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  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
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  • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
  • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/56—Nitrogen atoms
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  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
  • C07D231/46—Oxygen atom in position 3 or 5 and nitrogen atom in position 4
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  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
• • C—CHEMISTRY; METALLURGY
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  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
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  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
  • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
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  • C07D253/06—1,2,4-Triazines
  • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
  • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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  • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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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 prodrugs of compounds 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. Limbird, 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.
• 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.
• 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 prodrug compound, per se, to pharmaceutical compositions comprising the prodrug compound and a pharmaceutically acceptable carrier, and to methods of use.
• One aspect of the invention provides compounds that correspond to formula (I) :
• X comprises a 5- or 6-membered heterocyclic or aromatic ring, the ring atoms being X 17 X 2 , X 3 , X 4 , and X s for 5-membered heterocyclic rings and X_ , X 2 , X 3 , X 4 , X 5 and X 6 for 6-membered heterocyclic or aromatic rings, wherein X 2 is alpha to each of X_ and X 3 , X 3 is alpha to each of X 2 and X 4 , X 4 is alpha to each of X 3 and X 5 , X 5 is alpha to X 4 and alpha to X_ if X is a 5-membered ring or to X 6 if X is a 6- membered ring, and X s , when present, is alpha to each of X_ and X_ , wherein X_ , X 2 , X 3 , X 4 , X 5 and
• J__ , 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- or 6-membered heterocyclic or aromatic 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 , L 3 and L 4 independently being a covalent bond or comprising one or more atoms through which Z_ , 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 a derivatized amidine which, upon hydrolysis, oxidation, reduction or elimination yields an amidine group, and optionally further substituted with a halogen or hydroxy, the ring atoms of the 5- or 6-membered heterocyclic or aromatic ring of Z 3 being carbon, sulfur, nitrogen, or oxygen;
• Z 4 comprises a 5- or 6-membered heterocyclic or carbocyclic 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, the ring atoms of the 5- or 6-membered heterocyclic or carbocyclic ring of Z 4 being carbon, nitrogen, oxygen, or sulfur;
• R 42 is amino
• R 44 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus; provided, however, the derivatized amidine is other than amidine derivatized with t-butoxycarbonyl.
• Another aspect of the invention provides compounds corresponding to formula II:
• each of X_ , X 2 , X 3 , X 4 , X 5 and X 6 is carbon or nitrogen;
• X 2 is a hydrogen bond acceptor
• Xg is a direct bond or -(CH 2 ) m - where m is 1 to 5;
• R 42 and R 44 are as defined for formula (I) ;
• Z_ , Z 3 , and Z 4 are as defined for 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; (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.
• 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, lkynyloxyalkyl , 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.
• 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.
• 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 1 ⁇ -, R X R 2 N-, or R 1 S-, R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R 2 is hydrogen, hydrocarbyl or substituted hydrocarbyl.
• 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.”
• 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.
• 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 x 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- or 6-membered heterocyclic or aromatic ring, the ring atoms being X ⁇ ; X 2 , X 3 , X 4 , and X 5 for 5-membered heterocyclic rings and X x , X 2 , X 3 , X 4 , X 5 and X 6 for 6-membered heterocyclic or aromatic rings, wherein X 2 is alpha to each of X x and X 3 , X 3 is alpha to each of X 2 and X 4 , X 4 is alpha to each of X 3 and X 5 , X 5 is alpha to X 4 and alpha to X x if X is a 5-membered ring or to X 6 if X is a 6- membered ring, and X ⁇ , when present, is alpha to each of X_ and X 5 , wherein X x , X 2 , X 3 , X 4
• Z_ is hydrocarbyl or substituted hydrocarbyl
• Z 3 comprises a 5- or 6-membered heterocyclic or aromatic ring substituted with a derivatized amidine which, upon hydrolysis, oxidation, reduction or elimination yields an amidine group, and optionally further substituted with a halogen or hydroxy, the ring atoms of the 5- or 6-membered heterocyclic or aromatic ring of Z 3 being carbon, sulfur, nitrogen, or oxygen;
• Z 4 comprises a 5- or 6-membered heterocyclic or carbocyclic 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, the ring atoms of the 5- or 6-membered heterocyclic or carbocyclic ring of Z 4 being carbon, nitrogen, oxygen, or sulfur;
• R 42 is amino
• R 44 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or a substituted or unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus; provided, however, the derivatized amidine is other than amidine derivatized with t-butoxycarbonyl.
• each of X x , X 2 , X 3 , X 4 , X 5 and X s is carbon or nitrogen;
• X 2 is a hydrogen bond acceptor
• Lj . 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 x -C a 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 substituted with a derivatized amidine which, upon hydrolysis, oxidation, reduction or elimination yields an amidine group, and 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
• 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 L_ 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 I_ ⁇ 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 L 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 L 4 linkage is a direct bond.
• Z_ is a s2_-Q. s alkyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy or alkoxycarbonyl.
• the Q._-T._ 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_- C 5 alkyl is isopropyl or cyclobutyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl.
• R 300 is a 6-membered carbocyclic aromatic ring
• 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 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 (a)
• K-30 1 / R 3 0 2 an d R303 are independently selected from the group consisting of:
• R a is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, and heterocyclo, provided, however, that the carbon atom of R 3CU.
• R 302 an d R 303 directly bonded to the amidine is sp 2 hybridized when R 301 , R 302 , and 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 oxidized under physiological conditions to form benzamidine when Z 3 is a benzamidine derivative having formula (a) and R 3o ⁇ R 302 ' and R 303 are independently selected from hydrogen, optionally substituted hydrocarbyl and aryl, provided, however, the carbon atom of R 301 , 302 and R 303 directly bonded to the amidine is sp 3 hybridized when R 301 , 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 (a) and R 301 , R 302 and R 303 are independently selected from hydrogen, -OR b , -SR b , -NR b , or -N(R b ) 2 , wherein each R b is independently optionally substituted hydrocarbyl, and heterocyclo.
• the benzamidine derivative undergoes elimination at physiological conditions to form benzamidine when Z 3 is a benzamidine derivative having formula (a) and R 301 , R 302 ' and R 303 are independently selected from hydrogen, substituted hydrocarbyl wherein the carbon bonded to the amidine group is substituted with -0R 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)OR 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 .
• Z 3 may be any of the benzamidine derivatives illustrated in Table 1 or 3 below.
• a further embodiment embraces compounds having formula (I) where Z 4 is a substituted, 6-membered carbocyclic aromatic ring.
• Z 4 corresponds to formula (b)
• 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;
• 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-cyclohexyl
• 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 4S 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 4S 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 (c)
• 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, .
• R 41 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 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) , C0CH 3 , COR, C(SH), CSR, and CNR ⁇ 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.
• each of X_ , X 2 , X 3 , X 4 , X 5 and X 6 is carbon or nitrogen
• each of X 1# X 2 , X 4 , X 5 and X 6 is sp 2 or sp 3 hybridized
• X 3 is sp 3 hybridized
• L 1# L 3 , L 4 , Z x , Z 3 , Z 4 , R 42 , and R 44 are as described above.
• X_ , X 4 and X 5 are carbon
• X 2 is carbonyl
• X 3 and X s are nitrogen.
• X_ , X 4 and X s are carbon, X 2 is carbonyl and X 3 and X 5 are nitrogen.
• X_ , X 4 , X 5 and X 6 are carbon, X 2 is carbonyl and X 3 is nitrogen.
• a further embodiment embraces compounds having formula (I) , where X l t X 2 , X 3 , X 4 , X 5 , and X 6 form a 6-membered heterocyclic or carbocyclic ring selected from a pyrazinone, pyrimidinone, 2-pyridone, 4-pyrone, 4-pyridone, pyridine-N-oxide, 1,4-quinone, benzene, uracil, piperidinone, dihydropyrimidone , tetrahydropyrimidinone, dehydropiperidinedione , dihydropyrazinone, dihydroisoxazinone, tetrahydrotriazinedione , tetrahydrotriazinone, piperidine, and piperazine and Li, L 3 , L 4 , Z_ , Z 3 , Z 4 , R 42 , and R 44 are as described above.
• X x , X 2 , X 3 , X 4 , X 5 , and X 6 form a pyrazinone, pyrimidinone, 2-pyridone, 4-pyrone, 4-pyridone, pyridine-N-oxide, 1,4-quinone, benzene, or uracil ring.
• the ring is a pyrazinone, pyrimidinone, or 2-pyridone.
• X x , X 2 , X 3 , X 4 , and X 5 form a 5-membered heterocyclic or carbocyclic ring selected from a 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-amino-4-aryl-asexual, tetrahydrofuran, cyclopentadienone, and N-hydroxypyrrolidine and L x , L 3 , L 4 , Z_ , Z_ , Z 4 , R 42 , and R 44 are as described above.
• X_ , X 2 , X 3 , X 4 , and X 5 form a pyrazolinone, thiophene, pyrazole-N-oxide, 2-amino-5-aryl-thiazole, tetrahydrofuran, cyclopentadienone, or N-hydroxypyrrolidine ring.
• the ring is a pyrazolinone, pyrazole-N-oxide, cyclopentadienone, or N— hydroxypyrrolidine.
• the ring is a pyrazolinone .
• Yet another aspect of the invention embraces compounds that correspond to formula (II)
• each of X x , X 2 , X 3 , X 4 , X 5 and X 6 is carbon or nitrogen;
• X 2 is a hydrogen bond acceptor
• X 9 is a direct bond or -(CH 2 ) m - where i is 1 to 5;
• R 42 and R 44 are as defined for compounds having formula (I) ;
• Z x , Z 3 , and Z 4 are as defined for compounds having formula (I) .
• each of X_ , X 2 , X 3 , X 4 , X 5 and X 6 is carbon or nitrogen;
• X 2 is a carbonyl
• X 9 is selected from the group consisting of a direct bond, methylene, and ethylene;
• Z x 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 substituted with a derivatized amidine which, upon hydrolysis, oxidation, reduction or elimination yields an amidine group, and 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
• 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 x , X 2 , X 3 , X 4 , X 5 and X 6 is carbon or nitrogen;
• X 2 is a carbonyl
• X 9 is a direct bond
• 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 substituted phenyl ring
• 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, in-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2-methylbutylamide, isobutylacylamine, isobutylsulfoxy1, 2-cyclohexylamide, methoxy, sulf
• 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 3.01' , R 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 30 ⁇ R 3 o 2 R 303 is other than hydrogen; and Z 4 is a phenyl ring having formula (b) 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, m-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, and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl ;
• Z 3 may be any of the benzamidine derivatives illustrated in Table 1 or 3 below;
• 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;
• R ⁇ 301/ 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, provided at least one of R 301/ R 302/
• R 303 is other than hydrogen; and Z 4 is a phenyl ring having formula (b) 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, m-fluorobenzylamide, : 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 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 ;
• Z 3 may be any of the benzamidine derivatives illustrated in Table 1 or 3 below;
• Z 4/ R 42 and R 44 are as described for any of the embodiments involving compounds having formula (lib) .
• Still a further embodiment provides compounds having formula (II) that are represented by formula (lie)
• 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 (b) 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, m-fluorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2-methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, s
• 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_ 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;
• Z 3 may be any of the benzamidine derivatives illustrated in Table 1 or 3 below; and 2 and R 44 are as described for any of the embodiments involving compounds having formula (lie) .
• a further aspect of the invention embraces compounds having formula (III)
• X 5 is CH, C(C1) or C(F);
• 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- 1luorobenzylamide, 1- methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1- carboxyl-2-methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, me
• X 5 is CH
• Z 1# Z 3 , and R 44 are any of the groups detailed in Table 1 below.
• Zx R 44 Z, alkyl, hydroxy, l-carboxyl-2- substituted methylbutylamide, alkyl , isobutylsulfonyl, phenyl , isobutylacylamine , substituted trifluoromethyl , phenyl, isobutylsulfoxyl , cycloalkyl , carboxamidobenzyl , 2 - or eye1ohexy1 mide, substituted carboxamidobutyl-2-yl , cycloalkyl methoxyl, isobutyramido, sulfonamide, isobutoxy, isobutylsulfonamide, carboethoxy, aminoacyltrifluoro- methyl , carboxyl , carbmethoxy, amino, 3- aminomethylthiophene , benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1- carboxyl
• R 3 o ⁇ R 3 02 an d R303 are independently selected from the group consisting of:
• R a is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, and heterocyclo, provided, however, that the carbon atom of R 301 , R 302 ' an ⁇ R 303 directly bonded to the amidine is sp 2 hybridized when R 301 , R 302 an d R 303 is alkenyl,
• R 301' R 302 , and R 303 is optionally substituted hydrocarbyl, (iii) hydrogen, -0R b , -SR b , -NR b , or -N(R b ) 2 , wherein each R b is independently optionally substituted hydrocarbyl, and heterocyclo, and
• 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 3:o and R 311 is other than fluorine and hydrogen.
• each of Z, i- ⁇ ⁇ 3' 01 , R 3,02 / , R 310 and R 311 are as defined for any embodiment of compounds having formula (Ilia) .
• Another embodiment provides compounds having formula (IV) that are represented by formula (IVa)
• R 440 is Ci-C 3 alkyl, aryl, aralkyl, carboxy, or carboxyalkyl, wherein the alkyl, aryl, aralkyl, carboxy, or carboxyalkyl is optionally further substituted by fluorine .
• Still a further embodiment provides compounds having formula (IV) that are represented by formula (IVb)
• R 440 is C x -C 6 alkyl, aryl, aralkyl, carboxy, or carboxyalkyl, wherein the alkyl, aryl, aralkyl, carboxy, or carboxyalkyl is optionally further substituted by fluorine .
• Z_ is isopropyl or cyclopropyl optionally substituted with fluorine, hydroxy, carboxy, or alkoxycarbonyl; R 3o ⁇ K-30 2 anc 3- K-303 re independently selected from the . group consisting of:
• R a is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, and heterocyclo, provided, however, that the carbon atom of R 30: , _c 2 » an d R 303 directly bonded to the amidine is sp 2 hybridized when R 301 , R 302 » an ⁇ - R 303 is alkenyl,
• each R b is independently optionally substituted hydrocarbyl, and heterocyclo, and
• 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 elec-ron withdrawing group, provided, however, at least one of R 301 , 30 / d R 303 is other than hydrogen;
• R 305 when present, is hydroxy or hydrogen; and R 306 , when present, is hydroxy or hydrogen, provided if R 30S is hydroxy then R 30S is hydrogen and if R 305 is hydrogen then R 306 is hydroxy.
• X 5 is nitrogen, CH, C(F), C(C1), or C (Br) ;
• X 6 is carbon or nitrogen, provided the dashed line represents a double bond when X ⁇ is carbon and the dashed line represents a single bond when X s is nitrogen;
• X 7 and X 8 are independently carbon, nitrogen, oxygen or sulfur;
• Z x is selected from the group consisting of C 1 -C 8 alkyl, C 2 -C 8 alkenyl, and C 2 -C ⁇ alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen;
• Z 3 comprises a substituted phenyl, thienyl, or furanyl ring, the phenyl, thienyl or furanyl ring being substituted with a derivatized amidine group and optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, alkoxycarbonyl, or hydrocarbyloxy;
• Z 4 comprises a 5- or 6-membered heteroaryl or aryl 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 4: , 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 core 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
• R 42 is amino
• R 41 , R 43 , R 44 and R 45 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 R 4 R.
• R 44 or R 45 is other than hydrogen;
• R 70 and R 80 are independently selected from the group consisting of hydrogen, halogen, amino, hydrocarbyl, substituted hydrocarbyl, aryl, wherein aryl is phenyl optionally substituted by hydroxy, amino, C 1 -C 8 alkyl, 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; and n is 0 to 2.
• Still a further embodiment provides compounds having formula (V) that are represented by formula (Va)
• each of X s , X 7 , X 8 , Z x , Z 3 , Z 4 , R 70 , R 80 and n are as defined for compounds having formula (V) .
• the compound represented by any of formulas (I) - (V) is selected from the group of compounds listed in Table 3 below. Certain compounds listed in Table 3 are pharmaceutically acceptable salts of compounds having any of formulas (I)-(V) .
• compound 78- has 1.6 molecules of C(0)OHCF 3 salt per molecule of compound 78 and 0.3 molecules of 0H 2 per molecule of compound 78.
• compound 80 has 1 molecule of C (O) 0HCF 3 salt per molecule of compound 80.
• 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.
• 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.
• 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. 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.
• 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
• 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.
• 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, mtravascularly, mtraperitoneally, 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 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.
• 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.
• 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 agreggation 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.
• ACE angiotensin converting enzyme
• 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 S0 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.
• the compounds of the present invention can be synthesized, for example, according to the following procedures and Schemes given below.
• No.” represents Example Number
• ' ⁇ FNMR fluorine NMR
• Fmoc represents 9- fluorenylmethoxycarbonyl
• ⁇ l HNMR (MeOD) represents proton NMR taken in deuterated methanol
• HBt represents hydroxybenzoltriazole
• LDA lithium diisopropylamide
• MW represents molecular weight
• NMM represents N-methylmorpholine
• NMR represents nuclear amgnetic resonance
• 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
• RNH 2 represents a primary organic amine
• SEM represents 2- (trimethylsilyl) ethoxy-methyl chloride
• 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 replaced by an aryl group or a heteroaryl group.
• Suitable .leaving groups for the reaction include chloro, bromo, iodo, methylthio, triflates and other similar groups.
• the heterocyclic ring with the leaving group will typically 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 carbon ring atom substituted with bromo.
• 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:
• the organo palladium (Pd [P (phenyl) 3 ] 4 ) compound is used catalytically in a ratio of 1 to 40 mole percent.
• 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 C.
• Cu (I) -2-thiophenecarboxylate (Cu(I)-TC) is normally used in a mole percent of 110-150.
• Scheme 1 and Example 1 show specific applications 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 8 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.
• the compounds of the present invention may be synthesized in accordance with one or more of the following schemes :
• Example la A solution of 2-chloropyrazine (750 g, 6.55 mol) and isopopylamine (2 L, 23.45 mol) was heated to 130° C in a pressure reaction flask under 100 psi nitrogen with stirring for 24 hours. The reaction mixture was allowed to cool and diluted with 1 L methanol followed by 4 L of ethyl acetate and 4 L of water. The organic layer was separated and the aqueous solution was extracted with 2L of ethyl acetate. The combined organic solutions were washed with 2L of water, dried over magnesium sulfate, filtered, and concentrated. The crude product afforded a melting point of 46.3° C.
• Example lc To a suspension of 2- (N-isopropylamino) - 3 , 5-dibromopyrazine in water was added potassium hydroxide in water. The resulting suspension was heated to reflux for approximately 18 hours to afford the 5-Bromo-2- (N- isopropylamino) -3-hydroxypyrazine .
• Example Id To 3.3 L tetrahydrofuran was added 5- bromo-2- (N-isopropylamino) -3-hydroxypyrazine (600 g, 2.585 mol) and potassium t-butoxide (365.8 g, 3.1 mol). The resulting suspension was heated at 60 °C for 1 hour. A solution of tert-butyl bromoacetate (605.15 g, 3.1 mol) was then added to the mixture. This mixture was heated at 60 °C for four hours and then allowed to stand at room temperature overnight . The mixture was then diluted with 2.5 L of water and 2.5 L of ethyl acetate. The organic layer was washed with 2.5 L brine. The organic solution was dried over magnesium sulfate, filtered, concentrated, triturated with hexanes and filtered to afford 573 g of an off-white solid.
• 5- bromo-2- (N-isopropylamino) -3-hydroxypyrazine 600 g
• Example le To a 100 ml, 3 neck, round bottom flask, under nitrogen, magnetic stirrer, cold water condensor, heating mantel, and thermocouple was added 3-amino-5- bromobenzotrifluoride (1.0 g, 4.17 mmol), N,N-dimethyl formamide (50 ml, 645.7 mmol), Bis (pinacolato) diboron (1.06 g, 4.17 mmol) and stirred for one hour while nitrogen was bubbled through the reaction mixture. To the reaction mixture potassium acetate (1.23 g, 12.50 mmol) was added with continued stirring for 30 minutes.
• Example If To a 250 ml, 3 neck, round bottom flask, under nitrogen, magnetic stirrer, cold water condensor, and heating mantel was added the 3- (4,4,5,5 tetramethyl-1, 3 , 2- dioxaborolan-2-yl) -5- (trifluoromethyl) aniline from Example la, (2.0 g, 6.97 mmol), tert butyl [6-bromo-3- (isopropylamino) -2-oxopyrazin-l (2H) -yl] acetate (2.16 g, 6.25 mmol), and dioxane (100 ml, 1.17 mol).
• Example lh 3.32 g (10 mmol) N,N-di-Boc-4- aminobenzonitrile was deprotected in 50 mL CH 2 C1 2 /TFA (4:1) for 30 minutes and the solvent was evaporated thoroughly to dryness. 2.9 g (6.0 mmol) of the product of Example lg was coupled with the 4-aminobenzonitrile in 40 mL DMF in the presence of 2.25 g (7 mmol) TBTU and 3.5 mL (20 mmol) DIPEA with stirring for 12 hours. The DMF was evaporated and the product was precipitated by addition of 200 mL water and filtered. Yield: 2.2 g (4.5 mmol; 76%) white solid.
• Example 1 2.2 g (4.5 mmol) of the product of Example lh was dissolved in 50 mL EtOH. 1.44 g (20 mmol) hydroxylamine HCl and 4.4 mL (25 mmol) DIPEA were added to the solution and the mixture was refluxed for 3 hours. The EtOH was then evaporated and the product was precipitated by addition of 200 mL water. The product was filtered and dried. The crude product (1.1 g) was purified on preparative HPLC using a gradient of acetonitrile (10-50% AcN in 30 minutes) , yielding the title product at 33% AcN, 1.1 g (67%) white solid.
• Example 2 The product of Example 1 (258 mg; 0.0005 mole) and cyclohexanone dimethyl ketal (360 mg; 0.0025 mole) were dissolved in 4.0 ml of a 1:1 mixture of acetic acid and 1, 2-dichloroethane. The mixture was gently refluxed for 0.5 hours. HPLC [0 to 95% MeCN/H 2 0 * TFA over 6 minutes] indicated that the N-hydroxylbenzamidine was consumed ( " * TFA" represents "containing 0.05% TFA”). The reaction mixture was then concentrated. The residue was triturated with acetone and the solid was filtered and washed with Et 2 0 and suction dried to yield 233 mg of a solid.
• Example 1 The product of Example 1 (258 mg; 0.0005 mole) and cyclopentanone dimethyl ketal (325 mg; 0.0025 mole) were dissolved in 4.0 ml of a 1:1 mixture of acetic acid and 1, 2-dichloroethane. The mixture was gently refluxed for 0.5 hours and worked up as described above to yield 103 mg of a solid.
• N-hydroxylbenzamidine (258 mg; 0.0005 mole) and (1,1- dimethoxyethyl) benzene (415 mg; 0.0025 mole) were dissolved in 4.0 ml of a 1:1 mixture of acetic acid and 1,2- dichloroethane . The mixture was gently refluxed for 0.5 hours and concentrated. The residue was chromatographed over silica, eluting with a MeOH/ CH 2 C1 2 system, to yield 59 mg of a solid.
• Carboxylic acid (1.1 g; 0.0025 mole), benzylamine HCl (0.5 g; 0.0025 mole), diisopropylethyl amine (DIEA) (1.6 g; 0.0125 mole) and TBTU (0.882 g; 0.11275 mole) were dissolved in 15 ml of DMF and stirred for 18 hours. The reaction mixture was poured into 50 ml of water and the solid was filtered to yield 1.0 g.
• DIEA diisopropylethyl amine
• Example ⁇ a The product of Example 5 (1.0 g; 0.0019 mole) and ammonium formate (244 mg; 0.0038 mole) were dissolved in MeOH (20 ml) and N 2 gas was bubbled through the mixture. Pd Black (100 mg) was suspended in MeOH (3 ml) and added to the above mixture. Starting material was still present after 0.5 hours. An additional portion of ammonium acetate (244 mg) was added. After 0.5 hours, the remaining starting material was consumed. The reaction mixture was filtered and concentrated to yield 1.2 g of a solid.
• Example 6 The product of Example 6a (517 mg; 0.001 mole) and triethylamine (303 mg; 0.003 mole) were dissolved in DMF (5.0 ml). To the mixture, 1, 1' -carbonyldiimidazole (648 mg; 0.004 mole) was added and the mixture was stirred for 18 hours. The mixture was poured into 50 ml of water and the solid was filtered. The solid was triturated with MeOH and filtered to yield 211 mg of a solid.
• Example 6a The product of Example 6a (517 mg; 0.001 mole) and 2,2-dimethoxypropane (10 ml) were dissolved in 10.0 ml of a 1:1 mixture of acetic acid and 1, 2-dichloroethane and refluxed for 3 days. HPLC indicated two new components. The reaction mixture was concentrated and purified by RPLC (0 to 60% MeCN/ H 2 0 *THF over 6 minutes) . Retention time of the product was 3.79 minutes yielding 60 mg of a glass.
• Example 8a To a 250 mL RBF was added NaH (60%, 0.54 g, 14 mmol) in dry THF (30 mL) . The dibocaminobenzyl-4- hydroxamidine (5.0 g, 13.7 mmol) was then added to the slurry at 0° C. The reaction was stirred for 0.5 hrs. To the reaction was added isopropyl chloroformate (1 M solution in Toluene, 13.7 mL) . The reaction was stirred for three hours and then quenched with 50 ml of water and extracted with ethyl acetate (3X 50 mL) . The organics were dried over magnesium sulfate and then concentrated. The resulting solid was purified on silica using 40% ethyl acetate: 60% hexane to afford Example 8a 4.29 g (69%) as a white solid.
• Example 8b To a 250 ml RBF was added Example 8a (2.29 g, 5.1 mmol) in 4 N HCl in 50 ml of dioxane. The reaction was stirred for 4 hours. The reaction, monitored by mass spectrometry, was then concentrated in vacuo to afford 1.34 g of the dihydrochloride salt . Because of the hydroscopic nature of the intermediate, the amine was carried onto the next reaction without further manipulations.
• Example 8 To a 250 ml RBF was added Example 8b (1.34 g, 4.15 mmol) and the product of Example lg (2.29 g, 4.73 mmol) in 50 ml of DMF. To the solution was added DIEA (14.41 g, 20 ml) and TBTU (1.82 g, 5.7 mmol). The reaction was stirred over night. The reaction was then poured into ethyl acetate and washed with 10% KHS04 , then brine. The organics were dried over magnesium sulfate and concentrated. The resulting solid was purified on silica 20% ramped to 100% ethyl acetate : hexane to afford Example 8 (1.44 g) , 58% yield.
• Example 9a Following the method detailed in, Example- 8a dibocaminobenzyl-4-hydroxamidine (6.0 g, 16.4 mmol), NaH (60%, 0.69 g, 18.1 mmol), isobutyl chloroformate (2.19 g, 16.4 mmol) afforded 3.8 g in 50% yield.
• Example 9b Following the method detailed in Example 8b, the product of Example 9a (1.05 g, 2.25 mmol) in 4 N HCl/dioxane afforded 0.759 g of the dihydrochloride .
• Example 9 To a 250 RBF was added the product of Example lg (1.0 g, 2.27 mmol), HOBt (0.922 g, 6.82 mmol) and EDCI (2.03 g, 6.82 mmol) in 75 ml of DMF. To the solution was added Example 9b (0.759 g, 2.25 mmol) and DIEA (1.45 g, 11.35 mmol) . The reaction was stirred over night. To the reaction was added 5% citric acid and ethyl acetate. The organics were dried over magnesium sulfate and concentrated in vacuo . The resulting solid was purified on silica using 20% to 100% ethyl acetate:hexane to afford Example 9 (0.30 g, 21% yield)
• Example 10a Prepared by the method of Example 8a. dibocaminobenzyl-4-hydroxamidine (2.55g, 6.98mmol) , NaH(60%, 0.28g, 7.25mmol) , ethyl chloroformate (0.832g, 7.67mmol) afforded 1.16g in 53.78% yield.
• Example 10b Prepared by the method of Example 8b, The product of Example 10a (0.55 g, 1.24 mmol) in 4 N HCl/dioxane afforded 0.42 g of the dihydrochloride .
• Example 10c To a 100 RBF was added the product of Example lg (1.22 g, 2.77 mmol), HOBt (1.125 g, 8.31 mmol), EDCI (2.5 g, 8.31 mmol) in 45 ml of DMF. To the solution was added the product of Example 10b (0.74 g, 2.77 mmol) and DIEA (1.79 g, 13.85 mmol). The reaction was stirred over night. To the reaction was added 5% citric acid and ethyl acetate . The organics were dried over MgS0 4 and concentrated in vacuo.
• Example 10 (0.40 g, 25% yield) ' C 27 H 30 F 3 N 7 O 5 + 0.55 H 2 0 M. .589.57; Calculated C 55.00 H 5.13 N 16.63, found C 54.14 H 5.23 N 16.36;
• Example 11 Example Ila To a 50 mL RBF was added the dibocaminobenzyl-4-hydroxamidine (1.0 g, 2.736 mmol) and DIEA (0.523 g, 4.11 mmol). The reaction was stirred for one hour and n-butyl chloroformate (0.467 g, 3.42 mmol) was added at room temperature. The reaction was then stirred over night. To the reaction was added ethyl acetate and 5% citric acid. The organics were back washed with brine then dried over MgS0 4 . After the organics were concentrated, the resulting oil was purified on silica using 10%-50% ethylacetate : hexanes . This afforded Example Ila (0.43 g-) in 34% yield.
• Example lib By following the method of Example 8b, the product of Example Ila (0.43 g, 0.91 mmol) in 4 N HCl/dioxane afforded 0.31 g of the dihydrochloride .
• Example lie To a 100 RBF was added the product of Example lg (0.402 g, 0.9136 mmol), HOBT (0.370 g, 2.74 mmol) and EDCI (0.814 g, 2.74 mmol) in 25 ml of DMF. To the solution was added the product of Example lib (0.31 g, 0.9136 mmol) and DIEA (0.59 g, 4.575 mmol). The reaction was stirred over night. To the reaction was then added 5% citric acid and ethyl acetate. The organics were dried over MgS0 4 and concentrated in vacuo.
• Example lie (0.063 g, 11% yield) C 29 H 34 F 3 N 7 0 5 ; M. .617.62;
• Example 12a Synthesized by the method of Example 8a. Dibocaminobenzyl-4-hydroxamidine (2.3 g, 6.9 mmol), NaH (60%, 0.31 g, 7.7 mmol), p-methoxyphenyl chloroformate (1.21 g, 6.5 mmol) afforded 2.1 g in 62% yield.
• Example 12b Synthesized by the method of Example 8b, the product of Example 12a (1.05 g, 1.94 mmol) in 4 N HCl/dioxane afforded 0.746 g of the dihydrochloride .
• Example 12c To a 250 ml RBF was added the product of Example 12b (0.746 g, 1.94 mmol) and the product of Example lg (1.94 mmol) in 40 ml of DMF. To the solution was added DIEA (1.98 g, 2.75 mL) and TBTU (0.685 g, 2.1 mmol) . The reaction was stirred over night. The reaction was then poured into ethyl acetate and washed with 10% KHS04, then brine. The organics were dried over MgS04 and concentrated. The resulting solid was purified on silica 20% ramped to 100% ethyl acetate: hexane to afford Example 12c (0.71 g, 56% yield. C 32 H 32 F 3 N 7 0 s +0.7EA; M. .667.68;
• Example 13a To a solution of dibocaminobenzyl-4- hydroxamidine (0.51 g, 1.39 mmol) in 20 ml of dichloromethane was added pyridine (0.25 ml, 3.06 mmol) and pentafluoropropionic anhydride (0.29 ml, 1.46 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hrs. The reaction mixture was then diluted with water. The layers were separated and the aqeous layer extracted with dichlormethane (2x) . The organic extracts were washed with brine (lx) .
• Example 14a To a solution of dibocaminobenzyl-4- hydroxamidine (0.75 g, 2.05 mmol) in 20 ml dichloromethane was added pyridine (0.38 mL, 4.51 mmol) and heptafluoropropionic anhydride (0.53 mL, 2.15 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hrs. The reaction mixture was then diluted with water. The layers were separated and the aqueous layer extracted with dichloromethane (2x) . The organic extracts were washed with brine (lx) .
• Example 15 The product of Example 15 (87.3 mg, 0.163 mmol) and Compound 1 (prepared as in U.S. Patent No. 5,466,811) (53.0 mg, 0.180 mmol) were stirred overnight at room temperature in 2 ml of DMF. The bright yellow crude reaction mixture was purified by reverse phase HPLC and lyophilized to afford a colorless solid Example 16 (11.0 mg, 0.012 mmol) as a TFA salt. HPLC/MS calc. Mass Spec M+H: 691.2762. • Found: 691.29.
• Example 18a Dibocaminobenzyl-4-hydroxamidine (50.0 mg, 0.14 mmol), compound 3 (prepared as in U.S. Patent No, 5,466,811) (30.0 mg, 0.16 mmol) and KHC0 3 (16.0 mg, 0.16 mmol) were dissolved in 0.5 ml of DMF and 5 ml of acetonitrile at 60° C for 5 hours. The crude reaction mixture was concentrated under a stream of N 2 . To the resulting orange oil was added 4 N HCl (1 mL) in 1 ml of dioxane and stirred at room temperature for 5 hours. The crude reaction mixture was concentrated under a stream of N 2 to afford Example 18a as an orange solid.
• Example 19a To compound 5 (prepared analogously to Example la-lg) (1.5 g, 3.36 mmol) was added HOBT (0.45 g, 3.36 mmol) and EDC (0.71 g, 3.7 mmol) in 12 ml of DMF. The mixture was stirred at RT for 30 min. The amine HCl salt (0.62 g, 3.7 mmol) in DMF (8 ml) and NMM (0.67 g, 6.7 mmol) was then added to the mixture which was kept stirring overnight. Water was then added to the mixture and filtered to yield 2 g solid. MS confirmed the product. MS (ES, m/z) 562.23 (M+H) .
• Example 19b To the product of Example 19a (1.6 g) in THF (20 ml) was added Pd/C (10% 0.5 g) . The mixture was set on hydrogenation shake at 25 psi for 3 hr, then filtered and concentrated to yield 1.5 g solid without purification. MS (ES, m/z) 532.26 (M+H)
• Example 19c To the product of Example 19b (1.7 g, 3.22 mmol) in CH 2 C1 2 (15 ml) was added NMM (0.37 g, 3.5 mmol) and isobutryl chloride (0.37 g, 3.5 mmol). The mixture was kept stirring at room temperature for lhr. The mixture was then washed with 40 ml of 10% citric acid, 40 ml of saturated NaHC0 3 and 40 ml of water. Combined CH 2 C1 2 was dried with MgS0 4 , filtered and concentrated to yield 2 g crude products without purification. MS (ES, /z) 602.30 (M+H)
• Example 19d To the product of Example 19c (0.85 g,
• Example 19 To the product of Example 19d (0.24 g, 0.38 mmol) in 2 ' ml pyridine was added trifloroacetic anhydrate (99 mg, 0.47 mmol). The mixture was heated to 65° C for overnight, then concentrated and added with CH 2 C1 2 /TFA (1 ml/2 ml) . The mixture was stirred at room temperature for lhr, then purified on RP-HPLC to yield 85 mg white solid. mp 221-224°C.
• Example 20a To a mixture of dibocaminobenxyl-4- hydroxamidine (8.2 mmol, 3.0 g) and pyridine (31.5 mmol, 2.55 ml) was added trifluoroacetic acid anhydride (18.1 mmol, 2.55 ml) while cooling in a water bath. The reaction was stirred at room temperature for 2 hours.
• Example 20a was then concentrated in vacuo and the residue was mixed with ethyl acetate (100 ml) , washed with 1 N sodium hydrogen sulfate (3x 25 ml) , saturated sodium bicarbonate (2x 25 ml) and brine (25 ml) , dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3.49 g of Example 20a as an off-white solid.
• Example 20b A mixture of the product of Example 20a (7.5 mmol, 3.34 g) in 20 ml of dioxane was stirred with 4 N hydrogen chloride in 40 ml of dioxane at ambient temperature for 1 hour. The reaction was concentrated in vacuo to give 2.46 g of Example 20b as an off-white solid.
• Example 20c To the product of Example lg (0.97 mmol, 0.43 g) , N-methylmorpholine (1.0 mmol, 0.11 mL) , N- cyclohexylcarbodiimide-N' -methylpolystyrene (PS-DCC) (4.25 mmol, 2.5 g) , and HOBT (1.06 mmol, 0.144 g) in 15 ml of DCM, cooled in an ice bath, was added a warm solution of Example 20b (0.88 mmol, 0.247 g, ) in DMF (5 ml) and N- methylmorpholine (4.0 mmol, 0.44 mL) .
• PS-DCC N-cyclohexylcarbodiimide-N' -methylpolystyrene
• Example 21a A solution of di (tert-butyl) 4- tamino (i ino) methyl] benzylimidodicarbonate (2.34 g, 5,72 mmol), diisopropyl ethyl amine (2.22 g, 17.2 mmol), and O- benzylhydroxylamine hydrochloride (1.83 g, 11.4 mmol) in 200 ml of ethanol was refluxed in a 500 ml round bottom flask for 12 hours . The reaction mixture was then allowed to cool and concentrated to give 9.71 g of crude product-. The crude product was chromatographed on silica to give 1.54 g of a white crystalline product, 59% yield.
• Example 21b The product from Example 21a (0.40 g, 0.878 mmol) was dissolved in 4 M hydrochloride acid in dioxane (50 ml, 200 mmol) and stirred 2 hours. The reaction mixture was concentrated, redissolved in ethyl acetate and concentrated to give 0.33 g of a white powder, 4- (aminomethyl) -N' - (benzyloxy) benzenecarboximidamide hydrochloride .
• Example 21 A solution of the product from Example lg (0.35 g, 0.58 mmol), the product from Example 21b (0.33 g, 1.0 mmol), benzotriazol-1-yl tetramethyluronium tetrafluoroborate (1.1 g, 3.43 mmol), diisopropyl ethyl amine (0.84 g, 6.5 mmol), and in 50 ml of N,N-dimethyl formamide and stirred 3 hours. To the reaction mixture was added 20 ml of 10% Potassium hydrogen sulfate. A precipitate formed and was filtered off. The precipitate was concentrated and then dissolved in acetonitrile and water.
• the product was purified by HPLC to 300 mg of 1 N- (4- ⁇ (Z) -amino [ (benzyloxy) imino] methyl ⁇ benzyl) -2- [6- [3- amino-5- (trifluoromethyl) henyl] -3- (isopropylamino) -2- oxopyrazin-1 (2H) -yl] acetamide trifluoroacetate a whitish yellow solid, 71% yield.
• Example 22a A solution of di (tert-butyl) 4- [amino (imino) methyl] benzylimidodicarbonate (2.35 g, 5,74 mmol), diisopropyl ethyl amine (2.23 g, 17.2 mmol), and 0- phenylhydroxylamine hydrochloride (1.67 g, 11.4 mmol) in 100 ml of ethanol was refluxed in a 500 ml round bottom flask for 36 hours. The reaction mixture was allowed to cool and concentrated to give 5.8 g of crude product . The crude product was chromatographed on silica to give 0.65 g of a white crystalline product, 25% yield.
• Example 22b The product from Example 22a (0.650 g, 1.47 mmol) was dissolved in 4 M hydrochloride acid in dioxane (25 ml, 100 mmol) and stirred for 8 hours. The reaction mixture was concentrated, redissolved in ethyl acetate and concentrated to give 0.463 g of a white powder, 4- (aminomethyl) -N 1 - (phenyloxy) benzenecarboximidamide hydrochloride .
• Example 22c A solution of the product from Example lg (0.98 g, 2.21 mmol), the product from Example 22b (0.463 g, 1.47 mmol), benzotriazol-1-yl tetramethyluronium tetrafluoroborate (1.76 g, 5.48 mmol), diisopropyl ethyl amine (1.41 g, 10.9 mmol), and in 50 ml of N,N-dimethyl formamide and stirred 6 hours. A precipitate formed and was filtered off. The precipitate dissolved in acetonitrile and water.
• the product was purified by HPLC to 400 mg of 1 N-(4- ⁇ (Z)- amino [ (phenyloxy) imino] methyl ⁇ benzyl) -2- [6- [3 -amino-5- (trifluoromethyl) phenyl] -3- (isopropylamino) -2-oxopyrazin- 1 (2H) -yl] acetamide trifluoroacetate a whitish yellow solid, 45% yield.
• Example 23a 0.234 g (0.56 mmol) of compound 1 was hydrolyzed with 10 mL TFA for 2 hours stirring at room temperature. TFA was evaporated to dryness to yield 0.19 g (0.52 mmol) of Example 23a as a white solid.
• Example 23b Example 23a was dissolved in 15 mL DMF and coupled with 0.332 g (1 mmol) 4-aminobenzonitrile in the presence of 0.256 g (0.8 mmol) TBTU and 0.525 mL DIPEA for 16 hours. Adding 200 mL H 2 0, the product precipitated and it was filtered and dried to yield 0.205 g (0.43 mmol; 76%) of Example 23b as a yellow solid.
• Example 23c The product of Example 23b was dissolved in 20 mL MeOH and reduced with 0.126 g HC00NH 4 in the presence of 0.05 g Pd black stirring under N 2 for 15 minutes. The catalyst was filtered off and the solvent was evaporated to afford Example 23c.
• Example 23d The clear oily residue was dissolved in 10 mL EtOH and refluxed with H 2 N-0H xHCl in the presence of 1 mL DIPEA for 4 hours. The solvent was evaporated and the residue was purified on preparative HPLC using a gradient of acetonitrile (10-50% AcN in 30 minutes) , yielding the title product at 38% AcN, 0.092 g (23%) as a white hygroscopic solid.
• Example 24a 1 g (2.4 mmol) of 4- (N,N-diBoc-amino) - benzylamidine acetate was dissolved in 10 mL DMF and it was reacted with 0.67 mL (5 mmol) 1-chloroethyl ethyl carbonate in the presence of 7.5 mL (7.5 mmol) 1 N NaOH for 16 hours. Then DMF was evaporated and the residue was dissolved in 100 mL EtOAc. It was washed with brine, dried over MgS0 4 , filtered and the solvent was evaporated to afford Example 24a. Yield: 0.91 g (2.1 mmol; 90%) oil.
• Example 24b The product of Example 24a was dissolved in 40 mL CH 2 C1 2 and it was deprotected with 10 L TFA stirring for 30 minutes to afford Example 24b.
• Example 24 The product of Example 24b was coupled with 0.484 g (1 mmol) of the product of Example lg in the presence of 0.875 mL (5 mmol) DIPEA and 0.385 g (1.2 mmol) TBTU with stirring for 3 hours in 30 mL DMF. The solvent was evaporated and the residue was purified on preparative HPLC using a gradient of acetonitrile (10-50% AcN in 30 minutes), yielding the title product at 34% AcN, 0.46 g (57%) as a light brown solid.
• Example 25a 2.5 g (6.1 mmol) 4- (N,N-diBoc-amino) - benzylamidine acetate was dissolved in 30 mL MeOH and it was refluxed with 1.35 g (20 mmol) methylamine xHCl in the presence of 5.25 mL (30 mmol) DIPEA for 12 hours. MeOH was evaporated and the residue was dissolved in 100 mL EtOAc and it was washed with brine, dried over MgS0 4 and the solvent was evaporated to yield 1.5 g (4.2 mmol; 67%) of Example 25a as an oil.
• Example 25b The product of Example 25a was dissolved in 40 mL CH 2 C1 2 and it was deprotected with 10 mL TFA stirring for 30 minutes to afford Example 25b.
• Example 25 The product of Example 25b was coupled with 0.484 g (1 mmol) of the product of Example lg in the presence of 1.75 mL (20 mmol) DIPEA and 0.353 g (1.1 mmol) TBTU with stirring for 3 hours in 25 mL DMF. The solvent was evaporated and the residue was purified on preparative HPLC using a gradient of acetonitrile (10-50% AcN in 30 minutes), yielding the title product at 32% AcN, 0.27 g (36%) as a white solid.
• Step C
• the aqueous is extracted twice with 1000 mL of methylene chloride and the combined organic extracts is washed with 500 mL of brine.
• the methylene chloride solution is dried over MgS0 4 , concentrated, and then chromatographed to afford the desired aldehyde 26d.
• Example 27 Compound of Example 26 (10 mmol) and 10% Pd on activated carbon (0.100 g) are mixed with 100 mL methanol. The mixture is stirred for 2 hours under an atmosphere of hydrogen that is introduced through a rubber balloon. After filtering off the catalyst and removing the methanol, the remaining residue is obtained as Example 27.
• Step A
• Step B
• Step E
• nitro ketal 28d from Step D (250 mmol) is hydrolyzed and the tert-butyl ester removed by stirring with trifluoroacetic acid (50 mL) , water (200 mL) and THF (500 mL) until completion as monitored by chromatography.
• the reaction mixture is concentrated at ambient temperature to give the trifluroacetic acid salt of unpurified nitro ketone 28e and used as is in the next step.
• Example 28 Compound of Example 28 (10 mmol) and 10% Pd on activated carbon (0.100 g) are mixed with 100 mL methanol. The mixture is stirred for 2 hours under an atmosphere of hydrogen that is introduced through a rubber balloon. After filtering off the catalyst and removing the methanol, the remaining residue is obtained as Example 29. Using these methods and ordinary skill in the art of synthetic numerous novel compounds of the present invention have been or can be prepared.
• the following assay conditions were used: 100 mM phosphate buffer, 1.0 mM NADPH, 3.3 mM magnesium chloride, 2.0 mg/mL protein from Hepatic S9 Fraction and 1.0 ⁇ M of substrate.
• the assay was performed on a 96-well conical shaped plate with a volume of 200 ⁇ L, after addition of methanol. For each species, a set of samples was prepared as shown below (volumes are in ⁇ L) .
• the plate was sealed and incubated in a Thermal Mixer at 37°C for 30 minutes at 400 rpm. 100 ⁇ L of methanol was added to each well and the plate was mixed for several minutes and then covered with an aluminum seal. Finally, the plate was centrifuged at 1000 rpm for 10 minutes.
• the assay was analyzed using liquid chromatography and positive ion elctrospray mass spectrometry.
• the chromatography column used was Agilent Zorbax SB-C18 (3.0 x 150mm, 5 ⁇ m) with a flow rate of 0.5 mL/min.
• the Peak Area Ratio is defined as the peak area of the analyte divided by the peak area of the internal standard.
• Analyte is defined as the substrate of a specific measurable metabolite.
• BA represents bioavailability of prodrug after oral adminstration
• S9 rat and “S9 human” represent respectively rat and human liver S9 fractions.
• Healthy male rats [Crl :CD (SD) BR] were obtained from Charles River Breeding Laboratory (Canada) . The rats did not receive any drug treatments prior to the initiation of the study. The animals weighed 250 to 320 g and were individually identified by labeling on each metabolism cage. The rats were housed in individual metabolism cages during dosing and sample collections. The animals were acclimated to a diet of Purina Rodent Chow #5002 (Ralston Purina, St. Louis, MO) for at least 5 days and were fasted for 15-20 hours prior to the administration of the compound. Food was available from 4 hours after dose administration and ad libitum throughout the remainder of the study.
• Purina Rodent Chow #5002 Rosina, St. Louis, MO
• each animal received the prodrug orally at an equivalent dose of 10 mg of free base of active moiety per kg of body weight or active moiety orally at an equivalent dose of 10 mg equivalent free base per kg body weight.
• IV intravenous
• the animals received 1 mg free base/kg body weight.
• Sufficient amount of the test article was dissolved in appropriate vehicle (See table below) such that the final concentration of dose solution was 2.0 mg- free base/mL and 0.5 mg free base/mL for oral and IV doses, respectively.
• the dose volume was 5 mL/kg and 2 mL/kg for oral and IV doses, respectively
• AUC represents area under the curve.
• Example 27a A mixture of di- (tert-butyl) 4-cyano-2, 3- difluorobenzylimidodicarbonate (0.5 g, 1.4 mmol), hydroxylamine hydrochloride (0.28 g, 4.1 mmol), and triethylamine (0.57 ml, 4.1 mmol) in ethanol was heated to reflux for 1 hour. The reaction was concentrated in vacuo and the residue mixed with ethyl acetate, washed with IN potassium hydrogen sulfate, saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 0.5 g of Ex-27a (89% yield) .
• Example 27b To a stirred solution of Ex. 27a (0.45 g, 1.1 mmol) in pyridine (0.35 ml) and dichloromethane (0.5 ml) was added trifluoroacetic acid anhydride (0.35 ml, 2.5 mmol) while cooling in a water bath and stirring was continued at ambient temperature for 20 minutes. The reaction was concentrated in vacuo and the residue dissolved in ethyl acetate and washed with IN sodium hydrogen sulfate, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to gave 0.43 g as an off-white solid.
• Example 27c X HNMR (300 MHz, DMS0-d 6 ) ⁇ 4.25 (s, 2H) , 7.68- 7.75 (m, IH) , 7.97-8.05 (m, IH) , 8.73 (br s, 3H) .
• Example 33a Di (tert-butyl) 4- [amino (imino) methyl] - benzylimidodicarbonate (2g, 5mmol)in 10ml CH2C12 was added perchloromethylmercaptan (0.83g, .5mmol) . The mixture was added NaOH/H20 (lg/l.5ml) under -8°C and kept stirring for 7hrs, then quenched with water (50ml) and extracted with CH2C12 (3X25ml) . The combined CH2C12 was then dried over MgS04, concentrated and purified on silica gel column to yield 0.2g solid. The solid in CH2C12 (2ml) was then added TFA (1.5ml) at RT for lhr, then concentrated and purified on RP-HPLC to yield 1.3g solid (50%).
• Example 34a To a round bottom flask containing 2- hydroxymethyl pyridine (5.0 g, 45.8 mmol), N-hydroxy phthalimide (18.7 mg, 114.5 mmol) and triphenylphosphine (33.7g, 128 mmol) in 800 ml of tetrahydrofuran was added diisopropyl azodicarboxylate (25.3 ml, 128 mmol) dropwise. The solution was stirred overnight and then concentrated in vacuo. The residue was treated with 500 ml of ethyl acetate and extracted twice with 100 ml of IM HCl.
• Example 34b To the product from Ex. 34a) (7.2 g, 28.3 mmol) in 100 ml of methanol was added hydrazine ( 1.8 ml, 57.3 mmol) and the mixture was stirred over the weekend. The mixture was filtered and concentrated in vacuo . The residue was purified by chromatography (silica, 10-20% MeOH:CH 2 Cl 2 ) to give (1.23 g, 35% yield) of a solid.
• Example 35a This compound was isolated from the crude reaction mixture of example 23, on preparative HPLC using a gradient of acetonitrile (10-50% AcN in 30 minutes) , yielding the title product at 28% AcN, 0.05 g (15%) as a hygroscopic solid.
• Example 36c To a solution of Example 36b (0.58 g, 1.10 mmol) in ethanol (15 mL) at room temperature was added K 2 C0 3 (0.6 g, 4.84 mmol), DIEA (0.84 mL, 4.84 mmol) and H 2 NOH*HCl (0.17 g, 2.42 mmol) . The reaction mixture was heated to 75 °C for 2 hrs and then allowed to cool to room temperature. The solid was filtered and washed with ethanol. The filtrate was concentrated and acidified with TFA. The crude mixture was purified by RP-HPLC (CH 3 CN:H 2 0) to give after lypholization the desired product (0.28 g) .
• K 2 C0 3 0.6 g, 4.84 mmol
• DIEA 0.84 mL, 4.84 mmol
• H 2 NOH*HCl 0.17 g, 2.42 mmol
• Example 38b X E NMR (400 MHz, CD 3 OD) : ⁇ 7.65 (d, 2 H) , 7.51-7.19 (m, 13 H) , 7.05 (t, 1 H) , 6.86 (t, 1 H) , 6 .
• Example 39 Tert-butyl 3-[l-[2-( ⁇ 4- [amino (imino) methyl] benzyl ⁇ amino) -2-oxoethyl] -5- (isopropylamino) -6-oxo-l, 6-dihydropyrazin-2-yl] -5- (isobutyrylamino)phenylcarbamate (0.2g, 0.32mmol) and 2,6- difluorobenzyl 4-nitrophenyl carbonate (120mg, 0.39mmol) in THF (2ml) as added NMM (40mg, 0.40mmol) . The mixture was kept stirring for 3hr. The mixture was concentrated and then TFA/CH2C12 was added. The mixture was kept stirring at RT for lhr, then concentrated and purified on RP-HPLC to yield 125mg of solid (41%) .
• Example 40 Tert-butyl 3-[l-[2-( ⁇ 4- [amino (imino) methyl] benzyl ⁇ amino) -2-oxoethyl] -5- (isopropylamino) -6-oxo-l, 6-dihydropyrazin-2-yl] -5- (isobutyrylamino)phenylcarbamate (0.18g, 0.29mmol) and isocyanatobenzene (42mg, 0.35mmol) in THF (2ml) was added NMM (40mg, 0.40mmol). The mixture was kept stirring for 3hr. The mixture was concentrated and then TFA/CH2C12 was added. The mixture was kept stirring at RT for lhr, then concentrated and purified on RP-HPLC to yield 85mg of solid (33%) .
• Example 42 Tert-butyl 3-[l-[2-( ⁇ 4- [amino (imino) methyl] benzyl ⁇ amino) -2-oxoethyl] -5- (isopropylamino) -6-oxo-l, 6-dihydropyrazin-2 -yl] -5- (isobutyrylamino) phenylcarbamate (0.18g, 0.29mmol) and (isocyanatomethyl) benzene (52mg, 0.39mmol) in THF (2ml) was added NMM (40mg, 0.40mmol) . The mixture was kept stirring for 3hr. The mixture was concentrated and then TFA/CH2C12 was added. The mixture was kept stirring at RT for lhr, then concentrated and purified on RP-HPLC to yield 104mg of solid (40%) .

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