Disclosed is a method for treating the symptoms of an acute or chronic disorder mediated by the classical pathway of the complement cascade, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I

1. Field of the Invention
The present invention is in the field of inhibiting the enzyme C1s, a protease in the classical pathway of the complement system, and the use of this inhibition to treat or ameliorate acute or chronic disorders in mammals.
2. Related Art
The immune system of the human body is equipped with several defense mechanisms to respond to bacterial, viral, or parasitic infection and injury. One such defense mechanism involves the complement system. Complement consists of a complex series of approximately 30 plasma and membrane protein components, many of which are proteinases. Once activated, this system of enzymes non-specifically complements the immunologically specific effects of antibody by modulating the immune response, lysing target cells, stimulating vascular and other smooth muscle cells, facilitating the transport of immune complexes, producing anaphylatoxins which cause degranulation of mast cells and release of histamine, stimulating chemotaxis (migration) of leukocytes towards the area of complement activity, activating B lymphocytes and macrophages, and inducing phagocytosis and lysis of cells (Eisen, H. N., Immunology, Harper and Row Publishers, Inc. Hagerstown, Md., p. 512 (1974); Roitt, I. et al., Immunology, Gower Medical Publishing, London, New York, pp. 7.1-7.14 (1985); U.S. Pat. Nos. 5,472,939 and 5,268,363).
The complement system functions as a xe2x80x9ccascadexe2x80x9d. The enzyme cascades are initiated when inactive enzyme precursor molecules are activated, through limited proteolysis, by membrane-bound enzymes. A small fragment is lost from the enzyme precursor and a nascent membrane binding site is revealed. The major fragment then binds to the membrane as the next functionally active enzyme of the complement cascade. Since each enzyme is able to activate many enzyme precursors, the system forms an amplifying cascade, resembling the reactions seen in blood clotting and fibrinolysis (Roitt, I. et al., Immunology, Gower Medical Publishing, London, New York, pp. 7.1-7.14 (1985)).
The proteins of the complement system form two inter-related enzyme cascades, termed the classical and alternative pathways. The classical pathway is usually initiated by antigen-antibody complexes, while the alternative pathway is activated by specific polysaccharides, often found on bacterial, viral, and parasitic cell surfaces. The classical pathway consists of components C1-C9, while the alternative pathway consists of components C3 and several factors, such as Factor B, Factor D, and Factor H.
The sequence of events comprising the classical complement pathway consists of three stages: recognition, enzymatic activation, and membrane attack leading to cell death. The first phase of complement activation begins with C1. C1 is made up of three distinct proteins: a recognition subunit, C1q, and the serine proteinase subcomponents, C1r and C1s, which are bound together in a calcium-dependent tetrameric complex, C1r2s2. An intact C1 complex is necessary for physiological activation of C1 to result. Activation occurs when the intact C1 complex binds to immunoglobulin complexed with antigen. This binding activates C1s which then cleaves both the C4 and C2 proteins to generate C4a and C4b, as well as C2a and C2b. The C4b and C2a fragments combine to form the C3 convertase, which in turn cleaves C3 to form C3a and C3b (Makrides, Pharmacol. Rev. 50:59-87 (1998); and U.S. Pat. No. 5,268,363). Both the classical and alternative pathways are capable of individually inducing the production of the C3 convertase to convert C3 to C3b, the generation of which is the central event of the complement pathway. C3b binds to C3b receptors present on neutrophils, eosinophils, monocytes and macrophages, thereby activating the terminal lytic complement sequence, C5-C9 (Roitt, I. et al., Immunology, Gower Medical Publishing, London, New York, pp. 7.1-7.14 (1985)).
Complement is designed to fight infection and injury; however, this same mechanism, if inappropriately activated, can cause a significant amount of inflammation, tissue damage, and other disease states such as the autoimmune diseases, as a result of the rapid and aggressive enzyme activity. Disease states implicating the complement system in inflammation and tissue damage include: the intestinal inflammation of Crohn""s disease which is characterized by the lymphoid infiltration of mononuclear and polymorphonuclear leukocytes (Ahrenstedt et al., New Engl. J. Med. 322:1345-9 (1990)), thermal injury (burns, frostbite) (Gelfandetal, J. Clin. Invest. 70:1170 (1982); Demling et al., Surgery 106:52-9(1989)), hemodialysis (Deppisch et al., Kidney Inst. 37:696-706 (1990); Kojima et al., Nippon Jenzo Gakkai Shi 31:91-7 (1989)), and post pump syndrome in cardiopulmonary bypass (Chenoweth et al., Complement. Inflamm. 3:152-165 (1981); Chenoweth et al., Complement 3:152-165 (1986); Salama et al., N. Engl. J. Med. 318:408-14 (1988)). Both complement and leukocytes are reported to be implicated in the pathogenesis of adult respiratory distress syndrome (Zilow et al., Clin. Exp. Immunol. 79:151-57 (1990); Langlois et al., Heart Lung 18:71-84 (1989)). Activation of the complement system is suggested to be involved in the development of fatal complication in sepsis (Hack et al., Am. J. Med. 86:20-26 (1989)) and causes tissue injury in animal models of autoimmune diseases such as immune-complex-induced vasculitis (Cochrane, Springer Seminar Immunopathol. 7:263 (1984)), glomerulonephritis (Couser et al., Kidney Inst. 29:879 (1985)), hemolytic anemia (Schreiber and Frank, J. Clin. Invest. 51:575 (1972)), myasthenia gravis (Lennon et al., J. Exp. Med. 147:973 (1978); Biesecker and Gomez, J. Immunol. 142:2654 (1989)), type II collagen-induced arthritis (Watson and Townes, J. Exp. Med. 162:1878 (1985)), and experimental allergic neuritis (Feasby et al., Brain Res. 419:97 (1987)). The complement system is also involved in hyperacute allograft and hyperacute xenograft rejection (Knechtle et al., J. Heart Transplant 4(5):541 (1985); Guttman, Transplantation 17:383 (1974); Adachi et al., Trans. Proc. 19(1):1145 (1987)). Complement activation during immunotherapy with recombinant IL-2 appears to cause the severe toxicity and side effects observed from IL-2 treatment (Thijs et al., J. Immunol. 144:2419 (1990)).
Complement fragments generated by the classical portion of the complement cascade have been found to be present in the immune complexes formed against indigenous tissue in autoimmune diseases. Such diseases include, but are not limited to: Hashimoto""s thyroiditis, glomerulonephritis and cutaneous lesions of systemic lupus erythematosus, other glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis, Goodpasture""s syndrome, Graves"" disease, myasthenia gravis, insulin resistance, autoimmune hemolyic anemia, autoimmune thrombocytopenic purpura, and rheumatoid arthritis (Biesecker et al. J. Exp. Med. 154: 1779 (1981); Biesecker et al., N. Engl. J. Med. 306: 264 (1982); Falk et al., Clin. Research 32:503A (Abstract) (1984); Falk et al., J. Clin. Invest. 72:560 (1983); Dahl et al., J. Invest. Dermatol. 82:132 (1984); Dahl et al., Arch. Dermatol. 121:70 (1985); Sanders et al., Clin. Research 33:388A (Abstract) (1985); and U.S. Pat. Nos. 5,268,363 and 4,722,890).
Compounds that potently and selectively inhibit complement will have therapeutic applications in several acute and chronic immunological disorders, and a variety of neurodegenerative diseases. Evidence from both human and animal studies shows that activation of the classical complement pathway is primarily involved in neurodegenerative diseases of the central nervous system (CNS). Autoimmune diseases in which these inhibitors of the complement cascade system will be therapeutically useful include myasthenia gravis (MG), rheumatoid arthritis (in which the substance can be administered directly into a joint capsule to prevent complement activation), systemic lupus erythematosus. Neurodegenerative diseases in which inhibitors of the complement cascade system will be therapeutically useful include the demyelinating disorder multiple sclerosis (MS), the neuropathies Guillain-Barrxc3xa9 syndrome (GBS) and Miller-Fisher syndrome (MFS), and Alzheimer""s disease (AD). Other diseases and conditions include hereditary angioedema (in which a deficiency in complement control protein leads to an active complement consumption), septic shock, paroxysmal nocturnal hemoglobinurea, organ rejection (transplantation), burns (wound healing), brain trauma, asthma, platelet storage, hemodialysis, and cardiopulmonary bypass equipment (Makrides, Pharmacol. Rev. 50:59-87 (1998); Spiegel et al., Strategies for Inhibition of Complement Activation in the Treatment of Neurodegenerative Diseases in: Neuroinflammation: Mechanisms and Management, Wood (ed.), Humana Press, Inc., Totowa, N.J., Chapter 5, pp. 129-176; and U.S. Pat. No. 4,916,219).
A number of strategies have been proposed for the inhibition of primarily the classical complement pathway. Efforts to directly inhibit complement activation have focused on chemical compounds that inhibit complement components such as C1r and C1s. Small peptide inhibitors of convertases, such as the C3 and C5 convertases, have also been described (Liszewski and Atkinson, Exp. Opin. Invest. Drugs 7: 323-332 (1998). So far, the best studied xe2x80x98designerxe2x80x99 complement inhibitor for treatment of CNS disorders is soluble recombinant human complement receptor Type 1 (sCR1). sCR1 has proven effective in animal models of CNS diseases and is under investigation for use in man (Fearon, Clin. Exp. Immunol. 86 (Suppl.1):43-46 (1991)). However, there are several drawbacks to the use of sCR1 in disorders of the CNS: the agent is expensive, must be administered systemically, and has a short half-life in vivo. The next generation of complement inhibitors are likely to solve many of these drawbacks (Spiegel et al., Strategies for Inhibition of Complement Activation in the Treatment of Neurodegenerative Diseases in: Neuroinflammation: Mechanisms and Management, Wood (ed.), Humana Press, Inc., Totowa, N.J., Chapter 5, pp. 129-176).
A need continues to exist for non-peptidic compounds that are potent inhibitors of complement, specifically C1 s, and which possess greater bioavailability and fewer side-effects than currently available C1s inhibitors. Accordingly, new classes of potent C1s inhibitors, characterized by potent inhibitory capacity, are potentially valuable therapeutic agents for a variety of conditions.
It has been found that a class of furanyl and thienyl amidines and guanidines are capable of inhibiting C is activity. These compounds have Formula I below and are described in U.S. Provisional Application No. 60/119,364, filed Feb. 9, 1999 and U.S. application Ser. No. 09/372,748, filed Aug. 11, 1999. These applications are fully incorporated by reference herein. Based upon this enzyme inhibitory activity, compounds of Formula I can be employed to treat acute and chronic disorders associated with activation (often inappropriate) of the classical pathway of the complement cascade.
The present invention provides a method for treating acute and chronic immunological disorders associated with activation of the classical pathway of the complement system by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I. These acute and chronic conditions include inflammation, tissue damage, and other disease states such as the autoimmune diseases, as a result of rapid and aggressive enzyme activity of the complement cascade. Often inflammation is a causitive factor of tissue damage associated with many of these conditions.
In one embodiment, compounds of Formula I can be administered to a mammal to treat complement-mediated inflammation and tissue damage. Examples of conditions that can be treated include intestinal inflammation of Crohn""s disease, thermal injury (burns, frostbite), and post pump syndrome in cardiopulmonary bypass.
In a second embodiment, compounds of the present invention can be administered to a mammal suffering from the symptoms of adult respiratory distress syndrome
In a third embodiment, compounds of Formula I can be administered to a mammal to treat complement-mediated complications in sepsis and complement-mediated tissue injury associated with autoimmune diseases. Examples of conditions that can be treated include immune-complex-induced vasculitis glomerulonephritis, hemolytic anemia, myasthenia gravis, type II collagen-induced arthritis, and allergic neuritis.
The complement system is also involved in hyperacute allograft and hyperacute xenograft rejection. Complement activation during immunotherapy with recombinant IL-2 appears to cause the severe toxicity and side effects observed from IL-2 treatment. Thus, in a fourth embodiment, compounds of Formula I can be administered to a mammal before, during or after the transplant of an organ or a graft to ameliorate the rejection of such organ or graft by the mammal. Grafts can include an allograft or xenograft. In a fifth embodiment of the present invention, a compound of Formula I is administered to a mammal before, during or after treatment of said mammal with IL-2 in an amount effective to reduce the toxicity and side-effects of the IL-2 treatment.
A sixth embodiment of the present invention is directed to administering a therapeutically effective compound of Formula I to a mammal that has been diagnosed with an auto-immune disease. Autoimmune diseases that are treatable according to the present invention include Hashimoto""s thyroiditis, glomerulonephritis and cutaneous lesions of systemic lupus erythematosus, other glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis, Goodpasture""s syndrome, Graves"" disease, myasthenia gravis, insulin resistance, autoimmune hemolyic anemia, autoimmune thrombocytopenic purpura, and rheumatoid arthritis. Preferred autoimmune diseases which can be treated by inhibitors of the present invention are myasthenia gravis (MG), rheumatoid arthritis (in which the substance can be administered directly into a joint capsule to prevent complement activation), and systemic lupus erythematosus.
A seventh embodiment of the present invention is directed to administering a therapeutically effective compound of Formula I to a mammal that has been diagnosed with a neurodegenerative disease. Neurodegenerative diseases in which inhibitors of the complement cascade system will be therapeutically useful include the demyelinating disorder multiple sclerosis (MS), the neuropathies Guillain-Barrxc3xa9 syndrome (GBS) and Miller-Fisher syndrome (MFS), and Alzheimer""s disease (AD). Other diseases and conditions include hereditary angioedema, septic shock, paroxysmal nocturnal hemoglobinurea, organ rejection (transplantation), burns (wound healing), brain trauma, asthma, platelet storage, hemodialysis, and cardiopulmonary bypass equipment.
In an eighth embodiment, the present invention provides a pharmaceutical composition for treating a complement-mediated disease state comprsing a compound of Formula I in an amount effective to inhibit C1s protease function in a mammal, and a pharmaceutically acceptable carrier or diluent.
A ninth embodiment of the present invention is directed to novel compounds that are potent C1s inhibitors.
A pharmaceutical composition for treating a complement-mediated disease state comprising a compound of Formula I in an amount effective to inhibit C1s protease function in a mammal, and a pharmaceutically acceptable carrier or diluent are within the scope of the present invention.
Compounds useful in the present invention have the general Formula I:
or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:
X is O, S or NR7, where R7 is hydrogen, alkyl, aralkyl, hydroxy(C2-4)alkyl, or alkoxy(C2-4)alkyl;
Y is a direct covalent bond, CH2 or NH;
Z is NR5R6, hydrogen or alkyl, provided that Y is NH whenever Z is hydrogen or alkyl;
R1 is hydrogen, amino, hydroxy, halogen, cyano, C1-4 alkyl or xe2x80x94CH2R, where R is hydroxyamino or C1-3 alkoxy;
R2 and R3 are independently:
i. hydrogen,
ii. halogen,
iii. hydroxy,
iv. nitro,
v. cyano,
vi. amino, monoalkylamino, dialkylamino, monoarylamino, diarylamino, monoalkylmonoarylamino, monoaralkylamino, diaralkylamino, alkylarylamino, alkoxycarbonylamino, aralkoxycarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, aralkylsulfonylamino, arylsulfonylamino, formylamino, acylamino, H(S)CNHxe2x80x94, or thioacylamino,
vii. aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, acyl, aminoacyl, or arylaminocarbonyl,
viii. aminothiocarbonyl, monoalkylaminothiocarbonyl, dialkylaminothiocarbonyl, thioacyl or aminothioacyl,
ix. aminocarbonylamino, mono- and dialkylaminocarbonylamino, mono- and diarylaminocarbonylamino, or mono- and diaralkylaminocarbonylamino,
x. aminocarbonyloxy, mono- and dialkylaminocarbonyloxy, mono- and diarylaminocarbonyloxy, mono- and diaralkylaminocarbonyloxy,
xi. 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, aralkylthio, or arylthio, wherein the aryl portion of each group can be optionally substituted,
xiv. alkylsulfonyl, wherein the alkyl portion can be optionally substituted,
xv. aralkylsulfonyl, or arylsulfonyl, 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
R4, R5 and R6 are independently hydrogen, C1-4 alkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl, carboxyalkyl, cyano, amino, alkoxy, or hydroxy, or xe2x80x94CO2Rw, where
Rw is hydrogen, hydroxy, alkoxy, cyano, alkoxycarbonyl, alkyl, cycloalkyl, phenyl, benzyl,
xe2x80x83where Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl.
When an alkyl-containing group, heterocyclic-containing group or aryl-containing group of R2 or R3 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 include 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(C1-4)alkylamino, di(C1-4)alkylamino, formylamino, C2-6 acylamino, aminocarbonyl, C2-8 aminoacyl, C1-6 alkoxy, C6-14 aryloxy, carboxy, carboxy(C1-4)alkyl, C2-8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C1-6 alkylthio, C6-14 arylthio, C1-6 alkylsulfonylamino, C7-15 aralkylsulfonylamino, C6-10 arylsulfonylamino, mono- or di(C1-6)alkylaminocarbonyloxy, mono- or di-(C6-10)arylaminocarbonyloxy, mono- or di(C7-15)aralkylcarbonyloxy, C1-6 alkoxycarbonylamino, C7-C15 aralkoxycarbonylamino, and C6-C10 aryloxycarbonylamino.
Preferred values of optional substituents on aryl-containing and heterocyclic-containing groups include chloro, hydroxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, formylamino, C2-6 acylamino, aminocarbonyl, C2-8 amonoacyl, C3-7 cycloalkyl, C1-6 alkyl, C1-6 alkoxy, C6-14 aryloxy, carboxy, carboxy(C1-6)alkyl, C2-8 alkoxycarbonyl, nitro, cyano, trifluoromethyl, C1-6 alkylthio, C6-14 arylthio, C6-14 aryl, substituted phenyl, tetrazolyl, thienyl (further optionally substituted by one, two or three of chloro, hydroxy, C1-4 alkyl, C1-4 alkoxy, amino or carboxy), 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, C1-6 alkylsulfonylamino, C7-15 aralkylsulfonylamino, C1-6arylsulfonylamino, mono- or di(C1-6)alkylaminocarbonyloxy, mono- or di-C6-10 arylaminocarbonyloxy, mono- or di-(C7-15)aralkylcarbonyloxy, C1-6 alkoxycarbonylamino, C7-C15 aralkoxycarbonylamino, C6-C10 aryloxycarbonylamino, C2-6 thioacylamino, aminothiocarbonyl, and C2-8 aminothioacyl.
A first 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 xe2x80x94NHxe2x80x94; R1 is hydrogen, amino, hydroxy or halogen; R4, R5 and R6 are independently hydrogen, C1-6alkyl, amino, cyano, C1-4 alkoxy or hydroxy, and are preferably all hydrogen; one of R2 or R3 is hydrogen, C1-6alkyl (optionally substituted with hydroxy, amino, carboxy or aminocarbonyl), C1-6alkylthio or C1-6 alkoxy; and the other of R2 or R3 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.
Preferred values of R1 include hydrogen, amino, hydroxy and fluoro.
A preferred value of R2 is Formula II (see below) where Ar is phenyl, thiazolyl, thiazolinyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, thienyl (thiophenyl), pyrrolyl, oxazolinyl and benzothienyl.
Preferred values of R3 include C1-4 alkyl (optionally substituted), halogen, amino, acylamino, C1-6 alkylthio, (such as methylthio or ethylthio) C1-6 alkoxy (such as methoxy and ethoxy), trifluoromethyl, methylsulfonyl, and benzylthio.
A preferred value of X is divalent sulfur (S).
Preferred values of Y are a covalent bond or xe2x80x94NHxe2x80x94, most preferably a covalent bond.
Preferred values of R4, R5 and R6 include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, and ethoxy.
Preferred values of R4, R5 and R6 in Formula I also include prodrugs such as xe2x80x94CO2Rw, where Rw, in each instance, is preferably one of C1-4alkyl, C4-7cycloalkyl or benzyl. Suitable values of R4, R5 and R6 include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, xe2x80x94CO2CH3, xe2x80x94CO2CH2CH3 and xe2x80x94CO2CH2CH2CH3.
Also suitable at R4, R5 and R6 is the group xe2x80x94CO2Rw, where Rw is one of
where Rd-Rh are defined as above. When R4, R5 and R6 are xe2x80x94CO2Rw, where Rw 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 Rd, Re and Rg is hydrogen, Rf is methyl, and preferred values for Rh include benzyl and tert-butyl.
Preferred values of R7 include hydrogen, C1-6 alkyl, and C6-10 ar(C1-4)alkyl, C2-6 hydroxyalkyl. Suitable values are hydrogen, methyl, ethyl and benzyl.
The term xe2x80x9calkylxe2x80x9d 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, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.
The term xe2x80x9calkenylxe2x80x9d 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-1-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 xe2x80x9calkynylxe2x80x9d 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 xe2x80x9calkylthioxe2x80x9d as employed herein by itself or as part of another group refers to a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to a sulfur atom, including, but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and the like. Preferably the alkylthio chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
The term xe2x80x9calkoxyxe2x80x9d 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 xe2x80x9ccycloalkylxe2x80x9d 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 xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine with chlorine being preferred.
The term xe2x80x9cacylxe2x80x9d as employed herein by itself or as part of another group refers to the group xe2x80x94C(O)Rg where Rg is alkyl, alkenyl, alkynyl, aryl, or aralkyl. Preferred acyl groups are alkanoyl, aralkanoyl and aroyl groups (xe2x80x94C(O)Rg where Rg is C1-8 alkyl, C6-10 aryl(C1-4)alkyl or C6-10 aryl).
The term xe2x80x9cthioacylxe2x80x9d as employed herein by itself or as part of another group refers to the group xe2x80x94C(S)Rg where Rg is alkyl, alkenyl, alkynyl, aryl or aralkyl, preferably C1-8 alkyl.
The term xe2x80x9cthiocarbonylxe2x80x9d as employed herein by itself or as part of another group refers to the group xe2x80x94C(S)xe2x80x94.
The term xe2x80x9cmonoalkylaminexe2x80x9d 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 xe2x80x9cdialkyl aminexe2x80x9d 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 xe2x80x9carylxe2x80x9d 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 xe2x80x9caralkylxe2x80x9d or xe2x80x9carylalkylxe2x80x9d as employed herein by itself or as part of another group refers to C1-6alkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
The terms xe2x80x9cheterocyclic,xe2x80x9d xe2x80x9cheterocycloxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d 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, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, 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 xe2x80x9cheteroatomxe2x80x9d is used herein to mean an oxygen atom (xe2x80x9cOxe2x80x9d), a sulfur atom (xe2x80x9cSxe2x80x9d) or a nitrogen atom (xe2x80x9cNxe2x80x9d). It will be recognized that when the heteroatom is nitrogen, it may form an NRyRz moiety, wherein Ry and Rz are, independently from one another, hydrogen or C1 to C8 alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring.
The term xe2x80x9cheteroarylxe2x80x9d as employed herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14xcfx80 electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4xcex1H-carbazolyl, carbazolyl, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups).
The expression xe2x80x9cprodrugxe2x80x9d 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 R4, R5 and/or R6 are xe2x80x94CO2Rw, where Rw is defined above. See, U.S. Pat. No. 5,466,811 and Saulnier et al., Bioorg. Med. Chem. Lett. 4:1985-1990 (1994).
The term xe2x80x9csubstituted,xe2x80x9d 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 (i.e., xe2x95x90O), then 2 hydrogens attached to an atom of the moiety are replaced.
By xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable formulaxe2x80x9d 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.
Specific compounds for use in the method 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-hydroxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,
4-(4-(phenylthiazol-2-yl)-5-methylthiothiophene-2-carboxamidine,
4-[4-(4-nitrophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,
4-[4-(3,4-ethylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,
4-[4-(3,4-propylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine,
4-[4-(4-(naphth-2-yl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine, 4-isopropylsulfonyl-5-methylthiothiophene-2-carboxamidine;
4-phenyl-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-chlorophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-phenylphenyl)thiazol-2-yl]-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-trifluoromethylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3-bromophenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3,4-methylenedioxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-methylphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3,5-bis(trifluoromethyl)phenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(2-methoxyphenyl)thiazol-2-yl]-5-methylthiothiophene-2-carboxamidine;
4-(4-phenylimidazo-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]-5-methylthiothiophene-2-carboxamidine;
4-[4-(3,5-dimethoxyphenyl)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)thiazol4-yl-5-methylthiothiophene-2-carboxamidine;
4-[4-(2-chloro-3-pyridyl)thiazol-2-yl]-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-trimethoxyphenyl)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-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(4-dimethylaminophenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(4-methoxyphenylamino)thiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[4-(4-hydroxy-3-methoxyphenyl)thiazol-2-yl]-5-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)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(2-isopropylphenyl)aminothiazol-4-yl]-5-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-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(2,3-dichlorophenyl)aminothiazol-4-yl]-5-methylthiothiophene-2-carboxamidine;
4-[2-(3,4,5-trimethoxyphenyl)aminothiazol-4-yl-]5-methylthiothiophene-2-carboxamidine;
4-[2-(2-piperidinyletyl)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 preferred subgenus of compounds that can be employed in the present invention include compounds of Formula I wherein X is sulfur or oxygen; Y is a covalent bond or xe2x80x94NHxe2x80x94; Z is NR5R6; R1 is hydrogen, amino, hydroxy or halogen; R4, R5 and R6 are independently hydrogen, C1-4 alkyl, amino, C1-4 alkoxy or hydroxy, and are preferably all hydrogen; one of R2 or R3 is hydrogen, C1-6 alkylthio, C1-6 alkyl optionally substituted with OH, NH2, COOH or aminocarbonyl, or C1-6 alkoxy; and the other of R2 or R3 is:
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, benzothienyl, benzimidazolyl, 1,3-oxazolidin-2-onyl, imidazolin-2-onyl (preferably phenyl, thiazolyl, thiazolinyl, oxazolinyl, isothiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl and benzothienyl), any of which can optionally include an exocyclic xe2x95x90O (keto) or xe2x95x90NRv (imino) group, where Rv is alkyl, aryl, aralkyl, alkylamino, arylimino or aralkylimino; and
R8 and R9 are independently selected from the group consisting of hydrogen, halogen, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, arylamino, mono- and di-(C6-14)arylamino, mono- and di-(C6-14)ar(C1-6)alkylamino, formylamino, C2-6 acylamino, aminocarbonyl, C2-8 aminoacyl, C2-6 thioacylamino, aminothiocarbonyl, C2-8 aminothioacyl, C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, carboxy, carboxy(C1-6)alkyl, C2-8 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, C6-14 aryloxy, C1-6 alkylthio, C6-14 arylthio, C6-14 aryl, or C6-14 ar(C1-6)alkyl, wherein the aforementioned heteroaryl groups and the aryl portions of C6-14 aryloxy, mono- and di C6-14 aryl amino, mono- and di-C6-14 ar(C1-6)alkylamino, C6-14 arylthio, C6-14 ar(C1-6)alkyl, and C6-14 aryl can be further optionally substituted, preferably by one, two or three of halogen, hydroxy, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, formylamino, C1-4acylamino, C1-4aminoacyl, mono- or di-(C1-4)alkylaminocarbonyl, thiocarbonylamino, C1-4thioacylamino, aminothiocarbonyl, C1-4alkoxy, C6-10aryloxy, aminocarbonyloxy, mono- or di(C1-4)alkylaminocarbonyloxy, mono- or di(C6-10)arylaminocarbonyloxy, mono- or di(C7-15)aralkylaminocarbonyloxy, C1-4alkylsulfonyl, C6-10arylsulfonyl, (C7-15)aralkylsulfonyl, C1-4alkylsulfonylamino, C6-10arylsulfonylamino, (C7-15)aralkylsulfonylamino, aminosulfonyl, mono- and di-alkylaminosulfonyl, mono- and di-arylaminosulfonyl, mono- and di-aralkylaminosulfonyl, C1-4alkoxycarbonylamino, C7-15aralkoxycarbonylamino, C6-10aryloxycarbonylamino, mono- or di-(C1-4)alkylaminothiocarbonyl, C7-15aralkoxy, carboxy, carboxy(C1-4)alkyl, C1-4alkoxycarbonyl, C1-4alkoxycarbonylalkyl, carboxy(C1-4)alkoxy, alkoxycarbonylalkoxy, nitro, cyano, trifluoromethyl, C1-4alkylthio and C6-10arylthio, or by 3,4-methylenedioxy, 3,4-ethylenedioxy, and 3,4-propylenedioxy.
Preferred values of R8 and R9 are halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy, nitro, trifluoromethyl, C6-10 aryl (further optionally substituted by one or two of chloro, halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, or amino), 4-phenylphenyl(biphenyl), C1-6 aminoalkyl, carboxy, C1-6 alkyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, amino, C1-6 alkanoylamino, C6-14 aroylamino, C1-6 hydroxyalkyl, thienyl (further optionally substituted by one or two of chloro, amino, methyl, methoxy, or hydroxy) and tetrazolyl. More preferably, R2 is thienyl, oxazolyl, or thiazolyl, optionally substituted by any of the aforementioned groups.
Examples of preferred R8 and R9 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-2-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-chloro-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-dichlorophenyl, 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-chloro4-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.
Another preferred subgenus of compounds that can be employed in the present invention include compounds of Formula I wherein:
X is sulfur;
Y is a covalent bond;
Z is NR5R6;
R1 is hydrogen;
R3 is methylthio or methyl;
R4, R5 and R6 are all hydrogen; and
R2 is Formula II, where Ar is phenyl, thiazolyl, oxazolyl, benzothienyl, pyridyl, or imidazolyl; and R8 and R9 are independently hydrogen, or C6-10 aryl or heterocycle, either of which is optionally substituted by one, two or three of chloro, hydroxy, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, amino, carboxy, phenyl, naphthyl, biphenyl, hydroxyphenyl, methoxyphenyl, dimethoxyphenyl, carboxyalkoxyphenyl, alkoxycarbonylalkoxy, carboxyethoxy, alkylsulfonylaminophenyl, arylsulfonylaminophenyl, acylsulfonylaminophenyl, aralkylsulfonylaminophenyl, chlorophenyl, dichlorophenyl, aminophenyl, carboxyphenyl, nitrophenyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, or heteroarylsulfonylaminophenyl where the heteroaryl portion is further optionally halo or C1-6alkyl substituted.
Another preferred subgenus of compounds that can be employed in the present invention include compounds of Formula I wherein:
X is sulfur;
Y is a covalent bond;
Z is NR5R6;
R2 is hydrogen;
R2 is alkyl, ar(alkyl), alkylsulfonyl, aminocarbonyl, amidino, or
xe2x80x83where
Ar is an aromatic or heteroaromatic group selected from the group consisting of phenyl, thiazolyl, oxazolyl, imidazolyl and pyridyl;
R8 and R9 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, aralkyl, 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, dialkylaminoacyl, monoalkylaminoacyl, xe2x80x94SO2-heteroaryl, xe2x80x94SO2-aryl, or aryl;
R3 is xe2x80x94SO2-alkyl, trifluoromethyl, S(O)-alkyl, hydrogen, alkoxy, alkylthio, alkyl, or aralkylthio; and
R4, R5, R6 are hydrogen.
Preferred compounds of this subgenus are those where Ar is a thiazolyl, preferably thiazol-2-yl or thiazol-4-yl, and at least one of R8 and R9 is substituted phenyl, most preferably on the 4-position of the thiazol-2-yl group. Also preferred are compounds where R2 is a 4-phenylthiazol-2-yl group wherein said phenyl is further optionally substituted and R3 is methylthio.
Another preferred subgenus of compounds that can be employed in the present invention include compounds of Formula III:
or a pharmaceutically acceptable salt or prodrug thereof, where
A is methylthio or methyl;
Gxe2x80x2 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or a covalent bond;
n is an integer from 1-10, preferably from 1-6;
m is an integer from 0-1; and
Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, aryl or aralkyl, or Rxe2x80x2 and Rxe2x80x3 are taken together with the N atom to which they are attached to 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, C1-4alkyl, C6-10aryl, C6-10ar(C1-4)alkyl, acyl, alkoxycarbonyl or benzyloxycarbonyl.
Most preferred compounds of Formula III are those for which Rxe2x80x2 and Rxe2x80x3, taken together with the N atom to which they are attached, form a ring selected from piperazinyl, pyrrolidinyl, piperidinyl or morpholinyl, which are optionally further substituted with 1 to 4 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 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, where each of these substituents has the preferred values set forth for Formulae I and II above.
Examples of preferred compounds of Formula III for use in the method of the invention include:
5-methylthio-4-[4-(3-{[N-(2-morpholin-4-ylethyl)carbamoyl]methoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-2-carboxamidine;
5-methylthio-4-{4-[3-(2-morpholin4-yl-2-oxoethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine;
5-methylthio-4-{4-[3-(2-oxo-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;
methyl 2-{3-[2-(5-amidino-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetate;
5-methylthio-4-[4-(3-{2-oxo-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-oxo-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-oxo-2-pyrrolidinylethoxy)phenyl](1,3-thiazol-2-yl)}thiophene-2-carboxamidine;
5-methylthio-4-[4-(3-{2-oxo-2-[4-benzylpiperidyl]ethoxy}phenyl)(1,3-thiazol-2-yl)]thiophene-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-oxoethoxy]phenyl}(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;
5-methylthio-4-{4-[3-(2-oxo-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-yl]phenoxy}acetyl)piperidine-4-carboxylate;
4-(4-{3-[2-((3R)-3-hydroxypiperidyl)-2-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-yl)]-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.
Another preferred subgenus of compounds that can be employed in the present invention include compounds of Formula IV:
or a pharmaceutically acceptable salt or prodrug thereof, where
A is methylthio or methyl; and
Rxe2x80x2xe2x80x3 is hydrogen, C6-14aryl, C1-6alkyl, C1-6alkoxy (C1-6)aryl, amino(C1-6)aryl, monoalkylamino(C6-14)aryl, dialkylamino(C6-14)aryl, C6-10ar(C1-6)alkyl, heterocycle(C2-6)alkyl such as morpholinoalkyl, piperazinylalkyl and the like, C1-6alk(C6-14)aryl, amino(C1-6)alkyl, mono(C1-6)alkylamino(C1-6)alkyl, di(C1-6)alkylamino(C1-6)alkyl, hydroxy(C6-14)aryl, or hydroxy(C1-6)alkyl, where the aryl and heterocyclic rings are further optionally substituted by 1-4 substituents selected from halogen, hydroxy, amino, mono(C1-6)alkylamino, di(C1-6)alkylamino, formylamino, (C1-6)acylamino, amino(C1-6)acyl, mono- or di-(C1-6)alkylaminocarbonyl, thiocarbonylamino, (C1-6)thioacylamino, aminothiocarbonyl, (C1-6)alkoxy, (C6-10)aryloxy, aminocarbonyloxy, mono- or di-(C1-6)alkylaminocarbonyloxy, mono- or di-(C6-10)arylaminocarbonyloxy, mono- or di(C6-10)ar(C1-6)alkylaminocarbonyloxy, (C1-6)alkylsulfonyl, (C6-10)arylsulfonyl, (C6-10)ar(C1-6)alkylsulfonyl, (C1-6)alkylsulfonylamino, C6-10 arylsulfonylamino, (C6-10)ar(C1-6)alkylsulfonylamino,(C1-6)alkoxycarbonylamino, (C6-10)ar(C1-6)alkoxycarbonylamino, C6-10aryloxycarbonylamino, mono- or di-(C1-6)alkylaminothiocarbonyl, (C6-10)ar(C1-6)alkoxy, carboxy, (C1-6)carboxyalkyl, C1-6alkoxycarbonyl, (C1-6)alkoxycarbonyl(C1-6)alkyl, nitro, cyano, trifluoromethyl, (C1-6)alkylthio and C6-10arylthio.
Examples of preferred compounds of Formula IV for use in the present invention 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-methylthio4-{2-[(2,4,5-trimethylphenyl)amino](1,3-thiazol-4-yl)}thiophene-2-carboxamidine;
4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine;
4-{2-[(3-chloro-2-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine;
4-(2-{[2-(methylethyl)phenyl]amino}(1,3-thiazol-4-yl))-5-methylthiothiophene-2-carboximidine;
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](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxamidine;
5-methylthio4-{2-[(2-morpholin4-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]amino}(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-thiazol4-yl))-5-methylthiothiophene-2-carboxamidine;
5-methylthio-4-(2-{[4-(phenylamino)phenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine;
5-methylthio-4-(2-{[4-benzylphenyl]amino}(1,3-thiazol-4-yl))thiophene-2-carboxamidine;
5-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-thiazol4-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;
5-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-thiazol4-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))-5-methylthiothiophene-2-carboxamidine;
as well as pharmaceutically acceptable salts and prodrugs thereof.
Another preferred subgenus of compounds that can be employed in the present invention include compounds of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, wherein:
X is sulfur or oxygen, preferably sulfur;
Y is a covalent bond or xe2x80x94NHxe2x80x94, preferably a covalent bond;
Z is NR5R6;
R1 is hydrogen, amino, hydroxy or halogen, preferably hydrogen;
R4, R5 and R6 are independently hydrogen, C1-4 alkyl, amino, C1-4 alkoxy or hydroxy, and are preferably all hydrogen;
R3 is hydrogen, C1-6 alkylthio, C1-6 alkyl optionally substituted with OH, NH2, COOH or aminocarbonyl, or C1-6 alkoxy, preferably methylthio or methyl; and
R2 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 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 heteroaryl containing groups are 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, heteroarylalkanoylamino, 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 is optionally substituted on the aromatic ring; or
formylamino, H(S)CNHxe2x80x94, or thioacylamino.
Preferred optional substituents are halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy, nitro, trifluoromethyl, C6-10 aryl, C6-10 aryloxy, C6-10 arylmethoxy (wherein the aryl groups on these aryl-containing substituents are further optionally substituted by one or two of chloro, halogen, C1-6 alkyl, C1-6 alkoxy, phenyl, hydroxy, nitro, trifluoromethyl, carboxy, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, or amino), C1-6 aminoalkyl, carboxy, alkyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 3,4-propylenedioxy, amino, mono- or di-(C1-6)alkylamino, mono- or di-C6-10 arylamino, C1-6 alkylsulfonylamino, C6-10 arylsulfonylamino, C1-8 acylamino, C1-8 alkoxycarbonyl, C1-6 alkanoylamino, C6-14 aroylamino, C1-6 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 subgenus, R2 is preferably C1-6 alkylsulfonylamino, C6-10 ar(C1-6)alkylsulfonylamino, C6-10 ar(C2-6)alkenylsulfonylamino, C6-10 arylsulfonylamino, heteroarylsulfonylamino, di(C6-10 ar(C1-6)alkylsulfonyl)amino, di(C6-10 ar(C2-6)alkenylsulfonyl)amino, di(C6-10 arylsulfonyl)amino, or di-(heteroarylsulfonyl)amino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring.
Especially preferred R2 groups in this subgenus include C6-10 arylsulfonylamino, di-(C6-10 arylsulfonyl)amino, C6-10 ar(C1-3)alkylsulfonylamino, di-(C6-10 ar(C1-3)alkylsulfonyl)amino, thienylsulfonylamino, any of which is optionally substituted on the aromatic ring.
Useful values of R2, when R2 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-tert-butylphenylsulfonylamino, di-(4-tert-butylphenylsulfonyl)amino, 2-phenylethenylsulfonylamino, and 4-(phenylsulfonyl)thien-2-ylsulfonylamino.
In another aspect of this subgenus, R2 is preferably amino, mono(C1-6)alkylamino, di(C1-6)alkylamino, mono(C6-10)arylamino, di(C6-10)arylamino, mono(C1-6)alkylmono(C6-10)arylamino, monoar(C1-6)alkylamino, di(C6-10)ar(C1-6)alkylamino, mono(C1-6)alkylmono(C6-10)ar(C1-6) alkylamino, monoheteroarylamino, diheteroarylamino, mono(C1-6)alkylmonoheteroarylamino, wherein any of the aryl or heteroaryl containing groups can be optionally substituted on the aromatic ring.
Especially preferred R2 groups in this subgenus include mono(C6-10)arylamino, mono(C1-6)alkylmono(C6-10)arylamino, mono(C6-10)ar(C1-3)alkylamino, mono(C1-6)alkylmono(C6-10)ar(C1-3)alkylamino, monoheteroarylamino, and mono(C1-6)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 R2, when R2 is a substituted amino group include 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-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-methylthiophenyl amino.
In another aspect of this subgenus, R2 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 R2 groups in this subgenus include (C6-10)arylcarbonylamino, C6-10 ar(C1-3)alkylcarbonylamino, C6-10 ar(C2-3)alkenylcarbonylamino, C6-10 aryloxy(C1-3)alkylcarbonylamino, C3-8 cycloalkylcarbonylamino, C1-6 alkylcarbonylamino, and heteroarylcarbonylamino, such as furanylcarbonylamino, and quinolinylcarbonylamino.
Useful values of R2, when R2 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 subgenus, R2 is preferably C6-10 aryloxy, C6-10 ar(C1-6)alkoxy, C6-10 arylsulfonyl, C6-10 ar(C1-6)alkylsulfonyl, or C6-10 ar(C2-6)alkenylsulfonyl, any of which is optionally substituted on the aromatic ring. Especially preferred R2 groups in this subgenus include C6-10 aryloxy, and C6-10 arylsulfonyl.
Useful values of R2, when R2 is an aryloxy or arylsulfonyl group include phenoxy, naphthyloxy, phenylsulfonyl, and naphthylsulfonyl.
Representative compounds within the scope of this subgenus include:
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;
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-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-(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-methylthiothiophene-2-carboxamidine;
4-(cyclohexylcarbonylamino)-5-methylthiothiophene-2-carboxamidine;
methyl 4-[(4-methyl-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)]carbonylamino}-5-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;
5-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-methylthiothiophene-2-carboxamidine;
5-methylthio-4-{[4-(phenylmethoxy)phenyl]amino}thiophene-2-carboxamidine;
5-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]amino}thiophene-2-carboxamidine;
4-{bis[(4-phenylphenyl)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;
5-methylthio4-[(2-naphthylsulfonyl)-amino]thiophene-2-carboxamidine;
4-[bis(2-naphthylsulfonyl)amino]-5-methylthiothiophene-2-carboxamidine;
4-{[(6-bromo(2-naphthyl))sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;
4-{bis[(6-bromo(2-naphthyl))sulfonyl]amino}-5-methylthiothiophene-2carboxamidine;
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)sulfonyl]amino}-5-methylthiothiophene-2-carboxamidine;
4-{[(3-methylphenyl)sulfonyl]amino}-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; and
5-methylthio-4-(phenylsulfonyl)thiophene-2-carboxamidine;
as well as salts thereof, such as hydrochloride or trifluoracetate salts and prodrugs thereof.
Another preferred subgenus of compounds that can be employed in the present invention include compounds of Formula V:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Rx is arylsulfonyl or arylcarbonyl, wherein said aryl moiety of said arylsulfonyl or arylcarbonyl is optionally substituted by one or more substituents;
Ry is hydrogen or C1-6 alkyl, preferably hydrogen;
Z is NR5R6;
R1 is hydrogen, alkyl, amino, hydroxy or halogen, preferably hydrogen and C1-6 alkyl; and
R4, R5 and R6 are independently hydrogen, C1-4 alkyl, amino, C1-4alkoxy or hydroxy, and are preferably all hydrogen.
Preferred substituents for the aryl moiety of said arylsulfonyl or arylcarbonyl at Rx are hydrogen, halogen, aryl, alkyl and alkoxy, especially preferred substituents include C1-6 alkyl, fluorine, chlorine, methoxy and phenyl.
The following novel compounds are preferred compounds within this preferred subgenus:
4-(4-{3-[(4-fluorophenyl)sulfonylamino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;
4-(4-{3-[(2,4-difluorophenyl)sulfonylamino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;
4-(4-{3-[(4-fluorophenyl)carbonylamino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;
4-(4-{3-[(3,4-difluorophenyl)sulfonylamino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;
4-(4-{3-[(4-methoxyphenyl)carbonylamino]phenyl}l(1,3-thiazol-2-yl))-5-methylthiothophene-2-carboxamidine;
4-(4-{3-[(4-methoxyphenyl)sulfonylamino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine;
4-(4-{3-[(4-chlorophenyl)carbonylamino]phenyl}(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxamidine; and
4-(4-{3-[(2,4-difluorophenyl)carbonylamino]phenyl}(1,3-thiazol-2-yl))-2-yl))-5-methylthiothiophene-2-carboxamidine.
Another preferred subgenus of compounds that can be employed in the present invention include compounds of Formula VI:
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
Rx is aryl or aralkyl, wherein said aryl moiety of said aryl or aralkyl is optionally substituted by one or more substituents;
Rp is optionally substituted alkyl;
Z is NR5R6;
R1 is hydrogen, amino, hydroxy or halogen, preferably hydrogen; and
R4, R5 and R6 are independently hydrogen, C1-4 alkyl, amino, C1-4 alkoxy or hydroxy, and are preferably all hydrogen.
Preferred substituents for the aryl moiety of said aryl or aralkyl at Rx are hydrogen, halogen, alkyl and alkoxy.
The following novel compounds are preferred compounds within this preferred subgenus:
4-[4-(1-phenyl-5-propylpyrazol-4-yl)(1,3thiazol-2-yl)]-5-methylthiothiophene-2-carboxamide;
4-[4-(1-(4-chlorophenyl)-5-amidinopyrazol-4-yl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine; and
2-[4-(5-(tert-butyl)1-benzylpyrazol-4-yl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxamidine.
When any variable occurs more than one time in any constituent or in any Formula, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
Pharmaceutical compositions comprising an effective amount of the C1s inhibitors of the invention, in combination with any conventional pharmaceutically acceptable carrier or diluent, are included in the present invention.
Methods of Use
The present invention provides a method for treating acute and chronic immunological disorders associated with activation of the classical pathway of the complement system by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I. These acute and chronic conditions include inflammation, tissue damage, and other disease states such as the autoimmune diseases, as a result of rapid and aggressive enzyme activity of the complement cascade. Often inflammation causes tissue damage associated with many of these conditions.
In one embodiment, compounds of Formula I can be administered to a mammal to treat complement-mediated inflammation and tissue damage. Examples of conditions that can be treated include intestinal inflammation of Crohn""s disease, thermal injury (burns, frostbite), and post pump syndrome in cardiopulmonary bypass.
The compounds of Formula I can be used to treat chronic or acute inflammation that is the result of transplantation rejection, arthritis, rheumatoid arthritis, infection, dermatosis, inflammatory bowel disease, asthma, osteoporosis, osteoarthritis and autoimmune disease. Additionally, inflammation associated with psoriasis and restenosis can also be treated.
The term xe2x80x9ctreatment of inflammationxe2x80x9d or xe2x80x9ctreating inflammationxe2x80x9d is intended to include the administration of compounds of the present invention to a subject for purposes which can include prophylaxis, amelioration, prevention or cure of an inflammatory response. Such treatment need not necessarily completely ameliorate the inflammatory response. Further, such treatment can be used in conjunction with other traditional treatments for reducing the inflammatory condition known to those of skill in the art.
The compounds of Formula I can be provided as a xe2x80x9cpreventivexe2x80x9d treatment before detection of an inflammatory state, so as to prevent the same from developing in patients at high risk for the same, such as, for example, transplant patients.
In another embodiment, efficacious levels of the C1s inhibitors of the invention are administered so as to provide therapeutic benefits against the secondary harmful inflammatory effects of inflammation. By an xe2x80x9cefficacious levelxe2x80x9d of a composition of the invention is meant a level at which some relief is afforded to the patient who is the recipient of the treatment. By an xe2x80x9cabnormalxe2x80x9d host inflammatory condition is meant a level of inflammation in the subject at a site which exceeds the norm for the healthy medical state of the subject, or exceeds a desired level. By xe2x80x9csecondaryxe2x80x9d tissue damage or toxic effects is meant the tissue damage or toxic effects which occur to otherwise healthy tissues, organs, and the cells therein, due to the presence of an inflammatory response, including as a result of a xe2x80x9cprimaryxe2x80x9d inflammatory response elsewhere in the body.
In a second embodiment, compounds of the present invention can be administered to a mammal suffering from the symptoms of adult respiratory distress syndrome (ARDS). ARDS is a complex pulmonary disorder affecting 150,000 people in the U.S. yearly with a 50% mortality rate. Leukocytes, platelets and the proteolytic pathways of coagulation and complement mediate ARDS. ARDS involves activation of the contact activation pathway and depletion of C1 inhibitor. Sepsis induced ARDS results in more severe DIC and fibrinolysis, more fibrin degradation products and reduced ATIII levels compared to trauma induced ARDS (Carvalho et al., J. Lab. Clin. Med. 112:270-277 (1988)).
In a third embodiment, compounds of Formula I can be administered to a mammal to treat complement-mediated complications in sepsis and complement-mediated tissue injury associated with autoimmune diseases. Examples of conditions that can be treated include immune-complex-induced vasculitis glomerulonephritis, hemolytic anemia, myasthenia gravis, type II collagen-induced arthritis, and allergic neuritis.
Septic shock is the most common cause of death of humans in intensive care units in the United States (Parillo et al., Ann. Int. Med. 113:227-242 (1990); Schmeichel C. J. and McCormick D., BioTechnol. 10:264-267 (1992)). It is usually initiated by a local nidus of infection that invades the blood stream. Incidences of sepsis and shock can arise from infections with either gram negative bacteria, gram positive bacterial or fungal microorganisms. All these organisms seem to induce a common pattern of cardiovascular dysfunction. In recent years aggressive fluid infusion therapy has been accepted as a primary means of treatment for septic shock. Adequate repletion of fluid is associated with an elevated cardiac output and low vascular resistance. Despite treatment, septic shock results in a severe decrease in systemic vascular resistance and generalized blood flow maldistribution. Aggressive therapy reverses shock and death in about 50% of the cases. Unresponsive hypotension resulting from a very low vascular resistance cannot be corrected by fluid infusion. Among those subjects that die from septic shock, approximately 75% die from persistent hypotension and the remainder due to multiple organ system failure.
The complement system is also involved in hyperacute allograft and hyperacute xenograft rejection. Complement activation during immunotherapy with recombinant IL-2 appears to cause the severe toxicity and side effects observed from IL-2 treatment. Thus, in a fourth embodiment, compounds of Formula I can be administered to a mammal before, during or after the transplant of an organ or a graft to ameliorate the rejection of such organ or graft by the mammal. Grafts can include an allograft or xenograft. In a fifth embodiment of the present invention, a compound of Formula I is administered to a mammal before, during or after treatment of said mammal with IL-2 in an amount effective to reduce the toxicity and side-effects of the IL-2 treatment.
A sixth embodiment of the present invention is directed to administering a therapeutically effective compound of Formula I to a mammal that has been diagnosed with an auto-immune disease. Autoimmune diseases that are treatable according to the present invention include Hashimoto""s thyroiditis, glomerulonephritis and cutaneous lesions of systemic lupus erythematosus, other glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis, Goodpasture""s syndrome, Graves"" disease, myasthenia gravis, insulin resistance, autoimmune hemolyic anemia, autoimmune thrombocytopenic purpura, and rheumatoid arthritis. Preferred autoimmune diseases which can be treated by inhibitors of the present invention are myasthenia gravis (MG), rheumatoid arthritis (in which the substance can be administered directly into a joint capsule to prevent complement activation), and systemic lupus erythematosus.
A seventh embodiment of the present invention is directed to administering a therapeutically effective compound of Formula I to a mammal that has been diagnosed with a neurodegenerative disease. Neurodegenerative diseases in which inhibitors of the complement cascade system will be therapeutically useful include the demyelinating disorder multiple sclerosis (MS), the neuropathies Guillain-Barrxc3xa9 syndrome (GBS) and Miller-Fisher syndrome (MFS), and Alzheimer""s disease (AD).
Other diseases and conditions that can be treated include hereditary angioedema, septic shock, paroxysmal nocturnal hemoglobinurea, organ rejection (transplantation), bums (wound healing), brain trauma, asthma, platelet storage, hemodialysis, and cardiopulmonary bypass equipment.
Preferably, the treatment methods of the invention deliver the C1s inhibitor by either contacting cells of the animal with a C1s inhibitor described above or by administering to the animal a C1s inhibitor described above.
The xe2x80x9canimalsxe2x80x9d referred to herein are preferably mammals. Both terms are intended to include humans.
The compounds of the present invention are believed to inhibit the functioning of the protease activity of C1s. This protease-inhibition activity results in the inhibition or blocking of a variety of complement-mediated immunological functions.
The inhibitors can be used in vitro or in vivo. They can be administered by any number of known routes, including orally, intravenously, intramuscularly, subcutaneously, intrathecally, topically, and by infusion (Platt et al., U.S. Pat. No. 4,510,130; Badalamente et al., Proc. Natl. Acad. Sci. U.S.A. 86:5983-5987 (1989); Staubli et al., Brain Research 444:153-158 (1988)) and will generally be administered in combination with a physiologically acceptable carrier (e.g., physiological saline) or diluent. The effective quantity of inhibitor given will be determined empirically and will be based on such considerations as the particular inhibitor used, the condition of the individual, and the size and weight of the individual. It is to be expected that the general end-use application dose range will be about 0.01 to 100 mg per kg per day, preferably 0.1 to 75 mg per kg per day for an effective therapeutic effect.
Amounts and regimens for the administration of C1s inhibitors and compositions of the invention can be determined readily by those with ordinary skill in the clinical art of treating inflammation-related disorders such as arthritis, tissue injury and tissue rejection. Generally, the dosage of the composition of the invention will vary depending upon considerations such as: type of pharmaceutical composition employed; age; health; medical conditions being treated; kind of concurrent treatment, if any; frequency of treatment and the nature of the effect desired; extent of tissue damage; gender; duration of the symptoms; and, counter indications, if any, and other variables to be adjusted by the individual physician. A desired dosage can be administered in one or more applications to obtain the desired results. Pharmaceutical compositions containing the C1s inhibitors of the invention can be provided in unit dosage forms.
The C1s inhibitors are useful for treating such conditions as tissue rejection, arthritis, local infections, dermatoses, inflammatory bowel diseases, autoimmune diseases, etc. The C1s inhibitors of the present invention can be employed to prevent the rejection or inflammation of transplanted tissue or organs of any type, for example, heart, lung, kidney, liver, skin grafts, and tissue grafts.
Inhibition of the complement cascade is also expected to lead to downstream utilities associated with the contact system of coagulation and the complement system. This interaction between components of the complement and coagulation systems at the surface of blood platelets and endothelium can generate inflammatory and chemotactic peptides at sites of vascular thrombus formation and may contribute to the altered hemostasis associated with immune disease states. In addition, immune reactions affecting blood platelets and endothelium can lead to platelet aggregation, the secretion of proteolytic enzymes and vasoactive amines from platelet storage granules, and increase adherence of platelets and leukocytes to the endothelial lining of blood vessels.
It has been demonstrated that membrane-uptake of C3b and C5b-9 proteins can occur spontaneously during incubation of platelets in citrated plasma. Complement activation can also occur during blood collection as a result of exposure to plastic surfaces supporting the C3-convertase reaction. While the implications of complement activation during blood collection and in vitro storage for transfusion have not been directly addressed it is, nevertheless, known that plasma levels of coagulation factors V and VIII rapidly decline in stored platelet concentrates at a rate considerably faster than their decay in cell-free plasma, suggesting consumptive loss. Further, platelet collection and storage is associated with an increase in vesicular plasma membrane microparticles, a product of C5b-9 initiated platelet secretion. These physiological and enzymatic changes greatly reduce the potential shelf life of stored platelets, particularly platelet-rich plasma concentrates used for transfusions, which is generally only 72 hours at best. Furthermore, this interaction of activated C5b-9, platelets, and coagulation factors in stored platelet concentrates will adversely affect the hemostatic effectiveness of these units when infused.
In vitro human organ and tissue storage and survival of the transplanted graft is also adversely affected by the spontaneous activation of the complement system, resulting in membrane insertion of the C5b-9 proteins into vascular endothelium. Activation of C5 to C5a and C5b has been shown to be catalyzed by plastics and other synthetic membranes required to maintain perfusion of vascular beds during in vitro tissue and organ storage. In addition, membrane deposition of C5b-9 in vivo has been implicated in the acute rejection of transplanted tissue due to immune activation of the recipient""s plasma complement system against the endothelial cells within the donor""s organ.
Platelet and endothelial cell activation by C5b-9 also has ramifications in autoimmune disorders and other disease states. The importance of spontaneous complement activation and the resulting exposure of platelets and endothelium to activated C5b-9 to the evolution of vaso-occlusive disease is underscored by consideration that a) leukocyte infiltration of the subendothelium, which is known to occur in regions of atheromatous degeneration and suggests localized generation of C5a at the vessel wall, is potentially catalyzed by adherent platelets and b) local intravascular complement activation resulting in membrane deposition of C5b-9 complexes accompanies coronary vessel occlusion and may affect the ultimate extent of myocardial damage associated with infarction.
It is therefore an aspect of the present invention to provide a means and method for the modulation and inhibition of complement mediated platelet and endothelial cell activation in vivo and in vitro.
It is a further aspect of the present invention to provide a means and method for increasing the survival and therapeutic efficacy of platelets and tissues or organs collected and stored in vitro.
It is another aspect of the present invention to provide methods of treatment for selected autoimmune disorders and other disease states.
The contact system of intrinsic coagulation and the complement system are excessively activated in sepsis and septic shock, especially in cases of fatal septic shock. The contact system can participate in the generation of many vasoactive mediators such as bradykinin, FXIIa, FXIIf and C5a, which are thought to play a role in the pathogenesis of fatal shock. Bradykinin, FXIIa, and XIIf are potent inducers of hypotension while C5a is an inducer of vasodilation and vasopermeability. The levels of FXII, prekallikrein, and high molecular weight kininogen are decreased significantly during non-fatal shock, but are most severely depressed during fatal septic shock to approximately 30%, 57% and 27% of normal values respectively. These changes are noted regardless of whether the septic state is caused by gram positive or gram negative bacteria.
The contact activation pathway is also involved in both fibrin deposition and lysis, as well as triggering neutrophil activation, activation of complement and modulation of blood pressure.
The increase in cardiac output and vasodilation in septic shock is attributed to the action of inflammatory mediators. In septic shock, components of the kallikrein-kinin system are depleted suggesting activation of this system. This is not the case in cardiogenic shock suggesting that the kallikrein-kinin system is a key player in septic shock (Martinez-Brotons F. et al., Thromb. Haemostas. 58:709-713 (1987)). While the actual events leading to septic shock, DIC and hypotension have not been established, the known interactions among various components of the many physiological systems suggest that activation of the contact pathway may lead to a state of septic shock, multiorgan failure, and death (Bone, R. C., supra).
Disseminated intravascular coagulation (DIC) is a disorder that occurs in response to tissue injury and invading microorganisms characterized by widespread deposition of fibrin and depleted levels of fibrinogen (Muller-Berghaus, G., Semin. Thromb. Hemostasis, 15:58-87 (1989)). There are prolonged prothrombin and activated partial thromboplastin times. DIC has been observed in the clinical settings of a wide variety of diseases (Fruchtman, S. M. and Rand, J. H. in Thrombosis in Cardiovascular Disorders, Fuster, V. and Verstraete M. eds., (1992) pp 501-513 W. B. Saunders, Philadelphia).
Hypotension, DIC, and neutrophil activation are all triggered by the interaction of Factor XIIa, plasma kininogens and kallikrein. Deficiency of any of these 3 proteins does not give rise to hemostatic disorders due to redundancy in the system due to platelets, other coagulation factors, and endothelial cells.
It has been suggested that the contact activation system plays a significant role in a variety of clinical states including septic shock, cardiopulmonary bypass surgery, adult respiratory distress syndrome, and hereditary angioedema (Bone, R. C., Arch. Intern. Med. 152:1381-1389 (1992); Colman, R. W., N Engl. J. Med. 320:1207-1209 (1989)). Inhibitors of the contact system may therefore play important roles in the regulation of inflammatory and/or thrombotic disorders.
In one embodiment, dosing will be by intravenous injection or short term infusion. To achieve optimal therapeutic effect, maintenance dosing may be required. Such maintenance dosing may be given repeatedly during the course of a day by, for instance, repeated individual injections or by introduction into a continuous drip infusion. Effective dosages can be readily determined by one of ordinary skill in the art through routine trials establishing dose response curves.
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 I 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 HCl and acetic acid.
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, tri-calcium 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 hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as, glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. 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. Pat. 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 PEG400). 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.
When employed as thrombin 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 10 mg/kg body weight, on a regimen in single or 2-4 divided daily doses.
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. 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 xe2x88x9215xc2x0 C. and 5xc2x0 C., preferably at 0xc2x0 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
Scheme 1a illustrates a general approach to compounds of Formula I where X=O or S, R2=alkylthio, aralkylthio, arylthio, alkyloxy, aralkyloxy or aryloxy, Y=bond and Z=NR5R6. When R22 and R23 of compounds 2 and 3 are retained in the final product, they correspond to R2 and R3 of Formula I, respectively. Otherwise R22 and R21 represent groups which, after further transformations, will become R2 and R3 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 R21 or R22 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 illustrates approaches to providing the functionality of Y(CNR4)Z in compounds of Formula I where X=N, O or S, R22 and R21 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(CNR4)Z.
When W in 3 is a cyano group (CN), primary amide (CONH2) or ester (CO2R23), direct conversion to an unsubstituted amidine 5 (i.e. Formula I where Y=bond, Z=NR5R6 and R4, R5, R6=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., et 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 40-200xc2x0 C., more preferably 80-140xc2x0 C., and most preferably at the reflux temperature of a solvent in the range of 80-120xc2x0 C.
When W is a cyano group (CN), direct conversion to a mono- or disubstituted amidine 5 (R4, R5, R6=H) is also possible by treatment with a reagent consisting of a Lewis acid, preferably a tri alkyl aluminum, complexed to a mono- or disubstituted amine H2NR5 or HNR5R6 (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 (CO2H), indirect conversion to an unsubstituted amidine 5 can be carried out by initial esterification to 4 by any of a number of well-known dehydrating agents (for example, dicyclohexylcarbodiimide) with an alcohol (R23OH). 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 HCl and another acid, such as thionyl chloride, POCl3, PCl3, PCl5, or more preferably oxalyl chloride, with or without an added catalyst such as N,N-dimethylformamide (DMF), followed by the alcohol R23OH. Conversion to the unsubstituted amidine 5 (R4, R5, R6=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, HBF4 or other non-nucleophilic acid, preferably gaseous HCl in the presence of an alcohol R23OH (R23=alkyl, branched alkyl or cycloalkyl, preferably Me or Et) and most preferably with the alcohol as solvent. Alternatively when W=CONH2, conversion to an iminoether can be carried out by treatment with a trialkyloxonium salt (Meerwein""s salts). In either case, treatment of the iminoether with ammonia (R5, R6=H) or a mono- or disubstituted amine (HNR5R6) 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=NH2 in 3, treatment with a reagent Z(CNR4)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 I, where Y=NH, Z=H or alkyl). Examples of reagents for this reaction include methyl or ethyl acetimidate hydrochloride. Alternatively treatment of 3 (W=NH2) with a trialkyl orthoformate ester, preferably trimethyl- or triethyl orthoformate, followed by an amine R4NH2 affords the corresponding formidines 135 (Z=H) (Formula I, where Y=NH, Z=H).
Also, when W=NH2, 3 can be treated with a reagent Z(CNR4)L where R4=H and Z=NR5R6 and L is a leaving group such as pyrazole, methylpyrazole, SO3H, S-alkyl, S-aryl, trifluoromethanesulfonate (OTf) or trifluoromethanesulfonamide (NHTf), preferably pyrazole, SO3H or trifluoromethanesulfonamide (NHTf). Examples of these reagents include aminoiminosulfonic acid (Miller, A. E. and Bischoff, J. J., Synthesis, 777 (1986) and 1H-pyrazole-1-carboxamidine hydrochloride (Bernatowicz, M. S., et al., J. Org. Chem. 57:2497 (1992)). Such treatment provides guamidines 136 directly (Formula I where Y=NH, Z=NR5R6). Alternatively a reagent Z(CNP1)L may be also used where Z=NHP2 and L again a leaving group such as pyrazole, methylpyrazole, SO3H, S-alkyl, S-aryl, trifluoromethanesulfonate (OTf) or trifluoromethanesulfonamide (NHTf), to provide protected guamidines (P1, P2=alkoxylcarbonyl, aralkoxycarbonyl or polymer-bound alkoxylcarbonyl similar to those described below in Scheme 4a) where the protecting groups P1 and P2 can then be removed to give unsubstituted 136 (R4, R5 and R6=H). Protected guamidines are advantageous when further transformations are required after introduction of the guamidine functionality where an unprotected guamidine would not be stable. Examples of these protected reagents include reagents such as N,Nxe2x80x2-bis(tert-butoxycarbonyl)-5-methylthiourea (Bergeron, R. J. and McManis, J. S., J. Org. Chem. 52:1700 (1987)), N,Nxe2x80x2-bis(benzyloxycarbonyl)-1 H-pyrazole-1-carboxamidine or N,Nxe2x80x2-bis(tert-butoxycarbonyl)-1 H-pyrazole-1-carboxamidine (Bernatowicz, M. S., et al., Tetrahedron Letters, 34:3389 (1993)), N,Nxe2x80x2-bis(benzyloxycarbonyl)-Nxe2x80x3-trifluoromethanesulfonylguamidine, and N,Nxe2x80x2-bis(bis(tert-butoxycarbonyl)-Nxe2x80x3-trifluoromethanesulfonylguamidine (Feichtinger, K., et al, J. Org. Chem. 63:3804 (1998)). Detailed descriptions and examples of these protecting groups and their use as protection for amidines are further outlined in Schemes 4a, 4b and 5.
When W in 3 is an ester (CO2R23) or carboxyl group (CO2H), indirect conversion to an N-substituted or unsubstituted methylamidine (Formula I where Y=CH2, Z=NR5R6) can be carried out by initial reduction of the ester or carboxyl by any of a number of well-known reducing agents. When W in 3 is an ester (CO2R23), examples of reducing agents include reducing agents such lithium aluminum hydride (LAH) and lithium borohydride. When W in 3 is a carboxyl group (CO2H), examples of reducing agents include LAH and borane complexed to THF, dimethyl sulfide, dimethylamine or pyridine. The resulting hydroxymethyl derivative (W=CH2OH) is converted to a cyanomethyl derivative (W=CH2CN) by initial formation of a leaving group (W=CH2L) where the leaving group L is a halogen (chlorine, bromine or iodine) or sulfonate ester (for example methanesulfonate, toluenesulfonate or trifluoromethanesulfonate). Displacement of L by cyanide can then be performed by treatment with a metal cyanide such as LiCN, NaCN, KCN or CuCN in a polar solvent such as DMF and with or without a catalyst such as a crown ether, to afford the cyanomethyl derivative (see for example Mizuno, Y., et al, Synthesis, 1008 (1980)). More preferably, the conversion of W=CH2OH to W=CH2CN may be effected by a Mitsunobu reaction (Mitsunobu, O., Synthesis, 1 (1981)) using an azodicarboxylate ester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, Ph3P and a source of cyanide such as HCN or more preferably acetone cyanohydrin (Wilk, B. Synthetic Commun. 23:2481 (1993)). Treatment of the resulting cyanomethyl intermediate (W=CH2CN) under the conditions described for the conversion of 3 (W=CN) to 5 (either directly or indirectly via 6) provides the corresponding amidinomethyl products.
When not commercially available, alkylthiothiophenes (3, X=S, R1=OH or NH2, R21=SR54, W=CN, CO2R23, CONH2) can be synthesized by the methods illustrated in Scheme 1c. Condensation of carbon disulfide and a malonic acid derivative (R52CH2R22) in the presence of two alkylating agents R54L and WCH2L and a base in a suitable medium provide 3 (Dolman, H., European Patent Application No. 0 234 622 A1 (1987)). When R22=R52=CN, the resulting R1 will be NH2; when R22=R52=CO2R23, the resulting R1 will be OH; and when R22 and R52=CN, CO2R23, the resulting R1 can be selected to be OH or NH2 (and R22=CN or CO2R23) depending on the reaction conditions and order of reagent addition. Examples of malonic acid derivatives suitable for this transformation include but are not limited to malonate diesters such as dimethyl malonate or diethyl malonate (R52, R22=CO2R23, R23=Me or Et), malononitrile (R52, R22=CN), or methyl or ethyl cyanoacetate (R52=CO2R23 R22 CN, R23=Me or Et). Leaving groups L include halides such as chloride, bromide or iodide, preferably bromide or iodide, or sulfonates such as toluenesulfonate, benzenesulfonate, methanesulfonate or trifluoromethanesulfonate. Examples of alkylating agent R54L include primary or secondary alkyl, allyl or aralkyl halides or sulfonates, such as methyl iodide, isopropyl bromide, allyl bromide, benzyl chloride or methyl trifluoromethanesulfonate, or a 2-haloacetate ester such as tert-butyl 2-bromoacetate. Examples of alkylating agents WCH2L include 2-chloroacetonitrile, methyl 2-bromoacetate or 2-bromoacetamide. Suitable media are generally polar aprotic solvents, for example, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP) or dimethylsulfoxide (DMSO), preferably DMF.
Alternatively compounds 3 (R22=CN) can be synthesized from precursors 138 (derived from malononitrile, R54L and carbon disulfide), a thioglycolate WCHSH and a base in a suitable polar solvent, preferably methanol (Tominaga, Y., et al, J. Heterocyclic Chem. 31:771 (1994)).
When 3 contains an amino group at R1, it can be diazotized with subsequent loss of nitrogen to give 3, R1=H by treatment with a nitrosating agent in suitable solvent. Nitrosating agents include nitrosonium tetrafluoroborate, nitrous acid or, more preferably and alkyl nitrite ester such as tert-butyl nitrite. Suitable solvents are those which are stable to the nitrosating agents, preferably DMF, benzene or toluene.
When not commercially available, heterocyclic precursors 1 or 2 (X=O, S; W=CO2R23, COOH; L=halogen) used in Scheme 1a can be synthesized by the methods illustrated in Scheme 1c. Depending on the conditions used, treatment of compounds such as 139 with elemental halogen (Cl2, Br2 or I2, preferably Br2) or an N-halosuccinimide reagent, preferably N-bromosuccinimide (NBS), affords either 1 or 2 directly. Description of suitable solvents and conditions to selectively produce 1 or 2 are found in Karminski-Zamola, G. et al, Heterocycles 38:759(1994); Divald, S., et al, J. Org. Chem. 41:2835(1976); and Bury, P., et al, Tetrahedron 50:8793 (1994).
Scheme 2a illustrates the synthesis of compounds 12 representing the subclass of compounds for which R2 is Formula II, where Ar=2-thiazolyl, Y=bond and Z=NR5R6. Starting with compound 1 (L=Br) and using the sequential displacement methodology discussed for Scheme 1a, R21 can be first introduced to give 7. This is followed by a second displacement with a metal cyanide such as copper (I) cyanide, sodium cyanide or lithium cyanide and most preferably copper (I) cyanide at a temperature of 80-200xc2x0 C. and preferably at 100-140xc2x0 C., in a polar aprotic solvent, preferably DMF or DMSO, to give 8. After esterification by any of the means described for the conversion of 3 to 4, conversion to the thioamide is carried out by treatment of the nitrite with any of the methods well known in the art (see for example Ren, W., et al., J. Heterocyclic Chem. 23:1757 (1986) and Paventi, M. and Edward, J. T., Can. J. Chem. 65:282 (1987)). A preferable method is treatment of the nitrile with hydrogen sulfide in the presence of a base such as a trialkyl or heterocyclic amine, preferably triethylamine or pyridine, in a polar solvent such as acetone, methanol or DMF and preferably methanol. Conversion to the thiazole can be executed by classical Hantzsch thiazole synthesis followed by amidine formation as discussed in Scheme 1b.
Scheme 2b illustrates the synthesis of compounds representing the subclass of compounds for which R2 is Formula II where, in addition to being an alternate route to Ar=2-thiazolyl (20) (see 12, Scheme 2a) also provide compounds of Formula II where Ar=2-oxazolyl (16) or 2-imidazolyl (18) (Y=bond and Z=NR5R6). Starting with compound 9, a selective hydrolysis of the nitrile with a tetrahalophthalic acid, preferably tetrafluoro- or tetrachlorophthalic acid, can be used to give 7 according to the method of Gribble, G. W., et al., Tetrahedron Lett. 29: 6557 (1988). Conversion to the acid chloride can be accomplished using the procedures discussed for conversion of 3 to 4, preferably with oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF. Coupling of the acid chloride to an aminoketone (R26COCH(R27)NH2) can be performed in the presence of an acid scavenger, preferably N,N-diisopropylethylamine (DIEA) or pyridine in a suitable solvent such as DMF, dichloromethane or tetrahydrofuran (THF) to afford the common intermediate 14. Alternatively coupling of the acid chloride to a less-substituted aminoketone (R26COCH2NH2) can be used followed by optional alkylation with alkylating agent R27L in the presence of a base, preferably NaH or t-BuOK. Transformation of 14 to the corresponding 2-oxazolyl (15), 2-imidazolyl (17) or 2-thiazolyl (19) esters can carried out by the methodology of Suzuki, M., et al., Chem. Pharm. Bull. 34:3111 (1986) followed by amidination according to Scheme 1b. In addition, direct conversion of ketoamide 14 to imidazolyl derivative 18 is possible under the same conditions for conversion of 17 to 18 when conducted for extended periods, preferably greater than 2 h.
Scheme 2c describes a general route to the synthesis of oxazoles, imidazoles and thiazoles of structure 27, 29 and 31 respectively. Acid 2 (see Scheme 1a) is converted to the ester by methods that are well known in the art (Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, Inc. 1991). For example methyl ester 21 is formed by treating the acid in an appropriate solvent such as methanol with trimethylsilyldiazomethane. Alternatively the acid is treated with oxalyl chloride and catalytic amounts of dimethylformamide (DMF) in an appropriate solvent such as dichloromethane to form the acid chloride, which is then treated with methanol to give the methyl ester. Ester 21 is treated with a palladium (0) catalyst such as palladium tetrakistriphenylphosphine, and an alkylstannane such as hexa-n-butyldistannane or tri-n-butyltin chloride in an appropriate solvent such as DMF at elevated temperatures (50xc2x0 C.-120xc2x0 C.) to give the arylstannane of general structure 22 (Stille, J. K., Angew. Chem. Int. Ed. Engl. 25:508-524 (1986)). The stannane 22 is then treated with acid chlorides in the presence of a palladium(0) catalyst to give ketone 23. The ketone is treated with ammonia/ammonium chloride to give amine 24. Alternatively the ketone is reacted with an azide such as sodium azide in a suitable solvent such as DMF, and the resulting azidoketone is reduced to amine 23 with a suitable reducing agent such as catalytic hydrogenation in the presence of palladium on carbon and an acid such as HCl (Chem. Pharm. Bull. 33:509-514 (1985)). Ketoamides 25 are formed by coupling the ketoamine 24 with a variety of suitably functionalized acid chlorides. Alternatively amide coupling may be performed using any of a number of peptide coupling reagents such as 1,3-dicyclohexylcarbodiimide (Sheehan, J. C. et al., J. Am. Chem. Soc., 77:1067 (1955)) or Castro""s reagent (BOP, Castro, B., et al., Synthesis 413 (1976)). In another approach, amides 25 are formed directly from ketones 23 by reacting with various amide salts in an appropriate solvent such as DMF. The amide salts are generated by treating the amides with a suitable base such as sodium hydride (NaH). For example acetamide is treated with NaH in DMF at 0xc2x0 C. to give sodium acetamide. Keto amide 25 is cyclized to the oxazole 26, imidazole 28 and thiazole 30 using procedures similar to that shown in scheme 2b. Oxazole 26, imidazole 28 and thiazole 30 are treated with trimethylaluminum and ammonium chloride in refluxing toluene to give the amidines 27, 29 and 31 respectively.
Scheme 2d illustrates to the preparation of compounds of Examples 42-43, where R 21 and R43 correspond in Formula I to groups R3 and R2, respectively. The acids 2 can be converted to the stannane by treatment with base, such as n-butyl lithium or sec-butyl lithium, followed by trimethyltin chloride. The resulting acid can be then converted to the ester 22 by methods that are well known in the art (Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, Inc. 1991). For example the methyl ester can be made by treating the acid 2 in a suitable solvent such as methanol with trimethylsilyldiazomethane. The stannane 22 can be reacted with suitable halides in the presence of catalytic amounts of a palladium catalyst, such as palladium tetrakistriphenylphosphine, to give the esters 32 (Stille, J. K., Angew. Chem. Int. Ed. Engl. 25:508-524 (1986)). These esters are then treated with trimethylaluminum and ammonium chloride in refluxing toluene to give the amidines 33. In the case where R43Ln (n=2), this can be cross-coupled to an aryl, heteroaryl or vinyl boronic acid or ester to give compounds 34 (Miyaura, N. and Suzuki, A., Chem. Rev. 95:2457-2483 (1995)). This can usually be done in the presence of catalytic amounts of a palladium (0) catalyst such as tetrakistriphenylphosphine palladium and a base such as potassium carbonate in DMF at 90xc2x0 C. Similar cross-coupling reactions can also be achieved by using aryl, heteroaryl and vinyl stannanes instead of boronic acids or esters. These esters are converted to the amidines 35 in the manner previously described.
Scheme 2e represents a modification to the methodology outlined in Scheme 2b which allows synthesis of compounds of Formula II where Ar=2-thiazolyl, 2-oxazolyl or 2-imidazolyl (Y=bond and Z=NR5R6) but which are regioisomeric to 16, 18 or 20 in the relative positions of substituents R26 and R27. This is illustrated in Scheme 2b by the synthesis of 2-oxazolyl derivative 39. Thus, acid 13 can be coupled to an hydroxy-containing amine R27CH(NH2)CH(R26)OH to give amide 36 by any of a number of amide coupling reagents well known in the art (see Bodanszky, M. and Bodanszky, A., The Practice of Peptide Synthesis, Springer-Verlag, New York (1984)). More preferably 13 can be converted to the corresponding acid chloride using any of the procedures mentioned for conversion of 3 to 4 followed by treatment with the R27CH(NH2)CH(R26)OH in the presence of an acid scavenger, preferably N,N-diisopropylethylamine (DIEA) or pyridine in a suitable solvent such as DMF, dichloromethane or tetrahydrofuran (THF) to give 36. Oxidation of the alcohol 36 to the aldehyde 37 (R26=H) or ketone 37 (R26=alkyl, aryl, aralkyl, heterocycle) can be effected by any of a number of common methods known in the art (see for example F. Carey, F. A., Sundberg, R. J. Advanced Organic Chemistry, Part B: Reactions and Synthesis, 3rd Edition, Plenum Press, New York (1990)), preferably by a mild Moffatt-type oxidation such as a Swern oxidation (Mancuso, A. J., Huang, S. L. and Swern, D., J. Org. Chem. 3329 (1976)) or more preferably using Dess-Martin reagent (Dess, D. B. and Martin, J. C., J. Org. Chem. 48:4155 (1983)). Conversion to the heterocycle (in this case the oxazole) is effected with any of a number of reagents including phosphorus oxychloride, P2O5 or thionyl chloride (see Moriya, T., et al., J. Med. Chem. 31:1197 (1988) and references therein). Alternatively closure of 37 with either Burgess reagent or under Mitsunobu conditions affords the corresponding oxazolinyl derivatives (Wipf, P. and Miller, C. P., Tetrahedron Lett. 3: 907 (1992)). Final amidination to 39 as in Scheme 1b completes the synthesis.
Scheme 2f illustrates a general approach to the synthesis of thiazoles of structure 43 (Formula H, X=S, Ar thiazolyl). Nitriles of structure 40 can be treated with hydrogen sulfide (H2S) in a suitable solvent such as methanol, or pyridine in the presence of a base such as triethyamine to give thioamides 41 (Ren, W. et al., J. Heterocyclic Chem. 23:1757-1763 (1986)). Thioamides 41 can be then treated with various haloketones 42 preferably bromoketones under suitable reaction conditions such as refluxing acetone or DMF heated to 50xc2x0 C.-80xc2x0 C. to form the thiazoles 43 (Hantzsch, A. R. et al., Ber. 20:3118(1887)).
Scheme 2g illustrates one synthetic route to 2-haloketones of structure 42 which are employed in the synthesis of thiazolyl derivatives as in Schemes 2a and 2f. 2-Bromoketones 42 (L=Br) are prepared by treating the ketone 44 with a suitable brominating agent such as Br2 or N-bromosuccinimide in a suitable solvent such as chloroform or acetic acid (EP 0393936 A1). Alternatively, the ketone 44 is treated with a polymer-supported brominating agent such as poly(4-vinyl)pyridinium bromide resin (Sket, B., et al., Synthetic Communications 19:2481-2487 (1989)) to give bromoketones 42. In a similar fashion 2-chloroketones are obtained by treating 44 with copper (II) chloride in a suitable solvent such as chloroform (Kosower, E. M., et al., J. Org. Chem. 28:630 (1963)).
Scheme 2h illustrates another synthetic route to 2-haloketones of structure 42 which is particularly useful in that it employs acids 45 or activated carbonyl compounds such as 46 as precursors which are more readily available than the ketones 44. The acid 45 is converted to the acid halide 46 (L=Cl, Br or OCOR39) by treating with a suitable halogenating reagent. For example, an acid chloride is formed by treating 45 with oxalyl chloride and catalytic amounts of DMF in dichloromethane. The acid chloride is converted to a diazoketone by treatment with trimethysilyldiazomethane (Aoyama, T. et al., Tetrahedron Lett. 21:4461-4462 (1980)). The resulting diazoketone is converted to a 2-haloketone of structure 42 by treatment with a suitable mineral acid. For example a bromoketone is formed by treating the diazoketone in a suitable solvent such as acetonitrile (CH3CN) with a solution of 30% hydrogen bromide (HBr) in acetic acid (Organic Synthesis Collective Vol III, 119, John Wiley and Sons, New York, Ed. Horning E. C.). In an alternative approach the acid 45 is converted to the mixed-anhydride 46 by treatment with a suitable chloroformate such as isobutyl chloroformate or tert-butyl chloroformate in a suitable solvent, such as tetrahydrofuran or dichloromethane, in the presence of a base such as N-methylmorpholine. The mixed anhydride 46 is converted to a diazoketone by treatment with trimethylsilyldiazomethane and the resulting diazoketone is converted to a haloketone in the manner described above.
When amide coupling as described in Scheme 2e is followed directly by amidination, compounds of Formula I where R2 or R3 is aminoacyl or aminoiminomethyl can be derived. Thus, coupling of acid 13 (or the corresponding acid chloride as previously described) with an amine R51R52NH can afford 130 which can be carried on to the amidine 131. Upon either longer or more vigorous additional treatment (for example, higher temperatures) with a Lewis acid-ammonia reagent as described in Scheme 1b, the amide group can be converted to an aminoiminomethyl group to give a bisamidine compound 132.
Acid 13 can also be converted to an amine 47 from which sulfonamides, ureas and urethanes can be formed (Formula I where R2 or R3=NR32SO2R31, NHCONR51R52 or NHCOR31, respectively). Scheme 3a illustrates this methodology for introduction of these three groups at R2 of Formula I. Conversion of the acid 13 to an intermediate acyl azide can be followed by heating of such azide in the presence of an alcohol under Curtius rearrangement conditions to form the carbamate ester of the alcohol. Subsequent carbamate ester hydrolysis yields amine 47. The intermediate acyl azide may be synthesized by coupling the acid 13 to hydrazine through the acid chloride or by any of the amide coupling procedures discussed for Scheme 2e followed by nitrosation of the resulting hydrazide by any of the nitrosating agents discussed for conversion of 3 (R1=NH2) to 3 (R1=H) in Scheme 1c. More preferably conversion of 13 to 47 is carried out through treatment of acid 13 with diphenylphosphoryl azide in the presence of an alcohol, preferably tert-butanol, and a base, preferably triethylamine or DIEA, as shown in Scheme 3a, to give a tert-butylcarbamate that is readily decomposed to the salt of amine 47 on exposure to an acid, preferably HCl or trifluoroacetic acid in a suitable solvent such as CH2Cl2. Further treatment with a base such as NaOH or preferably K2CO3 or NaHCO3 provides the free base 47. Treatment of amine 47 with a sulfonyl chloride R31SO2Cl in the presence of an acid scavenger, such as pyridine or DIEA, followed by optional alkylation on nitrogen with an alkylating agent R32L in the presence of a base such as K2CO3, DIEA or more preferably sodium hydride, in a solvent such as THF, MeCN or CH2Cl2 affords the sulfonylamine functionality at R2 (48). When necessary, this transformation can be catalyzed by the presence of 4-dimethylaminopyridine for less reactive sulfonyl chlorides. Similar treatment of amine 47 with an isocyanate R51NCO or carbamyl chloride R51R52COCl affords the aminocarbonylamine functionality at R2 (50). Similar treatment of amine 47 with an acid chloride R31COCl affords the carbonylamine functionality at R2 (52). Conversion of the esters in 48, 50 and 52 to amidines as previously mentioned gives the products 49, 51 and 53. Further conversion of the acylamino group of 53 as discussed for synthesis of 132 also provides access to the iminomethylamino group at R2 (54).
Introduction of an aminosulfonyl group (including monoalkylaminosulfonyl and dialkylaminosulfonyl groups) for R2 of Formula I can be carried out starting from amine such as 47 as well. Conversion to a sulfonyl chloride by the method of Gengnagel, et al. (U.S. Pat. No. 3,947,512 (1976)) and treatment with an amine R34NH2 followed by optional alkylation on nitrogen with R35L (under the sulfonylation and alkylation conditions described in Scheme 3a) provides 56 which is further converted to amidines 57 as previously described.
Scheme 4a illustrates the preparation of the compounds of Formula III and Examples 48-59 and 61-77. The amidine moiety of compounds of structure 60 can be protected with a protecting group P1 that can be readily removed from 62 and 64 using methods known to those skilled in the art (Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, Inc. 1991). For example, a t-butoxycarbonyl (BOC) protecting group can be removed by exposure to strongly acidic medium such as hydrogen chloride in a suitable solvent such as dioxane, or by trifluoroacetic acid in a suitable solvent such as methylene chloride. Benzyloxycarbonyl (Cbz) protecting groups can be removed by catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran.
In some cases, P1 can be a solid support such as polystyrene or polyethyleneglycol-grafted polystyrene which can be attached to the amidine moiety via a cleavable linker such as 4-(benzyloxy)benzyloxy-carbonyl (using carbonate Wang resin). Attaching an amidine to a solid support can be achieved by treating a solid support having a linker containing an appropriately activated functional group with the amidine under suitable conditions. For example, an amidine can be attached to Wang resin by treating para-nitrophenylcarbonate Wang resin with the amidine and a suitable base such as DBU in a suitable solvent such as DMF. When D is OH or SH the protected amidines 61 can be alkylated with carboxy-protected (protecting group is R36) haloaliphatic acids, such as bromoacetic acid or bromopropionic acid in the presence of a suitable base such as cesium carbonate or DIEA, in a suitable solvent such as DMF with heating when necessary to give compounds of structure 62. When D is NO2, the nitro group can be reduced prior to alkylation using an appropriate reducing agent, such as tin (II) chloride, in a suitable solvent such as DMF, or by catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran. Other useful carboxy protecting groups are well known in the art (Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, Inc. 1991). For example, tert-butyl ester can be removed by exposure to strongly acidic medium such as hydrogen chloride in a suitable solvent such as dioxane or trifluoroacetic acid in a suitable solvent such as methylene chloride. Benzyl ester can be removed by catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as ethanol or tetrahydrofuran or by base hydrolysis.
When protecting groups P1 and R36 in compounds 62 are orthogonal (as defined by the ability to remove one protecting group preferentially in the presence of the other), R36 can be preferentially removed to give acids 63. For example when P1 is BOC and R36 is OME, the methyl ester can be removed by treating with a base such as sodium hydroxide in a suitable solvent such as aqueous tetrahydrofuran leaving the BOC group intact. When protecting groups P1 and R 36 in compounds 62 are not orthogonal, both protecting groups are removed, and the amidine can be protected with a suitable protecting group such as BOC or a suitably functionalized resin. The protected amidine 63 can be treated with various amines under suitable amide coupling conditions, such as in the presence 1-hydroxy-7-azabenzotriazole (HOAt), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and DIEA to form amides of structure 64. The amidine protecting group can be then removed, for example by treating with an acid, such as trifluoroacetic acid in a suitable solvent such as methylene chloride, when a BOC protecting group is employed, to give amidines 65 .
Scheme 4b illustrates a specific example which utilizes the method described in Scheme 4a. The amidine moiety of 66 can be monoprotected with a tert-butyloxycarbonyl group. The monoprotected phenoxyamidine 67 can be alkylated on the phenolic hydroxy group with an ester of 2-bromoacetic acid to give 68. In the case where the ester can be removed by base, it can be hydrolyzed with aqueous base, such as NaOH, to give the acid 69. This acid can be treated with various amines in the presence of 1-hydroxy-7-azabenzotriazole (HOAt), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and DIEA to form amides of structure 70. The amines are unsubstituted, di- or mono-substituted aliphatic or aromatic amines. In some cases the amines are cyclic-amines such as piperazine and piperidine. The amides 70 are then treated with trifluoroacetic acid to give the amidines 71. In the case where the ester 68 is acid-labile, it can be treated with trifluoroacetic acid to give the amidino-acid 72. This amidine can be loaded on to an insoluble support, such as polystyrene or polyethyleneglycol-grafted polystyrene via a cleavable linker, such as Wang, which is functionalized as an activated carbonate such as p-nitrophenylcarbonate or succinimidyl carbonate. Generally this can be done by treating the activated carbonate resin with the amidine and a suitable base such as DBU in a suitable solvent such as DMF. The support-bound acid 73 can be treated with various amines in the presence of 1-hydroxy-7-azabenzotriazole (HOAt), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and DEEA to form amides. These amides are then cleaved from the solid support by treating with trifluoroacetic acid to give compounds of structure 71.
Scheme 5 illustrates a synthetic route to amidines containing di-substituted thiazoles represented by compounds for which R2 is Formula II and both R8 and R9 are non-hydrogen substituents. The ketoamide 74 can be converted to the mono-bromoketoarnide by treating with bromine in acetic acid. Thiazoles 76 are formed by reacting the bromoketoamide with 10 under suitable conditions, preferably by heating the mixture in DMF or acetone. Amidines 77 are formed by heating 76 in toluene with trimethylaluminum and ammonium chloride. The amidines 77 are treated with strong acid such as HCl to give the acids 78. The amidines 78 are in one route protected with a suitable protecting group such as BOC to give 79. The protected amidines 79 are treated with various amines under suitable coupling conditions, such as in the presence of HOAt, HATU, and DIEA to form various amides. The amidine protecting group can be then removed, for example by treating with trifluoroacetic acid in a suitable solvent such as methylene chloride, when a BOC protecting group is employed to give amidines 80. In a second route, the amidines 78 can be loaded onto an insoluble support, such as polystyrene or polyethyleneglycol-grafted polystyrene via a cleaveable linker, such as Wang resin, which is functionalized as an activated carbonate ester, such as p-nitrophenylcarbonate or succinimidyl carbonate, to give a resin-bound scaffold 81. The resin-bound acid 81 can be treated with various amines under suitable coupling conditions such as in the presence of HOAT, HATU and DIEA to form amides. These amides are then cleaved from the solid support by treating with trifluoroacetic acid to give amidines 80.
Scheme 6a illustrates the preparation of compounds of Examples 34, 35, 36, 37, 38, 39, 40, and 41. Compounds of this invention correspond to those of Formula I where R2 is Formula II and where Ar is thiazole and R37 and R38 (R8 and R9 of Formula II) are phenyl, which can be additionally substituted. Starting from 2,5-dibromothiophene 90, treatment with lithium diisopropylamide followed by R21L, where L is a leaving group, preferably a halogen, mesylate, tosylate, or methyl sulfate, and more preferably iodomethane or methyl sulfate, according to the procedure of Kano, et al., Heterocycles 20(10):2035 (1983), gives 91. Compound 91 can be treated with an appropriate base, preferably a lithium alkyl like n-butyllithium, sec-butyllithium, or t-butyllithium, and more preferably n-butyllithium, followed by carbon dioxide gas and conversion of the resulting carboxylate salt to the free acid with a mineral acid, preferably hydrochloric acid. Conversion to ester 21 can be carried out by preparation of the acid chloride using oxalyl chloride and treatment of this intermediate acid chloride with an alcohol R23 in an appropriate solvent, preferably dichloromethane, with an appropriate base, preferably pyridine. Compound 21 can be treated with copper (I) cyanide in refluxing dimethylformamide to give compound 9. Compound 9 can be treated with hydrogen sulfide gas in an appropriate solvent, preferably methanol, containing an appropriate base, preferably triethylamine to give compound 10. Compound 10 can be treated with an appropriate ketone where L is a leaving group, preferably halogen, mesyl, or tosyl, and most preferably bromo, refluxing in a suitable solvent, preferably, acetone, dimethylformamide, dimethyl acetamide, methyl ethyl ketone, or other polar aprotic solvents, and most preferably acetone to give compound 92. Compound 92 is treated with an appropriate reagent, preferably the aluminum amide reagent to give amidine 93.
Scheme 6b illustrates the preparation of the compound of Example 34, which corresponds to a compound for which R2 is Formula II, and where Ar is thiazole and R8 and R9 (R37 and R38 in Scheme 6b) are phenyl, which can be optionally substituted. Starting from 2,5-dibromothiophene 90, treatment with n-butyllithium produces an anion which undergoes a rearrangement (Kano, S., et al, Heterocycles 20:2035 (1983)). Quenching with carbon dioxide gas and conversion of the resulting carboxylate salt to the free acid with a mineral acid, preferably hydrochloric acid, gives acid 94. Conversion to ester 95 can be carried out by preparation of the acid chloride using oxalyl chloride and treatment of this intermediate acid chloride with an alcohol R23xe2x80x94OH in an appropriate solvent, preferably dichloromethane, with an appropriate base, preferably pyridine. Compound 95 can be treated with copper (I) cyanide in refluxing dimethylformamide to give compound 96. Compound 96 can be treated with hydrogen sulfide gas in an appropriate solvent, preferably methanol, containing an appropriate base, preferably triethylamine to give compound 97. Compound 97 can be treated with an appropriate ketone where L is a leaving group, preferably halogen, mesyl, or tosyl, and most preferably bromo, refluxing in a suitable solvent, preferably, acetone, dimethylformamide, dimethyl acetamide, methyl ethyl ketone, or other polar aprotic solvents, and most preferably acetone to give compound 98. Compound 98 is treated with an appropriate reagent, preferably the aluminum amide reagent (Al(CH3)3/NH4Cl) to give amidine 99.
Scheme 7a illustrates the preparation of compounds for which R2 is Formula II and Ar is thiazol-4-yl. As illustrated, the acids 13 can be converted to their acid chlorides by treatment with oxalyl chloride with dimethylformamide catalysis in methylene chloride, or by using thionyl chloride, either neat or in an organic solvent, at ambient or elevated temperature. Compounds are then homologated to the desired a-haloketones 100 by sequential treatment with trimethylsilyldiazomethane and hydrogen bromide. An alternative would be to substitute diazomethane (generated from Diazald(copyright), Aldrich Chemical Co., Milwaukee, Wis.) for the trimethylsilyldiazomethane. Also, the conversion of 13 to 100 can be effected using the procedure derived for the synthesis of compound 42 from compound 46.
The alpha-haloketones 100 are then allowed to react with the appropriate thiourea (Scheme 7b) or thioamide derivative in an organic solvent, preferably acetone or dimethylformamide at 70xc2x0 C. to give 2-aminothiazoles or thiazoles 101.
The thiazoles 101 can be treated with the aluminum amine reagent (Al(CH3)3/NH4CL) formed at ambient temperature by the reaction of trimethylaluminum with ammonium chloride in an organic solvent, preferably toluene. The ester can then be converted to the amidines 102 at elevated temperatures, preferably higher than 80xc2x0 C.
As shown in Scheme 7b, amines 110 (or their hydrochloride salts) can be converted to their respective mono-substituted thioureas (methan-1-thiones) 112 by treatment with thiophosgene to form the intermediate isothiocyanates 111. Preferred conditions include treating the amine with thiophosgene in a biphasic solvent system composed of a halogenated solvent such as chloroform and an aqueous phase of saturated sodium bicarbonate. Alternatively, the reaction may be effected by treatment of 110 with a hindered amine and thiophosgene such as triethylamine or diisopropylethylamine in an organic solvent such as tetrahydrofuran or methylene chloride. Another alternative to forming isothiocyanates 111 is the direct treatment of primary amines and carbon disulfide in pyridine with dicyclohexylcarbodiimnide (Jochims, Chem. Ber. 101: 1746 (1968)).
Isothiocyanates 111 can be converted to thioureas 112 by treatment with an ammonia-alcohol solution, preferably a 2M ammonia in methanol or ethanol solution, at room temperature or elevated temperatures ( greater than 70xc2x0 C.). Alternatively, the thioureas 112 can be prepared directly form the appropriate urea (or thioamide from the appropriate amide when R8=alkyl or aryl)) by treatment with Lawesson""s reagent (Lawesson, S.-O., et. al. Bull. Soc. Chim. Belg. 87:223, 293 (1978)).
Scheme 8 illustrates the preparation of compounds of this invention where R2 is Formula II and Ar is thiazole and R37 and R38 are phenyl which is further substituted by a sulfonylamino or carbonylamino group. Starting from thioamide 10, treatment with a nitro substituted 2-halo-acetophenone, where the halogen is chloro, bromo, or iodo, preferably bromo, refluxing in a suitable solvent, preferably acetone, dimethylformamide, dimethyl acetamide, methyl ethyl ketone, or other polar aprotic solvents, and most preferably acetone. The reduction of nitroaryl compound 113 can be carried out with a suitable reducing agent, preferably tin (II) chloride, titanium (II) chloride, iron (III) chloride, lithium metal, sodium metal, catalytic hydrogenation over platinum or palladium catalyst, and most preferably 20% aqueous solution of titanium (III) chloride. The acylation of aniline 114 can be carried out with an appropriate acyl compound R42 where L is a halogen, preferably chloro, in an appropriate solvent, preferably dichloromethane, containing a base, preferably pyridine, N-methylmorpholine, or diisopropylethylamine. Alternatively, the acylation of aniline 114 is carried out with an activated carboxylic acid compound R42 where L is hydroxy activated with dicyclohexylcarbodiimide, ethyl-3-(diethylamino)propylcarbodiimide (EDAC), O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HATU), or pentafluorophenyl. The sulfonylation of aniline 114 can be carried out with and appropriate sulfonyl chloride compound R41 in an appropriate solvent, preferably dichloromethane, containing a base, preferably N-methyl morpholine, diisopropylethylamine, or pyridine, most preferably N-methyl morpholine, with or without a condensation catalyst, preferable dimethylaminopyridine (DMAP). The amidinylation of compounds 115 and 117 can be carried out with an appropriate reagent, preferably the aluminum amide reagent (Al(CH3)3/NH4Cl).
Scheme 9 illustrates the preparation of compounds of Formula I, for which one of R5 and R6 is a non-hydrogen substituent. The amidines 5 are converted to the amidoximes 119 by heating with hydroxylamine in a suitable solvent such as ethanol. The cyanoamidines 120 are prepared by heating the amidines 5 with cyanamide in a suitable solvent such as ethanol. (Huffman, K. R. and Schaeffer, F., J. Amer. Chem. Soc. 28:1812 (1963). Alternatively 5 can be heated with an amine such as methylamine to give the N-alkylated amidines 121.

Methods of treating C1s-mediated diseases and conditions and compositions thereof

Abstract: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein R1, R2, R3, R4, X, Y and Z are defined in the specification.