WO2000030632A1 - Composes aryles et heteroaryles utiles comme antagonistes du facteur de croissance des fibroblastes (fgf) - Google Patents

Composes aryles et heteroaryles utiles comme antagonistes du facteur de croissance des fibroblastes (fgf) Download PDF

Info

Publication number
WO2000030632A1
WO2000030632A1 PCT/US1998/024875 US9824875W WO0030632A1 WO 2000030632 A1 WO2000030632 A1 WO 2000030632A1 US 9824875 W US9824875 W US 9824875W WO 0030632 A1 WO0030632 A1 WO 0030632A1
Authority
WO
WIPO (PCT)
Prior art keywords
aryl
heteroaryl
alkyl
hydrogen
heteroaralkyl
Prior art date
Application number
PCT/US1998/024875
Other languages
English (en)
Inventor
Laura Schove
Kalyanaraman Ramnarayan
Venkatachalapathi Yalamoori
Ming Fai Chan
Vitukudi N. Balaji
Original Assignee
Eisai Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eisai Co., Ltd. filed Critical Eisai Co., Ltd.
Priority to PCT/US1998/024875 priority Critical patent/WO2000030632A1/fr
Priority to AU15960/99A priority patent/AU1596099A/en
Publication of WO2000030632A1 publication Critical patent/WO2000030632A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/39—Heterocyclic compounds having sulfur as a ring hetero atom having oxygen in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone

Definitions

  • the present invention relates to aryl and heteroaryl compounds, compositions and methods for treatment or prevention of fibroblast growth factor (FGF)-mediated diseases.
  • FGF fibroblast growth factor
  • the invention relates to the use of triphenylmethane, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzofuryl and benzopyrrolyl compounds as
  • Fibroblast growth factors are a family of polypeptide mitogens and are ubiquitous in mammals. FGFs and their corresponding receptors, FGFRs, are widely distributed in tissues throughout the body, i.e., the central and peripheral nervous system, retina, kidneys, and myocardium (see, e.g., Johnson et al. Adv. Cancer Res. 1993, 60, 1 ), and are expressed during embryogenesis (Kimelman et al. Science 1988, 242, 1 053) . FGFs exhibit potent mitogenic activity in these areas (see, e.g., Gospodarowicz Nature 1974, 249, 1 23), are also mitogenic for mesenchymal, neuronal, and epithelial cells (see.
  • FGFs Fibroblast growth factors
  • the FGFs consist of a family of peptides, of which ten have been identified (FGF-1 through 10) .
  • the first two peptides of this family to be isolated and characterized were FGF-1 and FGF-2, more commonly referred to as aFGF and bFGF, respectively, for their acidic and basic isoelectric points, respectively.
  • aFGF and bFGF were initially isolated from the bovine pituitary (Gospodarowicz J. Biol. Chem. 1975, 250, 251 5), then from bovine brain (Gospodarowicz et al. J . Biol. Chem. 1978, 253, 3736) and later isolated from human brain (Gimenez-Gallego et al. Biochem. Biophvs.
  • aFGF and bFGF have common biological properties, including the ability to bind to one or more FGF receptors. They also exhibit 55% homology in their amino acid sequences and are highly conserved among species (i.e., human and bovine bFGF exhibit 98.7% identity (see, e.g ., U.S. Patent No. 5,288,855; U.S. Patent No. 5, 1 55,21 4)) . Eight other FGFs have been identified based on these structures (FGF-3 through 1 0) : int-2 (FGF-3) (Moore et al. EMBO J . 1986, 5, 91 9; Jakobovits et al.
  • FGF-4 hst-1 /KS-FGF (identified from Kaposi's sarcoma DNA) (FGF-4) (Delli-Bovi et al. Cejj 1987, 50, 729; Taira et al. Proc. Nat. Acad. Sci. USA 1987, 84, 2980; Huang et al. J. Clin. Invest. 1993, 91, 1 1 91 ), FGF-5 (Zhan et al. Mol. Cell Biol. 1988, 8, 3487),
  • FGF-6/Hst-2 (Maries et al. Oncogene 1989, 4, 335), karatinocyte growth factor (KGF) (FGF-7) (Finch et al. Science 1989, 245, 752), FGF-8, FGF-9 and FGF-1 0 (PCT International Publication Number WO 95/24,41 4) .
  • KGF karatinocyte growth factor
  • FGF-7 Finch et al. Science 1989, 245, 752
  • FGF-8 FGF-9
  • FGF-1 0 PCT International Publication Number WO 95/24,41 4
  • the structures of aFGF and bFGF have also been determined through single- crystal x-ray diffraction (Eriksson Proc. Nat. Acad. Sci. USA 1991 , 88, 3441 ; Zhang et al. Proc. Nat. Acad. Sci. USA 1991 , 88, 3446; Zhu et al. Science 1991 , 251 , 90) .
  • Basic FGF is a 1 6kD, acid- and thermally-sensitive peptide. It is an angiogenic factor causing the migration, proliferation and differentiation of endothelial cells to form blood vessels (see, e.g., Montesano et al. Proc. Nat. Acad. Sci. USA 1986, 83, 7279; Folkman et al. Science 1987, 235, 442) . This effect indicates possible therapeutic uses of bFGF for wound healing (Folkman Science 1987, 235, 442; Buntrock et al. Exp. Pathol.
  • FGFs have also been reported to be useful as hypotensive agents for reducing high blood pressure and preventing myocardial infarction and cerebral hemorrhages (Saltis et al. Atherosclerosis 1995, 1 1 8, 77; PCT International Publication No. WO 92/08473) , for the treatment of ulcers (U.S. Patent No. 5,401 ,721 ; U.S. Patent No.
  • bFGF may, however, be harmful in some cases in that cell proliferation and angiogenesis are important aspects of tumor growth and tumor development, rheumatoid arthritis, restenosis, In-Stent restenosis, proliferative diabetic retinopathies and diabetes (see, e.g ., Folkman Adv. Cancer Res. 1985, 43, 1 75; Meinyk et al. Arthritis Rheum. 1990, 33, 493; Sivalingam Arch. Qphthalmol. 1990, 1 08, 869) .
  • bFGF also functions as an oncogene in melanoma.
  • FGFs are mediated by high and low affinity receptors: 4 FGF receptor genes have been identified and at least 2 produce multiple mRNA transcripts through alternative splicing of the primary transcript. This splicing creates a large number of forms of the receptors and leads to response of the cell to many FGF family members, i.e., one gene gives FGFR-2 and KGF receptors, and alternate FGFR-1 splicing gives a 50 fold decrease in bFGF binding with unchanged aFGF binding .
  • Receptor expression is also altered by injury and pathological conditions (restenosis, tumors and proliferative diseases) .
  • receptor mRNA and protein are present in melanoma cells (see, e.g., Becker et al. Oncogene 1992, 7, 2303), the receptor message is not usually found in palmar fascia, but is found in the proliferative hand disease Dupuytren's contracture (see, e.g ., Gonzales et al. Amer. J. Pathol.
  • SMCs smooth muscle cells
  • proliferating SMCs i.e., during restenosis after balloon angioplasty
  • bFGF smooth muscle cells
  • Aryl and heteroaryl compounds, and pharmaceutically acceptable derivatives, including salts, esters, acids bases, solvates, hydrates and prodrugs, thereof, of formulae (I) are provided.
  • Pharmaceutical compos- itions containing aryl or heteroaryl compounds, or pharmaceutically acceptable derivatives, including salts, esters, acids, bases, solvates, hydrates and prodrugs, thereof, of formulae (I), and methods for modulating the interaction of an FGF peptide with FGF receptors using such compounds and compositions are also provided .
  • methods for inhibiting the binding of an FGF peptide to FGF receptors using such compounds and compositions are provided .
  • the compounds and pharmaceutical compositions provided herein are those that are particularly active as bFGF antagonists, as evidenced by jn vitro assays described herein.
  • the methods are effected by contacting FGF receptors with one or more of the compounds or compositions prior to, simultaneously with, or subsequent to contacting the receptors with an FGF peptide.
  • the aryl and heteroaryl compounds have formulae (I) :
  • Ar 1 is a monocyclic or fused bicyclic, tricyclic or tetracyclic aromatic or heteroaromatic group, where the heteroaromatic group contains one or two, preferably two, heteroatoms selected from O, S and N;
  • Ar 2 is a monocyclic or fused bicyclic, tricyclic or tetracyclic arylidene or heteroarylidene group, where the heteroarylidene group contains one or two, preferably two, heteroatoms selected from O, S, and N;
  • V 1 is selected from diarylalkyl, diheteroarylalkyl, alkenyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy,
  • the aryl, heteroaryl, arylidene and heteroarylidene moieties of the compounds of formula (I) are unsubstituted or are substituted with one or more substituents each independently selected from Z, which, as defined herein, is halogen, hydroxy, nitrile, nitro, formyl, mercapto, carboxy, hydroxysulfonyl, hydroxyphosphoryl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyi, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylalky
  • the alkyl, alkynyl and alkenyl portions of each listed substituent are straight or branched chains or are cyclic, and preferably have from about 1 up to about 20 carbons; in more preferred embodiments they have from 1 -1 6 carbons, and they can have fewer than 6 carbons.
  • the carbocyclic, heterocyclic, aromatic and heteroaromatic groups can have from 3 to 1 9 members in the rings and may be single or fused rings.
  • the ring size and carbon chain length are selected up to a size such that the resulting molecule retains activity as an FGF antagonist, such that the resulting compound inhibits binding of an FGF peptide, compared to binding in the absence of the aryl or heteroaryl derivative, to an FGF receptor at a concentration of less than about 300 ⁇ M.
  • those that inhibit an FGF- mediated activity by about 50% at concentrations of less than about 300 ⁇ M are preferred. More preferred are those that inhibit an FGF- mediated activity by about 50% at concentrations of less than about 100 ⁇ M, more preferably less than about 1 0 ⁇ M, and most preferably less than about 1 ⁇ M.
  • any pharmaceutically-acceptable derivatives including salts, esters, acids, bases, solvates, hydrates and prodrugs of the aryl and heteroaryl compounds.
  • Pharmaceutically-acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N- methylglucamine, procaine, N-benzylphenethylamine, 1 -para-chloro- benzyl-2-pyrrolidin-1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not
  • compositions formulated for administration by an appropriate route and means containing effective concentrations of one or more of the compounds provided herein, or pharmaceutically acceptable salts, esters, acids, bases, solvates, hydrates or prodrugs, that deliver amounts effective for the treatment of FGF-mediated disorders, and other conditions that are in some manner mediated by an FGF peptide or whose symptoms can be ameliorated by administration of a bFGF-specific FGF antagonist, are also provided.
  • the effective amounts and concentrations are effective for ameliorating any of the symptoms of any of the disorders.
  • FGF-mediated diseases including, but not limited to, diabetes, cancer, including, but not limited to, melanoma and tumor growth and development, restenosis, In-Stent restenosis, rheumatoid arthritis, proliferative dermatological disorders, and ophthalmic disorders, including, but not limited to, corneal clouding following excimer laser surgery, closure of trabeculectomies, hyperproliferation of lens epithelial cells following cataract surgery, the recurrence of pterygii and diabetic retinopathy, and other proliferative diseases, including, but not limited to, Dupuytren's contracture, conditions that are in some manner mediated by an FGF peptide that binds to FGF receptors, or that are ameliorated by administration of an FGF receptor bFGF antagonist are provided .
  • diseases including, but not limited to, diabetes, cancer, including, but not limited to, melanoma and tumor growth and development, restenosis, In-Stent restenosis, r
  • Methods for inhibiting binding of an FGF peptide to an FGF receptor are provided. These methods are practiced by contacting the receptor with one or more of the compounds or compositions provided herein simultaneously, prior to, or subsequent to contacting the receptor with an FGF peptide.
  • methods of treating FGF-mediated disorders by administering effective amounts of the compounds, or salts, esters, acids, bases, solvates, hydrates, prodrugs or other suitable derivatives thereof are provided .
  • FGF-mediated disorders including, but not limited to, diabetes, cancer, including, but not limited to, melanoma and tumor growth and development, restenosis, In-Stent restenosis, rheumatoid arthritis, ophthalmic disorders, including, but not limited to, corneal clouding following excimer laser surgery, closure of trabeculectomies, hyperproliferation of lens epithelial cells following cataract surgery, the recurrence of pterygii and diabetic retinopathy, and other proliferative diseases, including, but not limited to, Dupuytren's contracture, and other proliferative diseases in which FGF receptor bFGF-mediated physiological responses are implicated, by administering effective amounts of one or more of the compounds provided herein in pharmaceutically acceptable carriers are provided.
  • compositions containing therapeutically effective concentrations of the compounds formulated for oral, intravenous, local and topical application for the treatment of FGF-mediated disorders including, but not limited to, diabetes, cancer, including, but not limited to, melanoma and tumor growth and development, restenosis, In-Stent restenosis, rheumatoid arthritis, ophthalmic disorders, including, but not limited to, corneal clouding following excimer laser surgery, closure of trabeculectomies, hyperproliferation of lens epithelial cells following cataract surgery, the recurrence of pterygii and diabetic retinopathy, and other proliferative diseases, including, but not limited to, Dupuytren's contracture, psoriasis, and other diseases in which FGF-mediated physiological responses are implicated are administered to an individual exhibiting the symptoms of one or more of these disorders.
  • the amounts are effective to ameliorate or eliminate one or more symptoms of the disorders.
  • fibroblast growth factor (FGF) peptides include peptides that have substantially the amino acid sequence of any one of FGF-1 through 1 0 and that act as potent endogenous proliferative peptides.
  • an FGF-mediated condition is a condition that is caused by abnormal FGF activity or one in which compounds that inhibit FGF activity have therapeutic use.
  • diseases include, but are not limited to diabetes, cancer, including, but not limited to, melanoma and tumor growth and development, restenosis, In-Stent restenosis, rheumatoid arthritis, ophthalmic disorders, including, but not limited to, corneal clouding following excimer laser surgery, closure of trabeculectomies, hyperproliferation of lens epithelial cells following cataract surgery, the recurrence of pterygii and diabetic retinopathy, and other proliferative diseases, including, but not limited to, Dupuytren's contracture, and other diseases in which FGF-mediated physiological responses are implicated.
  • an effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective. The amount may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms.
  • an FGF antagonist is a compound, such as a drug or an antibody, that inhibits FGF-stimulated proliferation and other FGF- mediated physiological responses.
  • the antagonist may act by interfering with the interaction of the FGF with an FGF-specific receptor or by interfering with the physiological response to or bioactivity of an FGF isopeptide, such as proliferation.
  • an FGF antagonist interferes with FGF-stimulated proliferation or other response or interferes with the interaction of an FGF peptide with an FGF-specific receptor, such as bFGF receptors, as assessed by assays known to those of skill in the art.
  • the effectiveness of potential FGF antagonists can be assessed using methods known to those of skill in the art. For example, the effectiveness may be measured by inhibition of binding of 125 l-bFGF to a human extracellular-domain FGFR1 -tPA fusion protein immobilized on a solid phase (hsRRA assay)(for the extracellular form of human FGFR, see U.S. Patent 5,288,855) . Effectiveness may also be measured through the use of a membrane-bound competitive binding assay, quantifying inhibition of binding of 125 l-bFGF to FGF receptors on cultured smooth muscle cells (SMCs) .
  • SMCs smooth muscle cells
  • Effectiveness may also be measured by determination of inhibition of 3 H-thymidine incorporation into DNA, which is promoted by bFGF stimulation of SMC proliferation (see, generally; Nachtigal et al. In Vitro Cellular and Developmental Biology 1989, 25, 892) .
  • the biological activity or bioactivity of an FGF peptide includes any activity induced, potentiated or influenced by FGF in vivo. It also includes the ability to bind to particular receptors and to induce a functional response, such as proliferation. It may be assessed by In vivo assays or by in vitro assays, such as those exemplified herein. The relevant activity includes, but is not limited to, proliferation. Any assay known to those of skill in the art to measure or detect such activity may be used to assess such activity (see, e.g . , Nachtigal et al. ]_ Vitro Cellular and Developmental Biology 1989, 25, 892; and the Examples herein) .
  • the IC 50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as binding of FGF to tissue receptors, in an assay that measures such response.
  • EC 50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.
  • pharmaceutically acceptable derivatives of a compound include salts, esters, acids, bases, solvates, hydrates or prodrugs thereof that may be readily prepared by those of skill in this art using known methods for such derivatization and that produce compounds that may be administered to animals or humans without substantial toxic effects and that either are pharmaceutically active or are prodrugs.
  • acidic groups can be esterified or neutralized .
  • treatment means any manner in which the symptoms of a condition, disorder or disease are ameliorated or otherwise beneficially altered . Treatment also encompasses any pharmaceutical use of the compositions herein, such as use as contraceptive agents.
  • amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
  • substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis and high performance liquid chromatography (HPLC), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art.
  • a substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.
  • biological activity refers to the in vivo activities of a compound or physiological responses that result upon jn vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmaceutical activity of such compounds, compositions and mixtures.
  • a prodrug is a compound that, upon in vivo administration, is metabolized or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes.
  • the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • alkyl, alkenyl and alkynyl carbon chains if not specified contain from 1 to 20 carbons, preferably 1 to 1 6 carbons, and are straight or branched.
  • Alkenyl carbon chains of from 2 to 20 carbons preferably contain 1 to 8 double bonds, and the alkenyl carbon chains of 2 to 1 6 carbons preferably contain 1 to 5 double bonds.
  • Alkynyl carbon chains of from 2 to 20 carbons preferably contain 1 to 8 triple bonds, and the alkynyl carbon chains of 2 to 1 6 carbons preferably contain 1 to
  • alkyl, alkenyl and alkynyl groups may be optionally substituted, with one or more groups, preferably alkyl group substituents that may be the same or different.
  • alkyl, lower alkenyl, and lower alkynyl refer to carbon chains having less than about
  • an alkyl group substituent includes halo, haloalkyl, preferably halo lower alkyl, aryl, hydroxy, alkoxy, aryloxy, alkyloxy, alkylthio, arylthio, aralkyioxy, aralkylthio, carboxy alkoxycarbonyl, oxo and cycloalkyl.
  • aryl refers to cyclic groups containing from 3 to 1 9 carbon atoms.
  • Aryl groups include, but are not limited to groups, such as phenyl, substituted phenyl, naphthyl, substituted naphthyl, in which the substituent is lower alkyl, halogen, or lower alkoxy.
  • an "aryl group substituent” includes alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl optionally substituted with 1 or more, preferably 1 to 3, substituents selected from halo, halo alkyl and alkyl, arylalkyl, heteroarylalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, halo, hydroxy, haloalkyl and polyhaloalkyl, preferably halo lower alkyl, especially trifluoromethyl, formyl, alkylcarbonyl, arylcarbonyl that is optionally substituted with 1 or more, preferably 1 to 3, substituents selected from halo, halo alkyl and alkyl, heteroarylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,
  • aryl groups include optionally substituted phenyl and optionally substituted pyrenyl.
  • cycloalkyl refers to a saturated mono- or multi- cyclic ring system, preferably of 3 to 1 9 carbon atoms, more preferably 3 to 6 carbon atoms;
  • cycloalkenyl and cycloalkynyl refer to mono- or multicyclic ring systems that respectively include at least one double bond and at least one triple bond.
  • Cycloalkenyl and cycloalkynyl groups may preferably contain 3 to 1 9 carbon atoms, with cycloalkenyl groups more preferably containing 4 to 7 carbon atoms and cycloalkynyl groups more preferably containing 8 to 1 0 carbon atoms.
  • the ring systems of the cycloalkyl, cycloalkenyl and cycloalkynyl groups may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro-connected fashion, and may be optionally substituted with one or more alkyl group substituents.
  • heteroaryl refers to a monocyclic or multicyclic ring system, preferably of about 3 to about 1 9 members where one or more, more preferably 1 to 3 of the atoms in the ring system is a heteroatom, that is, an element other than carbon, for example, nitrogen, oxygen and sulfur atoms.
  • the heteroaryl may be optionally substituted with one or more, preferably 1 to 3, aryl group substituents.
  • Exemplary heteroaryl groups include, for example, furyl, thienyl, pyridyl, pyrrolyl, N- methylpyrrolyl, quinolinyl and isoquinolinyl, with pyridyl and quinolinyl being preferred.
  • heteroarylium is a heteroaryl group that is positively charged on one or more of the heteroatoms.
  • heterocyclic refers to a monocyclic or multicyclic ring system, preferably of 3 to 1 9 members, more preferably 4 to 7 members, even more preferably 5 to 6 members, where one or more, preferably 1 to 3 of the atoms in the ring system is a heteroatom, that is, an element other than carbon, for example, nitrogen, oxygen and sulfur atoms.
  • the heterocycle may be optionally substituted with one or more, preferably 1 to 3 aryl group substituents.
  • Preferred substituents of the heterocyclic group include hydroxy, alkoxy containing 1 to 4 carbon atoms, halo lower alkyl, including trihalomethyl, such as trifluoromethyl, and halogen.
  • heterocycle may include reference to heteroaryl.
  • exemplary heterocycles include, for example, pyrrolidinyl, piperidinyl, alkylpiperidinyl, morpholinyl, oxadiazolyl or triazolyl.
  • alkyl refers to saturated carbon chains that contain one or more carbons; the chains may be straight or branched or include cyclic portions or be cyclic.
  • alicyclic refers to aryl groups that are cyclic.
  • halogen or “halide” refers to F, Cl, Br or I .
  • pseudohalides are compounds that behave substantially similar to halides. Such compounds can be used in the same manner and treated in the same manner as halides (X , in which X is a halogen, such as Cl or Br) .
  • Pseudohalides include, but are not limited to cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethyl and azide.
  • haloalkyl refers to a lower alkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1 -chloro-2-fluoroethyl and the like.
  • haloalkoxy refers to RO- in which R is a haloalkyl group.
  • sulfinyl refers to -S(O)-.
  • sulfonyl refers to -S(O) 2 -.
  • aminocarbonyl refers to -C(O)NH 2 .
  • alkylaminocarbonyl refers to -C(O)NHR in which R is hydrogen or alkyl, preferably lower alkyl.
  • dialkylaminocarbonyl refers to -C(O)NR ' R in which R ' and R are independently selected from hydrogen or alkyl, preferably lower alkyl;
  • carboxamide refers to groups of formula -NR COR.
  • diarylaminocarbonyl refers to -C(O)NRR' in which R and R' are independently selected from aryl, preferably lower aryl, more preferably phenyl.
  • arylalkylaminocarbonyl refers to -C(O)NRR' in which one of R and R' is aryl, preferably lower aryl, more preferably phenyl, and the other of R and R' is alkyl, preferably lower alkyl.
  • arylaminocarbonyl refers to -C(O)NHR in which R is aryl, preferably lower aryl, more preferably phenyl.
  • alkoxycarbonyl refers to -C(O)OR in which R is alkyl, preferably lower alkyl.
  • aryloxycarbonyl refers to -C(O)OR in which R is aryl, preferably lower aryl, more preferably phenyl.
  • alkoxy and arylthio refer to RO- and RS-, in which R is alkyl, preferably lower alkyl.
  • aryloxy and arylthio refer to RO- and RS-, in which R is aryl, preferably lower aryl, more preferably phenyl.
  • alkylene refers to a straight, branched or cyclic, preferably straight or branched, bivalent aliphatic hydrocarbon group, preferably having from 1 to about 20 carbon atoms, more preferably 1 to 1 2 carbons, even more preferably lower alkylene.
  • the alkylene group is optionally substituted with one or more "alkyl group substituents. " There may be optionally inserted along the alkylene group one or more oxygen, sulphur or substituted or unsubstituted nitrogen atoms, where the nitrogen substituent is alkyl as previously described.
  • alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene ( — (CH 2 ) 3 -), cyclohexylene (-C 6 H 10 -), methylenedioxy (-O-CH 2 - O-) and ethylenedioxy (-O-(CH 2 ) 2 -O-) .
  • the term "lower alkylene” refers to alkylene groups having 1 to 6 carbons. Preferred alkylene groups are lower alkylene, with alkylene of 1 to 3 carbon atoms being particularly preferred.
  • alkenylene refers to a straight, branched or cyclic, preferably straight or branched, bivalent aliphatic hydrocarbon group, preferably having from 2 to about 20 carbon atoms and at least one double bond, more preferably 2 to 1 2 carbons, even more preferably lower alkenylene.
  • the alkenylene group is optionally substituted with one or more "alkyl group substituents. " There may be optionally inserted along the alkenylene group one or more oxygen, sulphur or substituted or unsubstituted nitrogen atoms, where the nitrogen substituent is alkyl as previously described.
  • Exemplary alkenylene groups include
  • alkenylene refers to alkenylene groups having 2 to 6 carbons. Preferred alkenylene groups are lower alkenylene, with alkenylene of 3 to 4 carbon atoms being particularly preferred.
  • alkynylene refers to a straight, branched or cyclic, preferably straight or branched, bivalent aliphatic hydrocarbon group, preferably having from 2 to about 20 carbon atoms and at least one triple bond, more preferably 2 to 1 2 carbons, even more preferably lower alkynylene. The alkynylene group is optionally substituted with one or more "alkyl group substituents.
  • alkynylene groups include — C ⁇ C — C ⁇ C — , -C ⁇ C- and -C ⁇ C-CH 2 -.
  • lower alkynylene refers to alkynylene groups having 2 to 6 carbons. Preferred alkynylene groups are lower alkynylene, with alkynylene of 3 to 4 carbon atoms being particularly preferred .
  • arylene refers to a monocyclic or polycyclic, preferably monocyclic, bivalent aromatic group, preferably having from 3 to about 20 carbon atoms and at least one aromatic ring, more preferably 3 to 1 2 carbons, even more preferably lower arylene.
  • the arylene group is optionally substituted with one or more "alkyl group substituents. " There may be optionally inserted around the arylene group one or more oxygen, sulphur or substituted or unsubstituted nitrogen atoms, where the nitrogen substituent is alkyl as previously described .
  • Exemplary arylene groups include 1 ,2-, 1 ,3- and 1 ,4- phenylene.
  • lower arylene refers to arylene groups having 5 or 6 carbons. Preferred arylene groups are lower arylene.
  • heteroarylene refers to a bivalent monocyclic or multicyclic ring system, preferably of about 3 to about 1 5 members where one or more, more preferably 1 to 3 of the atoms in the ring system is a heteroatom, that is, an element other than carbon, for example, nitrogen, oxygen and sulfur atoms.
  • the heteroarylene group may be optionally substituted with one or more, preferably 1 to 3, aryl group substituents.
  • Exemplary heteroarylene groups include, for example, 1 ,4-imidazolylene.
  • arylalkylidene refers to an alkylidene group in which either R' or R" is and aryl group.
  • diarylalkylidene refers to an alkylidene group in which R' and R" are both aryl groups.
  • Diheteroarylalkylidene refers to an alkylidene group in which R' and R" are both heteroaryl groups.
  • arylidene refers to an unsaturated cyclic bivalent group where both points of attachment are on the same atom of the ring .
  • exemplary arylidene groups include, but are not limited to, quinone methide moieties that have the formula:
  • Heteroarylidene groups are arylidene groups where one or two, preferably two, of the atoms in the ring are heteroatoms, such as, but not limited to, O, S and N.
  • amido refers to a bivalent group, either -C(O)NH- or -HNC(O)-.
  • Thioamido refers to a bivalent group, either -C(S)CH- or - HNC(S)-.
  • Oxyamido refers to a bivalent group, either -OC(O)NH- or - HNC(O)O-.
  • Thiaamido refers to a bivalent group, either -SC(O)NH- or - HNC(O)S-.
  • Dithiaamido refers to a bivalent group, either -SC(S)NH- or -HNC(S)S-.
  • Ureido refers to the bivalent group -HNCONH-.
  • Thioureido refers to the bivalent group -HNCSNH-.
  • amino acid refers to ⁇ -amino acids which are racemic, or of either the D- or L-configuration.
  • any particular group such as phenyl or pyridyl, is specified, this means that the group is unsubstituted or is substituted.
  • Preferred substituents where not specified are halo, halo lower alkyl, and lower alkyl.
  • the abbreviations for any protective groups, amino acids and other compounds are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB
  • Ar 1 is a monocyclic or fused bicyclic, tricyclic or tetracyclic aromatic or heteroaromatic group, where the heteroaromatic group contains one or two, preferably two, heteroatoms selected from O, S and N;
  • Ar 2 is a monocyclic or fused bicyclic, tricyclic or tetracyclic arylidene or heteroarylidene group, where the heteroarylidene group contains one or two, preferably two, heteroatoms selected from O, S, and N;
  • V 1 is selected from diarylalkyl, diheteroarylalkyl, alkenyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy,
  • the aryl, heteroaryl, arylidene and heteroarylidene moieties of the compounds of formula (I) are unsubstituted or are substituted with one or more substituents each independently selected from Z, which, as defined herein, is halogen, hydroxy, nitrile, nitro, formyl, mercapto, carboxy, hydroxysulfonyl, hydroxyphosphoryl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyi, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylalky
  • FGF-mediated diseases that may be treated or prevented using the compounds or compositions provided herein include, but are not limited to, diabetes, cancer, including, but not limited to, melanoma and tumor growth and development, restenosis, In-Stent restenosis, rheumatoid arthritis, proliferative dermatological disorders, ophthalmic disorders, including, but not limited to, corneal clouding following excimer laser surgery, closure of trabeculectomies, hyperproliferation of lens epithelial cells following cataract surgery, the recurrence of pterygii and diabetic retinopathy, and other proliferative diseases, including, but not limited to, Dupuytren's contracture, conditions that are in some manner mediated by an FGF peptide that binds to FGF receptors, or that are ameliorated by administration of an FGF receptor bFGF antagonist. 1 . Triarylmethane
  • the compounds of formula (I) are triarylmethane derivatives of formulae (II) :
  • R 1 and R 5 are each independently selected from hydrogen, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, CO 2 R 20 , SO 3 R 20 and PO 3 (R 20 ) 2 , or, together with R 13 , form oxy;
  • R 2 and R 4 are each independently hydrogen, halide, pseudohalide, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, or, together with R 3 , form alkylenylamino;
  • R 3 is hydrogen, hydroxy, thioxy, alkoxy, aryloxy, SR 40 or NR 40 R 41 , or, together with R 2 or R 4 , forms alkylenylamino;
  • R 6 and R 10 are each independently selected from hydrogen, halide, pseudohalide, CO 2 R 20 , SO 3 R 20 and PO 3 (R 20 ) 2 ;
  • R 7 and R 9 are each independently hydrogen, halide, pseudohalide, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl;
  • R 8 is hydrogen, halide, pseudohalide, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, aryloxy, heteroaryloxy, NR 40 R 41 , CO 2 R 20 , PO 3 (R 20 ) 2 or SO n R 20 where n is 0-3;
  • R 1 1 is selected from hydrogen, halide and pseudohalide, or, together with X, forms alkylenylammonium;
  • R 12 is hydrogen, halide, pseudohalide, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, or, together with X, forms alkylenylammonium;
  • R 13 is hydrogen, or, together with R 1 or R 5 , forms oxy;
  • R 14 is selected from hydrogen, alkyl, aralkyl, heteroaralkyl, aryl and heteroaryl;
  • X is oxy, thio, NR 40 or N + R 40 R 41 , or, together with R 1 1 and/or R 12 , forms alkylenylammonium;
  • R 15 is CO 2 R 20 , SO 3 R 20 or PO 3 (R 20 ) 2 ;
  • R 16 is selected from hydrogen, alkoxy, aralkoxy, heteroaralkoxy, aryloxy and heteroaryloxy;
  • R 17 and R 18 are each independently hydrogen, halide or pseudohalide; R is selected from hydrogen, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl and Na; and
  • R 40 and R 41 are each independently hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, or together form alkylene or alkenylene.
  • the compounds are of formulae (lla) where R 1 -R 14 and X are selected as above.
  • the compounds are diphenylmethylidene quinone methides, diphenylmethylidene thiaquinone methides, and imminium derivatives thereof.
  • preferred compounds of formula (II) have formula (Ma) :
  • R 1 and R 5 are each independently selected from hydrogen, methyl, CO 2 Et and Br, or form oxy with R 13 ;
  • R 2 and R 4 are each independently hydrogen, Br or isopropyl, or form propylenylamino with R 3 ;
  • R 3 is selected from hydrogen, hydroxy, amino, (4-hydroxysulfonyl- phenylmethyl) (ethyl)amino and (3-hydroxysulfonylphenylmethyl) (ethyl)- amino, or forms propylenylamino with R 2 or R 4 ;
  • R 6 and R 10 are each independently hydrogen, Br or hydroxysulfonyl
  • R 7 and R 9 are each independently selected from hydrogen, Br and methyl
  • R 8 is hydrogen, hydroxy, Br, hydroxysulfonyl, ethylamino, amino or 4-ethoxyphenylamino;
  • R 1 1 is hydrogen or Br, or forms propylenylammonium with X;
  • R 12 is selected from hydrogen, Br and isopropyl, or forms propyleneylammonium with X;
  • R 13 is hydrogen or forms oxy with R or R 5 ;
  • R 14 is selected from hydrogen and methyl; and X is O, NH or (4-hydroxysulfonylphenylmethyl) (ethyl)imminium, or forms propylenylammonium with R 1 1 and R 12 .
  • Presently preferred compounds of formula (lla) are triphenylmeth- ane dyes including those where:
  • X is O; R ⁇ R 3 and R 14 are H; R 2 , R 4 -R 9 , R 1 1 and R 12 are Br; R 3 is OH; and R 10 is SO 3 Na (2-((4-oxo-3,5-dibromo-2,5-cyclohexadien-1 - ylidene) (4-hydroxy-3,5-dibromophenyl)methyl)-3,4,5,6-tetrabromophenyl- sulfonic acid sodium salt or tetabromophenol blue sodium salt);
  • X is O;
  • R 1 is CO 2 Et;
  • R 2 -R 6 , R 10 , R 13 and R 14 are H;
  • R 7 , R 9 , R 1 1 and R 12 are Br;
  • R 8 is OH (ethyl 2-((4-oxo-3,5-dibromo-2,5-cyclohexadien- 1 -ylidene)(4-hydroxy-3,5-dibromophenyl)methyl)benzoate or 3',3",5',5"- tetrabromophenolphthalein ethyl ester);
  • X is O; R 1 , R 5 -R 9 , R 13 and R 14 are H; R 2 , R 4 , R 1 and R 12 are Br; R 3 is OH; and R 10 is SO 3 Na (2-((4-oxo-3,5-dibromo-2,5-cyclohexadien-1 - ylidene)(4-hydroxy-3,5-dibromophenyl) methyl) phenylsulfonic acid sodium salt or bromophenol blue sodium salt);
  • X forms propylenylammonium with R 1 1 and R 12 ;
  • R 1 , R 6 , R 7 , R 9 and R 14 are H;
  • R 2 and R 4 form propylenylamino with R 3 ;
  • R 5 and R 13 form O;
  • R 8 is SO 3 H;
  • R 10 is SO 3 Na (2-(9a-aza-2,3,5,7,8,9-hexahydrobenzo- naphtheno[5,4-e]-3a-aza-2,3,4,5,6-pentahydrobenzonaphtheno[9,8-b]- 2H-pyran-4-yl)benzene-1 ,3-disulfonic acid monohydrate or sulforhodamine 1 01 hydrate);
  • X is (4-oxysulfonylphenylmethyl) (ethyl)ammonium; R 1 , R 2 , R 4 , R 6 , R 7 and R 9 -R 13 are H; R 3 is (4-SO 3 Na-phenylmethyl) (ethyl)amino; R 5 and R 14 are methyl; and R 8 is 4-ethoxyphenylamino (4-((4-(N-(3- hydroxysulfonylphenyl)methyl-N-ethyl)imminium-2-methyl-2,5- cyclohexadien-1 -ylidene) (2-methyl-4-(N-(3-hydroxysulfonylphenyl)methyl- N-ethyl)aminophenyl))methyl-N-(4-ethoxyphenyl)aniline sodium salt or brilliant blue G);
  • X is (4-oxysulfonylphenylmethyl)(ethyl)ammonium; R 1 , R 2 , R 4 -R 7 and R 9 -R 14 are H; R 3 is (4-SO 3 Na-phenylmethyl) (ethyl)amino; and R 8 is 4- ethoxyphenylamino (4-((4-(N-(3-hydroxysulfonylphenyl)methyl-N-ethyl)- imminium-2,5-cyclohexadien-1 -ylidene) (2-methyl-4-(N-(3- hydroxysulfonylphenyl)methyl-N-ethyl)aminophenyl))methyl-N-(4- ethoxyphenyl)aniline sodium salt or coomassie brilliant blue R-250);
  • X is (4-oxysulfonylphenylmethyl)(ethyl)ammonium; R 1 , R 2 , R 4 , R 6 , R 9 -R 13 are H; R 3 is (4-SO 3 Na-phenylmethyl) (ethyl)amino; R 5 , R 7 and R 14 are methyl; and R 8 is ethylamino (4-((4-(N-(4- hydroxysulfonylphenyl)methyl-N-ethyl)imminium-2-methyl-2,5- cyclohexadien-1 -ylidene) (2-methyl-4-(N-(3-hydroxysulfonylphenyl)methyl- N-ethyl)aminophenyl))methyl-N-ethyl-2-methylaniline sodium salt or page blue G90); X is O; R 1 , R 6 -R 9 and R 13 are H; R 2 and R 1 1 are Br; R 3 is OH
  • X is NH; R ⁇ R 2 , R 4 -R 6 and R 9 -R 14 are H; R 3 and R 8 are amino; and R 7 is methyl (4-((4-aminophenyl) (4-imino-2,5-cyclohexadien- 1 - ylidene)methyl)-2-methylaniline hydrochloride or fuchsine) .
  • lib Compounds of formula (lib)
  • Preferred compounds of formula (II) have formula (Mb) :
  • R 15 is methoxycarbonyl or hydroxysulfonyl
  • R 16 is selected from hydrogen, ethoxy and methoxy
  • R 17 and R 18 are each selected from hydrogen and Cl.
  • Presently preferred compounds of formula (Mb) include methyl 2- benzydrylbenzoate, ⁇ , ⁇ -bis(3,5-dichloro-2-ethoxyphenyl)-ortho- toluenesulfonic acid sodium salt and ⁇ , ⁇ -bis(3,5-dichloro-2- methoxyphenyl)-ortho-toluenesulfonic acid sodium salt.
  • the compounds of formula (I) are heteroaryl derivatives of formulae (III) :
  • Y is O, S or NR 40 ;
  • R 51 is selected from hydrogen, alkyl, alkenyl, hydroxycarbonylalkyl, hydroxyalkyl, aralkyl, heteroaralkyl, aryl and heteroaryl; n is 0 or 1 ;
  • R 40 and R 41 are each independently hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, or together form alkylene or alkenylene;
  • R 52 is selected from aryl, heteroaryl and NR 60 R 61 ;
  • R 55 is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, thioalkyl, thioaralkyl, thioheteroaralkyl, thioaryl or thioheteroaryl;
  • R 60 and R 61 are each independently hydrogen, aryl, heteroaryl or S(O) m -aryl or -heteroaryl, where m is 1 or 2, or together form alkylidene or cycloalkylidene;
  • R 70 is alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl;
  • R 80 , R 81 , R 82 and R 83 are selected as in (i) or (ii) as follows:
  • R 80 , R 81 , R 82 and R 83 are selected from Z, preferably from hydrogen, alkyl, alkoxy, halide, haloalkyl and pseudohalide; or (ii) R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene, 1 -aza- 1 ,3-butadienylene or 2-aza-1 ,3-butadienylene which are unsubstituted or substituted with 1 ,3-butadienylene, 1 - aza-1 ,3-butadienylene or 2-aza-1 ,3-butadienylene, and the others are selected as in (i); k is 0-6; and s is 0-2.
  • the nitrogen atom of formula (Ilia) or (Mid) is positively charged and the compounds are heteroarylium compounds, such as benzoxazolium, benzothiazolium and benzimidazolium compounds.
  • a counterion may be present, forming a salt with the positively-charged nitrogen of the heteroarylium group.
  • Such counterions include, but are not limited to, halide, sulfate, tetrahaloborate and perchlorate.
  • R 51 is absent from formula (Ilia) and (Mid), and the nitrogen atom is neutral.
  • the compounds are heteroaryl compounds, such as benzoxazoles, benzothiazoles and benzimidazoles.
  • the compounds of formula (I) are of formulae (Ilia) and (llld) :
  • Y is O, S or NR 40 ;
  • R 51 is selected from hydrogen, alkyl, alkenyl, hydroxycarbonylalkyl, hydroxyalkyl, aralkyl, heteroaralkyl, aryl and heteroaryl, preferably from alkyl, alkenyl, hydroxycarbonylalkyl and hydroxyalkyl; n is 0 or 1 ;
  • R 40 and R 41 are each independently hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, or together form alkylene or alkenylene;
  • R 55 is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, thioalkyl, thioaralkyl, thioheteroaralkyl, thioaryl or thioheteroaryl;
  • R 80 , R 81 , R 82 and R 83 are selected as in (i) or (ii) as follows:
  • R 80 , R 81 , R 82 and R 83 are selected from Z, preferably from hydrogen, alkyl, alkoxy, halide, haloalkyl and pseudohalide; or (ii) R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene, 1 -aza-1 ,3-butadienylene or 2-aza-1 ,3- butadienylene, and the others are selected as in (i) .
  • the compounds have formulae (Ilia) or (Mid) where:
  • Y is O, S or ethylamino
  • R 50 is selected from 3-(N-propyl-2-benzothiazolium)prop-1 -yl, 3-(N- (2-hydroxy-1 -ethyl)-2-benzothiazolium)prop-1 -yl, 3-(N-(2-propen-1 -yl)-2- benzothiazolium)prop-1 -yl, 3-(N-(3-hydroxycarbonyl-1 -propyl)-2- benzothiazolium)prop-1 -yl, 2-(4-dimethylaminophenyl)ethenyl, 3-(N- ocatadecylbenzoxazol-2-inylidene) propenyl, 2-ethyl-3-(N-ethylnaphtho- thiazol-2-inylidene) propenyl, 2-(N-acetyl-N-phenylamino)ethenyl, (N- methylbenzothiazolin-2-ylidene)amin
  • R 80 , R 81 , R 82 and R 83 are selected as in (i) or (ii) as follows: (i) R 80 , R 81 , R 82 and R 83 are selected from hydrogen, methyl, methoxy and Cl; or
  • R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene and the others are selected as in (i) .
  • R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene and the others are selected as in (i) .
  • R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene and the others are selected as in (i) .
  • (Mid) are N-ethyl-2-(2-(4-dimethylaminophenyl)ethenyl)naphtho[2, 1 - djthiazolium iodide, 3,3'-dioctadecyloxacarbocyanine perchlorate, N- ethyl-2-(2-ethyl-3-(N-ethylnaphtho[ 1 ,2-d]thiazolidin-2- ylidene)propenyl)naphtho[ 1 ,2-d]thiazolium bromide, N,N'- dioctadecyloxacarbocyanine para-toluenesulfonate, 2-(2-acetanilinovinyl)- 3-ethylbenzothiazolium iodide, 3-methyl-2-((3-methyl-2- benzothiazolinylidene)aminoazo)benzothia
  • Y is O, S or NR 40 ;
  • R 51 is selected from hydrogen, alkyl, aralkyl, heteroaralkyl, aryl and heteroaryl;
  • R 52 is selected from aryl, heteroaryl and NR 60 R 61 ;
  • R 60 and R 6 are each independently hydrogen, aryl, heteroaryl or S(O) m -aryl or -heteroaryl, where m is 1 or 2, or together form alkylidene or cycloalkylidene; and
  • R 80 , R 81 , R 82 and R 83 are selected as in (i) or (ii) as follows:
  • R 80 , R 81 , R 82 and R 83 are selected from Z, preferably from hydrogen, alkyl, alkoxy, halide, haloalkyl and pseudohalide; or (ii) R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene, 1 -aza-1 ,3-butadienylene or 2-aza-1 ,3- butadienylene, and the others are selected as in (i) .
  • the compounds are of formulae (1Mb) or (Hie) where Y is S; R 51 is methyl or ethyl; R 52 is (4- nitrophenylazo) (phenyl) methylimino, 2-imino-5,6-benzo-3-cyclohexen-1 - ylimino, 4-dimethylaminophenyl, 3,4-propylenylphenylmethylimino, 1 -(3- aminophenyDethylimino, 4-dimethylaminophenylmethylimino or 2- nitrophenylsulfonylamino; and R 80 , R 81 , R 82 and R 83 are all hydrogen.
  • the compounds of formula (I) are of formulae (lllc) and (lllf) :
  • Y is O, S or NR 40 ;
  • R 70 is alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl;
  • R 80 , R 81 , R 82 and R 83 are selected as in (i) or (ii) as follows:
  • R 80 , R 81 , R 82 and R 83 are selected from Z, preferably from hydrogen, alkyl, alkoxy, halide, haloalkyl and pseudohalide; or
  • R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene, 1 -aza-1 ,3-butadienylene or 2-aza-1 ,3- butadienylene, and the others are selected as in (i); k is 0-6; and s is 0-2. In more preferred embodiments, k is 1 and s is 0 or 2.
  • the compounds have formulae (lllc) or (lllf) where Y is O; R 70 is aryl; R 80 , R 81 , R 82 and R 83 are all halide or pseudohalide; k is 1 and s is 0 or 2. More preferably, Y is O, R 70 is selected from 3-trifluoromethylphenyl, 4-chlorophenyl and 4- methoxyphenyl; R 80 , R 81 , R 82 and R 83 are all fluoro; k is 1 and s is 0 or 2.
  • any pharmaceutically-acceptable derivatives including salts, esters, acids, bases, solvates, hydrates and prodrugs of the aryl and heteroaryl compounds.
  • these derivatives are preferred for use in the compositions and methods.
  • Such derivatives may be prepared by methods known to those of ordinary skill in the art.
  • Pharmaceutically-acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1 -para-chlorobenzyl-2-pyrrolidin-1 '-ylmethyl- benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as
  • Triarylmethane compounds of formula (II) may be prepared by the methods described below, by minor modification of the methods described below or by any other methods known to those of skill in the art.
  • certain of the compounds of formula (II) may be prepared by oxidation of compounds of formula (aryl 1 )(aryl 2 ) (aryl 3 )CH in the presence of a diluent, such as water, glacial acetic acid, chloroform, toluene, N,N-dimethylformamide, N-methylpyrrolidinone, alcohols, glycols or mixtures thereof, and an oxygen transfer catalyst that is a heavy metal (such as, but not limited to, Mn, Fe, Cu, or Cr) complex of a porphyrin, tetraaza[ 1 4]annulene, phthalocyanine, or tetraazacyclodecane, or molybdic acid and vanadium in the form of VO 2 + as catalyst.
  • a diluent such as water, glacial acetic acid, chloroform, toluene, N,N-dimethylformamide, N-methylpyrrolidinone, alcohols, glycols or mixtures
  • Suitable oxidants include, but are not limited to, H 2 O 2 , a H 2 O 2 donor compound, an organic hydroperoxide or peroxide, such as tert- butyl hydroperoxide or benzoyl peroxide, peroxomonosulfuric acid or its salts, benzoquinones, including chloranil, or a percarboxylic acid, or MnO 2 in the presence of an aqueous acid.
  • an organic hydroperoxide or peroxide such as tert- butyl hydroperoxide or benzoyl peroxide, peroxomonosulfuric acid or its salts, benzoquinones, including chloranil, or a percarboxylic acid, or MnO 2 in the presence of an aqueous acid.
  • an aqueous solution of the Na salt of a compound of the above formula where aryl is substituted with alkylSO 3 H may be mixed with 5, 1 4-dihydrodibenzo[b,i][5,9, 1 4, 1 8]tetraaza[ 1 4]annulene Fe complex, (H 2 O 3 PCH 2 ) 2 NCH 2 CH 2 N(CH 2 PO 3 H 2 ) 2 , N-methylimidazole, and finally dropwise with 30% H 2 O 2 at 80 °C and stirred 1 h at 60 °C and filtered to give the desired compounds of formula (II) .
  • the compounds of formula (II) are xanthene derivatives. These compounds may be prepared by ring closure of the appropriate alkoxy-substituted triphenylmethane derivative at 1 50 °C and pH ⁇ 7.
  • the compounds of formula (aryl 1 ) (aryl 2 )(aryl 3 )CH may be synthesized by reaction of the corresponding benzhydryl compounds (e.g. , (aryl 1 )(aryl 2 )CHOH) with aryl 3 H under acidic conditions. 2. Preparation of the heteroaryl compounds of formula (III)
  • Heteroaryl compounds of formula (III) may be prepared by the methods described below, by minor modification of the methods described below or by any other methods known to those of skill in the art.
  • a heterocyclic ketone such as, but not limited to, thiazolidinone, oxazolidinone, benzothiazolidinone or benzoxazolidinone
  • thiazolidinone is converted to the corresponding 2-vinylheteroarylium compound that is substituted on the ⁇ atom of the vinyl group with, for example, acetanilido.
  • This transformation may use the corresponding 2-alkylthio or alkoxyheteroarylium compound as an intermediate. Reaction of this compound with the anion of a heteroarylmethane results in conjugate addition followed by elimination of acetanilide to provide the desired compounds.
  • This synthetic route is illustrated below for benzothiazolidinone.
  • reaction of two equivalents of a 2- methylheteroarylium compound with trialkylorthoformate or 1,3,3- trialkoxypropene provides compounds of formula (III).
  • the requisite 2- methylheteroarylium compound is prepared by N-alkylation of the corresponding 2-methylheteroaryl compound.
  • This synthetic scheme may be represented as follows: t ⁇ ethylorthoformate 2 Het * -CH 3 • Het- Met
  • the reaction scheme is illustrated below.
  • Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess any biological activities of compounds that interfere with or inhibit FGF peptides.
  • Numerous assays are known to those of skill in the art for evaluating the ability of compounds to modulate the activity of one or more FGF peptides.
  • the properties of a potential antagonist may be assessed as a function of its ability to inhibit FGF activity including the ability jn vitro to compete for binding to FGF receptors present on the surface of tissues or recombinant cell lines, cell- based competitive assays (see, e.g . , Moscatelli et al. J . Cell. Physiol.
  • FGF isotype specific antagonists may be identified by the ability of a test compound to interfere with one or more FGF peptide binding to different tissues or cells expressing different endothelin receptor subtypes, or to interfere with the biological effects of an FGF peptide (see, e.g.. International Patent Application Publication No. WO 95/2441 4) .
  • the relative affinities Of the compounds for FGF receptors have been and can be assessed .
  • Those that possess the desired in vitro properties, such as specific inhibition of the binding of bFGF, are selected .
  • the selected compounds that exhibit desirable activities may be therapeutically useful in the methods described herein and are tested for such uses employing the above-described assays from which the in vivo effectiveness may be evaluated (Gospodarowicz et al. Endocrin. Rev. 1987, 8, 95-1 14; Buntrock et al. Exp. Pathol. 1982, 21_, 62-67; International Patent Application Publication No WO 92/08473) .
  • Compounds that exhibit the in vitro activities that correlate with the jn vivo effectiveness will then be formulated in suitable pharmaceutical compositions and used as therapeutics.
  • Chem. 270:21 869-21 874) This assay can be used to identify compounds provided herein that may be therapeutically useful for treating FGF-mediated disorders.
  • compositions for use in the methods herein contain therapeutically effective amounts of one or more of the compounds of formula (I) .
  • the compounds are preferably formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers.
  • suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers.
  • suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers
  • compositions effective concentrations of one or more compounds or pharmaceutically acceptable derivatives is (are) mixed with a suitable pharmaceutical carrier or vehicle.
  • the compounds may be derivatized as the corresponding salts, esters, acids, bases, solvates, hydrates and prodrugs of the aromatic acids prior to formulation, as described above.
  • concentrations of the compounds in the formulations are effective for delivery of an amount, upon administration, that ameliorates the symptoms of the FGF-mediated disease.
  • the compositions are formulated for single dosage administration.
  • the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated .
  • Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.
  • the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients.
  • Liposomal suspensions including tissue-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Patent No. 4,522,81 1 .
  • the active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated .
  • the therapeutically effective concentration may be determined empirically by testing the compounds in known in vitro and in vivo systems (see, e ⁇ ., Moscatelli et al. J . Cell. Physiol. 1987, 1 31 , 1 23- 1 30; Gospardarowicz et al. Proc. Natl. Acad. Sci. U.S.A. 1984, 81_, 6963-6967; Thomas et al. Proc. Natl. Acad. Sci. U.S.A. 1984, 81_, 357; European Patent Application No.
  • EP 645 451 International Application Publication No. WO 92/1 2245; Moscatelli et al. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 2091 -2095; Phadke Biochem. Biophys. Res. Comm. 1987, 1 42, 448-453; Togari et al. Biochem. Biophys. Res. Comm. 1983, 1 14, 1 1 89-1 193; and Wagner et al. J. Cell Biol. 1986, 103, 1 363-1 367) and then extrapolated therefrom for dosages for humans.
  • the concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to treat the symptoms of diabetes.
  • a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50-100 ⁇ g/ml.
  • the pharmaceutical compositions typically should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day.
  • Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1 000 mg and preferably from about 1 0 to about 500 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.
  • Preferred pharmaceutically acceptable derivatives include acids, salts, esters, hydrates, solvates and prodrug forms.
  • the derivative is selected such that its pharmacokinetic properties are superior to the corresponding neutral compound.
  • effective concentrations or amounts of one or more of the compounds provided herein or pharmaceutically acceptable derivatives thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions.
  • Compounds are included in an amount effective for ameliorating or treating the FGF-mediated disorder for which treatment is contemplated .
  • concentration of active compound in the composition will depend on absorption, inactivation, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art.
  • compositions are intended to be administered by an suitable route, which includes orally, parenterally, rectally and topically and locally depending upon the disorder being treated.
  • suitable route which includes orally, parenterally, rectally and topically and locally depending upon the disorder being treated.
  • capsules and tablets are presently preferred .
  • the compounds in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration. Preferred modes of administration include parenteral and oral modes of administration.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent
  • antimicrobial agents such as benzyl alcohol and methyl parabens
  • antioxidants such as ascorbic acid and sodium bisul
  • Parenteral preparations can be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.
  • methods for solubilizing compounds may be used . Such methods are known to those of skill in this art, and include, but are not limited to, using co-solvents, such as dimethylsulfoxide (DMSO), using surfactants, such as Tween ® , or dissolution in aqueous sodium bicarbonate.
  • co-solvents such as dimethylsulfoxide (DMSO)
  • surfactants such as Tween ®
  • dissolution in aqueous sodium bicarbonate such as sodium bicarbonate
  • Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
  • the resulting mixture may be a solution, suspension, emulsion or the like.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
  • pharmaceutically acceptable salts or other derivatives of the compounds may be prepared.
  • the compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the patient treated. It is understood that number and degree of side effects depends upon the condition for which the compounds are administered . For example, certain toxic and undesirable side effects are tolerated when treating life- threatening illnesses, such as tumors, that would not be tolerated when treating disorders of lesser consequence.
  • the concentration of compound in the composition will depend on absorption, inactivation and excretion rates thereof, the dosage schedule, and amount administered as well as other factors known to those of skill in the art.
  • the resulting mixture may be a solution, suspension, emulsion or the like.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
  • the formulations are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable derivatives thereof.
  • the pharmaceutically therapeutically active compounds and derivatives thereof are typically formulated and administered in unit-dosage forms or multiple-dosage forms.
  • Unit-dose forms as used herein refers to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent.
  • unit-dose forms include ampoules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof.
  • a multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging.
  • the composition can contain along with the active ingredient: a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant, such as magnesium stearate, calcium stearate and talc; and a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and other such binders known to those of skill in the art.
  • a diluent such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose
  • a lubricant such as magnesium stearate, calcium stearate and talc
  • a binder such as starch, natural gums, such as gum acaciagelatin, glucose, molasses, polvinylpyrrolidine, celluloses and derivatives thereof, povidone, crospovidones and
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.
  • auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine ole
  • compositions containing active ingredient in the range of 0.005% to 1 00% with the balance made up from non-toxic carrier may be prepared.
  • a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin.
  • compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these formulations are known to those skilled in the art.
  • the contemplated compositions may contain 0.001 %-1 00% active ingredient, preferably 0.1 -85%, typically 75-95%.
  • the active compounds or pharmaceutically acceptable derivatives may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.
  • the formulations may be include other active compounds to obtain desired combinations of properties.
  • the compounds of formula (I) or pharmaceutically acceptable derivatives thereof as described herein may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as beta-adrenergic blocker (for example atenolol), a calcium channel blocker (for example nifedipine), an angiotensin converting enzyme (ACE) inhibitor (for example lisinopril), a diuretic (for example furosemide or hydrochlorothiazide), an endothelin converting enzyme (ECE) inhibitor (for example phosphoramidon), a neutral endopeptidase (NEP) inhibitor, an HMGCoA reductase inhibitor, a nitric oxide donor, an anti-oxidant, a vasodilator, a dopamine agonist, a neuroprotective agent, a steroid, a beta-agonist, an anti-
  • Aryl and heteroaryl compounds and derivatives thereof for use in the compositions and methods Compounds and pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts, esters, acids, bases, solvates, hydrates and prodrugs of formulae (I) :
  • Ar 1 is a monocyclic or fused bicyclic, tricyclic or tetracyclic aromatic or heteroaromatic group, where the heteroaromatic group contains one or two, preferably two, heteroatoms selected from O, S and N
  • Ar 2 is a monocyclic or fused bicyclic, tricyclic or tetracyclic arylidene or heteroarylidene group, where the heteroarylidene group contains one or two, preferably two, heteroatoms selected from O, S, and N
  • the aryl, heteroaryl, arylidene and heteroarylidene moieties of the compounds of formula (I) are unsubstituted or are substituted with one or more substituents each independently selected from Z, which, as defined herein, is halogen, hydroxy, nitrile, nitro, formyl, mercapto, carboxy, hydroxysulfonyl, hydroxyphosphoryl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyi, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylalky
  • R 1 and R 5 are each independently selected from hydrogen, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, CO 2 R 20 , SO 3 R 20 and PO 3 (R 20 ) 2 , or, together with R 13 , form oxy;
  • R 2 and R 4 are each independently hydrogen, halide, pseudohalide, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, or, together with R 3 , form alkylenylamino;
  • R 3 is hydrogen, hydroxy, thioxy, alkoxy, aryloxy, SR 40 or NR 0 R 41 , or, together with R 2 or R 4 , forms alkylenylamino;
  • R 6 and R 10 are each independently selected from hydrogen, halide, pseudohalide, CO 2 R 20 , SO 3 R 20 and PO 3 (R 20 ) 2 ;
  • R 7 and R 9 are each independently hydrogen, halide, pseudohalide, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl;
  • R 8 is hydrogen, halide, pseudohalide, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, aryloxy, heteroaryloxy, NR 40 R 41 , CO 2 R 20 , PO 3 (R 20 ) 2 or SO n R 20 where n is 0-3;
  • R 1 1 is selected from hydrogen, halide and pseudohalide, or, together with X, forms alkylenylammonium
  • R 12 is hydrogen, halide, pseudohalide, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, or, together with X, forms alkylenylammonium
  • R 13 is hydrogen, or, together with R 1 or R 5 , forms oxy
  • R 14 is selected from hydrogen, alkyl, aralkyl, heteroaralkyl, aryl and heteroaryl;
  • X is oxy, thio, NR 40 or N + R 40 R 41 , or, together with R 1 1 and/or R 12 , forms alkylenylammonium;
  • R 15 is CO 2 R 20 , SO 3 R 20 or PO 3 (R 20 ) 2 ;
  • R 16 is selected from hydrogen, alkoxy, aralkoxy, heteroaralkoxy, aryloxy and heteroaryloxy;
  • R 17 and R 18 are each independently hydrogen, halide or pseudohalide;
  • R 20 is selected from hydrogen, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl and Na;
  • R 40 and R 41 are each independently hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, or together form alkylene or alkenylene.
  • the compounds are of formulae (lla) where R 1 -R 14 and X are selected as above.
  • the compounds are diphenylmethylidine quinone methides, diphenylmethylidene thiaquinone methides, and imminium derivatives thereof. i. Compounds of formula (lla)
  • R 1 and R 5 are each independently selected from hydrogen, methyl, CO 2 Et and Br, or form oxy with R 13 ;
  • R 2 and R 4 are each independently hydrogen, Br or isopropyl, or form propylenylamino with R 3 ;
  • R 3 is selected from hydrogen, hydroxy, amino, (4-hydroxysulfonyl- phenylmethyl)(ethyl)amino and (3-hydroxysulfonylphenylmethyl) (ethyl)- amino, or forms propylenylamino with R 2 or R 4 ;
  • R 6 and R 10 are each independently hydrogen, Br or hydroxysulfonyl;
  • R 7 and R 9 are each independently selected from hydrogen, Br and methyl
  • R 8 is hydrogen, hydroxy, Br, hydroxysulfonyl, ethylamino, amino or 4-ethoxyphenylamino;
  • R 1 1 is hydrogen or Br, or forms propylenylammonium with X;
  • R 12 is selected from hydrogen, Br and isopropyl, or forms propyleneylammonium with X;
  • R 13 is hydrogen or forms oxy with R 1 or R 5 ;
  • R 14 is selected from hydrogen and methyl;
  • X is O, NH or (4-hydroxysulfonylphenylmethyl)(ethyl)imminium, or forms propylenylammonium with R 1 1 and R 12 .
  • Presently preferred compounds of formula (lla) are triphenylmethane dyes including those where: X is O; R 1 , R 13 and R 14 are H; R 2 , R 4 -R 9 , R 1 1 and R 12 are Br; R 3 is
  • R 10 is SO 3 Na (2-((4-oxo-3,5-dibromo-2,5-cyclohexadien-1 - ylidene) (4-hydroxy-3,5-dibromophenyl)methyl)-3,4,5,6-tetrabromophenyl- sulfonic acid sodium salt or tetabromophenol blue sodium salt);
  • X is O;
  • R 1 is CO 2 Et;
  • R 2 -R 6 , R 10 , R 13 and R 14 are H;
  • R 7 , R 9 , R 1 1 and R 12 are Br;
  • R 8 is OH (ethyl 2-((4-oxo-3,5-dibromo-2,5-cyclohexadien- 1 -ylidene) (4-hydroxy-3,5-dibromophenyl) ethyl) benzoate or 3',3" ,5' ,5"- tetrabromophenolphthalein ethyl ester);
  • X is O; R 1 , R 5 -R 9 , R 13 and R 14 are H; R 2 , R 4 , R 1 1 and R 12 are Br; R 3 is OH; and R 10 is SO 3 Na (2-((4-oxo-3,5-dibromo-2,5-cyclohexadien-1 - ylidene) (4-hydroxy-3,5-dibromophenyl)methyl)phenylsulfonic acid sodium salt or bromophenol blue sodium salt);
  • X forms propylenylammonium with R 1 1 and R 12 ;
  • R 1 , R 6 , R 7 , R 9 and R 14 are H;
  • R 2 and R 4 form propylenylamino with R 3 ;
  • R 5 and R 13 form O;
  • R 8 is SO 3 H;
  • R 10 is SO 3 Na (2-(9a-aza-2,3,5,7,8,9-hexahydrobenzo- naphtheno[5,4-e]-3a-aza-2,3,4,5,6-pentahydrobenzonaphtheno[9,8-b]- 2H-pyran-4-yl)benzene-1 ,3-disulfonic acid monohydrate or sulforhodamine 1 01 hydrate);
  • X is (4-oxysulfonylphenylmethyl)(ethyl)ammonium; R 1 , R 2 , R 4 , R 6 , R 7 and R 9 -R 13 are H; R 3 is (4-SO 3 Na-phenylmethyl)(ethyl)amino; R 5 and R 14 are methyl; and R 8 is 4-ethoxyphenylamino (4-((4-(N-(3- hydroxysulfonylphenyl)methyl-N-ethyl)imminium-2-methyl-2,5- cyclohexadien-1 -ylidene)(2-methyl-4-(N-(3-hydroxysulfonylphenyl)methyl- N-ethyl)aminophenyl))methyl-N-(4-ethoxyphenyl)aniline sodium salt or brilliant blue G);
  • X is (4-oxysulfonylphenylmethyl) (ethyl)ammonium; R ⁇ R 2 , R 4 -R 7 and R 9 -R 14 are H; R 3 is (4-SO 3 Na-phenylmethyl)(ethyl)amino; and R 8 is 4- ethoxyphenylamino (4-((4-(N-(3-hydroxysulfonylphenyl)methyl-N-ethyl)- imminium-2,5-cyclohexadien-1 -ylidene)(2-methyl-4-(N-(3- hydroxysulfonylphenyl)methyl-N-ethyl)aminophenyl))methyl-N-(4- ethoxyphenyl)aniline sodium salt or coomassie brilliant blue R-250);
  • X is (4-oxysulfonylphenylmethyl)(ethyl)ammonium; R 1 , R 2 , R 4 , R 6 , R 9 -R 13 are H; R 3 is (4-SO 3 Na-phenylmethyl)(ethyl)amino; R 5 , R 7 and R 14 are methyl; and R 8 is ethylamino (4-((4-(N-(4- hydroxysulfonylphenyl)methyl-N-ethyl)imminium-2-methyl-2,5- cyclohexadien-1 -ylidene) (2-methyl-4-(N-(3-hydroxysulfonylphenyl)methyl- N-ethyl)aminophenyl))methyl-N-ethyl-2-methylaniline sodium salt or page blue G90);
  • X is O; R ⁇ R 6 -R 9 and R 13 are H; R 2 and R 1 1 are Br; R 3 is OH; R 4 and R 12 are isopropyl; R 5 and R 4 are methyl; and R 10 is SO 3 Na (2-((4-oxo-3- bromo-5-isopropyl-2-methyl-2,5-cyclohexadien-1 -ylidene) (3-bromo-4- hydroxy-5-isopropyl-2-methylphenyl) methyl) phenylsulfonic acid sodium salt or bromothymol blue sodium salt); and
  • X is NH; R ⁇ R 2 , R 4 -R 6 and R 9 -R 14 are H; R 3 and R 8 are amino; and R 7 is methyl (4-((4-aminophenyl) (4-imino-2,5-cyclohexadien-1 - ylidene)methyl)-2-methylaniline hydrochloride or fuchsine) .
  • ii Compounds of formula (lib)
  • Preferred compounds of formula (II) have formula (lib) :
  • R 15 is methoxycarbonyi or hydroxysulfonyl
  • R 16 is selected from hydrogen, ethoxy and methoxy
  • R 17 and R 18 are each selected from hydrogen and Cl.
  • Presently preferred compounds of formula (Mb) include methyl 2- benzydrylbenzoate, ⁇ , ⁇ -bis(3,5-dichloro-2-ethoxyphenyl)-ortho- toluenesulfonic acid sodium salt and , ⁇ -bis(3,5-dichloro-2- methoxyphenyl)-ortho-toluenesulfonic acid sodium salt.
  • the compounds of formula (I) are heteroaryl derivatives of formulae (III) :
  • Y is O, S or NR 40 ;
  • R 51 is selected from hydrogen, alkyl, alkenyl, hydroxycarbonylalkyl, hydroxyalkyl, aralkyl, heteroaralkyl, aryl and heteroaryl; n is 0 or 1 ;
  • R 40 and R 41 are each independently hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, or together form alkylene or alkenylene;
  • R 52 is selected from aryl, heteroaryl and NR 60 R 61 ;
  • R 55 is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, thioalkyl, thioaralkyl, thioheteroaralkyl, thioaryl or thioheteroaryl;
  • R 60 and R 61 are each independently hydrogen, aryl, heteroaryl or S(O) m -aryl or -heteroaryl, where m is 1 or 2, or together form alkylidene or cycloalkylidene;
  • R 70 is alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl;
  • R 80 , R 81 , R 82 and R 83 are selected as in (i) or (ii) as follows:
  • R 80 , R 81 , R 82 and R 83 are selected from Z, preferably from hydrogen, alkyl, alkoxy, halide, haloalkyl and pseudohalide; or (ii) R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene, 1 -aza-1 ,3-butadienylene or 2-aza-1 ,3-butadienylene which are unsubstituted or substituted with 1 ,3-butadienylene, 1 - aza-1 ,3-butadienylene or 2-aza-1 ,3-butadienylene, and the others are selected as in (i); k is 0-6; and s is 0-2.
  • the nitrogen atom of formulae (Ilia) and (Hid) is positively charged and the compounds are heteroarylium compounds, such as benzoxazolium, benzothiazolium and benzimidazolium compounds.
  • a counterion may be present, forming a salt with the positively-charged nitrogen of the heteroarylium group.
  • Such counterions include, but are not limited to, halide, sulfate, tetrahaloborate and perchlorate.
  • R 51 is absent from formulae (Ilia) and (Mid), and the nitrogen atom is neutral.
  • the compounds are heteroaryl compounds, such as benzoxazoles, benzothiazoles and benzimidazoles. i. Compounds of formulae (Ilia) and (Hid)
  • the compounds of formula (I) are of formula (Ilia) or (Hid) :
  • Y is O, S or NR 40 ;
  • R 51 is selected from hydrogen, alkyl, alkenyl, hydroxycarbonylalkyl, hydroxyalkyl, aralkyl, heteroaralkyl, aryl and heteroaryl, preferably from alkyl, alkenyl, hydroxycarbonylalkyl and hydroxyalkyl; n is 0 or 1 ;
  • R 40 and R 4 are each independently hydrogen, alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, or together form alkylene or alkenylene;
  • R 55 is alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, thioalkyl, thioaralkyl, thioheteroaralkyl, thioaryl or thioheteroaryl;
  • R 80 , R 81 , R 82 and R 83 are selected as in (i) or (ii) as follows:
  • R 80 , R 81 , R 82 and R 83 are selected from Z, preferably from hydrogen, alkyl, alkoxy, halide, haloalkyl and pseudohalide; or (ii) R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene, 1 -aza-1 ,3-butadienylene or 2-aza-1 ,3- butadienylene, and the others are selected as in (i) .
  • the compounds have formulae (Ilia) or (Hid) where:
  • Y is O, S or ethylamino
  • R 50 is selected from 3-(N-propyl-2-benzothiazolium)prop-1 -yl, 3-(N- (2-hydroxy-1 -ethyl)-2-benzothiazolium)prop-1 -yl, 3-(N-(2-propen-1 -yl)-2- benzothiazolium)prop-1 -yl, 3-(N-(3-hydroxycarbonyl-1 -propyl)-2- benzothiazolium)prop-1 -yl, 2-(4-dimethylaminophenyl)ethenyl, 3-(N- ocatadecylbenzoxazol-2-inylidene) propenyl, 2-ethyl-3-(N-ethylnaphtho- thiazol-2-inylidene) propenyl, 2-(N-acetyl-N-phenylamino)ethenyl, (N- methylbenzothiazolin-2-ylidene)amin
  • R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene and the others are selected as in (i) .
  • R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene and the others are selected as in (i) .
  • R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene and the others are selected as in (i) .
  • Y is O, S or NR 40 ;
  • R 51 is selected from hydrogen, alkyl, aralkyl, heteroaralkyl, aryl and heteroaryl;
  • R 52 is selected from aryl, heteroaryl and NR 60 R 61 ;
  • R 60 and R 61 are each independently hydrogen, aryl, heteroaryl or S(O) m -aryl or -heteroaryl, where m is 1 or 2, or together form alkylidene or cycloalkylidene; and
  • R 80 , R 81 , R 82 and R 83 are selected as in (i) or (ii) as follows:
  • R 80 , R 81 , R 82 and R 83 are selected from Z, preferably from hydrogen, alkyl, alkoxy, halide, haloalkyl and pseudohalide; or (ii) R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene, 1 -aza-1 ,3-butadienylene or 2-aza-1 ,3- butadienylene, and the others are selected as in (i) .
  • the compounds are of formulae (lllb) or (Hie) where Y is S; R 51 is methyl or ethyl; R 52 is (4- nitrophenylazo) (phenyl) methylimino, 2-imino-5,6-benzo-3-cyclohexen-1 - ylimino, 4-dimethylaminophenyl, 3,4-propylenylphenylmethylimino, 1 -(3- aminophenyDethylimino, 4-dimethylaminophenylmethylimino or 2- nitrophenylsulfonylamino; and R 80 , R 81 , R 82 and R 83 are all hydrogen.
  • Presently most preferred compounds of formulae (lllb) and (Hie) include 4-nitrophenylazobenzoyl N-methylbenzothiazolidinone hydrazine bishydrazone, 2-imino-5,6-benzo-3-cyclohexenone N- methylbenzothiazolidinone hydrazine bishydrazone, N- ethylbenzothiazolidinone 4-dimethylaminophenylimine, 3,4- propylenylbenzaldehyde N-methylbenzothiazolidinone hydrazine bishydrazone, 3-aminoacetophenone N-methylbenzothiazolidinone hydrazine bishydrazone, 4-dimethylaminobenzaldehyde N-methylbenzothiazolidinone hydrazine bishydrazone or N-methylbenzothiazolidinone 2- nitrophenylsulfonylhydrazone.
  • the compounds of formula (I) are of formulae (lllc) and (lllf) :
  • Y is O, S or NR 40 , preferably O or S;
  • R 70 is alkyl, aralkyl, heteroaralkyl, aryl or heteroaryl, preferably aryl or heteroaryl;
  • R 80 , R 81 , R 82 and R 83 are selected as in (i) or (ii) as follows: (i) R 80 , R 81 , R 82 and R 83 are selected from Z, preferably from hydrogen, alkyl, alkoxy, halide, haloalkyl and pseudohalide; or (ii) R 80 and R 81 , or R 81 and R 82 , or R 82 and R 83 form 1 ,3- butadienylene, 1 -aza-1 ,3-butadienylene or 2-aza-1 ,3- butadienylene, and the others are selected as in (i); k is 0-6; and s is 0-2.
  • k is 1 and s is 0 or 2.
  • the compounds have formulae (lllc) and (lllf) where Y is O; R 70 is aryl; R 80 , R 81 , R 82 and R 83 are all halide or pseudohalide; k is 1 and s is 0 or 2. More preferably, Y is O, R 70 is selected from 3-trifluoromethylphenyl, 4-chlorophenyl and 4- methoxyphenyl; R 80 , R 81 , R 82 and R 83 are all fluoro; k is 1 and s is 0 or 2.
  • Presently most preferred compounds of formulae (lllc) and (lllf) are 2-(3-trifiuoromethylphenylthiomethyl)-4,5,6,7-tetrafluorobenz[d]oxazole, 2-(4-chlorophenylsulfonylmethyl)-4,5,6,7-tetrafluorobenz[d]oxazole and 2-(4-methoxyphenylthiomethyl)-4,5,6,7-tetrafluorobenz[d]oxazole.
  • Aryl and heteroaryl Derivatives Also of interest for use in the compositions and methods are any pharmaceutically-acceptable derivatives, including salts, esters, acids, bases, solvates, hydrates and prodrugs of the aryl and heteroaryl compounds. Such derivatives may be readily prepared by methods known to those of ordinary skill in the art.
  • Pharmaceutically-acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choiine, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N- methylglucamine, procaine, N-benzylphenethylamine, 1 -para- chlorobenzyl-2-pyrrolidin-1 '-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not
  • Oral pharmaceutical dosage forms are either solid, gel or liquid .
  • the solid dosage forms are tablets, capsules, granules, and bulk powders.
  • Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric-coated, sugar-coated or film-coated .
  • Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.
  • the formulations are solid dosage forms, preferably capsules or tablets.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.
  • binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste.
  • Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid.
  • Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.
  • Glidants include, but are not limited to, colloidal silicon dioxide.
  • Disintegrating agents include crosscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose.
  • Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate.
  • Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of spray dried flavors.
  • Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether.
  • Emetic-coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates.
  • Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.
  • the compound could be provided in a composition that protects it from the acidic environment of the stomach.
  • the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
  • the composition may also be formulated in combination with an antacid or other such ingredient.
  • the dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents.
  • the compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics.
  • the compound is used for treating asthma or hypertension, it may be used with other bronchodilators and antihypertensive agents, respectively.
  • the active ingredient is a compound or pharmaceutically acceptable derivative thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.
  • Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents.
  • Enteric-coated tablets because of the enteric-coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines.
  • Sugar-coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied.
  • Film-coated tablets are compressed tablets which have been coated with a polymer or other suitable coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned.
  • Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar-coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil. Elixirs are clear, sweetened, hydroalcoholic preparations.
  • Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative.
  • An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid .
  • Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives.
  • Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form include diluents, sweeteners and wetting agents.
  • Pharmaceutically acceptable substance used in effervescent granules, to be reconstituted into a liquid oral dosage form include organic adds and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.
  • Solvents include glycerin, sorbitol, ethyl alcohol and syrup.
  • preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol.
  • non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil.
  • emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate.
  • Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia.
  • Diluents include lactose and sucrose.
  • Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as sodium cyclamate and saccharin.
  • Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.
  • Organic adds include citric and tartaric acid.
  • Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.
  • Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof.
  • Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.
  • the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule.
  • a gelatin capsule Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Patent Nos 4,328,245; 4,409,239; and 4,41 0,545.
  • the solution e.g ., in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. , water, to be easily measured for administration.
  • liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g ., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
  • Other useful formulations include those set forth in U.S. Patent Nos. Re 28,81 9 and 4,358,603.
  • tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate. 3. Injectables, solutions and emulsions
  • Parenteral administration generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol.
  • the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins.
  • Implantation of a slow-release or sustained-release system such that a constant level of dosage is maintained (see, e.g ., U.S. Patent No. 3,71 0,795) is also contemplated herein.
  • the percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the
  • Parenteral administration of the formulations includes intravenous, subcutaneous and intramuscular administrations.
  • Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as the lyophilized powders described herein, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions.
  • the solutions may be either aqueous or nonaqueous.
  • suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.
  • Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.
  • aqueous vehicles examples include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection.
  • Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil.
  • Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride.
  • Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (Tween ® 80) . A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.
  • the concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect.
  • the exact dose depends on the age, weight and condition of the patient or animal as is known in the art.
  • the unit-dose parenteral preparations are packaged in an ampoule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.
  • intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration.
  • Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.
  • Injectables are designed for local and systemic administration.
  • a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1 % w/w up to about 90% w/w or more, preferably more than 1 % w/w of the active compound to the treated tissue(s) .
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated.
  • the compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug.
  • the form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle.
  • the effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined .
  • Topical mixtures are prepared as described for the local and systemic administration.
  • the resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.
  • the compounds or pharmaceutically acceptable derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e ⁇ , U.S. Patent Nos. 4,044, 1 26, 4,41 4,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment inflammatory diseases, particularly asthma) .
  • These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the formulation will typically diameters of less than 50 microns, preferably less than 1 0 microns.
  • the compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application.
  • Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies.
  • Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered. These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01 % - 1 0% isotonic solutions, pH about 5-7, with appropriate salts.
  • compositions for ophthalmic administration are provided.
  • compositions are formulated in an ophthalmically acceptable carrier.
  • local administration either by topical administration or by injection is preferred.
  • Time release formulations are also desirable.
  • the compositions are formulated for single dosage administration, so that a single dose administers an effective amount. Ophthalmologically effective concentrations or amounts of one or more of the compounds are mixed with a suitable pharmaceutical carrier or vehicle.
  • concentrations or amounts of the conjugates that are effective requires delivery of an amount, upon administration, that prevents or substantially reduces the effects of FGF-mediated ophthalmological conditions, including, but not limited to, diabetic retinopathy, corneal clouding following excimer laser surgery, closure of trabeculectomies, hyperproliferation of lens epithelial cells following cataract surgery and the recurrence of pterygii.
  • the compounds can also be mixed with other active materials, that do not impair the desired action, or with materials that supplement the desired action, including viscoelastic materials, such as hyaluronic acid, which is sold under the trademark HEALON (solution of a high molecular weight (MW of about 3 million) fraction of sodium hyaluronate; manufactured by Pharmacia, Inc. see, e.g ., U.S. Patent Nos.
  • HEALON solution of a high molecular weight (MW of about 3 million) fraction of sodium hyaluronate
  • the viscoelastic materials are present generally in amounts ranging from about 0.5 to 5.0%, preferably 1 to 3% by weight of the conjugate material and serve to coat and protect the treated tissues.
  • the compositions may also include a dye, such as methylene blue or other inert dye, so that the composition can be seen when injected into the eye or contacted with the surgical site during surgery. 6.
  • an rectal administration are also contemplated herein.
  • rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.
  • Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used .
  • spermaceti and wax agents to raise the melting point of suppositories include spermaceti and wax.
  • Rectal suppositories may be prepared either by the compressed method or by molding.
  • the typical weight of a rectal suppository is about 2 to 3 g.
  • Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration. 7. Articles of manufacture
  • compositions containing compounds or pharmaceutically acceptable derivatives may be packaged as articles of manufacture containing packaging material, a composition containing a compound or pharmaceutically acceptable derivative thereof provided herein, which is effective for antagonizing the effects of an FGF peptide, preferably bFGF, ameliorating the symptoms of an FGF-mediated disorder, or inhibiting binding of an FGF peptide to an FGF receptor with an IC 50 of less than about 500 ⁇ M, within the packaging material, and a label that indicates that the composition containing the compound or derivative thereof is used for antagonizing the effects of FGF, treating FGF-mediated disorders or inhibiting the binding of an FGF peptide to an FGF receptor.
  • compositions containing therapeutically effective concentrations of the compounds of formula (I) or pharmaceutically acceptable derivatives thereof are also provided.
  • the compositions containing such compounds are used for treating FGF- mediated disorders, particularly proliferative disorders, in which FGF causes or contributes to the pathology.
  • methods for using the compositions to prevent the undesired growth and proliferation of FGF-sensitive cells occurring in vascular disorders characterized by accelerated smooth muscle cell proliferation such as rheumatoid arthritis, tumor angiogenesis, Kaposi's sarcoma, restenosis, In-Stent restenosis, certain ophthalmic disorders and dermatological disorders, such as psoriasis, are provided herein.
  • the medicament containing the compound is administered intravenously (IV), although treatment by localized administration may be tolerated in some instances.
  • IV intravenously
  • the medicament containing the compound is injected into the circulatory system of a subject in order to deliver a dose to the targeted cells.
  • Targeting may be effected by linking the compound to a targeting agent specific for FGF receptors, particularly bFGF receptors. Dosages may be determined empirically, but will typically be in the range of about 0.01 mg to about 1 00 mg of the compound per kilogram of body weight as a daily dosage.
  • Atherosclerosis also referred to as arteriosclerosis, results from the development of an intimal lesion and the subsequent narrowing of the vessel lumen.
  • atherosclerosis originally appears as a result of the buildup of plaque which lines the interior of blood vessels, particularly the arteries.
  • bypass surgery is sometimes employed to replace such clogged arteries, in recent years, a number of surgical procedures have been developed so as to interarterially remove such plaque, often by balloon catheterization or other such treatments in which the plaque is either compressed against or scraped away from the interior surface of the artery. This scraping of the interior wall removes endothelial cells, which constitute the lining of the blood vessel.
  • the smooth muscle cells which are normally located exterior of the endothelial cells (ECs) and form the blood vessel structure, begin to grow and multiply causing a narrowing of the vessel lumem.
  • the patient so treated finds a recurrence of such narrowing of the vessel lumen in a relatively short period thereafter as a result of this proliferation, generally referred to as restenosis, requiring a repetition of the surgical procedure to again remove the increasing blockage.
  • Proliferating SMCs express functional FGF receptors and are responsive to bFGF.
  • SMCs migrating smooth muscle cells
  • Basic FGF appears to play a pivotal role in the subsequent responses of the vascular wall.
  • Basic FGF is known to be synthesized by endothelial and smooth muscle cells (SMCs) and is thought to be stored in the subendothelial matrix, and in some instances, this growth factor is released from cells after injury. Therefore, compounds that inhibit FGF-mediated proliferation of SMCs may be used in methods for treating restenosis by preventing the proliferation that causes the narrowing of the vessel lumem.
  • Treatment is effected by administering a therapeutically effective amount of a medicament containing the compound in a physiologically acceptable carrier or recipient, in a manner so that the compound reaches regions in a human or other mammal where the compound will inhibit the proliferation of the target cells.
  • intraarterial infusion will be among the preferred methods.
  • IV administration over a period of time is preferred.
  • the compounds for treating restenosis may be formulated for intravenous or local administration .
  • compounds may be conjugated to an agent that specifically targets proliferating SMCs, such as antibodies, hormones, ligands or the like to improve delivery and uptake of the compound.
  • the therapeutically effective concentration may be determined empirically by testing the compounds in known jn vitro and in. vivo systems (see, e.g . , Moscatelli et a J . Cell. Physiol. 1987, 1 31 , 1 23-1 30); mitogenic assays (Gospardarowicz et al. Proc. Natl. Acad . Sci. U.S.A. 1984, 8J_, 6963-6967; Thomas et al. Proc. Natl. Acad. Sci. U.S.A. 1984, 81_, 357); stimulation of angiogenesis in vitro (see, e.g. , European Patent Application No.
  • EP 645 451 cell proliferation assays or heparin binding assays (see, e.g ., International Application Publication No. WO 92/1 2245); assays measuring the release of cellular proteases (Moscatelli et a Proc. Natl. Acad . Sci. U.S.A. 1986, 83, 2091 -2095; Phadke Biochem. Biophys. Res. Comm. 1987, 1 42, 448-453); and, assays for the promotion of FGF-mediated neurite outgrowth and neuron survival (Togari et al. Biochem. Biophys. Res. Comm. 1983, 1 1 4: 1 1 89- 1 1 93; Wagner et a J . Cell Biol. 1986, 1 03, 1 363-1 367) and then extrapolated therefrom for dosages for humans.
  • Rheumatoid arthritis is a systemic, chronic inflammatory disease, that is characterized by the destruction of the joint cartilage and inflammation of the synovium.
  • the hallmark feature of rheumatoid arthritis is the production circulating autoantibodies, also referred to as rheumatoid factors, which are reactive with the Fc portions of the patients own IgG molecules (e.g . , see Abbas et al , Cellular and Molecular Immunology, W.B. Saunders Co., Philadelphia, PA) .
  • rheumatoid arthritis One of the systemic complications of rheumatoid arthritis is the formation of injurious immune complexes in the synovial fluid of the joints that initiates vascular inflammation by activation of the complement cascade.
  • T-cells, activated B-cells, plasma cells and macrophages are often found in synovial fluid of affected joints as well as a variety of soluble proteins, such as cytokines (e.g ., interleukin-1 , IFN- and tumor necrosis factor (TNF)) and growth factors, such as bFGF. It has been suggested that cytokines act in concert with the inflammatory mediators, e.g. , bFGF, to cause local tissue destruction. Chronically, cytokines and bFGF stimulate fibroblast and epithelial proliferation resulting in angiogenesis, and prolonged exposure can result in hyperproliferation of epithelial cells that form fibrous tissue, referred to as fibrosis.
  • cytokines e.g ., interleukin-1 , IFN- and tumor necrosis factor (TNF)
  • TNF tumor necrosis factor
  • compounds that inhibit the FGF-mediated hyperproliferation of epithelial cells may be used to treat rheumatoid arthritis.
  • the compounds for treating rheumatoid arthritis may be formulated for oral administration or intravenous injection and an effective concentration may be administered.
  • the effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
  • Angiogenesis plays a critical role in embryonic development and in several physiologic and pathologic conditions, including wound healing, ovulation, diabetic retinopathy and malignancy. In particular, without the nutrients and oxygen provided via this neovascularization, solid tumors would be unable to grow beyond about 2 mm in diameter.
  • the compounds may be specifically targeted to tumorigenic tissues by linking the compound to an agent that specifically binds to the surface of the tumorigenic cell, e.g., an anti-tumor antigen antibody, or linking the compound to an agent that is preferentially interacts with or taken up by targeted tumor.
  • compounds may be encapsulated in tissue-targeted liposomal suspensions for targeted delivery of the compound.
  • the compounds for treating tumor angiogenesis may be formulated for topical application and administered to the skin, e.g. , for treatment of melanoma, or may be formulated for intravenous administration for treatment of solid tumors, such as carcinomas.
  • the therapeutically effective concentration may be determined empirically by testing the compounds in known jn vitro (e.g., inhibition of angiogenesis in vitro (see, e.g ., European Patent Application No. EP 645 451 )) and then extrapolated therefrom for dosages for humans.
  • Ophthalmic Disorders e.g., inhibition of angiogenesis in vitro (see, e.g ., European Patent Application No. EP 645 451 )
  • compositions provided herein may be used in methods of treating ophthalmic disorders resulting from FGF-mediated hyper-proliferation of lens epithelial cells, fibroblasts or keratinocytes.
  • ophthalmic disorders that may be treated using the methods and compositions provided herein include, but are not limited to, corneal clouding following excimer laser surgery, closure of trabeculectomies, hyperproliferation of lens epithelial cells following cataract surgery, the recurrence of pterygii and diabetic retinopathy (see, Dell Drug Discovery Today 1996, _, 221 ).
  • the compounds for treating ophthalmic disorders may be formulated for local or topical application and administered by topical application of an effective concentration to the skin and mucous membranes, such as in the eye.
  • the compositions may also include a dye, such as methylene blue or other inert dye, so that the composition can be seen when injected into the eye or contacted with the surgical site during surgery.
  • the effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.
  • the ophthalmologic indications herein are typically treated locally either by the application of drops to the affected tissue(s), contacting with a biocompatible sponge that has absorbed a solution of the conjugates or by injection of a composition.
  • the composition will be applied during or immediately after surgery in order to prevent closure of the trabeculectomy, prevent a proliferation of keratocytes following excimer laser surgery, prevent the proliferation of lens epithelial cells following cataract surgery or to prevent a recurrence of pterygii.
  • the composition may also be injected into the affected tissue following surgery and applied in drops following surgery until healing is completed. For example, to administer the formulations to the eye, it can be slowly injected into the bulbar conjunctiva of the eye.
  • Compounds of formulae (I) that exhibit FGF antagonist activity were and can be identified by testing their ability to compete with 125 l- bFGF for binding to one or more FGF receptor or FGF-binding fragment thereof. These compounds have been tested in a binding assay that uses a recombinant FGF receptor fusion protein in which the extracellular domain of a human FGF receptor, FGFR1 , was fused to the amino terminal fragment of tissue plasminogen activator (tPA) protein. This fusion protein retains the ability to bind FGF, such as bFGF (Zhu et al. J ⁇
  • FGFR1 human fibroblast growth factor receptor 1
  • the nucleotide sequence of the DNA encoding the shorter form of human basic fibroblast growth factor receptor 1 (FGFR1 ) has been determined (e.g., Itoh et al. Biochem. Biophys. Res. Comm. 1990, 1 69:680-685) .
  • This shorter form of FGFR1 is a 731 amino acid polypeptide that has a signal peptide, two extracellular immunoglobulin- like domains, a transmembrane domain and an intracellular tyrosine kinase domain.
  • PCR poiymerase chain reactions
  • a Hindlll restriction endonuclease site was introduced upstream of the FGFR1 initiation codon and a Sail site was introduced downstream of the second immunoglobulin-like extracellular domain (Igll) to facilitate cloning of the amplified product.
  • Igll immunoglobulin-like extracellular domain
  • the Hindlll site was introduced at nt -8 to -3 during the PCR reaction by synthesizing an oligonucleotide primer corresponding to nt - 1 2 to + 22 that introduced nucleotide changes at three positions in the FGFR1 sequence: nt -3 (G to T) , nt -6 (A to G) and nt -8 (G to A) .
  • the Sail site was introduced at nt 849 to nt 854 by synthesizing an oligonucleotide primer complementary to nt 823 to 857 containing nucleotide substitutions at three positions in the FGFR1 sequence: nt 849 (C to G), nt 851 (G to C) and nt 854 (G to C) .
  • the 857 bp PCR fragment was incubated with Hindlll and SaJI and purified by agarose gel electrophoresis according to the standard procedures (Sambrook et al. ( 1 989) Molecular Cloning, 2nd ed., Cold Spring Harbor Laboratory Press, New York) .
  • the DNA was isolated from gel by electroelution and recovered by precipitation with ethanol.
  • the resulting Hindlll to Sail DNA fragment consists of nt -7 to nt 849 of the FGFR1 cDNA described by Itoh et al. and encodes amino acid residues 1 to 284 of the shorter form of the bFGF receptor.
  • tPA tissue plasminogen activator
  • oligonucleotides complementary to sequences flanking the tPA coding region were synthesized and used as primers in PCR reactions to isolate a full-length cDNA encoding human tPA from a human placenta cDNA library (Clontech, Palo Alto, CA) .
  • An oligonucleotide corresponding to nt -6 to + 21 , relative to the A of the initiation codon of the of human tPA prepro polypeptide e.g . , see Pennica et al.
  • oligonucleotide complementary to nt 1 558 to nt 1 584 were used to amplify a 1 591 bp DNA encoding the entire human tPA prepro polypeptide.
  • the full-length DNA was used as a template for a subsequent PCR reaction to amplify a 599 bp DNA encoding the a portion of the signal peptide-finger-growth factor-first Kringle domains of tPA, and which also to introduce an in-frame amber stop codon (i.e. , UGA) at amino acid codon 1 80 of mature tPA sequence.
  • an in-frame amber stop codon i.e. , UGA
  • a Sail restriction endonuclease site and a mutation substituting a Pro for an Arg at position -6 were introduced upstream of the first Ser codon of mature tPA and a BamHI site was introduced downstream of newly introduced translational stop codon to allow for convenient subcloning of the amplified product.
  • the substitution of Pro for Arg at amino acid residue position -6 introduces a proteolytic cleavage site for thrombin in the linker sequence (i.e., Phe-Pro-Arg-Gly at positions -7 to -4) .
  • the Sail site and the amino acid substitution were introduced at nt
  • nt 76 A to G
  • nt 79 C to G
  • nt 81 T to C
  • nt 91 A to C
  • nt 92 G to C
  • nt 652 to nt 657 and translational stop codon at amino acid codon 1 80 were introduced by synthesizing an oligonucleotide primer complementary to nt 623 to 661 containing nucleotide substitutions at three positions in the tPA sequence: nt 644 (C to A), nt 655 (A to T) and nt 657 (G to C) .
  • the amplified PCR fragment was incubated with Sa]l and BamHI and subjected to agarose gel electrophoresis according to the standard procedures (Sambrook et al. ( 1 989) Molecular Cloning, 2nd ed., Cold Spring Harbor Laboratory Press, New York) .
  • the 585 bp DNA was isolated from gel by electroelution and recovered by precipitation with ethanol.
  • the isolated Sail to BamHI fragment encoding the portion of human tPA was ligated into the Sail and BamHI sites of pUC1 8 to generate plasmid HTPA3/4-pUC1 8.
  • HTPA3/4-pUC 1 8 was then digested with Hindlll and Sail into which the isolated Hindlll to Sajl FGFR1 - encoding fragment was inserted.
  • the plasmid carrying the FGFR1 -tPA chimeric DNA was digested with Hindlll and BamHI, subjected to agarose gel electrophoresis and the 1 ,426 bp DNA fragment was excised from the gel and isolated as described above.
  • the resulting DNA encodes a 472 amino acid peptide comprised of amino acids 1 -284 of human FGFR1 , a 1 0 amino acid linker sequence VDARFPRGAR, derived from the human tPA signal peptide, and amino acids 1 -1 78 from human tPA.
  • the resulting DNA encoding the FGFR1 -tPA fusion protein is shown in SEQ ID No: 1 and the deduced amino acid is shown in SEQ ID No: 2.
  • the DNA of SEQ ID No. 1 was digested with Hindlll to BamHI and the 1 ,434 bp fragment (nt 2-1435 of SEQ ID No: 1 ) was isolated and ligated into the mammalian expression vector pK4K for recombinant expression of the FGFR1 -tPA fusion protein (Niidome et al. Biochem. Biophys. Res. Commun. 1994, 203, 1 821 -1 827) .
  • the plasmid pK4K is a pBR322-based vector that has unique Hindlll and BamHI sites for directional cloning of heterologous DNAs whose expression is under the control of the SV40 early promoter. This plasmid also contains the ⁇ - lactamase and DHFR genes for use as selectable markers in prokaryotes and eukaryotic organisms, respectively.
  • the recombinant FGFR1 -tPA fusion protein Upon expression, the recombinant FGFR1 -tPA fusion protein is secreted into the surrounding culture medium. Recombinant FGFR1 -tPA fusion protein expression in BHK cells was monitored by sandwich enzyme-linked immunosorbent assays (sandwich ELISAs) . A mouse IgG monoclonal antibody specific for human tPA, designated 1 4-6, was used as the capture antibody and a polyclonal, rabbit anti-lgG antibody conjugated to horseradish peroxidase was used as the secondary-labelled antibody.
  • the soluble, recombinant FGFR1 -tPA fusion protein was immobilized to a solid support by attachment to the surface of the wells of an enzyme-linked immunosorbent assay plate (High binding plates, COSTAR) .
  • An enzyme-linked immunosorbent assay plate High binding plates, COSTAR
  • a 0.1 ml aliquot of a 1 0 ⁇ g/ml solution of rFGFR1 -tPA in PBS was added and the plate was incubated for approximately 1 6 hr at 4 °C. Unbound fusion protein was removed by washing three times with an equal volume of cold PBS.
  • blocking buffer 25 mM HEPES, pH 7.5, 100 mM NaCl and 0.5% gelatin
  • binding buffer 25 mM HEPES, pH 7.5, 100 mM NaCl and 0.3% gelatin
  • 1 ml of binding buffer supplemented with 2 ⁇ g/ml heparin and a range of 1 -20 ng/ml of labelled 125 l-bFGF (800-1 200 Ci/mmol; Amersham, Arlington Heights, IL) and incubated in the absence or presence of 2.5 vg/ml unlabelled bFGF or a test compound for 3 hr at ambient temperature.
  • the buffer was removed by aspiration and the wells were washed twice each with PBS and a solution of 25 mM HEPES, pH 7.5, containing 2 M NaCl.
  • Bound bFGF was dissociated from the immobilized fusion protein by the addition of two aliquots of a solution of 25 mM sodium acetate, pH 4.0, containing 2 M NaCl. The two sodium acetate washes were combined and the amount of radioactivity present was determined using a gamma counter. The amount of bound radiolabelled bFGF in each well was calculated and the specificity of bFGF binding was analyzed according to Scatchard (Scatchard Ann. N.Y. Acad. Sci. 1949, 5J_, 660) .
  • the rabbit aortic smooth muscle cell line, Rb-1 expresses high and low affinity FGF receptors (e.g., see Nachtigal et al. In Vitro Cell. & Develop. Biol.1 989, 25, 892-897) .
  • Compounds of formula (I) that have FGF antagonist activity were and can be identified by their ability to compete with 125 l-bFGF for binding to the FGF receptors expressed on cell surface of such cells (see e.g ., see, Moscatelli et al. J ⁇ Cell. Physiol. 1987, 131, 1 23-1 30) .
  • Rb-1 cells were grown in 24-well plates to near-confluence in
  • DMEM Dulbecco's modified Eagle's medium
  • penicillin 1 00 unit/ml
  • streptomycin 1 00 ⁇ g/ml
  • the culture medium was removed by aspiration and the cells were incubated in binding buffer (serum-free DMEM supplemented with 20 mM HEPES (pH 7.5) and 0.1 % BSA) containing 2.5 ng/ml recombinant human 125 l-bFGF (800-1 200 Ci/mmol; Amersham, Arlington Heights, IL) and varying concentrations of test compound, for 2 hr at ambient temperature.
  • binding buffer serum-free DMEM supplemented with 20 mM HEPES (pH 7.5) and 0.1 % BSA
  • recombinant human 125 l-bFGF 800-1 200 Ci/mmol; Amersham, Arlington Heights, IL
  • the nonspecific binding of iodinated bFGF to Rb-1 cells was estimated in parallel reactions performed in the presence of an
  • the cells were washed twice with cold phosphate-buffered saline (PBS) and the bFGF bound to low affinity heparan sulfate proteoglycan (HSPG) receptors was dissociated by the addition to each well of a 1 ml solution of 25 mM HEPES (pH 7.5) containing 2 M NaCl.
  • the bFGF bound to high affinity FGF receptors was dissociated by the addition to each well of a 1 ml solution of 25 mM sodium acetate (pH 4.0) containing 2 M NaCl.
  • a 1 ml aliquot from each well was transferred to a polypropylene tube and the amount of radioactivity present in the high affinity samples was determined using a gamma counter.
  • FGF epidermal growth factor
  • EGF EGF-binding protein
  • SMCs such as rabbit aortic SMCs, incorporate tritiated thymidine into DNA upon stimulation with bFGF or PDGF.
  • the cells were washed twice with serum-free medium (DMEM supplemented with 0.1 % BSA, 5 ⁇ g/ml transferrin, penicillin ( 1 00 unit/ml) and streptomycin (100 ug/ml)) and cultured for an additional three days in serum-free DMEM medium.
  • serum-free medium DMEM supplemented with 0.1 % BSA, 5 ⁇ g/ml transferrin, penicillin ( 1 00 unit/ml) and streptomycin (100 ug/ml)

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés aryles et hétéroaryles, des compositions pharmaceutiques contenant ces composés et des procédés d'utilisation de ces compositions pharmaceutiques permettant de moduler l'activité de la famille peptidique du facteur de croissance des fibroblastes. Les procédés d'inhibition de la liaison entre un peptide FGF et un récepteur FGF par la mise en contact du récepteur avec l'acide aromatique font aussi l'objet de cette invention. L'invention concerne en outre des procédés de traitement de troubles liés au FGF par l'administration de quantités efficaces d'un ou plusieurs de ces composés ou dérivés pharmaceutiquement acceptables inhibant l'activité d'un ou plusieurs de ces peptides FGF.
PCT/US1998/024875 1998-11-23 1998-11-23 Composes aryles et heteroaryles utiles comme antagonistes du facteur de croissance des fibroblastes (fgf) WO2000030632A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/US1998/024875 WO2000030632A1 (fr) 1998-11-23 1998-11-23 Composes aryles et heteroaryles utiles comme antagonistes du facteur de croissance des fibroblastes (fgf)
AU15960/99A AU1596099A (en) 1998-11-23 1998-11-23 Aryl and heteroaryl compounds useful as fibroblast growth factor antagonists

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1998/024875 WO2000030632A1 (fr) 1998-11-23 1998-11-23 Composes aryles et heteroaryles utiles comme antagonistes du facteur de croissance des fibroblastes (fgf)

Publications (1)

Publication Number Publication Date
WO2000030632A1 true WO2000030632A1 (fr) 2000-06-02

Family

ID=22268348

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/024875 WO2000030632A1 (fr) 1998-11-23 1998-11-23 Composes aryles et heteroaryles utiles comme antagonistes du facteur de croissance des fibroblastes (fgf)

Country Status (2)

Country Link
AU (1) AU1596099A (fr)
WO (1) WO2000030632A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074101A1 (fr) * 2002-02-28 2003-09-12 Eli Lilly And Company Procede servant a traiter l'atherosclerose et l'hypercholesterolemie
WO2004087158A2 (fr) * 2003-03-28 2004-10-14 Acadia Pharmaceuticals Inc. Traitement de la douleur au moyen d'agonistes du recepteur muscarinique m1
EP1819366A1 (fr) * 2004-12-06 2007-08-22 Kyushu University, National University Corporation Composition de coloration destinee a colorer une membrane ophtalmique
WO2014065440A1 (fr) 2012-10-26 2014-05-01 Canon Kabushiki Kaisha Médicament inhibiteur de cellules cancéreuses et sonde de détection de cellules souches cancéreuses
JP2015063693A (ja) * 2010-04-02 2015-04-09 ファーマコフォトニクス、インコーポレイテッド 新規なローダミン色素及び結合体
US9567291B2 (en) 2013-04-25 2017-02-14 Emory University N-(4-(bis(4-(dimethylamino)phenyl)methylene)-8-(dimethylamino)
CN116375612A (zh) * 2023-04-06 2023-07-04 吉林医药学院 一种3,4,5,6-四卤酚磺酞碱金属盐及其制备方法和应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5189056A (en) * 1989-12-19 1993-02-23 University Of North Carolina At Chapel Hill Protection of moist stratified squamous epithelia against damage from noxious luminal agents
US5434185A (en) * 1993-05-17 1995-07-18 The University Of Kentucky Research Foundation Method for inhibiting angiogenesis with aurintricarboxylic acid, its analogues or salts
WO1996008240A1 (fr) * 1994-09-16 1996-03-21 President And Fellows Of Harvard College Utilisation d'halogenures aromatiques pour traiter la proliferation cellulaire mammalienne
WO1997034589A1 (fr) * 1996-03-20 1997-09-25 President And Fellows Of Harvard College Composes de triaryle methane pour la drepanocytose
WO1998057922A1 (fr) * 1997-06-17 1998-12-23 Sumitomo Chemical Company, Limited Derives de triphenylmethane et leur utilisation
WO1999027921A2 (fr) * 1997-12-03 1999-06-10 Eisai Co., Ltd. Compositions et procedes de modulation de l'activite du facteur de croissance des fibroblastes (fgf)
WO1999029640A2 (fr) * 1997-12-05 1999-06-17 Eisai Co., Ltd. Compositions et procedes permettant de moduler l'activite du facteur de croissance des fibroblastes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5189056A (en) * 1989-12-19 1993-02-23 University Of North Carolina At Chapel Hill Protection of moist stratified squamous epithelia against damage from noxious luminal agents
US5434185A (en) * 1993-05-17 1995-07-18 The University Of Kentucky Research Foundation Method for inhibiting angiogenesis with aurintricarboxylic acid, its analogues or salts
WO1996008240A1 (fr) * 1994-09-16 1996-03-21 President And Fellows Of Harvard College Utilisation d'halogenures aromatiques pour traiter la proliferation cellulaire mammalienne
WO1997034589A1 (fr) * 1996-03-20 1997-09-25 President And Fellows Of Harvard College Composes de triaryle methane pour la drepanocytose
WO1998057922A1 (fr) * 1997-06-17 1998-12-23 Sumitomo Chemical Company, Limited Derives de triphenylmethane et leur utilisation
WO1999027921A2 (fr) * 1997-12-03 1999-06-10 Eisai Co., Ltd. Compositions et procedes de modulation de l'activite du facteur de croissance des fibroblastes (fgf)
WO1999029640A2 (fr) * 1997-12-05 1999-06-17 Eisai Co., Ltd. Compositions et procedes permettant de moduler l'activite du facteur de croissance des fibroblastes

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Merck Index, twelfth edition", 1996, MERK RESEARCH LABORATORIES, XP002122536 *
BENEZRA M ET AL: "Reversal of basic fibroblast growth factor-mediated autocrine cell transformation by aromatic anionic compounds.", CANCER RESEARCH, (1992 OCT 15) 52 (20) 5656-62., XP002122534 *
BENEZRA, MIRIAM ET AL: "Antiproliferative activity to vascular smooth muscle cells and receptor binding of heparin-mimicking polyarom. anionic compounds", ARTERIOSCLER. THROMB. (1994), 14(12), 1992-9, XP002122535 *
GAGLIARDI A R T ET AL.: "Inhibition of angiogenesis by Aurintricarboxylic acid", ANTICANCER RESEARCH, vol. 13, 1993, pages 475 - 480, XP002123278 *
LOZANO, ROSA M. ET AL: "Destabilization, oligomerization and inhibition of the mitogenic activity of acidic fibroblast-growth factor by aurintricarboxylic acid", EUR. J. BIOCHEM. (1997), 248(1), 30-36, XP002122533 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074101A1 (fr) * 2002-02-28 2003-09-12 Eli Lilly And Company Procede servant a traiter l'atherosclerose et l'hypercholesterolemie
WO2004087158A2 (fr) * 2003-03-28 2004-10-14 Acadia Pharmaceuticals Inc. Traitement de la douleur au moyen d'agonistes du recepteur muscarinique m1
WO2004087158A3 (fr) * 2003-03-28 2005-03-31 Acadia Pharm Inc Traitement de la douleur au moyen d'agonistes du recepteur muscarinique m1
EP1819366A1 (fr) * 2004-12-06 2007-08-22 Kyushu University, National University Corporation Composition de coloration destinee a colorer une membrane ophtalmique
EP1819366A4 (fr) * 2004-12-06 2008-04-16 Univ Kyushu Nat Univ Corp Composition de coloration destinee a colorer une membrane ophtalmique
JP2015063693A (ja) * 2010-04-02 2015-04-09 ファーマコフォトニクス、インコーポレイテッド 新規なローダミン色素及び結合体
US9938410B2 (en) 2010-04-02 2018-04-10 Pharmacophotonics, Inc. Rhodamine dyes and conjugates
US11130865B2 (en) 2010-04-02 2021-09-28 Pharmacophotonics, Inc. Rhodamine dyes and conjugates
US11618825B2 (en) 2010-04-02 2023-04-04 Pharmacophotonics, Inc. Rhodamine dyes and conjugates
WO2014065440A1 (fr) 2012-10-26 2014-05-01 Canon Kabushiki Kaisha Médicament inhibiteur de cellules cancéreuses et sonde de détection de cellules souches cancéreuses
EP2849752A4 (fr) * 2012-10-26 2015-07-22 Canon Kk Médicament inhibiteur de cellules cancéreuses et sonde de détection de cellules souches cancéreuses
US10220024B2 (en) 2012-10-26 2019-03-05 Canon Kabushiki Kaisha Method of inhibiting cancer cell, method for detecting cancer cell, and system for detecting cancer cell
US9567291B2 (en) 2013-04-25 2017-02-14 Emory University N-(4-(bis(4-(dimethylamino)phenyl)methylene)-8-(dimethylamino)
CN116375612A (zh) * 2023-04-06 2023-07-04 吉林医药学院 一种3,4,5,6-四卤酚磺酞碱金属盐及其制备方法和应用

Also Published As

Publication number Publication date
AU1596099A (en) 2000-06-13

Similar Documents

Publication Publication Date Title
EP0364417B1 (fr) Dérivés de prostaglandine pour traitement du glaucome ou hypertension oculaire
Selén et al. Prostaglandin-induced iridial pigmentation in primates
KR100364487B1 (ko) 혈관내피세포의성장인자와관련된안구질환의치료제
CN1617868A (zh) 作为EP2－受体激动剂的ω－环烷基17－杂芳基前列腺素E2 类似物
US6730707B2 (en) Method for reducing intraocular pressure using indole derivatives
JP2013531063A (ja) 二官能基Ｒｈｏキナーゼ阻害化合物、組成物およびその使用
EP1307191A2 (fr) Utilisation des derives d'indole pour la preparation d'un medicament pour reduire la pression intraocculaire
WO2004080943A1 (fr) Procede permettant d'ajouter du charbon actif dans la purification d'eau et procede de purification d'eau
WO2000030632A1 (fr) Composes aryles et heteroaryles utiles comme antagonistes du facteur de croissance des fibroblastes (fgf)
NZ543100A (en) Preventive/remedy for retinal nerve dieases containing alkyl ether derivatives or salts thereof
WO1999029640A2 (fr) Compositions et procedes permettant de moduler l'activite du facteur de croissance des fibroblastes
US7005448B2 (en) Aminoalkyl-benzofuran-5-ol compounds for the treatment of glaucoma
WO2002102780A1 (fr) Compose derive de tetrahydroquinoline et medicament contenant ledit compose comme principe actif
EP3902798B1 (fr) Dérivés de n-(4-(oxazol-5-yl)phényl)chromane-3-carboxamide et composés similaires en tant que stimulateurs de la production de cellules précurseurs rétiniennes pour le traitement de maladies neuro-rétiniennes
WO1999052936A2 (fr) Analogues du peptide d'arginine utilises en tant qu'antagonistes du facteur de croissance des fibroblastes
AU2006204317A2 (en) Rigidified compounds for modulating heparanase activity
WO1999027921A2 (fr) Compositions et procedes de modulation de l'activite du facteur de croissance des fibroblastes (fgf)
US4634698A (en) Antiglaucoma agents
JPH0525167A (ja) 緑内障の治療に有用な置換ベンゼン誘導体
KR20040013126A (ko) 녹내장 및 근시 치료용 벤조 [ｇ] 퀴놀린 유도체
RU2296760C2 (ru) Производные соединения карбоновой кислоты и средства, содержащие соединения в качестве активных ингредиентов
GB2085437A (en) Propanolamine derivatives
WO1998047877A1 (fr) Derives 2-benzoyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxamide et leur utilisation comme inhibiteurs de production hepatique de apob-100
CN103127520A (zh) 聚乙二醇与坦索罗辛的结合物及其药物组合物
Wroblewski et al. Brinzolamide< Prop INN; USAN

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase