WO2010059372A2 - Aminopyridines inhibant l'enzyme tryptase - Google Patents

Aminopyridines inhibant l'enzyme tryptase Download PDF

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WO2010059372A2
WO2010059372A2 PCT/US2009/062546 US2009062546W WO2010059372A2 WO 2010059372 A2 WO2010059372 A2 WO 2010059372A2 US 2009062546 W US2009062546 W US 2009062546W WO 2010059372 A2 WO2010059372 A2 WO 2010059372A2
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compound
alkyl
heteroaryl
alkenyl
aryl
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PCT/US2009/062546
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WO2010059372A3 (fr
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Randall S. Alberte
William P. Roschek, Jr.
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Herbalscience Group, Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to small molecule inhibitors of the tryptase enzyme that are useful for treating allergic rhinitis, asthma, vascular injury (e.g., restenosis and atherosclerosis), inflammatory bowel disease, arthritis, psoriasis, anaphylaxis, wounds, infections, and other allergy and inflammatory related diseases.
  • vascular injury e.g., restenosis and atherosclerosis
  • inflammatory bowel disease e.g., arthritis, psoriasis, anaphylaxis, wounds, infections, and other allergy and inflammatory related diseases.
  • Tryptase is a tetrameric serine protease with a molecular size of 134 kD comprised of four monomers of 32-34 kD, each with one catalytic site (C. P. Sommerhoff, W. Bode, P. J. Pereira, M. T. Stubbs, J. Sturzebecher, G. P. Piechottka, G. Matschiner and A.
  • Mast cells are becoming distinguished as essential sources of inflammatory cytokines, including interleukins 1, 4 and 6, tumor necrosis factor, transforming growth factor, and basic fibroblast growth factor which may have roles in controlling processes of inflammation and fibrosis(J. A. Cairns and A. F. Wells, 1997. Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts, J. Clin. Invest. 99:1313-1321).
  • Hastase Key control points in allergic rhinitis, an inflammatory response to particulates like pollen, dust and related allergens, include the enzymes that control the flow of arachidonic acid into an inflammatory cascade that generates prostaglandins and leukotrienes.
  • the major players in the cascade are histamine production and release (Hi receptors), prostaglandin D 2 Synthase responsible for the production of certain pro-inflammatory prostaglandins, the Leukotriene Receptor that controls pro -inflammatory leukotriene release, and Tryptase.
  • Tryptase in particular, controls the degranulation of Mast cells and certain Basophils that that contain a broad diversity of cytokines and chemokines that drive the inflammatory manifestation of allergic rhinitis; these include, runny nose, itchy and watery eyes, sneezing, itchy skin, and issue swelling (P. Edwards, 2006. Combinatorial approach towards the discovery of tryptase inhibitors, Drug Discov. Today. 11 :181-182; W. Cookson, 2002. Genetics and genomics of asthma and allergic diseases, Immunol. Rev. 190:195-206; J. W. Steinke, S. S. Rich and L. Borish, 2008. Genetics of allergic disease, J. Allergy CHn. Immunol. 121 :S384-S387).
  • Tryptase also plays a critical role in arthritis, as the presence of both major forms of tryptase in synovial fluid indicates that mast cell products are secreted constitutively, as well as by processes of anaphylactic degranulation in conditions of rheumatoid arthritis, seronegative spondylo arthritis and osteoarthritis (M. G. Buckley, C. Walters, W. M. Wong, M. I. Cawley, S. Ren, L. B. Schwartz and A. F. Walls, 1997. Mast cell activation in arthritis: detection of alpha- and beta-tryptase, histamine and eosinophil cationic protein in synovial fluid, CHn. Sci. (Lond.).
  • tryptase serves as a crucial activator of PAR-2-mediated actions (E. B. Kelso, L. Dunning, J. C. Lockart, W. R. Ferrell, R. Pelvin and C. P. Sommerhoff, 2005. Tryptase as a PAR-2 activator in joint inflammation, Arthrit. Res. Ther. 7:P99). Tryptase found in the synovium of rheumatoid arthritis patients was identical to human mast cell tryptase, which was composed of two subunits of 33 and 34 kDa.
  • Mast cell tryptase activity in rheumatoid arthritis synovial fluid was significantly higher than that in osteoarthritis synovial fluid, though it was elevated in osteoarthritis patients as well (S. Nakano, T. Mishiro, S. Takahara, H. Yokoi, D. Hamada, K. Yukata, Y. Takata, T. Goto, H. Egawa, S. Yasuoka, H. Furouchi, K. Hirasaka, T. Nikawa and N. Yasui, 2007. Distinct expression of mast cell tryptase and protease activated receptor-2 in synovia of rheumatoid arthritis and osteoarthritis, Clin. Rheumatol. 26:1284-1292).
  • Fibroblasts are the key mesenchymal cell accountable for the synthesis of interstitial collagen.
  • a characteristic of lung tissue from patients with fibrotic lung disease is an elevated number of mast cells, many of which are in a state of degranulation located in close proximity to proliferating fibroblasts (J. A. Cairns and A. F. Wells, 1997. Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts, J. Clin. Invest. 99:1313-1321).
  • the present invention relates to novel compounds and pharmaceutical compositions comprising these compounds.
  • the present invention relates to a substantially pure and isolated compound of formula I: Attorney Docket No. HXA-008.25
  • R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; wherein any of the aforementioned alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl may be optionally substituted with one or more groups selected from the group consisting of halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl,
  • a 1 is an aryl, such as a phenyl.
  • a 2 is heteroaryl, such as a pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine.
  • the heteroaryl is pyridine.
  • the heteroaryl is substituted Attorney Docke
  • SR 10 -S(O)OR 10 , -S(O) 2 OR 10 , -S(O) 2 N(R 10 ) 2 , Or-SC(O)R 10 .
  • the heteroaryl is substituted with SR 10 .
  • R 10 is hydrogen.
  • R is alkyl, heterocycloalkyl, alkenyl, alkynyl, aralkyl, or hetero aralkyl, wherein the alkyl, alkenyl, alkynyl, aralkyl, or hetero aralkyl may be optionally substituted with one or more groups selected from the group consisting of halo, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hetero aralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, amido, acyl, carboxyl, oxycarbonyl, acyloxy, thioether, sulfonate, sulfonyl, sulfonamido, formyl, cyano and isocyano.
  • R is alkyl, heterocycloalkyl
  • Another aspect of the invention relates to a substantially pure and isolated compound of formula II:
  • a 1 is aryl or heteroaryl
  • a 2 is aryl or heteroaryl
  • R' is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or hetero aralkyl; wherein any of the aforementioned alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or hetero aralkyl may be optionally substituted with one or more groups selected from the group consisting halo, azido, alkyl, haloalkyl, fluoroalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hetero aralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, arylamino, acylamino, hetero arylamino, nitro, sulfhydry
  • a 1 is phenyl, naphthyl, anthracyl, pyrenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl.
  • a 1 is a phenyl, such as a mono substituted phenyl.
  • a 2 is benzyl, naphthyl, anthracyl, pyrenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl.
  • a 2 is a pyridinyl, such as a monosubstituted pyridinyl.
  • R' is alkyl, aralkyl or heteroalkyl. In certain embodiments, R' is C 5 -Ci 5 alkyl. Another aspect of the invention relates to a substantially pure and isolated compound of formula III:
  • R is alkyl, alkenyl, alkynyl, aralkyl, or hetero aralkyl
  • R 1 to R 9 are halo, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hetero aralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, arylamino, acylamino, hetero arylamino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl, acyloxy, silyl, thioether, sulfonate, sulfonyl, sulfonamido, formyl, cyano or isocyano; wherein the aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and heteroaralkyl may be optionally substituted with
  • sulfhydryl imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl, acyloxy, silyl, thioether, sulfonate, sulfonyl, sulfonamido, formyl, cyano and isocyano.
  • R is alkyl or alkenyl aralkyl or heteroalkyl.
  • R 6 , R 7 , R 8 , or R 9 is haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, -OR 10 , -OC(O)R 10 , -SR 10 , -S(O)OR 10 , -S(O) 2 OR 10 , -S(O) 2 N(R 10 ) 2 , -SC(O)R 10 , -N(R 10 ) 2 or -N(R 10 )C(O)R 10 ; and R 10 is hydrogen, or alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • R 6 , R 7 , R 8 , or R 9 is hydrogen, or alkyl, haloal
  • -S(O)OR 10 , -S(O) 2 OR 10 , -S(O) 2 N(R 10 ) 2 , or -SC(O)R 10 .
  • at least one of R 6 , R 7 , R 8 , or R 9 is -SR 10 .
  • -R 10 is hydrogen.
  • Another aspect of the invention relates to a pure and isolated compound of formula IV:
  • R' is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; and Attorney Docket No. HXA-008.25
  • R 1 to R 9 are halo, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hetero aralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, arylamino, acylamino, hetero arylamino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl, acyloxy, silyl, thioether, sulfonate, sulfonyl, sulfonamido, formyl, cyano or isocyano; wherein the aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and heteroaralkyl may be optionally substituted with
  • R is C5-C15 alkyl, such as -CH 2 (CH 2 )4CH3.
  • R 1 is hydrogen.
  • R 2 is hydrogen. In other embodiments, R 3 is hydrogen.
  • R 3 is alkyl, such as -CH 3 , -CH 2 CH 3 or -CH 2 CH 2 CH 3 . In other embodiments, R is -CH 3 . In some embodiments, R 4 is hydrogen.
  • R 5 is hydrogen. In other embodiments, R 6 is hydrogen. In other embodiments, R 7 is hydrogen.
  • R 7 is -SR 10 ; and R 10 is hydrogen or alkyl.
  • R 7 is -SH.
  • R 8 is hydrogen. In other embodiments, R 9 is hydrogen. Attorney Docket No. HXA-008.25
  • Another aspect of the invention relates to a substantially pure and isolated compound represented by (v):
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any of the aforementioned compounds and a pharmaceutically acceptable carrier.
  • Another aspect of the invention provides a method of treating or preventing a tryptase enzyme mediated condition in a subject in need thereof comprising administering to the subject an effective amount of a compound of any of the aforementioned compounds or compositions.
  • the tryptase enzyme mediated condition is an inflammatory or allergic condition.
  • the tryptase enzyme mediated condition is allergic rhinitis, asthma, vascular injury, inflammatory bowel disease, psoriasis, arthritis, anaphylaxis, a wound, or an infection.
  • the vascular injury can be, for example, restenosis or atherosclerosis.
  • the arthritis is rheumatoid arthritis, osteoarthritis or seronegative spondy Io arthritis.
  • the subject is a mammal.
  • subject is a primate, such as a human.
  • the present invention relates to a mixture comprising at least 10% of any of the aforementioned compounds.
  • the compound comprises at least 25% of the mixture.
  • the compound comprises at least 75% of the mixture.
  • the compound comprises at least 95% of the mixture.
  • the present invention relates to a compound of the present invention that possesses tryptase inhibition activities in the range of 19 ⁇ M and 3.6 mM.
  • Figure 1 depicts the dose-dependent inhibition of the tryptase enzyme with a Attorney Docket No. HXA-008.25
  • Figure 2 depicts the interaction of a compound of the present invention with the tryptase enzyme active site indicating a strong hydrogen bond between the aromatic thiol of compound [V] and Glycine 60 of the tryptase active site.
  • the toluene (a.k.a. methylbenzene) functional group of compound [V] is efficiently incorporated into the hydrophobic pocket of the active site created by the amino acid residues Valine 35, Valine 59, Glycine 60, and Leucine 64 increasing the stability of the bound inhibitor.
  • R'n wherein R' ⁇ ⁇ represents hydrogen, alkyl, alkenyl, alkynyl, or -(CH2) m -Rg0' wherein RgQ is aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocyclyl; and m is an integer in the range 0 to 8, inclusive.
  • alkyl refers to a radical of a saturated straight or branched chain hydrocarbon group of, for example, 1-20 carbon atoms, or 1-12, 1-10, or 1-6 carbon atoms.
  • alkenyl refers to a radical of an unsaturated straight or branched chain hydrocarbon group of, for example, 2-20 carbon atoms, or 2-12, 2-10, or 2-6 carbon atoms, having at least one carbon-carbon double bond.
  • aliphatic includes linear, branched, and cyclic alkanes, alkenes, or alkynes.
  • aliphatic groups in the present invention are linear, branched or cyclic and have from 1 to about 20 carbon atoms.
  • aralkyl includes alkyl groups substituted with an aryl group or a heteroaryl group.
  • heteroatom includes an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur.
  • halo or halogen includes -F, -Cl, -Br, - or -I.
  • perfluoro refers to a hydrocarbon wherein all of the hydrogen atoms have been replaced with fluorine atoms.
  • -CF3 is a perfluorinated methyl group.
  • heterocycle refers to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered ring containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Heterocycles can be aromatic (heteroaryls) or non-aromatic.
  • Heterocycles can be substituted with one or more substituents including alkyl, alkenyl, alkynyl, aldehyde, alkylthio, alkanoyl, alkoxy, alkoxycarbonyl, amido, amino, aminothiocarbonyl, aryl, arylcarbonyl, arylthio, carboxy, Attorney Docket No. HXA-008.25
  • Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from aryls, cycloalkyls, and heterocycles.
  • Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, o
  • Each of the rings of the polycycle may be substituted with such substituents as described above and can be substituted with groups selected from alkyl, alkenyl, alkynyl, alkanoyl, alkoxy, alkoxy, alkylthio, amino, amido, aryl, aralkyl, azide, carbonyl, carboxy, cyano, cycloalkyl, ester, ether, halogen, haloalkyl, heterocyclyl, hydroxy, imino, ketone, nitro, perfluoroalkyl, phosphonate, phosphinate, silyl ether, sulfonamido, sulfonate, sulfonyl, and sulfhydryl.
  • carrier includes an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • amine and “amino” include both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
  • R51 R52 wherein R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, - (CH2) m -R61 , or R50 and R51 , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
  • only one of R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogen together do not form an imide.
  • R50 and R51 each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2) m -R61.
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
  • acylamino is art-recognized and includes a moiety that may be represented by the general formula:
  • R50 wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or (CH2) m -R61, where m and R61 are as defined above.
  • amino refers to an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:
  • alkylthio includes an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH 2 ) m -R61, wherein m and R61 are defined above.
  • Representative alkylthio groups include methyl thio, ethyl thio, and the like.
  • carbonyl includes such moieties as may be represented by the general formulas:
  • X50 is a bond or represents an oxygen or a sulfur
  • R55 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R61or a pharmaceutically acceptable salt
  • R56 represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -R61, where m and R61 are defined above.
  • X50 is an oxygen and R55 or R56 is not hydrogen
  • the formula represents an "ester”.
  • X50 is an oxygen
  • R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a
  • alkoxyl or "alkoxy” include an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -O- alkynyl, -O-(CH2) m -R61, where m and R61 are described above.
  • sulfonate includes a moiety that may be represented by the general formula:
  • R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • sulfate includes a moiety that may be represented by the general formula:
  • sulfonyl includes a moiety that may be represented by the general formula:
  • R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  • sulfoxido includes a moiety that may be represented by the general formula:
  • substitution is contemplated to include all permissible substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above and as follows. Substitution may be by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogen, trifluoromethoxy, trifluoromethyl, aralkyl, alkenyl, alkynyl, aryl, carboxyalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonamino
  • the linkers are typically short chains of 1-3 atoms containing any combination of -C-, -C(O)- -, -NH-, -S-, -S(O)-, -O-, -C(O)O- or -S(O)-.
  • alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, acyl, amino, amido, etc. may be optionally substituted.
  • aforementioned groups may be optionally substituted with halogen, hydroxy, alkoxy, carboxy, carboxylic ester, nitro, cyano, amino, amido, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heteroaryl, sulfonyl, or sulfonamido.
  • alkyl, cycloalkyl, aryl, and the like wherein one or more hydrogen atoms may be replaced with a substituent such as halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino, amido, nitro, cyano, sulfhydryl, imino, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or hetero aromatic moieties, perfluoroalkyl (e.g.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or Attorney Docket No. HXA-008.25
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • the definition of each expression, e.g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure unless otherwise indicated expressly or by the context.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, /?-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, /?-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms are art recognized and represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p- toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.
  • the term "hydrocarbon” includes all permissible compounds having at least one hydrogen and one carbon atom.
  • permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds that may be substituted or unsubstituted.
  • protecting group includes temporary substituents that protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed. Greene et al, Protective Groups in Organic Synthesis 2 nd ed., Wiley, New York, (1991). Attorney Docket No. HXA-008.25
  • hydroxyl-protecting group includes those groups intended to protect a hydroxyl group against undesirable reactions during synthetic procedures and includes, for example, benzyl or other suitable esters or ethers groups known in the art.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • the term "effective amount” as used herein refers to the amount necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a drug may vary depending on such factors as the desired biological Attorney Docket No. HXA-008.25
  • the drug to be delivered the composition of the encapsulating matrix, the target tissue, etc.
  • a "patient,” “subject” or “host” to be treated by the subject method may mean either a human or non-human animal.
  • the term “tryptase” refers to the most abundant secretory granule- derived serine protease contained in mast cells that has recently been used as a marker for mast cell activation. It is involved with an allergenic response and is suspected to act as a mitogen for fibroblast lines.
  • inhibitor refers to molecules that bind to enzymes and decrease their activity.
  • the binding of an inhibitor can stop a substrate from entering the enzyme's active site and/or hinder the enzyme from catalyzing its reaction.
  • Inhibitor binding is either reversible or irreversible.
  • Irreversible inhibitors usually react with the enzyme and change it chemically. These inhibitors modify key amino acid residues needed for enzymatic activity.
  • Reversible inhibitors bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind the enzyme, the enzyme- substrate complex, or both.
  • mast cell refers to a resident cell of several types of tissues containing many granules rich in histamine and heparin. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing and defense against pathogens.
  • the term "degranulation” refers to a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells. 1 1 is used by several different cells involved in the immune system, including granulocytes (neutrophils, basophils and eosinophils) and mast cells, and certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.
  • granulocytes neutrils, basophils and eosinophils
  • mast cells include granulocytes (neutrophils, basophils and eosinophils) and mast cells, and certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.
  • NK natural killer
  • allergen refers to a disorder of the immune system also referred to as atopy. Allergic reactions occur to environmental substances known as allergens; these reactions are acquired, predictable and rapid. Allergy is one of four forms of hypersensitivity and is called type I (or immediate) hypersensitivity. It is characterized by excessive activation of certain white blood cells called mast Attorney Docket No. HXA-008.25
  • anaphylaxis refers to an acute systemic (multi-system) and severe Type I Hypersensitivity allergic reaction in humans and other mammals causing anaphylactic shock due to the release of large quantities of immunological mediators (histamines, prostaglandins, leukotrienes) from mast cells leading to systemic vasodilation (associated with a sudden drop in blood pressure) and edema of bronchial mucosa (resulting in broncho constriction and difficulty breathing).
  • immunological mediators histamines, prostaglandins, leukotrienes
  • arthritis refers to an inflammatory disorder that includes osteoarthritis and rheumatoid arthritis.
  • the most common form of arthritis, osteoarthritis (degenerative joint disease) is a result of trauma to the joint, infection of the joint, or age.
  • Other arthritis forms are rheumatoid arthritis and psoriatic arthritis, autoimmune diseases in which the body attacks itself.
  • Septic arthritis is caused by joint infection.
  • Gouty arthritis is caused by deposition of uric acid crystals in the joint, causing inflammation.
  • the compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • pharmaceutically-acceptable salt is meant those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically-acceptable salts in J Pharm Sci, 1977, 66:1-19.
  • the salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic Attorney
  • nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates; long-chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; or arylalkyl halides, such as benzyl and phenethyl bromides and others. Water- or oil-soluble or -dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • the present invention includes all salts and all crystalline forms of such salts.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by combining a carboxylic acid-containing group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • Pharmaceutically acceptable basic addition salts include cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, and ethylamine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • preventing when used in relation to a condition, such as cancer, an infectious disease, or other medical disease or condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the Attorney Docket No. HXA-008.25
  • prevention of an infection includes, for example, reducing the number of diagnoses of the infection in a treated population versus an untreated control population, and/or delaying the onset of symptoms of the infection in a treated population versus an untreated control population.
  • treating is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disorder.
  • the present invention relates to novel compounds and pharmaceutical compositions comprising these compounds.
  • the present invention relates to a substantially pure and isolated compound of formula I:
  • a 1 is aryl or heteroaryl
  • a 2 is aryl or heteroaryl
  • R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; wherein any of the aforementioned alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl may be optionally substituted with one or more groups selected from the group consisting of halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl,
  • a 1 is an aryl, such as a phenyl.
  • the phenyl is substituted with at least one of a halo, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, Attorney Docket No. HXA-008.25
  • R 10 is hydrogen, or alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • the phenyl is substituted with an alkyl, such as methyl, ethyl, propyl, iso-propyl, butyl, n-butyl or t-butyl.
  • a 2 is heteroaryl, such as a pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine.
  • the heteroaryl is pyridine.
  • the heteroaryl is substituted with SR 10 , -S(O)OR 10 , -S(O) 2 OR 10 , -S(O) 2 N(R 10 ) 2 , Or-SC(O)R 10 .
  • the heteroaryl is substituted with SR 10 .
  • R 10 is hydrogen.
  • R is alkyl, heterocycloalkyl, alkenyl, alkynyl, aralkyl, or heteroaralkyl, wherein the alkyl, alkenyl, alkynyl, aralkyl, or heteroaralkyl may be optionally substituted with one or more groups selected from the group consisting of halo, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, amido, acyl, carboxyl, oxycarbonyl, acyloxy, thioether, sulfonate, sulfonyl, sulfonamido, formyl, cyano and isocyano.
  • R is alkyl, alkenyl, alkyny
  • Another aspect of the invention relates to a substantially pure and isolated compound of formula II:
  • a 1 is aryl or heteroaryl; Attorney Docket No. HXA-008.25
  • a 2 is aryl or heteroaryl
  • R' is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; wherein any of the aforementioned alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl may be optionally substituted with one or more groups selected from the group consisting halo, azido, alkyl, haloalkyl, fluoroalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, arylamino, acylamino, heteroarylamino, nitro, sulfhydryl, imin
  • a 1 is phenyl, naphthyl, anthracyl, pyrenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl.
  • a 1 is a phenyl, such as a mono substituted phenyl.
  • a 2 is benzyl, naphthyl, anthracyl, pyrenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl.
  • a 2 is a pyridinyl, such as a monosubstituted pyridinyl.
  • R' is alkyl, aralkyl or heteroalkyl. In certain embodiments, R' is C 5 -Ci 5 alkyl.
  • Another aspect of the invention relates to a substantially pure and isolated compound of formula III:
  • R is alkyl, alkenyl, alkynyl, aralkyl, or heteroaralkyl
  • R 1 to R 9 are halo, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, arylamino, acylamino, heteroarylamino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl, acyloxy, silyl, thioether, sulfonate, sulfonyl, sulfonamido, formyl, cyano or isocyano; wherein the aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and heteroaralkyl may be optionally substituted with one or
  • At least one of R 1 , R 2 , R 3 , R 3 or R 5 is halo, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, -OR 10 , -OC(O)R 10 , -SR 10 , -S(O)OR 10 , -S(O) 2 OR 10 , -S(O) 2 N(R 10 ) 2 , -SC(O)R 10 , -N(R 10 ) 2 or -N(R 10 )C(O)R 10 ; and R 10 is hydrogen, or alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. In other embodiments, at least one of R 1
  • R 6 , R 7 , R 8 , or R 9 is haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, -OR 10 , -OC(O)R 10 , -SR 10 , -S(O)OR 10 , -S(O) 2 OR 10 , -S(O) 2 N(R 10 ) 2 , -SC(O)R 10 , -N(R 10 ) 2 or -N(R 10 )C(O)R 10 ; and R 10 is hydrogen, or alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • R 6 , R 7 , R 8 , or R 9 is -SR 10 , -S(O)OR 10 , -S(O) 2 OR 10 , -S(O) 2 N(R 10 ) 2 , or -SC(O)R 10 .
  • at least one of R 6 , R 7 , R 8 , or R 9 is -SR 10 .
  • -R 10 is hydrogen.
  • Another aspect of the invention relates to a pure and isolated compound of formula IV: Attorney Docket No. HXA-008.25
  • R' is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
  • R 1 to R 9 are halo, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, arylamino, acylamino, heteroarylamino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, oxycarbonyl, acyloxy, silyl, thioether, sulfonate, sulfonyl, sulfonamido, formyl, cyano or isocyano; wherein the aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and heteroaralkyl may be optionally substituted with one or
  • R is C5-C15 alkyl, such as -CH 2 (CH 2 )4CH3.
  • R 1 is hydrogen.
  • R 2 is hydrogen. In other embodiments, R 3 is hydrogen.
  • R 3 is alkyl, such as -CH 3 , -CH 2 CH 3 or -CH 2 CH 2 CH 3 . In other embodiments, R 3 is -CH 3 . In some embodiments, R 4 is hydrogen. Attorney Docket No. HXA-008.25
  • R 5 is hydrogen. In other embodiments, R 6 is hydrogen. In other embodiments, R 7 is hydrogen.
  • R 7 is -SR 10 ; and R 10 is hydrogen or alkyl.
  • R 7 is -SH.
  • R 8 is hydrogen.
  • R 9 is hydrogen.
  • V or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention relates to relates to a substantially pure and isolated compound represented by formula V and posseses typtase inhibition activity in the range of 19 ⁇ M and 3.6 mM for compounds of the present invention.
  • Scheme II shows the reaction of neat dibromopyridine (3) with neat methylaniline (4) giving the secondary amine (5) in reasonable yield.
  • 2 prepared from 2-nonen-l-ol [1], carbon tetrabromide, and triphenylphosphine
  • Refluxing 6 and sodium ethanethiolate in DMF for 16 hours provides the aminopyridine tryptase inhibitor (7) as a disulfide.
  • compositions comprising the aforementioned compounds formulated together with one or more pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for topical administration.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, for rectal administration, or for vaginal administration.
  • the pharmaceutical compositions may encompass crystalline and amorphous forms of the active ingredient(s).
  • the phrase "pharmaceutically acceptable carrier” refers to any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art.
  • the compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
  • compositions may also be included in a container, pack, or dispenser together with instructions for administration.
  • compositions can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.
  • the compositions may also be administered through the lungs by inhalation.
  • parenteral administration refers to modes of administration, which include intravenous, intramuscular, intraperitoneal, intracisternal, subcutaneous and intra-articular injection and infusion.
  • compositions for parenteral injection comprise pharmaceutically acceptable aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. They may also contain taggants or other anti-counterfeiting agents, which are well known in the art. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, and phenol sorbic acid. It may also be desirable to include isotonic agents such as sugars, and sodium chloride. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents, which delay absorption such as aluminum monostearate and gelatin.
  • delayed absorption of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms can be made by forming microencapsulating matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(ortho esters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Suitable excipients include, for example, (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as cellulose and cellulose derivatives (such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose), alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as sodium starch glycolate, croscarmellose, agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (e) solution retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate, fatty acid esters of sorbitan, poloxa
  • Solid dosage forms including those of tablets, dragees, capsules, pills, and granules, can be prepared with coatings and shells such as functional and aesthetic enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and colorants. They may also be in a form capable of controlled or sustained release. Examples of embedding compositions that can be used for such purposes include polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers such as cyclodextrins, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifier
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Other ingredients include flavorants for dissolving or disintegrating oral or buccal forms.
  • Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxy ethylene sorbitol and sorbitan esters, cellulose or cellulose derivatives (for example micro crystalline cellulose), aluminum metahydroxide, bentonite, agar agar, and tragacanth, and mixtures thereof.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxy ethylene sorbitol and sorbitan esters, cellulose or cellulose derivatives (for example micro crystalline cellulose), aluminum metahydroxide, bentonite, agar agar, and tragacanth, and mixtures thereof.
  • compositions for rectal or vaginal administration may be suppositories that can be prepared by mixing the compounds of this invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, that are solid at Attorney Docket No. HXA-008.25
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes can be formed by lipid monolayer, bilayer, or other lamellar or multilamellar systems that are dispersed in an aqueous medium. Any nontoxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, and excipients.
  • Exemplary lipids include the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
  • the tableting powder is made by mixing in a dry powdered form the various components as described above, e.g., active ingredient (curcuma species extract composition), diluent, sweetening additive, and flavoring, etc.
  • active ingredient curcuma species extract composition
  • diluent e.g., diluent
  • sweetening additive e.g., diluent
  • sweetening additive e.g., diluent
  • flavoring e.g., a sweetening additive, etc.
  • An average in the range of about 10% to about 15% by weight of the active extract of the active ingredient can be added to compensate for losses during subsequent tablet processing.
  • the mixture is then sifted through a sieve with a mesh size preferably in the range of about 80 mesh to about 100 mesh to ensure a generally uniform composition of particles.
  • the tablet can be of any desired size, shape, weight, or consistency.
  • Administration modes useful for the delivery of the compositions of the present invention to a subject include administration modes commonly known to one of ordinary skill in the art, such as, for example, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the delivery system by be an inhalation delivery system, such as, for example, an inhaler or nebulizer.
  • an inhalation delivery system such as, for example, an inhaler or nebulizer.
  • the delivery system may be a transdermal delivery system, such as, for example, a hydrogel, cream, lotion, ointment, or patch.
  • a patch in particular may be used when a timed delivery of weeks or even months is desired.
  • parenteral routes of administration may be used.
  • Parenteral routes involve injections into various compartments of the body.
  • Parenteral routes include intravenous (iv), i.e. administration directly into the vascular system through a vein; intraarterial (ia), i.e. administration directly into the vascular system through an artery; intraperitoneal (ip), i.e. administration into the abdominal cavity; subcutaneous (sc), i.e. administration under the skin; intramuscular (im), i.e. administration into a muscle; and intradermal (id), i.e. administration between layers of skin.
  • the parenteral route is sometimes preferred over oral ones when part of the formulation administered would partially or totally degrade in the gastrointestinal tract. Similarly, where there is need for rapid response in emergency cases, parenteral administration is usually preferred over oral.
  • Methods of Treatment Methods of the present invention comprise providing the aforementioned compounds for the treatment and/or prevention of diseases and disorders involving the tryptase enzyme.
  • the composition of the present invention may be useful for treating or preventing allergic rhinitis, asthma, arthritis, vascular injury (e.g., restenosis and atherosclerosis), inflammatory bowel disease, psoriasis, anaphylaxis, wounds, infections, and other allergy and inflammatory related diseases in a mammal, such as a human.
  • Tryptase activity was determined by monitoring the production of chromophore /?- nitroaniline (pNA) generated by the cleavage of tosyl-gly-pro-lys-/?NA by the tryptase enzyme according to the manufacturer's protocol (Millipore Inc., Westbury, MA).
  • pNA chromophore /?- nitroaniline
  • 10 ⁇ L of tryptase was added to 10 ⁇ L of sample, followed by 20 ⁇ L of tosyl- gly-pro-lys-/?NA and 160 ⁇ L of IX reaction buffer and incubated for 2 h at 37 0 C. After the incubation, absorbance at 405 nm was measured in each well using a Tecan M200 microplate reader.
  • the JEOL DARTTM AccuTOF mass spectrometer (JMS-T lOOLC; Jeol USA, Peabody, MA) used for chemical analysis requires no sample preparation and yields masses with accuracies to 0.0001 mass units (R. B. Cody, J. A. Laramee, J. M. Miles, and H. D. Durst, 2005. Direct Analysis in Real Time (DARTTM) Mass Spectrometry. JEOL News 40:8-12).
  • D ART+ positive ion mode
  • the needle voltage was set to 3000V, heating element to 250 0 C, electrode 1 to 150V, electrode 2 to 250V, and helium gas flow to 2.52 liters per min.
  • orifice 1 set to 10V
  • ring lens voltage set to 5 V
  • orifice 2 set to 5 V
  • the peak voltage was set to 1000V in order to give peak resolution beginning at 100 m/z.
  • the microchannel plate detector (MCP) voltage was set at 2600V. Calibrations were performed internally with each sample using a 10% (w/v) solution of PEG that provided mass markers throughout the required mass range 100-1000 m/z. Calibration tolerances were held to 5 mmu.
  • Serum samples were prepared for DART TOF-MS analysis by extraction with an equal volume of neat ethanol (USP) to minimize background of proteins, peptides, and polysaccharides present in serum.
  • USP neat ethanol
  • the ethanol extract was centrifuged for 10 min at 4 0 C, the supernatant was removed, concentrated to 200 ⁇ L volume, and 50 ⁇ L of an internal standard was added.
  • Urine samples were not treated and used directly for DART TOF-MS. DART TOF-MS analyses were conducted as described above.
  • the IC50 values for tryptase inhibition range between 19 ⁇ M and 3.6 mM for compounds of the present invention.
  • Synthesized compound [7] (Section E below) as a disulfide dimer inhibits tryptase activity with an IC50 value of 789 ⁇ M relative to controls.
  • ADMET Absorption, Distribution, Metabolism, Excretion, and Toxicity
  • the compounds of the present invention when present in a mixture and ingested by humans were found in the bloodstream (serum) within 10 min of ingestion.
  • Compound (V) was present in the serum up to 480 min (8 h) post-ingestion.
  • Compound (V) appeared in urine within 1 h of ingestion and persisted in the urine up to 8 h post-ingestion.
  • the reaction mixture was allowed to warm to room temperature and stirred for 90 min. The mixture was again cooled to 0-5 0 C and neat bromide ([2], 2.6 g, 12.7 mmol) was added slowly over a period of 30 min. The reaction temperature was slowly heated to 50 0 C and maintained at this temperature for 12 h. The cooled reaction mixture was poured into ice cold water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), saturated NaCl (100 mL), and dried over sodium sulphate.
  • the pH of the aqueous layer was adjusted to 10 using IN sodium hydroxide and extracted with ethyl acetate (2 x 75 mL). The combined organic layer was washed with water (100 mL), saturated NaCl (100 mL), and dried over sodium sulphate. The filtered organic layer was concentrated under vacuum to give a pale yellow oil, which was purified by silica gel column chromatography, eluting with hexanes (200 mL, followed by hexanes and ethyl acetate (98:2, 300 mL). The hexanes/ethyl acetate fractions were collected and concentrated under vacuum to give [7] as a pale yellow oil (270 mg, yield: 51%).

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  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des nouveaux composés et des compositions pharmaceutiques incluant ces composés. Dans certains modes d'application, les composés sont des inhibiteurs de l'enzyme tryptase et peuvent être employés dans le traitement de la rhinite allergique, de l'asthme, des lésions vasculaires (par exemple resténose et athérosclérose), de l'affection abdominale inflammatoire, de l'arthrite, du psoriasis, de l'anaphylaxie, de plaies, d'infections et d'autres pathologies de type allergique et inflammatoire.
PCT/US2009/062546 2008-10-30 2009-10-29 Aminopyridines inhibant l'enzyme tryptase WO2010059372A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10971008P 2008-10-30 2008-10-30
US61/109,710 2008-10-30

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WO2010059372A2 true WO2010059372A2 (fr) 2010-05-27
WO2010059372A3 WO2010059372A3 (fr) 2010-09-10

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US (1) US20100113523A1 (fr)
TW (1) TW201022208A (fr)
WO (1) WO2010059372A2 (fr)

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Publication number Priority date Publication date Assignee Title
UY32582A (es) 2009-04-28 2010-11-30 Amgen Inc Inhibidores de fosfoinositida 3 cinasa y/u objetivo mamífero
US10260089B2 (en) 2012-10-29 2019-04-16 The Research Foundation Of The State University Of New York Compositions and methods for recognition of RNA using triple helical peptide nucleic acids
CN104884452A (zh) 2012-11-20 2015-09-02 沃泰克斯药物股份有限公司 用作吲哚胺2,3-二氧化酶的抑制剂的化合物

Citations (1)

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Publication number Priority date Publication date Assignee Title
US6107301A (en) * 1993-10-12 2000-08-22 Dupont Pharmaceuticals Company 1N-alkyl-N-arylpyrimidinamines and derivatives thereof

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Publication number Priority date Publication date Assignee Title
US6022884A (en) * 1997-11-07 2000-02-08 Amgen Inc. Substituted pyridine compounds and methods of use
US6881737B2 (en) * 2001-04-11 2005-04-19 Amgen Inc. Substituted triazinyl acrylamide derivatives and methods of use
US20070049611A1 (en) * 2005-06-10 2007-03-01 Talamas Francisco X Phosphodiesterase 4 inhibitors

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US6107301A (en) * 1993-10-12 2000-08-22 Dupont Pharmaceuticals Company 1N-alkyl-N-arylpyrimidinamines and derivatives thereof

Non-Patent Citations (1)

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Title
SCHMID, SYLVIA ET AL.: 'Synthesis of 1,2,2a,3-Tetrahydro-1,4,7b-triazacyclop enta[cd]indenes.' SYNTHESIS. vol. 18, 2005, pages 3107 - 3118 *

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WO2010059372A3 (fr) 2010-09-10
US20100113523A1 (en) 2010-05-06

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