WO2000061545A1 - Methodes de synthese combinatoire en phase solide d'inhibiteurs d'integrines - Google Patents

Methodes de synthese combinatoire en phase solide d'inhibiteurs d'integrines Download PDF

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WO2000061545A1
WO2000061545A1 PCT/US2000/010027 US0010027W WO0061545A1 WO 2000061545 A1 WO2000061545 A1 WO 2000061545A1 US 0010027 W US0010027 W US 0010027W WO 0061545 A1 WO0061545 A1 WO 0061545A1
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carbon atoms
formula
compound
optionally substituted
produce
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Ariamala Gopalsamy
Hui Yu Yang
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American Home Products Corporation
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C2601/14—The ring being saturated
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    • C07—ORGANIC CHEMISTRY
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    • C07C2603/58—Ring systems containing bridged rings containing three rings
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Definitions

  • the present invention relates to integrin inhibitors useful for their ability to antagonize/block biological processes mediated by ⁇ v ⁇ 3 and related integrin receptors, to combinatorial and solid phase methods for preparing libraries of compounds, and utilization of libraries of the compounds for drug discovery.
  • the present invention further provides pharmaceutical compositions for administration to mammals, including man, and methods for their use in the treatment of various disorders including, but not limited to, cancer (tumor metathesis, tumorgenesis/tumor growth), angiogenesis (as in cancer, diabetic retinopathy, rheumatoid arthritis), restenosis (following balloon angioplasty or stent implantation), inflammation (as in rheumatoid arthritis, psoriasis), bone diseases (osteopenia induced by bone metastases, immobilization and glucocortocoid treatment, periodontal disease, hyperparathyroidism and rheumatoid arthritis), and as antiviral agents.
  • cancer tumor metathesis, tumorgenesis/tumor growth
  • angiogenesis as in cancer, diabetic retinopathy, rheumatoid arthritis
  • restenosis followeding balloon angioplasty or stent implantation
  • inflammation as in rheumatoid arthritis, psorias
  • the integrin ⁇ v ⁇ 3 has been shown to mediate the invasion of cancerous melanoma cells into healthy tissue and to protect these cells against natural cell death cycle (apoptosis).
  • Vitronectin receptor( ⁇ y ⁇ 3 ) antagonists have been shown to inhibit the growth of various solid tumors of human origin. More recently, ⁇ v ⁇ 3 has been shown to be involved in liver metastasis.
  • angiogenesis is an important and natural process in growth and wound healing, it is now appreciated that a variety of clinically relevant conditions are pathologically related to these processes, and that the integrin ⁇ v ⁇ 3 is involved.
  • ⁇ v ⁇ 3 was shown to be expressed on human wound tissue but not on normal skin and is preferentially expressed on angiogenic blood vessels, such as those feeding a growing/invading tumor. It has also been shown that antagonists of ⁇ v ⁇ 3 promote tumor regression by inducing apoptosis of the tumor cells. This process of neovascularization (new blood vessel growth, angiogenesis), which is critical for tumor growth and metastasis, is also an important event in occular tissue, leading to diabetic retinopathy, glaucoma and blindness and in joints, promoting rheumatoid arthritis.
  • angiogenesis new blood vessel growth, angiogenesis
  • v ⁇ 3 has been shown to play a pivotal role in the proliferation and migration of smooth muscle and vascular endothetial cells, a pathological process leading to restenosis after balloon angioplastly (Choi et al., J. Vase. Surgery, 1994, 19, 125-134; Matsumo et al., Circulation, 1994, 90, 2203-2206). At least one type of virus (adenovirus) has been shown to utilize oc v ⁇ 3 for entering host cells (White et al., Current Biology, 1993, 596-599).
  • ⁇ v ⁇ 3 Various bone diseases involve bone resorption-the dissolution of bone matter, which is mediated by only one known class of cells, the osteoclasts. When activated for resorption, these motile cells initially bind to bone, a process well known to be mediated by ⁇ v ⁇ 3 (Davies et al., J. Cell. Biol., 1989, 109, 1817-1826; Helfrich et al., J Bone Mineral Res., 1992, 7, 335-343). It is also well known that blockade of ⁇ v ⁇ 3 with antibodies or RGD containing peptides block osteoclast cell adhesion and bone resorption in vitro (Horton et al., Exp. Cell Res.
  • Combinatorial chemistry is becoming an important tool for drug discovery and lead optimization (Borman, S. Chemical and Engineering News 1997, 75 (8), 43- 63).
  • a combinatorial synthesis requires that at least two components of the product molecules be independently variable, so that all of the combinations of these components can be prepared.
  • a synthesis with three independently variable components is preferable since greater diversity in structure can be produced in the resultant library.
  • integrin inhibitors are RGD mimics and they use a ⁇ - amino acid like substituted 2,3-diaminopropionic acid as the carboxylic acid terminus. While a cyclic or acyclic guanidino moiety is preferred for the basic end of the molecule, substituted ureas and amidines are used as well.
  • the central scaffold, connecting these two pieces, itself can be varied widely. By developing a convenient route to appropriately protected fragments and a mild solid phase synthesis that incorporates all the three components in an independent fashion, it is possible to prepare combinatorial libraries of this important class of integrin inhibitors. A solid-phase synthesis of integrin antagonist has been reported recently
  • R, and R-. independently are optionally substituted alkyl of 1-8 carbon atoms, optionally substituted alkenyl of 2-8 carbon atoms, optionally substituted alkynyl of 2-8 carbon atoms, optionally substituted cycloalkyl of 3-12 carbon atoms, optionally substituted aryl, optionally substituted aralkyl of 6-10 carbon atoms, optionally substituted aralkenyl of 6-10 carbon atoms, optionally substituted heterocycloalkyl of 5-10 members consisting of carbon atoms and from 1-3 heteroatoms selected from N, S and O, optionally substituted heterocycloalkyl-alkyl where the heterocycloalkyl has 5-10 members consisting of carbon atoms and from 1-3 heteroatoms selected from N, S and O, and the alkyl has 1-8 carbon atoms, optionally substituted heteroalkyl-alkenyl where the heteroalkyl has 5-10 members consisting of carbon atoms and from 1-3 heteroatoms selected from N
  • R 3 is H, optionally substituted alkyl of 1-6 carbon atoms, optionally substituted aralkoxy of 1-6 carbon atoms;
  • X is NHCOO, NHCO, NHCONH, NHSO 2 ;
  • G may preferably be pyrimidinyl, guanidine, pyridyl-urea, benzyl-urea, azepinyl, imidazolinyl or tetrahydropyrimidinyl.
  • R. may be methyl, ethyl, n-propyl, i-propyl, allyl, homoallyl, propargyl, pentyl, n-hexyl, octyl, neopentyl, trichloroethyl, n-butyl, i-butyl, butynyl, phenyl, methylphenyl, dimethylphenyl, halophenyl, methoxyphenyl, acetylphenyl, biphenyl, naphthyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, trimethylcyclopropyl, phenylcyclopropyl, adamantyl, adamantylmethyl, cinnamic, pyridyl, or dimethylfuranyl.
  • Alkyl whether used alone or as part of a group such as “alkoxy”, means an optionally substituted branched or straight chain having from 1 to 8 carbon atoms.
  • exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl and hexyl.
  • Lower alkyl refers to alkyl having from 1 to 6 carbon atoms.
  • Alkyl groups may be substituted with one or more substituents selected from halogen, lower alkyl, lower alkoxy, lower alkylthio, amino, nitro, cyano, carboxy, alkylamino, perhaloalkyl, hydroxy, oxy, phenyl, phenylalkyl, or naphthyl.
  • substituents selected from halogen, lower alkyl, lower alkoxy, lower alkylthio, amino, nitro, cyano, carboxy, alkylamino, perhaloalkyl, hydroxy, oxy, phenyl, phenylalkyl, or naphthyl.
  • a substituted alkyl group is trichloroethyl.
  • Cycloalkyl refers to optionally substituted mono or polycyclic alkyl group of 3-12 carbon atoms.
  • exemplary cycloalkyl groups include cyclopropyl, cyclohexyl and adamantyl. Cycloalkyl groups may be substituted by one or more substituents e.g. those described above in relation to the optionally substituted alkyl group. Preferred substituents include aromatic groups such as phenyl and alkyl groups such as methyl. Examples of substituted cycloalkyl groups include trimethylcyclopropyl and phenylcyclopropyl.
  • Aryl whether used alone or as part of a group such as “aralkyl”, means optionally substituted mono or bicyclic aromatic ring having from 5 to 10 carbon atoms.
  • exemplary aryl groups include phenyl and naphthyl.
  • the aryl may be substituted with one or more substituents.
  • Substituents include halogen, lower alkyl, lower alkoxy, lower alkylthio, amino, nitro, cyano, carboxy, carboxyalkyl, alkanoyl, alkylamino, perhaloalkyl, hydroxy, oxy, phenyl, phenylalkyl, or naphthyl.
  • aryl group is phenyl which may be denoted as Ph in some instances.
  • substituted aryls include methylphenyl, dimethylphenyl, halophenyl, methoxyphenyl, acetylphenyl and biphenyl.
  • Heterocycloalkyl whether used alone or as part of a group such as “heterocycloalkyl-alkyr' means an optionally substituted stable 5 to 10 membered mono or bicyclic ring of carbon atoms and from 1 to 3 heteroatoms selected from N, O and S.
  • heterocycloalkyls include pyrazinyl, pyrazolyl, tetrazolyl, furanyl, thienyl, pyridyl, imidazolyl, pyrimidinyl, tetrahydropyrimidinyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, indolyl, isoquinolinyl, oxazolyl and oxadiazolyl.
  • Preferred heterocycloalkyl groups include pyrimidinyl, tetrahydropyrimidinyl, pyridyl, azepinyl, and imidazolyl.
  • heterocycloalkyls include pyridin-2yl, and tetrahydropyrimidine.
  • the heterocycloalkyl may also be substituted with one or more substituents.
  • substituents include halogen, lower alkyl, lower alkoxy, lower alkylthio, amino, nitro, cyano, carboxy, carboxyalkyl, alkanoyl, alkylamino, perhaloalkyl, hydroxy, oxy, phenyl, phenylalkyl or naphthyl.
  • Preferred substituents include amino and oxy.
  • Preferred substituted heterocyloalkyls include 6 aminopyridin-2yl and tetrahydropyrirnid-4-one.
  • Alkyl means an optionally substituted aryl-alkyl group in which the aryl, alkyl and the optional substitutents are as previously described.
  • exemplary aralkyl groups include benzyl and phenethyl. Used in this context, the alkyl group may include one or more double bonds.
  • Heterocycloa-lkyl-alkyl means an optionally substituted heterocycloalkyl-alkyl group in which the heterocycloalkyl, alkyl and optional substitutents are as previously described. Used in this context the alkyl group may include one or more double bonds.
  • Exemplary heterocycloalkyl-alkyls include pyridylmethyl, pyridylethyl, thienylethyl, thienylmethyl, indolylmethyl, and furylmethyl.
  • Alkoxy means an optionally substituted alkyl-O group in which the alkyl group is as previously described.
  • exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
  • Alkoxy means an optionally substituted aryl-alkoxy group in which aryl and alkoxy are as previously described.
  • Halogen includes fluorine, chlorine, iodine and bromine.
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I.
  • Compounds of the present invention include all crystalline forms, pharmaceutically acceptable salts, enantiomers, racemic mixtures, and diasteromeric mixtures thereof.
  • Some preferred compounds of the present invention include:
  • ?N may be prepared in accordance with the steps of:
  • P is preferably a polystyrene resin cross-linked with divinylbenzene and functionalized with a linker such as a hydroxymethylphenoxy group, which is more preferably Wang's resin; b) deblocking the fluorenylmethyloxy carbonyl group of said compound of formula (1) with piperidine to produce a compound of formula (2);
  • compounds of Formula I may be prepared in accordance with steps a) through f) to produce compound of formula (7).
  • This aspect of the methods of the invention further comprises the steps of : i) reacting said compound of formula (7) with isocyanates or with p-nitrophenyl chloroformate, followed by amine to produce a compound of formula (12)
  • a solid support P which is preferably a resin of polystyrene cross- linked with divinylbenzene and with a linker such as 4-hydroxymethylphenoxy, most preferably Wang's resin as described below, in the presence of a coupling reagent such as 2-(lH-benzotriazole-l- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU)/ N-hydroxybenzo- triazole (HOBT) to produce a compound of formula (1).
  • the compound of formula (1) is deprotected using 20% piperidine in DMF to yield a compound of formula (2), which provides the first handle for diversification.
  • a compound of formula (2) is reacted with either chloroformates or isocyantes or carboxylic acid chlorides or sulfonyl chlorides in a solvent like dichloromethane or tetrahydrofuran to yield a compound of formula (3).
  • a carboxylic acid is coupled directly with the compound of formula (2) in the presence of a coupling reagent like 1 ,3-diisopropylcarbodiimide (DIC) to produce the compound of formula (3).
  • DIC 1 ,3-diisopropylcarbodiimide
  • a compound of formula (3) is treated with 2% hydrazine to deprotect the (4,4-dimethyl-2,6-dioxocyclohex-l-ylidene)ethyl (dde) protecting group to yield a compound of formula (4), which provides a second handle for diversification.
  • a compound of formula (4) is reacted with a Fmoc protected amino carboxylic acid of formula (5) in the presence of a coupling reagent like DIC to produce the compound of formula (6).
  • the compound of formula (6) is deprotected using 20% piperidine in DMF to yield a compound of formula (7), which provides the third handle for diversification.
  • the compound of formula (7) is reacted with N,N-bis-Boc-S-ethylthiourea or 2-(3,5-dimethylpyrazolyl)-4,5-dihydroimidazole or 2-bromopyrimidine or l-methoxy-2-azacylohept-l-ene to give a compound of formula (12).
  • the compound of formula (7) is reacted with p- nitrophenyl chloroformate and the resulting carbamate was reacted with amines to give ureas of formula (12).
  • the compounds of the present invention are integrin inhibitors useful for their ability to antagonize biological processes mediated by ⁇ v ⁇ 3 and related integrin receptors including, but not limited to, cancer (tumor metastatis, tumorgensis, tumor growth), angiogenesis (as in cancer, diabetic retinopathy, rheumatoid arthritis), restenosis (following balloon angioplasty or stent implantation), inflammation (as in rheumatoid arthritis, psoriasis), bone diseases (osteopenia induced by bone metastases, immobilization and glucocortocoid treatment, periodontal disease, hyperparathyroidism and rheumatoid arthritis), and as antiviral agents.
  • cancer tumor metastatis, tumorgensis, tumor growth
  • angiogenesis as in cancer, diabetic retinopathy, rheumatoid arthritis
  • restenosis followeding balloon angioplasty or stent implantation
  • inflammation as in rhe
  • This assay is to measure the effect of various compounds on the ⁇ - ligand interaction.
  • D-PBS Dulbecco's phosphate buffered saline
  • the cell suspension is homogenized with 2x30 seconds bursts of a Polytron homogenizer.
  • the homogenate is centrifuged at 3000g for 10 minutes at 4 C.
  • the supernatant is collected, measured, and made 100 mM in NaCl and 0.2 mM in MgSO4.
  • the pellet is resuspended in 0.5 mL/flask of membrane buffer (stock membranes) and frozen at -80C. Prior to use, stock membranes are Dounce homogenized and diluted 2 ⁇ L to 1000 ⁇ L in membrane buffer. See References
  • Multiscreen-FB assay plates (Millipore MAFB NOB 50) are blocked with 150 mL of 0.1 % polyethylenimine for 2 hours at 4° C. Following incubation the wells are aspirated and washed with isotonic saline solution. Binding Assay
  • 125 ⁇ L of assay buffer is added to each well.
  • 25 ⁇ L of labeled ligand is added to each well.
  • 25 ⁇ L of unlabeled ligand is added to non-specific binding wells (NSB).
  • 25 ⁇ L of assay buffer is added to all other wells.
  • 2 ⁇ L of compound is added to appropriate sample wells, and 2 ⁇ L of DMSO is added to NSB and total binding (TB) wells.
  • 25 ⁇ L of membrane is added to each well.
  • the plates are covered and incubated at 37° C for 2 hours in a humidified incubator.
  • Wells are aspirated on a Millipore vacuum manifold, and the wells are washed with 150 ⁇ L isotonic saline solution.
  • Wells are again aspirated.
  • the plates are then dried for 1 hour in an 80° C vacuum drying oven. Plates are placed on a Millipore filter punch apparatus, and filters are placed in 12 x 75 mm polypropylene culture tubes. The samples are counted on a Packard gamma counter.
  • the individual well activity is expressed as a percentage of the specific binding; % Max, and reported as the mean + standard deviation.
  • Dose-inhibition relationships are generated for dose (X-axis) vs. % Max (Y-axis) for active compounds using a non-linear regression computer program (PS-NONLIN), and IC50 values with corresponding 95% confidence intervals are estimated from 50% of maximal attachment.
  • PS-NONLIN non-linear regression computer program
  • Arginine-Glycine-Aspartic Acid (RGD)-containing peptides were assessed for the ability to inhibit a v b 3 binding and the corresponding IC50 values with 95% confidence intervals were generated; peptide structures are given by the standard single letter designation for amino acids. Values obtained compared favorably with adhesion assay results.
  • This assay is to measure the effect of various compounds on the RGD-dependent attachment of cells to osteopontin mediated by the ⁇ v ⁇ 3 integrin.
  • Cell Suspension Media The cells are suspended for assay in the tissue culture media used for normal culture maintenance buffered with 25 mM HEPES (pH 7.4) without serum supplementation.
  • Compound Dilution Media The stock compounds are dissolved in an appropriate vehicle (typically DMSO) and subsequently diluted in the tissue culture media used for normal culture maintenance buffered with 25 mM HEPES (pH 7.4) supplemented with 0.2% BSA (no serum); final vehicle concentration is ⁇ 0.5%. Plate Preparation
  • Human recombinant osteopontin (Structural Biology Group, W-AR) is diluted to an appropriate concentration in Dulbecco's phosphate buffered saline (D-PBS) without calcium or magnesium, pH 7.1. 100 mL of this solution is incubated in the wells of PRO-BIND assay plates (Falcon 3915) for 2 hours at 37° C. Following incubation the wells are aspirated and washed once with D-PBS; plates can either be used immediately or stored for up to 1 week at 4° C. Prior to assay, the wells are blocked with 1% bovine serum albumin (BSA) in cell suspension media for 1 hour at 37° C. Following the blocking period, wells are aspirated and washed once with D- PBS.
  • D-PBS Dulbecco's phosphate buffered saline
  • BSA bovine serum albumin
  • Cell Suspension ⁇ v ⁇ 3-expressing cell lines are maintained by standard tissue culture techniques.
  • the cell monolayer is washed three times with D-PBS, and the cells are harvested with 0.05% trypsin/0.53 mM EDTA (GIBCO).
  • the cells are pelleted by low-speed centrifugation and washed three times with 0.5 mg/mL trypsin inhibitor in D-PBS (Sigma).
  • the final cell pellet is resuspended in cell suspension media at a concentration of 10 ⁇ cells/mL.
  • Incubation 100 mL of diluted test compound is added to osteopontin-coated wells (in triplicate) followed by 100 mL of cell suspension; background cell attachment is determined in uncoated wells.
  • the plate is incubated at 25° C in a humidified air atmosphere for 1.5 hours. Following the incubation period, the wells are gently aspirated and washed once with D-PBS.
  • MTT dye conversion assay Promega
  • MTT dye is diluted in cell suspension media (15:85) and 100 mL is added to each well.
  • the assay plates are incubated for 4 hours at 37° C in a humidified 5% CO2/95% air atmosphere, followed by the addition of 100 mL stopping/solubilization solution.
  • the assay plates are covered and incubated at 37° C in a humidified air atmosphere overnight. After the solubilization period, the optical density of the wells is measured at a test wavelength of 570 nM with a reference measurement taken simultaneously at 630 nM. Analysis of Results:
  • the individual well optical density is expressed as a percentage of the maximal attachment (% Max) wells minus background attachment, and reported as the mean + standard deviation.
  • Dose-inhibition relationships are generated for dose (X-axis) vs. % Max (Y-axis) for active compounds using a non-linear regression computer program (PS-NONLIN), and IC50 values with corresponding 95% confidence intervals are estimated from 50% of maximal attachment.
  • Arginine-Glycine-Aspartic Acid (RGD)-containing peptides, and monoclonal antibodies were assessed for the ability to inhibit osteopontin- ⁇ y ⁇ 3 attachment and the corresponding IC50 values with 95% confidence intervals were generated in the SK-MEL-24 human malignant melanoma cell line; peptide structures are given by the standard single letter designation for amino acids:
  • GPenGRGDSPCA 0.58 mM (0.51 TO 0.67) n-Me-GRGDSP 4.0 mM (3.4 TO 4.7) GRGDSP 4.1 mM (3.4 TO 4.9) GRGDTP 5.2 mM (3.4 TO 4.9)
  • the assay is conducted as described in Murrills and Dempster (1990) Bone 11:333- 344. Briefly, 4 x 4 x 0.2mm slices of devitalized bovine cortical bone are numbered, placed in the wells of 96- well culture plates and wetted with lOOul of Medium 199 containing Hanks salts, lOmM HEPES, pH 7.0 (Medium 199/Hanks). Bone cell suspensions containing osteoclasts are prepared by mincing the long bones of neonatal rats (Sprague-Dawley , 4-6 days old) in Medium 199/Hanks. IOOUL of the suspension are then plated onto each slice and incubated 30 minutes to allow osteoclasts to adhere.
  • the slices are rinsed to remove non-adherent cells and incubated 24h in Medium 199 containing Earle's salts, lOmM HEPES and 0.7g/L NaHCO3, which equilibrates at pH 6.9 in a 5% CO2 atmosphere. At this pH the adherent osteoclasts excavate an adequate number of resorption pits for assay purposes.
  • Slices are fixed in 2.5% glutaraldehyde and osteoclasts counted following tartrate-resistant acid phosphatase staining. In experiments in which osteoclast numbers are significantly reduced in a particular treatment, a check is made for nonspecific cytotoxicity by counting the number of contaminant fibroblast-like cells following toluidine staining. All cells are stripped from the slice by sonication on 0.25M NH4OH and the resorption pits formed by the osteoclasts during the experiment stained with toluidine blue. Resorption pits are quantified by manually counting.
  • the experiments are conducted according to a block design with osteoclasts from each animal exposed to each treatment. Three replicate slices are used per treatment per animal, such that a total of 96 slices are examined for an experiment involving four animals and eight treatments (including control). Several parameters are recorded on a "per slice” basis: number of pits, number of osteoclasts, number of pits per osteoclast, number of fibroblast-like bone cells. SAS or JMP statistical software are used for statistical analysis. If analysis of variance reveals significant effects in the experiment, those treatments differing significantly from control are identified using Dunnett's test. IC50S are calculated for active compounds using dose-response curves.
  • Osteoclasts are responsible for the bone loss that occurs in the onset of osteoporosis and anti-resorptive drugs directed against the osteoclast are a requirement for patients losing bone.
  • Calcitonin and bisphosphonates both used as anti-resorptives in the clinic, show significant osteoclast inhibitory activity in this assay. Hence it is a reasonable assay in which to identify novel anti-resorptives.
  • Dpr(Dde)-OH) (Nova Biochem) (4.513g; 9.2 mmol) in DMF (30mL) was treated with N-hydroxybenzotriazole (HOBT) (1.242g; 9.2 mmol), 2-(lH-benzotriazole-l- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU) (3.487g; 9.2 mmol) and N,N-diisopropylethylamine (DIE A) (3.2 mL; 18.4 mmol) and added to the resin. The mixture was shaken at room temperature for 8 h.
  • HOBT N-hydroxybenzotriazole
  • HBTU 2-(lH-benzotriazole-l- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate
  • DIE A N,N-diisopropylethylamine
  • the resin prepared according to example 1 (7.085 g) in DMF was treated with 20% piperidine in DMF (40mL) for 10 min and filtered. Another 40mL portion of 20% piperidine in DMF was added to the resin and shaken at room temperature for 20 min. The resin was filtered and washed with DMF (3X40mL), MeOH (3X40mL) and DCM (3X 40mL). The resin was dried in vacuo.
  • reaction vessels were shaken at room temperature using orbital shaker (Thermolyne RotoMix Type 50800) for 18 h.
  • the mixtures were filtered and the resin in each vessel was washed with dichloromethane (4 x 4 mL), methanol (4 x mL) and dichloromethane (2 x 4 mL).
  • the resins were dried under vacuum.
  • a sample of resin from each vessel was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.
  • Step 1 Methyl 4-[2-N-(t-butoxycarbonyl)ethoxy]-2-hydroxy benzoate (13)
  • Methyl 2, 4-dihydroxy benzoate (14.5g, Aldrich), 2-(N-t-butoxycarbonyl)- ethanol (13.9g, -Aldrich) and triphenyl phosphine (22.6g, Aldrich) were combined in 350 mL of THF and cooled in ice under N 2 atmosphere.
  • Diethyl diazodicarboxylate (DEAD) (15g, Aldrich) was added, the ice bath removed and the reaction mixture allowed to stir at ambient temperature for 15h.
  • Ester (13) (7.2g) from Step 1 was treated with 5eq. KOH (dissolved in minimum amount of water and equal volume of 1, 4-dioxane) at room temperature until TLC indicated complete absence of starting material (3-12h).
  • the crude product (5.34g) was recrystallized from ether, then dissolved in 1, 4-dioxane and treated with an excess of anhydrous HCI (4M in dioxane, -Aldrich).
  • the Amino acid (14) (1.864g; 8 mmol) from Step 2 was dissolved in 1:1 acetone - water (50 mL) containing Sodium Carbonate (1.696g; 16 mmol). To the solution was added Fmoc-Osu (2.696 g; 8 mmol) in acetone (25 mL) dropwise at room temperature. The solution was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was dissolved in water and extracted with ether (2x50 mL). The aqueous layer was cooled in an ice bath and acidified with 6N HCI to pH 3. The solid obtained was filtered and washed with water and dried under vacuo (3.22g).
  • Example 7 was transferred to 14 new reaction vessels and the resin was swollen in DMF. To each vessel was added a solution of 2-(3,5-dimethylpyrazolyl)-4,5- dihydroimidazole hydrobromide (123 mg; 0.5 mmole) in DMF (1.5 mL) followed by diisopropylamine (0.15 mL; 1 mmole). The reaction vessels were shaken at 60 °C for 18h. The mixtures were filtered and the resin in each vessel was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resins were dried under vacuum.
  • the resin in each vessel was suspended in DMF (1.5 mL) and benzyl amine (54 mg; 0.5 mmole) was added followed by triethylamine (101 mg; 1 mmole). The mixtures were filtered and the resin in each vessel was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resins were dried under vacuum.
  • reaction vessels were shaken at room temperature for 16h. The mixtures were filtered and the resin in each vessel was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resins were dried under vacuum. A sample of resin from each vessel was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.
  • the resin prepared according to the example 2 was placed in the reaction vessel (750 mg per vessel; 0.75 mmol). The resin in each vessel was swollen with DMF. A solution of appropriate carboxylic acid (1.5 mmole) in DMF was mixed with diisopropylcarbodiimide (189 mg; 1.5 mmole), hydroxybenzotriazole (202.5 mg; 1.5 mmole) and dimethylaminopyridine (18.33 mg; 0.15 mmole) and the mixture was added each reaction vessel. The reaction vessels were shaken at room temperature for 16h.
  • the compound was prepared by following the procedures detailed in examples 1-4, 6,7 and 11, but for example 6, wherein the 4-[(2-fluorenylmethyloxycarbonyl- amino)-ethoxy]-2-hydroxybenzoic acid was substituted by Fmoc-4-(2-aminoethyl)-l- carboxymethyl-quinazoline-2,4-dione (Neosystem Lab).
  • the purified product was characterized by MS: 617 (M+H); LC: 4.41 min; 98% @ 220 nm.
  • IH MNR (DMSO-d6 + D2O): d: 8.05 (dd, IH), 7.6 (t, IH), 7.2-7.4 (m, 10H), 7.0 (t, 2H) 5.0 (s, 2H), 4.7 (m, 2H), 3.8-4.0 (m, 4H), 3.45 (m, IH), 3.25-3.35 (m, 4H).
  • the compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases.
  • These salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and salts with organic acids such as acetic acid, oxalic acid, succinic acid, and maleic acid.
  • Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium.
  • the compounds of the present invention can also be used in the form of esters at the C-terminus; carbamates, amides and the like at the N-terminus or other conventional ⁇ pro-drug!
  • Compounds of the present invention may be administered in combination with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like.
  • Solid carriers include starch, lactose, dicalcium phosphate, microcrysta-lline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils.
  • Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
  • formulations may contain, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, or elixirs containing, for example, from about 20 to 50% ethanol, and the like.
  • formulation may be, for example, sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium.
  • Such pharmaceutical preparations may contain, for example, from about 25 to about 90% by weight of active ingredient in combination with a carrier, and more preferably between about 5% and 60% by weight of active ingredient.
  • compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
  • the dosage requirements can be determined by one skilled in the art and will vary with the particular composition employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. However, in general, satisfactory results are obtained when compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release form. Preferably, the total daily dosage is from about 1 to about 100 mg, preferably about 2 to about 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of active compound in intimate admixture with solid or liquid pharmaceutically acceptable carrier.

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Abstract

L'invention se rapporte à des composés représentés par la formule (I) qui s'avèrent utiles pour le traitement d'affections diverses telles que, entre autres, le cancer (métathèse tumorale, genèse/croissance tumorale), angiogenèse (comme dans les cancers, la rétinopathie diabétique, la polyarthrite rhumatoïde), la resténose (qui fait suite à une angioplastie percutanée transluminale ou à une implantation de stent), les inflammations (comme dans la polyarthrite rhumatoïde, le psoriasis), les maladies des os (ostéopénie induite par métastases osseuses, immobilisation et traitement aux glucocorticoïdes, parodontopathie, hyperparathyroïdie et polyarthrite rhumatoïde), et en tant qu'agents antiviraux. L'invention se rapporte également à un nouveau procédé de fabrication de ces composés de formule (I).
PCT/US2000/010027 1999-04-14 2000-04-13 Methodes de synthese combinatoire en phase solide d'inhibiteurs d'integrines WO2000061545A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002024697A1 (fr) * 2000-09-25 2002-03-28 Toray Industries, Inc. Composes spiro et inhibiteurs de molecules d'adhesion contenant ces composes comme ingredient actif
US6818659B2 (en) 2001-11-06 2004-11-16 Bristol-Myers Squibb Pharma, Inc. (2S)-2-amino-4-(2-amino-(3,4,5,6-tetrahydropyrimidin-4-yl) butanoyl and its use in cyclic and acyclic peptides
WO2008009655A3 (fr) * 2006-07-17 2008-05-29 Univ Muenster Wilhelms Utilisation médicale de dérivés d'acides n-phénylpropénoyl-aminés et de composés apparentés
US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997008145A1 (fr) * 1995-08-30 1997-03-06 G.D. Searle & Co. Derives de la meta-guanidine, de l'uree, de la thio-uree ou de l'acide aminobenzoique azacyclique utilises comme antagonistes de l'integrine
US5681820A (en) * 1995-05-16 1997-10-28 G. D. Searle & Co. Guanidinoalkyl glycine β-amino acids useful for inhibiting tumor metastasis
WO1999052879A1 (fr) * 1998-04-14 1999-10-21 American Home Products Corporation Derives d'acylresorcinol inhibiteurs selectifs de la vitronectine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5681820A (en) * 1995-05-16 1997-10-28 G. D. Searle & Co. Guanidinoalkyl glycine β-amino acids useful for inhibiting tumor metastasis
WO1997008145A1 (fr) * 1995-08-30 1997-03-06 G.D. Searle & Co. Derives de la meta-guanidine, de l'uree, de la thio-uree ou de l'acide aminobenzoique azacyclique utilises comme antagonistes de l'integrine
WO1999052879A1 (fr) * 1998-04-14 1999-10-21 American Home Products Corporation Derives d'acylresorcinol inhibiteurs selectifs de la vitronectine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002024697A1 (fr) * 2000-09-25 2002-03-28 Toray Industries, Inc. Composes spiro et inhibiteurs de molecules d'adhesion contenant ces composes comme ingredient actif
US6919349B2 (en) 2000-09-25 2005-07-19 Toray Industries, Inc. Spiro compounds and adhesion molecule inhibitors containing the same as the active ingredient
US6818659B2 (en) 2001-11-06 2004-11-16 Bristol-Myers Squibb Pharma, Inc. (2S)-2-amino-4-(2-amino-(3,4,5,6-tetrahydropyrimidin-4-yl) butanoyl and its use in cyclic and acyclic peptides
WO2008009655A3 (fr) * 2006-07-17 2008-05-29 Univ Muenster Wilhelms Utilisation médicale de dérivés d'acides n-phénylpropénoyl-aminés et de composés apparentés
US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof

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