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  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—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
  • 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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  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
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  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to novel heteroaryl compounds that function as enzyme inhibitors, and particularly to a new class of non-peptidic inhibitors of proteolytic enzymes such as urokinase (uPa).
• uPa urokinase
• Proteases are enzymes that cleave proteins at single, specific peptide bonds. Proteases can be classified into four generic classes: serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases (Cuypers et al., J. Biol. Chem. 257:7086 (1982)). Proteases are essential to a variety of biological activities, such as digestion, formation and dissolution of blood clots, reproduction and the immune reaction to foreign cells and organisms. Aberrant proteolysis is associated with a number of disease states in man and other mammals. The human neutrophil proteases, elastase and cathepsin G, have been implicated as contributing to disease states marked by tissue destruction.
• proteases such as plasmin, C-l esterase, C-3 convertase, urokinase and tissue-type plasminogen activators, acrosin, and kallikreins play key roles in normal biological functions of mammals. In many instances, it is beneficial to disrupt the function of one or more proteolytic enzymes in the course of therapeutically treating a mammal.
• Serine proteases include such enzymes as elastase (human leukocyte), cathepsin G, plasmin, C-l esterase, C-3 convertase, urokinase and tissue-type plasminogen activators, acrosin, chymotrypsin, trypsin, thrombin, factor Xa and kallikreins.
• Human leukocyte elastase is released by polymorphonuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease states.
• Cathepsin G is another human neutrophil serine protease.
• Compounds with the ability to inhibit the activity of these enzymes are expected to have an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema.
• Chymotrypsin and trypsin are digestive enzymes.
• Inhibitors of these enzymes are useful in treating pancreatitis.
• Inhibitors of urokinase plasminogen activator are useful in treating excessive cell growth disease states, such as benign prostatic hypertrophy, prostatic carcinoma and psoriasis.
• Urokinase (urinary-type plasminogen activator or uPA; International Union of Biochemistry Classification Number: EC3.4.21.31) is a proteolytic enzyme which is highly specific for a single peptide bond in plasminogen. It is a multidomain serine protease, having a catalytic "B" chain (amino acids (aa) 144-411), and an amino-terminal fragment ("ATF", aa 1-143) consisting of a growth factor-like domain (4-43) and a Kringle domain (aa 47-135). The uPA Kringle domain appears to bind heparin, but not fibrin, lysine, or aminohexanoic acid.
• the growth factor-like domain bears some similarity to the structure of epidermal growth factor (EGF) and is thus also referred to as "EGF-like” domain.
• the single chain pro-uPA is activated by plasmin, cleaving the chain into a two- chain active form that is stabilized by a disulfide bond.
• plasminogen activation results in the formation of a potent general protease, plasmin.
• urokinase as a key initiator of plasmin-mediated proteolytic degradation or modification of extracellular support structures (e.g., the extracellular matrix (ECM) and the basement membrane (BM)).
• ECM extracellular matrix
• BM basement membrane
• urokinase receptors which concentrate urokinase on the cell surface, leading to the generation of locally high plasmin concentrations between cells and ECM or BM (Blasi, F., et al., Cell Biol. 704:801-804 (1987); Roldan, A.L., et al, EMBO J. 9:467-74
• Plasmin can activate or degrade extracellular proteins such as fibrinogen, fibronectin, and zymogens, including matrix metalloproteinases. Plasminogen activators thus can regulate extracellular proteolysis, fibrin clot lysis, tissue remodeling, developmental cell and smooth muscle cell migration, inflammation, and metastasis.
• Cellular invasiveness initiated by urokinase is central to a wide variety of normal and disease-state physiological processes (reviewed in Blasi, F., etal.,J. CellBiol. 704:801-804 (1987); Oan ⁇ , K.., etal.,Adv. Cancer Res.44:139- 266 (1985); Littlefield, .A., Ann. N. Y. Acad. Sci. (522:167-175 (1991); Saksela, O., Biochim. Biophys. Ada 8233- 5-65 (1985); Testa, J.E., and Quigley, J.P.,
• Such processes include, but are not limited to, angiogenesis (neovascularization), bone restructuring, embryo implantation in the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue remodeling during wound repair, restenosis and organ differentiation, fibrosis, local invasion of tumors into adjacent areas, metastatic spread of tumor cells from primary to secondary sites, and tissue destruction in arthritis.
• Inhibitors of urokinase therefore have mechanism-based anti-angiogenic, anti-arthritic, anti-inflammatory, anti-restenotic, anti-invasive, anti-metastatic, anti-osteoporotic, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive, and tumoristatic activities.
• Inhibitors of urokinase are useful agents in the treatment of a variety of disease states, including but not limited to, benign prostatic hypertrophy, prostatic carcinoma and psoriasis.
• anti-urokinase monoclonal antibodies have been reported to block tumor cell invasiveness in vitro (Hollas, W., et al, Cancer Res. 57:3690-3695, (1991); Meissauer, A., et al, Exp. Cell Res. 792:453-459 (1991)), tumor metastasis and invasion in vivo (Ossowski, L., J. Cell Biol. 707:2437-2445 (1988); Ossowski, L., etal.,J. Cancer Res.
• Urokinase plays a significant role in vascular wound healing and arterial neointima formation after injury, most likely affecting cellular migration. Urokinase mediates plasmin proteolysis, which in turn promotes vascular wound- healing and associated neointima formation (Carmeliet et al., Circ. Res. 81:829- 839 (Nov. 1997), Lupu et al., Fibrinolysis 10 Supp 2:33-35 (1996)).
• SERP-1 A viral serine proteinase inhibitor
• SERP-1 has been employed to reduce plaque formation after primary balloon angioplasty in rabbits. This activity has been attributed to the inhibition by SERP-1 of cellular proteinases, such as plasmin or urokinase (Lucas et al., Circulation 94:2890-2900 (1996)).
• the present invention is broadly directed to the use of heteroaryl amidines, methylamidines and guanidines having Formula (below) as protease inhibitors, preferably as urokinase inhibitors.
• Compounds of the present invention exhibit anti-urokinase activity via direct, selective inhibition of urokinase, or are intermediates useful for forming compounds having such activity.
• Compounds of the present invention inhibit urokinase and are, therefore, useful anti-angiogenic, anti-arthritic, anti- inflammatory, anti-restenotic, anti-invasive, anti-metastatic, anti-osteoporotic, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive, and tumoristatic treatment agents.
• such treatment agents are useful in the treatment of a variety of disease states, including but not limited to, benign prostatic hypertrophy, prostatic carcinoma, tumor metastasis and psoriasis.
• compositions comprising a compound of Formula /and one or more pharmaceutically acceptable carriers or diluents and said pharmaceutical compositions further comprising athrombolytic agent such as tissue plasminogen activator and streptokinase.
• the present invention is broadly directed to a method of inhibiting proteases, particularly serine proteases, by contacting a serine protease with a compound of the general Formula /:
• X is O, S or NR 7 , where R 7 is hydrogen, alkyl, aralkyl, hydroxy(C 2.4 )alkyl, or alkoxy(C 2.4 )alkyl;
• Y is a direct covalent bond, CH 2 or NH
• Z is NR 5 R 6 , hydrogen or alkyl, provided that Y is NH whenever Z is hydrogen or alkyl;
• R 1 is hydrogen, amino, hydroxy, halogen, cyano, C M alkyl or -CH 2 R, where R is hydroxy, amino or C i alkoxy;
• R 2 and R 3 are independently: i. hydrogen; ii. halogen; iii. hydroxy; iv. nitro; v. cyano; vi. amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocycleamino, diheterocycleamino, mo no alky lmono hetero cy c leamino , alko xycarbony lamino , aralkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, di(aralkyls
• aminocarbonyl monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, aminoacyl, monoarylaminocarbonyl, diarylaminocarbonyl or monoalkylmonoarylaminocarbonyl; viii. aminothiocarbonyl, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or aminothioacyl; ix. aminocarbonylamino, mono- and dialkylaminocarbonylamino, mono - and di ary laminocarbonylamino , or mono - and diaralkylaminocarbonylamino; x.
• R 4 , R 5 and R 6 are independently hydrogen, C,_ 4 alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C 2 . I0 )alkyl, dialkylamino(C 2 _ 10 )alkyl, carboxyalkyl, cyano, amino, alkoxy, or hydroxy, or -CO 2 R w , where R w is alkyl, cycloalkyl, phenyl, benzyl,
• R d and R e are independently hydrogen, C,_ 6 alkyl, C 2.6 alkenyl or phenyl
• R f is hydrogen, C,. 6 alkyl, C 2.6 alkenyl or phenyl
• R s is hydrogen, C,. 6 alkyl, C 2 . 6 alkenyl or phenyl
• R h is aralkyl or C,. 6 alkyl.
• the present invention is also directed to novel compounds of Formula /, where X, Y and R'-R 6 are as defined above; provided that at least one of R 2 or R 3 is selected from the group consisting of:
• an optionally substituted alkyl group preferably C,-C 6 alkyl, more preferably C,-C 3 ;
• Values of optional substituents on alkyl groups are halogen, hydroxy, thiol, amino, monoalkylamino, dialkylamino, formylamino, aminoiminomethyl, acylamino, aminoacyl, mono- or di- alkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, mono- or diarylaminocarbonyloxy, mono- or diaralkylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfonylamino, arylsulforfylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonyla
• Preferred values of optional substituents on an alkyl group are chloro, hydroxy, amino, mono(C M )alkylamino, di(C,. 4 )alkylamino, formylamino, C 2.6 acylamino, aminocarbonyl, C 2 . 8 aminoacyl, C,. 6 alkoxy, C 6 . 14 aryloxy, carboxy, carboxy (C,_ 6 )alkyl, C 2 . 8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C,. 6 alkylthio, C 6 . 14 arylthio, C,. 6 alkylsulfonylamino, C 7 .
• aralkylsulfonylamino C 6.10 arylsulfonylamino, mono- or di(C,. 6 )alkylaminocarbonyloxy, mono- or di- (C 6 . 10 )arylaminocarbonyloxy, mono- or di(C 7 . 15 )aralkylcarbonyloxy, C,_ 6 alkoxycarbonylamino, C 7 -C 15 aralkoxycarbonylamino, and C 6 -C, 0 aryloxycarbonylamino.
• Preferred values of optional substituents on aryl-containing and heterocyclic-containing groups include chloro, hydroxy, amino, mono(C M ) alkylamino, di(C M )alkylamino, formylamino, C 2 . 6 acylamino, aminocarbonyl, C 2.g aminoacyl, C 3 . 7 cycloalkyl, C,. 6 alkyl, C,_ 6 alkoxy, C 6 ., 4 aryloxy, carboxy, carboxy(C,. 6 )alkyl, C 2.g alkoxycarbonyl, nitro, cyano, trifluoromethyl, C,. 6 alkylthio, C 6 .
• R 1 arylsulfonyl, mono- or di(C, .6 )alkylaminocarbonyloxy, mono- or di- C 6 . ]0 arylaminocarbonyloxy, mono- or di-(C 7 . I 5 )aralkylcarbonyloxy, C,. 6 alkoxycarbonylamino, C 7 -C ] 5 aralkoxycarbonylamino, C 6 -C ]0 aryloxycarbonylamino, C 2 . 6 thioacylamino, aminothiocarbonyl, and C 2 . g aminothioacyl.
• Preferred values of R 1 include hydrogen, amino, hydroxy and fluoro.
• R 2 is Formula//:
• Ar is phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), pyrrolyl, oxazolinyl and benzothienyl.
• R 3 examples include C alkyl (optionally substituted), halogen, amino, acylamino, C,_ 6 alkylthio (such as methylthio or ethylthio), C, .6 alkoxy (such as methoxy and ethoxy), trifluoromethyl, methylsulfonyl, and benzylthio.
• a preferred value of X is divalent sulfur (S).
• Preferred values of Y are a covalent bond or — NH — , most preferably a covalent bond.
• R 4 , R 5 and R 6 in Formula / are hydrogen, hydroxy, cyano, C,_ 6 alkyl, or C,. 6 alkoxy.
• Suitable values of R 4 , R 5 and R 6 include hydrogen, methyl, ethyl, propyl, H-butyl, hydroxy, methoxy, and ethoxy. In the most preferred embodiments, R 4 , R 5 and R 6 are each hydrogen.
• Suitable values of R 4 , R 5 and R 6 include hydrogen, methyl, ethyl, propyl, «-butyl, hydroxy, methoxy, ethoxy, cyano, -CO 2 CH 3 , -CO 2 CH 2 CH 3 and -CO-CK CH-CHj.
• R 4 , R 5 and R 6 are each hydrogen.
• R 4 , R 5 and R 6 is the group -CO 2 R ⁇ , where R w is one of
• R d -R h are defined as above.
• R 4 , R 5 and R 6 are -CO 2 R w , where R w is one of one of these moieties, the resulting compounds are prodrugs that possess desirable formulation and bioavailability characteristics.
• a preferred value for each of R d , R e and R g is hydrogen, R f is methyl, and preferred values for R h include benzyl and tert-butyl.
• Preferred values of R 7 include hydrogen, C,_ 6 alkyl, C 6.10 ar(C, .4 )alkyl, and
• alkyl refers to both straight and branched chain radicals of up to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.
• alkenyl is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1 -butenyl, 2-butenyl, and the like.
• the alkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length most preferably from 2 to 4 carbon atoms in length.
• alkynyl is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, 1 -propylene, 2-propylene, and the like.
• the alkynyl chain is 2 to 10 carbon atoms in length, more preferably,
• the unsaturated linkage i.e., the vinylene or acetylene linkage is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.
• alkylthio as employed herein by itself or as part of another group refers to a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to a sulfur atom, including, but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and the like.
• the alkylthio chain is 1 to 10 carbon atoms in length, more preferably
• alkoxy refers to a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, w-propoxy, isopropoxy, and the like.
• the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
• cycloalkyl as employed herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
• halogen or "halo"as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine with chlorine being preferred.
• acyl as employed herein by itself or as part of another group refers to the group -C(O)R g where R is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl.
• Preferred acyl groups are alkanoyl, aralkanoyl and aroyl groups (-C(O)R g where R is C,_ g alkyl, C 6.
• thioacyl as employed herein by itself or as part of another group refers to the group -C(S)R where R is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl, preferably C,. g alkyl.
• thiocarbonyl as employed herein by itself or as part of another group refers to the group -C(S)-.
• monoalkylamine as employed herein by itself or as part of another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms.
• dialkylamine as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms
• aryl as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 14 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
• aralkyl or “arylalkyl” as employed herein by itself or as part of another group refers to C,. 6 alkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
• heterocyclic refers to a saturated or wholly or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
• rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms are especially useful.
• heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl.
• heteroatom is used herein to mean an oxygen atom ("O"), a sulfur atom (“S”) or a nitrogen atom (“N”). It will be recognized that when the heteroatom is nitrogen, it may form an NR y R z moiety, wherein R y and R z are, independently from one another, hydrogen or C, to C g alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7- membered ring.
• heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 ⁇ electrons shared in a cyclic array; and containing carbon atoms and 1 , 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl
• prodrug denotes a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process.
• Useful prodrugs are those where R 4 , R 5 and/or R 6 are -CO 2 R w , where R w is defined above. See, U.S. Patent No. 5,466,811 and Saulnier et al, Bioorg. Med. Chem. Lett. 4: 1985-1990 (1994).
• substituted means that one or more hydrogens of the designated moiety are replaced with a selection from the indicated group, provided that no atom's normal valency is exceeded, and that the substitution results in a stable compound.
• 2 hydrogens attached to an atom of the moiety are replaced.
• stable compound or “stable formula” is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.
• a first preferred group of compounds falling within the scope of the present invention include compounds of Formula/ wherein X is sulfur or oxygen; Y is a covalent bond or -NH-; R 1 is hydrogen, amino, hydroxy or halogen; R 4 , R 5 and R 6 are independently hydrogen, C,.
• Specific compounds within the scope of the invention include the compounds described in the Examples, such as the following: 4-[4-(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine; 4-phenyl-5-methylthiothiophene-2-carboxamidine; 4-[4-(2,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
• a second preferred group of compounds falling within the scope of the present invention include compounds of Formula/ wherein X is sulfur or oxygen;
• Y is a covalent bond or -NH-;
• Z is NR 5 R 6 ;
• R 1 is hydrogen, amino, hydroxy or halogen;
• R 4 , R 5 and R 6 are independently hydrogen, C,_ 4 alkyl, amino, C M alkoxy or hydroxy, and are preferably all hydrogen;
• one of R 2 or R 3 is hydrogen, C,_ 6 alkylthio, C,_ 6 alkyl optionally substituted with OH.
• NH 2 , COOH or aminocarbonyl, or C,. 6 alkoxy; and the other of R 2 or R 3 is:
• Ar is a group selected from the group consisting of phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), tetrazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl, benzimidazolyl, l,3-oxazolidin-2-onyl, imidazolin- 2-onyl (preferably phenyl, thiazolyl, thiazolinyl, oxazolinyl, isothiazolyl, isoxazolyl,
• R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, amino, mono(C,. 4 )alkylamino, di(C )alkylamino, arylamino, mono- and di- (C 6 _ ⁇ 4 )arylamino, mono- and di-(C 6 ., 4 )ar(C 1 . 6 )alkylamino, formylamino, C 2 . 6 acylamino, aminocarbonyl, C 2 . g aminoacyl, C 2 . 6 thioacylamino, aminothiocarbonyl, C 2.8 aminothioacyl, C,_ 6 alkyl, C 3 .
• cycloalkyl C, .6 alkoxy, carboxy, carboxy(C ⁇ .6 )alkyl, C 2 . g alkoxycarbonyl, nitro, cyano, trifluoromethyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), tetrazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, oxazolinyl, isoxazolinyl, imidazolinyl, triazolyl, pyrrolinyl, benzothiazolyl, benzothienyl, benzimidazolyl, l,3-oxazolidin-2-onyl, imidazolin-2-onyl, C
• aryl can be further optionally substituted, preferably by one, two or three of halogen, hydroxy, amino, mono(C )alkylamino, di(C, .4 )alkylamino, formylamino.
• C 6 . 10 aryloxycarbonylamino, mono- or di-(C M )alkylaminothiocarbonyl, C 7 _ ⁇ 5 aralkoxy, carboxy, carboxy(C,. 4 )alkyl, C,. 4 alkoxycarbonyl, C, . 4 alkoxycarbonylalkyl, carboxy(C )alkoxy, alkoxycarbonylalkoxy, nitro, cyano, trifluoromethyl, C M alkylthio and C 6 . 10 arylthio, or by 3,4-methylenedioxy, 3,4- ethylenedioxy, and 3,4-propylenedioxy.
• R 8 and R 9 are halogen, C , _ 6 alkyl, C , . 6 alkoxy, hydroxy, nitro, trifluoromethyl, C 6 . 10 aryl (further optionally substituted by one or two of chloro, halogen, C,. 6 alkyl, C, profession 6 alkoxy, hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, or amino), 4-phenylphenyl (biphenyl), C,. 6 aminoalkyl, carboxy, C,.
• R 2 is thienyl, oxazolyl, or thiazolyl, optionally substituted by any of the aforementioned groups.
• R 8 and R 9 groups include 4-chlorophenyl,
• 2,4-dichlorophenyl methyl, 4-nitrophenyl, 3-nitrophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3-(2,4-dimethylthien-5-yl)phenyl, 3-hydroxyphenyl, 5-(carboxymethyl)thien-2-yl, phenyl, 3,4-ethylenedioxyphenyl, 3,4-propylenedioxyphenyl, naphfh-2-yl, 3-phenyl-4-(tetrazol-5-yl)phenyl, 2,4-dichlorophenyl), 4-phenylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl,
• a third preferred group of compounds are those of Formula/ wherein: X is sulfur;
• Y is a covalent bond
• Z is NR 5 R 6
• R 1 is hydrogen
• R 3 is methylthio or methyl; R 4 , R 5 and R 6 are all hydrogen; and
• R 2 is Formula //, where Ar is phenyl, thiazolyl, oxazolyl, benzothienyl, pyridyl, or imidazolyl; and R 8 and R 9 are independently hydrogen, or C 6 . 10 aryl or heterocycle, optionally substituted by one, two or three of chloro, hydroxy, C M alkyl, C 3.6 cycloalkyl, C M alkoxy, amino, carboxy, phenyl, naphthyl, biphenyl, hydroxyphenyl, methoxyphenyl, dimethoxyphenyl, carboxyalkoxyphenyl, alkoxycarbonylalkoxy, carboxyethoxy, alkylsulfonylaminophenyl, arylsulfonylaminophenyl, acylsulfonylaminophenyl, aralkylsulfonylaminophenyl, heteroarylsulfonylaminophenyl where
• a fourth preferred group of compounds are those of Formula /wherein: X is sulfur;
• Y is a direct covalent bond
• Z is NR 5 R 6 ;
• R 1 is hydrogen
• R 2 is alkyl, ar(alkyl), alkylsulfonyl, -SO 2 -alkyl, amido, amidino, or where
• Ar is an aromatic or heteroaromatic group selected from the group consisting of phenyl, thiazolyl, oxazolyl, imidazolyl and pyridyl;
• R 8 and R 9 are independently selected from the group consisting of hydrogen, carboxy, phenyl, naphthyl, alkyl, pyridyl, oxazolyl, furanyl, cycloalkyl and amino, any of which may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, alkyl, haloalkyl, alkaryl, heteroaryl, phenyl, naphthyl, alkoxy, aryloxy, hydroxy, amino nitro, thiophenyl, benzothiophenyl, fluorenyl, 3,4-ethylenedioxy, 3,4-methylenedioxy, 3 ,4-propylenedioxy, arylsulfonamido, alkylsulfonamido and aryloxy.
• substituents may be further optionally substituted with one or more groups selected from alkoxy, haloalkyl, halogen, alkyl, amino, acetyl, hydroxy, dialkylamino, dialkylamino acyl, monoalkylaminoacyl, -SO : -heteroaryl,
• R 3 is -SO 2 -alkyl, trifluoromethyl, S(O)-alkyl, hydrogen, alkoxy, alkylthio, alkyl, aralkylthio;
• R 4 , R 5 , R 6 are hydrogen.
• Preferred compounds of this embodiment are those where Ar is a thiazolyl, preferably thiazol-2-yl or thiazol-4-yl, and at least one of R 8 and R 9 is substituted phenyl, most preferably on the 4-position of the thiazol-2-yl group.
• R 2 is a 4-phenylthiazol-2-yl group wherein said phenyl is further optionally substituted, and R 3 is methylthio.
• a fifth preferred group of compounds are those of Formula///:
• A is methylthio or methyl
• G' is -O-, -S-, -NH-, or a covalent bond; n is an integer from 1-10, preferably from 1-6; m is an integer from 0-1 ; and
• R' and R" are independently selected from hydrogen, alkyl, aryl or aralkyl, or R' and R" are taken together with the N atom to which they are attached form a 3-8 membered heterocyclic ring, optionally containing an additional O, N, or S atom, and when said 3-8 membered heterocyclic ring contains an additional N atom, said additional N atom is optionally substituted by hydrogen, C alkyl, C 6 seemingly, 0 aryl, C 6 _ 10 ar(C ⁇ _ 4 )alkyl, acyl, alkoxycarbonyl or benzyloxycarbonyl.
• a sixth preferred group of compounds are those of Formula IV:
• R"' is hydrogen, C 6 . 14 aryl, C,. 6 alkyl, C,. 6 alkoxy (C 6 . ]4 )aryl, amino(C 6. , 4 )aryl, monoalkylamino(C 6.14 )aryl, dialkylamino(C 6.]4 )aryl, C 6. , 0 ar(C, .6 )alkyl, heterocycle(C 2 . 6 )alkyl such as mo ⁇ hdlinoalkyl, piperazinylalkyl and the like, C, .6 alk(C 6 . 14 )aryl, amino(C,. 6 )alkyl, mono(C,. 6 )alkylamino(C,.
• Examples of preferred compounds of Formula IV include: 4- ⁇ 2-[(3 -methoxyphenyl)amino]( 1 ,3 -thiazol-4-y 1) ⁇ -5 -methylthiothiophene-2- carboxamidine,
• a seventh preferred group of compounds are compounds of Formula /, or a pharmaceutically acceptable salt or prodrug thereof, wherein: X is sulfur or oxygen, preferably sulfur; Y is a covalent bond or -NH-, preferably a covalent bond; Z is NR 5 R 6 ; R 1 is hydrogen, amino, hydroxy or halogen, preferably hydrogen;
• R 4 , R 5 and R 6 are independently hydrogen, C alkyl, amino, C,. 4 alkoxy or hydroxy, and are preferably all hydrogen;
• R 3 is hydrogen, C,_ 6 alkylthio, C,_ 6 alkyl optionally substituted with OH, NH 2 COOH or aminocarbonyl, or C,. 6 alkoxy, preferably methylthio or methyl;
• R 2 is alkylsulfonylamino, aralkylsulfonylamino, aralkeny lsulfony lamino, arylsulfonyl amino, heteroarylsulfonylamino, di(aralkylsulfonyl)amino, di(aralkenylsulfonyl)amino, di(ary lsulfony l)amino, or di- (heteroarylsulfonyl)amino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring; or amino, monoalky lamino, dialkylamino, monoarylamino, diarylamino, monoalky lmonoarylamino, mo no ar alky 1 amino , di ar alky lamino , monoalkylmonoaralkylamino, monoheterocycleamino, diheterocycleamino,
• Preferred optional substituents are halogen, C,. 6 alkyl, C,_ 6 alkoxy, hydroxy, nitro, trifluoromethyl, C 6 ., 0 aryl, C 6.10 aryloxy, C 6.]0 arylmethoxy (wherein the aryl groups on these aryl-containing substituents are further optionally substituted by one or two of chloro, halogen, C,.
• alkoxycarbonyl C,. 6 alkanoylamino, C 6 . !4 aroylamino, C, .6 hydroxyalkyl, methylsulfonyl, phenylsulfonyl, thienyl (further optionally substituted by one or two of chloro, amino, methyl, methoxy, or hydroxy) and tetrazolyl.
• R 2 is preferably C,. 6 alkylsulfonylamino, C 6. 1 0 ar(C , .6 )alkylsulfonylamino, C 6.10 ar(C 2.6 )alkenylsulfonylamino, C 6 . 10 arylsulfonylamino, heteroarylsulfonylamino, di(C 6.10 ar(C,. 6 )alkylsulfonyl)amino, di(C 6 . 10 ar(C 2 . 6 )alkenylsulfonyl)amino, di(C 6 . 10 arylsulfonylamino, or di-(heteroarylsulfonyl)amino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring.
• R 2 groups in this embodiment of the invention include C 6.10 arylsulfonylamino, di-(C 6 . 10 arylsulfonylamino, C 6 . 10 ar(C, .3 )alky lsulfony lamino, di-(C 6 . 10 ar(C,. 3 )alkylsulfonyl)amino, thienylsulfonylamino, any of which is optionally substituted on the aromatic ring.
• R 2 when R 2 is a substituted sulfonylamino group include biphenylsulfonylamino,bis(biphenylsulfonyl)amino, naphth-2-ylsulfonylamino, di(naphth-2-ylsulfonyl)amino, 6-bromonaphth-2-ylsulfonylamino, di(6- bromonaphth-2-ylsulfonyl)amino, naphth- 1 -ylsulfony lamino, di(naphth- 1 - y lsulfonyl)amino , 2-methylpheny l sulfonyl amino , di- (2- methylphenylsulfonyl)amino, 3-methylphenylsulfonylamino, di-(3- methylphenylsulfonyl)amin
• R 2 is preferably amino, mono(C,. 6 )alkylamino, di(C,. 6 )alkylamino, mono(C 6 . 10 )arylamino, di ( C 6. l 0 ) ary lamino , mono (C , . 6 )alky lmono ( C 6 . , 0 )ary lamino , monoar(C, .6 )alkylamino, di(C 5.10 )ar(C,. 6 )alkylamino, mono(C,. 6 )alkylmono(C 6 .
• R 2 groups in this embodiment of the invention include mono(C 6 . 10 )arylamino, mono(C,. 6 )alkylmono(C 6 . 10 )arylamino, mono(C 6 . 10 )ar(C,. 3 )alkylamino, mono(C,. 6 )alkylmono(C 6 . I0 )ar(C,. 3 )alkylamino, monoheteroarylamino, and mono(C 1 . 6 )alkylmonoheteroarylamino.
• heteroarylamino groups examples include l,3-thiazol-2-ylamino, imidazol-4- ylamino, quinolin-2-ylamino and quind ⁇ in-6-ylamino.
• Useful values of R 2 , when R 2 is a substituted amino group include anilino, naphth-2-ylamino, naphth-1 -y lamino, 4-(biphenyl)thiazol-2-ylamino, 4-(phenyl)thiazol-2-ylamino, 4-pheny 1-5 -methylthiazol-2-y lamino, 4-hydroxy-4- trifluoromethylthiazol-2-ylamino, 3-phenylphenylamino, pyrimidin-2-ylamino, 4-isopropylphenylamino, 3-isopropylphenylamino, 4-phenylphenylamino, 3- fluoro-4-phenylphenylamino, 3,4-methylenedioxyphenyla
• R 2 is preferably an acylamino group, such as alkanoylamino, alkenoylamino, aroylamino, aralkanoy lamino, aralkenoylamino, heteroaroylamino, heteroarylalkanoylamino, any of which is optionally substituted on the aromatic ring.
• acylamino group such as alkanoylamino, alkenoylamino, aroylamino, aralkanoy lamino, aralkenoylamino, heteroaroylamino, heteroarylalkanoylamino, any of which is optionally substituted on the aromatic ring.
• R 2 groups in this embodiment of the invention include (C 6 . 10 )arylcarbonylamino, C 6 . l0 ar(C,. 3 )alkylcarbonylamino, C 6 ., 0 ar(C 2 . 3 )alkenylcarbony lamino, C 6 . 10 aryloxy(C ⁇ _ 3 )alkylcarbonylamino, C 3 . g cycloalkylcarbonylamino, C,. 6 alkylcarbonylamino, andheteroarylcarbonylamino, such as furanylcarbony lamino, and quinolinylcarbony lamino.
• R 2 when R 2 is an acylamino group include 3 -hydroxyphenylcarbony lamino, 2-phenylethenylcarbony lamino, phenylcarbonylamino, cyclohexylcarbonylamino, 4-methyl-3- nitrophenylcarbonylamino, furan-2-ylcarbonylamino, tert-butylcarbonylamino, 5-(3,5-dichlorophenoxy)furan-2-ylcarbonylamino, naphth-1 -ylcarbony lamino, quinolin-2-ylcarbonylamino, 4 -ethoxy phenylcarbonylamino , phenoxymethylcarbonylamino, and 3-methylphenylcarbonylamino.
• R 2 is preferably C 6 ., 0 aryloxy, C 6 . 10 ar(C,. 6 )alkoxy, C 6 . 10 arylsulfonyl, C 6 . ]0 ar(C,. 6 )alkylsulfonyl, or C 6 . 10 ar(C 2 . 6 )alkenylsulfonyl, any of which is optionally substituted on the aromatic ring.
• Especially preferred R 2 groups in this embodiment of the invention include C 6 . 10 aryloxy, and C 6 .
• R 2 when R 2 is an aryloxy or arylsulfonyl group include phenoxy, naphthyloxy, phenylsulfonyl, and naphthylsulfonyl.
• Representative compounds within the scope of this seventh embodiment of the invention include:
• the pharmaceutically acceptable acid addition salts those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation, are preferred.
• the acid addition salts are obtained either by reaction of an organic base of Formula / with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature available to any practitioner skilled in the art.
• useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, cyclamic acid, pivalic acid and the like; useful inorganic acids are hydrohalide acids such as HC1, HBr, HI; sulfuric acid; phosphoric acid and the like.
• Preferred acids for forming acid addition salts include HC1 and acetic acid.
• the compounds of the present invention represent a novel class of potent inhibitors of metallo, acid, thiol and serine proteases.
• Examples of the serine proteases inhibited by compounds within the scope of the invention include leukocyte neutrophil elastase, a proteolytic enzyme implicated in the pathogenesis of emphysema; chymotrypsin and trypsin, digestive enzymes; pancreatic elastase, and cathepsin G, a chymotrypsin-like protease also associated with leukocytes; thrombin and factor Xa, proteolytic enzymes in the blood coagulation pathway.
• Inhibition of thermolysin, a metalloprotease, and pepsin, an acid protease are also contemplated uses of compounds of the present invention.
• the compounds of the present invention are preferably employed to inhibit trypsin-like proteases.
• Compounds of the present invention that inhibit urokinase plasminogen activator are potentially useful in treating excessive cell growth disease state.
• Compounds of the present that inhibit urokinase are, therefore, useful as anti-angiogenic, anti-arthritic, anti-inflammatory, anti-invasive, anti- metastatic, anti-restenotic, anti-osteoporotic, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive, and tumoristatic treatment agents.
• such treatment agents are useful in the treatment of a variety of disease states, including but not limited to, benign prostatic hypertrophy, prostatic carcinoma, tumor metastasis, restenosis and psoriasis.
• the potency and other biochemical parameters of the enzyme inhibiting characteristics of compounds of the present invention are readily ascertained by standard biochemical techniques well known in the art.
• Actual dose ranges for this application will depend upon the nature and severity of the disease state of the patient or animal to be treated as determined by the attending diagnostician. It is to be expected that a general dose range will be about 0.01 to 50 mg, preferably 0.1 to about 20 mg per kg per day for an effective therapeutic effect.
• an end use application of the compounds that inhibit chymotrypsin and trypsin is in the treatment of pancreatitis.
• the potency and other biochemical parameters of the enzyme-inhibiting characteristics of the compounds of the present invention is readily ascertained by standard biochemical techniques well known in the art.
• Actual dose ranges for their specific end-use application will, of course, depend upon the nature and severity of the disease state of the patient or animal to be treated, as determined by the attending diagnostician. It is expected that a useful dose range will be about 0.01 to about 50 mg, preferably about 0.1 to about 20 mg per kg per day for an effective therapeutic effect.
• Compounds of the present invention that are distinguished by their ability to inhibit either factor Xa or thrombin may be employed for a number of therapeutic pu ⁇ oses.
• As factor Xa or thrombin inhibitors compounds of the present invention inhibit thrombin production. Therefore, these compounds are useful for the treatment or prophylaxis of states characterized by abnormal venous or arterial thrombosis involving either thrombin production or action. These states include, but are not limited to.
• thrombosis deep vein thrombosis; disseminated intravascular coagulopathy which occurs during septic shock, viral infections and cancer; myocardial infarction; stroke; coronary artery bypass; fibrin formation in the eye; hip replacement; and thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PCTA).
• PCTA percutaneous transluminal coronary angioplasty
• the compounds of the present invention find additional use in the treatment or prophylaxis of adult respiratory distress syndrome; inflammatory responses; wound healing; reperfusion damage; atherosclerosis; and restenosis following an injury such as balloon angioplasty, atherectomy, and arterial stent placement.
• the compounds of the present invention may be useful in treating neoplasia and metastasis as well as neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.
• the compounds of the present invention may be administered in an effective amount within the dosage range of about 0.1 to about 500 mg/kg, preferably between 0.1 to 30 mg/kg body weight, on a regimen in single or 2-4 divided daily doses.
• Human leucocyte elastase is released by polymo ⁇ honuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease states.
• Compounds of the present invention are expected to have an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema.
• the leucocyte elastase inhibitory properties of compounds of the present invention are determined by the method described below.
• Cathepsin G has also been implicated in the disease states of arthritis, gout and emphysema, and in addition, glomerulonephritis and lung infestations caused by infections in the lung.
• the enzyme inhibitory properties of the compounds of Formula / is readily ascertained by standard biochemical techniques that are well-known in the art.
• Cathepsin G inhibitory properties of compounds within the scope of the present invention are determined by the following method.
• a preparation of partially purified human Cathepsin G is obtained by the procedure of Baugh et al, Biochemistry 15: 836 (1979).
• Leukocyte granules are a major source for the preparation of leukocyte elastase and cathepsin G
• Leukocytes are lysed and granules are isolated.
• the leukocyte granules are extracted with 0.20 M sodium acetate, pH 4.0, and extracts are dialyzed against 0.05 M Tris buffer, pH 8.0 containing 0.05 M NaCl overnight at 4°C.
• a protein fraction precipitates during dialysis and is isolated by centrifugation. This fraction contains most of the chymotrypsin- like activity of leukocyte granules.
• Specific substrates are prepared for each enzyme, namely N-Suc-Ala-Ala-Pro-Val-p-nitroanilide and Suc-Ala-Ala-Pro- Phe- 7-nitroanilide.
• Enzyme preparations are assayed in 2.00 mL of 0.10 M Hepes buffer, pH 7.5, containing 0.50 M NaCl, 10% dimethylsulfoxide and 0.0020 M Suc-Ala-Ala- Pro-Phe-p-nitroanilide as a substrate. Hydrolysis of the p-nitroanilide substrate is monitored at 405 nm and at 25°C.
• Useful dose range for the application of compounds of the present invention as neutrophil elastase inhibitors and as Cathepsin G inhibitors depend upon the nature and severity of the disease state, as determined by the attending diagnostician, with a range of 0.01 to 10 mg/kg body weight, per day, being useful for the aforementioned disease states.
• chymotrypsin is supplied as a standard reagent for use in clinical quantitation of chymotrypsin activity in pancreatic juices and feces. Such assays are diagnostic for gastrointestinal and pancreatic disorders.
• Pancreatic elastase is also supplied commercially as a reagent for quantitation of ,- antitrypsin in plasma. Plasma ⁇ , -antitrypsin increases in concentration during the course of several inflammatory diseases, and , -antitrypsin deficiencies are associated with increased incidence of lung disease.
• Compounds of the present invention can be used to enhance the accuracy and reproducibility of these assays by titrametric standardization of the commercial elastase supplied as a reagent. See, U.S. Patent No. 4,499,082.
• proteases present in such extracts can be inhibited during purification steps by compounds of the present invention, which bind tightly to various proteolytic enzymes.
• the pharmaceutical compositions of the invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited.
• compositions of the present invention can be administered by any means that achieve their intended pu ⁇ ose.
• administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes.
• administration can be by the oral route.
• the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
• the new pharmaceutical preparations can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
• compositions of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
• pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
• Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
• fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacan
• disintegrating agents can be added, such as, the above-mentioned starches and also carboxymethyl-starch, cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as, sodium alginate.
• Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as, magnesium stearate or calcium stearate, and/or polyethylene glycol.
• Dragee cores are provided with suitable coatings that, if desired, are resistant to gastric juices.
• concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
• suitable cellulose preparations such as, acety lcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used.
• Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
• Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as, glycerol or sorbitol.
• the push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds are preferably dissolved or suspended in suitable liquids, such as, fatty oils or liquid paraffin.
• stabilizers may be added.
• Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts, alkaline solutions and cyclodextrin inclusion complexes.
• Especially preferred salts are hydrochloride and acetate salts.
• One or more modified or unmodified cyclodextrins can be employed to stabilize and increase the water solubility of compounds of the present invention. Useful cyclodextrins for this pu ⁇ ose are disclosed in U.S. Patent Nos. 4,727,064, 4,764,604, and 5,024,998.
• suspensions of the active compounds as appropriate oily injection suspensions can be administered.
• suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
• Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
• the suspension may also contain stabilizers.
• a Lewis acid such as trimethylaluminum
• a source of ammonia such as ammonium chloride
• an aprotic solvent such as a toluene
• an inert atmosphere e.g., under an atmosphere of nitrogen or argon gas
• An appropriate carboxylic acid derivative is added to the mixture and the mixture is heated at reflux for a predetermined period of time, preferably between 1 hr. and 24 hrs., and most preferably between 1 hr. and 4 hrs.
• the resulting solution is allowed to cool to room temperature and the amidine product isolated by known methods.
• R 22 and R 21 of compounds 2 and 3 are retained in the final product, they correspond to R 2 and R 3 of Formula/, respectively. Otherwise R 22 and R 21 represent groups which, after further transformations, will become R 2 and R 3 of Formula /.
• the leaving groups can be sequentially displaced by appropriate nucleophiles (preferably the anion of the group R 21 or R 22 to be substituted) to produce the mono- or disubstituted heterocycles.
• suitable nucleophiles preferably the anion of the group R 21 or R 22 to be substituted
• leaving groups include halogens (chlorine, bromine or iodine), sulfonates (methanesulfonate, toluenesulfonate or trifluoromethanesulfonate) or sulfones (methylsulfonyl).
• nucleophiles include anions of thiols or alcohols having as the counterion an alkali or alkali earth metal such as sodium, lithium, potassium, magnesium or cesium, or in some cases, a transition group metal such as zinc, copper or nickel.
• alkali or alkali earth metal such as sodium, lithium, potassium, magnesium or cesium
• transition group metal such as zinc, copper or nickel.
• catalysts would include compounds containing palladium, silver or Ni salts.
• W in 3 is a cyano group (CN), primary amide (CONH 2 ) or ester
• suitable solvents include unsaturated hydrocarbons such as benzene, toluene, xylenes, or mesitylene, preferably toluene, or halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene.
• the amidination reaction is generally carried out at elevated temperatures, preferably 40-200 °C, more preferably 80-140 °C, and most preferably at the reflux temperature of a solvent in the range of 80-120 °C.
• W in 3 is a carboxyl group (CO 2 H)
• indirect conversion to an unsubstituted amidine 5 can be carried out by initial esterification to 4 by any of a number of well-known dehydrating agents (for example, dicyclohexylcarbodumide) with an alcohol (R 23 OH).
• More preferably 4 can be made by initial formation of an acid chloride by treatment of 3 with any of a number of anhydrides of HC1 and another acid, such as thionyl chloride, POCl 3 , PC1 3 , PC1 5 , or more preferably oxalyl chloride, with or without an added catalyst such as NN-dimethylformamide (DMF), followed by the alcohol R 23 OH.
• a number of well-known dehydrating agents for example, dicyclohexylcarbodumide
• R 23 OH More preferably 4 can be made by initial formation of an acid chloride by treatment of 3 with any of a number of anhydrides of HC1 and
• R 23 alkyl, branched alkyl or cycloalkyl, preferably Me or Et
• conversion to an iminoether can be carried out by treatment with a trialkyloxonium salt (Meerwein's salts).
• W NH 2
• these reagents include aminoiminosulfonic acid (Miller, A.E.
• a leaving group such as pyrazole, methylpyrazole, SO 3 H, S-alkyl, S-aryl, trifluoromethanesulfonate (OTf) or trifluoromethanesulfonamide (NHTf)
• Protected guanidines are advantageous when further transformations are required after introduction of the guanidine functionality where an unprotected guanidine would not be stable.
• protected reagents include reagents such as NN'-bis(tert-butoxycarbonyl)-S- methylthiourea (Bergeron, R.J. and McManis, J.S, J. Org. Chem.
• examples of reducing agents include reducing agents such lithium aluminum hydride (LAH) and lithium borohydride.
• LAH lithium aluminum hydride
• examples of reducing agents include LAH and borane complexed to THF, dimethyl sulfide, dimethylamine or pyridine.
• Leaving groups L include halides such as chloride, bromide or iodide, preferably bromide or iodide, or sulfonates such as toluenesulfonate, benzenesulfonate, methanesulfonate or trifluoromethanesulfonate.
• alkylating agent R 54 L examples include primary or secondary alkyl, allyl or aralkyl halides or sulfonates, such as methyl iodide, isopropyl bromide, allyl bromide, benzyl chloride or methyl trifluoromethanesulfonate, or a 2-haloacetate ester such as tert-butyl 2- bromoacetate.
• alkylating agents WCH 2 L include 2- chloroacetonitrile, methyl 2-bromoacetate or 2-bromoacetamide.
• Suitable media are generally polar aprotic solvents, for example, NN- dimethylformamide (DMF), NN-dimethylacetamide (DMA), ⁇ - methylpyrrolidinone ( ⁇ MP) or dimethylsulfoxide (DMSO), preferably DMF.
• NN- dimethylformamide DMF
• DMA NN-dimethylacetamide
• ⁇ MP ⁇ - methylpyrrolidinone
• DMSO dimethylsulfoxide
• Alternatively compounds 3 (R 22 C ⁇ ) can be synthesized from precursors 138 (derived from malononitrile, R 54 L and carbon disulfide), a thioglycolate WCHSH and a base in a suitable polar solvent, preferably methanol (Tominaga, Y., et al, J. Heterocyclic Chem. 31:111 (1994)).
• Nitrosating agents include nitrosonium tetrafluoroborate, nitrous acid or, more preferably and alkyl nitrite ester such as tert-butyl nitrite.
• Suitable solvents are those which are stable to the nitrosating agents, preferably DMF, benzene or toluene.
• treatment of compounds such as 139 with elemental halogen (Cl 2 , Br 2 or I 2 , preferably Br 2 ) or an N-halosuccinimide reagent, preferably N- bromosuccinimide (NBS) affords either 1 or 2 directly.
• elemental halogen Cl 2 , Br 2 or I 2 , preferably Br 2
• N-halosuccinimide reagent preferably N- bromosuccinimide (NBS)
• R 21 can be first introduced to give 7.
• R 21 can be first introduced to give 7.
• a metal cyanide such as copper (I) cyanide, sodium cyanide or lithium cyanide and most preferably copper (I) cyanide at a temperature of 80-200 °C and preferably at 100-140 °C, in a polar aprotic solvent, preferably DMF or DMSO, to give 8.
• a metal cyanide such as copper (I) cyanide, sodium cyanide or lithium cyanide and most preferably copper (I) cyanide at a temperature of 80-200 °C and preferably at 100-140 °C, in a polar aprotic solvent, preferably DMF or DMSO, to give 8.
• conversion to the thioamide is carried out by treatment of the nitrile with any of the methods well known in the art (see for example Ren, W., et al, J. Heterocyclic Chem. 23:1151 (1986) and Paventi, M. and Edward, J.T., Can. J. Chem. 65:282 (1987)).
• a preferable method is treatment of the nitrile with hydrogen sulfide in the presence of a base such as a trialkyl or heterocyclic amine, preferably triethylamine or pyridine, in a polar solvent such as acetone, methanol or DMF and preferably methanol.
• Conversion to the thiazole can be executed by classical Hantzsch thiazole synthesis followed by amidine formation as discussed in Scheme lb.
• a selective hydrolysis of the nitrile with a tetrahalophthalic acid preferably tetrafluoro- or tetrachlorophthalic acid, can be used to give 7 according to the method of Gribble, G.W. et al, Tetrahedron Lett. 29: 6557 (1988).
• Conversion to the acid chloride can be accomplished using the procedures discussed for conversion of 3 to 4, preferably with oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF.
• Coupling of the acid chloride to an aminoketone (R 26 COCH(R 27 )NH 2 ) can be performed in the presence of an acid scavenger, preferably NN-diisopropylethylamine (DIEA) or pyridine in a suitable solvent such as DMF, dichloromethane or tetrahydrofuran (THF) to afford the common intermediate 14.
• an acid scavenger preferably NN-diisopropylethylamine (DIEA) or pyridine in a suitable solvent such as DMF, dichloromethane or tetrahydrofuran (THF)
• Scheme 2c describes a general route to the synthesis of oxazoles, imidazoles and thiazoles of structure 27, 29 and 31 respectively.
• Acid 2 (see Scheme la) is converted to the ester by methods that are well known in the art (Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, Inc. 1991).
• methyl ester 21 is formed by treating the acid in an appropriate solvent such as methanol with trimethylsilyldiazomethane.
• the acid is treated with oxalyl chloride and catalytic amounts of dimethylformamide (DMF) in an appropriate solvent such as dichloromethane to form the acid chloride, which is then treated with methanol to give the methyl ester.
• DMF dimethylformamide
• Ester 21 is treated with a palladium (0) catalyst such as palladium tetrakistriphenylphosphine, and an alkylstannane such as hexa-n- butyldistannane or tri-n-butyltin chloride in an appropriate solvent such as DMF at elevated temperatures (50 °C - 120 °C) to give the arylstannane of general structure 22 (Stille, J.K., Angew. Chem. Int. Ed. Engl. 25:508-524 (1986)).
• the stannane 22 is then treated with acid chlorides in the presence of a palladium(O) catalyst to give ketone 23.
• the ketone is treated with ammonia/ammonium chloride to give amine 24.
• the ketone is reacted with an azide such as sodium azide in a suitable solvent such as DMF, and the resulting azidoketone is reduced to amine 23 with a suitable reducing agent such as catalytic hydrogenation in the presence of palladium on carbon and an acid such as HC1 (Chem. Pharm. Bull. 55:509-514 (1985)).
• Ketoamides 25 are formed by coupling the ketoamine 24 with a variety of suitably functionalized acid chlorides.
• amide coupling may be performed using any of a number of peptide coupling reagents such as 1,3- dicyclohexylcarbodiimide (Sheehan, J. C. et al, J. Am. Chem. Soc, 77:1067 (1955)) or Castro's reagent (BOP, Castro, B., et al, Synthesis 413 (1976)).
• amides 25 are formed directly from ketones 23 by reacting with various amide salts in an appropriate solvent such as DMF.
• the amide salts are generated by treating the amides with a suitable base such as sodium hydride (NaH).
• a suitable base such as sodium hydride (NaH).
• NaH sodium hydride
• acetamide is treated with NaH in DMF at 0 °C to give sodium acetamide.
• Keto amide 25 is cyclized to the oxazole 26, imidazole
• Scheme 2d illustrates to the preparation of compounds of Examples 42-43, where R 21 and R 43 correspond in Formula /to groups R 3 and R 2 , respectively.
• the acids 2 can be converted to the stannane by treatment with base, such as «-butyl lithium or .see-butyl lithium, followed by trimethyltin chloride.
• the resulting acid can be then converted to the ester 22 by methods that are well known in the art (Theodora W. Greene and Peter G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley and Sons, Inc. 1991).
• the methyl ester can be made by treating the acid 2 in a suitable solvent such as methanol with trimethylsilyldiazomethane.
• a palladium catalyst such as palladium tetrakistriphenylphosphine
• This is illustrated in Scheme 2b by the synthesis of 2-oxazolyl derivative 39.
• acid 13 can be coupled to an hydroxy-containing amine R 27 CH(NH 2 )CH(R 26 )OH to give amide 36 by any of a number of amide coupling reagents well known in the art (see Bodanszky, M.
• More preferably 13 can be converted to the corresponding acid chloride using any of the procedures mentioned for conversion of 3 to 4 followed by treatment with the R 27 CH(NH 2 )CH(R 26 )OH in the presence of an acid scavenger, preferably NN-diisopropylethylamine (DIEA) or pyridine in a suitable solvent such as DMF, dichloromethane or tetrahydrofuran (THF) to give 36.
• an acid scavenger preferably NN-diisopropylethylamine (DIEA) or pyridine in a suitable solvent such as DMF, dichloromethane or tetrahydrofuran (THF)
• Nitriles of structure 40 can be treated with hydrogen sulfide (H 2 S) in a suitable solvent such as methanol, or pyridine in the presence of a base such as triethylamine to give thioamides 41 (Ren,W. et al, J. Heterocyclic Chem. 25:1757-1763 (1986)).
• Thioamides 41 can be then treated with various haloketones 42 preferably bromoketones under suitable reaction conditions such as refluxing acetone or DMF heated to
• Scheme 2g illustrates one synthetic route to 2-haloketones of structure 42 which are employed in the synthesis of thiazolyl derivatives as in Schemes
• a suitable brominating agent such as Br 2 or N-bromosuccinimide in a suitable solvent such as chloroform or acetic acid (EP 0393936 Al).
• the ketone 44 is treated with a polymer-supported brominating agent such as poly(4-vinyl)pyridinium bromide resin (Sket, B., et al, Synthetic Communications 79:2481-2487 (1989)) to give bromoketones 42.
• 2-chloroketones are obtained by treating 44 with copper (II) chloride in a suitable solvent such as chloroform (Kosower, E. M., et al, J. Org. Chem. 25:630 (1963)).
• Scheme 2h illustrates another synthetic route to 2-haloketones of structure 42 which is particularly useful in that it employs acids 45 or activated carbonyl compounds such as 46 as precursors which are more readily available than the ketones 44.
• an acid chloride is formed by treating 45 with oxalyl chloride and catalytic amounts of DMF in dichloromethane.
• the acid chloride is converted to a diazoketone by treatment with trimethysilyldiazomethane (Aoyama, T. et al, Tetrahedron Lett. 27:4461-4462 (1980)).
• the resulting diazoketone is converted to a 2-haloketone of structure 42 by treatment with a suitable mineral acid.
• a bromoketone is formed by treating the diazoketone in a suitable solvent such as acetonitrile (CH 3 CN) with a solution of 30% hydrogen bromide (HBr) in acetic acid (Organic Synthesis Collective Vol III, 119, John Wiley and Sons, New York, Ed. Horning E. C).
• the acid 45 is converted to the mixed-anhydride 46 by treatment with a suitable chloroformate such as isobutyl chloro formate or tert- butyl chloroformate in a suitable solvent, such as tetrahydrofuran or dichloromethane, in the presence of a base such as N-methylmo ⁇ holine.
• a suitable chloroformate such as isobutyl chloro formate or tert- butyl chloroformate
• a suitable solvent such as tetrahydrofuran or dichloromethane
• a base such as N-methylmo ⁇ holine
• Scheme lc More preferably conversion of 13 to 47 is carried out through treatment of acid 13 with diphenylphosphoryl azide in the presence of an alcohol, preferably tert-butanol, and a base, preferably triethylamine or DIEA, as shown in Scheme 3a, to give a tert-butylcarbamate that is readily decomposed to the salt of amine 47 on exposure to an acid, preferably HC1 or trifluoroacetic acid in a suitable solvent such as CH 2 C1 2 . Further treatment with a base such as NaOH or preferably K 2 CO 3 or NaHCO 3 provides the free base 47.
• a base such as NaOH or preferably K 2 CO 3 or NaHCO 3
• R 2 of Formula / Introduction of an aminosulfonyl group (including monoalky laminosulfonyl and dialkylaminosulfonyl groups) for R 2 of Formula / can be carried out starting from amine such as 47 as well.
• Conversion to a sulfonyl chloride by the method of Gengnagel, et al. (U.S. Patent No. 3,947,512 (1976)) and treatment with an amine R 34 NH 2 followed by optional alkylation on nitrogen with R 35 L (under the sulfonylation and alkylation conditions described in Scheme 3a) provides 56 which is further converted to amidines 57 as previously described.
• amine 47 may also be produced as illustrated in Scheme 3c.
• a nitrothienyl ester 122 (Dell'Erba, C. and Spinelli, D., Tetrahedron, 21: 1061 (1965), Dell'Erba, C. et al, J. Chem. Soc, Perkin Trans 2, 1779 (1989)) with a suitable leaving group L may be substituted with an anion of R 21 to give intermediate 123.
• Amine 47 is then derived from reduction of the nitro group.
• Appropriate reagents to effect reduction of the nitro functionality include hydrogen gas in the presence of a catalyst such as palladium or platinum metal deposited on carbon or barium sulfate in any of a number of solvents such as methanol, ethanol, ethyl acetate,
• tin (II) chloride may be employed as a reductant in solvents such as DMF or THF, or in the presence of HC1 in a solvent such as methanol or ethanol.
• solvents such as DMF or THF
• metals such as zinc or iron (Stanetty, P. and Kremslehner, M., Heterocycles 48: 259 (1998)) may also be used.
• Scheme 4a illustrates the preparation of the compounds of Formula/// and Examples 48-59 and 61-77.
• the amidine moiety of compounds of structure 60 can be protected with a protecting group P 1 that can be readily removed from 62 and 64 using methods known to those skilled in the art (Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, Inc. 1991).
• a tert-butoxycarbonyl (BOC) protecting group can be removed by exposure to strongly acidic medium such as hydrogen chloride in a suitable solvent such as dioxane, or by trifluoroacetic acid in a suitable solvent such as methylene chloride.
• Benzyloxycarbonyl (Cbz) protecting groups can be removed by catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran.
• P 1 can be a solid support such as polystyrene or polyethyleneglycol-grafted polystyrene which can be attached to the amidine moiety via a cleavable linker such as 4-(benzyloxy)benzyloxy-carbonyl (using carbonate Wang resin).
• a cleavable linker such as 4-(benzyloxy)benzyloxy-carbonyl (using carbonate Wang resin).
• Attaching an amidine to a solid support can be achieved by treating a solid support having a linker containing an appropriately activated functional group with the amidine under suitable conditions.
• an amidine can be attached to Wang resin by treating para- nitrophenylcarbonate Wang resin with the amidine and a suitable base such as DBU in a suitable solvent such as DMF.
• the protected amidines 61 can be alkylated with carboxy -protected (protecting group is R 36 ) haloaliphatic acids, such as bromoacetic acid or bromopropionic acid in the presence of a suitable base such as cesium carbonate or DIEA, in a suitable solvent such as DMF with heating when necessary to give compounds of structure 62.
• haloaliphatic acids such as bromoacetic acid or bromopropionic acid in the presence of a suitable base such as cesium carbonate or DIEA
• a suitable solvent such as DMF
• the nitro group can be reduced prior to alkylation using an appropriate reducing agent, such as tin (II) chloride, in a suitable solvent such as DMF, or by catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran.
• tert-butyl ester can be removed by exposure to strongly acidic medium such as hydrogen chloride in a suitable solvent such as dioxane, or such as trifluoroacetic acid in a suitable solvent such as methylene chloride.
• Benzyl ester can be removed by catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran or by base hydrolysis.
• R 36 can be preferentially removed to give acids 63.
• the methyl ester can be removed by treating with a base such as sodium hydroxide in a suitable solvent such as aqueous tetrahydrofuran leaving the BOC group intact.
• a suitable protecting group such as BOC or a suitably functionalized resin.
• the protected amidine 63 can be treated with various amines under suitable amide coupling conditions, such as in the presence 1 -hydroxy-7-azabenzotriazole (HOAt), O-(7- azabenzotriazol- 1 -y 1)- 1 , 1 ,3 ,3-tetramethyluronium hexafluorophosphate
• HOAt 1 -hydroxy-7-azabenzotriazole
• HATU HATU
• DIEA DIEA
• the amidine protecting group can be then removed, for example by treating with an acid, such as trifluoroacetic acid in a suitable solvent such as methylene chloride, when a BOC protecting group is employed, to give amidines 65.
• Scheme 4b illustrates a specific example which utilizes the method described in Scheme 4a.
• the amidine moiety of 66 can be monoprotected with a tert-butyloxycarbonyl group.
• the monoprotected phenoxyamidine 67 can be alkylated on the phenolic hydroxy group with an ester of 2-bromoacetic acid to give 68.
• the ester can be removed by base, it can be hydro lyzed with aqueous base, such as NaOH, to give the acid 69.
• This acid can be treated with various amines in the presence of l-hydroxy-7- azabenzotriazole (HO At), O-(7-azabenzotriazol-l-yl)-l,l,3,3- tetramethyluronium hexafluorophosphate (HATU) and DIEA to form amides of structure 70.
• the amines are unsubstituted, di- or mono-substituted aliphatic or aromatic amines. In some cases the amines are cyclic-amines such as piperazine and piperidine.
• the amides 70 are then treated with trifluoroacetic acid to give the amidines 71.
• ester 68 In the case where the ester 68 is acid-labile, it can be treated with trifluoroacetic acid to give the amidino-acid 72.
• This amidine can be loaded on to an insoluble support, such as polystyrene or polyethyleneglycol-grafted polystyrene via a cleavable linker, such as Wang, which is functionalized as an activated carbonate such as p- nitrophenylcarbonate or succinimidyl carbonate.
• an activated carbonate such as p- nitrophenylcarbonate or succinimidyl carbonate.
• a suitable base such as DBU
• suitable solvent such as DMF
• the support-bound acid 73 can be treated with various amines in the presence of l-hydroxy-7-azabenzotriazole (HO At), O-(7-azabenzotriazol- 1 -yl)- 1,1,3 ,3-tetramethyluronium hexafluorophosphate (HATU) and DIEA to form amides. These amides are then cleaved from the solid support by treating with trifluoroacetic acid to give compounds of structure 71.
• HO At l-hydroxy-7-azabenzotriazole
• HATU O-(7-azabenzotriazol- 1 -yl)- 1,1,3 ,3-tetramethyluronium hexafluorophosphate
• DIEA difluoroacetic acid
• Scheme 5 illustrates a synthetic route to amidines containing disubstituted thiazoles represented by compounds for which R 2 is Formula // and both R 8 and R 9 are non-hydrogen substituents .
• the ketoamide 74 can be converted to the mono-bromoketoamide by treating with bromine in acetic acid.
• Thiazoles 76 are formed by reacting the bromoketoamide with 10 under suitable conditions, preferably by heating the mixture in DMF or acetone.
• Amidines 77 are formed by heating 76 in toluene with trimethylaluminum and ammonium chloride.
• the amidines 77 are treated with strong acid such as HC1 to give the acids 78.
• the amidines 78 are in one route protected with a suitable protecting group such as BOC to give 79.
• the protected amidines 79 are treated with various amines under suitable coupling conditions, such as in the presence of HO At, HATU, and DIEA to form various amides.
• the amidine protecting group can be then removed, for example by treating with trifluoroacetic acid in a suitable solvent such as methylene chloride, when a
• amidines 80 is employed to give amidines 80.
• the amidines 78 can be loaded onto an insoluble support, such as polystyrene or polyethyleneglycol-grafted polystyrene via a cleaveable linker, such as Wang resin, which is functionalized as an activated carbonate ester, such as p- nitrophenylcarbonate or succinimidyl carbonate, to give a resin-bound scaffold
• the resin-bound acid 81 can be treated with various amines under suitable coupling conditions such as in the presence of HO AT, HATU and DIEA to form amides. These amides are then cleaved from the solid support by treating with trifluoroacetic acid to give amidines 80.
• Scheme 6a illustrates the preparation of compounds of Examples 144, 145, 146, 147, 148, 149, 150 and 151.
• Compounds of this invention correspond to those of Formula / where R 2 is Formula // and where Ar is thiazole and R 37 and R 38 (R 8 and R 9 of Formula II) are phenyl, which can be additionally substituted.
• Compound 91 can be treated with an appropriate base, preferably a lithium alkyl like n-butyllithium, sec- butyllithium, or t-butyllithium, and more preferably /7-butyllithium, followed by carbon dioxide gas and conversion of the resulting carboxylate salt to the free acid with a mineral acid, preferably hydrochloric acid.
• Conversion to ester 21 can be carried out by preparation of the acid chloride using oxalyl chloride and treatment of this intermediate acid chloride with an alcohol R 23 in an appropriate solvent, preferably dichloromethane, with an appropriate base, preferably pyridine.
• Compound 21 can be treated with copper (I) cyanide in refluxing dimethylformamide to give compound 9.
• Compound 9 can be treated with hydrogen sulf ⁇ de gas in an appropriate solvent, preferably methanol, containing an appropriate base, preferably triethylamine to give compound 10.
• Compound 10 can be treated with an appropriate ketone where L is a leaving group, preferably halogen, mesyl, or tosyl, and most preferably bromo, refluxing in a suitable solvent, preferably, acetone, dimethylformamide, dimethyl acetamide, methyl ethyl ketone, or other polar aprotic solvents, and most preferably acetone to give compound 92.
• L is a leaving group, preferably halogen, mesyl, or tosyl, and most preferably bromo, refluxing in a suitable solvent, preferably, acetone, dimethylformamide, dimethyl acetamide, methyl ethyl ketone, or other polar aprotic solvents, and most preferably acetone to give compound 92.
• Compound 92 is treated with an appropriate reagent, preferably the aluminum amide reagent to give amidine 93.
• Scheme 6b illustrates the preparation of the compound of Example 144, which corresponds to a compound for which R 2 is Formula //, and where
• Ar is thiazole and R 8 and R 9 (R 37 and R 38 in Scheme 6b) are phenyl, which can be optionally substituted.
• R 8 and R 9 R 37 and R 38 in Scheme 6b
• R 8 and R 9 are phenyl, which can be optionally substituted.
• treatment with rc-butyllithium produces an anion which undergoes a rearrangement (Kano, S., et al, Heterocycles 20:2035 (1983)).
• Conversion to ester 95 can be carried out by preparation of the acid chloride using oxalyl chloride and treatment of this intermediate acid chloride with an alcohol R 23 - OH in an appropriate solvent, preferably dichloromethane, with an appropriate base, preferably pyridine.
• Compound 95 can be treated with copper (I) cyanide in refluxing dimethylformamide to give compound 96.
• Compound 96 can be treated with hydrogen sulfide gas in an appropriate solvent, preferably methanol, containing an appropriate base, preferably triethylamine to give compound 97.
• Compound 97 can be treated with an appropriate ketone where L is a leaving group, preferably halogen, mesyl, or tosyl, and most preferably bromo, refluxing in a suitable solvent, preferably, acetone, dimethylformamide, dimethyl acetamide, methyl ethyl ketone, or other polar aprotic solvents, and most preferably acetone to give compound 98.
• Compound 98 is treated with an appropriate reagent, preferably the aluminum amide reagent (A1(CH 3 ) 3 NH 4 C1) to give amidine 99.
• Scheme 7a illustrates the preparation of compounds for which R 2 is Formula // and Ar is thiazol-4-yl.
• the acids 13 can be converted to their acid chlorides by treatment with oxalyl chloride with dimethylformamide catalysis in methylene chloride, or by using thionyl chloride, either neat or in an organic solvent, at ambient or elevated temperature.
• Compounds are then homologated to the desired a-haloketones 100 by sequential treatment with trimethylsilyldiazomethane and hydrogen bromide.
• An alternative would be to substitute diazomethane (generated from Diazald ® , Aldrich Chemical Co., Milwaukee, WI) for the trimethylsilyldiazomethane.
• the conversion of 13 to 100 can be effected using the procedure derived for the synthesis of compound 42 from compound 46.
• the alpha-haloketones 100 are then allowed to react with the appropriate thiourea (Scheme 7b) or thioamide derivative in an organic solvent, preferably acetone or dimethylformamide at 70 °C to give 2- amino thiazoles or thiazoles 101.
• the thiazoles 101 can be treated with the aluminum amine reagent (A1(CH 3 ) 3 /NH 4 C1) formed at ambient temperature by the reaction of trimethylaluminum with ammonium chloride in an organic solvent, preferably toluene.
• the ester can then be converted to the amidines 102 at elevated temperatures, preferably higher than 80 °C.
• amines 110 can be converted to their respective mono-substituted thioureas (median- 1- thiones) 112 by treatment with thiophosgene to form the intermediate isothiocyanates 111.
• Preferred conditions include treating the amine with thiophosgene in a biphasic solvent system composed of a halogenated solvent such as chloroform and an aqueous phase of saturated sodium bicarbonate.
• reaction may be effected by treatment of 110 with a hindered amine and thiophosgene such as triethylamine or diisopropylethylamine in an organic solvent such as tetrahydrofuran or methylene chloride.
• a hindered amine and thiophosgene such as triethylamine or diisopropylethylamine in an organic solvent such as tetrahydrofuran or methylene chloride.
• organic solvent such as tetrahydrofuran or methylene chloride.
• isothiocyanates 111 is the direct treatment of primary amines and carbon disulfide in pyridine with dicyclohexylcarbodumide (Jochims, Chem. Ber. 101:11 '46 (1968)).
• Isothiocyanates 111 can be converted to thioureas 112 by treatment with an ammonia-alcohol solution, preferably a 2M ammonia in methanol or ethanol solution, at room temperature or elevated temperatures (>70°C).
• an ammonia-alcohol solution preferably a 2M ammonia in methanol or ethanol solution, at room temperature or elevated temperatures (>70°C).
• Scheme 8 illustrates the preparation of compounds of this invention where R 2 is Formula // and Ar is thiazole and R 37 and R 38 are phenyl which is further substituted by a sulfonylamino or carbonylamino group.
• R 2 is Formula // and Ar is thiazole and R 37 and R 38 are phenyl which is further substituted by a sulfonylamino or carbonylamino group.
• thioamide 10 treatment with a nitro substituted 2-halo-acetophenone, where the halogen is chloro, bromo, or iodo, preferably bromo, refluxing in a suitable solvent, preferably acetone, dimethylformamide, dimethyl acetamide, methyl ethyl ketone, or other polar aprotic solvents, and most preferably acetone.
• the reduction of nitroaryl compound 113 can be carried out with a suitable reducing agent, preferably tin (II) chloride, titanium (II) chloride, iron (III) chloride, lithium metal, sodium metal, catalytic hydrogenation over platinum or palladium catalyst, and most preferably 20% aqueous solution of titanium (III) chloride.
• a suitable reducing agent preferably tin (II) chloride, titanium (II) chloride, iron (III) chloride, lithium metal, sodium metal, catalytic hydrogenation over platinum or palladium catalyst, and most preferably 20% aqueous solution of titanium (III) chloride.
• the acylation of aniline 114 can be carried out with an appropriate acyl compound R 42 L where L is a halogen, preferably chloro, in an appropriate solvent, preferably dichloromethane, containing a base, preferably pyridine, N-methylmo ⁇ holine, or dusopropylethylamine.
• the acylation of aniline 114 is carried out with an activated carboxylic acid compound R 42 COL where L is hydroxy activated with dicyclohexylcarbodumide, ethyl-3-(diethylamino)propylcarbodiimide (ED AC), O-(7-azabenzotriazol- 1 -y ⁇ )-N,N,N ',N -tetramethyluronium hexafluorophosphate (HATU), or pentafluorophenyl.
• L is hydroxy activated with dicyclohexylcarbodumide, ethyl-3-(diethylamino)propylcarbodiimide (ED AC), O-(7-azabenzotriazol- 1 -y ⁇ )-N,N,N ',N -tetramethyluronium hexafluorophosphate (HATU), or pentafluorophenyl.
• the sulfonylation of aniline 114 can be carried out with and appropriate sulfonyl chloride compound R 41 SO 2 L in an appropriate solvent, preferably dichloromethane, containing a base, preferably N-methyl mo ⁇ holine, dusopropylethylamine, or pyridine, most preferably N-methyl mo ⁇ holine, with or without a condensation catalyst, preferable dimethylaminopyridine (DMAP).
• DMAP dimethylaminopyridine
• the amidinylation of compounds 115 and 117 can be carried out with an appropriate reagent, preferably the aluminum amide reagent (A1(CH 3 ) 3 /NH 4 C1).
• Scheme 9 illustrates the preparation of compounds of Formula /, for which one of R 5 and R 6 is a non-hydrogen substituent.
• the amidines 5 are converted to the amidoximes 119 by heating with hydroxy lamine in a suitable solvent such as ethanol.
• the cyanoamidines 120 are prepared by heating the amidines 5 with cyanamide in a suitable solvent such as ethanol. (Huffman, K.R. and Schaeffer, F., J. Amer. Chem. Soc. 25:1812 (1963).
• 5 can be heated with an amine such as methylamine to give the N-alkylated amidines 121.
• Scheme 10 illustrates the preparation of compounds of Formula /, for which one of R 5 and R 6 is a non-hydrogen substituent.
• the amidines 5 are converted to the amidoximes 119 by heating with hydroxy lamine in a suitable solvent such as ethanol.
• the cyanoamidines 120 are prepared by heating the amidines 5 with cyanamide in a suitable solvent such
• Suitable catalysts include any of a number of Pd(0) or Pd(II) salts, such as tetrakis(triphenylphosphino) palladium (0), dichlorobis(acetonitrile)palladium (II) or preferably palladium (II) acetate or tris(dibenzylideneacetone)dipalladium.
• ligands for any given reaction are often compound-dependent and are discussed in detail in the aforementioned references but may include 1,1'- bis(diphenylphosphino)ferrocene (DPPF), l-[2- (diphenylphosphino)ferrocenyljethyl methyl ether (PPF-OMe), or preferably
• BINAP 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl
• Appropriate bases include sodium t-butoxide or preferably cesium carbonate or potassium phoshate.
• Useful solvents include DMF, dioxane, dimethoxyethane or preferably toluene. Conversion of the ester to amidine 128 is carried out in the manner previously described in Scheme lb.
• Scheme 13 illustrates an approach to compounds of Formula / where R 2 is a 2-thiazolylamino and R 3 , Y and Z are as described in Scheme 10.
• amine 47 can be first converted to a thiourea 131 using the various procedures outlined in Scheme 7b. Further reaction of the thiourea with a leaving group-substituted ketone R 37 COCH(L)R 38 , preferably a 2-haloketone as described in Schemes 2f, 2g or 2h, can provide thiazolylaminothiophenes 132 which are then converted to the corresponding amidines 133 by the previously described methodology of Scheme lb.
• Scheme la illustrates an approach to compounds of Formula / where R 2 is a 2-thiazolylamino and R 3 , Y and Z are as described in Scheme 10.
• Trimethylaluminum (2.0 M in toluene, 2 mL) was added dropwise over 10 min to a suspension of ammonium chloride (216 mg) in toluene (2 mL), stirred under N 2 at 0 °C.
• ammonium chloride 216 mg
• toluene 2 mL
• N 2 N 2
• methyl 4-[4-(4-chlorophenyl)(l,3-thiazol- 2-yl)]-5-methylthiothiophene-2-carboxylate 100 mg, Maybridge Chemical Co., Cornwall, U.K.
• Methyl 5-methylthio-4-phenylthiophene-2-carboxylate (100 mg, Maybridge Chemical Company, Cornwall, UK) was treated in a manner similar to that for Example 1, to give 50 mg of 4-phenyl-5-methylthiothiophene-2-carboxamidine as an off-white solid.
• 'H-NMR DMSO-d 6 ; 300 MHz) ⁇ 2.65 (s, 3H), 7.39-7.60 (m, 5H), 8.27 (s, IH), 9.2 (broad s, 4H).
• Mass spectrum MALDI-TOF, m/z: Calcd. for C 12 H I2 N 2 S 2 , 248.4 (M+H), found 249.0.
• Example 6 a) Methyl 5-methylthio-4-(4-(2-naphthyl)(l,3-thiazol-2-yl))thiophene-2- carboxylate: Methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (40 mg, Maybridge Chemical Company, Cornwall, UK) was reacted with 2-bromo-2'- acetonaphthone (1.1 eq) in a manner similar to Example 13 step (a) to give 40 mg of methyl 5-methylthio-4-(4-(2-naphthyl)(l ,3-thiazol-2-yl))thiophene-2-carboxylate.
• the silica was poured onto a sintered glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated.
• the crude product was purified on a 1 mm silica prep plate eluting with 10% methanol/CH 2 Cl 2 to afford 4.4 mg (15% yield) of 4-[4-(3-methoxyphenyl)(l,3-thiazol-2-yl)]-5-methylthiothiophene-2- carboxamidine hydrochloride and 4.2 mg (15% yield) of 4-[4-(3-hydroxyphenyl)(l,3-thiazol- 2-yl)]-5-methylthiothiophene-2-carboxamidine hydrochloride.
• the reaction mixture was quenched by pouring over a slurry of 500 mg of silica in 10 mL of chloroform.
• the silica was poured onto a sintered glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated.
• the crude product was purified on a 2 g silica silica SPE column eluting with 10% methanol/CH 2 Cl 2 to afford 32.5 mg (75% yield) of 5- methylthio-4-(4-phenyl(l ,3-thiazol-2-yl))thiophene-2-carboxamidine hydrochloride.
• the reaction mixture was quenched by pouring over a slurry of 500 mg of silica in 10 mL of chloroform.
• the silica was poured onto a sintered-glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated.
• the crude product was purified on a 1 mm silica prep plate eluting with 10% methanol/CH 2 Cl 2 to afford 12 mg (19% yield) of 5-methylthio-4-[4-(4- nitrophenyl)(l,3-thiazol-2-yl)]thiophene-2-carboxamidine hydrochloride.
• the reaction mixture was quenched by pouring over a slurry of 500 mg of silica in 10 mL of chloroform.
• the silica was poured onto a sintered glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated.
• the crude product was purified on a 1 mm silica prep plate eluting with 10% methanol/CH 2 Cl 2 to afford 47 mg (75% yield) of 4-[4-(3,4- ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine hydrochloride.
• the reaction mixture was quenched by pouring over a slurry of 500 mg of silica in 10 mL of chloroform.
• the silica was poured onto a sintered glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated.
• the crude product was purified on a 1 mm silica prep plate eluting with 10% methanol/CH 2 Cl 2 to afford 32 mg (73% yield) of 4-[4-(4- methoxyphenyl)(l,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine hydrochloride.
• 3',4'-Propylenedioxy-2-bromoacetophenone (0.170 mmol; 28 mg; Maybridge Chemical Co. LTD., Cornwall, U.K.) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and a solid was filtered and purified on a 1 mm silica prep plate eluting with 20%) ethyl acetate/hexane and dried in vacuo to afford 42 mg (59% yield) of methyl 4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5- methylthiothiophene-2-carboxylate.
• reaction mixture was quenched by pouring over a slurry of 500 mg of silica in 20 mL of chloroform.
• the silica was poured onto a sintered glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated to afford 20 mg (50% yield) of 4-[4-(3,4- propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine hydrochloride.
• the reaction mixture was quenched by pouring over a slurry of 5 g of silica in 25 mL of chloroform.
• the silica was poured onto a sintered glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated.
• the crude product was purified on 1 mm silica plates eluting with 10% methanol/CH 2 Cl 2 to afford 63 mg (90% yield) of 4-[4-(3- bromophenyl)( 1 ,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine hydrochloride.
• the reaction mixture was quenched by pouring over a slurry of 5 g of silica in 50 mL of chloroform.
• the silica was poured onto a sintered glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated.
• the crude product was purified on 1 mm silica plates eluting with 10% methanol/CH 2 Cl 2 to afford 17 mg (32% yield) of 4-[4-(4-chloro-3- nitrophenyl)(l ,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine hydrochloride.
• 2-carboxylate 155 mg (0.627 mmol) of methyl 4-(aminothioxomethyl)-5- methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 10 mL of reagent grade acetone. 2-Bromo-l-(4-chloro-3 -methy lphenyl)ethan-l - one (0.658 mmol; 163 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and the reaction mixture was concentrated and dissolved in 50 mL of CH 2 C1 2 .
• reaction mixture was quenched by pouring over a slurry of 5g silica in chloroform.
• the silica was poured onto a sintered glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated to afford 1 17 mg (73% yield) of 4- [4-(4-chloro-3-methylphenyl)(l,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine hydrochloride.
• the reaction mixture was quenched by pouring over a slurry of 5 g of silica in 50 mL of chloroform.
• the silica was poured onto a sintered glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated.
• the crude product was then purified on a 1 mm silica prep plate eluting with 10% methanol/CH 2 Cl 2 with 1% CH 3 COOH.
• the product was then basified with aq. NaOH and extracted with CHC1 3 and concentrated.
• the reaction mixture was quenched by pouring over a slurry of 5 g of silica in 30 mL of chloroform.
• the silica was poured onto a sintered glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated.
• the crude product was then purified on a 2 mm silica prep plate eluting with 10% methanol/CH 2 Cl 2 with 1% NH 4 OH.
• the product was then dissolved in 2 mL of 4N HCl/dioxane and concentrated to afford 45 mg (29% yield) of 4-[4-(2-methoxyphenyl)(l,3-thiazol-2-yl)]-5- methylthiothiophene-2-carboxamidine hydrochloride.
• the reaction mixture was quenched by pouring over a slurry of silica in chloroform.
• the silica was poured onto a sintered glass funnel and washed with a 10% methanol/CH 2 Cl 2 solution and concentrated.
• the crude product was then purified on a 0.5 mm silica prep plate eluting with 10% methanol/CH 2 Cl 2 to afford 32 mg (37% yield) of 4-[4-(2,4-dimethoxyphenyl)(l,3-thiazol-2- yl)]-5-methylthiothiophene-2-carboxamidine hydrochloride.
• l-(3,4-Dimethoxyphenyl)-2-bromoethan-l-one 2 g of l-(3,4- dimethoxyphenyl)ethan-l-one (11.1 mmol) was reacted in a manner similar to Example 15 , step (a), to yield 1.2 g (42% yield) of l-(3,4-dimethoxyphenyl)-2-bromoethan-l-one.
• Example 33 4-(4-Cyclohexyl(l,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine a) Methyl 4-(4-cyclohexyl(l,3-thiazol-2-yl))-5-methylthiothiophene-2- carboxylate: Cyclohexanecarbonyl chloride (300 mg, 2.0 mmol) was treated in a manner similar to that for Example 32 to give 2-bromo-l-cyclohexylethan-l-one. The dry solid (125 mg) was dissolved in acetone (10 ml).
• Example 41 2- ⁇ 2-[2-(5-Amidino-2-methylthio-3-thienyl)-l,3-thiazol-4-yl]phenoxy ⁇ acetic acid a) tert-Butyl 2- ⁇ 2-[2-(5- ⁇ [(tert-butoxy)carbonylamino]iminomethyl ⁇ -2- methylthio-3-thienyl)-l,3-thiazol-4-ylJphenoxy ⁇ acetate: 4-[4-(2- Hy droxypheny 1)(1 ,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine (100 mg, 0.29 mmol) as prepared in Example 196 step (b) was treated in a manner similar to that shown in Example 40 step (c) to give 100 mg (0.22 mmol, 77%) of (tert-butoxy)- N-( ⁇ 4-[4-(2-hydroxyphenyl)(l,3-thiazol-2-yl)]-5-methylthio
• n- butyllithium (20.3 mL, 40.6 mmol, 2M in cyclohexane) was introduced in a dropwise manner. The resulting solution was stirred at -78 °C for 45 min and then allowed to warm up to -60 °C.
• trimethyltin chloride (40.6 mL, 40.6 mmol, 1M in THF) was added dropwise. This solution was stirred at -60 °C for 30 min and then allowed to warm up to room temperature. The THF was removed under vacuum and the residue was treated with H 2 O and extracted with hexane. The hexane layer was evaporated and the residue was dissolved in Et 2 O.
• Methyl 5-methylthio-4-(6-phenyl(2-pyridyl))thiophene-2-carboxylate Methyl 4-(6-bromo(2-pyridyl))-5-methylthiothiophene-2-carboxylate (78 mg, 0.23 mmol) as prepared in previous step, phenylboronic acid (33 mg, 0.27 mmol) and tetrakistriphenylphosphine-palladium (10 mg) were taken in DMF (1 mL). To this solution K 2 CO 3 (75 mg, 0.54 mmol) and H 2 O (0.3 mL) were added and the mixture was stirred and heated at 90 °C for 18h.
• Example 43 5-Methylthio-4-(3-phenylphenyl)thiophene-2-carboxamidine a) Methyl 5-methylthio-4-(3-phenylphenyl)thiophene-2-carboxylate: Methyl 4-( 1,1 -dimethyl- l-stannaethyl)-5-methylthiothiophene-2-carboxylate (200 mg, 0.57 mmol, as prepared in Example 42, step a) and l-bromo-3-phenylbenzene (266 mg, 1.14 mmol) were taken in anhydrous PMF (2 mL).
• Example 44 5-Methylthio-4-[4-(phenylthiomethyl)(l,3-thiazol-2-yl)]thiophene-2-carboxamidine a) Methyl 5-methylthio-4-[4-(phenylthiomethyl)(l,3-thiazol-2-yl)]thiophene- 2-carboxylate: 2-Phenylthioacetyl chloride (1.0 g, 5.4 mmol) was treated in a manner similar to that for Example 32 step (a) to give 2-bromo-l-phenylthiomethylethan-l- one. The dry solid (1.3 g, 5.3 mmol) was dissolved in acetone (25 ml).
• step (c) To a solution of 42 mg (0.094 mmol) of (tert-butoxy)-N-( ⁇ 4-[4-(3- hydroxyphenyl)(l,3-thiazol-2-yl)]-5-methylthio(2-thienyl) ⁇ iminomethyl)carboxamide, prepared in a manner similar to Example 40, step (c), in 2 mL of anhydrous NN- dimethylformamide (DMF) was added potassium iodide (0.006 mmol, 1 mg, Aldrich Chemical Co.), cesium carbonate (0.187 mmol, 61 mg, Aldrich Chemical Co.), and methyl bromoacetate (0.187 mmol, 18 ⁇ L, Aldrich Chemical Co.) and heated to 60 °C overnight.
• potassium iodide 0.006 mmol, 1 mg, Aldrich Chemical Co.
• cesium carbonate (0.187 mmol, 61 mg, Aldrich Chemical Co.
• methyl bromoacetate
• HATU O-(7-azabenzotriazol-l-yl)-l,l,3,3- tetramethyluronium hexafluorophosphate
• HATU 0.5 M, 190 mg
• HOAt l-hydroxy-7- azabenzotriazole
• ethyl piperidine-2-carboxylate 0.5 M; 78 ⁇ L
• dusopropylethylamine (0.233 mmol, 40 ⁇ L
• HATU O-(7-azabenzotriazol-l-yl)-l,l,3,3- tetramethyluronium hexafluorophosphate
• HATU 0.5 M, 190 mg
• HOAt l-hydroxy-7- azabenzotriazole
• pyrrolidine 0.5 M; 42 ⁇ L
• dusopropylethylamine 0.233 mmol, 40 ⁇ L
• HATU O-(7-azabenzotriazol-l-yl)-l,l,3,3- tetramethyluronium hexafluorophosphate
• HATU 0.5 M, 190 mg
• HOAt l-hydroxy-7- azabenzotriazole
• 4-benzyl piperidine 0.5 M; 88 ⁇ L
• dusopropylethylamine (0.185 mmol, 32 ⁇ L
• Example 70 4-(4- ⁇ 3-[2-((3R)-3-Hydroxypiperidyl)-2-oxoethoxy]phenyl ⁇ (l,3-thiazol-2-yl))-5- methylthiothiophene-2-carboxamidine trifluoroacetate
• the reaction mixture was quenched by pouring over a slurry of 10 g of silica in 50 mL of chloroform.
• the silica was poured onto a sintered glass funnel and washed with ethyl acetate and eluting with a 15% methanol/CH 2 Cl, solution and concentrated.
• the crude product was purified on 1 mm silica prep plates eluting with 15% methanol/CH 2 Cl 2 and treated with 4N HCl/dioxane to afford 37 mg (5% yield) of 5- methylthio-4- ⁇ 4-[3-(trifluoromethoxy)phenyl](l,3-thiazol-2-yl) ⁇ thiophene-2-carboxamidine hydrochloride.
• Methyl 5-methylthio-4-[N-(2-oxo-2-phenylethyl)carbamoyl]thiophene-2- carboxylate (39.4 mg, 0.100 mmol, as prepared in Example 79, step (a)) was treated according to the procedure in Example 10, step (b) using 64.2 mg (1.20 mmol) of ammonium chloride in 0.2 mL of toluene and 0.600 mL (1.20 mmol) of 2 M trimethylaluminum in toluene.
• Triethylamine (5.50 mL, 39.5 mmol) was added and hydrogen sulfide gas was bubbled into the solution at a vigorous rate for 5 min and then at a minimal rate (as measured through an outlet oil bubbler) for 5 h with stirring. The gas introduction was stopped and the mixture was capped and stirred for 19 h at room temperature. The mixture was concentrated in vacuo to a yellow solid which was suspended in 10 mL of EtOH, cooled to -20 °C, and filtered washing with 5 mL of cold (-20 °C) EtOH. The resulting solid was dried under suction followed by high vacuum to afford the title compound as a beige solid (1.31 g, 82 %).
• Methyl 4-(4-phenyl-l,3-thiazol-2-yl)thiophene-2-carboxylate 160 mg, 0.531 mmol, as prepared in the previous step
• step (b) was treated according to the procedure in Example 10, step (b) using 284 mg (5.31 mmol) of ammonium chloride in 2.6 mL of toluene and 2.65 mL (5.30 mmol) of 2 M trimethylaluminum in toluene.
• the resulting yellow solid was dissolved in 20 mL of anhyd CH 2 C1 2 , cooled (0°C) and 1.85 mL of NN-diisopropylethylamine (10.6 mmol) and 1.02 g (7.41 mmol) of phenylglycinol was added and the mixture stirred for 1 h at room temperature.
• the mixture was concentrated to an oil and partitioned between 200 mL of EtOAc and 200 mL of saturated ⁇ aHCO 3 .
• the organic phase was washed with saturated NaHCO 3 (200 mL), 10 % (w/v) citric acid, and brine (200 mL), and dried over Na 2 SO 4 .
• step (a) 3-(Chlorocarbonyl)-6-methoxyphenyl acetate: Using the procedure in Example 85, step (a), 400 mg (1.90 mmol) of 3-acetyloxy-4-methoxybenzoic acid (as prepared in the previous step) was treated with 663 mL (7.60 mmol) of oxalyl chloride and 25 mL of anhyd DMF for 2 h to afford, after workup, the title compound as a beige crystalline solid which was used in the following step without further purification.
• step (a) 400 mg (1.90 mmol) of 3-acetyloxy-4-methoxybenzoic acid (as prepared in the previous step) was treated with 663 mL (7.60 mmol) of oxalyl chloride and 25 mL of anhyd DMF for 2 h to afford, after workup, the title compound as a beige crystalline solid which was used in the following step without further purification.
• Example 85 step (b), the entire sample of 3-(chlorocarbonyl)-6-methoxyphenyl acetate (as prepared in the previous step) in 5 mL of anhyd CH 2 C1 2 was treated with 2.09 mL (4.18 mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane and 456 mL (2.28 mmol) of 30 wt % HBr in acetic acid. Chromatography as in Example 85, step (b) followed by recrystallization from CH 2 Cl 2 -hexane afforded the title compound as a faintly yellow solid (366 mg. 67 %).
• step b To 100 mg (0.302 mmol) of 5-methylthio-4-(4-phenyl( 1 ,3-thiazol-2- yl))thiophene-2-carboxamidine (as prepared in Example 10, step b) in 3 mL of EtOH was added 29.6 mg (0.604 mmol) of cyanamide as a solution in 0.3 mL of water. The mixture was heated to reflux and 0.302 mL (0.302 mmol) of 1 M aqueous KOH was added. After 3 h, the mixture was cooled (0°C) and filtered washing with ice-cold EtOH. The resulting solid was dried in vacuo to afford the title compound as a light yellow powder (78.4 mg, 73 %).
• the resulting solution was extracted with saturated NaHCO 3 (4 x 30 mL) and the combined aqueous extracts acidified to pH 1 -2 with cone HCI and filtered to provide a light tan solid.
• dissolving the solid in a minimum of 1 M K 2 CO 3 (35- 40 mL) and filtering (washing with 10-20mL of water) to clarify the solution it was slowly acidified to pH 6.5-7.0 with stirring and filtered (Celite) to remove a brown precipitate.
• the pH adjustment and filtration was repeated and the resulting solution was saturated with solid NaCl and acidified to pH 1 -2 with cone HCI.

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