WO1999029640A2 - Compositions et procedes permettant de moduler l'activite du facteur de croissance des fibroblastes - Google Patents

Compositions et procedes permettant de moduler l'activite du facteur de croissance des fibroblastes Download PDF

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WO1999029640A2
WO1999029640A2 PCT/US1998/025789 US9825789W WO9929640A2 WO 1999029640 A2 WO1999029640 A2 WO 1999029640A2 US 9825789 W US9825789 W US 9825789W WO 9929640 A2 WO9929640 A2 WO 9929640A2
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acid
group
compound
phenylene
formula
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WO1999029640A3 (fr
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Ming Fai Chan
Vitukudi Narayanaiyengar Balaji
Kalyanaraman Ramnarayan
Laura Schove
Rosario Silvestre Castillo
Adam Kois
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Eisai Co., Ltd.
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Publication of WO1999029640A3 publication Critical patent/WO1999029640A3/fr

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    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
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    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • C07D317/64—Oxygen atoms

Definitions

  • the present invention relates to aromatic acids, compositions and methods for treatment or prevention of fibroblast growth factor (FGF)- mediated diseases.
  • the invention relates to the use of aromatic acids as FGF antagonists.
  • 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.
  • 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. 5,228,855; U.S. Patent No. 5, 1 55,214)) .
  • FGF-5 Zhan et al. Mol. Cell Biol. 1988, 8, 3487
  • FGF- 6/Hst-2 Maries et al. Oncogene 1989, 4, 335
  • KGFMFGF-7 karatinocyte growth factor
  • FGF-8 FGF-9
  • FGF-10 PCT International Publication Number WO 95/24,414.
  • the structures of aFGF and bFGF have also been determined through single- crystal x-ray diffraction (Erickson 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 92/08,473), 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; Melnyk et al. Arthritis Rheum. 1990, 33, 493; Sivalingam Arch. Ophthalmol. 1990, 108, 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, 1_, 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
  • Aromatic acids and pharmaceutically acceptable salts, esters, acids, bases, solvates, hydrates and prodrugs thereof of formulae (I), (II) or (ill) are provided.
  • Pharmaceutical compositions containing aromatic acids or pharmaceutically acceptable salts, esters, acids, bases, solvates, hydrates and prodrugs thereof of formulae (I), (II) or (III), and methods for modulating the interaction of an FGF peptide with FGF receptors using such compositions are also provided .
  • aromatic acids of formulae (I), (II) or (III) pharmaceutical compositions containing aromatic acids of formulae (I), (II) or (III), and methods for inhibiting the binding of an FGF peptide to FGF receptors using such compositions are provided.
  • aromatic acids and pharmaceutical compositions provided herein are those that are particularly active as bFGF antagonists, as evidenced by in vitro assays described herein.
  • the methods are effected by contacting FGF receptors with one or more aromatic acids prior to, simultaneously with, or subsequent to contacting the receptors with an FGF peptide.
  • aromatic acids are substituted or unsubstituted monocyclic or polycyclic aryl- or heteroaryl- substituted carboxylic, sulfonic, boronic or phosphonic acids, such as aryl- or heteroaryl-substituted amino acids, aryl- or heteroaryl-substituted aliphatic carboxylic, sulfonic, boronic or phosphonic acids, and aryl, heteroaryl, alkynyl and alkenyl carboxylic, sulfonic, boronic or phosphonic acids.
  • aromatic acids have the formula: A r-M -Y where Ar is selected from monocyclic or polycyclic aryl, arylalkynyl, arylalkenyl, aryloxy, arylthio, arylamino, arylsulfinyl, arylsulfonyl, arylcarbonyl, heteroaryl, heteroarylalkynyl, heteroarylalkenyl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylsulfinyl, heteroarylsulfonyl or heteroarylcarbonyl, and is unsubstituted or substituted with one or more substituents designated Q, which are each independently selected, and which, as defined herein, is halogen, hydroxy, nitrile, nitro, formyl, mercapto, carboxy, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl
  • M is alkylene, alkenylene, alkynylene, arylene, heteroarylene, alkylenoxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, oxyalkylenoxy, oxyalkylenoxycarbonyl, alkylenoxycarbonyloxy, amido, thioamido, oxyamido, thiaamido, dithiaamido, ureido, thioureido, amino, oxy, thio, sulfinyl or sulfonyl, and is unsubstituted or substituted with one or more Q substituents; Y is a carboxylic, boronic, sulfonic or phosphonic acid group; selected such that the resulting aromatic acid modulates the interaction of an FGF peptide with an FGF receptor, preferably the aromatic acid inhibits the binding of an FGF peptide with an FGF receptor with an IC 50 of less than preferably
  • the distance between Ar and the Y group is between about 1 5 and 1 8 A, more preferably about 1 6 ⁇ 0.5 ⁇ .
  • the aromatic acids have formula (I) :
  • Ar 1 is selected from monocyclic or polycyclic aryl, arylalkynyl, arylalkenyl, aryloxy, arylthio, arylamino, arylsulfinyl, arylsulfonyl, arylcarbonyl, heteroaryl, heteroarylalkynyl, heteroarylalkenyl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylsulfinyl, heteroarylsulfonyl and heteroarylcarbonyl, and is unsubstituted or substituted with one or more Q substituents; m is 0-6, preferably 1 -6, more preferably 1 -4 or 6; X 1 is alkylene, arylene, amido, thioamido, oxyamido, thiaamido, dithiaamido, ureido, thioureido, amino, oxy, thio, sulfiny
  • R 1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl or heteroarylalkyi and is unsubstituted or substituted with one or more Q substituents; p is 0 or 1 ; and Y 1 is a carboxylic, sulfonic, boronic or phosphonic acid group, preferably a carboxylic or sulfonic acid group.
  • the aromatic acids are of formula (I) with the provisos that when p is 0 and Y 1 is a carboxylic acid group, and (i) the combination of m, n and X 1 is decylene, then Ar 1 is not 4- methylphenyloxy, phenylsulfonyl, 2-naphthyloxy or 3-methylphenyloxy; (ii) the combination of m, n and X 1 is undecylene, then Ar 1 is not phenyloxy and (iii) the combination of m, n, and X 1 is alkylene, then Ar 1 is not unsubstituted phenyl; and with the further provisos that when n is 0, p is 1 , m is 0-2 and Y 1 is a carboxylic acid group, then X 1 is not oxyamido, amido or amino; and that the compound is not 6-aza-7-oxo- 1 0-phenyldecanoic
  • Ar 1 is monocyclic or polycyclic aryl, phenylethynyl, phenylamino, phenyloxy, 8- quinolinyloxy, 2-quinolinyloxy, 2-oxoquinolin-1 -yl, 9-fluorenyl, phenylsulfonyl, phenylthio, 1 -naphthyloxy, 2-naphthyloxy, 1 -pyrenyl, 1 - pyrenyicarbonyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl-2-thio, benzothiazolyl-2-thio or benzimidazolyl-2-thio and is unsubstituted or substituted with one or more Q substituents; m is 1 -4 or 6;
  • X 1 is methylene, amido, thioamido, oxyamido, ureido, thioureido, oxy, or thio, and is unsubstituted or substituted with one or more Q substituents; n is 0-4 or 6, preferably 0 when p is 1 ; R 1 is alkyl, aryl, arylalkyl or heteroarylalkyi, and is unsubstituted or substituted with one or more Q substituents; p is 0 when m is 2, 3, 4, or 6, or 1 when m is 1 or 4; and
  • Y 1 is a carboxylic acid group.
  • aromatic acids have formula (II) :
  • Ar 2 is monocyclic or polycyclic aryl or heteroaryl, and is unsubstituted or substituted with one or more Q substituents;
  • R 3 , R 4 and R 5 are each independently H, alkyl, cycloalkyi, or aryl, or any two form alkylene;
  • Ar 3 is 1 ,2-, 1 ,3- or 1 ,4-arylene or heteroarylene, and is unsubstituted or substituted with one or more Q substituents;
  • X 3 is selected from among alkylene, alkenylene, alkynylene, oxyalkylene, carbonylalkylene, carbonylalkenylene, carbonylalkynylene and -CH 2 CH(NHR 6 )-, where R 6 is H, alkoxycarbonyl, aryloxycarbonyl, arylalkyloxycarbonyl, diarylalkyloxycarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, or diarylalkylcarbonyl; q is 0 or 1 ; and
  • Y 2 is a carboxylic, sulfonic, boronic or phosphonic acid group.
  • the aromatic acids have formula (II), with the provisos that (a) when Ar 2 is phenyl, q is 1 and Y 2 is a carboxylic acid group, then (i) X 2 is not methylenoxy when Ar 3 is 3-methoxy-1 ,4- phenylene and X 3 is ethenylene, (ii) X 2 is not oxy when Ar 3 is 1 ,4- phenylene and X 3 is carbonylethylene, and (iii) X 2 is not ethyenylcarbonyl when Ar 3 is 1 ,4-phenylene and X 3 is methylene or oxymethylene; (b) the aromatic acid is not 4-(3-(4-(carboxylmethyl)phenyl)propyl)phenylacetic acid, 3-(2-aza-4-(3,4-dichlorophen-1 -yl)-2-methyl-3-oxo-1 -(N- pyrrolidinyl)methylbut-1
  • Ar 2 is phenyl, benzoxazolyl, benzothiazolyl or benzimidazolyl, and is unsubstituted or substituted with one or more Q substituents;
  • X 2 is methylenoxy, sulfonyl, methylenoxycarboxy, ethynylene, oxy, oxyethylenyloxy, oxyethylenyloxycarbonyl, ethenylenylcarbonyl, propylene, thioureido, -COCH 2 CONH-, (2-ureido-4-chlorophenyl-1 -en)oxy,
  • -C(NR 3 R 4 ) N-N(R 5 )-, where R 3 and R 4 are each independently alkyl or together form alkylene, and R 5 is H;
  • Ar 3 is 1 ,2-, 1 ,3- or 1 ,4-phenylene or imidazolylene, and is unsubstituted or substituted with one or more Q substituents;
  • X 3 is alkylene, alkenylene, alkynylene, oxyalkylene, oxyalkylenoxy, oxyalkylenoxycarbonyl, carbonylalkylene, carbonylalkenylene, carbonylalkynylene, -C(OH)(C(CH 3 ) 3 )C ⁇ C- and -CH 2 CH(NHR 6 )-, where R 6 is H, alkoxycarbonyl, or diarylalkylcarbonyl; q is 0 or 1 , preferably 0 when X 2 is -ZSO 2 -, -COCH 2 CONH-, (2- ureido-4-chlorophenyl-1 -en)oxy, oxyethylenyloxy, oxyethylenyloxycarbonyl, or thioureido; and
  • Y 2 is a carboxylic or sulfonic acid group, preferably a sulfonic acid group when X 2 is -COCH 2 CONH- or (2-ureido-4-chlorophenyl-1 -en)oxy.
  • the aromatic acids have formula (III):
  • Ar 4 and Ar 5 are monocyclic or polycyclic aryl or heteroaryl, and are unsubstituted or substituted with one or more Q substituents; t is 1 -6; and Y 3 is a carboxylic, boronic, sulfonic, or phosphonic acid group.
  • the aromatic acids have formula (III), with the proviso that the aromatic acid is not (2E,4E)-2,5-diphenylpenta-2,4- dienoic acid or ( 1 Z,3E)-1 ,4-bis(4-methoxyphenyl)-2-carboxyl-1 ,3- butadiene.
  • Ar 4 and Ar 5 are selected from among monocyclic aryl and heteroaryl, and are unsubstituted or substituted with one or more Q substituents; t is 1 ; and Y 3 is a carboxylic acid group.
  • 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 aryl, carbocyclic, aromatic rings and heterocyclic 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 aromatic acid, 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 500 ⁇ M are preferred. More preferred are those that inhibit an FGF-mediated activity by about 50% at concentrations of less than about 300 ⁇ M, more preferably less than about 30 ⁇ M, and most preferably less than about 1 5 ⁇ M.
  • any pharmaceutically-acceptable derivatives including salts, esters, acids, bases, solvates, hydrates and prodrugs of the aromatic acids.
  • 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 '-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 limited to
  • 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, rhe
  • 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 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 aromatic acids, or salts, esters, acids, bases, solvates, hydrates, prodrugs or other suitable derivatives thereof are provided.
  • methods for treating 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
  • 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 jn 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 iri 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. j ⁇ ⁇ 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 conditions, 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
  • 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 1 to 20 carbons preferably contain 1 to 8 double bonds, and the alkenyl carbon chains of 1 to 1 6 carbons preferably contain 1 to 5 double bonds.
  • Alkynyl carbon chains of from 1 to 20 carbons preferably contain 1 to 8 triple bonds, and the alkynyl carbon chains of 1 to 1 6 carbons preferably contain 1 to 5 triple bonds.
  • the 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.
  • lower alkyl, lower alkenyl, and lower alkynyl refer to carbon chains having less than about 6 carbons.
  • an alkyl group substituent includes halo, haloalkyl, preferably halo lower alkyl, aryl, hydroxy, alkoxy, aryloxy, alkyloxy, alkylthio, arylthio, aralkyloxy, aralkylthio, carboxy alkoxycarbonyl, oxo and cycloalkyi.
  • 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, cycloalkyi, cycloalkylalkyi, aryl, heteroaryl optionally substituted with 1 or more, preferably 1 to 3, substituents selected from halo, halo alkyl and alkyl, arylalkyl, heteroarylalkyi, 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,
  • cycloalkyi refers to a saturated mono- or multi- cyclic ring system, preferably of 3 to 1 0 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 0 carbon atoms, with cycloalkenyl groups more preferably containing 4 to 7 carbon atoms and cycloalkynyl groups more preferably containing 8 to 10 carbon atoms.
  • ring systems of the cycloalkyi, 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 5 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.
  • 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.
  • heterocyclic refers to a monocyclic or multicyclic ring system, preferably of 3 to 1 0 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 alkylthio 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 1 to about 20 carbon atoms and at least one double bond, more preferably 1 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.
  • the term "lower 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 1 to about 20 carbon atoms and at least one triple bond, more preferably 1 to 1 2 carbons, even more preferably lower alkynylene.
  • the alkynylene group is optionally substituted with one or more "alkyl group substituents. " There may be optionally inserted along the alkynylene group one or more oxygen, sulphur or substituted or unsubstituted nitrogen atoms, where the nitrogen substituent is alkyl as previously described.
  • alkynylene groups include — CC — CC — , -CC- and -CC-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 1 to about 20 carbon atoms and at least one aromatic ring, more preferably 1 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.
  • the term "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 5 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.
  • 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
  • Aromatic acids and derivatives thereof for use in treatment or prevention of FGF-mediated diseases are aromatic acids and derivatives thereof for use in treatment or prevention of FGF-mediated diseases
  • Ar is selected from monocyclic or polycyclic aryl, arylalkynyl, arylalkenyl, aryloxy, arylthio, arylamino, arylsulfinyl, arylsulfonyl, arylcarbonyl, heteroaryl, heteroarylalkynyl, heteroarylalkenyl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylsulfinyl, heteroarylsulfonyl or heteroarylcarbonyl, and is unsubstituted or substituted with one or more substituents designated Q, which are each independently selected, and which, as defined herein, is halogen, hydroxy, nitrile, nitro, formyl, mercapto, carboxy, alkyl, haloalkyl, polyhaloalkyi, aminoalkyl, diaminoalkyi, alkenyl containing 1 to 2 double bonds, alkynyl containing
  • M is alkylene, alkenylene, alkynylene, arylene, heteroarylene, alkylenoxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, oxyalkylenoxy, oxyalkylenoxycarbonyl, alkylenoxycarbonyloxy, amido, thioamido, oxyamido, thiaamido, dithiaamido, ureido, thioureido, amino, oxy, thio, sulfinyl or sulfonyl, and is unsubstituted or substituted with one or more Q substituents;
  • Y is a carboxylic, boronic, sulfonic or phosphonic acid group; and each is selected such that the resulting aromatic acid modulates the interaction of an FGF peptide with an FGF receptor, preferably the aromatic acid inhibits the binding of an FGF peptide with an FGF receptor with an IC 50 of less than preferably about 500 ⁇ M, more preferably about 300 ⁇ M, more preferably about 1 00 M, and most preferably about 50 ⁇ M.
  • IC 50 of less than preferably about 500 ⁇ M, more preferably about 300 ⁇ M, more preferably about 1 00 M, and most preferably about 50 ⁇ M.
  • the compounds for use in the compositions and methods have formulae (I), (II) or (III) .
  • Aromatic acids of formula (I)
  • aromatic acids have formula (I) :
  • Ar 1 is monocyclic or polycyclic aryl, phenylethynyl, phenylamino, phenyloxy, 8-quinolinyloxy, 2-quinolinyloxy, 2-oxoquinolin-1 -yl, 9- fluorenyl, phenylsulfonyl, phenylthio, 1 -naphthyloxy, 2-naphthyloxy, 1 - pyrenyl, 1 -pyrenylcarbonyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl-2-thio, benzothiazolyl-2-thio or benzimidazolyl-2-thio, and is unsubstituted or substituted with one or more Q substituents; m is 1 -4 or 6;
  • X 1 is methylene, amido, thioamido, oxyamido, ureido, thioureido, oxy, or thio, and is unsubstituted or substituted with one or more Q substituents; n is 0-4 or 6, preferably 0 when p is 1 ; R 1 is alkyl, aryl, arylalkyl or heteroarylalkyi, and is unsubstituted or substituted with one or more Q substituents; p is 0 when m is 2, 3, 4, or 6, or 1 when m is 1 or 4; and Y 1 is a carboxylic acid group; with the provisos that when p is 0 and Y 1 is a carboxylic acid group and (i) the combination of m, n and X 1 is decylene, then Ar 1 is not 4-methylphenyloxy, phenylsulfonyl, 2-naphthyloxy or 3-methylphenyloxy;
  • R 1 is preferably phenyl, 4-hydroxyphenylmethyl, 4-tert- butyloxyphenylmethyl, triphenylmethylthiomethyl, tert- butyloxycarbonylmethyl, 2-(tert-butyloxycarbonyl)ethyl, 4-(tert- butyloxycarbonylamino)butyl, phenylmethyl, 3-(guanidinyl)prop-1 -yl, iso- butyl, tert-butyloxymethyl, 1 -tert-butyloxyeth-1 -yl, 2-methylthioeth-1 -yl, 1 -hydroxyeth-1 -yl, sec-butyl, methyl, aminocarbonylmethyl, 3- indolylmethyl, iso-propyl or 3-(R 2 )-propyl, where R 2 is
  • compounds of formula (I) are those that have formula (IV) :
  • Ar 1 and Y 1 are as described for formula (I) and r is 7-1 1 ; with the proviso that when Y 1 is a carboxylic acid group and (i) r is 1 0, then Ar 1 is not 4-methylphenyloxy, phenylsulfonyl, 2-naphthyloxy or 3- methylphenyloxy; (ii) r is 1 1 , then Ar 1 is not phenyloxy; or (iii) r is 7-1 1 , then Ar 1 is not unsubstituted phenyl.
  • preferred compounds of formula (IV) are those in which: Ar 1 is phenylamino, phenylethynyl, phenyloxy, 8-quinolinyloxy, 2-quinolinyloxy, 2-oxoquinolin-1 -yl, phenylthio, phenylsulfonyl, 1 -pyrenyl, 1 -pyrenylcarbonyl, 1 -naphthyloxy, 2-naphthyloxy, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl-2-thio, benzothiazolyl-2-thio or benzimidazolyl-2-thio, and is unsubstituted or substituted with one or more Q substituents; and Y 1 is a carboxylic acid group.
  • Presently preferred compounds of formula (IV) include 1 1 - phenylundec-10-ynoic acid, 1 1 -phenyloxyundecanoic acid, 1 1 -( 1 - naphthyloxy)undecanoic acid, 1 2-phenylthioundecanoic acid, 1 1 -(4- acetylphenyloxy)undecanoic acid, 10-(1 -pyrenyl)decanoic acid, 10-oxo- 10-(1 -pyrenyl)decanoic acid, 1 1 -(2-methylphenyl)oxyundecanoic acid, 1 1 -(2-methoxyphenyl)oxyundecanoic acid, 1 1 -(3-methoxyphenyl)- oxyundecanoic acid, 1 1 -(4-bromophenyl)oxyundecanoic acid, 1 1 -(3,4- methylenedioxyphenyl)oxyundecanoic acid, 1 1
  • compounds of formula (I) are those that have formula (V) :
  • Ar 1 , X 1 , m, n and Y 1 are as described for formula (I); with the proviso that the compound is not 6-aza-7-oxo-1 0-phenyldecanoic acid.
  • preferred compounds of formula (V) are those in which: Ar 1 is monocyclic or polycyclic aryl, and is unsubstituted or substituted with one or more Q substituents; m is 2, 3, 4, or 6; X 1 is amido, thioamido, ureido, thioureido, oxy, or thio, and is unsubstituted or substituted with one or more Q substituents; n is 1 -4 or 6; and Y 1 is a carboxylic acid group.
  • the compounds of formula (V) are those in which: Ar 1 is monocyclic or polycyclic aryl, and is unsubstituted or substituted with one or more Q substituents; m is 2, 3, 4, or 6; X 1 is amido,
  • (V) are those in which Ar 1 is monocyclic or polycyclic aryl, preferably phenyl or 1 -pyrenyl; the combination of m and n is 5-9; X 1 is thioamido, ureido, thioureido, oxy, or thio, and is unsubstituted or substituted with one or more Q substituents, preferably phenyl; and Y 1 is a carboxylic acid group. More preferred compounds of formula (V) are those in which X 1 is amido or ureido, preferably amido or N-benzylureido.
  • Presently preferred compounds of formula (V) include 5-aza-4-oxo- 8-phenyloctanoic acid, 6-aza-5-oxo-9-phenylnonanoic acid, 6-aza-5-oxo- 10-phenyldecanoic acid, 7-aza-6-oxo-1 1 -phenylundecanoic acid, 4-aza-5- oxo-1 1 -phenylundecanoic acid and 3-benzyl-3,5-diaza-4-oxo-9-( 1 - pyrenyl)nonanoic acid.
  • compounds of formula (I) are those that have formula (VI): A r 1 -(C H 2 m -X 1 -(C H R 1 ) p
  • preferred compounds of formula (VI) are those in which Ar 1 is monocyclic or polycyclic aryl, and is unsubstituted or substituted with one or more Q substituents; m is 4; X 1 is ureido, thioureido or oxyamido, and is unsubstituted or substituted with one or more Q substituents; R 1 is phenyl, 4-hydroxyphenylmethyl, 4-tert- butyloxyphenylmethyl, tert-butyloxycarbonylmethyl, 2-(tert-butyloxy- carbonyl)ethyl, triphenylmethylthiomethyl, 4-(tert-butyloxyamido) butyl, phenylmethyl, 3-(guanidinyl)prop-1 -yl, iso-butyl, tert-butyloxymethyl, 1 - tert-butyloxyeth-1 -yl, 2-methylthioeth-1 -yl, 1 -
  • p is 1 ; and Y 1 is a carboxylic acid group.
  • Ar 1 is 1 -pyrenyl; X 1 is unsubstituted ureido or thioureido, most preferably unsubstituted ureido; and R 1 is phenyl.
  • Presently preferred compounds of formula (VI) include 3,5-diaza-4- oxo-2-phenyl-9-( 1 -pyrenyl)nonanoic acid.
  • the compounds for use in the compositions and methods provided herein are aromatic acids that have formula (II) :
  • Ar 2 is phenyl, benzoxazolyl, benzothiazolyl or benzimidazolyl, and is unsubstituted or substituted with one or more Q substituents;
  • X 3 is alkylene, alkenylene, alkynylene, oxyalkylene, carbonylalkylene, carbonylalkenylene, carbonylalkynylene, -
  • Y 2 is a carboxylic or sulfonic acid group; with the provisos that (a) when Ar 2 is phenyl, q is 1 and Y 2 is a carboxylic acid group, then (i) X 2 is not methylenoxy when Ar 3 is 3- methoxy-1 ,4-phenylene and X 3 is ethenylene, (ii) X 2 is not oxy when Ar 3 is 1 ,4-phenylene and X 3 is carbonylethylene, and (iii) X 2 is not ethyenylcarbonyl when Ar 3 is 1 ,4-phenylene and X 3 is methylene or oxymethylene; (b) the aromatic acid is not 4-(3-(4-(carboxylmethyl)- phenyDpropyDphenylacetic acid, 3-(2-aza-4-(3,4-dichlorophen-1 -yl)-2- methyl-3-oxo-1 -(N-pyrrolidinyDmethyl
  • Ar 2 is phenyl, 4- methylphenyl, 4-hydroxyphenyl, 3,5-diiodo-4-hydroxyphenyl, 2-bromo- phenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-carboxymethylphenyl, 4-methoxyphenyl, 4-( 1 , 1 ,3,3-tetramethyl)but-1 -ylphenyl, 3,4-dimethoxy- phenyl, 3-methoxy-4-dodeca-1 ,3,5,7,9, 1 1 -hexaenyloxyphenyl, 4-hexa- decanyloxyphenyl, 4-chlorophenyl, benzoxazolyl, benzothiazolyl or benzimidazolyl; R 3 is hexadecanyl and R 4 is methyl, or R 3 and R 4 together form pentylene;
  • Ar 3 is 1 ,4-phenylene, 1 ,4-imidazolylene, 3,5-diiodo-1 ,4-phenylene, 3-methoxy-1 ,4-phenylene, 1 ,3-phenylene, 1 ,2-phenylene, 4-chloro-1 ,2- phenylene, or 5-carboxy-1 ,3-phenylene; and q is 0 when X 2 is -ZSO 2 -, -COCH 2 CONH-, (2-ureido-4-chlorophenyl- 1 -en)oxy, oxyethylenoxy, oxyethylenyloxycarbonyl, or thioureido.
  • compounds of formula (II) are those that have formula (VII) :
  • Ar 2 , X 2 , Ar 3 , R 6 and Y 2 are as described for formula (II) .
  • preferred compounds of formula (VII) are those in which: Ar 2 is phenyl, 4-methylphenyl, 2-bromophenyl, 2,4- dichlorophenyl, 4-hydroxyphenyl, or 3,5-diiodo-4-hydroxyphenyl; X 2 is methylenoxy, sulfonyl, methylenoxycarboxy, ethynylene, or oxy; Ar 3 is 1 ,4-phenylene, 1 ,4-imidazolylene, or 3,5-diiodo-1 ,4-phenylene; and Y 2 is a carboxylic acid group.
  • preferred compounds of formula (VII) include N- diphenylacetyl derivatives of aryl ⁇ -amino acids.
  • Presently preferred compounds of formula (VII) include O-benzyl-N- diphenylacetyl-L-tyrosine, O-(3,4-dichlorobenzyl)-N-diphenylacetyl-L or D- tyrosine, O-(2-bromobenzyloxycarbonyl)-N-diphenylacetyl-L or D-tyrosine, N 1 -(4-methylphenylsulfonyl)-N-diphenylacetyl-L or D-histidine, and 3-(4- (4-methylphen-1 -yl)-4-ethynylphen-1 -yl)-N-diphenylacetyl-D-alanine.
  • compounds of formula (II) are those that have formula (VIM) :
  • preferred compounds of formula (VIII) are those in which: Ar 2 is phenyl, 4-methylphenyl, 4-carboxymethylphenyl, or 3,4- dichlorophenyl; X 2 is methyleneoxy, oxy, ethenylenylcarbonyl, propylene, ethynylene, or -CH 2 CON(CH 3 )CH(CH 2 -pyrrolidinyl); Ar 3 is 1 ,4-phenylene, 1 ,3-phenylene, or 3-methoxy-1 ,4-phenylene; X 3 is ethynylene, carbonylethylene, methylene, oxymethylene, or -C(OH) (C(CH 3 ) 3 )C ⁇ C-; and Y 2 is a carboxylic acid group.
  • Presently preferred compounds of formula (VIM) include 4-(3-(4- methylphenyl)prop-1 -yDphenylacetic acid, 4-(phenylethynyl)phen-1 -yloxyacetic acid and 5,5-dimethyl-4-hydroxy-4-(4-phenyloxy)phenylhex-2- ynoic acid .
  • compounds of formula (II) are those that have formula (IX): D
  • a r -C N -N R -S O .-A r -Y (iX)
  • Ar 2 , Ar 3 , R 5 and Y 2 are as described for formula (II); and D is NR 3 R 4 , where R 3 is hexadecanyl and R 4 is methyl, or R 3 and R 4 together form pentylene, with the proviso that the compound is not N-methyl-N- hexadecanyl-3,4-dimethoxybenzamide 4-carboxyphenylsulfonyl hydrazide.
  • preferred compounds of formula (IX) are those in which: Ar 2 is 3,4-dimethoxyphenyl, 4-hexadecanyloxyphenyl, 3- methoxy-4-dodeca-1 ,3,5,7,9, 1 1 -hexaenyloxyphenyl or 4-chlorophenyl; Ar 3 is 1 ,4-phenylene, 1 ,3-phenylene, or 5-carboxy-1 ,3-phenylene; and Y 2 is a carboxylic acid group.
  • the aromatic acids of formula (IX) are carboxyl-substituted arylsulfonyl hydrazides of arylcarboxylic amides.
  • Presently preferred compounds of formula (IX) include N- pentylenyl-3-methoxy-4-dodeca-1 ,3,5,7,9, 1 1 -hexaenyloxybenzamide 3,5- dicarboxyphenylsulfonyl hydrazide, N-pentylenyl-4-hexadecanyl- oxybenzamide 3-carboxyphenylsufonyl hydrazide, N-hexadecanyl-N- methylbenzamide 3-carboxyphenylsulfonyl hydrazide, N-hexadecanyl-N- methylbenzamide 4-carboxyphenylsulfonyl hydrazide, N-pentylenyl- benzamide 3-carbox
  • preferred compounds of formula (X) are those in which: Ar 2 is phenyl, 4-methoxyphenyl, 3,4-dichlorophenyl, or 4- ( 1 , 1 ,3,3-tetramethyl)but-1 -ylphenyl; X 2 is oxyethylenoxycarbonyl, oxyethylenoxy, thioureido, -COCH 2 CONH- or (2-ureido-4-chlorophenyl-1 - en)oxy; Ar 3 is 1 ,2-phenylene, 1 ,4-phenylene, or 4-chloro-1 ,2-phenylene; and Y 2 is a carboxylic or sulfonic acid group.
  • More preferred compounds of formula (X) are those in which Ar 2 is phenyl or 4-( 1 , 1 ,3,3-tetramethyl)but-1 -ylphenyl; X 2 is oxyethylenoxy, oxyethylenoxycarbonyl, or thioureido; Ar 3 is 1 ,4-phenylene or 1 ,2- phenylene; and Y 2 is a carboxylic acid group.
  • Presently more preferred compounds of formula (X) include mono- 2-((4-( 1 , 1 ,3,3-tetramethyl)buty-1 -yl)phen-1 -yloxy)ethyl ortho-phthalate.
  • Most preferred compounds of formula (X) are those in which Ar 2 is 4-methoxyphenyl or 3,4-dichlorophenyl; X 2 is -COCH 2 CONH- or (2- ureido-4-chlorophenyl-1 -en)oxy; Ar 3 is 1 ,4-phenylene, or 4-chloro-1 ,2- phenylene; and Y 2 is a sulfonic acid group.
  • Presently most preferred compounds of formula (X) include 4-(3- (4-methoxyphen-1 -yl)-1 ,3-dioxoprop-1 -yl)aminophenylsulfonic acid or 5- chloro-2-((2-(2-(3,4-dichlorophenyl)-2-aza-1 -oxoethyl)amino)-4-chloro- phenyDoxyphenylsulfonic acid.
  • compounds of formula (II) are those that have formula (XI) : H A r 2 - N - S O ⁇ A r— Y 2 (XI)
  • Ar 2 is heteroaryl; Ar 3 is arylene or heteroarylene; and Y 2 is (CH 2 ) x COOH or (CH 2 ) x SO 3 H, where x is 0-6.
  • preferred compounds of formula (XI) are those in which: Ar 2 is heteroaryl, preferably 2-benzoxazolyl, 2-benzothiazolyl or 2-benzimidazolyl; Ar 3 is 1 ,2-, 1 ,3-, or 1 ,4-arylene, preferably 1 ,2-, 1 ,3-, or 1 ,4-phenylene; and Y 2 is a carboxylic (COOH) or sulfonic (SO 3 H) acid group.
  • R 10 is alkyl, cycloalkyi or aryl and X 4 is oxy, thio or NR 1 1 , where R 1 1 is selected from hydrogen, alkyl, cycloalkyi, aryl or alkoxyalkyl; Ar 3 is 1 ,2-, 1 ,3- or 1 ,4-phenylene; and Y 2 is a carboxylic acid group.
  • Aromatic acids of formula (III) In another embodiment, the compounds for use in the methods and compositions provided herein have formula (III) :
  • Ar 4 and Ar 5 are selected from among monocyclic or polycyclic aryl and heteroaryl, and are unsubstituted or substituted with one or more Q substituents; t is 1 ; and Y 3 is a carboxylic acid group, with the proviso that the aromatic acid is not (2E,4E)-2,5-diphenylpenta-2,4-dienoic acid or (1 Z,3E)-1 ,4-bis(4-methoxyphenyl)-2-carboxyl-1 ,3-butadiene.
  • Ar 4 and Ar 5 are phenyl, and are unsubstituted or substituted with one or more Q substituents; and Y 3 is located at either the 1 - or 2-position of the butadienyl chain.
  • the geometry of the double bond possessing the Y 3 group is either E or Z. 4.
  • any pharmaceutically-acceptable derivatives including salts, esters, acids, bases, solvates, hydrates and prodrugs of the aromatic acids 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
  • the product is then hydrolyzed under basic conditions (e.g., with NaOH) to provide the desired acids.
  • the product is then oxidized to the desired ⁇ -substituted alkanoic acid by methods known to those of skill in the art, e.g., chromic acid (Jones' oxidation)(Millar et al. J . Org . Chem. 1983, 48, 4404), potassium permanganate (Kaisaki et al. Tetrahedron Lett.
  • w-Arylcarbonyl-substituted alkanoic acids may be prepared by addition of the corresponding aryllithium to the requisite ⁇ , ⁇ - alkanedioic acid cyclic anhydrides, which are also readily available from commercial sources known to those of skill in the art (e.g .
  • the corresponding ⁇ -arylalkylthioalkanoic acids may be prepared in an analogous manner starting from the ⁇ /-haloalkanoic acids.
  • the requisite - -arylalkylthiols may be prepared by reaction of the previously- described 6o/-arylalkan-1 -ols with, e.g. , methanesulfonyl chloride to provide the corresponding ⁇ -arylalkyl methanesulfonates, followed by a sulfur nucleophile, e.g ., sodium hydrogen sulfide.
  • the substituted and unsubstituted amido derivatives may be prepared in the following two ways or by other methods known to those of skill in the art.
  • One method involves reaction of the previously- described ⁇ -arylalkyl methanesulfonates with an unsubstituted or substituted amine to provide an ⁇ -arylalkylamine. Reaction of this ⁇ - arylalkylamine with an ⁇ , ⁇ -alkanedioc acid anhydride, or an mono-alkyl ⁇ , ⁇ -alkanedioate derivative (such as an acyl chloride or acyl imidazole) followed by basic hydrolysis of the ester, affords the desired compounds.
  • a second method involves reaction of an ⁇ -haloalkanoic acid with a substituted or unsubstituted amine, providing an cc-aminoalkanoic acid.
  • the substituted and unsubstituted ureido derivatives may be prepared by reacting equimolar amounts of a previously-described ⁇ - arylalkylamine, a previously-described ⁇ -aminoalkanoic acid, and phosgene or a phosgene equivalent (e.g., triphosgene, carbonyldiimidazole, 4-nitrophenyl chloroformate) or by other methods known to those of skill in the art.
  • phosgene or a phosgene equivalent e.g., triphosgene, carbonyldiimidazole, 4-nitrophenyl chloroformate
  • the substituted and unsubstituted thioureido derivatives may be prepared by equimolar amounts of a previously-described ⁇ -arylalkylamine, a previously-described ⁇ - aminoalkanoic acid, and thiophosgene or a thiophosgene equivalent (e.g., thiocarbonyldiimidazole) .
  • the substituted or unsubstituted ureido derivatives may be converted to the substituted or unsubstituted thioureido derivatives by treatment with Lawesson's reagent, or by other methods known to those of skill in the art.
  • N-Fmoc-amino acid derivatives may be made either by reacting the appropriate amino acid derivative with 9-fluorenylmethyl chloroformate, or by first derivatizing the amino acid as its N-Fmoc derivative followed by derivation of the side chain functional group.
  • N-e- Boc-lysine is prepared by reaction of lysine with di-tert-butyl dicarbonate. Subsequent reaction with 9-fluorenylmethyl chloroformate provides the desired compound.
  • Arginine may be converted to N-Fmoc-(Pmc)arginine by the following method. Chlorosulfonation of 2,2,5,7,8-pentamethyichroman with chlorosulfonic acid affords 2,2,5,7,8-pentamethyl-6-chromylsulfonyl chloride. Alternatively, 2,2,5,7,8-pentamethylchroman may be sulfonated by reaction with, e.g. , sulfur trioxide in sulfuric acid, to give 2,2,5,7,8-pentamethyl-6-chromylsulfonic acid.
  • Subsequent conversion of the sulfonic acid to the desired sulfonyl chloride may be accomplished by treatment with, e.g. , chlorosulfonic acid, phosphorous pentoxide, phosphorous oxychloride, or oxalyl chloride. Reaction of this sulfonyl chloride with arginine gives the guanidyl sulfonamide. This compound is then reacted with 9-fluorenylmethyl chloroformate to provide the desired compound.
  • Other compounds of formula (VI) may be prepared by reaction of equimolar amounts of an ⁇ -arylalkylamine, an amino acid, and phosgene or a suitable phosgene equivalent, e.g . , triphosgene, carbonyldiimidazole, 4-nitrophenyl chloroformate. 2. Preparation of compounds of formula (II) a. Preparation of compounds of formula (VII) Compounds of formula (VII), which are amino acid derivatives, may be purchased from commercial sources known to those of skill in the art (e.g . , Sigma, St. Louis, MO), or prepared by the methods described below or by other methods known to those of skill in the art.
  • these compounds may be prepared by reacting the appropriate N-Boc-amino acid (commercially available or prepared by treatment of an amino acid with di-tert-butyl dicarbonate) with an appropriate derivatizing agent, e.g., 2,4-dichlorobenzyl chloride or 4- methylphenylsulfonyl chloride. Additionally, reaction of equimolar amounts of 2-bromobenzyl alcohol, phosgene or a phosgene equivalent (e.g ., triphosgene, carbonyldiimidazole, 4-nitrophenyl chloroformate), and the N-Boc-amino acid also provides the desired compounds.
  • an appropriate derivatizing agent e.g., 2,4-dichlorobenzyl chloride or 4- methylphenylsulfonyl chloride.
  • 2-bromobenzyl alcohol, phosgene or a phosgene equivalent e.g ., triphosgene, carbony
  • a substituted or unsubstituted benzoic carboxamide is derivatized as the corresponding imminium chloride by reaction with, e.g. , phosphorous pentachloride or phosphorous oxychloride.
  • the carboxamide in converted to the thioamide with, e.g ., Lawesson's reagent (Org. Synth., Coll. Vol. VII 1990, 372) .
  • the thioamide is then activated by reaction with iodomethane.
  • Subsequent reaction of this derivative or the iminium chloride with a substituted phenylsulfonyl hydrazide, wherein the phenyl group is substituted with at least one carboxylic acid group provides the desired compounds.
  • Other compounds of formula (X) may be prepared by reaction of a substituted or unsubstituted phenoxide with oxirane.
  • the resulting alcohol may be reacted with phthalic anhydride to afford certain members of this class.
  • Conversion of the resulting alcohol to a leaving group by reaction with, e.g., tosyl chloride, methanesulfonyl chloride or diiodotriphenylphosphorane, followed by reaction with 4-hydroxybenzoic acid provides other members of this class.
  • Compounds of formula (XI) may be prepared by the methods described below or by any other methods known to those of skill in the art. For example, reaction of 2-, 3- or 4-sulfobenzoic acid with one equivalent of, e.g., 9-fluorenylmethanol under dehydrating conditions (e.g ., molecular sieves, azeotropic removal of water, etc.) provides the corresponding 2-, 3- or 4-(9-fluorenylmethylsulfo)benzoic acids. Esterification of the carboxy group with, e.g., 2-methylpropene, under acidic conditions provides the corresponding tert-butyl 2-, 3- or 4-(9- fluorenylmethylsulfo)benzoates.
  • dehydrating conditions e.g ., molecular sieves, azeotropic removal of water, etc.
  • 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 in 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 ., Mostacelli 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 FGF receptor subtypes, or to interfere with the biological effects of an FGF peptide (see, e.g., International Patent Application Publication No. WO 95/24414) .
  • the relative affinities of the compounds for FGF receptors have been and can be assessed. Those that possess the desired jn 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 i 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.
  • the compounds preferably have formulae (I), (II) or (III) .
  • 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.
  • the compounds described above are formulated into pharmaceutical compositions using techniques and procedures known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition 1985, 1 26) .
  • 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.g., Mostacelli et al. J . Cell. Phvsiol. 1987, 1 31 , 1 23-1 30; Gospardarowicz et al. Proc. Natl. Acad . Sci. U.S.A. 1984, 8_1, 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; Mostacelli et al. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 2091 -2095; Phadke Biochem. Biophys. Res. Comm. 1987, 142, 448-453; Togari et al. Biochem. Biophys. Res. Comm. 1983, 1 14, 1 1 89-1 1 93; and Wagner et al. J . Cell Biol. 1986, 1 3, 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 1000 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.
  • 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.
  • compositions 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.
  • the 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. For oral administration, capsules and tablets are presently preferred.
  • 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.
  • Parenteral preparations can be enclosed in ampules, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.
  • solubilizing compounds may be used .
  • Such methods 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 aqueous sodium bicarbonate
  • Derivatives of the compounds, such as prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions.
  • the 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.
  • 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. If necessary, 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.
  • 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. 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.
  • 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 %-100% 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), (II) or (III) 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 dop
  • Ar, Y and M are as defined above. More particularly, compounds of the above formula or formulae (I), (II) or (III) are provided for use in the compositions and methods.
  • Ar 1 is monocyclic or polycyclic aryl, phenylethynyl, phenylamino, phenyloxy, 8-quinolinyloxy, 2-quinolinyloxy, 2-oxoquinolin-1 -yl, 9- fluorenyl, phenylsulfonyl, phenylthio, 1 -naphthyloxy, 2-naphthyloxy, 1 - pyrenyl, 1 -pyrenylcarbonyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl-2-thio, benzothiazolyl-2-thio or benzimidazolyl-2-thio, and is unsubstituted or substituted with one or more Q substituents; m is 1 -4 or 6; X 1 is methylene, amido, thioamido, oxyamido, ureido, thioure
  • Y 1 is a carboxylic acid group.
  • R 1 is preferably phenyl, 4-hydroxyphenylmethyl, 4-tert- butyloxyphenylmethyl, triphenylmethylthiomethyl, tert- butyloxycarbonylmethyl, 2-(tert-butyloxycarbonyl)ethyl, 4-(tert- butyloxycarbonylamino)butyl, phenylmethyl, 3-(guanidinyl)prop-1 -yl, iso- butyl, tert-butyloxymethyl, 1 -tert-butyloxyeth-1 -yl, 2-methylthioeth-1 -yl, 1 -hydroxyeth-1 -yl, sec-butyl, methyl, aminocarbonylmethyl, 3- indolylmethyl, iso-propyl or 3-(R 2 )-propyl, where R 2 is
  • compositions contain compounds of formula (I) that have formula (IV) :
  • preferred compounds of formula (IV) are those in which: Ar 1 is phenyl, phenylamino, phenylethynyl, phenyloxy, 8- quinolinyloxy, 2-quinolinyloxy, 2-oxoquinolin-1-yl, phenylthio, phenylsulfonyl, 1-pyrenyl, 1-pyrenylcarbonyl, 1-naphthyloxy, 2- naphthyloxy, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxazolyl- 2-thio, benzothiazolyl-2-thio or benzimidazolyl-2-thio, and is unsubstituted or substituted with one or more Q substituents; and Y 1 is a carboxylic acid group.
  • Presently preferred compounds of formula (IV) include 8- phenyloctanoic acid, 9-phenylnonanoic acid, 10-phenyldecanoic acid, 11- phenylundecanoic acid, 12-phenyldodecanoic acid, 1 l-phenylundec-10- ynoic acid, 11-phenyloxyundecanoic acid, 11-(1-naphthyloxy)undecanoic acid, 11-(2-naphthyloxy)undecanoic acid, 12-phenylthioundecanoic acid, 11-(4-acetylphenyloxy)undecanoic acid, 10-(1-pyrenyl)decanoic acid, 10- oxo-10-(1-pyrenyl)decanoic acid, 11-(2-methylphenyl)oxyundecanoic acid, 11-(3-methylphenyl)oxyundecanoic acid, 11 -(4- methyl
  • compounds of formula (I) are those that have formula (V):
  • Ar 1 , X 1 , m, n and Y 1 are as described for formula (I).
  • preferred compounds of formula (V) are those in which: Ar 1 is monocyclic or polycyclic aryl, and is unsubstituted or substituted with one or more Q substituents; m is 2, 3, 4, or 6; X 1 is amido, thioamido, ureido, thioureido, oxy, or thio, and is unsubstituted or substituted with one or more Q substituents; n is 1 -4 or 6; and Y 1 is a carboxylic acid group.
  • the compounds of formula (V) are those in which Ar 1 is phenyl or 1 -pyrenyl; the combination of m and n is 5-9; X 1 is thioamido, ureido, thioureido, oxy, or thio, and is unsubstituted or substituted with one or more Q substituents; and Y 1 is a carboxylic acid group.
  • More preferred compounds of formula (V) are those in which X 1 is amido or ureido, preferably amido or N-benzylureido.
  • Presently preferred compounds of formula (V) include 6-aza-7-oxo- 10-phenyldecanoic acid, 5-aza-4-oxo-8-phenyloctanoic acid, 6-aza-5-oxo- 9-phenylnonanoic acid, 6-aza-5-oxo-10-phenyldecanoic acid, 7-aza-6- oxo-1 1 -phenylundecanoic acid, 4-aza-5-oxo-1 1 -phenylundecanoic acid and 3-benzyl-3,5-diaza-4-oxo-9-( 1 -pyrenyl)nonanoic acid .
  • compounds of formula (I) are those that have formula (VI):
  • preferred compounds of formula (VI) are those in which Ar 1 is monocyclic or polycyclic aryl, and is unsubstituted or substituted with one or more Q substituents; m is 1 or 4; X 1 is amido, amino, ureido, thioureido or oxyamido, and is unsubstituted or substituted with one or more Q substituents; R 1 is phenyl, 4- hydroxyphenylmethyl, 4-tert-butyloxyphenylmethyl, tert- butyloxycarbonylmethyl, 2-(tert-butyloxycarbonyl)ethyl, triphenylmethylthiomethyl, 4-(tert-butyloxyamido)butyl, phenylmethyl, 3- (guanidinyDprop-1 -yl, iso-butyl, tert-butyloxymethyl, 1 -tert-butyloxyeth-1 - yl, 2-methylthioeth-1 -
  • p is 1 ; and Y 1 is a carboxylic acid group.
  • Ar 1 is 1 -pyrenyl or 9- fluorenyl; and X 1 is ureido, thioureido or oxyamido, most preferably ureido or oxyamido.
  • aromatic acids having formula (VI) are 9- fluorenylmethyloxycarbonyl (Fmoc) protected amino acids.
  • Presently preferred compounds of formula (VI) include 3,5-diaza-4- oxo-2-phenyl-9-(1 -pyrenyl)nonanoic acid, Fmoc-Arg(Pmc)-OH, Fmoc- Cys(trt)-OH, Fmoc-Tyr(OtBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Glu(OtBu)- OH, Fmoc-D-Phe-OH, Fmoc-Arg-OH, Fmoc-Asp(OtBu)-OH, Fmoc-e-amino caproic acid, Fmoc-D-Tyr-OH, Fmoc-D-Leu-OH, Fmoc-Ser(OtBu)-OH, Fmoc-Thr(OtBu)-OH, Fmoc-D-Met-OH, Fmoc-Thr-OH, Fmoc-lle-
  • compositions contain aromatic acids which have formula (II) :
  • Ar 2 is phenyl, benzoxazolyl, benzothiazolyl or benzimidazolyl, and is unsubstituted or substituted with one or more Q substituents;
  • Ar 3 is selected from among 1 ,2-, 1 ,3- and 1 ,4-phenylene and imidazolylene, and is unsubstituted or substituted with one or more Q substituents;
  • X 3 is alkylene, alkenylene, alkynylene, oxyalkylene, carbonylalkylene, carbonylalkenylene, carbonylalkynylene, -
  • Ar 2 is phenyl, 4- methylphenyl, 4-hydroxyphenyl, 3,5-diiodo-4-hydroxyphenyl, 2- bromophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4- carboxymethylphenyl, 4-methoxyphenyl, 4-( 1 , 1 ,3,3-tetramethyl)but-1 - ylphenyl, 3,4-dimethoxyphenyl, 3-methoxy-4-dodeca-1 ,3,5,7,9, 1 1 - hexaenyloxyphenyl, 4-hexadecanyloxyphenyl, 4-chlorophenyl, benzoxazolyl, benzothiazolyl or benzimidazolyl; R 3 is hexadecanyl and R 4 is methyl, or R 3 and R 4 together form pentylene;
  • Ar 3 is 1 ,4-phenylene, 1 ,4-imidazolylene, 3,5-diiodo-1 ,4-phenylene, 3-methoxy-1 ,4-phenylene, 1 ,3-phenylene, 1 ,2-phenylene, 4-chloro-1 ,2- phenylene, or 5-carboxy-1 ,3-phenylene;
  • R 6 is H, tert-butoxycarbonyl, or diphenylacetyl; and q is 0 when X 2 is -ZSO 2 -, -COCH 2 CONH-, (2-ureido-4-chlorophenyl- 1 -en)oxy, oxyethylenyloxy, oxyethylenyloxycarbonyl, or thioureido.
  • compounds of formula (II) are those that have formula (VII) :
  • preferred compounds of formula (VII) are those in which: Ar 2 is phenyl, 4-methylphenyl, 2-bromophenyl, 2,4- dichlorophenyl, 4-hydroxyphenyl, or 3,5-diiodo-4-hydroxyphenyl; X 2 is methylenoxy, sulfonyl, methylenoxycarboxy, ethynylene, or oxy; Ar 3 is 1 ,4-phenylene, 1 ,4-imidazolylene, or 3,5-diiodo-1 ,4-phenylene; and Y 2 is a carboxylic acid group.
  • preferred compounds of formula (VII) include aryl ⁇ -amino acids which are optionally derivatized as the corresponding N-(Boc) or N- diphenylacetyl compounds.
  • Presently preferred compounds of formula (VII) include O-benzyl-N- diphenylacetyl-L-tyrosine, O-(3,4-dichlorobenzyl)-N-diphenylacetyl-L or D- tyrosine, O-(2-bromobenzyloxycarbonyl)-N-diphenylacetyl-L or D-tyrosine, N 1 -(4-methylphenylsulfonyl)-N-diphenylacetyl-L or D-histidine, 3-(4-(4- methylphen-1 -yl)-4-ethynylphen-1 -yl)-N-diphenylacetyl-D-alanine, O- benzyl-N-(Boc
  • compounds of formula (II) are those that have formula (VIM) :
  • preferred compounds of formula (VIM) are those in which: Ar 2 is phenyl, 4-methylphenyl, 4-carboxymethylphenyl, or 3,4- dichlorophenyl; X 2 is methyleneoxy, oxy, ethenylenylcarbonyl, propylene, ethynylene, or -CH 2 CON(CH 3 )CH(CH 2 -pyrrolidinyl); Ar 3 is 1 ,4-phenylene, 1 ,3-phenylene, or 3-methoxy-1 ,4-phenylene; X 3 is ethynylene, carbonylethylene, methylene, oxymethylene, or -C(OH)(C(CH 3 ) 3 )C ⁇ C-; and Y 2 is a carboxylic acid group.
  • Presently preferred compounds of formula (VIM) include 4- benzyloxy-3-methoxycinnamic acid, 4-oxo-4-(4-phenyloxyphen-1 - yDbutanoic acid, 4-( 1 -oxo-3-phenylprop-2-en- 1 -yl)phenylacetic acid, 4-( 1 - oxo-3-phenylprop-2-en-1 -yl)phen-1 -yloxyacetic acid, 4-(3-(4- carboxymethylphen-1 -yl)prop-1 -yl)phenylacetic acid, 3-(2-aza-4-(3,4- dichlorophen-1 -yl)-2-methyl-3-oxo-1 -(N-pyrrolidinyDmethylbut-1 -yDphen- 1 -yloxyacetic acid, 4-(3-(4-methylphenyl)prop-1 -yl)phenylacetic acid, 4- (phenylethynyDphen-1 -yloxyacetic acid
  • a r -C N -N R S O -A r -Y (IX) where Ar 2 , Ar 3 , R 5 and Y 2 are as described for formula (II); and D is NR 3 R 4 , where R 3 is hexadecanyl and R 4 is methyl, or R 3 and R 4 together form pentylene.
  • preferred compounds of formula (IX) are those in which: Ar 2 is phenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 4-hexadecanyloxyphenyl, 3-methoxy-4-dodeca-1 ,3,5,7,9, 1 1 - hexaenyloxyphenyl or 4-chlorophenyl; Ar 3 is 1 ,4-phenylene, 1 ,3- phenylene, or 5-carboxy- 1 ,3-phenylene; and Y 2 is a carboxylic acid group.
  • the aromatic acids of formula (IX) are carboxyl-substituted arylsulfonyl hydrazides of arylcarboxylic amides.
  • Presently preferred compounds of formula (IX) include N-methyl-N-hexadecanyl-3,4-dimethoxybenzamide 4- carboxyphenylsulfonyl hydrazide, N-pentylenyl-3-methoxy-4-dodeca- 1 ,3,5,7,9, 1 1 -hexaenyloxybenzamide 3,5-dicarboxyphenylsulfonyl hydrazide, N-pentylenyl-4-hexadecanyloxybenzamide 3- carboxyphenylsufonyl hydrazide, N-hexadecanyl-N-methylbenzamide 3- carboxyphenylsulfonyl hydrazide, N-hexadecanyl-N-methylbenzamide
  • N-methyl-4-chlorobenzamide 4-carboxyphenylsulfonyl hydrazide.
  • compounds of formula (II) are those that have formula (X) :
  • Ar 2 , X 2 , Ar 3 and Y 2 are as described for formula (II) .
  • preferred compounds of formula (X) are those in which: Ar 2 is phenyl, 4-methoxyphenyl, 3,4-dichlorophenyl, or 4- (1,1 ,3,3-tetramethyl)but-1-ylphenyl; X 2 is oxyethylenoxycarbonyl, oxyethylenoxy, thioureido, -COCH 2 CONH- or (2-ureido-4-chlorophenyl-1- en)oxy; Ar 3 is 1,2-phenylene, 1,4-phenylene, or 4-chloro-1 ,2-phenylene; and Y 2 is a carboxylic or sulfonic acid group.
  • More preferred compounds of formula (X) are those in which Ar 2 is phenyl or 4-(1,1,3,3-tetramethyl)but-1-ylphenyl; X 2 is oxyethylenoxy, oxyethylenoxycarbonyl, or thioureido; Ar 3 is 1,4-phenylene or 1,2- phenylene; and Y 2 is a carboxylic acid group.
  • Presently more preferred compounds of formula (X) include mono- 2-((4-(1,1,3,3-tetramethyl)buty-1-yl)phen-1-yloxy)ethyl ortho-phthalate, N-phenyl-N'-2-carboxyphenylthiourea, 4-(2-(4-(1,1,3,3-tetramethyl)but-1- ylphenyloxy)ethoxy)benzoic acid and 4-(2-(phenyloxy)ethoxy)benzoic acid.
  • Most preferred compounds of formula (X) are those in which Ar 2 is 4-methoxyphenyl or 3,4-dichlorophenyl; X 2 is -COCH 2 CONH- or (2- ureido-4-chlorophenyl-1-en)oxy; Ar 3 is 1,4-phenylene, or 4-chloro-1 ,2- phenylene; and Y 2 is a sulfonic acid group.
  • Presently most preferred compounds of formula (X) include 4-(3- (4-methoxyphen-1-yl)-1,3-dioxoprop-1-yl)aminophenylsulfonic acid or 5- chloro-2-((2-(2-(3,4-dichlorophenyl)-2-aza-1-oxoethyl)amino)-4- chlorophenyDoxyphenylsulfonic acid.
  • compounds of formula (II) are those that have formula (XI): H
  • Ar 2 is heteroaryl; Ar 3 is arylene or heteroarylene; and Y 2 is (CH 2 ) x COOH or (CH 2 ) x SO 3 H, where x is 0-6.
  • preferred compounds of formula (XI) are those in which: Ar 2 is heteroaryl, preferably 2-benzoxazolyl, 2-benzothiazolyl or 2-benzimidazolyl; Ar 3 is 1 ,2-, 1 ,3-, or 1 ,4-arylene, preferably 1 ,2-, 1 ,3-, or 1 ,4-phenylene; and Y 2 is a carboxylic (COOH) or sulfonic (SO 3 H) acid group.
  • R 10 is alkyl, cycloalkyi or aryl and X 4 is oxy, thio or NR 1 1 , where
  • R 1 1 is selected from hydrogen, alkyl, cycloalkyi, aryl or alkoxyalkyl;
  • Ar 3 is 1 ,2-, 1 ,3- or 1 ,4-phenylene; and
  • Y 2 is a carboxylic acid group.
  • Aromatic acids of formula (III) In another embodiment, the compositions contain aromatic acids which have formula (III):
  • Ar 4 and Ar 5 are selected from among monocyclic or polycyclic aryl and heteroaryl, and are unsubstituted or substituted with one or more Q substituents; t is 1 ; and Y 3 is a carboxylic acid group.
  • Ar 4 and Ar 5 are phenyl, and are unsubstituted or substituted with one or more Q substituents; and Y 3 is located at either the 1 - or 2-position of the butadienyl chain.
  • the geometry of the double bond possessing the Y 3 group is either E or Z.
  • Presently most preferred compounds of formula (III) are (2E,4E)- 2,5-diphenylpenta-2,4-dienoic acid or ( 1 Z,3E)-1 ,4-bis(4-methoxyphenyl)- 2-carboxyl-1 ,3-butadiene. d.
  • Aromatic acid 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 aromatic acids. 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, choline, 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 limited to
  • 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.
  • 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 4,410,545.
  • the solution e.g., for example, 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.
  • they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate.
  • enterically digestible coating such as phenylsalicylate, waxes and cellulose acetate phthalate.
  • 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.
  • 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 subject.
  • 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.
  • PBS physiological saline or phosphate buffered saline
  • 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 include Sodium Chloride 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.
  • 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. 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 formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations.
  • 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 . 4.
  • 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.g ., U.S. Patent Nos. 4,044, 1 26, 4,414,209, 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.
  • 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. 6.
  • routes of administration Depending upon the condition treated other routes of administration, such as topical application, transdermal patches, 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. E. Methods of treating of FGF-mediated disorders
  • 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. Restenosis and vascular injury
  • 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.
  • 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.
  • 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 in vitro and in vivo systems (see, e.g. , Mostacelli et al. 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.
  • 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 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 , ⁇ FN-y and tumor necrosis factor (TNF)) and growth factors, such as bFGF.
  • cytokines e.g., interleukin-1 , ⁇ FN-y and tumor necrosis factor (TNF)
  • TNF tumor necrosis factor
  • bFGF growth factors
  • cytokines act in concert with the inflammatory mediators, e.g. , bFGF, to cause local tissue destruction.
  • cytokines and bFGF stimulate fibroblast and collagen proliferation resulting in angiogenesis, and prolonged exposure can result in hyperproliferation of epithelial cells that form fibrous tissue, referred to as fibrosis.
  • 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 in 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, 1 , 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.
  • EXAMPLE 3 6-Aza-5-oxo-10-phenyldecanoic Acid Using the method described in Example 2, 5-aza-6-oxo-10- phenyldecanoic acid was synthesized from 4-phenylbutylamine (299 mg, 2.0 mmol) and glutaric anhydride (228 mg, 2.0 mmol) . Workup as before gave a white solid in 82% yield, mp 73 °C.
  • EXAMPLE 9 11-2-(Naphthoxy)undecanoic Acid Using the method described in Example 13, with 2-naphthol (219 mg, 1.5 mmol, 50% molar excess) in place of 4-bromophenol, 11 -(2- naphthoxy)undecanoic acid was obtained in 45% overall yield as an off- white solid after recrystallization from ethyl acetate/hexanes, mp 97-98 °C.
  • Triethylamine (0.710 mL, 5.1 mmol) was added to a suspension of 1-(4-aminobutyl)pyrene (400 mg, 1.7 mmol) in CH 2 CI 2 (10 mL) at 0 °C.
  • a solution of 4-nitrophenyl chloroformate (530 mg, 2.6 mmol) in CH 2 CI 2 (2 mL) was added dropwise and the mixture was stirred at 25 °C for 4h. The solvent was evaporated in vacuo and the yellow solid that remained was dissolved in EtOAc (15 mL).
  • Methyl 1 1 -phenyl-1 0-undecynoate 200 mg, 0.7 mmol was saponified with 5N NaOH (0.6 mL, 3 mmol) in a mixture of THF (0.8 mL) and methanol (0.6 mL). Usual extractive work-up (see Example 1 1 ) gave 1 69 mg (93%) of a white solid, mp 43-44 °C.
  • the aqueous phase was acidified with 6N HCl at 0 °C and extracted with ethyl acetate (3 x 7 mL) .
  • the combined extracts was washed with water (7 mL), dried (MgSO 4 ) and concentrated to give 1 55 mg (96%) of crude product. Further purification was achieved by recrystallization from hot MeOH to give white crystals, mp 75-78 °C.
  • EXAMPLE 16 11-(3-Methylphenyl)oxyundecanoic Acid Using the method described in Example 13, with ⁇ ?-cresol (130 mg, 1.2mmol) in place of 4-bromophenol and methyl 11- bromoundecanoate (279 mg, 1.0 mmol) in place of its ethyl analog, 11- (3-methylphenyl)oxyundecanoic acid was obtained in 66% overall yield as white crystals after recrystallization from hot MeOH, mp 55-57 °C.
  • Methyl 11-(2-Oxo-1-quinolinyl)undecanoate and Methyl 11- (2-Quinolinyl)oxyundecanoate Using the method described in Example 13, with 2- hydroxyquinoline (330 mg, 2.3 mmol, 50% molar excess) in place of 4- bromophenol and methyl 11-bromoundecanoate (419 mg, 1.5 mmol) in place of its ethyl analog, methyl 11-(2-quinolinyl)oxyundecanoate (R f 0.61 using 10% ethyl acetate in hexanes as eluent; 116 mg, 22.5% yield) and methyl 11-(2-oxo-1-quinolinyl)undecanoate (R f 0.22, 95 mg, 18% yield) were obtained. These products were readily separated by column chromatography (10% ethyl acetate/hexanes).
  • EXAMPLE 18 11-(3,4-Dimethyoxyphenyl)oxyundecanoic Acid Using the method described in Example 13, with 3,4- dimethoxypenol (358 mg, 2.3 mmol, 50% molar excess) in place of 4- bromophenol and methyl 11-bromoudecanoate (419 mg, 1.5 mmol) in place of its ethyl analog, 11-(3,4-dimethoxyphenyl)oxyundecanoic acid (192 mg, 40% overall yield was obtained as an off-white solid after recrystallization from ethyl acetate/hexanes, mp 62-63 °C.
  • Boc group was removed under standard conditions using a solution of 25% TFA in CH 2 CI 2 ( 1 mL) at 25 °C for 30 min and the crude product was reacted with diphenylacetyl chloride ( 1 equivalent) and diisopropylethylamine ( 1 .5 equivalents) in CH 2 CI 2 to give ⁇ /-diphenylacetyl-4-( ⁇ -tolylethynyl)- - phenylalanine methyl ester.
  • N- diphenylacetyl-4-(p-tolylethynyl)-D-phenylalanine was saponified in a mixture of 2N LiOH (2 equivalents) and THF (2mL) at 25 °C for 2h. A crude product was obtained as a light yellow solid. Further purification was achieved by preparative HPLC to give pure ⁇ /-diphenylacetyl-4-(p- tolylethynyD- -phenylalanine as a as a white solid (43% overall yield from ⁇ /-Boc-4-iodo-£>-phenylalanine methyl ester), mp 1 92 °C (dec) .
  • EXAMPLE 24 4-(3-(4-Methylphenyl)propyl)phenylacetic Acid This compound was prepared according to the method of Cram and Dewhirst (J. Am. Chem. Soc. 1959, 81, 5963) .
  • This compound was prepared as described by the method of Wang (Huaxue, Shiiie 1988, .29, 538-540) from 4,4'-dichloro-2-amino-2'- sulfodiphenyl ether and 3,4-dichlorophenyl isocyanate in the presence of
  • N-Hexadecyl-N-methylbenzamide 4-Carboxyphenylsulfonylhydrazide ⁇ /-Methyl- ⁇ /-hexadecylbenzamide was converted into the corresponding thioamide using Lawesson's reagent as described in Org.
  • 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.
  • tPA tissue plasminogen activator
  • FGFR1 human basic fibroblast growth factor receptor 1
  • 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 polymerase 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 Sail and purified by agarose gel electrophoresis according to the standard procedures (Sambrook et al.
  • the DNA was isolated from gel by electroelution and recovered by precipitation with ethanol.
  • the resulting Hindlll to SaJI 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
  • Human tPA is a 562 amino acid polypeptide which is processed during secretion to its mature form by cleavage of a 35 amino acid signal peptide.
  • Several regions of the primary structure of mature tPA have a high degree of homology to known structural domains of other proteins, such as homology to the finger and growth factor domains, the Kringle 1 and Kringle 2 domains of plasminogen and prothrombin and the C-terminal serine protease domain (e.g ., see Ny et al. Proc. Natl. Acad. Sci. USA 1984, 8J_* 5355) .
  • 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 180 of mature tPA sequence.
  • UGA in-frame amber stop codon
  • a Sajl 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) .
  • nt 76 to 81 and 91 and 92 (nt -30 to -25 and -1 5 and -1 4, respectively, relative to the first nucleotide of mature tPA) during the PCR reaction by synthesizing an oligonucleotide primer corresponding to nt 72 to nt 1 1 1 containing nucleotide substitutions at six positions in the tPA sequence: nt 76 (A to G), nt 79 (C to G), nt 81 (T to C), nt 91 (A to C) and 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 isolated SaJI to BamHI fragment encoding the portion of human tPA was ligated into the SaJI and BamHI sites of pUC1 8 to generate plasmid HTPA3/4-pUC1 8.
  • HTPA3/4-pUC1 8 was then digested with Hindlll and SaJI into which the isolated Hindlll to SaJI 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 10 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 2-1 435 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. Biophvs. Res. Commun. 1994, 203, 1821 -1827) .
  • 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.
  • Baby hamster kidney cells BHK cells; Waechter, D.E., et al. Proc.
  • 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.
  • blocking buffer 25 mM HEPES, pH 7.5, 1 00 mM NaCl and 0.5% gelatin
  • binding buffer 25 M HEPES, pH 7.5, 1 00 mM NaCl and 0.3% gelatin
  • binding buffer 25 M HEPES, pH 7.5, 1 00 mM NaCl and 0.3% gelatin
  • 0.1 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 ⁇ g/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) . From this analysis, a 280 pM dissociation constant (K D ) for the binding of bFGF to the recombinant FGFR1 -tPA fusion protein of was calculated . This value correlates well with 1 30 pM K D value reported for bFGF binding to native FGFR1 receptors expressed in smooth muscle cells (Saltis et al. Arteriosclerosis 1995, 1 1 8, 77-87) .
  • 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), (II) or (III) 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, Mostacelli et al. A Cell. Phvsiol. 1987, 1 31 , 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.
  • EGF was dissociated from the cells by addition of a solution of 0.1 % Triton-X-100 and 5 min incubation at ambient temperature. The amount of radioactivity in each supernatant was measured using a gamma counter.
  • 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 ( 1 00 ug/ml)) and cultured for an additional three days in serum-free DMEM medium. After washing twice in serum-free DMEM medium, the follow was added to each well: 400 ⁇ l of serum-free DMEM, 50 ⁇ l of 3 ng/ml bFGF in DMEM and 50 ⁇ l of known concentration test compound in DMEM 1 .0% DMSO for 23 hr at 37° C.
  • serum-free medium DMEM supplemented with 0.1 % BSA, 5 ⁇ g/ml transferrin, penicillin ( 1 00 unit/ml) and streptomycin ( 1 00 ug/ml)
  • the percent inhibition of bFGF for each of the compounds described in detail above has been measured. Almost all of the compounds exhibited some inhibition of bFGF at concentrations of less than 500 ⁇ M. Many of the compounds exhibited some inhibition of bFGF at concentrations of less than 300 ⁇ M. Several of these compounds exhibited some inhibition of bFGF at concentrations of less than 30 ⁇ M, while a few had measured IC 50 values of less than 1 5 ⁇ M.

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Abstract

L'invention concerne des acides aromatiques et des compositions pharmaceutiques d'acides aromatiques présentant la formule Ar-M-Y. L'invention a aussi pour objet des procédés permettant d'utiliser les compositions pharmaceutiques pour moduler l'activité de la famille de peptides, facteurs de croissance des fibroblastes. L'invention traite également de procédés permettant d'inhiber la liaison d'un peptide facteur de croissance de fibroblaste à un récepteur de ce facteur en plaçant ce récepteur en contact avec l'acide aromatique. L'invention concerne aussi des procédés permettant de traiter les troubles induits par le facteur de croissance des fibroblastes. Ces derniers procédés consistent à administrer des quantités efficaces d'un ou plusieurs acides aromatiques ou dérivés pharmaceutiquement acceptables de ces derniers qui inhibent l'activité d'un ou plusieurs peptides facteurs de croissance de fibroblastes.
PCT/US1998/025789 1997-12-05 1998-12-04 Compositions et procedes permettant de moduler l'activite du facteur de croissance des fibroblastes WO1999029640A2 (fr)

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AU19037/99A AU1903799A (en) 1997-12-05 1998-12-04 Compositions and methods for modulating the activity of fibroblast growth factor

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US98624897A 1997-12-05 1997-12-05
US08/986,248 1997-12-05
US7934398A 1998-05-15 1998-05-15
US09/079,343 1998-05-15

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WO1999029640A2 true WO1999029640A2 (fr) 1999-06-17
WO1999029640A3 WO1999029640A3 (fr) 2000-01-13

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WO2000030632A1 (fr) * 1998-11-23 2000-06-02 Eisai Co., Ltd. Composes aryles et heteroaryles utiles comme antagonistes du facteur de croissance des fibroblastes (fgf)
US6207126B1 (en) 1998-07-16 2001-03-27 Chemetall Foote Corporation Recovery of lithium compounds from brines
US6596751B2 (en) 1999-04-06 2003-07-22 Sankyo Company Limited α-substituted carboxylic acid derivatives
AU780506B2 (en) * 1999-12-17 2005-03-24 Astrazeneca Ab Adamantane derivatives
US7276539B2 (en) 2001-12-19 2007-10-02 Astrazeneca Ab 3-Phenyl-2-arylalkylthiopropionic acid derivatives as selective agonists of ppar-alpha
US20110152315A1 (en) * 2008-07-28 2011-06-23 Syddansk Universitet Compounds for the treatment of metabolic diseases
US8026280B2 (en) * 2001-03-27 2011-09-27 Errant Gene Therapeutics, Llc Histone deacetylase inhibitors
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CN103153061A (zh) * 2010-10-04 2013-06-12 住友化学株式会社 用于减少植物中的水胁迫的方法
RU2530889C2 (ru) * 2004-05-14 2014-10-20 Эмисфире Текнолоджис, Инк. Соединения и составы для доставки активных веществ

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207126B1 (en) 1998-07-16 2001-03-27 Chemetall Foote Corporation Recovery of lithium compounds from brines
WO2000030632A1 (fr) * 1998-11-23 2000-06-02 Eisai Co., Ltd. Composes aryles et heteroaryles utiles comme antagonistes du facteur de croissance des fibroblastes (fgf)
US6596751B2 (en) 1999-04-06 2003-07-22 Sankyo Company Limited α-substituted carboxylic acid derivatives
AU780506B2 (en) * 1999-12-17 2005-03-24 Astrazeneca Ab Adamantane derivatives
US8026280B2 (en) * 2001-03-27 2011-09-27 Errant Gene Therapeutics, Llc Histone deacetylase inhibitors
US7276539B2 (en) 2001-12-19 2007-10-02 Astrazeneca Ab 3-Phenyl-2-arylalkylthiopropionic acid derivatives as selective agonists of ppar-alpha
RU2530889C2 (ru) * 2004-05-14 2014-10-20 Эмисфире Текнолоджис, Инк. Соединения и составы для доставки активных веществ
US20110152315A1 (en) * 2008-07-28 2011-06-23 Syddansk Universitet Compounds for the treatment of metabolic diseases
JP2012503595A (ja) * 2008-07-28 2012-02-09 シダンスク ユニバーシティ 代謝病の治療用の化合物
US8586607B2 (en) 2008-07-28 2013-11-19 Syddansk Universitet Compounds for the treatment of metabolic diseases
JP2015120698A (ja) * 2008-07-28 2015-07-02 シダンスク ユニバーシティＳｙｄｄａｎｓｋ Ｕｎｉｖｅｒｓｉｔｅｔ 代謝病の治療用の化合物
CN105152919A (zh) * 2008-07-28 2015-12-16 赛丹思科大学 用于治疗代谢疾病的化合物
JP2013518888A (ja) * 2010-02-02 2013-05-23 アーガシナ インコーポレイテッド 非ペプチドｇｌｐ−１受容体調節因子としてのフェニルアラニン誘導体およびその使用
JP2016166182A (ja) * 2010-02-02 2016-09-15 アーガシナ インコーポレイテッド 非ペプチドｇｌｐ−１受容体調節因子としてのフェニルアラニン誘導体およびその使用
CN103153061A (zh) * 2010-10-04 2013-06-12 住友化学株式会社 用于减少植物中的水胁迫的方法

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