ZA200106849B - Heteroaryl amidines, methylamidines and guanidines as protease inhibitors. - Google Patents

Heteroaryl amidines, methylamidines and guanidines as protease inhibitors. Download PDF

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ZA200106849B
ZA200106849B ZA200106849A ZA200106849A ZA200106849B ZA 200106849 B ZA200106849 B ZA 200106849B ZA 200106849 A ZA200106849 A ZA 200106849A ZA 200106849 A ZA200106849 A ZA 200106849A ZA 200106849 B ZA200106849 B ZA 200106849B
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carboxamidine
amino
methylthiothiophene
methylthio
thiophene
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ZA200106849A
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Carl R Illig
Nalin L Subasinghe
James B Hoffman
Kenneth J Wilson
M Jonathan Rudolph
Juan Jose Marugan
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Dimensional Pharm Inc
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • 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

Description

HETEROARYL AMIDINES, METHYLAMIDINES AND GUANIDINES AS PROTEASE INHIBITORS
Background of the Invention Field of the Invention
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).
Related Art
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. These disease states include emphysema, rheumatoid arthritis, corneal ulcers and glomerular nephritis. (Barret, in Enzyme Inhibitors as Drugs, Sandler, ed., University Park Press,
Baltimore, (1980)). Additional proteases such as plasmin, C-1 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-1 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.
Cleavage of the peptide bond in plasminogen by urokinase ("plasminogen activation") results in the formation of a potent general protease, plasmin. Many cell types use 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)). Cells exist, move, and interact with each other in tissues and organs within the physical framework provided by the ECM and BM. Movement of cells within the ECM or across the BM requires local proteolytic degradation or modification of these structures, allowing cells to "invade" into adjacent areas that were previously unavailable.
Central to the ability of urokinase to mediate cellular migration and invasiveness is the existence of specific high affinity urokinase receptors (uPARSs) 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. 104:801-804 (1987); Roldan, AL, et al, EMBO J. 9:467-74 (1990)). The binding interaction is apparently mediated by the EGF-like domain (Rabbani, S.A., et al, J. Biol. Chem. 267:14151-56 (1992)). Cleavage of pro-uPA into active uPA is accelerated when pro-uPA and plasminogen are receptor-bound. Thus, plasmin activates pro-uPA, which in turn activates more plasmin by cleaving plasminogen. This positive feedback cycle is apparently limited to the receptor-based proteolysis on the cell surface, since a large excess of protease inhibitors is found in plasma, including a, antiplasmin, PAI-1 and
PAI-2. High plasmin concentrations between invasive cells and ECM or BM are necessary in order to overcome inhibitory effect of these ubiquitous plasmin inhibitors. Thus, it is cell surface receptor-bound urokinase, and not simply free urokinase secreted by cells, which plays the predominantrole in initiating cellular invasiveness.
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. Cell Biol. 104:801 -804 (1987); Dane, K., er al. , Adv. Cancer Res.44:139- 266 (1985); Littlefield, B.A., Ann. N.Y. Acad. Sci. 622:167-175 (1991); Saksela,
O., Biochim. Biophys. Acta 823:35-65 (1985); Testa, J.E., and Quigley, 1.P.,
Cancer Metast. Rev. 9:353-367 (1990). 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.
Beneficial effects of urokinase inhibitors have been reported using anti- urokinase monoclonal antibodies and certain other known urokinase inhibitors.
For instance, anti-urokinase monoclonal antibodies have been reported to block tumor cell invasiveness in vitro (Hollas, W., et al., Cancer Res. 51:3690-3695, (1991); Meissauer, A., ef al., Exp. Cell Res. 192:453-459 (1991)), tumor metastasis and invasion in vivo (Ossowski, L., J. Cell Biol. 107:2437-2445 (1988); Ossowski, L., ef al.,J. Cancer Res. 51:274-81 (1991)), and angiogenesis in vivo (Jerdan, J. A. et al., J. Cell Biol. 115(3 Pt 2]:402a (1991)). In addition, amiloride, a known urokinase inhibitor of only moderate potency, has been reported to inhibit tumor metastasis in vivo (Kellen, J.A., et al., Anticancer Res. 8:1373-1376 (1988)) and angiogenesis/capillary network information in vitro (Alliegro, M.A, et al., J. Cell Biol. 115[3 Pt 2]:402a (1991)).
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)). 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)).
A need continues for non-peptidic compounds that are potent and selective urokinase inhibitors, and which possess greater bioavailability and fewer side-effects than currently available urokinase inhibitors. Accordingly, new classes of potent urokinase inhibitors, characterized by potent inhibitory capacity and low toxicity, are potentially valuable therapeutic agents for a variety of conditions. : Summary of the Invention
The present invention is broadly directed to the use of heteroaryl amidines, methylamidines and guanidines having Formula I (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. For example, 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.
Also provided are methods to inhibit extracellular proteolysis, methods to treat benign prostatic hypertrophy, prostatic carcinoma, tumor metastasis, psoriasis, and other conditions by administering the compound of Formula I.
A number of the heteroaryl compounds described herein are novel compounds. Therefore, the present invention is also directed to novel compounds of Formula I.
Further provided are pharmaceutical compositions comprising a compound of Formula I and one or more pharmaceutically acceptable carriers or diluents and said pharmaceutical compositions further comprising a thrombolytic agent such as tissue plasminogen activator and streptokinase.
Further provided are methods of synthesizing compounds of Formula I.
Detailed Description of the Preferred Embodiments
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 I: 2
R! all
NR or a solvate, hydrate or pharmaceutically acceptable salt thercof; wherein:
Xis 0, S or NR’, where R’ is hydrogen, alkyl, aralkyl, hydroxy (C,.,)alkyl, or alkoxy(C,.»alkyl;
Y is a direct covalent bond, CH, or NH; 7 is NR°R®, hydrogen or alkyl, provided that Y is NH whenever Z is hydrogen or alkyl;
R' is hydrogen, amino, hydroxy, halogen, cyano, C,, alkyl or —-CH,R, where R is hydroxy, amino or C, ; alkoxy;
R? and R’ are independently: 1. hydrogen; 1. halogen; iii. hydroxy; v. nitro; v. cyano;
vi. amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocycleamino, diheterocycleamino, monoalkylmonoheterocycleamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, di(aralkylsulfonyl)amino, di(aralkenylsulfonyl)amino, di(arylsulfonyl)amino, or di-(heteroarylsulfonyl)amino, formylamino, alkanoylamino, alkenoylamino, alkynoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroaralkanoylamino, H(S)CNH-, or thioacylamino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring and wherein any of the heterocycle containing groups can be optionally ring substituted,
Vil. aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, aminoacyl, monoarylaminocarbonyl, diarylaminocarbonyl or monoalkylmonoarylaminocarbonyl; viii. aminothiocarbonyl, monoalkylaminothiocarbonyl, diatkylaminothiocarbonyl, thioacyl or aminothioacyl; 1X. aminocarbonylamino, mono- and dialkylaminocarbonylamino, mono- and diarylaminocarbonylamino, or mono- and diaralkylaminocarbonylamino;
X. aminocarbonyloxy, mono- and dialkylaminocarbonyloxy, mono- and diarylaminocarbonyloxy, mono- and diaralkylaminocarbonyloxy;
Xl. aminosulfonyl, mono- and dialkylaminosulfonyl, mono- and diarylaminosulfonyl, or mono- and diaralkylaminosulfonyl; xii. alkoxy, or alkylthio, wherein the alkyl portion of each group may be optionally substituted, xiii. aralkoxy, aryloxy, heteroaryloxy, aralkylthio, arylthio, or heteroarylthio, wherein the aryl portion of each group can be optionally substituted;
xiv. alkylsulfonyl, wherein the alkyl portion can be optionally substituted;
XV. aralkylsulfonyl, aralkenylsulfonyl, arylsulfonyl or heteroarylsulfonyl, wherein the aryl portion of each group can be optionally substituted; xvi. alkenyl, or alkynyl; xvii. optionally substituted aryl; xviii. optionally substituted alkyl; xix. optionally substituted aralkyl;
XX. optionally substituted heterocycle; or xxi. optionally substituted cycloalkyl; and
R®, R® and R® are independently hydrogen, C, , alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C, ,)alkyl, dialkylamino(C, ,)alkyl, carboxyalkyl, cyano, amino, alkoxy, or hydroxy, or -CO,R¥, where
RY is alkyl, cycloalkyl, phenyl, benzyl,
Rl o ho RM
Pi =o or hig 0) RI ©
Rd Re where R¢ and R® are independently hydrogen, C, 4 alkyl,
C,, alkenyl or phenyl, R' is hydrogen, C, alkyl, Cy alkenyl or phenyl, R® is hydrogen, C, , alkyl, Cy alkenyl or phenyl, and R" is aralkyl or C, ¢ alkyl.
The present invention is also directed to novel compounds of Formula I, where X, Y and R'-R® are as defined above; provided that at least one of R? or R’ is selected from the group consisting of: (a) an optionally substituted alkyl group, preferably C,-C, alkyl, more preferably C,-C;; (b) alkoxy, aryloxy, alkylthio or arylthio, any of which is optionally substituted;
(c) optionally substituted C-C,, aryl, or optionally substituted aralkyl, except that R? is not nitrophenyl or aminophenyl, when R' and R? are both hydrogen or methyl; (d) optionally substituted heterocycle; and (e) optionally substituted cycloalkyl.
When an alkyl-containing group, heterocyclic-containing group or aryl- containing group of R? or R? is optionally substituted, the optional substituents can be 1 to 4 non-hydrogen substituents, provided that the resulting compound is stable. 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, arylsulfonylamino, aralkylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, mono- or di- alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio.
Preferred values of optional substituents on an alkyl group are chloro, hydroxy, amino, mono(C, ,)alkylamino, di(C,,)alkylamino, formylamino, C, acylamino, aminocarbonyl, C, ; aminoacyl, C, ; alkoxy, Cq_,, aryloxy, carboxy, carboxy(C, s)alkyl, C,, alkoxycarbonyl, nitro, cyano, trifluoromethyl, C, alkylthio, Cg.,,arylthio, C, ¢alkylsulfonylamino, C, ,; aralkylsulfonylamino, Cg ,, arylsulfonylamino, mono- or di(C, ;)alkylaminocarbonyloxy, mono- or di- (Cq.10)arylaminocarbonyloxy, mono- or di(C, )aralkylcarbonyloxy, C,, alkoxycarbonylamino, C,-C,s; aralkoxycarbonylamino, and C,-C,, aryloxycarbonylamino.
Preferred values of optional substituents on aryl-containing and heterocyclic-containing groups include chloro, hydroxy, amino, mono(C,,) alkylamino, di(C,_,)alkylamino, formylamino, C, ; acylamino, aminocarbonyl, C, aminoacyl, C,, cycloalkyl, C,4 alkyl, C,, alkoxy, C,,, aryloxy, carboxy,
carboxy(C, 4)alkyl, C,; alkoxycarbonyl, nitro, cyano, trifluoromethyl, C, alkylthio, C¢_, arylthio, Cy, aryl, substituted phenyl, tetrazolyl, thienyl (further optionally substituted by one, two or three of chloro, hydroxy, C,, alkyl, C,, alkoxy, amino or carboxy), 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, C,4 alkylsulfonylamino, C, aralkylsulfonylamino, Cis arylsulfonylamino, C,, alkyl/sulfonyl, Cg, arylsulfonyl, mono- or di(C, ¢)alkylaminocarbonyloxy, mono- or di- C;_,, arylaminocarbonyloxy, mono- or di-(C, s)aralkylcarbonyloxy, C,, alkoxycarbonylamino, C,-C,; aralkoxycarbonylamino, C,-C,, aryloxycarbonylamino, C,, thioacylamino, aminothiocarbonyl, and C, ; aminothioacy]l.
Preferred values of R' include hydrogen, amino, hydroxy and fluoro.
A preferred value of R? is Formula IT:
R® as : — SR? where Ar is phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), pyrrolyl, oxazolinyl and benzothienyl.
Preferred values of R’ include C, , alkyl (optionally substituted), halogen, amino, acylamino, C, alkylthio (such as methylthio or ethylthio), C, , 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.
Preferred values of R*, R’ and R® in Formula I are hydrogen, hydroxy, cyano, C,¢ alkyl, or C, alkoxy. Suitable values of R*, R*® and R® include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, and ethoxy. In the most preferred embodiments, R*, R® and R® are each hydrogen.
Preferred values of R*, R® and R® in Formula J also include prodrugs such as —-CO,R™, where RY", in each instance, is preferably one of C, alkyl,
C,..cycloalky! or benzyloxycarbonyl. Suitable values of R*, R® and R® include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, -CO,CH,, -CO,CH,CH, and -CO,CH,CH,CH,. In the most preferred embodiments, R*, R® and R® are each hydrogen.
Also preferred at R*, R® and R® is the group —CO,R*, where R is one of
Rf o) ho RP
LL =o or hg lo} RI. ©
Rd Re where R%-R" are defined as above. When R*, R® and R® are -CO,R", where R¥ 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 RY, R® and R® is hydrogen, R' is methyl, and preferred values for R" include benzyl and rert-butyl.
Preferred values of R” include hydrogen, C, 4 alkyl, C,_,, ar(C, ,)alkyl, and
C, hydroxyalkyl. Suitable values are hydrogen, methyl, ethyl, and benzyl.
The term "alkyl" as employed herein by itself or as part of another group refers to both straight and branched chain radicals of up to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, r-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.
The term "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. Preferably, 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.
The term "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.
Preferably, the alkynyl 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.
In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly attached to a nitrogen, oxygen or sulfur moiety.
The term "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 atorns, 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.
Preferably the alkylthio chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
The term "alkoxy" 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 an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
The term "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.
The term "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.
The term "acyl" as employed herein by itself or as part of another group refers to the group -C(O)R® 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® where R¥ is C,, alkyl, C_,, aryl(C, alkyl or Cg, aryl).
The term "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, ; alkyl.
The term "thiocarbonyl" as employed herein by itself or as part of another group refers to the group -C(S)-.
The term "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.
The term "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
The term "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.
The term "aralkyl" or "arylalkyl" as employed herein by itself or as part of another group refers to C, calkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
The terms "heterocyclic," "heterocyclo” or "heterocycle" as employed herein by themselves or as part of larger groups 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. Especially useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-
oxoazepinyl, azepinyl, pyrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl. imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
The term "heteroatom" is used herein to mean an oxygen atom ("0"), a sulfur atom ("S") or a nitrogen atom ("N"). It will be recognized that when the heteroatom is nitrogen, it may form an NRYR? moiety, wherein R’ and R? are, independently from one another, hydrogen or C, to Cj alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7- membered ring.
The term “heteroaryl” as employed herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14 7 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, xantheny!, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, B-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazoly], phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups).
The expression "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*, R® and/or R® are
—CO,R™, where R* is defined above. See, U.S. Patent No. 5,466,811 and Saulnier et al., Bioorg. Med. Chem. Lett. 4:1985-1990 (1994).
The term "substituted", as used herein, 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. When a substituent is keto (1.e., =0), then 2 hydrogens attached to an atom of the moiety are replaced.
By "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 J wherein X is sulfur or oxygen,
Y is a covalent bond or -NH-; R' is hydrogen, amino, hydroxy or halogen; R*, R° and R® are independently hydrogen, C,, alkyl, amino, cyano, C,, alkoxy or hydroxy, and are preferably all hydrogen; one of R? or R’ is hydrogen, C, , alkyl (optionally substituted with hydroxy, amino, carboxy or aminocarbonyl), C, alkylthio or C,4 alkoxy; and the other of R? or R® is aminoacyl, acylamino, aminosulfonyl, sulfonylamino, aminocarbonylamino, alkoxycarbonylamino, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted benzothienyl, optionally substituted furanyl. optionally substituted pyrazolyl or optionally substituted pyridyl.
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; 4-(4-methylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine; methyl 4-[4-(4-phenylphenyl)thiazol-2-yl}-5-methylthiothiophene-2-carboxylate; 4-[4-(3-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine, 4-[4-(3-hydroxyphenylthiazol-2-yl]-5-methylthiothiophene-2-carboxamidine, 4-(4-phenylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine,
4-[4-(4-nitrophenyl)thiazol-2-y1]-5-methylthiothiophene-2-carboxamidine, 4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-y1}-5-methylthiothiophene-2- carboxamidine, 4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2- carboxamidine,
4-[4-(4-(naphth-2-yl)thiazol-2-y1]-5-methylthiothiophene-2-carboxamidine, 4-isopropylsulfonyl-5-methylthiothiophene-2-carboxamidine; 4-phenyl-5-mcthylthiothiophene-2-carboxamidine; 4-[4-(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine; 4-[4-(4-phenylphenyljthiazol-2-y1]-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine; 4-(2-naphthylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine; 4-[4-(4-chloro-3-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2- carboxamidine; 4-(5-methyl-4-phenylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-chloro-3-nitrophenyl)thiazol-2-yl]-5-methylthiothiophene-2- carboxamidine; 4-(5-phenyloxazol-2-yl)-5-methylthiothiophene-2-carboxamidine; 4-[4-(3-fluoro-5-trifluoromethylphenyl)-5-methylthiazol-2-yl]-5- methylthiothiophene-2-carboxamidine;
4-[4-(3,5-bis(trifluoromethyl)phenyl)-5-methyl-thiazol-2-yl]-5- methylthiothiophene-2-carboxamidine; 4-[4-(3-fluoro-5-triflucromethylphenyl)thiazol-2-y1]-5-methylthiothiophene-2- carboxamidine; 4-[4-(3-bromophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3,4-methylenedioxyphenyl)thiazol-2-y1]-5-methylthiothiophene-2- carboxamidine; 4-[4-(4-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine; 4-[4-(3,5-bis(tnfluoromethyl)phenyl)thiazol-2-yl]-5-methylthiothiophene-2- carboxamidine;
4-[4-(2-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-(4-phenylimidazol-2-yl)-5-methylthiothiophene-2-carboxamidine; 4-[4-(2,4-dimethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2- carboxamidine; 4-(4-benzylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine; 4-[4-(3,4-dichlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3-methylphenyl)thiazol-2-yl]-S-methylthiothiophene-2-carboxamidine; 4-[4-(3,5-dimethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2- carboxamidine; 4-[4-(2-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine; 4-[4-(2,5-dimethoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-
carboxamidine; 4-(4,5-diphenylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine; 4-(2-phenyl)thiazol-4-yl-5-methylthiothiophene-2-carboxamidine; 4-[4-(2-chloro-3-pyridyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine; 4-[4-(phenoxymethyl)thiazol-2-y1]-5-methylthiothiophene-2-carboxamidine;
4-(4-cyclohexylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine; 4-[4-(4-chlorophenyl)thiazol-2-yl}-5-methylthiothiophene-2-carboxamidine; 4-[4-(2-hydroxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine; 4-[4-(3-trifluoromethoxyphenyl)thiazol-2-yl}-5-methylthiothiophene-2- carboxamidine;
4-[4-(2-chloro-4-pyridyl)thiazol-2-yl]}-5-methylthiothiophene-2-carboxamidine; 4-(5-phenyl-2-pyridyl)-5-methylthiothiophene-2-carboxamidine; 4-[2-(2-chlorophenylamino)thiazol-4-yl]-5-methylthiothiophene-2- carboxamidine; 4-[2-(3-methoxyphenylamino)thiazol-4-yl]-5-methylthiothiophene-2-
carboxamidine; 4-[2-(phenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine; 4-[2-(2,5-dimethoxyphenylamino)thiazol-4-yl]-5-methylthiothiophene-2- carboxamidine; 4-(2-aminothiazol-4-yl)-5-methylthiothiophene-2-carboxamidine;
4-[2-(4-chloro-2-methylphenylamino)thiazol-4-y1]-5-methylthiothiophene-2- carboxamidine; 4-[2-(4-dimethylaminophenylamino)thiazol-4-yl]-5-methylthiothiophene-2- carboxamidine; 4-[2-(4-methoxyphenylamino)thiazol-4-y1]-5-methylthiothiophene-2-
carboxamidine; 4-[4-(4-hydroxy-3-methoxyphenyl)thiazol-2-y1]-S-methylthiothiophene-2- carboxamidine; 4-[4-(3-hydroxy-4-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2- carboxamidine;
4-[2-(2-fluorophenylamino)thiazol-4-yl]-5 -methylthiothiophene-2- carboxamidine; 4-[2-(2,4,5-trimethylphenyl)aminothiazol-4-yl] -5-methylthiothiophene-2- carboxamidine; 4-[2-(3-chloro-2-methylphenyl)amindthiazol-4-y1]-S-methylthiothiophene-2-
carboxamidine; 4-[2-(2-isopropylphenyl)aminothiazol-4-yl]-S-methylthiothiophene-2- carboxamidine; 4-[2-(4-benzyloxyphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2- carboxamidine;
4-[2-(2-bromophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2- carboxamidine; 4-[2-(2,5-dichlorophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2- carboxamidine; 4-[2-(2-bromo-4-methylphenyl)aminothiazol-4-y!]-S-methylthiothiophene-2-
carboxamidine; 4-[2-(2,3-dichlorophenyl)aminothiazol-4-y1]-5-methylthiothiophene-2- carboxamidine;
4-[2-(3 ;4,5-trimethoxyphenyl)aminothiazol-4-yl]-5-methylthiothiophene-2- carboxamidine;
4-[2-(2-piperidinylethyl)aminothiazol-4yl}-5-methylthiothiophene-2- carboxamidine; 4-[2-(4-methylphenyl)aminothiazol-4-yl}-5-methylthiothiophene-2- carboxamidine; 4-(4-phenyloxazol-2-yl)-5-methylthiothiophene-2-carboxamidine; 4-[2-(diphenylmethyl)aminothiazol-4-yl]-5-methylthiothiophene-2- carboxamidine; and 4-[2-(3-phenylpropyl)aminothiazol-4-yl]-5-methylthiothiophene-2- carboxamidine, as well as pharmaceutically acceptable salts thereof, for example the hydrochloride, hydrobromide and acetate salts thereof, or a prodrug thereof.
A second preferred group of compounds falling within the scope of the present invention include compounds of Formula I wherein X is sulfur or oxygen;
Y is a covalent bond or -NH-; Z is NR°R® R'is hydrogen, amino, hydroxy or halogen; R*, R® and R® are independently hydrogen, C, , alkyl, amino, C,_, alkoxy or hydroxy, and are preferably all hydrogen; one of R? or R’ is hydrogen, C, alkylthio, C,, alkyl optionally substituted with OH, NH,, COOH or aminocarbonyl, or C, ; alkoxy; and the other of R? or R? is:
R® — u
R® where:
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, benzothieny!, benzimidazoly!, 1,3-oxazolidin-2-onyl, imidazolin- 2-onyl (preferably phenyl, thiazolyl, thiazolinyl, oxazolinyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, oxazoliny! and benzothienyl), any of which can optionally include an exocyclic = O (keto) or =
NR" (imino) group, where RY is alkyl, aryl, aralkyl, alkylamino, arylimino or aralkylimino; and
R® and R® are independently selected from the group consisting of hydrogen, halogen, amino, mono(C, ,)alkylamino, di(C, ,)alkylamino, arylamino, mono- and di- (C4 )arylamino, mono- and di-(C ,)ar(C,)alkylamino, formylamino, C, ;acylamino, aminocarbonyl, C, 4 aminoacyl, C,.¢ thioacylamino, aminothiocarbonyl, C,, aminothioacyl, C, alkyl, C, cycloalkyl, C, , alkoxy, carboxy, carboxy(C, (alkyl, C, 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, 1,3-oxazolidin-2-onyl, imidazolin-2-onyl, Cg, aryloxy, C, 4 alkylthio, Cy, arylthio, C_,, aryl, or C,_,, ar(C, ¢)alkyl, wherein the aforementioned heteroaryl groups and the aryl portions of Cg, aryloxy, mono- and di C;,, aryl amino, mono- and di- Cea ar(C, ¢)alkylamino, C, ,, arylthio, Cq.,, ar(C, c)alkyl, and C,,, aryl can be further optionally substituted, preferably by one, two or three of halogen, hydroxy, amino, mono(C, ,)alkylamino, di(C, ,)alkylamino, formylamino, C, ,acylamino,
C,.,aminoacyl, mono- or di-(C,,)alkylaminocarbonyl, thiocarbonylamino,
C,thioacylamino, aminothiocarbonyl, C, ,alkoxy, C ,aryloxy, aminocarbonyloxy, mono- or di(C,,)alkylaminocarbonyloxy, mono- or di(Cs. g)arylaminocarbonyloxy, mono- or di(C,.,s)aralkylaminocarbonyloxy, C,. salkylsulfonyl, Cg jsarylsulfonyl, (C,. s)aralkylsulfonyl, C, ,alkylsulfonylamino,
Cs.1parylsulfonylamino, (C,.s)aralkylsulfonylamino, aminosulfonyl, mono- and di-alkylaminosulfonyl, mono- and di-arylaminosulfonyl, mono- and di- aralkylaminosulfonyl, C, , alkoxycarbonylamino, C, saralkoxycarbonylamino,
Cs.paryloxycarbonylamino, mono- or di-(C,,)alkylaminothiocarbonyl, C,, isaralkoxy, carboxy, carboxy(C, alkyl, C, alkoxycarbonyl, C,. salkoxycarbonylalkyl, carboxy(C, alkoxy, alkoxycarbonylalkoxy, nitro, cyano, trifluoromethyl, C, ,alkylthio and Cq,arylthio, or by 3,4-methylenedioxy, 3,4- ethylenedioxy, and 3,4-propylenedioxy.
Preferred values of R® and R® are halogen, C, 4 alkyl, C, ¢ alkoxy, hydroxy, nitro, trifluoromethyl, C,_,, aryl (further optionally substituted by one or two of chloro, halogen, C, , alkyl, C, ¢ alkoxy, hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ecthylenedioxy, 3,4-propylenedioxy, or amino), 4-phenylphenyl (biphenyl), C,, aminoalkyl, carboxy, C,. alkyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, amino, C, alkanoylamino, C,_,, aroylamino, C, ; hydroxyalkyl, thieny! (further optionally substituted by onc or two of chloro, amino, methyl, methoxy, or hydroxy) and tetrazolyl. More preferably, R? is thienyl, oxazolyl, or thiazolyl, optionally substituted by any of the aforementioned groups.
Examples of preferred R® and R® 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, naphth-Z-yl, 3-phenyl-4-(tetrazol-5-yl)phenyl, 2,4-dichlorophenyl), 4-phenylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-phenylphenyl, phenylthiomethyl, 2-chloro-4,5-dimethoxyphenyl, 4-chioro-3- methylphenyl, 5-methyl-4-phenyl, 4-chloro-3-nitrophenyl, 3-fluoro-5-trifluoromethylphenyl, 3,5-bis(trifluoromethyl), 3-fluoro-5- trifluoromethylphenyl, 3-bromophenol, 3,4-methylenedioxyphenyl, 4-methylphenyl, 3-methylphenyl, 3,5-bis(trifluoromethyl)phenyl, 2-methoxyphenyl, 6-phenyl-2-pyridyl, 2,4-dimethoxyphenyl, 3,4- dimethoxyphenyl, benzyl, 3,4-dichloropheny!l, 3-methylphenyl, 3,5- dimethoxyphenyl, 2-methylphenyl, 2,5-dimethoxyphenyl, 2-chloro-3-pyridyl, phenoxymethyl, cyclohexyl, 2-hydroxyphenyl, 3-trifluoromethoxyphenyl, 2- chloro-4-pyridyl, 3-chloro-4-pyridyl, 2-chlorophenylamino, 3- methoxyphenylamino, phenylamino, 2,5-dimethoxyphenylamino, amino, 4- chloro-2-methylphenylamino, 4-dimethylaminophenylamino, 4-methoxyphenylamino, 4-hydroxy-3-methoxyphenyl, 3-hydroxy-4- methoxyphenyl, 2-fluorophenylamino, 2,4,5-trimethylphenylamino, 3-chloro-2- methylphenylamino, 2-isopropylphenylamino, 4-benzyloxyphenylamino, 2-
bromophenylamino, 2,5-dichlorophenylamino, 2-bromo-4-methylphenylamino, 2,3-dichlorophenylamino, 3,4,5-trimethoxyphenylamino, 2-piperidinylethylamino, 4-methylphenylamino, 2-thienyl, 2-5.6,7,8- tetrahydronaphthyl, 3-(2-phenoxyacetic acid)phenyl, 2-(2-phenoxyacetic acid)phenyl, diphenylmethylamino, 3-phenylpropylamino, 3-phenylphenyl, phenylthiomethyl, 2-chloro-4,5-dimethoxyphenyl, and isopropyl.
A third preferred group of compounds are those of Formula I wherein:
X 1s sulfur;
Y is a covalent bond;
Z is NR°RS;
R'is hydrogen;
R’ is methylthio or methyl;
R*, R?® and R® are all hydrogen; and
R? is Formula II, where Ar is phenyl, thiazolyl, oxazoly], benzothienyl, pyridyl, or imidazolyl; arid R® and R°® are independently hydrogen, or C4. aryl or heterocycle, optionally substituted by one, two or three of chloro, hydroxy, C, alkyl, C; (cycloalkyl, C, 4 alkoxy, amino, carboxy, phenyl, naphthyl, biphenyl, hydroxyphenyl, methoxyphenyl, dimethoxyphenyl, carboxyalkoxyphenyl, alkoxycarbonylalkoxy, carboxyethoxy, alkylsulfonylaminophenyl, arylsulfonylaminophenyl, acylsulfonylaminopheny], aralkylsulfonylaminophenyl, heteroarylsulfonylaminopheny! where the heteroaryl portion is optionally halo or C, calkyl substituted, chlorophenyl, dichlorophenyl, aminophenyl, carboxyphenyl, nitrophenyl, or by 3,4-methylenedioxy, 3,4- ethylenedioxy, and 3,4-propylenedioxy.
A fourth preferred group of compounds are those of Formula I wherein:
X is sulfur;
Y is a direct covalent bond;
Z is NR°R®;
R'is hydrogen;
R? is alkyl, ar(alkyl), alkylsulfonyl, -S0,-alkyl, amido, amidino, or
RS
| i
R? where
Ar is an aromatic or heteroaromatic group selected from the group consisting of phenyl, thiazolyl, oxazolyl, imidazolyl and pyridyl;
R® and R’ 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. each of said 1 to 3 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, —-S0,-aryl, or aryl;
R? is -SO,-alkyl, trifluoromethyl, S(O)-alkyl, hydrogen, alkoxy, alkylthio, alkyl, aralkylthio; and
R%, R?, R® 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® and R® is substituted phenyl, most preferably on the 4-position of the thiazol-2-yl group.
Also preferred are compounds where R? is a 4-phenylthiazol-2-yl group wherein said phenyl is further optionally substituted. and R* is methylthio.
A fifth preferred group of compounds are those of Formula I71:
oO ya — CN "
Spr
ZN
\S / ar
RaW
A S
NH, or a pharmaceutically acceptable salt or prodrug thereof, where
A is methylthio or methyl;
G' 1s ~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, .aryl, C,ar(C, alkyl, acyl, alkoxycarbonyl or benzyloxycarbony!.
Most preferred compounds of Formula ITT are those for which R'and R", taken together with the N atom to which they are attached, form a ring selected from piperazinyl, pyrrolidinyl, piperidinyl or morpholinyl, which are further optionally substituted with 1 to 4 non-hydrogen substituents selected from halogen, hydroxy, amino, monoalkylamino, dialkylamino, formylamino, acylamino, aminoacyl, mono- or di- alkylaminocarbonyl, thiocarbonylamino, thioacylamino, aminothiocarbonyl, alkoxy, aryloxy, aminocarbonyloxy, mono- or di-alkylaminocarbonyloxy, mono- or diarylaminocarbonyloxy, mono- or diarakylaminocarbonyloxy, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,
alkylsulfonylamino, arylsulfonylamino, arakylsulfonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, mono- or di- alkylaminothiocarbonyl, aralkoxy, carboxy, carboxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, nitro, cyano, trifluoromethyl, alkylthio and arylthio, where each of these substituents has the preferred values set forth for Formulae I and 11 above.
Examples of preferred compounds of Formula IIT include: 5-methylthio-4-[4-(3-{[N-(2-morpholin-4- ylethyl)carbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2- carboxamidine, 5-methylithio-4-{4-[3-(2-morpholin-4-yl-2-oxoethoxy)phenylj(1,3-thiazol-2- yl)}thiophene-2-carboxamidine, 5-methylthio-4-{4-[3-(2-ox0-2-piperazinylethoxy)phenyl](1,3-thiazol-2- yl)}thiophene-2-carboxamidine, 4-[4-(3-{[N-(2-aminoethyl)carbamoyl]methoxy } phenyl)(1,3-thiazol-2-yl)]-5- methylthiothiophene-2-carboxamidine, 4-(4-{3-[2-(4-acetylpiperazinyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5- methylthiothiophene-2-carboxamidine, 4-(4-{3-[2-(4-methylpiperazinyl)-2-oxoethoxy |phenyl}(1,3-thiazol-2-yl))-5- methylthiothiophene-2-carboxamidine, the compound described in Example 151, 5-methylthio-4-[4-(3-{2-ox0-2-[4-benzylpiperazinyl}ethoxy } phenyl)(1,3-thiazol- 2-yl)]thiophene-2-carboxamidine, (D,L)-4-(4-{3-[2-(3-aminopyrrolidinyl)-2-oxoethoxy phenyl} (1,3-thiazol-2-yl))- 5-methylthiothiophene-2-carboxamidine, 5-methylthio-4-{4-[3-(2-0x0-2-piperidylethoxy)phenyl](1,3-thiazol-2- yl)}thiophene-2-carboxamidine, (D,L)-ethyl 1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4- yl]phenoxy }acetyl)piperidine-2-carboxylate, 5-methylthio-4-{4-[3-(2-0x0-2-pyrrolidinylethoxy)phenyl]}(1,3-thiazol-2- yl)}thiophene-2-carboxamidine,
5-methylthio-4-[4-(3-{2-0x0-2-[4-benzylpiperidyl]ethoxy } phenyl)(1,3-thiazol-2- yl)jthiophene-2-carboxamidine, (D,L)-4-(4-{3-[2-(3-methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5- methylthiothiophene-2-carboxamidine, 4-(4-{3-[2-(4-methylpiperidyl)-2-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5- methylthiothiophene-2-carboxamidine, 4-(4-{3-[2-(2-azabicyclo[4.4.0]dec-2-yl)-2-0xoethoxy Jphenyl } (1,3-thiazol-2-yl))- 5-methylthiothiophene-2-carboxamidine, (D,L)-ethyl 1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4- yl]phenoxy }acetyl)piperidine-3-carboxylate,
S-methylthio-4-{4-[3-(2-0x0-2-(1,2,3,4-tetrahydroquinolyl)ethoxy)phenyl](1,3- thiazol-2-yl) }thiophene-2-carboxamidine, ethyl 1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4- ylJphenoxy }acetyl)piperidine-4-carboxylate, 4-(4-{3-[2-((3R)-3-hydroxypiperidyl)-Z-oxoethoxy]phenyl}(1,3-thiazol-2-yl))-5- methylthiothiophene-2-carboxamidine,
D,L-4-(4-{3-[2-(2-ethylpiperidyl)-2-oxoethoxy phenyl} (1,3-thiazol-2-yl))-5- methylthiothiophene-2-carboxamidine, 4-(4-{3-[2-((3S)-3-hydroxypyrrolidinyl)-2-oxoethoxy phenyl} (1,3-thiazol-2-yl))- 5-methylthiothiophene-2-carboxamidine,
D,L-4-[4-(3-{2-[3-(hydroxymethyl)piperidyl]-2-oxoethoxy } phenyl)(1,3-thiazol-2- y1)]-5-methylthiothiophene-2-carboxamidine, 4-{4-[3-(2-{(2R)-2-[(phenylamino)methyl]pyrrolidinyl}-2- oxoethoxy)phenyl](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxamidine, 4-[4-(3-{2-[(3R)-3-(methoxymethyl)pyrrolidinyl]-2-oxoethoxy } phenyl)(1,3- thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine, 1-(2-{3-[2-(5-amidino-2-methylthio-3-thienyl)-1,3-thiazol-4- yl]phenoxy }acetyl)piperidine-3-carboxamide, and 2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3- thiazol-4-yl]phenoxy }acetic acid; or pharmaceutically acceptable salts or prodrugs thereof.
A sixth preferred group of compounds are those of Formula IV:
R"
HA
BN N
— 1 24 ) / . Nam
NH, or a pharmaceutically acceptable salt or prodrug thereof, where
A is methylthio or methyl; and
R"is hydrogen, Cg ,qaryl, C, alkyl, C, calkoxy (Cg. 4)aryl, amino(Cq. ,)aryl, monoalkylamino(Cq_ aryl, dialkylamino(Cq,,)aryl, C,_ ,ar(C, ¢)alkyl, heterocycle(C, ¢)alkyl such as morpholinoalkyl, piperazinylalkyl and the like,
C,«alk(Cq 4)aryl, amino(C, (alkyl, mono(C, ¢)alkylamino(C, )alkyl, di(C, ()alkylamino(C, ¢)alkyl, hydroxy(Cq.,,)aryl, or hydroxy(C, (alkyl, where the aryl and heterocyclic rings can be further optionally substituted by1-4 non- hydrogen substituents selected from halogen, hydroxy, amino, mono(C, c)alkylamino, di(C,¢)alkylamino, formylamino, (C,)acylamino, amino(C, ¢)acyl, mono- or di-(C,)alkylaminocarbonyl, thiocarbonylamino, (C,.o)thioacylamino, aminothiocarbonyl, (C, alkoxy, (C¢,o)aryloxy, aminocarbonyloxy, mono- or di-(C,¢)alkylaminocarbonyloxy, mono- or di- (Cs. o)arylaminocarbonyloxy, mono- or di(C.,o)ar(C, ¢)alkylaminocarbonyloxy, (C,.¢)alkylsulfonyl, (Cq.jo)arylsulfonyl, (Cq. 0)ar(C, ¢)alkylsulfonyl, (C,.¢)alkylsulfonylamino, Cg. ,, arylsulfonylamino, (Cq.10)ar(C, ¢)alkylsulfonylamino,(C, 4)alkoxycarbonylamino, (C,.0)ar(C, ¢)alkoxycarbonylamino, C4 yaryloxycarbonylamino, mono- or di- (C,. ¢Jalkylaminothiocarbonyl, (C4-jo)ar(C, ¢)alkoxy, carboxy, (C,,)carboxyalkyl,
C, calkoxycarbonyl, (C, s)alkoxycarbonyl(C, )alkyl, nitro, cyano, trifluoromethyl, (C, ¢)alkylthio and Cq_sarylthio.
Examples of preferred compounds of Formula IV include:
4-{2-[(3-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2- carboxamidine, 4-{2-[(4-methoxyphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2- carboxamidine, 4-(2-{[4-(dimethylamino)phenyl]amino}(1,3-thiazol-4-yl))-5-
methylthiothiophene-2-carboxamidine, 4-{2-[(4-chloro-2-methylphenyl)amino}(1,3-thiazol-4-yl)}-5- methylthiothiophene-2-carboxamidine, 4-{2-[(diphenylmethyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2- carboxamidine,
5-methylthio-4-{2-[(3-phenylpropyl)amino](1,3-thiazol-4-yl)}thiophene-2- carboxamidine, 5-methylthio-4-{2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-4-yl) } thiophene-2- carboxamidine, 4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-y1)}-5-methylthiothiophene-2-
carboxamidine, 4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5- methylthiothiophene-2-carboxamidine, 4-(2-{[2-(methylethyl)phenyljamino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2- carboxamidine,
5-methylthio-4-(2-{[4-(phenylmethoxy)phenyl]amino}(1,3-thiazol-4- yl))thiophene-2-carboxamidine, 4-{2-[(2-bromophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2- carboxamidine, 4-{2-[(2,6-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-
carboxamidine, 4-{2-[(2-bromo-4-methylphenyl)amino](l,3-thiazol-4-yl)}-5- methylthiothiophene-2-carboxamidine, 5-methylthio~4-{2-[(2-morpholin-4-ylethyl)amino](1,3-thiazol-4-yl)} thiophene-2- carboxamidine,
4-{2-[(2,3-dichlorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2- carboxamidine, 5-methylthio-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl)} thiophene- 2-carboxamidine, 5-methylthio-4-{2-[(2-piperidylethyl)amino](1 ,3-thiazol-4-yl)} thiophene-2- carboxamidine, 4-(2-{[(4-methylphenyl)methyl]Jamino}(1,3-thiazol-4-yl))-5-methylthiothiophene- 2-carboxamidine, 4-(2-{[4-(4-chlorophenoxy)phenyl}amino}(1,3-thiazol-4-yl))-5- methylthiothiophene-2-carboxamidine, 4-(2-{[4-phenoxyphenyl]amino }(1,3-thiazol-4-yl))-5-methylthiothiophene-2- carboxamidine, 5-methylthio-4-(2-{[4-(phenylamino)phenyljamino } (1,3-thiazol-4-yl))thiophene- 2-carboxamidine, 5-methylthio-4-(2-{[4-benzylphenylJamino}(1,3-thiazol-4-yl))thiophene-2- carboxamidine,
S5-methylthio-4-(2-{[4-(piperidylsulfonyl)phenyl}amino}(1,3-thiazol-4- yl))thiophene-2-carboxamidine, 5-methylthio-4-[2-(3-quinolylamino)(1,3-thiazol-4-yl)]thiophene-2- carboxamidine, 5-methylthio-4-[2-(2-naphthylamino)(1,3-thiazol-4-yl)]thiophene-2- carboxamidine, 4-[2-(2H-benzo[3,4-d]1,3-dioxolan-5-ylamino)(1,3-thiazol-4-yl)]-5- methylthiothiophene-2-carboxamidine, 4-{2-[(7-bromofluoren-2-yl)amino](1,3-thiazol-4-yl) } -5-methylthiothiophene-2- carboxamidine, 4-{2-[(4-cyclohexylphenyl)amino](1,3-thiazol-4-yl) }-5-methylthiothiophene-2- carboxamidine, 5-methylthio-4-(2-{[4-(phenyldiazenyl)phenyl]amino}(1,3-thiazol-4- yl))thiophene-2-carboxamidine,
S-methylthio 4-(2-{[3-(hydroxymethyl)phenyl]amino}(1,3-thiazol-4-yl))- thiophene-2-carboxamidine, 4-[2-({3-[(3-methylpiperidyl)methyl]phenyl}amino)(1,3-thiazol-4-yl)}-5- methylthiothiophene-2-carboxamidine, 4-{2-[(3-hydroxyphenyl)amino](1,3-thiazol-4-yl) }-5-methylthiothiophene-2- carboxamidine, 4-(2-{[4-(carbamoylmethoxy)phenyl]amino}(1,3-thiazol-4-yl))-5- methylthiothiophene-2-carboxamidine, 5-methyl-4-{2-[(3,4,5-trimethoxyphenyl)amino](1,3-thiazol-4-yl) } thiophene-2- carboxamidine, 5-methyl-4-{2-[(4-phenoxyphenyl)amino](1,3-thiazol-4-yl)}thiophene-2- carboxamidine, 5-methyl-4-[2-(phenylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidine, and 4-(4-isoxazol-5-yl(1,3-thiazol-2-yl))-5S-methylthiothiophene-2-carboxamidine; as well as pharmaceutically acceptable salts and prodrugs thereof.
A seventh preferred group of compounds are compounds of Formula 7, 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°R®;
R' is hydrogen, amino, hydroxy or halogen, preferably hydrogen;
R% R’ and R® are independently hydrogen, C, , alkyl, amino, C, , alkoxy or hydroxy, and are preferably all hydrogen;
R® is hydrogen, C, alkylthio, C, ; alkyl optionally substituted with OH,
NH, COOH or aminocarbonyl, or C, alkoxy, preferably methylthio or methyl; and
R?is alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, di(aralkylsulfonyl)amino, di(aralkenylsulfonyl)amino, di(arylsulfonyl)amino, or di-
(heteroarylsulfonyl)amino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic nng; or amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocycleamino, diheterocyclcamino, monoalkylmonoheterocycleamino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring and wherein any of the heterocycle containing groups can be optionally ring substituted; or alkanoylamino, alkenoylamino, alkynoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroarylalkandylamino, any of which is optionally substituted on the aromatic ring; or alkoxy and alkylthio, either of which is optionally substituted, or aryloxy, aralkoxy, arylthio, aralkylthio, arylsulfonyl, aralkylsulfonyl, aralkenylsulfonyl, any of which is optionally substituted on the aromatic ring; or alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, wherein any of the aryl containing groups can be optionally substituted on the aromatic ring; or formylamino, H(S)CNH-, or thioacylamino.
Preferred optional substituents are halogen, C, alkyl, C, alkoxy, hydroxy, nitro, trifluoromethyl, C,, aryl, C4, aryloxy, Cs, arylmethoxy (wherein the aryl groups on these aryl-containing substituents are further optionally substituted by one or two of chloro, halogen, C, ; alkyl, C, ; alkoxy, phenyl, hydroxy, nitro, trifluoromethyl, carboxy, 3.4-methylenedioxy, 3 4-ethylenedioxy, 3,4-propylenedioxy, or amino), C, aminoalkyl, carboxy,
alkyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, amino, mono- ordi- (C, ¢)alkylamino, mono- or di- Cq.,o arylamino, C, , alkylsulfonylamino, Ce. oarylsulfonylamino, C, gacylamino, C, ; alkoxycarbonyl, C, ¢alkanoylamino, C. .aroylamino, C, , hydroxyalkyl, methylsulfonyl, phenylsulfonyl, thienyl (further optionally substituted by one or two of chloro, amino, methyl, methoxy, or hydroxy) and tetrazolyl.
In one aspect of this embodiment, R® is preferably C,, alkylsulfonylamino, Cg4.,, ar(C,¢)alkylsulfonylamino, Cg ar(C, ¢)alkenylsulfonylamino, C,_,, arylsulfonylamino, heteroarylsulfonylamino, di(Cq.,o ar(C, ¢)alkylsulfonyl)amino, di(C,_,, ar(C,_¢)alkenylsulfonyl)amino, di(C,. 10 arylsulfonyl)amino, or di-(heteroarylsulfonyl)amino, wherein any ofthe aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring.
Especially preferred R* groups in this embodiment of the invention include C,,, arylsulfonylamino, di-(Cq4,, arylsulfonyl)amino, Cg, ar(C,_;)alkylsulfonylamino, di-(C4.,, ar(C,.)alkylsulfonyl)amino, thienylsulfonylamino, any of which is optionally substituted on the aromatic ring.
Useful values of R?, when R? 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-ylsulfonylamino, di(naphth-1- ylsulfonyl)amino, 2-methylphenylsulfonylamino, di-(2- methylphenylsulfonyl)amino, 3-methylphenylsulfonylamino, di-(3- methylphenylsulfonyl)amino, 4-methylphenylsulfonylamino, di-(4- methylphenylsulfonyl)amino, benzylsulfonylamino, 4- methoxyphenylsulfonylamino, di-(4-methoxyphenylsulfonyl)amino, 4- iodophenylsulfonylamino, di-(4-iodophenylsulfonyl)amino, 3,4- dimethoxyphenylsulfonylamino, bis-(3,4-dimethoxyphenylsulfonyl)amino, 2-chlorophenylsulfonylamino, di-(2-chlorophenylsulfonyl)amino, 3-chlorophenylsulfonylamino, di-(3-chlorophenylsulfonyl)amino, 4-chlorophenylsulfonylamino, di-(4-chlorophenylsulfonyl)amino, phenylsulfonylamino, di-(phenylsulfonyl)amino, 4-rert-
butylphenylsulfonylamino, di-(4-rert-butylphenylsulfonyl)amino, 2- phenylethenylsulfonylamino, and 4-(phenylsulfonyl)thien-2-ylsulfonylamino.
In another aspect of this embodiment, R’ is preferably amino, mono(C, ¢)alkylamino, di(C,¢)alkylamino, mono(Cq_,)arylamino, di(C4.,,)arylamino, mono(C, ¢)alkylmono(C,4_ ,,)arylamino, monoar(C, ()alkylamino, di(Cq.,)ar(C, 4)alkylamino, mono(C, ¢)alkylmono(Cs, o)ar(C, )alkylamino, monoheteroarylamino, diheteroarylamino, mono(C, ¢)alkylmonoheteroarylamino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring.
Especially preferred R? groups in this embodiment of the invention include mono(C,. ,)arylamino, mono(C, ()alkylmono(Cs ,z)arylamino, mono(C,_,o)ar(C, ;)alkylamino, mono(C,)atkylmono(Cq ,)ar(C, ;)alkylamino, monoheteroarylamino, and mono(C, ¢)alkylmonoheteroarylamino. Examples of suitable heteroarylamino groups include 1,3-thiazol-2-ylamino, imidazol-4- ylamino, quinolin-2-ylamino and quinolin-6-ylamino.
Useful values of R?, when R? is a substituted amino group include anilino, naphth-2-ylamino, naphth-1-ylamino, 4-(biphenyl)thiazol-2-ylamino, 4-(pheny))thiazol-2-ylamino, 4-phenyl-5-methylthiazol-2-ylamino, 4-hydroxy-4- trifluoromethylthiazol-2-ylamino, 3-phenylphenylamino, pyrimidin-2-ylamino, 4-isopropylphenylamino, 3-isopropylphenylamino, 4-phenylphenylamino, 3- fluoro-4-phenylphenylamino, 3,4-methylenedioxyphenylamino, n- butylphenylamino, N-methyl-N-(2-methylphenyl)amino, 3-nitrophenylamino, 4- methoxyphenylamino, 3-methoxyphenylamino, 2-methoxyphenylamino, 2- methylphenylamino, 3-methylphenylamino, 3,4-dimethylphenylamino, 3- chlorophenylamino, 4-chlorophenylamino, 4-(3-fluoro-4-methylphenyl)amino, 4-(indan-S-yl)amino, benzylamino, indanylmethylamino, 2,3- dihydrobenzofuranylmethyl, 2-phenylimidazol-5-yl, 3-hydroxybenzyl, 3- phenoxyphenylamino, 4-phenoxyphenylamino, 3-benzyloxyphenylamino, 4- benzyloxyphenylamino, quinolin-6-ylamino, quinolin-3-ylamino, 4- (phenylamino)phenylamino, 4-(4-ethylphenyl)phenylamino, 4-
(dimethylamino)phenylamino, 4-cyclohexylphenylamino, 4-(9-ethylcarbazol-3- yl)amino, 4-(t-butyl)phenylamino, and 4-methylthiopheny! amino.
In another aspect of this embodiment, R? is preferably an acylamino group, such as alkanoylamino, alkenoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroarylalkanoylamino, any of which is optionally substituted on the aromatic ring.
Especially preferred R? groups in this embodiment of the invention include (Cg o)arylcarbonylamino, C.,, ar(C,)alkylcarbonylamino, Cg, ar(C,;)alkenylcarbonylamino, C,,, aryloxy(C,j)alkylcarbonylamino, C,, cycloalkylcarbonylamino, C, ¢alkylcarbonylamino, and heteroarylcarbonylamino, such as furanylcarbonylamino, and quinolinyicarbonylamino.
Useful values of R?% when R? is an acylamino group include 3-hydroxyphenylcarbonylamino, 2-phenylethenylcarbonylamino, phenylcarbonylamino, cyclohexylcarbonylamino, 4-methyl-3- nitrophenylcarbonylamino, furan-2-ylcarbonylamino, tert-butylcarbonylamino, 5-(3,5-dichlorophenoxy)furan-2-ylcarbonylamino, naphth-1-ylcarbonylamino, quinolin-2-ylcarbonylamino, 4-ethoxyphenylcarbonylamino, phenoxymethylcarbonylamino, and 3-methylphenylcarbonylamino.
In another aspect of this embodiment, R” is preferably C;_,, aryloxy, Cg. ar(C, ¢)alkoxy, C,, arylsulfonyl, C,,, ar(C, ¢)alkylsulfonyl, or Cg, ar(C, ¢)alkenylsulfonyl, any of which is optionally substituted on the aromatic ring. Especially preferred R? groups in this embodiment of the invention include C,_,, aryloxy, and C, , arylsulfonyl.
Useful values of R%, when R? 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: 5-methylthio-4-(6-quinolylamino)thiophene-2-carboxamidine 5-methylthio-4-[(3-phenylphenyl)amino]jthiophene-2-carboxamidine 5-methylthio-4-(3-quinolylamino)thiophene-2-carboxamidine 5-methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidine
4-[(4-cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxamidine methyl 4-amino-5-methylthiothiophene-2-carboxylate methyl 4-[(aminothioxomethyl)amino}-5-methylthiothiophene-2-carboxylate 5-methylthio-4-[(4-phenyl(1,3-thiazol-2-yl))amino]thiophene-2-carboxamidine 5-methylthio-4-{[4-(4-phenylphenyl)(1,3-thiazol-2-yl)]amino}thiophene-2-
carboxamidine 4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2- carboxamidine 4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5- methylthiothiophene-2-carboxamidine
5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine 4-[(4-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine 4-[(3-methylphenyl)amino}-5-methylthiothiophene-2-carboxamidine 4-[(3-methoxyphenyl)amino}-5-methylthiothiophene-2-carboxamidine 4-{[3-(methylethyl)phenyl]amino }-5-miethylthiothiophene-2-carboxamidine
5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine 4-{[4-(methylethyl)phenyl}jamino}-5-methylthiothiophene-2-carboxamidine 4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine 5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxamidine 4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxamidine
4-(2H-benzo[d}1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxamidine 4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine 5-methylthio-4-[benzylamino]thiophene-2-carboxamidine 4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine 4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxamidine
5-methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxamidine 5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine 4-{[(3-hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxamidine 5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine 4-((2E)-3-phenylprop-2-enoylamino)-5-methylthiothiophene-2-carboxamidine
4-{(4-chlorophenyl)carbonylamino]-5-methyithiothiophene-2-carboxamidine
4-(cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine methyl 4-[(4-methy!-3-nitrophenyl)carbonylamino}-5-methylthiothiophene-2- carboxylate 4-(2-furylcarbonylamino)-5-methylthiothiophene-2-carboxamidine 4-(2,2-dimethylpropanoylamino)-5-methylthiothiophene-2-carboxamidine 4-{ [5-(3,5-dichlorophenoxy)(2-furyl)jcarbonylamino} -S-methylthiothiophene-2- carboxamidine 5-methylthio-4-(naphthylcarbonylamino)-thiophene-2-carboxamidine 5-methylthio-4-(2-quinolylcarbonyl-amino)thiophene-2-carboxamidine 4-[(3-methoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine 4-[2-(2-hydroxy-5-methoxyphenyl)acetylamino]-5-methylthiothiophene-2- carboxamidine 4-[(4-ethoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine 5-methylthio-4-(2-phenoxyacetylamino)-thiophene-2-carboxamidine 4-[(3-methylphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine 5-methylthio-4-{[3-(phenylmethoxy)phenyl]amino } thiophene-2-carboxamidine
S-methylthio-4-{(3-phenoxyphenyl)amino]thiophene-2-carboxamidine 5-methylthio-4-{(4-phenoxyphenyl)amino]thiophene-2-carboxamidine 4-[(2-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine 4-[(2-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine 4-[{(3-chlorophenyl)amino}-5-methylthiothiophene-2-carboxamidine 4-(methylphenylamino)-5-methylthiothiophene-2-carboxamidine 5-methyl-4-(phenylamino)thiophene-2-carboxamidine 4-{[4-(dimethylamino)phenyl]amino }-5-methylthiothiophene-2-carboxamidine 4-[(4-ethylphenyl)amino]-5-methylthiothiophenec-2-carboxamidine 5-methylthio-4- {[4-(phenylmethoxy)phenyl]amino } thiophene-2-carboxamidine
S-methylthio-4-{[4-(phenylamino)phenyl]amino }thiophene-2-carboxamidine 4-[(4-methoxyphenyl)amino}-5-methylthiothiophene-2-carboxamidine 4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine 4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine 4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidine
5-methylthio-4- {[(4-phenylphenyl)sulfonyl]Jamino } thiophene-2-carboxamidine 4-{bis[(4-phenylphenyl)sulfonyl]Jamino}-5-methylthiothiophene-2-carboxamidine 5-methylthio-4-[(2-naphthylsulfonyl)-amino]thiophene-2-carboxamidine 4-[bis(2-naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidine 4-{[(6-bromo(2-naphthyl))sulfonyljamino} -5-methylthiothiophene-2- carboxamidine 4-{bis[(6-bromo(2-naphthyl))sulfonyljamino} -5-methylthiothiophene-2- carboxamidine 5-methylthio-4-[(naphthylsulfonyl)-amino]thiophene-2-carboxamidine 4-[bis(naphthylsulfonyl)amino]-5-methyithiothiophene-2-carboxamidine 4-{{(2-methylphenyl)sulfonyl]Jamino }-5-methylthiothiophene-2-carboxamidine 4-{bis[(2-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine 4-{[(3-methylphenyl)sulfonylJamino}-5-methylthiothiophene-2-carboxamidine 4-{bis[(3-methylphenyl)sulfonyl]amino }-5-methylthiothiophene-2-carboxamidine 4-{[(4-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine 4-{bis[(4-methylphenyl)sulfonyl]amino }-5-methylthiothiophene-2-carboxamidine 5-methylthio-4-{[benzylsulfonyl]amino}-thiophene-2-carboxamidine 5-methylthio-4-phenoxythiophene-2-carboxamidine 5-methylthio-4-(phenylsulfonyl)thiophene-2-carboxamidine as well as salts thereof, such as hydrochloride or trifluoracetate salts and prodrugs thereof.
Methods of Use and Pharmaceutical Compositions
For medicinal use, 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 J 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. Examples of 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 HCl, HBr, HI; sulfuric acid; phosphoric acid and the like. Preferred acids for forming acid addition salts include HCI 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. For example, 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. Also provided are methods to inhibit extracellular proteolysis, methods to treat benign prostatic hypertrophy, prostatic carcinoma, tumor metastasis, restenosis and psoriasis by administering the compound of Formula
I. For their end-use application, 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. For their end-use application, 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 purposes. 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, 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).
By virtue of the effects of both factor Xa and thrombin on a host of cell types, such as smooth muscle cells, endothelial cells and neutrophils, 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.
When employed as thrombin or factor Xa inhibitors, 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 polymorphonuclear 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. In their end-use application the enzyme inhibitory properties of the compounds of Formula [I is readily ascertained by standard biochemical techniques that are well-known in the art.
The 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 er al., Biochemistry 15: 836 (1979). Leukocyte granules are a major source for the preparation of leukocyte elastase and cathepsin G (chymotrypsin-like activity). 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-p-nitroanilide. The latter is not hydrolyzed by leukocyte elastase.
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 40S 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 uscful for the aforementioned disease states.
Additional uses for compounds of the present invention include analysis of commercial reagent enzymes for active site concentration. For example, 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 o,-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 areagent. See, U.S. Patent No. 4,499,082.
Protease activity in certain protein extracts during purification of particular proteins is a recurring problem which can complicate and compromise the results of protein isolation procedures. Certain 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.
The pharmaceutical compositions of the present invention can be administered by any means that achieve their intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes. Alternatively, or concurrently, 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.
In addition to the pharmacologically active compounds, 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.
The pharmaceutical preparations 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. Thus, 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. If desired, 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. For this purpose, 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. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as, acetylcellulose phthalate or hydroxypropyimethyl-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. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as, fatty oils or liquid paraffin. In addition, 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 purpose are disclosed in U.S. Patent Nos. 4,727,064, 4,764,604, and 5,024,998.
In addition, 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. Optionally, the suspension may also contain stabilizers.
Methods of Making
Many synthetic methods used to form compounds of the present invention generally involve the formation of an amidine from a carboxylic acid derivative, such as an ester or a nitrile. In the process a Lewis acid, such as trimethylaluminum, is added to a source of ammonia, such as ammonium chloride in an aprotic solvent, such as a toluene, under an inert atmosphere (e.g., under an atmosphere of nitrogen or argon gas) at a temperature between -15°C and 5°C, preferably at 0°C. 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.
Description of Syntheses
The chemical schemes appear after the description of the schemes.
Scheme la
Scheme 1a illustrates a general approach to compounds of Formula I where X = O or S, R* = alkylthio, aralkylthio, arylthio, alkyloxy, aralkyloxy or aryloxy, Y = bond and Z = NR’R®. When R* and R?*' of compounds 2 and 3 are retained in the final product, they correspond to R? and R* of Formula 1, respectively. Otherwise R* and R?' represent groups which, after further transformations, will become R? and R* of Formula I.
Starting with the heterocycle where X = O or S appropriately substituted by two leaving groups, the leaving groups can be sequentially displaced by appropriate nucleophiles (preferably the anion of the group R?' or
R2 to be substituted) to produce the mono- or disubstituted heterocycles.
Examples of leaving groups include halogens (chlorine, bromine or iodine), sulfonates (methanesulfonate, toluenesulfonate or trifluoromethanesulfonate) or sulfones (methylsulfonyl). Preferable 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. In certain cases where the nucleophile used contains an anion on carbon, catalysis of the displacement may be useful for this transformation. Examples of catalysts would include compounds containing palladium, silver or Ni salts.
Scheme 1b
Scheme 1b illustrates approaches to providing the functionality of
Y(CNR*Z in compounds of Formula where X = N, O or S, R? and R?' are defined as in Scheme 1a. Depending on the nature of the group W in 3, several methods may be employed in the transformation of W to Y(CNR*)Z.
When W in 3 is a cyano group (CN), primary amide (CONH,) or ester (CO,R?), direct conversion to an unsubstituted amidine 5 (i.e. Formula J where Y = bond, Z = NR°R® and R*, R’, R® = H) can be effected by treatment with a reagent consisting of a Lewis acid complexed to ammonia. This complex is produced by treatment of ammonia or an ammonium salt, preferably an ammonium halide and most preferably ammonium chloride or bromide, with an appropriate Lewis acid, preferably a trialkylaluminum and most preferably trimethyl- or triethylaluminum in a solvent inert to the Lewis acid employed. For example, when a trialkylaluminum Lewis acid is employed with an ammonium halide, reaction occurs with loss of one equivalent of alkane to produce the dialkylhaloaluminum complex of ammonia (see for example Sidler, D.R., er al, J. Org. Chem., 59:1231 (1994)). Examples of 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.
When W is a cyano group (CN), direct conversion to a mono- or disubstituted amidine 5 (R*, R®, R® = H) is also possible by treatment with a reagent consisting of a Lewis acid, preferably a trialkylaluminum, complexed to a mono- or disubstituted amine H,NR® or HNR’R® (Garigipati, R.,
Tetrahedron Lett. 31: 1969 (1990)). Alternatively the same addition of a mono- or disubstituted amine may catalyzed by a copper salt such as Cu(I) chloride (Rousselet, G., et al, Tetrahedron Lett. 34: 6395 (1993)).
When W in 3 is a carboxyl group (CO,H), indirect conversion to an unsubstituted amidine S can be carried out by initial esterification to 4 by any of a number of well-known dehydrating agents (for example, dicyclohexylcarbodiimide) with an alcohol (R”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 HCI and another acid, such as thionyl chloride,
POCI,, PCl;, PCI, or more preferably oxalyl chloride, with or without an added catalyst such as N, N-dimethylformamide (DMF), followed by the alcohol R”OH. Conversion to the unsubstituted amidine 5 (R¢, R®, R® = H) can be carried out by treatment with a Lewis acid complexed to ammonia.
Amidines 5 also can be produced indirectly by conversion of 3 (W =
CN) to iminoethers 6 by exposure to a strong acid such as a hydrogen halide,
HBF, or other non-nucleophilic acid, preferably gaseous HCI in the presence of an alcohol R*OH (R? = alkyl, branched alkyl or cycloalkyl, preferably Me or Et) and most preferably with the alcoho! as solvent. Alternatively when W = CONH,, conversion to an iminoether can be carried out by treatment with a trialkyloxonium salt (Meerwein’s salts). In either case, treatment of the iminoether 6 with ammonia (R?, R® = H) or a mono- or disubstituted amine (HNR’R®) provides the corresponding unsubstituted or substituted amidines 5 (i.e. via classical Pinner synthesis: Pinner, A., Die Iminoaether und ihre
Derivate, Verlag R. Oppenheim, Berlin (1892)).
When W = NH, in 3, treatment with a reagent Z(CNR*)L where Z = alkyl and L is a leaving group such as O-alkyl and preferably OMe, provides the subclass of amidines 135 (Z = alkyl ) which are isomeric to 5 (Formula 7, where Y = NH, Z = H or alkyl). Examples of reagents for this reaction include methyl or ethyl acetimidate hydrochloride. Alternatively treatment of 3 (W =
NH,) with a trialkyl orthoformate ester, preferably trimethyl- or triethyl orthoformate, followed by an amine R‘NH, affords the corresponding formidines 135 (Z = H) (Formula I, where Y = NH, Z = H).
Also, when W = NH,, 3 can be treated with a reagent Z(CNR*)L where
R,=Hand Z =NR’R® and L is a leaving group such as pyrazole, methylpyrazole, SO,H, S-alkyl, S-aryl, trifluoromethanesulfonate (OT) or trifluoromethanesulfonamide (NHTY), preferably pyrazole, SO,H or trifluoromethanesulfonamide (NHTf). Examples of these reagents include aminoiminosulfonic acid (Miller, A.E. and Bischoff, J.J., Synthesis, 777 (1986) and 1 H-pyrazole-1-carboxamidine hydrochloride (Bernatowicz, M.S., etal.,J Org. Chem. 57:2497 (1992)). Such treatment provides guanidines

Claims (1)

  1. : bo What is Claimed Is:
    1. A compound of Formula I: R! R? Zz Y T NR? I ‘or a solvate, hydrate or pharmaceutically-acceptable salt thereof, wherein: X is sulfur; Y is a covalent bond; Z is NRRS; _ R! is a hydrogen, amino, hydroxy or halogen; R? is alkylsulfonylamino, aralkylsulfonylamino, aralkenylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, di(aralkylsulfonyl)amino, di(aralkenylsulfonyl)amino, di(arylsulfonyl)amino, or di(heteroarylsulfonyl)amino, wherein any of the ary! or heteroaryl containing groups are optionally substituted on the aromatic ring; or amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, monoalkylmonoaralkylamino, monoheterocycleamino, diheterocycleamino, monoalkylmonoheterocycleamino, wherein any of the aryl or heterocycle containing groups is optionally substituted; or alkanoylamino, alkenoylamino, alkynoylamino, aroylamino, AMENDED SHEET 19 NOVEMBER 2002 aralkanoylamino, aralkenoylamino, heteroaroylamino, heteroarylalkanoylamino, any of which is optionally substituted on the aromatic ring; or alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, wherein any of the aryl containing groups is optionally substituted on the aromatic ring; or formylamino, H(S)CNH-, or thioacylamino; R?is hydrogen, C; alkylthio, C,¢ alkyl optionally substituted with OH, NH,, COOH or aminocarbonyl, or C,_¢ alkoxy; and R* R® and R® are independently hydrogen, C4 alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C,. ¢)alkyl, dialkylamino(C,. jo)alkyl, carboxyalkyl, cyano, amino, alkoxy, or hydroxy, or -CO,R", where RY is alkyl, cycloalkyl, phenyl, benzyl, R' 0 Pi > ° : o} R" ; TT RY R® or Rr lo} where R’ and R® are independently hydrogen, C,.¢ alkyl, Cy alkenyl or phenyl, R'is hydrogen, C,. alkyl, Cy. alkenyl or phenyl, R® is hydrogen, C).¢ alkyl, Ca. alkenyl or phenyl, and R" is aralkyl or C;. alkyl.
    2. A compound of claim 1, wherein the optional substituents on the aromatic ring 'of any group containing an optionally substituted aromatic ring is selected from the group consisting of halogen, Ci alkyl, Ci. alkoxy, hydroxy, nitro, trifluoromethyl, : optionally substituted Cs.jo aryl, optionally substituted Cg.9 aryloxy, optionally substituted Cq.1o arylmethoxy, Cis aminoalkyl, carboxy, 3,4-methylenedioxy, 3,4- ethylenedioxy, 3,4-propylenedioxy, amino, mono(C,¢)alkylamino, di(C,. ¢)alkylamino, mono(Cs.p)arylamino, di(Cs.j¢)arylamino, C,.¢ alkylsulfonylamino, AMENDED SHEET 19 NOVEMBER 2002
    Cé-10 arylsulfonylamino, Cg acylamino, Cg alkoxycarbonyl, C,- alkanoylamino, Cg. 14 aroylamino, C,, hydroxyalkyl, methylsulfonyl, phenylsulfonyl, thienyl and tetrazolyl.
    3. A compound of claim I, wherein R?is C\.¢ alkylsulfonylamino,
    Cs.10 ar(Cj¢)alkylsulfonylamino, Cg. par(Cs.¢)alkenylsulfonylamino, Ce-10 arylsulfonylamino, heteroarylsulfonylamino, di(Cs.10ar(Cj.e)alkylsulfonyl)amino, di(Ce. o(ar(C;.¢)alkenylsulfonyl)amino, di(Ce.10arylsulfonyl)amino or di-(heteroarylsulfonyl)amino, wherein any of the aryl or heteroaryl containing groups is optionally substituted on the aromatic ring.
    4. A compound of claim 3, wherein R? is Ce.10 arylsulfonylamino, di(Ce.10arylsulfonyl)amino, Ce. jpar(C;.3)alkylsulfonylamino, di(Cs.10ar(C;.3)alkylsulfonyl)amino or thienylsulfonylamino, wherein any of the aryl or thienyl containing groups is further optionally substituted.
    5. A compound of claim 1, wherein R? is biphenylsulfonylamino, bis(biphenylsulfonyl)amino, naphth-2-ylsulfonylamino,
    . di(naphth-2-ylsulfonyl)amino, 6-bromonaphth-2-ylsulfonylamino, : di(6-bromonaphth-2-ylsulfonyl)amino, naphth-1-ylsulfonylamino, di(naphth-1-ylsulfonyl)amino, 2-methylphenylsulfonylamino, di-(2-methylphenylsulfonyl)amino, 3-methylphenylsulfonylamino, di-(3-methylphenylsulfonyl)amino, 4-methylphenylsulfonylamino, di-(4-methylphenylsulfonyl)amino, benzylsulfonylamino, 4-methoxyphenylsulfonylamino, di-(4-methoxyphenylsulfonyl)amino, 4-iodophenyisulfonylamino, di-(4-iodophenylsulfonyl)amino, - 3,4-dimethoxyphenylsulfonylamino, bis-(3,4-dimethoxyphenylsulfonyl)amino, 2-chlorophenylsulfonylamino, di-(2-chlorophenylsulfonyl)amino, 3-chlorophenylsulfonylamino, di-(3-chlorophenylsulfonyl)amino, 4-chlorophenylsulfonylamino, di-(4-chlorophenylsulfonyl)amino, . phenylsulfonylamino, di-(phenylsulfonyl)amino, 4-tert-butylphenylsulfonylamino, di-(4-tert-butylphenylsulfonyl)amino, 2-phenylethenylsulfonylamino or 4-(phenylsulfonyl)thien-2-ylsulfonylamino. AMENDED SHEET 19 NOVEMBER 2002
    6. A compound of claim 1, wherein R? is amino, mono(C.¢)alkylamino, di(C,.g)alkylamino, mono(Cg.10)arylamino, di(C. | g)arylamino, mono(C,. s)alkylmono(Cs.j¢)arylamino, monoar(C,.¢)alkylamino, di(Cs.-10)ar(C,.¢)alkylamino, mono(C,.¢)alkylmono(Ce.10)ar(C;.¢)alkylamino, monoheteroarylamino, diheteroarylamino, mono(C,.¢)alkylmonoheteroarylamino, wherein any of the aryl or heteroaryl containing groups is optionally substituted on the aromatic ring.
    7. A compound of claim 6, wherein R?is mono(Cq.jg)arylamino, mono(C,.¢)alkylmono(Cs.j9)arylamino, mono(Cs. ¢)ar(Cy.3)alkylamino, mono(C,.¢)alkylmono(Cs.0)ar(C,.3)alkylamino, monoheteroarylamino or mono(C,.¢)alkylmonoheteroarylamino.
    8. A compound of claim 7, wherein R?is 1,3-thiazol-2-ylamino, imidazol-4-ylamino, quinolin-2-ylamino or quinolin-6-ylamino.
    9. A compound of claim 1, wherein R” is anilino, naphth-2-ylamino, naphth-1-ylamino, 4-(biphenyl)thiazol-2-ylamino, 4-(phenyl)thiazol-2-ylamino, 4-phenyl-5-methylthiazol-2-ylamino, 4-hydroxy-4-trifluoromethylthiazol-2-ylamino, 3-phenylphenylamino, pyrimidin-2-ylamino, 4-isopropylphenylamino, 3-isopropylphenylamino, 4-phenylphenylamino, 3-fluoro-4-phenylphenylamino, 3,4-methylenedioxyphenylamino, n-butylphenylamino, N-methyl-N-(2-methylphenyl)amino, 3-nitrophenylamino, 4-methoxyphenylamino, 3-methoxyphenylamino, 2-methoxyphenylamino, 2-methylphenylamino, 3-methylphenylamino, 3,4-dimethylphenylamino, 3-chlorophenylamino, 4-chlorophenylamino, 4-(3-fluoro-4-methylphenyl)amino, 4-(indan-5-yl)amino, benzylamino, indanylmethylamino, 2,3-dihydrobenzofuranylmethylamino, 2-phenylimidazol-5-ylamino, 3-hydroxybenzylamino, 3-phenoxyphenylamino, 4-phenoxyphenylamino, 3-benzyloxyphenylamino, 4-benzyloxyphenylamino, quinolin-6-ylamino, quinolin-3-ylamino, 4-(phenylamino)phenylamino, 4-(4-ethylphenyl)phenylamino, 4-(dimethylamino)phenylamino, 4-cyclohexylphenylamino, 4-(9-ethylcarbazol-3-yl)amino, 4-(t-butyl)phenylamino or 4-methylthiophenylamino. AMENDED SHEET 19 NOVEMBER 2002
    10. A compound of claim 1, wherein R? is alkanoylamino, alkenoylamino, aroylamino, aralkanoylamino, aralkenoylamino, heteroaroylamino, or heteroarylalkanoylamino, any of which is optionally substituted on the aryl or heteroaryl moiety.
    11. A compound of claim 10, wherein R? is (Ce. ¢)arylcarbonylamino, Ce-10ar(C\.3)alkylcarbonylamino, Ce.1gar(C,.3)alkenylcarbonylamino, Ce-10 aryloxy(C,.3)alkylcarbonylamino, Cj_scycloalkylcarbonylamino,
    C).¢ alkylcarbonylamino or heteroarylcarbonylamino.
    12. A compound of claim 11, wherein Ris 3-hydroxyphenylcarbonylamino, 2-phenylethenylcarbonylamino, phenylcarbonylamino, cyclohexylcarbonylamino, 4-methyl-3-nitrophenylcarbonylamino, furan-2-ylcarbonylamino, tert-butylcarbonylamino, 5-(3,5-dichlorophenoxy)furan-2-ylcarbonylamino, naphth-1-ylcarbonylamino, quinolin-2-ylcarbonylamino, 4-ethoxyphenylcarbonylamino, phenoxymethylcarbonylamino or 3-methylphenylcarbonylamino.
    13. A compound of claim I, which is one of: 5-methylthio-4-(6-quinolylamino)thiophene-2-carboxamidine; 5-methylthio-4-[(3-phenylphenyl)amino]thiophene-2-carboxamidine; 5-methylthio-4-(3-quinolylamino)thiophene-2-carboxamidine; 5-methylthio-4-(pyrimidin-2-ylamino)thiophene-2-carboxamidine; 4-[(4-cyclohexylphenyl)amino]-5-methylthiothiophene-2-carboxamidine; S-methylthio-4-{(4-phenyl(1 ,3-thiazol-2-yl))amino]thiophene-2-carboxamidine; 5-methylthio-4-{[4-(4-phenylphenyl)(1,3-thiazol-2-yl)Jamino} thiophene-2- carboxamidine; 4-[(5-methyl-4-phenyl(1,3-thiazol-2-yl))amino]-5-methylthiothiophene-2- carboxamidine; 4-{[4-hydroxy-4-(trifluoromethyl)(1,3-thiazolin-2-yl)]amino}-5-methylthiothiophene- 2-carboxamidine; 5-methylthio-4-(2-naphthylamino)thiophene-2-carboxamidine; 4-[(4-chlorophenyl)amino}-5-methylthiothiophene-2-carboxamidine; 4-[(3-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine; AMENDED SHEET 19 NOVEMBER 2002
    4-[(3-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine; 4-{[3-(methylethyl)phenylJamino}-5-methylthiothiophene-2-carboxamidine; 5-methylthio-4-[(3-nitrophenyl)amino]thiophene-2-carboxamidine; 4-{[4-(methylethyl)phenyl]amino }-5-methylthiothiophene-2-carboxamidine; 4-[(3,4-dimethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine; 5-methylthio-4-[(4-phenylphenyl)amino}thiophene-2-carboxamidine; 4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxamidine; 4-(2H-benzo[d]1,3-dioxolen-5-ylamino)-5-methylthiothiophene-2-carboxamidine; 4-[(4-butylphenyl)amino]-5-methylthiothiophene-2-carboxamidine; 5-methylthio-4-[benzylaminojthiophene-2-carboxamidine; 4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine; 4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxamidine; 5-methylthio-4-[(2-phenylimidazol-4-yl)amino]thiophene-2-carboxamidine; 5-methylthio-4-[(2-quinolylmethyl)amino]thiophene-2-carboxamidine; 4-{[(3-hydroxyphenyl)methyl]lamino}-S-methylthiothiophene-2-carboxamidine; 5-methylthio-4-(phenylcarbonylamino)thiophene-2-carboxamidine; 4-((2E)-3-phenylprop-2-enoylamino)-5-methylthiothiophene-2-carboxamidine; 4-[(4-chlorophenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine; 4-(cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine; 4-(2-furylcarbonylamino)-5-methylthiothiophene-2-carboxamidine; 4-(2,2-dimethylpropanoylamino)-5-methylthiothiophene-2-carboxamidine; 4-{[5-(3,5-dichlorophenoxy)(2-furyl)]carbonylamino}-5-methylthiothiophene-2- carboxamidine; 5-methylthio-4-(1-naphthylcarbonylamino)thiophene-2-carboxamidine; 5-methylthio-4-(2-quinolylcarbonylamino)thiophene-2-carboxamidine; 4-[(3-methoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine; 4-[2-(2-hydroxy-5-methoxyphenyl)acetylamino]-5-methylthiothiophene-2- carboxamidine; 4-[(4-ethoxyphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine; 5-methylthio-4-(2-phenoxyacetylamino)thiophene-2-carboxamidine; 4-[(3-methylphenyl)carbonylamino]-5-methylthiothiophene-2-carboxamidine; 5-methylthio-4-{[3-(phenylmethoxy)phenyl]amino } thiophene-2-carboxamidine; 5-methylthio-4-[(3-phenoxyphenyl)amino]thiophene-2-carboxamidine; 5-methylthio-4-[(4-phenoxyphenyl)amino]thiophene-2-carboxamidine; AMENDED SHEET 19 NOVEMBER 2002
    4-[(2-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine; 4-[(2-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine; 4-[(3-chlorophenyl)amino]-5-methylthiothiophene-2-carboxamidine; 4-(methylphenylamino)-5-methylthiothiophene-2-carboxamidine; S-methyl-4-(phenylamino)thiophene-2-carboxamidine; 4-{[4-(dimethylamino)phenyl}amino }-5-methylthiothiophene-2-carboxamidine; 4-[(4-ethylphenyl)amino]-5-methylthiothiophene-2-carboxamidine; 5-methylthio-4- {[4-(phenylmethoxy)phenyl]amino } thiophene-2-carboxamidine; 5-methylthio-4- {[4-(phenylamino)phenyl]jamino } thiophene-2-carboxamidine; 4-[(4-methoxyphenyl)amino]-5-methylthiothiophene-2-carboxamidine; 4-[(3-fluoro-4-methylphenyl)amino]-5-methylthiothiophene-2-carboxamidine; 4-(indan-5-ylamino)-5-methylthiothiophene-2-carboxamidine; 4-[(9-ethylcarbazol-3-yl)amino]-5-methylthiothiophene-2-carboxamidine; S-methylthio-4-{[(4-phenylphenyl)sulfonyl]amino } thiophene-2-carboxamidine; 4-{bis[(4-phenylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine; 5-methylthio-4-[(2-naphthylsulfonyl)amino]thiophene-2-carboxamidine; 4-[bis(2-naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidine; 4-{[(6-bromo(2-naphthyl))sulfonyljamino}-5-methylthiothiophene-2-carboxamidine; 4-{bis[(6-bromo(2-naphthyl))sulfonyl}amino}-5-methylthiothiophene-2- carboxamidine; 5-methylthio-4-[(naphthylsulfonyl)amino]thiophene-2-carboxamidine;
    4-[bis(naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidine; 4-{[(2-methylphenyl)sulfonyl]amino }-5-methylthiothiophene-2-carboxamidine; 4-{bis[(2-methylphenyl)sulfonyljamino}-5-methylthiothiophene-2-carboxamidine; 4-{[(3-methylphenyl)sulfonyljamino}-5-methylthiothiophene-2-carboxamidine; 4-{bis[(3-methylphenyl)sulfonyljamino}-5-methylthiothiophene-2-carboxamidine; 4-{[(4-methylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine; 4-{bis{(4-methylphenyl)sulfonyljamino} -S-methylthiothiophene-2-carboxamidine; 5-methylthio-4-{[benzylsulfonyl]Jamino}-thiophene-2-carboxamidine; 4-{[(4-methoxyphenyl)sulfonylJamino}-5-methylthiothiophene-2-carboxamidine; 4-{bis[(4-methoxyphenyl)sulfonyl]Jamino}-5-methylthiothiophene-2-carboxamidine; 4-{[(4-iodophenyl)sulfonylJamino}-5-methylthiothiophene-2-carboxamidine; 4-{[(3,4-dimethoxyphenyl)sulfonylJamino}-5-methylthiothiophene-2-carboxamidine; ) AMENDED SHEET 19 NOVEMBER 2002
    4-{bis[(3,4-dimethoxyphenyl)sulfonyljamino}-5-methylthiothiophene-2- carboxamidine; 4-{[(2-chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine; 4-{[(3-chlorophenyl)sulfonyljamino}-5-methylthiothiophene-2-carboxamidine; 4-{bis[(3-chlorophenyl)sulfonyljamino}-5-methylthiothiophene-2-carboxamidine; 4-{[(4-chlorophenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine; 4-{bis[(4-chlorophenyl)sulfonylJamino }-S-methylthiothiophene-2-carboxamidine; 5-methylthio-4-[(phenylsulfonyl)amino]thiophene-2-carboxamidine; 4-[bis(phenylsulfonyl)amino]-5-methylthiophene-2-carboxamidine; 4-({[4-tert-butyl)phenyl]sulfonyl }amino)-5-methylthiothiophene-2-carboxamidine; 4-(bis{[4-tert-butyl)phenyl]sulfonyl}amino)-5-methylthiothiophene-2-carboxamidine; 4-{[((1E)-2-phenylvinyl)sulfonylJamino }-5-methylthiothiophene-2-carboxamidine; 5-methylthio-4-({[4-(phenylsulfonyl)(2-thienyl)sulfonyl}amino)thiophene-2- carboxamidine; or a solvate, hydrate, prodrug, or pharmaceutically-acceptable salt thereof.
    14. A compound which is one of 5-methylthio-4-phenoxythiophene-2-carboxamidine; or 5-methylthio-4-(phenylsulfonyl)thiophene-2-carboxamidine; or a solvate, hydrate, prodrug, or pharmaceutically-acceptable salt thereof.
    15. A compound according to any of claims 1-14, in the form of a hydrochloride or trifluoroacetate salt.
    16. A pharmaceutical composition comprising a compound of any of claims 1-15, or a solvate, hydrate or pharmaceutically-acceptable ester, salt or ether thereof, and a pharmaceutically-acceptable carrier.
    17. A pharmaceutical composition according to claim 16, wherein said compound is present in an amount between 0.01 and 100 milligrams.
    18. A pharmaceutical composition according to claim 16, suitable for parenteral, oral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal or ocular administration. AMENDED SHEET 19 NOVEMBER 2002
    19. A pharmaceutical composition according to claim 18, suitable for oral administration, wherein said compound is present in an amount between about 0.01 and about 100 milligrams.
    20. A pharmaceutical composition according to claim 18, suitable for oral administration, wherein said compound is present in an amount between about 25 and about 100 milligrams.
    21. A pharmaceutical composition according to claim 18, suitable for parenteral administration, wherein said compound is present in an amount between about 0.01 and about 100 milligrams.
    22. A pharmaceutical composition according to claim 18, suitable for parenteral administration, wherein said compound is present in an amount between about 0.5 and about 10 milligrams.
    23. The use of a compound according to any one of claims 1-15 in a method of making a medicament for use in a method of inhibiting a protease selected from the group consisting of leukocyte neutrophil elastase, chymotrypsin, trypsin, pancreatic elastase, cathepsin G, thrombin, urokinase, factor Xa, plasmin, thermolysin, C-] esterase, C-3 convertase, acrosin, kallikreins, and pepsin, comprising contacting said protease with the compound. Co
    24. The use according to claim 23 wherein said protease is trypsin, chymotrypsin, plasmin or urokinase.
    25. The use of a compound according to any one of claims 1-15 in a method of making a medicament for use in a method of inhibiting urokinase, comprising contacting urokinase with the compound AMENDED SHEET 19 NOVEMBER 2002
    26. The use of a compound according to any one of claims 1-15 in a method of making a medicament for use in a method of treating neoplasia, metastasis, benign prostatic hypertrophy or prostatic carcinoma, comprising administering to a patient in need of such treatment an effective amount of the compound.
    27. The use according to claim 26, wherein said effective amount is between about
    0.01 and about 50 milligrams per kilogram per day.
    28. The use according to claim 26, wherein said effective amount is between about
    0.1 and about 20 milligrams per kilogram per day.
    20. The use of a compound according to any one of claims 1-15 in a method of making a medicament for use in a method of treating arthritis, adult respiratory distress syndrome, rheumatoid arthritis, pancreatitis or inflammatory disease, comprising administering to a patient in need of such treatment an effective amount of the compound.
    30. The use according to claim 29, wherein said effective amount is between about
    0.01 and about 50 milligrams per kilogram per day.
    31. The use according to claim 29, wherein said effective amount is between about
    0.1 and about 20 milligrams per kilogram per day.
    32. The use of a compound according to any one of claims 1-15 in a method of making a medicament for use in a method of treating reperfusion damage, angiogenesis-dependent retinopathy, atherosclerosis or restenosis, comprising administering to a patient in need of such treatment an effective amount of the compound.
    33. The use according to claim 32, wherein said effective amount is between about
    0.01 and about 50 milligrams per kilogram per day. AMENDED SHEET 19 NOVEMBER 2002
    34. The use according to claim 32, wherein said effective amount is between about
    0.1 and about 20 milligrams per kilogram per day.
    35. The use of a compound according to any one of claims 1-15 in a method of making a medicament for use in a method of treating wound healing, gout, emphysema, Alzheimer's disease, psoriasis or Parkinson's disease, comprising administering to a patient in need of such treatment an effective amount of the compound.
    36. The use according to claim 35, wherein said effective amount is between about
    0.01 and about 50 milligrams per kilogram per day.
    37. The use according to claim 35, wherein said effective amount is between about
    0.1 and about 20 milligrams per kilogram per day.
    38. The use of a compound according to any one of claims 1-15 in a method of making a medicament for use in a method of treating prostatic carcinoma, tumor ‘metastasis, arthritis or restenosis, comprising administering to a patient in need of such treatment an effective amount of the compound.
    30. The use according to claim 38, wherein said effective amount is between about
    0.01 and about 50 milligrams per kilogram per day.
    40. The use according to claim 38, wherein said effective amount is between about
    0.1 and about 20 milligrams per kilogram per day.
    41. A compound according to any of claims 1-15 for use in inhibiting a protease selected from the group consisting of leukocyte neutrophil elastase, chymotrypsin, trypsin, pancreatic elastase, cathepsin G, thrombin, urokinase, factor Xa, plasmin, thermolysin, C-1 esterase, C-3 convertase, acrosin, kallikreins, and pepsin.
    42. A compound according to claim 41 wherein said protease is trypsin, chymotrypsin, plasmin or urokinase. AMENDED SHEET 19 NOVEMBER 2002
    I "H.
    43. A compound according to any of claims 1-15 for use in inhibiting urokinase.
    44. A compound according to any of claims 1-15 for use in treating neoplasia, metastasis, benign prostatic hypertrophy or prostatic carcinoma.
    45. A compound according to any of claims 1-15 for use in treating arthritis, adult respiratory distress syndrome, rheumatoid arthritis, pancreatitis or inflammatory disease.
    46. A compound according to any of claims 1-15 for use in treating reperfusion ‘damage, angiogenesis-dependent retinopathy, atherosclerosis or restenosis.
    47. A compound according to any of claims 1-15 for use in treating wound healing, gout, emphysema, Alzheimer’s disease, psoriasis or Parkinson’s disease.
    48. A compound according to any of claims 1-15 for use in treating prostatic carcinoma, tumor mestasis, arthritis or restenosis. AMENDED SHEET 19 NOVEMBER 2002
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