WO2007098835A1 - Dérivés de l'aminopyrymidine - Google Patents

Dérivés de l'aminopyrymidine Download PDF

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Publication number
WO2007098835A1
WO2007098835A1 PCT/EP2007/000708 EP2007000708W WO2007098835A1 WO 2007098835 A1 WO2007098835 A1 WO 2007098835A1 EP 2007000708 W EP2007000708 W EP 2007000708W WO 2007098835 A1 WO2007098835 A1 WO 2007098835A1
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WIPO (PCT)
Prior art keywords
carcinoma
diseases
hsp90
compounds
salts
Prior art date
Application number
PCT/EP2007/000708
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German (de)
English (en)
Inventor
Hans-Peter Buchstaller
Hans-Michael Eggenweiler
Michael Wolf
Christian Sirrenberg
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Merck Patent Gmbh
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Publication of WO2007098835A1 publication Critical patent/WO2007098835A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the cells of a tissue are responsive to external stress, e.g. Heat, hypoxia, oxidative stress, or toxins such as heavy metals or alcohols with the activation of a number of chaperones known as "heat shock proteins” (HSPs) .
  • HSPs heat shock proteins
  • the activation of HSPs protects the cell against injuries caused by such stressors triggers the restoration of the physiological state and leads to a stress-tolerant state of the cell.
  • HSPs are related to the stage of tumor progression (Martin et al., 2000; Conroy et al., 1996; Kawanishi et al., 1999;
  • HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG), a derivative of geldanamycin, is currently undergoing clinical trials.
  • HSP90 represents about 1-2% of the total cellular protein mass. It is usually present in the cell as a dimer and is associated with a variety of proteins, so-called co-chaperones (see, e.g., Pratt, 1997). HSP90 is essential for the vitality of cells (Young et al., 2001) and plays a key role in the response to cellular stress by interacting with many proteins whose native folding by external stress, e.g. Heat shock, was changed to restore the original folding or the aggregation of
  • HSP90 is important as a buffer against the effects of mutations, presumably by correcting for incorrect protein folding induced by the mutation (Rutherford and Lindquist, 1998).
  • HSP90 also has a regulatory significance. Under physiological conditions, HSP90, along with its endoplasmic reticulum homolog, GRP94, plays a role in the cell balance to ensure the stability of the conformation and maturation of various "serving" key proteins, which can be divided into three groups: steroid hormone receptors, sera / Thr or tyrosine kinases (eg ERBB2, RAF-1, CDK4 and LCK) and a
  • the conserved human HSP90 family consists of four genes, the cytosolic HSP90 ⁇ , the inducible HSP90 ⁇ isoform (Hickey et - A -
  • ERBB2 is a specific "serving" protein of GRP94 (Argon et al., 1999 ), while the type 1 receptor of tumor necrosis factor (TNFR1) or the retinoblastoma protein (Rb) were detected as "clients" of TRAP1 (Song et al., 1995; Chen et al., 1996).
  • TNFR1 tumor necrosis factor
  • Rb retinoblastoma protein
  • HSP90 inhibitors were benzoquinone ansamycins with the compounds herbimycin A and geldanamycin. Originally, they were used to detect the reversion of the malignant phenotype in fibroblasts induced by transformation with the v-Src oncogene (Uehara et al., 1985).
  • geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17AAG) showed an unchanged property in the inhibition of HSP90, the degradation of "serving" proteins and antitumoral activity in
  • Radicicol a macrocyclic antibiotic, also demonstrated a revision of the v-Src and v-Ha-Ras-induced malignant phenotype of fibroblasts (Kwon et al 1992, Zhao et al, 1995). Radicicol downgrades one
  • PU3 a purine-derived HSP90 inhibitor, the degradation of signaling proteins, e.g. ERBB2, are shown. PU3 causes cell cycle arrest and differentiation in breast cancer cell lines (Chiosis et al., 2001).
  • Heterocomplexes that "serve" proteins via the ubiquitin-proteasome pathway of degradation see, eg, Neckers et al., 1999; Kelland et al., 1999) .Treating tumor cells with HSP90 inhibitors leads to the selective degradation of important proteins fundamental for processes such as cell proliferation, cell cycle regulation and apoptosis. These processes are often deregulated in tumors (see, eg, Hostein et al., 2001).
  • the present invention relates to compounds which inhibit, regulate and / or modulate HSP90, compositions containing these compounds, and methods for their use in the treatment of HSP90-related diseases such as tumor diseases, viral diseases such as hepatitis B (Waxman , 2002); ⁇ c Immunosuppression in transplantations (Bijlmakers, 2000 and Yorgin, 2000); Inflammatory Diseases (Bucci, 2000) such as Rheumatoid Arthritis, Asthma, Multiple Sclerosis, Type 1 Diabetes, Lupus Erythematosus, Psoriasis and Inflammatory Bowel Disease; cystic
  • HSP90-related diseases such as tumor diseases, viral diseases such as hepatitis B (Waxman , 2002); ⁇ c Immunosuppression in transplantations (Bijlmakers, 2000 and Yorgin, 2000); Inflammatory Diseases (Bucci, 2000) such as Rheumatoid Arthritis, Asthma, Multiple Sclerosis, Type
  • fibrogenetic diseases e.g. Scleroderma, polymyositis, systemic lupus, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis (Strehlow, WO 02/02123).
  • the present invention therefore relates to the compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases
  • Preparation of a pharmaceutical for the treatment and / or prophylaxis of said diseases, as well as a method for the treatment of said diseases comprising administering one or more of the compounds of the invention to a patient in need of such administration.
  • the host or patient may be of any mammalian species, e.g. An O Q primate species, especially humans; Including rodents
  • mice Mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, being a model for the treatment of a disease of the
  • WO 01/72779 purine compounds are described, as well as their use for the treatment of GRP94 (homolog or paralogue to HSP90) -related diseases, such as tumors, wherein the GRP94 (homolog or paralogue to HSP90) -related diseases, such as tumors, wherein the GRP94 (homolog or paralogue to HSP90) -related diseases, such as tumors, wherein the GRP94 (homolog or paralogue to HSP90) -related diseases, such as tumors, wherein the
  • Adenovirus herpes simplex type I (HSV-I), herpes simplex type II (HSV-I) II), rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus (RSV), papillomavirus, papovavirus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackievirus, mumpsvirus, measles virus, rotten virus, poliovirus, human immunodeficiency virus type I (HIV-I) and human Immunodeficiency virus type II (HIV-II).
  • WO 01/72779 further describes the use of the compounds mentioned there for GRP94 modulation, wherein the modulated biological GRP94 activity is an immune reaction in an individual,
  • the disorder is a type of cancer, an infectious disease, i c a disorder associated with a disordered one Protein transport from the endoplasmic reticulum, a disorder associated with ischemia / reperfusion, or combinations thereof, wherein the ischemia / reperfusion-associated disorder is a consequence of cardiac arrest;
  • WO 01/72779 describes the use of an effective amount of a GRP94 protein modulator for the manufacture of a medicament for altering a subsequent cellular response to an ischemic condition in a human
  • ischemic condition Activity in cells is so much enhanced that a subsequent Cellular response to an ischemic condition, the subsequent ischemic condition being preferably the result of cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation,
  • Stroke hemorrhagic stroke, cerebral vasospasm, hypotension, hypoglycemia, status epilepticus, epileptic seizure, anxiety, schizophrenia, neurodegenerative disorder, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), or neonatal stress, or wherein the tissue site which is donor tissue for a transplant.
  • tissue site which is donor tissue for a transplant.
  • F508 cystic fibrosis transmembrane conductance regulator (CFTR) - molecular chaperone complex with geldanamycin stabilizes delta F508 CFTR in the rabbit reticulocyte lysate ", J. Biol. Chem., Vol. 275 (48), pp.
  • the starting materials can, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of the invention.
  • Tetrahydrofuran (THF) or dioxane Tetrahydrofuran (THF) or dioxane; Glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitrites such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents.
  • Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ke
  • acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, e.g. Hydrogen halides such as
  • compositions which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,
  • the term "pharmaceutically acceptable salt” in the present context means an active ingredient which is a compound of the invention in
  • Salt form imparts improved pharmacokinetic properties to the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient which has previously been used.
  • diastereomers are formed from the mixture by reaction with an optically active release agent.
  • Suitable release agents are e.g. optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid,
  • N-protected amino acids e.g., N-benzoylproline or N-benzenesulfonylproline
  • suitable N-protected amino acids e.g., N-benzoylproline or N-benzenesulfonylproline
  • optically active camphorsulfonic acids e.g., chromatographic enantiomer separation using an optically active resolving agent (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or silica gel-fixed chirally derivatized methacrylate polymers).
  • Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures such. Hexane / isopropanol / acetonitrile e.g. in the ratio 82: 15: 3.
  • the invention further provides the use of the compounds and / or their physiologically acceptable salts for the preparation of a pharmaceutical preparation (pharmaceutical preparation), in particular by a non-chemical route.
  • a pharmaceutical preparation pharmaceutical preparation
  • they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or excipient and optionally in combination with one or more further active ingredients.
  • compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
  • a moiety may contain, for example, from 0.1 mg to 3 g, preferably from 1 mg to 700 mg, more preferably from 5 mg to 100 mg of a compound of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be in the form of dosage units containing a predetermined amount of active ingredient per
  • dosage unit included, to be presented.
  • Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction of an active ingredient.
  • such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
  • compositions may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) Ways, adapt.
  • Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).
  • compositions adapted for oral administration may be presented as separate entities, such as capsules or tablets; powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the active component when administered orally in the form of a tablet or capsule, may be mixed with an oral, non-toxic and pharmaceutically acceptable inert carrier such as e.g. Ethanol, glycerin, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as j-starch or mannitol. A flavor, preservative, dispersant and dye may also be present.
  • an oral, non-toxic and pharmaceutically acceptable inert carrier such as e.g. Ethanol, glycerin, water and the like. combine.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as j-starch or mannitol.
  • a flavor, preservative, dispersant and dye may also be present
  • Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith. 0
  • Lubricants such as e.g. fumed silica, talc,
  • Magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
  • a disintegrants or solubilizers e.g. Agar-agar, calcium carbonate 5 or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia,
  • a powder mixture is prepared by treating the suitably comminuted compound with a diluent or base as described above and optionally with a binder such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution initiator such as paraffin Resorptionsbevanter, such as a quaternary salt and / or an absorbent, such as bentonite, kaolin or dicalcium phosphate, is mixed.
  • the powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials and pressing it through a sieve.
  • Granulation can be run through the powder mixture through a tabletting machine, resulting in irregularly shaped lumps in
  • Granules are broken up.
  • the granules may be greased by adding stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds.
  • the greased mixture is then compressed into tablets.
  • the compounds according to the invention can also be combined with a free-flowing inert carrier and then pressed directly into tablets without carrying out the granulation or dry-pressing steps.
  • a transparent or opaque protective layer consisting of a shellac sealant, a layer of sugar or polymeric material, and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.
  • Oral fluids such as solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound.
  • Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, among others, may also be added.
  • the unit dosage formulations for oral administration may optionally be encapsulated in microcapsules.
  • the formulation may also be prepared to prolong or retard release, such as by coating or embedding particulate material in polymers, wax, and the like.
  • the compounds of the invention can also be administered in the form of liposome delivery systems, e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes can be prepared from various phospholipids, such as e.g. Cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the invention as well as the salts, solvates and physiologically functional derivatives thereof can also be prepared using monoclonal antibodies as individual carriers to which the
  • Coupled connection molecules are supplied.
  • Drug carriers are coupled.
  • Such polymers can be polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals.
  • the compounds may be useful in a class of biodegradable polymers suitable for controlled release of a drug, eg, polylactic acid, polyepsilone-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of 10 Hydrogels, coupled.
  • compositions adapted for transdermal administration may be presented as discrete patches for prolonged, close s c contact with the epidermis of the recipient.
  • the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be either paraffinic or water-miscible
  • 2Q cream base can be used.
  • the active ingredient can become a
  • Cream can be formulated with an oil-in-water cream base or a water-in-oil base.
  • 35 ceutical formulations include eye drops, wherein the active ingredient in a suitable carrier, in particular an aqueous solvent, dissolved or suspended.
  • Formulations include lozenges, lozenges and mouthwashes. 5
  • compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
  • Formulations in which the vehicle is a solid include a coarse powder having a particle size, for example, in the range of 20-500 microns, which is administered in the manner in which snuff is received, i. by rapid inhalation over the
  • Suitable formulations for administration as a nasal spray or nasal drops with a liquid carrier include drug solutions in water or oil.
  • Fine particulate dusts or mists which may be generated by various types of pressurized dosing dispensers with 5 aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be used as pessaries, tampons, creams, gels, pastes,
  • Foams or spray formulations are presented. 0
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes, by which the formulation is isotonic with the blood of the subject
  • Recipient is included; as well as aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
  • the formulations may be presented in single or multi-dose containers, such as sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, eg water for injections, is required immediately before use.
  • Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
  • formulations may include other means conventional in the art with respect to the particular type of formulation; so can
  • . c suitable for example for oral administration, formulations flavors.
  • an effective amount of a salt or solvate or a physiologically functional derivative thereof may be determined as a proportion of the effective amount of the compound of the invention per se. It It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
  • chemotherapeutic agents are preferred, in particular those which inhibit angiogenesis and thereby inhibit the growth and spread of tumor cells; are preferred
  • VEGF receptor inhibitors including Robozyme and antisense, which are directed to VEGF receptors, and angiostatin and endostatin.
  • Compounds of the invention can be used generally include alkylating agents, antimetabolites; Epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor;
  • Antineoplastic agents are preferably selected from the following classes:
  • Anthracycline Vinca drugs, mitomycins, bleomycins, cytotoxic O Q nucleosides, epothilones, discodermolides, pteridines, Diynenes and
  • Mitomycin C 1 porfiromycin, 5-fluorouracil, 5-fluorodeoxyuridine
  • Vindesine, Leurosine, Docetaxel and Paclitaxel are selected from the group
  • antibiotics are preferred.
  • Preferred antibiotics are selected from the group dactinomycin, daunorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, plicamycin, mitomycin.
  • enzyme inhibitors are preferred.
  • Preferred enzyme inhibitors are selected from the group of histone deacetylation inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA]) and tyrosine kinase inhibitors (e.g., ZD 1839 [Iressa]). 5
  • histone deacetylation inhibitors e.g., suberoylanilide hydroxamic acid [SAHA]
  • tyrosine kinase inhibitors e.g., ZD 1839 [Iressa]
  • nuclear export inhibitors prevent the removal of biopolymers (e.g., RNA) from the nucleus.
  • biopolymers e.g., RNA
  • 3Q inhibitors are selected from the group Callystatin, Leptomycin B, Ratjadone.
  • nuclear export inhibitors are preferred. Nuclear export inhibitors prevent the discharge of
  • Biopolymers eg RNA from the cell nucleus.
  • Preferred nuclear export Inhibitors are selected from the group Callystatin, Leptomycin B, Ratjadone.
  • immunosuppressants are preferred.
  • Preferred immunosuppressants are selected from the group rapamycin, CCI-779 (Wyeth), RAD001 (Novartis), AP23573 (Ariad Pharmaceuticals).
  • the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
  • the set may e.g. containing separate ampoules, in each of which an effective amount of a compound of the invention and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance dissolved or in lyophilized form.
  • the present compounds are useful as pharmaceutical
  • the invention thus relates to the use of compounds according to the invention, as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their
  • the present invention comprises the use of the compounds according to the invention and / or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment of tumor diseases, such as, for example, Fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer,
  • tumor diseases such as, for example, Fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcom
  • HSV-I herpes simplex type I
  • the binding of geldanamycin or 17-allylamino-17-demethoxy-geldanamycin (17AAG) and their competitive inhibition to HSP90 can be used to determine the inhibitory activity of the compounds of the invention (Carreras et al., 2003, Chiosis et al., 2002).
  • a radioligand filter binding test is used.
  • the radioligand used is tritium-labeled 17-allylamino-geldanamycin, [3H] 17AAG. This filter binding assay allows a targeted search for inhibitors that interfere with the ATP binding site.
  • Multiscreen FB (1 ⁇ m) filter plate (Millipore, MAFBNOB 50).
  • the 96 well microtiter filter plates are first watered and with
  • the test is carried out under the following conditions:
  • the supernatant in the filter plate is aspirated using a vacuum manifold (Millipore Multiscreen Separation System) and the filter washed twice.
  • the filter plates are then measured in a beta counter (Microbeta, Wallac) with scintillator (Microscint 20, Packard).
  • solvent A H2O (0.1% TFA)
  • solvent B ACN (0.1% TFA)
  • Solvent B ACN (0.01% TFA) 99% A ⁇ 100% B: run time 5 minutes / flow rate 2.75 ml / minute
  • Solvent B ACN (0.01% TFA)
  • Example A Injection glasses
  • Disodium hydrogen phosphate is adjusted to pH 6.5 in 2 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and sealed in a sterile manner. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • Benzalkonium chloride in 940 ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation.
  • Solution can be used in the form of eye drops.
  • 500 mg of an active ingredient according to the invention are mixed with 99.5 g of Vaseline under aseptic conditions.
  • a mixture of 1 kg of active ingredient, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is added in the usual manner
  • Example F dragees
  • Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.
  • a solution of 1 kg of an active ingredient according to the invention in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

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Abstract

De nouveaux dérivés d'aminopyrimidine selon la revendication 1 sont des inhibiteurs de HSP90 et peuvent être utilisés pour la production d'un médicament destiné au traitement de maladies pour lesquelles l'inhibition, la régulation et/ou la modulation de HSP90 jouent un rôle.
PCT/EP2007/000708 2006-02-27 2007-01-26 Dérivés de l'aminopyrymidine WO2007098835A1 (fr)

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DE102006008880.8 2006-02-27
DE102006008880A DE102006008880A1 (de) 2006-02-27 2006-02-27 Aminopyrimidinderivate

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WO2007098835A1 true WO2007098835A1 (fr) 2007-09-07

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GB2449293A (en) * 2007-05-17 2008-11-19 Evotec Compounds having Hsp90 inhibitory activity
US20130324566A1 (en) * 2011-02-28 2013-12-05 USTAV EXPERIMENTALNI MEDICINY AKADEMIE VED CR, v.v.i. Pyrimidine compounds inhibiting the formation of nitric oxide and prostaglandin e2, method of production thereof and use thereof
WO2020257261A1 (fr) * 2019-06-17 2020-12-24 Northwestern University Hétérocycles substitués servant d'agents de ciblage de c-myc

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EP2519519A4 (fr) 2009-12-30 2013-04-24 Arqule Inc Composés naphthalényl-pyrimidine substitués
US10336768B2 (en) 2014-06-13 2019-07-02 Yuma Therapeutics, Inc. Pyrimidine compounds and methods using the same
EP3575301A4 (fr) 2017-03-16 2020-08-05 Jiangsu Hengrui Medicine Co., Ltd. Dérivé d'hétéroaryl[4,3-c]pyrimidine-5-amine, son procédé de préparation et ses utilisations médicales

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WO1986004583A1 (fr) * 1985-02-05 1986-08-14 The Upjohn Company Composes de 4-substitue-6-aryl-pyrimidine
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WO2004014871A1 (fr) * 2002-08-08 2004-02-19 Amgen Inc. Ligands de recepteur vanilloide et leur utilisation dans des traitements
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WO1986004583A1 (fr) * 1985-02-05 1986-08-14 The Upjohn Company Composes de 4-substitue-6-aryl-pyrimidine
WO2001062233A2 (fr) * 2000-02-25 2001-08-30 F. Hoffmann La Roche Ag Modulateurs de recepteurs de l'adenosine
WO2004014871A1 (fr) * 2002-08-08 2004-02-19 Amgen Inc. Ligands de recepteur vanilloide et leur utilisation dans des traitements
WO2006123165A2 (fr) * 2005-05-19 2006-11-23 Astex Therapeutics Limited Composes pharmaceutiques

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MATASI ET AL: "2-(2-Furanyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin-5-amine analogs: Highly potent, orally active, adenosine A2A antagonists. Part 1", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 15, no. 16, 15 August 2005 (2005-08-15), pages 3670 - 3674, XP005003383, ISSN: 0960-894X *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2449293A (en) * 2007-05-17 2008-11-19 Evotec Compounds having Hsp90 inhibitory activity
US20130324566A1 (en) * 2011-02-28 2013-12-05 USTAV EXPERIMENTALNI MEDICINY AKADEMIE VED CR, v.v.i. Pyrimidine compounds inhibiting the formation of nitric oxide and prostaglandin e2, method of production thereof and use thereof
US8883798B2 (en) * 2011-02-28 2014-11-11 USTAV ORGANICKE CHEMIE A BIOCHEMIE AKADEMIE VED CR, v.v.i. Pyrimidine compounds inhibiting the formation of nitric oxide and prostaglandin E2, method of production thereof and use thereof
CZ305457B6 (cs) * 2011-02-28 2015-09-30 Ústav organické chemie a biochemie, Akademie věd ČR v. v. i. Pyrimidinové sloučeniny inhibující tvorbu oxidu dusnatého a prostaglandinu E2, způsob výroby a použití
WO2020257261A1 (fr) * 2019-06-17 2020-12-24 Northwestern University Hétérocycles substitués servant d'agents de ciblage de c-myc
US11420957B2 (en) 2019-06-17 2022-08-23 Northwestern University Substituted heterocycles as c-MYC targeting agents

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