
43. The compound of claim 10 having the structure
Figure imgf000107_0001
wherein: each of Z1# Z3, and Z4 are as defined in claim 10.
44. The compound of claim 10 having the structure
Figure imgf000107_0002
wherein: each of Z-, Z3, and Z4 are as defined in claim 10.
45. The compound of claim 10 having the structure
Figure imgf000108_0001
wherein: each of Z , Z3, and Z4 are as defined in claim 10.
46. The compound of claim 10 having the structure
Figure imgf000108_0002
wherein: each of Z1# Z3, and Z4 are as defined in claim 10
47. The compound of each of claims 43 to 46 wherein: Zx is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl ;
Z3 is -R300C (=NR301)NR302R303, wherein R300 is a phenyl ring, R01. R 302 R 303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur; and Z4 is a phenyl ring having the structure
Figure imgf000109_0001
wherein: R42 is amino;
R44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl, carboxamidobenzyl, carboxamidobutyl-2 -yl , isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3 -aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, —fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl -2 -methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl , and carbmethoxy; and
R41, R43 and R45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
48. The compound of claim 47 wherein: Z- is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl; and
Z, is as defined in claim 28.
49. The compound of claim 10 having the structure
Figure imgf000110_0001
wherein:
Zx is isopropyl, cyclopropyl, cyclobutyl or cycylopentyl optionally substituted by fluorine, hydroxy, carboxy, or alkoxycarbonyl;
Z3 is -R300C (=NR301)NR302R303, wherein R300 is a 6-membered carbocyclic aromatic ring, R301, R302 R 303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur; and
R44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl , carboxamidobenzyl, carboxamidobutyl-2 -yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, zn-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl -2 -methylbutylamide , isobutylacylamine , isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl , and carbmethoxy.
50. The compound of claim 10 having the structure
Figure imgf000111_0001
wherein:
Z is isopropyl, cyclopropyl, cyclobutyl or cycylopentyl optionally substituted by fluorine, hydroxy, carboxy, or alkoxycarbonyl;
R44 is selected from the group consisting of hydroxy, isobutylsulfonyl , trifluoromethyl , carboxamidobenzyl, carboxamidobutyl-2 -yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p- fluorobenzylamide, cyclobutylamide, m-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2 -methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl , and carbmethoxy; and
R310 and R311 are independently selected from the group consisting of hydrogen, fluorine, hydroxy, alkoxy, and carboxy, provided at least one of R310 and R311 is other than fluorine and hydrogen.
51. The compound of claim 50 having the structure
Figure imgf000112_0001
wherein:
Z is isopropyl, cyclopropyl, cyclobutyl or cycylopentyl optionally substituted by fluorine, hydroxy, carboxy, or alkoxycarbonyl;
Z3 is as defined in claim 28; and
R440 is
Figure imgf000112_0002
alkyl, aryl, aralkyl, carboxy, hydroxy or carboxyalkyl, wherein the alkyl, aryl, aralkyl, carboxy, hydroxy or carboxyalkyl is optionally further substituted by fluorine .
52. The compound of claim 50 having the structure
Figure imgf000112_0003
wherein:
Z is isopropyl, cyclopropyl, cyclobutyl or cycylopentyl optionally substituted by fluorine, hydroxy, carboxy, or alkoxycarbonyl;
Z3 is as defined in claim 28; and R440 is Ci-Cg alkyl, aryl, aralkyl, carboxy, or carboxyalkyl, wherein the alkyl, aryl, aralkyl, carboxy, or carboxyalkyl is optionally further substituted by fluorine.
53. A composition for substantially inhibiting thrombotic conditions in blood comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
54. A method for substantially inhibiting thrombotic conditions in blood comprising adding to blood the composition of claim 53.
55. A method for substantially inhibiting formation of platelet aggregates in blood comprising adding to blood the composition of claim 53.
56. A method for substantially inhibiting thrombus formation in blood comprising adding to blood the composition of claim 53.
57. A method for treating or preventing venous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal the composition of claim 53.
58. A method for treating or preventing deep vein thrombosis in a mammal comprising administering to the mammal the composition of claim 53.
59. A method for treating or preventing cardiogenic thromboembolism in a mammal comprising administering to the mammal the composition of claim 53.
60. A method for treating or preventing thromboembolic stroke in a mammal comprising administering to the mammal the composition of claim 53.
61. A method for treating or preventing thrombosis associated with cancer and cancer chemotherapy in a mammal comprising administering to the mammal the composition of claim 53.
62. A method for treating or preventing unstable angina in a mammal comprising administering to the mammal the composition of claim 53.
63. A method for inhibiting thrombus formation in blood comprising adding to blood the composition of claim 53 along with a fibrinogen receptor antagonist .
PCT/US2002/031770 2001-10-03 2002-10-03 Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade Ceased WO2003093242A2 (en)

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EP02807360A EP1432687A2 (en) 2001-10-03 2002-10-03 Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade
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US33285701P 2001-11-06 2001-11-06
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