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WO1998010767A9 - Utilisation de derives de la quinazoline pour la fabrication d'un medicament destine au traitement de troubles cutanes hyperproliferatifs - Google Patents

Utilisation de derives de la quinazoline pour la fabrication d'un medicament destine au traitement de troubles cutanes hyperproliferatifs

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Publication number
WO1998010767A9
WO1998010767A9 PCT/US1997/016145 US9716145W WO9810767A9 WO 1998010767 A9 WO1998010767 A9 WO 1998010767A9 US 9716145 W US9716145 W US 9716145W WO 9810767 A9 WO9810767 A9 WO 9810767A9
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Prior art keywords
alkyl
dimethoxyquinazoline
alkoxy
compound
alkylamino
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PCT/US1997/016145
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English (en)
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WO1998010767A2 (fr
WO1998010767A3 (fr
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Priority to AU43429/97A priority Critical patent/AU4342997A/en
Priority to CA002265630A priority patent/CA2265630A1/fr
Priority to EP97941542A priority patent/EP0954315A2/fr
Publication of WO1998010767A2 publication Critical patent/WO1998010767A2/fr
Publication of WO1998010767A9 publication Critical patent/WO1998010767A9/fr
Publication of WO1998010767A3 publication Critical patent/WO1998010767A3/fr

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Definitions

  • the present invention relates to methods, compositions and formulations for treating skin diseases and disorders characterized by keratinocyte hyperproliferation.
  • the present invention relates to formulations of quinazoline compounds and processes for the manufacture of quinazoline derivatives.
  • Psoriasis is a skin disease often confined to localized areas of skin. It is typified by dry, scaly skin, abnormal thickening of epidermis, and rapid cell turnover in the skin. Psoriasis can be exacerbated by external factors including sun exposure, viral infections, and corticosteroid or beta- blocker use. Histologically, it is characterized by abnormalities including keratinocyte hyperplasia, abnormal differentiation sequence of keratinocytes in affected epidermis, and accumulation of leukocytes within the epidermis (Wright and Camplejohn, Eds., Psoriasis: Cell Proliferation. (Churchill Livingstone, Edinburgh, 1983) , pp. 147-295; Weinstein, et al . , J. Invest. Dermatol.. 85:579, 1985) .
  • Other skin disorders characterized by skin cell hyperproliferation include actinic keratoses, seborrheic keratoses and skin cancers such as basal cell carcinoma.
  • Keratinocyte hyperplasia in psoriasis is linked to overproduction of cytokines such as TGF and interleukin-6 (IL-6) and overexpression of epidermal growth factor receptor (EGF-R) in affected skin (Krueger, et al., J. Invest. Dermatol . , 94:1355-1405, 1990).
  • EGF-R is a 180-kD cell-surface receptor whose activity is regulated by both EGF and TGF ⁇ .
  • EGF-R persists throughout the epidermis from the basal layers to the stratum corneum.
  • Such persistent EGF-R has been shown to be biologically active in vivo in nude mice (Nanney, et al., J. Invest. Dermatol .. 98:296-301, 1992).
  • Suggested treatment for psoriasis includes direct inhibition of keratinocyte growth and inhibition of activated lymphocyte proliferation (Dvir et al . , J. Cell Biol. 113:857-865, 1991). Many topical products currently available are irritating, messy or simply ineffective. Topical steroids account for 90% of the psoriasis market in the United States and have many side effects including cutaneous atrophy, telangiectasia, formation of striae and tachyphylaxis .
  • SUBSTITUTE SHEET (RULE 28) 4- (3-Chlorophenylamino) -6-methylquinazoline, 4 - [ 3 - ( t r i f l u o r o e t h y l ) p h e n y l a m i n o ] - 6 , 7 - d i m e t h o x y q u i n a z o l i n e , 4- (3-Cyanophenylamino) -6, 7-dimethoxyquinazoline, 4- [ 3- (trifluoromethyl) phenylamino] -6-methylquinazoline (identified as Al, A2, A3, A4 , A5, and A6 in Table 1) have the properties of inhibiting or reducing the EGF-R tyrosine kinase activity and skin cell hyperproliferation.
  • the administration of an effective amount of an above mentioned compound to a patient suffering from psoriasis or other hyperprolif erative skin diseases will be able to inhibit the abnormal proliferation of skin cells, and decrease cornif ication, scaling or uneven thickness and other undesirable symptoms of psoriasis.
  • the present invention is based on the aforementioned finding and is accordingly concerned with the novel use of the compounds in the treatment or prevention of skin diseases and disorders characterized by hyperproliferation.
  • the present invention relates to methods and compositions for the treatment or prevention of hyperprolif erative skin disorders, including, but not limited to, psoriasis (e.g. psoriasis vulgaris, psoriasis pustulosa, psoriasis erythrodermica, psoriasis arthropathica, parapsoriasis, palmoplantar pustulosis) and skin cancer.
  • psoriasis e.g. psoriasis vulgaris, psoriasis pustulosa, psoriasis erythrodermica, psoriasis arthropathica, parapsoriasis, palmoplantar pustulosis
  • a host e.g.
  • compositions of this invention cure, reduce or prevent keratinocyte hyperproliferation or skin lesions in the host.
  • a preferred drug is highly potent and selective with low toxicity.
  • other diseases or pathological conditions characterized by hyperproliferation and/or EGF-R overexpression and hyperactivity can be treated with the above-described compositions. These diseases and pathological conditions include, but are not limited to, keratinocyte proliferation and skin lesions caused or induced by
  • Papilloma virus infection seborrheic keratoses, acanthosis nigricans, ichthyosis (e.g. ichthyosis vulgaris and congenital ichthyoses), keratodermias, genodermatoses with pathological cornification disorders ( e . g. Darier' s disease), further lichen ruber planus, pityriasis rubra pilaris, and skin cancers such as basal cell carcinoma, squamous cell carcinoma and melanoma.
  • ichthyosis e.g. ichthyosis vulgaris and congenital ichthyoses
  • keratodermias e.g. ichthyosis vulgaris and congenital ichthyoses
  • keratodermias e.g. genodermatoses with pathological cornification disorders (e . g. Darier' s disease
  • composition containing a pharmaceutically effective ingredient may be administered topically or systemically . In a preferred embodiment, it is administered topically to an affected skin area.
  • Al or its pharmaceutically acceptable salts are used in the composition.
  • Such a composition is especially suitable for topical treatment vis-a -vis systemic treatment of skin conditions because of the following properties of Al : (1) low toxicity, (2) short plasma half-life, and (3) relative high solubility in nonirritant solvents among anticancer compounds.
  • Low toxicity is a desirable feature for a drug used to treat a non-life threatening disease.
  • Short plasma half-life helps to keep the drug's therapeutic effects localized to where it is topically applied.
  • SUBSTITUTE SHEH (RULE 28) nonirritant solvents alleviate the suffering of patients who have to use the drug repeatedly to receive the desired therapeutic effects.
  • this invention features a pharmaceutical composition for the treatment of a hyperproliferative skin disorder containing a pharmaceutically effective amount of a compound selected from the group consisting of Al, A2, A3, A4 , A5, A6 and their pharmaceutically acceptable salts; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is for topical application to a host.
  • the compound is selected from the group consisting of Al and its pharmaceutically acceptable salts.
  • the composition may be in a unit dosage form or a multiple use dosage form.
  • the composition is held within a container which includes a label stating to the effect that the composition is approved by the FDA in the United States (or an equivalent regulatory agency in a foreign country) for treating a hyperproliferative skin disorder such as psoriasis (e.g. psoriasis vulgaris, psoriasis pustulosa, psoriasis erythrodermica, psoriasis arthropathica, parapsoriasis, palmoplantar pustulosis) , skin lesions caused by Papilloma virus infection, seborrheic keratoses, acanthosis nigricans, ichthyosis (e.g.
  • psoriasis e.g. psoriasis vulgaris, psoriasis pustulosa, psoriasis erythrodermica, psoriasis arthropathica, parapsoria
  • ichthyosis vulgaris and congenital ichthyoses ichthyosis vulgaris and congenital ichthyoses
  • keratodermias genodermatoses with pathological cornification disorders (e.g. Darier' s disease), further lichen ruber planus, pityriasis rubra pilaris, or a skin cancer such as basal cell carcinoma, squamous cell carcinoma or melanoma.
  • a skin cancer such as basal cell carcinoma, squamous cell carcinoma or melanoma.
  • this invention features a method of making a composition for the treatment of a hyperproliferative skin disorder by providing a pharmaceutically effective amount of a compound selected from the group consisting of Al, A2 , A3, A4 , A5, A6 and their pharmaceutically acceptable salts, and admixing the compound with a pharmaceutically acceptable carrier.
  • the composition is further packaged into a container in a unit dosage or a multiple use dosage.
  • This invention also features a method of preparing a compound for treating a hyperproliferative skin disorder by providing a plurality of compounds of Formula V, testing these compounds' ability to specifically inhibit EGF-R tyrosine kinase activity using the assays deseribed and disclosed in this application (such as those in Examples 1-8), and selecting those with activity in the range of Al, A2 , A3, A , A5, and A6.
  • a pharmaceutically effective amount of such compounds is further packaged in a container with a pharmaceutically acceptable carrier.
  • Figures 1(a), 1(b), 1(c), 1(d), 2(a), 2(b), 2(c) and 2 (d) are general formulae of compounds that can be prepared with a process of this invention.
  • Cl in Figures 1 (b) and 2 (b) may be replaced by another displaceable group which includes, but is not limited to, halogen, alkoxy, aryloxy and sulphonyloxy groups.
  • the displaceable group is chloro, bromo, methoxy, phenoxy, methanesulphonyloxy or toluene-p-sulphonyloxy .
  • Figures 3a, 3b and 3c are flow charts showing the general process for preparing compounds of the formulae in Figures 1 and 2.
  • Ethanol is used as solvent only as an example .
  • Figure 4a shows the structure of a compound of formula I.
  • Figure 4b shows the structure of a compound of formula II.
  • Figure 4c shows the structure of a compound of formula III.
  • Figure 4d shows the structure of a compound of formula IV.
  • Figure 4e shows the structure of a compound of formula V.
  • This invention concerns treating or preventing psoriasis and other conditions characterized by keratinocyte hyperproliferation by inhibiting or reducing EGF-R activity with quinazoline derivatives.
  • Psoriatic epidermis is associated with altered protein tyrosine kinase, phospholipase C (PLC) and protein kinase C (PKC) activities, all of which are changed by chronic EGF-R activation.
  • Growth factors, cytokines and their receptors are involved with the disease process of psoriasis (Krueger, et al . , J. Invest. Dermatol., 94:1355- 1405, 1990) .
  • EGF-R plays a crucial role in the hyperproliferation of keratinocytes in psoriatic lesions .
  • EGF-R is overexpressed in psoriatic keratinocytes (Nanney, et al .
  • EGF receptors in epidermal keratinocytes are markedly altered in psoriasis vulgaris where they are also observed in the upper keratinocyte compartment (Nanney et al . , J. Invest. Dermatol. 83:385-393, 1984; Green et al . , J. Invest. Dermatol. 85:239-245, 1985).
  • EGF receptor expression throughout the epidermis returned to a basal layer distribution when the lesion resolved (Ellis et al . , N. Engl . J. Med. 317:1582-1587, 1987) .
  • TGF ⁇ Psoriatic keratinocytes persistently secrete TGF ⁇ due to the overexpression of the TGF ⁇ gene (Gott Kunststoff, et al., J. Exp. Med., 167:670-675, 1988; Elder, et al . , Science. 243:811-814, 1989; Vassar, et al . , Genes and Develop.. 5:714-727, 1991).
  • TGF ⁇ overexpression causes enhanced autocrine stimulation of the keratinocyte EGF-R (Grossman, et al., Proc. Natl Acad Sci USA, 86:6367-6371, 1989).
  • IGF-1 receptor is also overexpressed in the psoriatic epidermis (Krane, et al . , J. Invest. Dermatol., 96:419- 424, 1991; Krane, et al . , J. Exp. Med., 175:1081-1090, 1992) .
  • Activation by IGF-1 stimulates the synthesis of EGF-R and thus amplifies the effect of the EGF-R/TGF ⁇ autocrine loop.
  • the finding that transgenic mice overexpressing TGF ⁇ in their skin develop lesions (Vassar, et al . , Genes and Develop., 5:714-727, 1991) supports the crucial role of EGF-R in the pathogenesis of the disease.
  • An EGF-R has three functional domains: an extracellular ligand binding domain, a transmembrane domain and a cytoplasmic domain capable of phosphorylating tyrosine residues .
  • Ligand binding to the extracellular ligand binding domain of membrane-bound EGF-R induces the formation of receptor dimers and allosteric changes that activate the intracellular kinase domain to result in the phosphorylation (autophosphorylation and/or transphosphor- ylation) of tyrosine residues.
  • the phospho-tyrosine residues of the cytoplasmic domains of EGF-R then interact with a host of cytoplasmic signaling molecules to activate signal transduction pathways (Ullrich and Schlessinger, Cell 61:203-212, 1990).
  • EGF-R phospholipase C
  • PLC protein kinase C
  • DAG diacylglycerols
  • IP3 inositol-triphosphate
  • EGF-R blockers arrest the growth of psoriatic keratinocytes and are considered for clinical use (Ben-Bassat, et al . , Exper. Dermatol., 4(2):82-84, 1995).
  • Tyrosine kinase blockers of the tyrphostin family have been shown to block the proliferation of psoriatic keratinocytes grown in culture (Dvir, et al . , J. Cell Biol.. 113:857-865, 1991; Ben- Bassat, et al., Exp. Dermatol. , 4:82-88, 1995).
  • Tyrphostins inhibit EGF-R autophosphorylation and
  • Skin cancers have also been associated with the expression of EGF-R ligands and anti-EGF-R antibodies have been shown to inhibit the growth of a skin cancer cell line expressing EGF-R.
  • EGF-R ligands See Hagedorn, M. and T. Baukrecht, 7,. Hautkr 65 ( 6) : 575-577 , 1990; Kawamoto, T., et al . . Rio! . Chem. 259 (12 ): 7761-7766, 1984).
  • quinazoline derivatives of this invention i.e., Al , A2 , A3, A4 , A5 and A6, are able to inhibit EGF-stimulated EGF-R phosphorylation. These compounds also are capable of inhibiting EGF-mediated skin cell growth in vitro and psoriatic skin cell proliferation in vitro .
  • Al potently inhibited ligand- induced autophosphorylation of the EGF receptor, and downstream signal transduction events, including DNA replication and cell cycle progression.
  • the compound is specific for the EGF receptor, since it displayed little or no activity against unrelated receptor tyrosine kinases such as the receptors for platelet-derived growth factor or insulin-like growth factor-1.
  • Al was shown to block EGF receptor-dependent growth of tumor cells and fibroblasts engineered to overexpress EGF receptor. At micromolar concentrations, Al was shown to inhibit the proliferation of keratinocytes isolated from psoriatic lesions. In skin penetration studies, radiolabelled compound penetrated human cadaver skin, reaching biologically effective concentrations in the epidermis within a 24-hour period.
  • Al was prepared essentially as described in Barker, AJ. European Patent Application 0 566 226 Al, October 20, 1993; and Gazit et al . , Bioor ⁇ . Med. Chem. 4:1203-1207, 1996. Briefly, methyl 2-amino-4 , 5-dimethoxybenzoate was treated with formamide at 180°C. The reaction was cooled and diluted with water. The precipitate was collected by filtration, washed with water and dried to give 6, 7-dimethoxyquinazolone, which was treated with thionyl chloride and dimethylformamide at reflux, concentrated, and stirred with sodium bicarbonate solution.
  • the above identified compounds may be used to treat skin diseases or pathological conditions in mammals, especially in humans .
  • the hyperproliferative diseases which cause abnormal scaling and cornification of the skin include all forms of psoriasis, e.g. psoriasis vulgaris, psoriasis pustulosa, psoriasis erythrodermica, psoriasis arthropathica, parapsoriasis, palmoplantar pustulosis, all forms of ichthyoses, e.g. ichthyosis vulgaris and congenital ichthyoses, keratodermias of all types, e.g., palmoplantar keratodermia, other genodermatoses with pathological cornification disorders, e.g. Darier' s disease, further lichen ruber planus and pityriasis rubra pilaris.
  • psoriasis e.g. psoriasis vulgaris, psoriasis pustulosa,
  • diseases and pathological conditions include, but are not limited to, keratinocyte proliferation and skin lesions caused or induced by Papilloma virus infection, seborrheic keratoses, acanthosis nigricans, ichthyosis (e.g. ichthyosis vulgaris and congenital ichthyoses), keratodermias, genodermatoses with pathological cornification disorders (e.g. Darier' s disease) , further lichen ruber planus, pityriasis rubra pilaris, and skin cancers such as basal cell carcinoma, squamous cell carcinoma and melanoma.
  • diseases and pathological conditions include, but are not limited to, keratinocyte proliferation and skin lesions caused or induced by Papilloma virus infection, seborrheic keratoses, acanthosis nigricans, ichthyosis (e.g. ichthyos
  • Toxicity and therapeutic efficacy of the above identified compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals.
  • a measure of the effectiveness and cell toxicity of a compound can be obtained by determining the therapeutic index: LD 50 /IC 50 .
  • I 0 the dose required to achieve 50% EGF-R tyrosine kinase activity inhibition, can be measured using standard techniques such as those described herein.
  • LD 50 the dose lethal to 50% of the population, can be measured by standard techniques, such as using an MTT assay as described by Mossman, J. Immunol. Methods 65:55-63 (1983), by measuring the amount of LDH released as described by Korzeniewski and Callewaert, J. Immunol .
  • LD 50 /ED 50 is the dose therapeutically effective in 50% of the population. Compounds which exhibit large therapeutic indices are preferred. The therapeutic index should be greater than 2, preferably at least 10, more preferably at least 50.
  • the therapeutically effective dose can be estimated initially from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 as determined in cell culture.
  • Plasma half-life and biodistribution of the drug and metabolites in plasma and major organs can be determined to facilitate the selection of drugs most appropriate for the inhibition of a disorder. Such measurements can be carried out, for example, using HPLC analysis.
  • Compounds that show potent inhibitory activity in the screening assays, but have poor pharmacokinetic characteristics can be optimized by altering their chemical structure and retesting. In this regard, compounds displaying good pharmacokinetic characteristics can be used as models for the synthesis of other compounds.
  • Toxicity studies can also be carried out by measuring the blood cell composition.
  • toxicity studies can be carried out as follows: (1) the compound is administered to mice (an untreated control mouse should also be used); (2) blood samples are periodically obtained via the tail vein from one mouse in each treatment group; and 3) the samples are analyzed for red and white blood cells for indication of toxicity.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans .
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • 3T3-EGFR All tumor cell lines were obtained from the American Type Culture Collection (Rockville, MD) , unless otherwise specified.
  • SUBSTITUTE SHEET (RULE 28) 3T3-IGF1R, 3T3-IR, 3T3-PDGF-bR, and 3T3-EGFR/Her-2 , respectively. All cell culture media and supplements were purchased from Gibco Life Technologies (Grand Island, NY) unless otherwise specified. All cells were grown in a humid atmosphere of 90-95% air and 5-10% C0 2 at 37°C. Cell lines were maintained under standard conditions in culture media recommended by the ATCC, unless otherwise specified. 3T3-EGFR, 3T3-PDGF-bR, and 3T3-EGFR/Her-2 cells were maintained in DMEM containing 10% calf serum (CS) and 2 mM GLN.
  • CS calf serum
  • 3T3-IGF1R and 3T3-IR cells were maintained in DMEM containing 10% FBS and 2 mM GLN.
  • Keratinocytes were obtained from small biopsy specimens of split-thickness skin from patients with psoriasis and from healthy control donors. The biopsy specimens were treated to yield a population of cells enriched for keratinocytes, which were maintained in keratinocyte growth medium as described (Ben-Bassat et al . , Exp. Dermatol. 4:82-88, 1995).
  • the vehicle formulation consisted of a petrolatum based topical ointment containing 5.0% mineral oil, 3.0% glyceryl monostearate, 1.5% benzyl alcohol and 2.5% oleic acid. Six replicates of each Al concentration (0.5%, 1.0%, 2.0%, and 4.0% drug) were evaluated during each study. The formulations were spiked with radiolabeled 14 C-A1 to obtain a specific radioactivity of 25 ⁇ Ci/g. Radiolabeled 14 C-A1 was provided by SynPep Corp, Alameda, California (specific activity 5.89 mCi/mmol, lot #020196CL001 ) .
  • the formulation was applied (16.9 mg/cm 2 ) to human cadaver skin (1.77 cm 2 surface area and approximately 200 ⁇ m split thickness) mounted on a Franz static dffusion chamber.
  • the chambers were filled with 4% BSA isotonic saline solution (6-10 mL reservoir volume) and equilibrated to a temperature of 37°C by a circulating pump. Percent penetration through the skin was determined by measuring cumulative radioactivity in the reservoir medium at the end of 24 hours or at regular intervals during the 24 hour period. Tissue distribution of the drug in the stratum corneum, epidermis and dermis was determined at the end of 24 hours. The stratum corneum was separated by tape stripping with cellophane tape until "glistening".
  • EGF-R Whole Cell Kinase Assay NIH3T3 clone C7 engineered to over-express human EGF- R and the human glioblastoma line U1242 that expresses PDGFR-beta were used for cellular kinase assays.
  • EGF-R kinase activity (EGF-R-3T3 assay) in whole cells was measured as described below:
  • Coat ELISA plates (Corning, 96 well, Cat. #25805-96) with 05-101 antibody at 0.5 ⁇ g per well in PBS, 150 ⁇ l final volume/well, and store overnight at 4 ⁇ C. Coated plates are good for up to 10 days when stored at 4 ⁇ C.
  • EGF-R/C7 cell line was used for this assay.
  • CS DMEM medium 10% calf serum (CS) DMEM medium.
  • DMEM medium 10% calf serum (CS) DMEM medium
  • DMEM seeding medium
  • seeding medium 0.5% bovine serum
  • seed cells in DMEM medium (0.5% bovine serum) at a density of 10,000 cells per well, 100 ⁇ l per well, in a 96 well microtiter plate.
  • EGF ligand dilute stock EGF in DMEM so that upon transfer of 10 ⁇ l dilute EGF (1:12 dilution), 25 nM final concentration is attained.
  • EGF ligand After two hours of incubation with a drug, add prepared EGF ligand to cells, 10 ⁇ l per well, to yield a final concentration of 25 nM. Control wells receive DMEM alone. Incubate and shake at room temperature for 5 minutes .
  • IgG antibody anti-rabbit IgG antibody: 1:3000 dilution in
  • Stop reaction by adding 50 ⁇ l 5N H 2 S0 4 (optional) , and determine O.D. at 410 nm.
  • the maximal phosphotyrosine signal is determined by subtracting the value of the negative controls from the positive controls.
  • the percent inhibition of phosphotyrosine content for extract-containing wells is then calculated after subtraction of the negative controls .
  • UBI 05-101
  • TAGO antibody Goat anti-rabbit IgG horse radish peroxidase conjugate, TAGO, Inc., Burlingame, CA.
  • Triton X-100 1.0% 1 ABTS stock:
  • Table 2 shows the activities of the quinazoline derivatives in the cellular EGF-R kinase assay and the ligand dependent cellular proliferation assay. Specifically, it shows the effectiveness of Al, A2, A3, A4, A6 and A5 in inhibiting EGF-R tyrosine kinase activity and curtailing EGF stimulated cell proliferation and the selectivity of the compounds.
  • Table 2 shows IC 50 ( ⁇ M) of the above identified compounds. IC 50 is the dose required to achieve 50% inhibition. In the order of decreasing activity, these compounds are Al, A4 , A2 , A3, A5 and A6.
  • NIH 3T3 cells engineered to express EGF receptors (3T3-EGFR) were pretreated with titrated doses of Al prior to the addition of ligand.
  • ELISA analysis showed that EGF-stimulated receptor phosphorylation was decreased in a dose-dependent manner. The average IC 50 of six determinations was 13 nM.
  • RTK receptor tyrosine kinases
  • PDGF-bR platelet-derived growth factor receptor
  • IGF-1R insulin-like growth factor receptor
  • IR insulin receptor
  • EGF-R/Her-2 denotes a chimeric receptor consisting of the extracellular (ligand-binding) domain of EGFR, and the transmembrane and cytoplasmic domains of Her-2.
  • the efficacy of the above identified compounds in inhibiting or reducing EGF-R stimulated proliferation is measured by the 3T3 cell growth assay.
  • the 3T3 growth assay was carried out as follows:
  • EGF-RC7 NIH 3T3 C7 cells engineered to express EGF- R
  • NIH 3T3C7 cells (as the control) were used for this assay.
  • NIH3T3C7 cells were seeded at 2500 cells/well, 10 ⁇ l/well in 10% CS + 2 mM Glutamine/DMEM, in a 96 well plate
  • EGF-RC7 cells were seeded at 6000 cells/well, 100 ⁇ l/well in 2% FBS + 2 mM Glutamine/DMEM, in a 96 well plate. Cells were incubated at 37 ° C, 5% C0 2 overnight to allow for cell attachment to the plate.
  • a quinazoline compound was added to the cells at day 2.
  • the compound was prepared in the appropriate growth medium (10% CS + 2 mM glutamine in DMEM for NIH3T3C7 cells; 2% FBS+2 mM Glutamine in DMEM for EGF-RC7 cells) in a 96 well plate, and serially diluted. A total of 100 ⁇ l/well medium of the diluted compounds was added into the cells. The total volume of each well was 200 ⁇ l .
  • the cells were washed with PBS and fixed with 200 ⁇ l/well ice-cold 10% TCA for one hour at 0-5°C.
  • EGF-R C7 cells were modified, replacing EGF-R C7 cells with human glioblastoma line U1242 that expresses PDGFR-beta.
  • Example 1 demonstrates that the compounds of the invention are highly potent inhibitors of EGF-R enzymatic activity.
  • Example 2 demonstrates that the compounds of the invention are also highly potent inhibitors of EGF-R mediated cellular proliferation and that they are highly selective as well.
  • the most potent and most selective compound is Al .
  • D-MEM Dulbecco's Modified Eagle Medium
  • D-PBS Dulbecco' 5 Phosphate-Buffered Saline
  • SRB Sulforhodamine B
  • the toxicity of each of the compounds of the invention was evaluated by determining the LD 10 and LD 50 (the dose lethal to 10% or 50% of a population) in mice.
  • mice Female BALB/c mice (5 per group) were injected with a single dose of compound IP in 50 ⁇ l DMSO.
  • SUBSTITUTE SHEET Plasma was prepared from blood samples taken 30 or 60 min. following application (2 mice per time point) and examined by HPLC. In a second experiment, approximated .50 mg of the 2% (w/v) ointment was applied in the same manner. Blood samples were taken at 15 and 30 min and at 1, 2.25 and 30 hours. The mice exhibited no discomfort or increased grooming behavior for the duration of the experiments. Only trace ( ⁇ 2 ⁇ g/ml) amounts of Al were detected at 30 min. or later time points. The lower limit of quantitation for the HPLC assay is l.O ⁇ g/ml.
  • 3T3-EGFR and 3T3-PDGF-bR cells were incubated with drug and ligand (EGF and PDGF, respectively) for 20 hours.
  • the percentage of cells in various phases of the cell cycle was determined by propidium iodide staining and fluorescence activated cell sorting (FACS) analysis.
  • FACS fluorescence activated cell sorting
  • Example 7 Al inhibits cellular proliferation driven by the EGFR/Her family of RTKs
  • Example 8 Al inhibits growth of psoriatic human keratinocytes
  • Keratinocytes were obtained from psoriasis patients after informed consent, and the effect of Al on the growth of the keratinocytes was examined as described by Ben-Bassat et al . , Exp. Dermatol. 4:82-88, 1995. Al inhibited the growth of psoriatic keratinocytes, with an IC 50 of ⁇ 1.0 ⁇ M on days 5 through 12 of culture. These results indicate that blocking EGF-R signaling is sufficient to inhibit the proliferation of psoriatic keratinocytes . V . Formulations and Administration
  • the compounds of the present invention can be administered to a host alone, or in a pharmaceutical composition comprising the active compound and a carrier or excipient.
  • the compounds also can be prepared as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts include acid addition salts such as those containing hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methane sulfonate, ethane sulfonate, benzene sulfonate, p- toluene sulfonate, cyclohexylsulfamate and quinate (e.g.
  • Such salts can be derived using acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid.
  • acids such as hydrochloric acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid.
  • Pharmaceutically acceptable salts also include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, ammonium salts or salts with an organic base which afford a physiologically-acceptable cation such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine .
  • salts can be prepared by standard techniques. For example, the free base form of the compound is first dissolved in a suitable solvent such as an aqueous or aqueous-alcohol solution containing the appropriate acid. The salt is then isolated by evaporating the solution. In another example, the salt is prepared by reacting the free base and acid in an organic solvent.
  • a suitable solvent such as an aqueous or aqueous-alcohol solution containing the appropriate acid.
  • suitable solvent such as an aqueous or aqueous-alcohol solution containing the appropriate acid.
  • the salt is then isolated by evaporating the solution.
  • the salt is prepared by reacting the free base and acid in an organic solvent.
  • the aforementioned quinazoline derivatives can be administered to a subject for reducing or inhibiting keratinocyte proliferation.
  • the compounds are useful as a prophylaxis or means for treating disorders such as psoriasis.
  • the pharmaceutical compositions of the invention contain the compounds in association with a compatible pharmaceutically acceptable carrier material .
  • the carrier material can be an organic or inorganic carrier material suitable for topical, enteral, percutaneous or parenteral administration.
  • Carriers or excipients can be used to facilitate administration of the compound, for example, to increase the solubility of the compound. Suitable carriers and excipients include, but are not limited to, water, ethanol, polysorbate-80, triacetin, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, petroleum jelly, benzyl alcohol, polyethylene glycols (e.g.
  • the pharmaceutical preparations may contain other pharmaceutically active agents. Additional additives such as flavoring agents, preservatives, stabilizers, emulsifying agents, buffers and the like may be added in accordance with accepted practices of pharmaceutical compounding .
  • Table 4 lists the excipients used for solubility testing of Al . The amount of compound for each test was between 1 to 15 mg/mL unless otherwise indicated. Visual solution clarity was recorded immediately and 24 Hrs. after rocking at room temperature in a type I glass container. Table 5 shows the solubility of Al in more excipients .
  • the pharmaceutical preparations can be made up in any conventional form including: (a) a solid form for oral administration such as tablets, capsules, pills, powders, granules, and the like; (b) a liquid form for oral administration such as solutions, syrups, suspensions, elixirs and the like; (c) preparations for parenteral administration such as sterile solutions, suspensions or emulsions; and (d) preparations for topical administrations such as solutions, suspensions, ointments, creams, gels, micronized powders, aerosols, aqueous gels, Petrolatum ointments, PEG ointments and the like.
  • the pharmaceutical preparations may be sterilized and/or may contain adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, salts for varying the osmotic pressure and/or buffers.
  • the aforementioned compounds are preferably prepared as ointments, tinctures, creams, gels, solutions, lotions, sprays, suspensions, shampoos, hair soaps, perfumes and the like.
  • any conventional composition utilized for application to the scalp or skin can be utilized in accordance with this invention.
  • Preferred formulations include gels, lotions and creams.
  • the pharmaceutical preparation for topical administration to the skin can be prepared by mixing the aforementioned active ingredient
  • these preparations contain at least about 0.0005 percent by weight, of the active ingredient based upon the total weight of the composition.
  • the active ingredient, the compound may be used in topical compositions in amounts significantly exceeding 10 percent. It is preferred that these preparations contain about 0.01 to 10 percent by weight of the active ingredient based upon the total weight of the composition.
  • these preparations are applied once or twice daily to the skin. These preparations can be applied according to the need of the patient.
  • the active ingredient can be applied in an aqueous solution or an alcohol solution such as ethyl alcohol.
  • additives such as preservatives, thickeners, perfumes and the like conventional in the art of pharmaceutical compounding can be used.
  • conventional antioxidants or mixtures of conventional antioxidants can be incorporated into the topical preparations containing the aforementioned active agent.
  • conventional antioxidants which can be utilized in these preparations are included N-methyl- ⁇ -tocopherolamine, tocopherols, butylated hydroxyanisole, butylatedhydroxytoluene, ethoxyquin and the like.
  • Cream-base pharmaceutical formulations containing the active agent used in accordance with this invention, are composed of aqueous emulsions containing a fatty acid alcohol, semi-solid petroleum hydrocarbon, 1, 2-ethyleneglycol and an emulsifying agent.
  • Ointment formulations containing the active agent in accordance with this invention comprise admixtures of a semi-solid petroleum hydrocarbon with a solvent dispersion of the active material.
  • Cream compositions containing the active ingredient for use in this invention preferably comprise emulsions formed from a water phase of a humectant, a viscosity stabilizer and water, an oil phase of fatty acid alcohol, a semisolid petroleum hydrocarbon and an emulsifying agent and a phase containing the active agent dispersed in an aqueous stabilizer-buffer solution.
  • Stabilizers may be added to the topical preparation. Any conventional stabilizer can be utilized in accordance with this invention.
  • fatty acid alcohol components function as a stabilizer.
  • fatty acid alcohol components are derived from the reduction of a long-chain saturated fatty acid at least about 14 carbon atoms.
  • conventional perfumes and lotions generally utilized in topical preparation for the hair can be utilized in accordance with this invention.
  • conventional emulsifying agents can be utilized in the topical preparations of this invention.
  • Parenteral dosage forms can be infusions or injectable solutions. Such dosage forms can be injected, e.g., intravenously, subcutaneously or intramuscularly. These preparations can also contain other medicinally active substances. In preferred embodiments, a daily dosage of from about 0.01 mg to about 2 mg per Kg of body weight is utilized in parenteral formulations.
  • a daily dosage of from about 0.025 mg to about 0.5 mg per kg of body weight of the patient is utilized.
  • Additional additives such as flavoring agents, preservatives, stabilizers, emulsifying agents, buffers and the like may be added in accordance with accepted practices of pharmaceutical compounding.
  • a preferred oral dosage form comprises capsules of hard or soft gelatin methylcellulose or of another suitable material easily dissolved in the digestive tract.
  • the enteral dosages contemplated in accordance with the present invention will vary in accordance with the needs of the individual patient as determined by the prescribing physician. In preferred embodiments a daily dosage of from about 0.01 mg. to about 2 mg per Kg of body weight is utilized. In further preferred embodiments a daily dosage of from about 0.025 mg to about 0.5 mg per kg of body weight of the patient is utilized. This dosage may be administered according to any dosage schedule determined by the physician in accordance with the requirements of the patient.
  • each dose contains from about 0.05 mg to about 100 mg, particularly from about 0.1 mg to about 10 mg of the active substance with suitable therapeutically inert fillers and diluents. It is especially preferred to incorporate such a dosage into soft gelatin capsules and tablets.
  • the present invention is concerned with novel formulations of quinazoline, quinazoline derivatives, and pharmaceutically acceptable salts thereof which are suitable for topical application for treatment of psoriasis and other skin diseases.
  • Topical formulations include ointments, tinctures, creams, gels, solutions, lotions, sprays, suspensions, shampoos, hair soaps, perfumes and so on. It is an object of the present invention to provide a vehicle for quinazoline, quinazoline derivatives, and pharmaceutically acceptable salts thereof.
  • vehicle possesses one or more of the following characteristics : 1. Non-irritating or low-irritating, and non-allergenic or low-allergenic to skin. 2. High capacity in storing pharmaceutically effective amount of quinazoline, quinazoline derivatives, and pharmaceutically acceptable salts thereof. 3. Physically and chemically stable at ambient temperature . 4. Efficient drug release and delivery, good skin penetration.
  • this invention generally features a topical formulation containing a pharmaceutically effective amount of quinazoline, a quinazoline derivative, or a pharmaceutically acceptable salt thereof dispersed in a nonpolar hydrocarbon mixture composed of compounds made of carbon and hydrogen, and an excipient which in combination with the nonpolar hydrocarbon mixture enhances the penetration of quinazoline or its derivative through the skin.
  • the nonpolar hydrocarbon mixture is a petrolatum ointment, including, but not limited to, white petrolatum USP ointment.
  • nonpolar hydrocarbon mixtures include, but are not limited to, mineral oil USP, light mineral oil NF, paraffin NF, synthetic paraffin NF, squalane NF, microcrystalline was NF, hexane, isohexane, heptane, decane, decene, decyne, octadecane, benzene, toluene, naphthalene, polyethylene, polypropylene, and polystyrene.
  • the concentration of quinazoline or its derivative in the topical formulation is preferably from about 0.01% to about 10.0% w/w, more preferably from about 0.1% to about 4.0% w/w, and even more preferably from about 0.25% to about 1.0% w/w.
  • Quinazoline or its derivative in the topical formulation may be micronized to facilitate suspension in the ointment, dispersion and/or skin absorption.
  • Various known methods of particle size reduction may be utilized to reduce the size of the quinazoline particles.
  • the majority of the particles have a maximum dimension (i.e., diameter) of no more than about 50 microns, and more preferably 90% or more of the particles have a maximum dimension of no more than about 20 microns.
  • excipient which increases the percentage of quinazoline or its derivative that reaches dermis and epidermis (as measured by % penetrated to reservoir, dermis, epidermis and stratum corneum (R + D + E + SC) ) is selected for the topical formulation of this invention.
  • a method for selecting excipients is described in Example 2 in the Detailed Description of the Preferred Embodiments.
  • the excipient increases % penetrattion (R + D + E + SC) by more than fifty percent.
  • skin penetration enhancer include, but are not limited to, low molecular weight alcohol such as benzyl alcohol, NF, and unsaturated fatty acid such as oleic acid, NF, or unsaturated fatty alcohol.
  • the unsaturated fatty acid or unsaturated fatty alcohol preferably has at least one double bond and no fewer than twelve carbons.
  • Other excipients disclosed or described in Percutaneous Penetration Enhancers, CRC Press (E. W. Smith and H. I. Maibach ed. 1995, ISBN 0-8493-2605-2) as enhancing skin penetration of drugs can be used in the formulations of this invention as well, especially those described in Chapter 9.1 — "Fatty Acids as Skin Permeation Enhancers". The entire content of the book is incorporated by reference herein. Excipients may be used alone or in combination with each other in the topical formulation.
  • Benzyl alcohol may be used in a concentration from about 0.050% to about 5.0% w/w, preferably no more than about 3.0% w/w, and more preferably no more than about 1.0% w/w.
  • Oleic acid may be used in a concentration from about 0.050% to about 10.0% w/w, preferably no more than about 5.0% w/w, and more preferably no more than about 2.5% w/w.
  • An antioxidant may be used in combination with oleic acid to reduce oxidation damage.
  • Candidate antioxidants include, but are not limited to, butylated hydroxytoluene
  • Vitamin C hydroquinone, ascorbyl palmitate, acetyl cysteine, N-methyl- ⁇ -tocopherolamine, , ethoxyquin, nordihydroguaiaretic acid (NDGA) , sodium bisulfite, propyl gallate and ⁇ -tocopherol (Vitamin E) .
  • NDGA ethoxyquin, nordihydroguaiaretic acid
  • NDGA ethoxyquin, nordihydroguaiaretic acid
  • sodium bisulfite propyl gallate
  • ⁇ -tocopherol Vitamin E
  • Inert ingredients which stabilize the petrolatum suspension may be added, including, but not limited to, an emollient stabilizer (e.g. mineral oil) and an nonionic emulsifier (e.g. glyceryl monostearate) .
  • an emollient stabilizer e.g. mineral oil
  • an nonionic emulsifier e.g. glyceryl monostearate
  • topically active medicaments as the anti-inflammatory corticosteroids and antimicrobials may also be incorporated.
  • Al or a pharmaceutically acceptable thereof is used in the composition.
  • Such a composition is especially suitable for topical treatment vis-a -vis systemic treatment of skin conditions because of Al's low toxicity and short plasma half-life. Low toxicity is a desirable feature for a drug used to treat a non-life threatening disease. Short plasma half-life helps to keep the drug' s therapeutic effects localized to where it is topically applied.
  • the formulation may be in a unit dosage form or a multiple use dosage form.
  • a formulation of this invention is held within a container which includes a label stating to the effect that the composition is approved by the FDA in the United States (or an equivalent regulatory agency in a foreign country) for treating a hyperproliferative skin disorder such as psoriasis (e.g.
  • psoriasis vulgaris psoriasis pustulosa
  • psoriasis erythrodermica psoriasis arthropathica
  • parapsoriasis palmoplantar pustulosis
  • skin lesions caused by Papilloma virus infection seborrheic keratoses, acanthosis nigricans, ichthyosis (e.g. ichthyosis vulgaris and congenital ichthyoses), keratodermias, genodermatoses with pathological cornification disorders (e.g.
  • Such a container provides a therapeutically effective amount of the active ingredient to be administered to a host.
  • this invention features a method of administering quinazoline, a quinazoline derivative, or a pharmaceutically acceptable salt thereof topically by applying a topical formulation described above.
  • a topical formulation containing a pharmaceutically effective amount of quinazoline, a quinazoline derivative, or a pharmaceutically acceptable salt thereof dispersed in a nonpolar hydrocarbon mixture, and an excipient which in
  • SUBSTITUTE SHEET (RULE 2 combination with the nonpolar hydrocarbon mixture enhances the penetration of quinazoline or its salt through skin.
  • the nonpolar hydrocarbon mixture is a petrolatum ointment or mineral oil.
  • Ointment formulations containing the active agent comprise admixtures of a semi-solid petroleum hydrocarbon with a dispersion of the active material in an inert liquid ingredient.
  • Cream-base pharmaceutical formulations are composed of oil-in-water emulsions containing a wide variety of excipients, including, but not limited to, fatty alcohol, semi-solid petroleum hydrocarbon, propylene glycol or 1,2- propanediol .
  • Cream compositions containing the active ingredient preferably comprise emulsions formed from a "water” phase containing one or more humectants, a viscosity stabilizer, a preservative and water, an "oil” phase containing one or more fatty alcohols, a semisolid petroleum hydrocarbon, and one or more emulsifying agents. Stabilizers may be added to the topical preparation.
  • the petrolatum formulations initially developed are shown in Table 13. These formulations were put on a three month stability screening protocol as described in Example 9. The petrolatum formulations were also sent for in vi tro skin penetration studies with human cadaver skin; six replicates were run for each formulation. A summary of the test protocol is given in Example 10 and a summary of the skin penetration results is given in Table 13.
  • SUBSTITUTE SHEET (RULE 28) containing dissolved drug substance (Creams and PEG ointments are not shown in Table 13) .
  • the petrolatum ointments containing suspended drug showed total skin penetration (R+D+E+SC) of about 4% and 6%.
  • Formulation FI delivered 47 micrograms to R+D+E+SC, at an efficiency of 7.9%.
  • Formulation F2 also gave good penetration at 34 micrograms (5.6%) delivered to (R+D+E+SC).
  • the lack of a penetration enhancer in this formula probably accounts for its lower delivery compared to FI .
  • Table 14 A second series of five petrolatum formulations for skin penetration evaluation are shown in Table 14. This group consists of the formulation from Series I showing the highest penetration (FI) and four new petrolatum ointments which were variations of FI designed for improved penetration. Four new cream formulations were also prepared which were variations of the best cream from Series I designed for improved penetration (not shown in Table 14) .
  • the mineral oil used in the petrolatum ointment formulations was changed from NF grade (Light Mineral Oil, NF) to USP grade (Mineral Oil, USP) .
  • NF grade Light Mineral Oil
  • USP grade Mineral Oil
  • the USP grade has a higher viscosity.
  • the USP grade was used in all subsequent work.
  • SUBSTITUTE SHEET (RULL 26) tocopherol or approximately 10 pp (0.001%) BHT is added to the petrolatum ointment formulation to help prevent possible oleic acid oxidation.
  • the penetration results of the petrolatum formulations are shown in Table 14.
  • the petrolatum ointments (except F6) gave substantially better penetration than the creams in this series . Due to the large errors present in this type of test, a general rule is that a significant difference exists between two formulations if there is at least a 2-fold difference between results. In this case, the average penetration difference between the four best ointments and the four creams is a factor of about 3-fold.
  • Formulation F5 containing 2.5% oleic acid and 1.5% benzyl alcohol, also gave very good penetration at 36 micrograms (6.1%) delivered to (R+D+E+SC). This result can be considered equal to FI . Because oleic acid is a potential irritant, this formulation is not as irritant as FI.
  • Formulations F3 and F4 were modifications of FI containing additional excipients (benzyl alcohol and laureth 4) which have relatively high drug solubility. These formulations did not perform as well as FI; the reason may be that addition of a good solvent to a suspended drug formulation favors the drug remaining in the formulation rather than moving toward and through the skin.
  • Formulation F6 containing 5% propylene glycol (PG, a penetration enhancer), gave poor penetration results. This may be because PG is not miscible with petrolatum and
  • SUBSTITUTE SHEET OUiLE 2@ forms a two-phase system.
  • the PG which shows very low drug solubility, may have interfered with the penetration enhancing properties of the oleic acid.
  • the third series of eight petrolatum formulations for skin penetration evaluation is shown in Table 15. This series was designed to study the effects of varying the drug concentration, and also for optimization of the concentrations of the excipients benzyl alcohol and oleic acid. The penetration results are shown in Table 15.
  • PROPYLENE GLYCOL USP 5.00
  • the penetration result of the cream formulation is 3.6% (R+D+E+SC) .
  • the petrolatum ointment control sample in this test, F10 was identical to F5 in Series II except that the Series II formula also contained 0.2% tocopherol, which should not have substantially affected penetration.
  • the results for F10 in this test are very close to those of F5 : only a 2 microgram difference in total reservoir + dermis + epidermis + stratum corneum (R+D+E+SC) penetration.
  • the drug substance is present as a solid suspension in the formulated ointment, it was micronized for the formulations to be used in toxicology studies and clinical studies. Micronization produces smaller particles and increases the total drug substance surface area and dispersion of the suspension in the ointment; these characteristics may result in more efficient skin penetration of the drug substance. Drug micronization contributes to better characterization and definition of drug substance particle size for future bioequivalence needs. The drug micronizing process also improves the cosmetic elegance of the formulation as an emollient by eliminating palpable detection of solids in the ointment. The micronized drug substance was tested by HPLC which indicated that the micronization did not reduce the drug's purity.
  • FI, Fll and F13 were screened for stability with HPLC. FI and F13 are stable at ambient temperature for at least three months. Fll is stable at ambient temperature for at least two months.
  • a 5 to 15 gram sample is placed in a 20 ml glass scintillation vial and capped with a urea screw cap having a PE cone liner.
  • the 50°C sample is typically terminated at 1 month. Samples at any test station may be terminated based on gross instability or other pertinent reason.
  • Evaluation is by physical examination for general appearance, color, odor, consistency/viscosity, separation/syneresis, etc.
  • Test Formulations Test formulations provided by Dow Dermatologies, Inc., containing non-radioactive drug substance at the formulated concentration, are spiked with 1 C or 3 H-radiolabeled drug substance and mixed thoroughly with a spatula; this is done immediately prior to application to the skin chamber.
  • the target for specific activity is about 0.050 ⁇ Ci/mg test formulation. Spiked formulations are tested for uniform specific activity by liquid scintillation counting.
  • Test formulations are applied to the skin surface with a Gilson positive displacement pipet. The amount applied is 17 mg/cm 2 ; therefore, about 30 mg of test formulation is applied to each cell.
  • Time Points A sample of 1.0 mL is taken with a Gilson pipet from the reservoir under the skin sample at the following time points: 0, 1, and 24 hours. The sample is placed in a vial containing Ecoscint scintillation fluor. At the 0 and 1 hour time points the 1.0 mL volume is replaced with the BSA saline solution. The 0 and 1 hour time points are used to assess the integrity of the skin sample. If any holes or other defects exist, the 1 hour reservoir sample will show unusually high radioactivity. In such cases that cell is removed from the study. It is common that several cells are omitted from the data calculations for each study. The endpoint can be varied from 3-24 hours. Additional time points can be added to the test protocol, at additional cost.
  • the skin is tape- stripped with cellophane tape until "glistening" (approximately 22 strips) .
  • the first two strips that remove the excess drug adhering to the outer surface of the stratum corneum (SC) are counted separately. These counts are included in total recovery but excluded from SC compartment recovery.
  • Four groups each consisting of five consecutive tape strips are placed in a scintillation vial containing Scintilene.
  • Dermis and epidermis are separated by microwave technique and placed in vials containing ReadyProt cocktail for tissue digestion. All samples are counted in a Beckman LSC counter and corrected for quenching.
  • Recovery in the reservoir, washes, gauze wipes, and the respective skin compartments (SC, epidermis, and dermis) is calculated by determining the percent of the total counts applied.
  • Total radioactive recovery is typically 70-100%.
  • Example 11 Process for Making 1% and 4% Al Ointment
  • Step 1 With continuous mixing, add Step 1 to Step 4. Mix for approximately 20 minutes to ensure Homogeneity.
  • This invention features new and improved processes for the preparation of quinazolone, chloroquinazoline, 4- arylamino quinazoline, and their derivatives. Much better yields of the intermediate molecules and the final product are achieved with the processes of this invention than with conventional methods.
  • the reaction to prepare quinazolone is conducted at a lower and more convenient temperature. In the isolation and purification of choloroquinazoline, column chromatography is not required.
  • the final free base form of the 4-arylamino quinazoline is obtained in high purity from the reaction mixture by simply adding an alkaline solution.
  • this invention features a process of preparing a substituted monocyclic, bicyclic, heterocyclic or polycyclic fused ring compound containing a pyrimidone ring by reacting a precursor which has a ⁇ - amino acrylic acid functionality with formamidine or a formamidine salt to fuse the pyrimidone ring.
  • the reaction is conducted with a formamidine salt in refluxing alcohol (e.g., ethanol) .
  • the reaction is conducted at a temperature of no less than 20°C (preferably no less than 60°C, and more preferably no less than 80°C) and no more than 150°C (preferably no more than 120°C, and more preferably no more than 100°C) .
  • the fused ring compound is quinazolone or a quinazolone derivative and the precursor is an aminobenzoate or amino benzoic acid. Specific compounds which can be prepared by this process are described in the detailed description of the invention.
  • this invention features a process of preparing a 4-halogen-pyrimidine (e.g. chloroquinazoline) by reacting a pyrimidone (e.g. quinazolone or a quinazolone derivative) with a halogenating agent (e.g. chlorinating agent) and isolating or purifying the end product, 4-halogen-pyrimidine (e.g. chloroquinazoline) , by precipitation, crystallization or sublimation.
  • a pyrimidone e.g. quinazolone or a quinazolone derivative
  • a halogenating agent e.g. chlorinating agent
  • the pyrimidone reacts with the halogenating agent in the presence of a catalyst such as dimethylformamide which promotes the formation of the 4-halogen-pyrimidine.
  • the halogenating agent includes, but is not limited to, thionyl chloride, phosphorus oxychloride and oxalyl chloride. This process may be modified by replacing the halogenating agent with another displacement agent to prepare a quinazoline whose displaceable group is alkoxy, aryloxy or sulphonyloxy .
  • the displaceable group may be methoxy, phenoxy, methanesulphonyloxy or toluene-p-sulphonyloxy.
  • this invention features a process for preparing a 4-arylaminopyrimidine hydrochloride salt by dissolving a substitued aniline in an alcohol solution (e.g., ethanol) , adding a chloropyrimidine to the alcohol solution to react with the substituted aniline, and isolating the end product, 4- arylaminopyrimidine hydrochloride salt.
  • an alcohol solution e.g., ethanol
  • the 4-arylaminopyrimidine hydrochloride salt is a 4-arylamino quinazoline hydrochloride salt and the chloropyrimidine is chloroquinazoline or a chloroquinazoline derivative.
  • this invention features a process for preparing a free base 4-arylaminopyrimidine directly by dissolving a substitued aniline in an alcohol solution (e.g., ethanol), adding a chloropyrimidine to the alcohol solution to react with the substituted aniline, adding an alkaline solution to the alcohol solution, and isolating the end product, 4-arylaminopyrimidine.
  • an alcohol solution e.g., ethanol
  • the 4-arylaminopyrimidine is a 4-arylamino quinazoline
  • the chloropyrimidine is chloroquinazoline or a chloroquinazoline derivative.
  • this invention features a process for converting an isolated 4-arylaminopyrimidine hydrochloride salt to its free base form by mixing it with an alkaline solution and isolating the end product, 4- arylaminopyrimidine (e.g. 4-arylamino quinazoline).
  • 4- arylaminopyrimidine e.g. 4-arylamino quinazoline
  • an "alkyl” group refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain, and cyclic alkyl groups.
  • the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, more preferably 1 to 4 carbons, such as, e.g.. methyl, ethyl, ⁇ -propyl, iso-propyl, ⁇ -butyl, sec-butyl, iso-butyl, tert-butyl, and
  • alkyl group may be substituted or unsubstituted.
  • An "alkoxy” group refers to an "-0-alkyl” group, where "alkyl” is defined as described above, such as methoxy, ethoxy, ⁇ -propoxy, iso-propoxy, ⁇ -butoxy, sec-butoxy, iso-butoxy, tert-butoxy, trifluoromethoxy,
  • alkenyl group refers to an unsaturated hydrocarbon group containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups.
  • the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 2 to 7 carbons, more preferably 2 to 4 carbons.
  • alkynyl refers to an unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups.
  • the alkynyl group has 2 to 12 carbons. More preferably, it is lower alkynyl of from 2 to 7 carbons, more preferably 2 to 4 carbons.
  • a “heterocycle” denotes a chain of carbon and at least one non-carbon atoms which together form one or more aromatic or non-aromatic rings having preferrably between about 5-14 atoms, such as, e.g.. furyl , thienyl, imidazolyl, indolyl, pyridinyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl, dibenzthienyl . These rings may be optionally substituted with one or more functional groups which are attached commonly to such rings, such as, e.g.
  • aryl group refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted.
  • the aryl is a substituted or unsubstituted phenyl or pyridyl.
  • Preferred aryl substituent (s) are halogen, trihalomethyl, hydroxyl, SH, OH, N0 2 , amine, thioether, cyano, alkoxy, alkyl, and amino groups.
  • alkylaryl refers to an alkyl as described above covalently joined to an aryl group as described above.
  • the alkyl is a lower alkyl.
  • Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms . The carbon atoms are optionally substituted.
  • Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms . Suitable heteroatoms include oxygen, sulfur, and nitrogen.
  • the heterocyclic aryl groups of this invention include, but are not limited to, furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted.
  • aryloxy denotes -OAr, where Ar is an aryl group as defined above.
  • aralkyl denotes -RAr, where R is alkyl and Ar is aryl, both as defined above.
  • amide refers to an -C(0)-NH-R, where R is either alkyl, aryl, alkylaryl or hydrogen.
  • amine refers to a -N(R")R"', where R" and R"' , is independently either hydrogen, alkyl, aryl, or alkylaryl, provided that R" and R"' are not both hydrogen.
  • amino denotes the group NRR', where R and R 1 may independently be alkyl, aryl or acyl as defined above, or hydrogen .
  • a “cyanoamido” refers to the group -NH-C ⁇ N.
  • Rl is either hydrogen, hydroxy, halogen, trifluoromethyl, C1-C6 alkoxy, C1-C6 alkyl, nitro, cyano, or amino.
  • R2 and R3 are independently either hydrogen, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, cyclo (C1-C3 alkenedioxy) , nitro, halogen, C1-C6 alkoxycarbonyl, cyano, or amido.
  • M and N are independently either single or double bonds. If M and N are single bonds then the bonds between atoms B and C can be a double bond.
  • Each of A, B, C and D is independently carbon or a heteroatom such as N, 0, or S to give bicycles including, but not limited to, quinazoline derivatives.
  • a heteroatom such as N, 0, or S to give bicycles including, but not limited to, quinazoline derivatives.
  • N C 0 oxazo [ 4 , 5-d] pyrimidine The process may also be employed for preparing substituted mono-, bi- and tricyclic fused ring compounds containing a pyrimidone ring by starting with any compound with a ⁇ -amino acrylic acid functionality.
  • the following tricyclic compounds can be prepared by this method: naptho [1, 2-d] pyrimidine, naptho [2 , 3-d] pyrimidine, quinolino [2 , 3-d] pyrimidine, and quinolino [ 3 , 4 - d] pyrimidine .
  • Quinazoline derivatives of formula V in Figure 4e and their pharmaceutically-acceptable salts and their precursors of formulae II and III may be prepared by the processes of this invention.
  • m is 1, 2 or 3 and n is 1 or 2.
  • Each R 1 is independently selected from the group consisting of hydroxy, amino, carboxy, carbamoyl, ureido, (1-6C) alkoxycarbonyl, N- (1-6C) alkylcarbamoyl, N,N- di- [ (1-6C) alkyl] carbamoyl, hydroxyamino, (1-6C) alkoxyami-
  • each R 2 of formula IV or V is independently selected from the group consisting of hydrogen, hydroxy, halogen, trifluoromethyl, amino, nitro, cyano, (1-6C) alkyl, (1-6C) alkoxy, cyclo[(l-
  • Z of formula IV is a displaceable group which includes, but is not limited to, halogen, alkoxy, aryloxy and sulphonyloxy groups.
  • Z is selected from the group consisting of chloro, bromo, methoxy, phenoxy, methanesulphonyloxy and toluene-p- sulphonyloxy groups .
  • each R 1 is independently selected from the group consisting of hydroxy, amino, ureido, methoxycarbonyl, ethoxycarbonyl, hydroxyamino, trif luoromethoxy, methyl, ethyl methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylenedioxy, ethylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, piperidino, morpholino, mehtylthio, ethylthio, bromomethyl, dibr omome t hy 1 , me t hoxyme t hy 1 , piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, me thoxye t hoxyme t hyl , me t hy 1 t h i ome t hy 1 , 2- hydroxye
  • (R 1 ), is selected from the group consisting of 6-hydroxy, 7-hydroxy, 6,7- dihydroxy, 6-amino, 7-amino, 6-ureido, 6-trif luoromethoxy,
  • SUBSTITUTE SHEET (RULE 28) 6-methyl, 6, 7-dimethyl, 6-methoxy, 7-methoxy, 6,7- dimethoxy, 6, 7-diethoxy, 6-hydroxy-7-methoxy, 7-hydroxy-6- methoxy, 6-amino-7-methoxy, 6-amino-7-methylthio, 5-amino- 6, 7-dimethoxy, 6-methoxy-7-isopropoxy, 6, 7-methylenedioxy, 6, 7-ethylenedioxy, 6-methylamino, 7-methylamino, 6- dimethyiamino, 6-amino-7-methylamino, 6-methoxymethyl, 6- bromomethyl, 6- (2-methoxyethoxymethyl) , 6-cyanomethyl, 6- methylthiomethyl, 6-phenylthiomethyl, 7- (2-hydroxyethoxy) - 6-methoxy, 6, 7-di- (2-hydroxyethoxy) , 6- (2-bromoethoxy) , 6- (2-methoxye
  • (R 2 ) n is selected from the group consisting of hydrogen, 4'-fluoro, 3'- chloro, 3'-bromo, 3 ' , 4 ' -dichloro, 4 ' -fluoro-3 ' -chloro, 3'- trifluoromethyl, 4 ' -fluoro-3 ' -trifluoromethyl, 3 '-nitro, 3 ' -nitro-4 ' -chloro, 3 ' -nitro-4 ' -flouro and 3 ' -methyl groups .
  • a quinazoline derivative as depicted in Figures 1 and 2 can be prepared by the processes shown in Figures 3a, 3b and 3c .
  • An aspect of this invention is the improved yield and low reaction temperature in the first step accomplished by the use of formamidine or a formamidine salt instead of formamide .
  • formamidine or a formamidine salt instead of formamide .
  • the commercially available 6, 7-dimethoxyanthranilic acid methyl ester is condensed with formamidine acetate by refluxing in ethanol to give 6, 7-dimethoxyquinazolone in greater than 90% yield.
  • 6, 7-dimethoxyanthranilic acid is also condensed with formamidine to give >80% yield.
  • This reaction is not restricted to unsubstituted formamidines but may employ substituted formamidines to give 3- substituted quinazolones .
  • This step converts a substituted ortho-aminobenzoic ester or a substituted isatoic anhydride or hydrochloride to give a quinazolone.
  • the reaction is preferably carried out by heating in the presence of an inert solvent such as methanol, ethanol, isopropanol, a chlorinated solvent such as dichloromethane or chloroform, an ether such as tetrahydrofuran or dioxane, an amide such as dimethylformamide or dimethylacetamide, water or any other inert solvent.
  • the reaction is heated to between 20°C and the boiling point of the solvent, preferably heating to between 20°C and 120°C.
  • the quinazolone is obtained by cooling the reaction to ambient temperature or below and filtering the solid product, and, optionally, recrystallizing .
  • condensing with formamide at a temperature of about 170° C gives a yield of 75%, which is not as high as with a formamidine in ethanol and at a less convenient temperature.
  • Step 2 The compound prepared in Step 1 is reacted with an excess of thionyl chloride with a catalyst such as dimethylformamide in the absence of solvent or in the presence of a trapping agent such as toluene, benzene, or xylene to remove free chlorine.
  • a trapping agent such as toluene, benzene, or xylene
  • another chlorinating agent can be used such as phosphorus oxychloride or oxalyl chloride.
  • the crude product is isolated by evaporating the solvent and/or adding a co- solvent to precipitate it.
  • the crude product is washed with dilute aqueous base, such as sodium carbonate or bicarbonate and isolated by evaporation or precipitation with an inert co-solvent such as toluene, benzene or hexane .
  • dilute aqueous base such as sodium carbonate or bicarbonate
  • an inert co-solvent such as toluene, benzene or hexane .
  • the washed product is satisfactory for conversion to the quinazoline in Step 3 or can be further purified by crystallization or sublimation.
  • 6, 7-dimethoxy-4-quinazolone can be reacted with thionyl chloride and dimethylformamide to form 4-chloro-6, 7-dimethoxyquinazoline, which is purified by precitation and washing or sublimation.
  • Such process requires no solvent and produces 4-chloro-6, 7-dimethoxyquinazoline of high purity. Compared to conventional methods, this process has a much better yield (about 89% versus about 27%) and eliminates the chromatography step.
  • the chloroquinazoline of Step 2 is reacted with a substituted aniline present in slight excess in the absence of solvent or in an inert solvent, or with an equivalent of aniline and a suitable base such as pyridine, triethylamine, ethyl morpholine, or any other unreactive base or an inorganic base such as sodium or potasium carbonate or bicarbonate.
  • a suitable base such as pyridine, triethylamine, ethyl morpholine, or any other unreactive base or an inorganic base such as sodium or potasium carbonate or bicarbonate.
  • the inert solvent can be methanol, ethanol, isopropanol, a chlorinated solvent such as dichloromethane or chloroform, an ether such as tetrahydrofruan, 1, 2-dimethoxyethane or dioxane, an amide such as dimethylformamide or dimethylacetamide, or dimethylsulfoxide .
  • the reaction is carried out between 20°C and the boiling point of the solvent, preferably between 20°C and 150°C.
  • the solid product quinazoline hydrochloride salt is isolated by cooling and/or concentrating and filtering.
  • 4-chloro-6, 7-dimethoxyquinazoline is reacted with 3 - chl or oani 1 ine to form 4- (3-chlorophenylamino) -6, 7-dimethoxyquinazoline .
  • denatured alcohol was used as solvent instead of 2-propanol used in conventional methods.
  • Applicant found that 4-chloro-6, 7-dimethoxyquinazoline does not react with the alcoholic solvent as long as the aniline is already present in the mixture.
  • the quinazoline hydrochloride salt prepared in Step 3 is converted into its free base by treatment of the salt alone, or suspended in an inert organic solvent as described above, with a suitable organic or inorganic base as described above.
  • the product is isolated by filtration with or without concentrating.
  • formamide (73.71g) and 82.80 g of methyl 2-amino-4 , 5-dimethoxybenzoate were stirred and heated at 170°C in a 250 ml flask maintained in a nitrogen atmosphere for 5.7 hours. Heating was discontinued and the reaction was allowed to cool. The mixture was diluted with 150 ml of water and the solids collected by vacuum filtration and washed three times with 50 ml of water. The product was dried at 60°C under a vacuum of 0.1 mm Hg to give 59.0 g (about 73%) of 6, 7-dimethoxy-4-quinazolone .
  • SUBSTITUTE SHEET (RULE 28) transferred to an evaporating flask using 100 ml of methylene chloride, and evaporated to dryness at 50°C. The resulting solid was stirred with 400 ml of saturated sodium bicarbonate, collected by vacuum filtration, and washed repeatedly with water (400 ml total) . The product was dried at 50 - 60°C under a vacuum of 0.1 mm Hg to give 63.7 g (-100 % yield) of crude 4-chloro-6, 7-dimethoxyquinazoline .
  • 4-chloro-6,7 -dimethoxyquinazoline can be prepared with the method described in Step 2 of Example 13 below.
  • Step 1 2.500 kg of 2-amino-4 , 5-dimethoxybenzoate and 1.48 kg of formamidine acetate in 9.300 kg of ethanol were refluxed for 10 hours (at which time thin layer chromatography showed completion of the reaction) .
  • the mixture was cooled to room temperature and the crude product isolated by vacuum filtration.
  • the crude product was resuspended in 5.75 kg of ethanol and stirred at 40° C for 30 minutes.
  • the mixture was cooled to room temperature, the product isolated by vacuum filtration and dried under vacuum at 55° C until the loss on drying was ⁇ 1%.
  • the yield was 2.351 kg (96.8%) of 6,7- dimethoxyquinazolone at a purity of 99.48% by HPLC relative area %.
  • This compound was prepared from the 4-chloro-6, 7-dimethoxyquinazoline of Example 12 and 3- (trifluoromethyl) aniline by the method of Example 12.
  • This compound was prepared from the 4-chloro-6, 7-dimethoxyquinazoline of Example 12 and 3-cyanoaniline by the method of Example 12.
  • 2-Amino-5-methyl benzoic and formamide were condensed as in Example 12 to give 6-methyl-4-quinazolone in about 70% yield.
  • 6-Methyl-4-quinazolone was chlorinated mith thionyl chloride as in Example 12 to give 4-chloro-6-methylquinazoline in about 84% yield and p u r i f i e d b y s u b l i m a t i o n .
  • 4- (3-Chlorophenylamino) -6-methylquinazoline was prepared from 4-chloro-6-methylquinazoline and 3-chloroaniline as in Example 12 in about 60% yield.
  • Creams Suspended Aqueous phase propylene glycol, water, surfactants, Oil phase: mineral oil, stearyl alcohol .

Abstract

Cette invention se rapporte à des procédés et à des compositions permettant de traiter des troubles cutanés hyperprolifératifs, qui font usage d'un dérivé de la quinazoline en tant qu'ingrédient actif.
PCT/US1997/016145 1996-09-13 1997-09-11 Utilisation de derives de la quinazoline pour la fabrication d'un medicament destine au traitement de troubles cutanes hyperproliferatifs WO1998010767A2 (fr)

Priority Applications (3)

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AU43429/97A AU4342997A (en) 1996-09-13 1997-09-11 Use of quinazoline derivatives for the manufacture of a medicament in the reatment of hyperproliferative skin disorders
CA002265630A CA2265630A1 (fr) 1996-09-13 1997-09-11 Utilisation de derives de la quinazoline pour la fabrication d'un medicament destine au traitement de troubles cutanes hyperproliferatifs
EP97941542A EP0954315A2 (fr) 1996-09-13 1997-09-11 Utilisation de derives de la quinazoline pour la fabrication d'un medicament destine au traitement de troubles cutanes hyperproliferatifs

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US2606796P 1996-09-13 1996-09-13
US60/026,067 1996-09-13
US3143696P 1996-11-20 1996-11-20
US60/031,436 1996-11-20
US3498197P 1997-01-08 1997-01-08
US60/034,981 1997-01-08
US4837297P 1997-06-03 1997-06-03
US60/048,372 1997-06-03

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Families Citing this family (137)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ330868A (en) 1996-02-13 2000-01-28 Zeneca Ltd 4-phenoxy, phenylthio or phenylamino substituted quinazoline derivatives ane medicaments useful as VEGF inhibitors
DE69709319T2 (de) 1996-03-05 2002-08-14 Astrazeneca Ab, Soedertaelje 4-anilinochinazolin derivate
GB9718972D0 (en) 1996-09-25 1997-11-12 Zeneca Ltd Chemical compounds
US6258820B1 (en) * 1999-03-19 2001-07-10 Parker Hughes Institute Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines
US6126917A (en) * 1999-06-01 2000-10-03 Hadasit Medical Research Services And Development Ltd. Epidermal growth factor receptor binding compounds for positron emission tomography
ATE330954T1 (de) 1999-11-05 2006-07-15 Astrazeneca Ab Quinazolin-derivate als vegf-hemmer
CN1240688C (zh) 2000-04-07 2006-02-08 阿斯特拉曾尼卡有限公司 喹唑啉化合物
CA2414406A1 (fr) * 2000-06-26 2002-01-03 The Regents Of The University Of Michigan Utilisation d'inhibiteurs de proteine tyrosine kinase du recepteur de facteur de croissance epidermique (egf-r) pour la prevention du photovieillissement de la peau humaine
AU2002217999A1 (en) 2000-11-01 2002-05-15 Cor Therapeutics, Inc. Process for the production of 4-quinazolinylpiperazin-1-carboxylic acid phenylamides
LT3351246T (lt) 2001-02-19 2019-07-10 Novartis Pharma Ag Rapamicino darinys, skirtas kieto naviko, susijusio su nereguliuojama angiogeneze, gydymui
WO2002092091A1 (fr) 2001-05-16 2002-11-21 Novartis Ag Combinaison comprenant n-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2pyrimidine-amine et agent chimiotherapeutique
GB0206215D0 (en) 2002-03-15 2002-05-01 Novartis Ag Organic compounds
KR20120125398A (ko) 2002-05-16 2012-11-14 노파르티스 아게 암에서 ｅｄｇ 수용체 결합제의 용도
JP4944613B2 (ja) 2003-05-19 2012-06-06 アイアールエム・リミテッド・ライアビリティ・カンパニー 免疫抑制化合物および組成物
MY150088A (en) 2003-05-19 2013-11-29 Irm Llc Immunosuppressant compounds and compositions
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
US7419975B2 (en) 2004-04-07 2008-09-02 Novartis Ag Organic compounds
GB0512324D0 (en) 2005-06-16 2005-07-27 Novartis Ag Organic compounds
JP2008526776A (ja) * 2005-01-03 2008-07-24 ミリアド ジェネティクス， インコーポレイテッド 脳癌の治療の方法
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
GB0519879D0 (en) 2005-09-30 2005-11-09 Astrazeneca Ab Chemical process
CN103446138A (zh) 2005-11-21 2013-12-18 诺瓦提斯公司 利用mTOR抑制剂治疗神经内分泌肿瘤
AU2007218725B2 (en) 2006-02-21 2011-12-01 Eisai R & D Management Co., Ltd. 4-(3-benzoylaminophenyl)-6,7-dimethoxy-2- methylaminoquinazoline derivative
GB0605120D0 (en) 2006-03-14 2006-04-26 Novartis Ag Organic Compounds
CN102671196B (zh) 2006-04-05 2014-12-03 诺华股份有限公司 用于治疗癌症的治疗剂的组合
WO2007115289A2 (fr) 2006-04-05 2007-10-11 Novartis Ag Combinaisons d'agents thérapeutiques destinées à traiter le cancer
NZ572299A (en) 2006-05-09 2010-07-30 Novartis Ag Combination comprising a substituted 3,5-diphenyl-1,2,4-triazole and a platinum compound and use thereof
BRPI0717564A2 (pt) 2006-09-29 2013-10-22 Novartis Ag Pirazolopirimidinas como inibidores de pi3k lipídeo cinase
AU2008216327A1 (en) 2007-02-15 2008-08-21 Novartis Ag Combination of LBH589 with other therapeutic agents for treating cancer
CA2678477A1 (fr) 2007-02-16 2008-08-21 Eisai R&D Management Co., Ltd. Cristal, forme amorphe et sel d'acide terephtalique de methyle n-[3-(6,7-dimethoxy- 2-methylaminoquinazoline-4-yl)phenyle]
EP2189450B1 (fr) 2007-08-17 2011-12-21 Eisai R&D Management Co., Ltd. Procédé de fabrication d'un dérivé de quinazoline
KR20100042246A (ko) * 2007-08-17 2010-04-23 에자이 알앤드디 매니지먼트 가부시키가이샤 신규 외용제
PL2268612T3 (pl) 2008-03-24 2015-02-27 Novartis Ag Arylosulfonamidowe inhibitory metaloproteinaz macierzy
GEP20125708B (en) 2008-03-26 2012-12-10 Novartis Ag Hydroxamate-based inhibitors of deacetylases b
ES2704986T3 (es) 2008-10-16 2019-03-21 Celator Pharmaceuticals Inc Combinaciones de una camptotecina liposomal soluble en agua con cetuximab o bevacizumab
US20120115840A1 (en) 2008-12-18 2012-05-10 Lech Ciszewski Hemifumarate salt of 1-[4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl]-azetidine-3-carboxylic acid
BRPI0922466A2 (pt) 2008-12-18 2018-10-23 Novartis Ag sais
AU2009327405A1 (en) 2008-12-18 2011-06-30 Novartis Ag New polymorphic form of 1- (4- { l- [ (E) -4-cyclohexyl--3-trifluoromethyl-benzyloxyimino] -ethyl) -2-ethyl-benzy l) -azetidine-3-carboxylic
WO2010083617A1 (fr) 2009-01-21 2010-07-29 Oncalis Ag Pyrazolopyrimidines en tant qu'inhibiteurs de protéines kinases
TW201031406A (en) 2009-01-29 2010-09-01 Novartis Ag Substituted benzimidazoles for the treatment of astrocytomas
JO2892B1 (en) 2009-06-26 2015-09-15 نوفارتيس ايه جي CYP inhibitors 17
US8389526B2 (en) 2009-08-07 2013-03-05 Novartis Ag 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives
JP5781510B2 (ja) 2009-08-12 2015-09-24 ノバルティス アーゲー ヘテロ環式ヒドラゾン化合物および癌および炎症の処置のためのそれらの使用
AU2010284254B2 (en) 2009-08-17 2015-09-17 Intellikine, Llc Heterocyclic compounds and uses thereof
IN2012DN01453A (fr) 2009-08-20 2015-06-05 Novartis Ag
CA2771936A1 (fr) 2009-08-26 2011-03-03 Novartis Ag Composes heteroaryliques tetrasubstitues et leur utilisation comme modulateurs de mdm2 et/ou mdm4
CN102596963A (zh) 2009-09-10 2012-07-18 诺瓦提斯公司 二环杂芳基的醚衍生物
EA201200651A1 (ru) 2009-11-04 2012-12-28 Новартис Аг Гетероциклические сульфонамидные производные, применимые в качестве ингибиторов мек
BR112012012210B8 (pt) 2009-11-23 2021-05-25 Cerulean Pharma Inc conjugado de (cdp)-taxano de polímero contendo ciclodextrina, composição, composição farmacêutica, forma de dosagem, kit e uso de um conjugado de cdp-taxano
CN102712648A (zh) 2009-11-25 2012-10-03 诺瓦提斯公司 双环杂芳基的与苯稠合的6元含氧杂环衍生物
WO2012168884A1 (fr) 2011-06-09 2012-12-13 Novartis Ag Dérivés de sulfonamide hétérocyclique
PH12012501142A1 (en) 2009-12-08 2012-10-22 Novartis Ag Heterocyclic sulfonamide derivatives
US8440693B2 (en) 2009-12-22 2013-05-14 Novartis Ag Substituted isoquinolinones and quinazolinones
CU24130B1 (es) 2009-12-22 2015-09-29 Novartis Ag Isoquinolinonas y quinazolinonas sustituidas
US20110178287A1 (en) 2010-01-19 2011-07-21 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutic delivery
WO2011119995A2 (fr) 2010-03-26 2011-09-29 Cerulean Pharma Inc. Formulations et procédés d'utilisation
CN102947275A (zh) 2010-06-17 2013-02-27 诺瓦提斯公司 哌啶基取代的1,3-二氢-苯并咪唑-2-亚基胺衍生物
EP2582680A1 (fr) 2010-06-17 2013-04-24 Novartis AG Dérivés de 1,3 dihydro-benzoimidazol-2-ylidène-amine à substitution biphényle
UA112517C2 (uk) 2010-07-06 2016-09-26 Новартіс Аг Тетрагідропіридопіримідинові похідні
EP2627648A1 (fr) 2010-09-16 2013-08-21 Novartis AG INHIBITEURS DE LA 17a-HYDROXYLASE/C17,20-LYASE
KR20130130030A (ko) 2010-12-21 2013-11-29 노파르티스 아게 Vps34 억제제로서의 비-헤테로아릴 화합물
WO2012107500A1 (fr) 2011-02-10 2012-08-16 Novartis Ag Composés de [1, 2, 4] triazolo [4, 3 -b] pyridazine en tant qu'inhibiteurs de la tyrosine kinase c-met
JP5808826B2 (ja) 2011-02-23 2015-11-10 インテリカイン， エルエルシー 複素環化合物およびその使用
JP2014507465A (ja) 2011-03-08 2014-03-27 ノバルティス アーゲー フルオロフェニル二環式ヘテロアリール化合物
CA2834224A1 (fr) 2011-04-28 2012-11-01 Novartis Ag Inhibiteurs de 17.alpha.-hydroxylase/c17,20-lyase
EP2721007B1 (fr) 2011-06-20 2015-04-29 Novartis AG Composés de cyclohexyl-isoquinolinone
WO2012175520A1 (fr) 2011-06-20 2012-12-27 Novartis Ag Dérivés d'isoquinolinone substitués par un hydroxy
JP2014518256A (ja) 2011-06-27 2014-07-28 ノバルティス アーゲー テトラヒドロ−ピリド−ピリミジン誘導体の固体形態および塩類
AU2012389562A1 (en) 2011-08-17 2014-07-24 Dennis Brown Compositions and methods to improve the therapeutic benefit of subotimally administered chemical compounds including substituted hexitols such as dibromodulcitol
ES2691650T3 (es) 2011-09-15 2018-11-28 Novartis Ag 3-(quinolin-6-il-tio)-[1,2,4]-triazolo-[4,3-a]-piridinas 6-sustituidas como inhibidores de tirosina quinasa c-Met
US8969341B2 (en) 2011-11-29 2015-03-03 Novartis Ag Pyrazolopyrrolidine compounds
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
EP2794594A1 (fr) 2011-12-22 2014-10-29 Novartis AG Dérivés quinoline
CN104011045B (zh) 2011-12-22 2016-08-24 诺华股份有限公司 二氢苯并噁嗪和二氢吡啶并噁嗪衍生物
US20130178520A1 (en) 2011-12-23 2013-07-11 Duke University Methods of treatment using arylcyclopropylamine compounds
CN104136428A (zh) 2011-12-23 2014-11-05 诺华股份有限公司 用于抑制bcl2与结合配偶体相互作用的化合物
JP2015503517A (ja) 2011-12-23 2015-02-02 ノバルティス アーゲー Ｂｃｌ２と結合相手の相互作用を阻害するための化合物
EP2794591A1 (fr) 2011-12-23 2014-10-29 Novartis AG Composés inhibiteurs de l'interaction entre bcl2 et des partenaires de liaison
WO2013096049A1 (fr) 2011-12-23 2013-06-27 Novartis Ag Composés permettant d'inhiber l'interaction de bcl-2 avec des partenaires de liaison
BR112014015339A8 (pt) 2011-12-23 2017-06-13 Novartis Ag compostos para inibição da interação de bcl2 com parceiros de ligação
UY34591A (es) 2012-01-26 2013-09-02 Novartis Ag Compuestos de imidazopirrolidinona
RU2660354C2 (ru) 2012-04-03 2018-07-05 Новартис Аг Комбинированные продукты, содержащие ингибиторы тирозинкиназ, и их применение
JP6171003B2 (ja) 2012-05-24 2017-07-26 ノバルティス アーゲー ピロロピロリジノン化合物
AU2013274101B2 (en) 2012-06-15 2017-09-07 The Brigham And Women's Hospital, Inc. Compositions for treating cancer and methods for making the same
WO2014025395A1 (fr) 2012-08-06 2014-02-13 Duke University Composés et procédés pour le ciblage de hsp90
US9950047B2 (en) 2012-11-05 2018-04-24 Dana-Farber Cancer Institute, Inc. XBP1, CD138, and CS1 peptides, pharmaceutical compositions that include the peptides, and methods of using such peptides and compositions
TW201422625A (zh) 2012-11-26 2014-06-16 Novartis Ag 二氫－吡啶并－□衍生物之固體形式
WO2014115077A1 (fr) 2013-01-22 2014-07-31 Novartis Ag Composés de purinone substitués
US9556180B2 (en) 2013-01-22 2017-01-31 Novartis Ag Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the P53/MDM2 interaction
BR112015019603A2 (pt) 2013-02-20 2017-08-22 Novartis Ag Moléculas de ácido nucleico isoladas, molécula de polipeptídeo isolada, molécula isolada de car, domínio de ligação anti-egfrviii, vetor, célula e uso de uma quantidade eficaz da mesma e métodos para produção de uma célula e para a produção de uma população de células modificadas por rna
WO2014128612A1 (fr) 2013-02-20 2014-08-28 Novartis Ag Dérivés de quinazolin-4-one
CA2906542A1 (fr) 2013-03-15 2014-09-25 Intellikine, Llc Combinaison d'inhibiteurs de kinase et ses utilisations
WO2014155268A2 (fr) 2013-03-25 2014-10-02 Novartis Ag Inhibiteurs de kinase tyrosine fgf-r et leur utilisation dans le traitement de maladies associées à un manque ou à une absence d'activité snf5
US20150018376A1 (en) 2013-05-17 2015-01-15 Novartis Ag Pyrimidin-4-yl)oxy)-1h-indole-1-carboxamide derivatives and use thereof
UY35675A (es) 2013-07-24 2015-02-27 Novartis Ag Derivados sustituidos de quinazolin-4-ona
WO2015022663A1 (fr) 2013-08-14 2015-02-19 Novartis Ag Composés et compositions utiles comme inhibiteurs de mek
WO2015022664A1 (fr) 2013-08-14 2015-02-19 Novartis Ag Composés et compositions utiles comme inhibiteurs de mek
US9227969B2 (en) 2013-08-14 2016-01-05 Novartis Ag Compounds and compositions as inhibitors of MEK
CA2920059A1 (fr) 2013-09-22 2015-03-26 Calitor Sciences, Llc Composes d'aminopyrimidine substituee et procedes d'utilisation
WO2015084804A1 (fr) 2013-12-03 2015-06-11 Novartis Ag Combinaison d'un inhibiteur de mdm2 et d'un inhibiteur de braf, et leur utilisation
WO2015148714A1 (fr) 2014-03-25 2015-10-01 Duke University Ligands de récepteurs de la protéine de choc thermique 70 (hsp-70)
WO2015145388A2 (fr) 2014-03-27 2015-10-01 Novartis Ag Procédés de traitement de cancers colorectaux avec mutations en amont de la voie wnt
US9403801B2 (en) 2014-03-28 2016-08-02 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
BR112016022499A2 (pt) 2014-04-03 2017-08-15 Invictus Oncology Pvt Ltd Produtos terapêuticos combinatórios supramoleculares
WO2016011658A1 (fr) 2014-07-25 2016-01-28 Novartis Ag Polythérapie
EP3174869B1 (fr) 2014-07-31 2020-08-19 Novartis AG Polythérapie avec un inhibiteur de met et un inhibiteur d'egfr
US9938257B2 (en) 2015-09-11 2018-04-10 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
US11261187B2 (en) 2016-04-22 2022-03-01 Duke University Compounds and methods for targeting HSP90
WO2018039203A1 (fr) 2016-08-23 2018-03-01 Oncopep, Inc. Vaccins peptidiques et durvalumab pour le traitement du myélome multiple
CA3034666A1 (fr) 2016-08-23 2018-03-01 Oncopep, Inc. Vaccins peptidiques et durvalumab pour le traitement du cancer du sein
AU2017335634A1 (en) 2016-09-27 2019-03-14 Cero Therapeutics, Inc. Chimeric engulfment receptor molecules
US10207998B2 (en) 2016-09-29 2019-02-19 Duke University Substituted benzimidazole and substituted benzothiazole inhibitors of transforming growth factor-β kinase and methods of use thereof
US10927083B2 (en) 2016-09-29 2021-02-23 Duke University Substituted benzimidazoles as inhibitors of transforming growth factor-β kinase
AU2018341244A1 (en) 2017-09-26 2020-03-05 Cero Therapeutics, Inc. Chimeric engulfment receptor molecules and methods of use
WO2019083960A1 (fr) 2017-10-24 2019-05-02 Oncopep, Inc. Vaccins peptidiques et inhibiteurs d'hdac pour le traitement du myélome multiple
CA3079422A1 (fr) 2017-10-24 2019-05-02 Oncopep, Inc. Vaccins peptidiques et pembrolizumab pour le traitement du cancer du sein
WO2019099311A1 (fr) 2017-11-19 2019-05-23 Sunshine Lake Pharma Co., Ltd. Composés hétéroaryle substitués et leurs méthodes d'utilisation
EP3730483B1 (fr) 2017-12-21 2023-08-30 Hefei Institutes of Physical Science, Chinese Academy of Sciences Classe d'inhibiteurs de kinase dérivés de pyrimidine
EP3740468A4 (fr) 2018-01-20 2021-10-06 Sunshine Lake Pharma Co., Ltd. Composés d'aminopyrimidine substitués et procédés d'utilisation
CN112218886A (zh) 2018-03-28 2021-01-12 森罗治疗公司 嵌合吞噬受体的表达载体、基因修饰的宿主细胞及其用途
US12291557B2 (en) 2018-03-28 2025-05-06 Cero Therapeutics Holdings, Inc. Chimeric TIM4 receptors and uses thereof
AU2019243154A1 (en) 2018-03-28 2020-10-01 Cero Therapeutics, Inc. Cellular immunotherapy compositions and uses thereof
WO2020023628A1 (fr) 2018-07-24 2020-01-30 Hygia Pharmaceuticals, Llc Composés, dérivés et analogues contre le cancer
EP4038097A1 (fr) 2019-10-03 2022-08-10 Cero Therapeutics, Inc. Récepteurs tim4 chimériques et leurs utilisations
US20220395553A1 (en) 2019-11-14 2022-12-15 Cohbar, Inc. Cxcr4 antagonist peptides
WO2021185844A1 (fr) 2020-03-16 2021-09-23 Pvac Medical Technologies Ltd Utilisation d'une substance et composition pharmaceutique correspondante et traitements médicaux ou utilisations correspondants
WO2021233534A1 (fr) 2020-05-20 2021-11-25 Pvac Medical Technologies Ltd Utilisation d'une substance et composition pharmaceutique associée, et traitements médicaux ou utilisations associées
EP4192509A1 (fr) 2020-08-05 2023-06-14 Ellipses Pharma Ltd Traitement du cancer à l'aide d'un conjugué polymère contenant de la cyclodextrine-inhibiteur de la topoisomérase et d'un inhibiteur de parp
WO2022036287A1 (fr) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Récepteurs chimériques anti-cd72 et utilisations de ceux-ci
WO2022036285A1 (fr) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Compositions et méthodes de traitement du cancer à l'aide de récepteurs tim chimériques en association avec des inhibiteurs de la poly(adp-ribose)polymérase
WO2022036265A1 (fr) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Récepteurs chimériques tim et leurs utilisations
WO2022047259A1 (fr) 2020-08-28 2022-03-03 California Institute Of Technology Circuits de signalisation de mammifère synthétiques pour la régulation de population cellulaire robuste
TW202237638A (zh) 2020-12-09 2022-10-01 日商武田藥品工業股份有限公司 烏苷酸環化酶ｃ（ｇｃｃ）抗原結合劑之組成物及其使用方法
CA3212006A1 (fr) 2021-02-26 2022-09-01 Kelonia Therapeutics, Inc. Vecteurs lentiviraux ciblant les lymphocytes
JP2024529474A (ja) 2021-07-28 2024-08-06 セロ・セラピューティクス・インコーポレイテッド キメラＴｉｍ４受容体およびその使用
WO2023240105A1 (fr) * 2022-06-07 2023-12-14 Biomimetix Jv, Llc Compositions hydrophobes contenant un principe actif hydrophile et méthodes associées
KR20250065819A (ko) 2022-08-02 2025-05-13 국립대학법인 홋가이도 다이가쿠 소기관 복합체를 이용한 세포 치료 개선 방법

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9300059D0 (en) * 1992-01-20 1993-03-03 Zeneca Ltd Quinazoline derivatives
GB9510757D0 (en) * 1994-09-19 1995-07-19 Wellcome Found Therapeuticaly active compounds
AU5117896A (en) * 1995-03-08 1996-09-23 Hospital for Sick Children Research and Development Limited Partnership, The Zap 70 inhibitors and methods for treatment of zap 70 signal transduction disorders

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