WO1998010767A2 - 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 Download PDF

Info

Publication number
WO1998010767A2
WO1998010767A2 PCT/US1997/016145 US9716145W WO9810767A2 WO 1998010767 A2 WO1998010767 A2 WO 1998010767A2 US 9716145 W US9716145 W US 9716145W WO 9810767 A2 WO9810767 A2 WO 9810767A2
Authority
WO
WIPO (PCT)
Prior art keywords
dimethoxyquinazoline
alkyl
alkoxy
compound
alkylamino
Prior art date
Application number
PCT/US1997/016145
Other languages
English (en)
Other versions
WO1998010767A9 (fr
WO1998010767A3 (fr
Inventor
Gerald Mcmahon
Laura Kay Shawver
Blair Narog
Peng Cho Tang
Klaus Peter Hirth
Original Assignee
Sugen, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sugen, Inc. filed Critical Sugen, Inc.
Priority to EP97941542A priority Critical patent/EP0954315A2/fr
Priority to CA002265630A priority patent/CA2265630A1/fr
Priority to AU43429/97A priority patent/AU4342997A/en
Publication of WO1998010767A2 publication Critical patent/WO1998010767A2/fr
Publication of WO1998010767A9 publication Critical patent/WO1998010767A9/fr
Publication of WO1998010767A3 publication Critical patent/WO1998010767A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

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.
  • 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 . SUMMARY OF THE INVENTION Epidermal hyperproliferation and angiogenesis are hallmarks of psoriasis.
  • quinazoline derivatives such as 4- (3-Bromophenylamino) -6, 7-dimethoxyquinazoline, 4- (3-Chlorophenylamino) -6 , 7-dimethoxyquinazoline, 4- (3-Chlorophenylamino) -6-methylquinazoline, 4- [3- (trifluoromethyl ) phenylamino] -6, 7-dimethoxyquinazoline, 4- (3-Cyanophenylamino) -6 , 7-dimethoxyquinazoline, 4- [3- (trifluoromethyl) phenylamino] -6-methylquinazoline
  • the present invention relates to methods and compositions for the treatment or prevention of hyperproliferative 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.
  • 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 planu ⁇ , pityriasis rubra pilari ⁇ , 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
  • pharmaceutically effective is meant the ability to cure, reduce or prevent one or more clinical symptoms of keratinocyte hyperproliferation, including, but not limited to, cornification, scaling, uneven thickness, inflammation, and rapid cell turnover in the skin.
  • 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.
  • Formulations with 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. 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 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, A4 , A5, and A6.
  • a pharmaceutically effective amount of such compounds is further packaged in a container with a pharmaceutically acceptable carrier.
  • Figures 1(a), Kb), 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.
  • PX.SEASES 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, nsrmatnl .. 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 . , J. Invest. Dermatol .. 86:260-265, 1986).
  • the normal basilar distribution of EGF receptors in epidermal keratinocytes is 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).
  • TGF ⁇ Psoriatic keratinocytes persistently secrete TGF ⁇ due to the overexpression of the TGF ⁇ gene (Gott Kunststoff, et al . , . Ex . 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 Develo p .. 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 transphosphorylation) 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 . , Ex . Dgrmatol .. 4:82- 88, 1995).
  • Tyrphostins inhibit EGF-R autophosphorylation and EGF-dependent tyrosine phosphorylation of intracellular target proteins in keratinocytes.
  • 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 , Z. Hautkr 65 (6) : 575-577, 1990; Kawamoto, T. , et al . J. Biol . CJI ⁇ L-. 259 (12) : 7761-7766, 1984).
  • A6 are able to inhibit EGF-stimulated EGF-R phosphorylation. These compounds also are capable of inhibiting EGF-mediated skin cell growth in vi tro and psoriatic skin cell proliferation in vi tro.
  • 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.
  • 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.
  • diseases or pathological conditions characterized by hyperproliferation and/or EGF-R overexpression and hyperactivity can be treated with the above-described compositions.
  • 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 .
  • 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 .
  • IC 50 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, . Immunol . Methods 65:55-63 (1983), by measuring the amount of LDH released as described by Korzeniewski and Callewaert, J . Immunol .
  • 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.
  • 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.
  • NIH3T3 mouse fibroblasts overexpressing the EGF receptor, IGF-1 receptor, insulin receptor, PDGF-b receptor, or a chimera of the EGF receptor extracellular domain fused to the Her-2 cytoplasmic domain were engineered using retroviral vectors. These cells will be referred to as 3T3-EGFR, 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.
  • 3T3-EGFR, 3T3-PDGF-bR, and 3T3 -EGFR/Her-2 cells were maintained in DMEM containing 10% calf serum (CS) and 2 mM GLN.
  • 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).
  • keratinocyte growth medium as described (Ben-Bassat et al . , Exp. Dermatol. 4:82-88. 1995).
  • Al The effect of Al on receptor phosphorylation, DNA replication, cell cycle progression, and cell growth was studied.
  • Cell lines examined in receptor phosphorylation ELISA were 3T3-EGFR, 3T3-EGFR/Her-2, 3T3-PDGF-bR, 3T3-IGF1R, and 3T3-IR.
  • 3T3-EGFR and 3T3-PDGF-bR cell lines were used for analysis of DNA replication (measured as incorporation of BrdU) and cell cycle progression.
  • Cell growth studies were carried out on A431 (EGF-R+) , BT474 (Her-2+) , and C6 (PDGF-bR+) cell lines.
  • the effect of Al on the growth of human psoriatic keratinocytes was determined as previously described (Ben-Bassat et al . , Ex . 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 ⁇ 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" .
  • 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.
  • the activity of the above identified compounds in inhibiting EGF-stimulated EGF-R phosphorylation was measured in an ELISA assay.
  • 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 D C.
  • EGF-R/C7 cell line was used for this assay.
  • 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.
  • anti-Ptyr anti-phosphotyrosine
  • 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.
  • TAGO antibody Goat anti-rabbit IgG horse radish peroxidase conjugate, TAGO, Inc., Burlingame, CA.
  • 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
  • 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.
  • 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
  • Example 3 Toxicitv Studies 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. Survival was measured at seven days. The results are presented in Table 3 below and demonstrated that the compounds of the invention are relatively non-toxic. Multiple dose toxicity studies were also conducted. Al in DMSO was administered IP to Balb/c nude mice at doses ranging from 5 to 30 mg/kg/day for 17, 20 or 30 days. The results are shown below: Exp Dose Duration % Mortality
  • Plasma levels of Al were measured in nu/nu mice. Approximately 60 mg of a 2% (w/w/ointment was applied to the backs of four female mice using a stainless steel spatula. The dose was spread evenly over the back surface of each mouse .
  • 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 1. O ⁇ g/ml .
  • Example 7 Al inhibits cellular proli eration driven by the EGFR/Her family of RTKs
  • Example 8 Al inhibits growth of psoriatic human ratinocvtes
  • 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., Ex . 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.
  • 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 sul onate, 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.
  • Pharmaceutically acceptable 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 .
  • 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. PEG-300 and PEG- 400), propylene carbonate, propylene glycol, Transcutol, Petrolatum, vegetable oils, mineral oil, stearyl alcohol, Laureth-4, calcium carbonate, calcium phosphate, various sugars or types of starch, cellulose derivatives and mixtures thereof.
  • 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 (i.e., a pharmaceutically effective amount of a compound) with non- toxic, therapeutically inert, solid or liquid carriers customarily used in such preparations .
  • 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. It is also preferred that 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.
  • the 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 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.
  • a daily dosage of from about 0.01 mg to about 2 mg per Kg of body weight is utilized in parenteral formulations. 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. 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. It is likewise within the purview of the present invention to incorporate the therapeutically active substances enumerated herein in any desired amount for enteral administration within the oral unit dosage form.
  • 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. Such vehicle possesses one or more of the following characteristics:
  • 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
  • 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.
  • antioxidants include, but are not limited to, butylated hydroxytoluene (BHT) , NF, butylated hydroxyanisole (BHA) , ascorbic acid (Vitamin C) , hydroquinone , ascorbyl palmitate, acetyl cysteine, N-methyl- ⁇ -tocopherolamine, , ethoxyquin, nordihydroguaiaretic acid (NDGA) , sodium bisulfite, propyl gallate and ⁇ -tocopherol (Vitamin E) . They may be used in a- concentration from about 0.001% to about 1.0% w/w. In the case of BHT, preferably it is used in a concentration from about 0.0005% to about 0.1% w/w, and more preferably no more than 0.01% w/w.
  • 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 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.
  • Formulation Series I 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.
  • the drug concentration was equal in all the formulations tested.
  • Petrolatum ointments and emollient creams containing dispersed drug substance show substantially better drug delivery in terms of micrograms delivered and percent of dose delivered than PEG ointments 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 . Formulation Series II
  • 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) .
  • the USP grade has a higher viscosity.
  • the USP grade was used in all subsequent work.
  • alpha tocopherol (Vitamin E, USP) was added to several formulations (see Table 14) . However, it was found that this high level of tocopherol caused a darkening of the color of the formulated product after two weeks at 40°C. In the alternative, a lower level of tocopherol or approximately 10 ppm (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 forms a two-phase system. In this case, the PG, which shows very low drug solubility, may have interfered with the penetration enhancing properties of the oleic acid.
  • the creams did not perform as well in this study (maximum 2% penetration) as they did in Series I, while the petroleum ointments continued to show excellent penetration (up to 6%) . Therefore, petrolatum was chosen as the preferred vehicle, and another penetration experiment was performed to optimize the formulations.
  • Formulation Series III 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.
  • the penetration result of the cream formulation is the penetration result of the cream formulation.
  • 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 .
  • 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:
  • Evaluation is by physical examination for general appearance, color, odor, consistency/viscosity, separation/syneresis, etc.
  • SET-UP Franz static diffusion chambers are filled with a 4% BSA isotonic buffered saline solution (6-10 mL reservoir volume) and equilibrated to a temperature of 37°C by a circulating water pump.
  • TEST FORMULATIONS Test formulations provided by Dow Dermatologies, Inc., containing non-radioactive drug substance at the formulated concentration, are spiked with 14 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 FORMULATION APPLICATION 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.
  • WASHES AND GAUZE SWTPF.fi At the end of the experiment, the skin is removed from the cell. To recover excess formulation from the skin surface, the skin is first washed with three 1.0 mL volumes of 2% Oleth-20 in water; this is retained for counting. The skin is then gently wiped with three separate cotton gauzes which are saved and Counted.
  • SKIN COMPARTMENT DETERMINATIONS 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.
  • 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.
  • the reaction to prepare quinazolone is conducted at a lower and more convenient temperature .
  • 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.
  • 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 4-halogen-pyrimidine e.g. chloroquinazoline
  • 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 and 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, n-propyl, iso-propyl, ⁇ -butyl, sec-butyl, iso-butyl, tert-butyl, and 2-methylpentyl.
  • alkoxy group refers to an "-0-alkyl” group, where "alkyl” is defined as described above, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy, trifluoromethoxy, 3-hydroxyhexyloxy, 2-carboxypropyloxy, 2-fluoroethoxy, carboxymethoxy and cyanobutyloxy and the like.
  • alkenyl group refers to an unsaturated hydrocarbon group containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkenyl group has 1 to 12 carbons.
  • alkenyl group is a lower alkenyl of from 2 to 7 carbons, more preferably 2 to 4 carbons.
  • the alkenyl group may be substituted or unsubstituted.
  • An "alkynyl” group 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.
  • alkynyl of from 2 to 7 carbons, more preferably 2 to 4 carbons.
  • the alkynyl group may be substituted or unsubstituted.
  • 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...
  • 2-aminothiazol-4-yl 2-amino-5-chlorothiazol-4-yl , 2-amino- thiadiazol-4-yl, 2 , 3-dioxopiperazinyl, 4-alkylpiperazinyl , 2-iodo-3 -dibenzfuranyl and 3 -hydroxy-4 -dibenzthienyl and the like.
  • 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.
  • An "alkylaryl” group 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.
  • An "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' 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.
  • 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 - [ ( l - 6C) alkyl] carbamoyl, hydroxyamino , (1-6C) alkoxyamino, (2- 6C) alkanoyloxyamino, trifluoromethoxy, (1-6C) alkyl, (1-
  • 6C) alkyl carbamoyl- (1-6C) alkylamino, amino- (2-6C) alkylamino, (1-6C) alkylamino- (2-6C) alkylamino, di- [ (1-6C) alkyl] amino- (2- 6C) alkylamino, phenyl- (1-6C) alkylamino, phenoxy- (2- 6C) alkylamino, anilino- (2-6C) alkylamino, phenylthio- (2- 6C) alkylamino, (2 -6C) alkanoylamino, (1-6C) alkoxycarbonylamino, (1-6C) alkylsulphonylamino, benzamido, benzenesulphonamido, 3- phenylureido, 2-oxopyrrolidin-l-yl, 2, 5-dioxopyrrolidin-l-yl, halogen- (2 -6C) alkanoyla
  • 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 [ (1-3C) alkenedioxy] , (1-6C) alkylamino, di- [ (1-6C) alkyl] amino, (1-6C) alkylthio, (1-6C) alkylsulphinyl and (1-6C) alkylsulphonyl .
  • 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, trifluoromethoxy, methyl, ethyl methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylenedioxy, e hylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, piperidino, morpholino, mehtylthio, ethylthio, bromomethyl, dibromomethyl , methoxymethyl , piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl , methoxyethoxymethyl, methylthiomethyl, 2-hydroxyethylthiomethyl, anilinomethyl, phenylthiomethyl, cyanomethyl, 2-bromoethoxy, 2-hydroxyethoxy, 3-hydroxyprop
  • (R 1 ) m is selected from the group consisting of 6-hydroxy, 7-hydroxy, 6,7- dihydroxy, 6-amino, 7-amino, 6-ureido, 6-trifluoromethoxy, 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
  • (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- di ethoxyquinazolone 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 .
  • 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 xy ⁇ ene to remove free chlorine.
  • a trapping agent such as toluene, benzene, or xy ⁇ ene
  • 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. For example, 4-chloro-6 , 7-dimethoxyquinazoline is reacted with 3 -chloroaniline to form
  • an alkaline solution can be added directly to the reaction mixture of Step 3, stirred, and the free base isolated in Step 3 instead of the hydrochloride salt. This is simpler than conventional methods in which an additional step is required to obtain the free base quinazoline from its hydrochloride salt .
  • 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.
  • 4-chloro-6,7 -dimethoxyquinazoline can be prepared with the method described in Step 2 of Example 13 below.
  • This compound was prepared from the 4 -chloro- 6, 7-dimethoxyquinazoline of Example 12 and
  • 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 purified by sublimation.
  • This compound was prepared from the 4 -chloro-6-methylquinazoline of Example 13.
  • Creams Suspended Aqueous phase propylene glycol , water, surfactants, Oil phase: mineral oil, stearyl alcohol
  • Creams Suspended Water (60%), 2.5 - 3.4 surfactant, alcohol propylene carb., mineral oil

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)

Application Number Priority Date Filing Date Title
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
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
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

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
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

Publications (3)

Publication Number Publication Date
WO1998010767A2 true WO1998010767A2 (fr) 1998-03-19
WO1998010767A9 WO1998010767A9 (fr) 1998-07-02
WO1998010767A3 WO1998010767A3 (fr) 1998-08-06

Family

ID=27487474

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/016145 WO1998010767A2 (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

Country Status (4)

Country Link
EP (1) EP0954315A2 (fr)
AU (1) AU4342997A (fr)
CA (1) CA2265630A1 (fr)
WO (1) WO1998010767A2 (fr)

Cited By (134)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000056720A1 (fr) * 1999-03-19 2000-09-28 Parker Hughes Institute Quinazolines et leur utilisation therapeutique
US6184225B1 (en) 1996-02-13 2001-02-06 Zeneca Limited Quinazoline derivatives as VEGF inhibitors
US6291455B1 (en) 1996-03-05 2001-09-18 Zeneca Limited 4-anilinoquinazoline derivatives
WO2002000183A2 (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
JP2003500450A (ja) * 1999-06-01 2003-01-07 ハダシット、メディカル、リサーチ、サーヴィセズ、アンド、デヴェロップメント、リミテッド 陽電子放射断層撮影法のための表皮成長因子受容体に結合する新規化合物
US6673803B2 (en) 1996-09-25 2004-01-06 Zeneca Limited Quinazoline derivatives and pharmaceutical compositions containing them
WO2004103306A2 (fr) 2003-05-19 2004-12-02 Irm Llc Composes immunosuppresseurs et compositions
WO2005000833A1 (fr) 2003-05-19 2005-01-06 Irm, Llc Composes immunosuppresseurs et compositions
WO2006074187A3 (fr) * 2005-01-03 2008-01-10 Myriad Genetics Inc Methode de traitement du cancer du cerveau
WO2008037477A1 (fr) 2006-09-29 2008-04-03 Novartis Ag PYRAZOLOPYRIMIDINES UTILISÉES COMME INHIBITEURS DES LIPIDES KINASES Pl3K
EP1944026A2 (fr) 2002-05-16 2008-07-16 Novartis AG Utilisation d'agents de liaison de récepteur EDG dans un cancer
EP2022498A2 (fr) 2005-11-21 2009-02-11 Novartis AG Traitement de tumeur neuroendocrine
EP2053048A1 (fr) 2005-09-30 2009-04-29 AstraZeneca AB Procédé pour la sulfonation chimique in-situ
EP2065368A1 (fr) 2004-04-07 2009-06-03 Novartis Ag Inhibiteurs de IAP
WO2009118292A1 (fr) 2008-03-24 2009-10-01 Novartis Ag Inhibiteurs de métalloprotéases matricielles à base d'arylsulfonamides
WO2010043050A1 (fr) 2008-10-16 2010-04-22 Celator Pharmaceuticals Corporation Combinaisons d'une camptothécine de liposome soluble dans l'eau avec du cetuximab ou du bevacizumab
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
WO2010071794A1 (fr) 2008-12-18 2010-06-24 Novartis Ag Nouvelle forme polymorphe de 1-(4-{l-[(e)-4-cyclohexyl-3-trifluorométhyl-benzyloxyimino]-éthyl}-2-éthyl-benzyl)-azétidine-s-carboxylique
EP2202229A1 (fr) * 2007-08-17 2010-06-30 Eisai R&D Management Co., Ltd. Nouvelle préparation pour une utilisation externe
WO2010080455A1 (fr) 2008-12-18 2010-07-15 Novartis Ag Nouveaux sels
WO2010080409A1 (fr) 2008-12-18 2010-07-15 Novartis Ag Sel hémifumarate d'acide 1-[4-[1-(4-cyclohexyl-3-trifluorométhyl-benzyloxyimino]-éthyl]-2-éthyl-benzyl]-azétidine-3-carboxylique
WO2010083617A1 (fr) 2009-01-21 2010-07-29 Oncalis Ag Pyrazolopyrimidines en tant qu'inhibiteurs de protéines kinases
WO2010088335A1 (fr) 2009-01-29 2010-08-05 Novartis Ag Benzimidazoles substitués destinés au traitement d'astrocytomes
EP2253319A1 (fr) 2001-05-16 2010-11-24 Novartis AG Combinaison comprenant N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2pyrimidine-amine et agent chimiothérapeutique
WO2010149755A1 (fr) 2009-06-26 2010-12-29 Novartis Ag Dérivés d'imidazolidin-2-one 1,3-disubstitués en tant qu'inhibiteurs de cyp 17
EP2269603A1 (fr) 2001-02-19 2011-01-05 Novartis AG Traitement de tumeurs solides avec des dérivés de la rapamycine
EP2270008A1 (fr) 2005-05-20 2011-01-05 Novartis AG 1,3-dihydro-imidazo[4,5-c]quinolin-2-ones comme inhibiteurs de kinases lipidiques et/ou de la pi3 kinase
EP2272511A1 (fr) 2006-05-09 2011-01-12 Novartis AG Combinaison d'un chélateur du fer et un agent antinéoplasique et ses applications
WO2011015652A1 (fr) 2009-08-07 2011-02-10 Novartis Ag Dérivés 3-hétéroarylméthyl-imidazo[1,2-b]pyridazin-6-yliques comme modulateurs de la tyrosine kinase c-met
WO2011018454A1 (fr) 2009-08-12 2011-02-17 Novartis Ag Composés hydrazone hétérocycliques et leurs utilisations pour traiter le cancer et l'inflammation
WO2011020861A1 (fr) 2009-08-20 2011-02-24 Novartis Ag Composés d'oximes hétérocycliques
WO2011022439A1 (fr) 2009-08-17 2011-02-24 Intellikine, Inc. Composés hétérocycliques et leurs utilisations
WO2011023677A1 (fr) 2009-08-26 2011-03-03 Novartis Ag Composés hétéroaryliques tétrasubstitués et leur utilisation comme modulateurs de mdm2 et/ou mdm4
WO2011029915A1 (fr) 2009-09-10 2011-03-17 Novartis Ag Dérivés éthers d'hétéroaryles bicycliques
EP2308855A1 (fr) 2002-03-15 2011-04-13 Novartis AG Dérivés de 2,4-Diaminopyrimidine
EP2314297A1 (fr) 2006-04-05 2011-04-27 Novartis AG Combinaisons d'inhibiteurs de bcr-abl/c-kit/pdgf-r tk pour traiter le cancer
US7939540B2 (en) 2006-02-21 2011-05-10 Eisai R&D Management Co., Ltd. 4-(3-benzoylaminophenyl)-6,7-dimethoxy-2-methylaminoquinazoline derivatives
WO2011054828A1 (fr) 2009-11-04 2011-05-12 Novartis Ag Derives sulfonamides heterocycliques utilises comme inhibiteurs de mek
WO2011063421A1 (fr) 2009-11-23 2011-05-26 Cerulean Pharma Inc. Polymères à base de cyclodextrine pour une administration thérapeutique
WO2011064211A1 (fr) 2009-11-25 2011-06-03 Novartis Ag Dérivés hétérocycliques d'hétéroaryles bicycliques à 6 cycles benzéniques accolés de benzène contenant de l'oxygène
WO2011070030A1 (fr) 2009-12-08 2011-06-16 Novartis Ag Dérivés sulfonamides hétérocycliques
WO2011076786A1 (fr) 2009-12-22 2011-06-30 Novartis Ag Isoquinolinones et quinazolinones substituées
WO2011090940A1 (fr) 2010-01-19 2011-07-28 Cerulean Pharma Inc. Polymères à base de cyclodextrine pour administration thérapeutique
EP2359818A1 (fr) 2007-02-15 2011-08-24 Novartis AG Combinaisons de LBH589 avec des inhibiteurs de HSP 90 pour le traitement du cancer
WO2011119995A2 (fr) 2010-03-26 2011-09-29 Cerulean Pharma Inc. Formulations et procédés d'utilisation
EP2371822A1 (fr) 2006-03-14 2011-10-05 Novartis AG Carboxamides hétérobicycliques en tant qu'inhibiteurs de kinases
WO2011157793A1 (fr) 2010-06-17 2011-12-22 Novartis Ag Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution pipéridinyle
WO2011157787A1 (fr) 2010-06-17 2011-12-22 Novartis Ag Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution biphényle
WO2012004299A1 (fr) 2010-07-06 2012-01-12 Novartis Ag Dérivés de tétrahydro-pyrido-pyrimidine
EP2409969A1 (fr) 2004-06-24 2012-01-25 Novartis AG Dérivés d'urée de pyrimidine en tant qu'inhibiteurs de kinase
WO2012035078A1 (fr) 2010-09-16 2012-03-22 Novartis Ag Inhibiteurs de la 17α-hydroxylase/c17,20-lyase
WO2012066095A1 (fr) 2010-11-19 2012-05-24 Novartis Ag Forme cristalline d'un inhibiteur d'interaction entre mdm2/4 et p53
WO2012085815A1 (fr) 2010-12-21 2012-06-28 Novartis Ag Composés bi-hétéroaryles en tant qu'inhibiteurs de vps34
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
WO2012116237A2 (fr) 2011-02-23 2012-08-30 Intellikine, Llc Composés hétérocycliques et leurs utilisations
WO2012120469A1 (fr) 2011-03-08 2012-09-13 Novartis Ag Composés hétéroaryliques bicycliques de type fluorophényle
WO2012149413A1 (fr) 2011-04-28 2012-11-01 Novartis Ag Inhibiteurs de 17α-hydroxylase/c17,20-lyase
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
WO2012168884A1 (fr) 2011-06-09 2012-12-13 Novartis Ag Dérivés de sulfonamide hétérocyclique
WO2012175520A1 (fr) 2011-06-20 2012-12-27 Novartis Ag Dérivés d'isoquinolinone substitués par un hydroxy
WO2012175487A1 (fr) 2011-06-20 2012-12-27 Novartis Ag Composés de cyclohexyl-isoquinolinone
WO2013001445A1 (fr) 2011-06-27 2013-01-03 Novartis Ag Formes solides et sels de dérivés de tétrahydro-pyrido-pyrimidine
WO2013038362A1 (fr) 2011-09-15 2013-03-21 Novartis Ag 3-(quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyradines substituées en position 6 à activité tyrosine kinase
EP2591775A1 (fr) 2006-04-05 2013-05-15 Novartis AG Combinaisons comprenant des inhibiteurs de mTOR pour le traitement du cancer
WO2013080141A1 (fr) 2011-11-29 2013-06-06 Novartis Ag Composés pyrazolopyrrolidine
WO2013093849A1 (fr) 2011-12-22 2013-06-27 Novartis Ag Dérivés de dihydro-benzo-oxazine et de dihydro-pyrido-oxazine
WO2013096051A1 (fr) 2011-12-23 2013-06-27 Novartis Ag Composés pour inhiber l'interaction de bcl-2 avec des partenaires de liaison
WO2013096059A1 (fr) 2011-12-23 2013-06-27 Novartis Ag Composés inhibiteurs de l'interaction entre bcl2 et des partenaires de liaison
WO2013093850A1 (fr) 2011-12-22 2013-06-27 Novartis Ag Dérivés quinoline
WO2013096060A1 (fr) 2011-12-23 2013-06-27 Novartis Ag Composés inhibiteurs de l'interaction entre bcl2 et des partenaires de liaison
WO2013096055A1 (fr) 2011-12-23 2013-06-27 Novartis Ag Composés pour inhiber l'interaction de bcl-2 avec 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
US8492543B2 (en) 2007-08-17 2013-07-23 Eisai R&D Management Co., Ltd. Method for producing quinazoline derivative
EP2628726A1 (fr) 2008-03-26 2013-08-21 Novartis AG Inhibiteurs à hydroxamate de désacétylases B
US8530654B2 (en) 2007-02-16 2013-09-10 Eisai R&D Management Co., Ltd. Crystals, amorphous substances or salts of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid
WO2013149581A1 (fr) 2012-04-03 2013-10-10 Novartis Ag Produits combinés comprenant des inhibiteurs de tyrosine kinase et leur utilisation
WO2013175417A1 (fr) 2012-05-24 2013-11-28 Novartis Ag Composés pyrrolopyrrolidinones
WO2013188763A1 (fr) 2012-06-15 2013-12-19 The Brigham And Women's Hospital, Inc. Compositions pour le traitement du cancer et leurs procédés de préparation
WO2014071402A1 (fr) 2012-11-05 2014-05-08 Dana-Farber Cancer Institute, Inc. Xbp1, cd138 et cs1, compositions pharmaceutiques qui comprennent les peptides et procédés d'utilisation de tels peptides et compositions
WO2014102630A1 (fr) 2012-11-26 2014-07-03 Novartis Ag Forme solide d'un dérivé de dihydro-pyrido-oxazine
WO2014115077A1 (fr) 2013-01-22 2014-07-31 Novartis Ag Composés de purinone substitués
WO2014115080A1 (fr) 2013-01-22 2014-07-31 Novartis Ag Composés pyrazolo[3,4-d]pyrimidinone utilisés en tant qu'inhibiteurs de l'interaction p53/mdm2
WO2014130657A1 (fr) 2013-02-20 2014-08-28 The Trustees Of The University Of Pennsylvania Traitement du cancer au moyen d'un récepteur d'antigènes chimériques anti-egfrviii humanisés
WO2014128612A1 (fr) 2013-02-20 2014-08-28 Novartis Ag Dérivés de quinazolin-4-one
WO2014151147A1 (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
WO2014184778A1 (fr) 2013-05-17 2014-11-20 Novartis Ag Dérivés de pyrimidine-4-yl)oxy)-1 h-indole-1-carboxamide et leur utilisation
WO2015010641A1 (fr) 2013-07-24 2015-01-29 Novartis Ag Dérivés quinazolin-4-one substitués
WO2015022663A1 (fr) 2013-08-14 2015-02-19 Novartis Ag Composés et compositions utiles comme inhibiteurs de mek
WO2015022662A1 (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
WO2015042078A2 (fr) 2013-09-22 2015-03-26 Calitor Sciences, Llc Composés d'aminopyrimidine substituée et procédés 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
WO2015145388A2 (fr) 2014-03-27 2015-10-01 Novartis Ag Procédés de traitement de cancers colorectaux avec mutations en amont de la voie wnt
WO2016011956A1 (fr) 2014-07-25 2016-01-28 Novartis Ag Polythérapie
WO2016016822A1 (fr) 2014-07-31 2016-02-04 Novartis Ag Polythérapie
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
EP3064502A1 (fr) 2012-01-26 2016-09-07 Novartis AG Imidazopyrrolidinones
US9585850B2 (en) 2011-12-23 2017-03-07 Duke University Methods of treatment using arylcyclopropylamine compounds
WO2017044434A1 (fr) 2015-09-11 2017-03-16 Sunshine Lake Pharma Co., Ltd. Composés hétéroaryle substitués et leurs méthodes d'utilisation
US9738643B2 (en) 2012-08-06 2017-08-22 Duke University Substituted indazoles for targeting Hsp90
WO2018039205A1 (fr) 2016-08-23 2018-03-01 Oncopep, Inc. Vaccins peptidiques et durvalumab pour le traitement du cancer du sein
WO2018039203A1 (fr) 2016-08-23 2018-03-01 Oncopep, Inc. Vaccins peptidiques et durvalumab pour le traitement du myélome multiple
WO2018064076A1 (fr) 2016-09-27 2018-04-05 Cero Therapeutics, Inc. Molécules de récepteurs d'engloutissement chimériques
EP3312164A1 (fr) 2014-03-28 2018-04-25 Calitor Sciences, LLC Composés d'hétéroaryle substitués et procédés d'utilisation
US10000469B2 (en) 2014-03-25 2018-06-19 Duke University Heat shock protein 70 (hsp-70) receptor ligands
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
WO2019067328A1 (fr) 2017-09-26 2019-04-04 Cero Therapeutics, Inc. Molécules de récepteur d'engloutissement chimérique et méthodes d'utilisation
WO2019083962A1 (fr) 2017-10-24 2019-05-02 Oncopep, Inc. Vaccins peptidiques et pembrolizumab pour le traitement du cancer du sein
WO2019083960A1 (fr) 2017-10-24 2019-05-02 Oncopep, Inc. Vaccins peptidiques et inhibiteurs d'hdac pour le traitement du myélome multiple
WO2019099311A1 (fr) 2017-11-19 2019-05-23 Sunshine Lake Pharma Co., Ltd. Composés hétéroaryle substitués et leurs méthodes d'utilisation
WO2019119486A1 (fr) 2017-12-21 2019-06-27 中国科学院合肥物质科学研究院 Classe d'inhibiteurs de kinase dérivés de pyrimidine
WO2019143874A1 (fr) 2018-01-20 2019-07-25 Sunshine Lake Pharma Co., Ltd. Composés d'aminopyrimidine substitués et procédés d'utilisation
US10426753B2 (en) 2014-04-03 2019-10-01 Invictus Oncology Pvt. Ltd. Supramolecular combinatorial therapeutics
WO2019191339A1 (fr) 2018-03-28 2019-10-03 Cero Therapeutics, Inc. Vecteurs d'expression pour récepteurs d'envahissement chimériques, cellules hôtes génétiquement modifiées, et leurs utilisations
WO2019191334A1 (fr) 2018-03-28 2019-10-03 Cero Therapeutics, Inc. Récepteurs tim4 chimériques et leurs utilisations
WO2019191340A1 (fr) 2018-03-28 2019-10-03 Cero Therapeutics, Inc. Compositions d'immunothérapie cellulaire et utilisations associées
US10457664B2 (en) 1999-11-05 2019-10-29 Genzyme Corporation Quinazoline derivatives as VEGF inhibitors
WO2020023628A1 (fr) 2018-07-24 2020-01-30 Hygia Pharmaceuticals, Llc Composés, dérivés et analogues contre le cancer
US10927083B2 (en) 2016-09-29 2021-02-23 Duke University Substituted benzimidazoles as inhibitors of transforming growth factor-β kinase
WO2021067875A1 (fr) 2019-10-03 2021-04-08 Cero Therapeutics, Inc. Récepteurs tim4 chimériques et leurs utilisations
WO2021097256A1 (fr) 2019-11-14 2021-05-20 Cohbar, Inc. Peptides antagonistes de cxcr4
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
WO2022029220A1 (fr) 2020-08-05 2022-02-10 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
WO2022036265A1 (fr) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Récepteurs chimériques tim et leurs utilisations
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
US11261187B2 (en) 2016-04-22 2022-03-01 Duke University Compounds and methods for targeting HSP90
WO2022123316A1 (fr) 2020-12-09 2022-06-16 Takeda Pharmaceutical Company Limited Compositions d'agents de liaison à l'antigène guanylyle cyclase c (gcc) et leurs méthodes d'utilisation
WO2022183072A1 (fr) 2021-02-26 2022-09-01 Kelonia Therapeutics, Inc. Vecteurs lentiviraux ciblant les lymphocytes
WO2023010097A1 (fr) 2021-07-28 2023-02-02 Cero Therapeutics, Inc. Récepteurs tim4 chimériques et leurs utilisations
WO2023240105A1 (fr) * 2022-06-07 2023-12-14 Biomimetix Jv, Llc Compositions hydrophobes contenant un principe actif hydrophile et méthodes associées
WO2024030441A1 (fr) 2022-08-02 2024-02-08 National University Corporation Hokkaido University Procédés d'amélioration d'une thérapie cellulaire avec des complexes d'organites

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5457105A (en) * 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
WO1996009294A1 (fr) * 1994-09-19 1996-03-28 The Wellcome Foundation Limited Composes heteroaromatiques substitues et leur utilisation en medecine
WO1996027797A2 (fr) * 1995-03-08 1996-09-12 Hsc Research And Development Limited Partnership Inhibiteurs de zap 70 et procedes de traitement de troubles de la transduction de signaux de zap 70

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5457105A (en) * 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
WO1996009294A1 (fr) * 1994-09-19 1996-03-28 The Wellcome Foundation Limited Composes heteroaromatiques substitues et leur utilisation en medecine
WO1996027797A2 (fr) * 1995-03-08 1996-09-12 Hsc Research And Development Limited Partnership Inhibiteurs de zap 70 et procedes de traitement de troubles de la transduction de signaux de zap 70

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
A. LEVITZKI: "Receptor activation by antigens, cytokines, hormones and growth factors" ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 766, 1995, pages 363-8, XP002053500 *
A. LEVITZKI: "Signal-transduction therapy" EUR. J. BIOCHEM., vol. 226, no. 1, 1994, pages 1-13, XP002053501 *
BEN-BASSAT ET AL: "Inhibitors of epidermal growth factor receptor kinase and cyclin dependent kinase 2 activation induce growth arrest, differentiation, and apoptosis of human papilloma virus 16-immortalized human keratinocytes " CANCER RESEARCH, vol. 57, September 1997, pages 3741-50, XP002053502 *
BRIDGES ET AL: "Tyrosine kinase inhibitors. 8. An unusually step structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazolin e (PD153035), a potent inhibitor of the epidermal growth factor receptor" J MED CHEM, vol. 39, 1996, pages 267-76, XP002064936 *
TRAXLER ET AL: "4-Phenyl-amino(pyrrolopyrimidines): potent and selectzive,ATP site directed inhibitors of the EGF-receptor protein tyrosine kinase" J. MED. CHEM., vol. 39, no. 12, December 1996, pages 2285-92, XP002053503 *

Cited By (180)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6184225B1 (en) 1996-02-13 2001-02-06 Zeneca Limited Quinazoline derivatives as VEGF inhibitors
US6291455B1 (en) 1996-03-05 2001-09-18 Zeneca Limited 4-anilinoquinazoline derivatives
US6673803B2 (en) 1996-09-25 2004-01-06 Zeneca Limited Quinazoline derivatives and pharmaceutical compositions containing them
US6897210B2 (en) 1996-09-25 2005-05-24 Zeneca Limited Quinazoline derivatives and pharmaceutical compositions containing them
US6258820B1 (en) 1999-03-19 2001-07-10 Parker Hughes Institute Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines
WO2000056720A1 (fr) * 1999-03-19 2000-09-28 Parker Hughes Institute Quinazolines et leur utilisation therapeutique
US6358962B2 (en) 1999-03-19 2002-03-19 Parker Hughes Institute 6,7-Dimethoxyquinazolines and therapeutic use thereof
US7038049B2 (en) 1999-03-19 2006-05-02 Parker Hughes Institute Haloanilino quinazolines and therapeutic use thereof
US6638939B2 (en) 1999-03-19 2003-10-28 Parker Hughes Institute 6,7-dimethoxyquinazolines and therapeutic use thereof
JP2003500450A (ja) * 1999-06-01 2003-01-07 ハダシット、メディカル、リサーチ、サーヴィセズ、アンド、デヴェロップメント、リミテッド 陽電子放射断層撮影法のための表皮成長因子受容体に結合する新規化合物
US10457664B2 (en) 1999-11-05 2019-10-29 Genzyme Corporation Quinazoline derivatives as VEGF inhibitors
WO2002000183A3 (fr) * 2000-06-26 2002-07-25 Univ 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
WO2002000183A2 (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
USRE43098E1 (en) 2000-11-01 2012-01-10 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
EP2783686A1 (fr) 2001-02-19 2014-10-01 Novartis AG Association d'un dérivé de rapamycine et de létrozole pour le traitement du cancer du sein
EP2269604A1 (fr) 2001-02-19 2011-01-05 Novartis AG Traitement de tumeurs solides avec des dérivés de la rapamycine
EP2269603A1 (fr) 2001-02-19 2011-01-05 Novartis AG Traitement de tumeurs solides avec des dérivés de la rapamycine
EP2762140A1 (fr) 2001-02-19 2014-08-06 Novartis AG Traitement de tumeurs solides du cerveau avec un dérivé de la rapamycine
EP2764865A2 (fr) 2001-02-19 2014-08-13 Novartis AG Traitement du cancer
US8410131B2 (en) 2001-02-19 2013-04-02 Novartis Pharmaceuticals Corporation Cancer treatment
US8877771B2 (en) 2001-02-19 2014-11-04 Novartis Pharmaceuticals Corporation Treatment of solid tumors with rapamycin derivatives
EP3342411A1 (fr) 2001-02-19 2018-07-04 Novartis AG Dérivé de rapamycine pour le traitement du cancer du pancréas
EP3345602A1 (fr) 2001-02-19 2018-07-11 Novartis AG Dérivé de rapamycine pour traiter des tumeurs solides avancées
EP3406249A1 (fr) 2001-02-19 2018-11-28 Novartis AG Traitement de tumeurs du sein avec un dérivé de rapamycine en combinaison avec un inhibiteur de l'aromatase
EP3351246A1 (fr) 2001-02-19 2018-07-25 Novartis AG Dérivé de rapamycine pour le traitement d'une tumeur solide associée à une angiogenèse dérégulée
EP2253319A1 (fr) 2001-05-16 2010-11-24 Novartis AG Combinaison comprenant N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2pyrimidine-amine et agent chimiothérapeutique
EP2308855A1 (fr) 2002-03-15 2011-04-13 Novartis AG Dérivés de 2,4-Diaminopyrimidine
EP1944026A2 (fr) 2002-05-16 2008-07-16 Novartis AG Utilisation d'agents de liaison de récepteur EDG dans un cancer
EP1955696A2 (fr) 2002-05-16 2008-08-13 Novartis AG Utilisation d'agents de liaison de récepteur EDG dans un cancer
EP2644195A1 (fr) 2003-05-19 2013-10-02 Irm Llc Composes Immunosuppresseurs et Compositions
WO2005000833A1 (fr) 2003-05-19 2005-01-06 Irm, Llc Composes immunosuppresseurs et compositions
EP3272736A1 (fr) 2003-05-19 2018-01-24 Novartis Ag Composés d'immunosuppression et compositions
EP2514743A1 (fr) 2003-05-19 2012-10-24 Irm Llc Composés d'immunosuppression et compositions
WO2004103306A2 (fr) 2003-05-19 2004-12-02 Irm Llc Composes immunosuppresseurs et compositions
US8309562B2 (en) 2003-07-03 2012-11-13 Myrexis, Inc. Compounds and therapeutical use thereof
EP2253614A1 (fr) 2004-04-07 2010-11-24 Novartis AG Inhibiteurs de IAP
EP2065368A1 (fr) 2004-04-07 2009-06-03 Novartis Ag Inhibiteurs de IAP
EP2409969A1 (fr) 2004-06-24 2012-01-25 Novartis AG Dérivés d'urée de pyrimidine en tant qu'inhibiteurs de kinase
EP2418205A1 (fr) 2004-06-24 2012-02-15 Novartis AG Dérivés d'urée de pyrimidine en tant qu'inhibiteurs de kinase
WO2006074187A3 (fr) * 2005-01-03 2008-01-10 Myriad Genetics Inc Methode de traitement du cancer du cerveau
EP2270008A1 (fr) 2005-05-20 2011-01-05 Novartis AG 1,3-dihydro-imidazo[4,5-c]quinolin-2-ones comme inhibiteurs de kinases lipidiques et/ou de la pi3 kinase
EP2292617A1 (fr) 2005-05-20 2011-03-09 Novartis AG Dérivés de 1,3-dihydro-imidazo[4,5-c]quinolin-2-one comme inhibiteurs de kinase lipidique et/ou de kinase pi3
US8865899B2 (en) 2005-09-30 2014-10-21 Astrazeneca Ab Chemical process for the synthesis of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
US9815816B2 (en) 2005-09-30 2017-11-14 Genzyme Corporation Chemical process for the synthesis of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
EP2053048A1 (fr) 2005-09-30 2009-04-29 AstraZeneca AB Procédé pour la sulfonation chimique in-situ
US10344015B2 (en) 2005-09-30 2019-07-09 Genzyme Corporation Chemical process for the synthesis of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
US8163926B2 (en) 2005-09-30 2012-04-24 Astrazeneca Ab Process for the synthesis of piperidinyl sulphonate esters
EP2022498A2 (fr) 2005-11-21 2009-02-11 Novartis AG Traitement de tumeur neuroendocrine
EP2275103A2 (fr) 2005-11-21 2011-01-19 Novartis AG Inhibiteurs du mTOR pour le traitement des tumeurs endocriniennes
US7939540B2 (en) 2006-02-21 2011-05-10 Eisai R&D Management Co., Ltd. 4-(3-benzoylaminophenyl)-6,7-dimethoxy-2-methylaminoquinazoline derivatives
EP2371822A1 (fr) 2006-03-14 2011-10-05 Novartis AG Carboxamides hétérobicycliques en tant qu'inhibiteurs de kinases
EP2591775A1 (fr) 2006-04-05 2013-05-15 Novartis AG Combinaisons comprenant des inhibiteurs de mTOR pour le traitement du cancer
EP2314297A1 (fr) 2006-04-05 2011-04-27 Novartis AG Combinaisons d'inhibiteurs de bcr-abl/c-kit/pdgf-r tk pour traiter le cancer
EP2272511A1 (fr) 2006-05-09 2011-01-12 Novartis AG Combinaison d'un chélateur du fer et un agent antinéoplasique et ses applications
WO2008037477A1 (fr) 2006-09-29 2008-04-03 Novartis Ag PYRAZOLOPYRIMIDINES UTILISÉES COMME INHIBITEURS DES LIPIDES KINASES Pl3K
EP2491923A2 (fr) 2007-02-15 2012-08-29 Novartis AG Combinaisons d'agents thérapeutiques pour traiter le cancer
EP2359818A1 (fr) 2007-02-15 2011-08-24 Novartis AG Combinaisons de LBH589 avec des inhibiteurs de HSP 90 pour le traitement du cancer
US8530654B2 (en) 2007-02-16 2013-09-10 Eisai R&D Management Co., Ltd. Crystals, amorphous substances or salts of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl) phenyl] terephthalamic acid
US8513269B2 (en) 2007-08-17 2013-08-20 Eisai R&D Management Co., Ltd. Preparation for external use
US8492543B2 (en) 2007-08-17 2013-07-23 Eisai R&D Management Co., Ltd. Method for producing quinazoline derivative
EP2202229A4 (fr) * 2007-08-17 2010-09-08 Eisai R&D Man Co Ltd Nouvelle préparation pour une utilisation externe
EP2202229A1 (fr) * 2007-08-17 2010-06-30 Eisai R&D Management Co., Ltd. Nouvelle préparation pour une utilisation externe
WO2009118292A1 (fr) 2008-03-24 2009-10-01 Novartis Ag Inhibiteurs de métalloprotéases matricielles à base d'arylsulfonamides
EP2628726A1 (fr) 2008-03-26 2013-08-21 Novartis AG Inhibiteurs à hydroxamate de désacétylases B
WO2010043050A1 (fr) 2008-10-16 2010-04-22 Celator Pharmaceuticals Corporation Combinaisons d'une camptothécine de liposome soluble dans l'eau avec du cetuximab ou du bevacizumab
WO2010080455A1 (fr) 2008-12-18 2010-07-15 Novartis Ag Nouveaux sels
WO2010071794A1 (fr) 2008-12-18 2010-06-24 Novartis Ag Nouvelle forme polymorphe de 1-(4-{l-[(e)-4-cyclohexyl-3-trifluorométhyl-benzyloxyimino]-éthyl}-2-éthyl-benzyl)-azétidine-s-carboxylique
WO2010080409A1 (fr) 2008-12-18 2010-07-15 Novartis Ag Sel hémifumarate d'acide 1-[4-[1-(4-cyclohexyl-3-trifluorométhyl-benzyloxyimino]-éthyl]-2-éthyl-benzyl]-azétidine-3-carboxylique
WO2010083617A1 (fr) 2009-01-21 2010-07-29 Oncalis Ag Pyrazolopyrimidines en tant qu'inhibiteurs de protéines kinases
WO2010088335A1 (fr) 2009-01-29 2010-08-05 Novartis Ag Benzimidazoles substitués destinés au traitement d'astrocytomes
WO2010149755A1 (fr) 2009-06-26 2010-12-29 Novartis Ag Dérivés d'imidazolidin-2-one 1,3-disubstitués en tant qu'inhibiteurs de cyp 17
WO2011015652A1 (fr) 2009-08-07 2011-02-10 Novartis Ag Dérivés 3-hétéroarylméthyl-imidazo[1,2-b]pyridazin-6-yliques comme modulateurs de la tyrosine kinase c-met
WO2011018454A1 (fr) 2009-08-12 2011-02-17 Novartis Ag Composés hydrazone hétérocycliques et leurs utilisations pour traiter le cancer et l'inflammation
WO2011022439A1 (fr) 2009-08-17 2011-02-24 Intellikine, Inc. Composés hétérocycliques et leurs utilisations
WO2011020861A1 (fr) 2009-08-20 2011-02-24 Novartis Ag Composés d'oximes hétérocycliques
WO2011023677A1 (fr) 2009-08-26 2011-03-03 Novartis Ag Composés hétéroaryliques tétrasubstitués et leur utilisation comme modulateurs de mdm2 et/ou mdm4
WO2011029915A1 (fr) 2009-09-10 2011-03-17 Novartis Ag Dérivés éthers d'hétéroaryles bicycliques
WO2011054828A1 (fr) 2009-11-04 2011-05-12 Novartis Ag Derives sulfonamides heterocycliques utilises comme inhibiteurs de mek
WO2011063421A1 (fr) 2009-11-23 2011-05-26 Cerulean Pharma Inc. Polymères à base de cyclodextrine pour une administration thérapeutique
WO2011064211A1 (fr) 2009-11-25 2011-06-03 Novartis Ag Dérivés hétérocycliques d'hétéroaryles bicycliques à 6 cycles benzéniques accolés de benzène contenant de l'oxygène
WO2011070030A1 (fr) 2009-12-08 2011-06-16 Novartis Ag Dérivés sulfonamides hétérocycliques
WO2011076786A1 (fr) 2009-12-22 2011-06-30 Novartis Ag Isoquinolinones et quinazolinones substituées
WO2011090940A1 (fr) 2010-01-19 2011-07-28 Cerulean Pharma Inc. Polymères à base de cyclodextrine pour administration thérapeutique
WO2011119995A2 (fr) 2010-03-26 2011-09-29 Cerulean Pharma Inc. Formulations et procédés d'utilisation
WO2011157787A1 (fr) 2010-06-17 2011-12-22 Novartis Ag Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution biphényle
WO2011157793A1 (fr) 2010-06-17 2011-12-22 Novartis Ag Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution pipéridinyle
WO2012004299A1 (fr) 2010-07-06 2012-01-12 Novartis Ag Dérivés de tétrahydro-pyrido-pyrimidine
WO2012035078A1 (fr) 2010-09-16 2012-03-22 Novartis Ag Inhibiteurs de la 17α-hydroxylase/c17,20-lyase
WO2012066095A1 (fr) 2010-11-19 2012-05-24 Novartis Ag Forme cristalline d'un inhibiteur d'interaction entre mdm2/4 et p53
WO2012085815A1 (fr) 2010-12-21 2012-06-28 Novartis Ag Composés bi-hétéroaryles en tant qu'inhibiteurs de vps34
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
US9127000B2 (en) 2011-02-23 2015-09-08 Intellikine, LLC. Heterocyclic compounds and uses thereof
WO2012116237A2 (fr) 2011-02-23 2012-08-30 Intellikine, Llc Composés hétérocycliques et leurs utilisations
WO2012120469A1 (fr) 2011-03-08 2012-09-13 Novartis Ag Composés hétéroaryliques bicycliques de type fluorophényle
WO2012149413A1 (fr) 2011-04-28 2012-11-01 Novartis Ag Inhibiteurs de 17α-hydroxylase/c17,20-lyase
WO2012168884A1 (fr) 2011-06-09 2012-12-13 Novartis Ag Dérivés de sulfonamide hétérocyclique
WO2012175487A1 (fr) 2011-06-20 2012-12-27 Novartis Ag Composés de cyclohexyl-isoquinolinone
WO2012175520A1 (fr) 2011-06-20 2012-12-27 Novartis Ag Dérivés d'isoquinolinone substitués par un hydroxy
WO2013001445A1 (fr) 2011-06-27 2013-01-03 Novartis Ag Formes solides et sels de dérivés de tétrahydro-pyrido-pyrimidine
WO2013038362A1 (fr) 2011-09-15 2013-03-21 Novartis Ag 3-(quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyradines substituées en position 6 à activité tyrosine kinase
WO2013080141A1 (fr) 2011-11-29 2013-06-06 Novartis Ag Composés pyrazolopyrrolidine
US9408885B2 (en) 2011-12-01 2016-08-09 Vib Vzw Combinations of therapeutic agents for treating melanoma
WO2013093849A1 (fr) 2011-12-22 2013-06-27 Novartis Ag Dérivés de dihydro-benzo-oxazine et de dihydro-pyrido-oxazine
WO2013093850A1 (fr) 2011-12-22 2013-06-27 Novartis Ag Dérivés quinoline
WO2013096051A1 (fr) 2011-12-23 2013-06-27 Novartis Ag Composés pour inhiber l'interaction de bcl-2 avec 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
WO2013096059A1 (fr) 2011-12-23 2013-06-27 Novartis Ag Composés inhibiteurs de l'interaction entre bcl2 et des partenaires de liaison
WO2013096060A1 (fr) 2011-12-23 2013-06-27 Novartis Ag Composés inhibiteurs de l'interaction entre bcl2 et des partenaires de liaison
US9585850B2 (en) 2011-12-23 2017-03-07 Duke University Methods of treatment using arylcyclopropylamine compounds
WO2013096055A1 (fr) 2011-12-23 2013-06-27 Novartis Ag Composés pour inhiber l'interaction de bcl-2 avec des partenaires de liaison
EP3064502A1 (fr) 2012-01-26 2016-09-07 Novartis AG Imidazopyrrolidinones
EP3272754A1 (fr) 2012-01-26 2018-01-24 Novartis AG Composés d'imidazopyrrolidinone
EP3964513A1 (fr) 2012-04-03 2022-03-09 Novartis AG Produits combinés comprenant des inhibiteurs de tyrosine kinase et leur utilisation
WO2013149581A1 (fr) 2012-04-03 2013-10-10 Novartis Ag Produits combinés comprenant des inhibiteurs de tyrosine kinase et leur utilisation
WO2013175417A1 (fr) 2012-05-24 2013-11-28 Novartis Ag Composés pyrrolopyrrolidinones
WO2013188763A1 (fr) 2012-06-15 2013-12-19 The Brigham And Women's Hospital, Inc. Compositions pour le traitement du cancer et leurs procédés de préparation
US9738643B2 (en) 2012-08-06 2017-08-22 Duke University Substituted indazoles for targeting Hsp90
US10112947B2 (en) 2012-08-06 2018-10-30 Duke University Substituted 6-aminopurines for targeting HSP90
US10442806B2 (en) 2012-08-06 2019-10-15 Duke University Substituted heterocycles for targeting HSP90
US10927115B2 (en) 2012-08-06 2021-02-23 Duke University Substituted heterocycles for targeting Hsp90
WO2014071402A1 (fr) 2012-11-05 2014-05-08 Dana-Farber Cancer Institute, Inc. Xbp1, cd138 et cs1, compositions pharmaceutiques qui comprennent les peptides et procédés d'utilisation de tels peptides et compositions
EP3919069A1 (fr) 2012-11-05 2021-12-08 Dana-Farber Cancer Institute, Inc. Peptides xbp1, cd138 et cs1, compositions pharmaceutiques qui comprennent les peptides et procédés d'utilisation de tels peptides et compositions
WO2014102630A1 (fr) 2012-11-26 2014-07-03 Novartis Ag Forme solide d'un dérivé de dihydro-pyrido-oxazine
WO2014115077A1 (fr) 2013-01-22 2014-07-31 Novartis Ag Composés de purinone substitués
WO2014115080A1 (fr) 2013-01-22 2014-07-31 Novartis Ag Composés pyrazolo[3,4-d]pyrimidinone utilisés en tant qu'inhibiteurs de l'interaction p53/mdm2
WO2014130657A1 (fr) 2013-02-20 2014-08-28 The Trustees Of The University Of Pennsylvania Traitement du cancer au moyen d'un récepteur d'antigènes chimériques anti-egfrviii humanisés
WO2014128612A1 (fr) 2013-02-20 2014-08-28 Novartis Ag Dérivés de quinazolin-4-one
EP3626741A1 (fr) 2013-02-20 2020-03-25 The Trustees Of The University Of Pennsylvania Traitement du cancer à l'aide d'un récepteur d'antigène chimérique anti-egfrviii humanisé
WO2014151147A1 (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
WO2014184778A1 (fr) 2013-05-17 2014-11-20 Novartis Ag Dérivés de pyrimidine-4-yl)oxy)-1 h-indole-1-carboxamide et leur utilisation
WO2015010641A1 (fr) 2013-07-24 2015-01-29 Novartis Ag Dérivés quinazolin-4-one substitués
WO2015022663A1 (fr) 2013-08-14 2015-02-19 Novartis Ag Composés et compositions utiles comme inhibiteurs de mek
WO2015022662A1 (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
WO2015042078A2 (fr) 2013-09-22 2015-03-26 Calitor Sciences, Llc Composés d'aminopyrimidine substituée et procédés d'utilisation
WO2015042077A1 (fr) 2013-09-22 2015-03-26 Calitor Sciences, Llc Composés substitués d'aminopyrimidine et procédés 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
US10000469B2 (en) 2014-03-25 2018-06-19 Duke University Heat shock protein 70 (hsp-70) receptor ligands
WO2015145388A2 (fr) 2014-03-27 2015-10-01 Novartis Ag Procédés de traitement de cancers colorectaux avec mutations en amont de la voie wnt
EP3327006A1 (fr) 2014-03-28 2018-05-30 Calitor Sciences, LLC Composés d'hétéroaryle substitués et procédés d'utilisation
EP3312164A1 (fr) 2014-03-28 2018-04-25 Calitor Sciences, LLC Composés d'hétéroaryle substitués et procédés d'utilisation
US10426753B2 (en) 2014-04-03 2019-10-01 Invictus Oncology Pvt. Ltd. Supramolecular combinatorial therapeutics
WO2016011956A1 (fr) 2014-07-25 2016-01-28 Novartis Ag Polythérapie
WO2016016822A1 (fr) 2014-07-31 2016-02-04 Novartis Ag Polythérapie
WO2017044434A1 (fr) 2015-09-11 2017-03-16 Sunshine Lake Pharma Co., Ltd. Composés hétéroaryle substitués et leurs méthodes d'utilisation
US11261187B2 (en) 2016-04-22 2022-03-01 Duke University Compounds and methods for targeting HSP90
WO2018039205A1 (fr) 2016-08-23 2018-03-01 Oncopep, Inc. Vaccins peptidiques et durvalumab pour le traitement du cancer du sein
WO2018039203A1 (fr) 2016-08-23 2018-03-01 Oncopep, Inc. Vaccins peptidiques et durvalumab pour le traitement du myélome multiple
WO2018064076A1 (fr) 2016-09-27 2018-04-05 Cero Therapeutics, Inc. Molécules de récepteurs d'engloutissement chimériques
EP4089116A1 (fr) 2016-09-27 2022-11-16 Cero Therapeutics, Inc. Molécules de récepteurs d'engloutissement chimériques
US10927083B2 (en) 2016-09-29 2021-02-23 Duke University Substituted benzimidazoles as inhibitors of transforming growth factor-β kinase
US11767298B2 (en) 2016-09-29 2023-09-26 Duke University Substituted benzimidazoles as inhibitors of transforming growth factor-β kinase
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
WO2019067328A1 (fr) 2017-09-26 2019-04-04 Cero Therapeutics, Inc. Molécules de récepteur d'engloutissement chimérique et méthodes d'utilisation
US11708423B2 (en) 2017-09-26 2023-07-25 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
WO2019083962A1 (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
US11602534B2 (en) 2017-12-21 2023-03-14 Hefei Institutes Of Physical Science, Chinese Academy Of Sciences Pyrimidine derivative kinase inhibitors
WO2019119486A1 (fr) 2017-12-21 2019-06-27 中国科学院合肥物质科学研究院 Classe d'inhibiteurs de kinase dérivés de pyrimidine
WO2019143874A1 (fr) 2018-01-20 2019-07-25 Sunshine Lake Pharma Co., Ltd. Composés d'aminopyrimidine substitués et procédés d'utilisation
WO2019191340A1 (fr) 2018-03-28 2019-10-03 Cero Therapeutics, Inc. Compositions d'immunothérapie cellulaire et utilisations associées
WO2019191339A1 (fr) 2018-03-28 2019-10-03 Cero Therapeutics, Inc. Vecteurs d'expression pour récepteurs d'envahissement chimériques, cellules hôtes génétiquement modifiées, et leurs utilisations
WO2019191334A1 (fr) 2018-03-28 2019-10-03 Cero Therapeutics, Inc. Récepteurs tim4 chimériques et leurs utilisations
WO2020023628A1 (fr) 2018-07-24 2020-01-30 Hygia Pharmaceuticals, Llc Composés, dérivés et analogues contre le cancer
WO2021067875A1 (fr) 2019-10-03 2021-04-08 Cero Therapeutics, Inc. Récepteurs tim4 chimériques et leurs utilisations
WO2021097256A1 (fr) 2019-11-14 2021-05-20 Cohbar, Inc. Peptides antagonistes de cxcr4
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
WO2022029220A1 (fr) 2020-08-05 2022-02-10 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
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
WO2022036287A1 (fr) 2020-08-14 2022-02-17 Cero Therapeutics, Inc. Récepteurs chimériques anti-cd72 et utilisations de ceux-ci
WO2022123316A1 (fr) 2020-12-09 2022-06-16 Takeda Pharmaceutical Company Limited Compositions d'agents de liaison à l'antigène guanylyle cyclase c (gcc) et leurs méthodes d'utilisation
WO2022183072A1 (fr) 2021-02-26 2022-09-01 Kelonia Therapeutics, Inc. Vecteurs lentiviraux ciblant les lymphocytes
WO2023010097A1 (fr) 2021-07-28 2023-02-02 Cero Therapeutics, Inc. Récepteurs tim4 chimériques et leurs utilisations
WO2023240105A1 (fr) * 2022-06-07 2023-12-14 Biomimetix Jv, Llc Compositions hydrophobes contenant un principe actif hydrophile et méthodes associées
WO2024030441A1 (fr) 2022-08-02 2024-02-08 National University Corporation Hokkaido University Procédés d'amélioration d'une thérapie cellulaire avec des complexes d'organites

Also Published As

Publication number Publication date
CA2265630A1 (fr) 1998-03-19
WO1998010767A3 (fr) 1998-08-06
AU4342997A (en) 1998-04-02
EP0954315A2 (fr) 1999-11-10

Similar Documents

Publication Publication Date Title
US6004967A (en) Psoriasis treatment with quinazoline compounds
WO1998010767A2 (fr) Utilisation de derives de la quinazoline pour la fabrication d'un medicament destine au traitement de troubles cutanes hyperproliferatifs
WO1998010767A9 (fr) Utilisation de derives de la quinazoline pour la fabrication d'un medicament destine au traitement de troubles cutanes hyperproliferatifs
US11219624B2 (en) Topical formulation for a JAK inhibitor
DE69924500T2 (de) Chinazolinderivate
US20170172971A1 (en) Parenteral formulations of lipophilic pharmaceutical agents and methods for preparing and using the same
JP6953468B2 (ja) 新規の使用
JP2002275095A (ja) レチノイド皮膚損傷の抑制方法
CN105541836A (zh) 激酶抑制剂的前药形式及其在治疗中的用途
KR20020086946A (ko) 비스테로이드성 항안드로겐 및 ｅｇｆｒ 티로신 키나제억제제를 포함하는 조합 산물
CN110343090A (zh) 喹唑啉衍生物盐型晶型及制备方法和应用
KR20190018486A (ko) 암의 예방 및/또는 치료를 위한 화합물, 조성물 및 방법
EP2697206B1 (fr) Composés hétérocycliques et leurs utilisations dans le traitement de troubles sexuels
US6288112B1 (en) Use of pyrethroid compounds to promote hair growth
CN101898979A (zh) 含二苯乙烯片段的苯基硝酮类化合物及其用途
WO2021197334A1 (fr) Association pharmaceutique et son utilisation
RU2277910C2 (ru) Средство "форинит-гель" для лечения и профилактики сердечно-сосудистых заболеваний
KR20190046695A (ko) 수베르산을 유효성분으로 포함하는 탈모 방지 또는 발모 촉진용 조성물
SA99200836B1 (ar) صيغ مضادة للفيروسات antiviral formulations تتضمن propylene glycol واستر أيزويروبيلي لحمض الكانوي isopropyl alkanoic acid ester

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

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

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
COP Corrected version of pamphlet

Free format text: PAGES 1-94, DESCRIPTION, REPLACED BY NEW PAGES 1-82; PAGES 95-111, CLAIMS, REPLACED BY NEW PAGES 83-97; PAGES 1/6-6/6, DRAWINGS, REPLACED BY NEW PAGES 1/6-6/6; DUE TO LATE TRANSMITTAL BY THE RECEIVING OFFICE

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

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

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT

ENP Entry into the national phase in:

Ref country code: CA

Ref document number: 2265630

Kind code of ref document: A

Format of ref document f/p: F

Ref document number: 2265630

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 1997941542

Country of ref document: EP

NENP Non-entry into the national phase in:

Ref country code: JP

Ref document number: 1998513877

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1997941542

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1997941542

Country of ref document: EP