EP1853550A1 - Indanes - Google Patents

Indanes

Info

Publication number
EP1853550A1
EP1853550A1 EP06706895A EP06706895A EP1853550A1 EP 1853550 A1 EP1853550 A1 EP 1853550A1 EP 06706895 A EP06706895 A EP 06706895A EP 06706895 A EP06706895 A EP 06706895A EP 1853550 A1 EP1853550 A1 EP 1853550A1
Authority
EP
European Patent Office
Prior art keywords
methyl
formula
compounds
phenyl
bis
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP06706895A
Other languages
German (de)
English (en)
Inventor
Dirk Finsinger
David Bruge
Hans-Peter Buchstaller
Ulrich Emde
Kai Schiemann
Wolfgang Staehle
Christiane Amendt
Nina Heiss
Frank Zenke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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 Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1853550A1 publication Critical patent/EP1853550A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/08—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/657—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings
    • C07C49/665—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings a keto group being part of a condensed ring system
    • C07C49/67—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings a keto group being part of a condensed ring system having two rings, e.g. tetralones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms

Definitions

  • the present invention relates to compounds of formula I which preferentially inhibit, regulate and / or modulate one or more mitotic motor proteins, compositions containing these compounds, and methods for their use in the treatment of diseases and conditions such as angiogenesis, cancer , Tumorigenesis, growth and spread, arteriosclerosis, ocular disorders, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, wound healing or graft rejection.
  • diseases and conditions such as angiogenesis, cancer , Tumorigenesis, growth and spread, arteriosclerosis, ocular disorders, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, wound healing or graft rejection.
  • the compounds according to the invention are suitable for the therapy or prophylaxis of cancerous diseases.
  • the compounds according to the invention bring about a specific inhibition of the mitotic motor proteins, in particular Eg5.
  • Show the compounds of the invention o _ preferably exhibit an advantageous biological activity which can, for example, described in the herein assays is readily detectable.
  • the compounds of the invention preferably exhibit and effect an inhibiting effect, usually by IC 50 values in a suitable range, preferably in the micromolar range, and more preferably
  • the present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the
  • the invention relates to compounds of the formula I:
  • R 1 is H, A, Ar, Het, phenyl, methyl, OR 4 , SR 4 , OAr, SAr, N (R 4 ) 2 , NR 4 Ar, Hal, NO 2 , CN, (CH 2 ) m COOR 4 , (CH 2 ) m COOAr, (CH 2 ) m CON (R 4 ) 2 , (CH 2 ) m CONHAr, COR 4 , COAr, S (O) n AS (O) m Ar, NHCOA, NHCOAr, NHSO 2 A, NHSO 2 Ar or SO 2 N (R 4 ) 2 , R 2 , R 3 are each independently A, Het, H, -OH, -OA, -OAr, Ar, -O-CO-A, -OSO 3 R 5 , -OSO 2 R 5 , -OAr 2 R 5 , SO 2 R 5 , Hal, COOR 5 , CON (R 5 ) 2 , NHSO 2 A
  • Such bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; such as
  • N-methyl-glutamine N-methyl-glutamine.
  • the aluminum salts of the compounds of formula I are also included.
  • acid addition salts can be formed by reacting these compounds with
  • c pharmaceutically acceptable organic and inorganic acids for example hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and
  • Monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate,
  • 2-naphthalenesulfonate nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, Persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.
  • Preferred among the above salts are ammonium; the
  • Alkali metal salts sodium and potassium, as well as the alkaline earth metal salts sodium and potassium, as well as the alkaline earth metal salts
  • Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, e.g.
  • Arginine betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, Glucosamine, histidine,
  • Tromethamine Hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl) -methylamine ( Tromethamine), which is not
  • Compounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C 4 ) alkyl halides, eg, methyl, ethyl, isopropyl, and tert-butyl chloride, bromide, and iodide; Di (C 1 -C 4 ) alkyl sulfates, eg dimethyl, diethyl and diamylsulfate; (Ci 0 - Ci 8 ) alkyl halides, eg decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl- (C 1 -C 4 ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize.
  • agents such as (C 1 -C 4 ) alkyl halides, eg, methyl, e
  • Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate,
  • Drug provides improved pharmacokinetic properties compared to the free form of the drug or any other salt form of the drug previously used.
  • the pharmaceutically acceptable salt form of the active substance may also first impart a desired pharmacokinetic property to this active ingredient which it has not previously possessed, and may even positively influence the pharmacodynamics of this active ingredient in terms of its therapeutic efficacy in the body.
  • the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
  • Pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
  • 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).
  • 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.
  • Disintegrants or solubilizers e.g. Agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
  • Gelatin natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like.
  • the lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the compounds of the formula I as well as salts, solvates and physiologically functional derivatives thereof can also be prepared in the form of liposome delivery systems, such as e.g. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • compositions adapted for transdermal administration may be used as stand-alone patches for longer, narrower patches
  • Cream base can be used.
  • the active ingredient may become a
  • the pharmaceutical formulations adapted for topical application to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Fine particulate dusts or mists which may be delivered by inhalation various types of pressurized dispensers with aerosols, nebulizers or insufflators can be produced.
  • Foams or spray formulations are presented.
  • compositions adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
  • the formulations may be administered in single or multiple dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use.
  • Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
  • the 5 actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six). can be given per day, so that the total daily dose is the same.
  • ⁇ g disease states are suitable.
  • CapCell TM CYP450-N-acetylcysteine
  • Point MX6 apoptosis promoter
  • CDA-il apoptosis-Ro-31-7453 (apoptosis
  • SDX-101 apoptosis-brostallicin (apoptosis)
  • Rhizoxin (Fujisawa) LU 223651 (BASF)
  • Auristatin PE (Teikoku NeuroPharma)
  • Taxoprexin Protarga
  • CA-4 OXiGENE
  • Retinoic Acid Fenretinide Johnson & Alitretinoin (Ligand) R-agonist Johnson
  • Cytotoxic agents refers to compounds which result in primarily through direct action on the cellular function 5 to cell death or inhibit cell myosis or interfere with, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors and topoisomerase inhibitors.
  • a c dioxy) -5-methyl-7-hydroxy-8-methoxybenzo [c] phenanthridinium, 6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline-5,10-dione, 5- (3 Aminopropylamino) - 7,10-dihydroxy-2- (2-hydroxyethylaminomethyl) ⁇ 6H-pyrazolo [4,5,1-de] acridin-6-one, N- [1- [2 (diethylamino) ethylamino] ⁇ 7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4-
  • Antiproliferative agents include antisense RNA and DNA
  • antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,
  • Doxifluridine trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazo- furin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2 ', 30 methylidenecytidine, 2 I - Fluoromethylene-2'-deoxycytidine, N- [5- (2,3-
  • Particularly preferred is the use of the compound according to the invention for the treatment and prophylaxis of tumor diseases.
  • first and second compounds are administered simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of the neoplasm.
  • Suitable pentamidine analogs include stilbamidine (G-1) and hydroxystilbamidine (G-2) and their indole analogs (eg G-3):
  • Each amidineinethite can be independently replaced by one of the units shown above as D-2, D-3, D-4, D-5 or D-6.
  • salts of stilbamidine, hydroxystilbamidine and their indole derivatives are also useful in the process of the present invention.
  • Preferred salts include, for example, dihydrochloride and methanesulfonate salts.
  • Exemplary analogs include 1, 5-bis (4 '- (N-hydroxyamidino) phenoxy) pentane, 1, 3-bis (4' - (N-hydroxyamidino) phenoxy) propane, 1, 3-bis (2 I -methoxy-4 I - (N-hydroxyamidino) phenoxy) - propane, 1, 4-bis (4 I - (N-hydroxyamidino) phenoxy) butane, 1, 5-bis- (4 '- (N- hydroxyamidino) phenoxy) pentane, 1,4-bis (4 '- (N-hydroxyamidino) phenoxy) butane, 1, 3-bis- (4' - (4-hydroxyamidino) phenoxy) propane, 1, 3-bis - (2'-methoxy-4 '- (N-hydroxyamidino) phenoxy) propane, 2,5-bis [4-amidinophenyl] furan, 2,5-bis- [4-amidinophenyl] furan-bis-amidoxime, 2 , 5-Bis- [4-
  • Combination therapy may be performed alone or in conjunction with another therapy (eg surgery, radiation, chemotherapy, biological therapy).
  • another therapy eg surgery, radiation, chemotherapy, biological therapy.
  • a person whose risk of developing a neoplasm is greater eg, someone who is genetically predisposed or someone who previously had a neoplasm
  • the dosage and frequency of administration of each compound of the combination can be independently controlled. For example, one compound may be administered orally three times a day while the second
  • Compound once a day can be administered intramuscularly.
  • Compounds may also be formulated together so that administration will deliver to both compounds.
  • Components of a pharmaceutical package can be provided.
  • the two drugs can be taken together or separately and in single
  • Dosage amounts are formulated.
  • the invention includes a method of treating a patient having a neoplasm, such as a cancer
  • Administering a compound of formula (I), and (VI) in combination with an antiproliferative agent Administering a compound of formula (I), and (VI) in combination with an antiproliferative agent.
  • Suitable antiproliferative agents include those provided in Table 1.
  • “usual workup” means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracted with ethyl acetate or dichloromethane, separating, drying organic phase over sodium sulfate, evaporated and purified by chromatography
  • APCI-MS atmospheric pressure chemical ionization - mass spectrometry
  • the determination of the activity of the compounds of the formula I according to the invention can e.g. via the Eg5-ATPase activity, which is measured by enzymatic regeneration of the product ADP to ATP by means of pyruvate kinase (PK) and subsequent coupling to an NADH-dependent lactate dehydrogenase (LDH) reaction.
  • PK pyruvate kinase
  • LDH lactate dehydrogenase
  • the reaction can be monitored by changing the absorbance at 340 nm.
  • the regeneration of the ATP simultaneously ensures that the substrate concentration remains constant.
  • the absorbance change per unit time is analyzed graphically and a linear regression is performed in the vusually linear region of the reaction.
  • 10 3 to 10 4 cells of a defined cell line (HCT116, CoIo 205, MDA-MB 231, etc.) are seeded per well in a 96-well microtiter plate and cultured overnight under standard conditions.
  • 10-50 mM stock solutions in DMSO were prepared. Dilution series (usually 3-fold dilution steps) of the individual substances were in the form of a pipetting scheme (see scheme below), while maintaining a DMSO final concentration of 0.5%
  • Example C Injection glasses
  • a solution of 100 g of an active compound of the formula I and 5 g of 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 closed under sterile conditions. Each injection jar contains 5 mg of active ingredient.
  • Example D Suppositories
  • each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active compound of the formula I, 9.38 g of NaH 2 PO 4 • 2H 2 O, 28.48 g of Na 2 HPO 4 • 12H 2 O and 0.1 g of benzalkonium chloride in 940 is prepared ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.
  • Example F ointment
  • 500 mg of an active compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the usual way into tablets, such that each tablet contains 10 mg of active ingredient.
  • Example E tablets are pressed, which are then in the usual
  • a solution of 1 kg of active compound of the formula I 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des composés de formule (I) dans laquelle R<SUP>1</SUP>, R<SUP>2</SUP>, R<SUP>3</SUP>, R<SUP>4</SUP> et q ont les significations énoncées dans la revendication 1. Ces composés peuvent être utilisés pour traiter des tumeurs.
EP06706895A 2005-03-04 2006-02-13 Indanes Withdrawn EP1853550A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005010000A DE102005010000A1 (de) 2005-03-04 2005-03-04 Indane
PCT/EP2006/001283 WO2006094602A1 (fr) 2005-03-04 2006-02-13 Indanes

Publications (1)

Publication Number Publication Date
EP1853550A1 true EP1853550A1 (fr) 2007-11-14

Family

ID=36572071

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06706895A Withdrawn EP1853550A1 (fr) 2005-03-04 2006-02-13 Indanes

Country Status (8)

Country Link
US (2) US20090118267A1 (fr)
EP (1) EP1853550A1 (fr)
JP (1) JP2008531612A (fr)
AR (1) AR053156A1 (fr)
AU (1) AU2006222341B2 (fr)
CA (1) CA2600606C (fr)
DE (1) DE102005010000A1 (fr)
WO (1) WO2006094602A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CL2008003063A1 (es) 2007-10-19 2010-01-04 Schering Corp Compuestos derivados de 1,3,4-tiadiazol espiro condensado, inhibidores de la actividad quinesina ksp; composicion farmaceutica; y su uso en el tratamiento de enfermedades proliferativas tales como el cancer, hiperplasia, hipertrofia cardiaca, enfermedades autoinmune, trastornos fungicos, artritis, rechazo a imjertos, entre otras.
CA2706171C (fr) * 2007-11-28 2013-10-08 Astellas Pharma Inc. Compose d'indane fusionne
JP5641054B2 (ja) * 2010-12-03 2014-12-17 富士通株式会社 新規化合物、並びに、キネシンスピンドルタンパク質阻害剤及びその応用
TW202200554A (zh) * 2020-03-16 2022-01-01 瑞士商諾華公司 作為ｙａｐ／ｔａｚ—ｔｅａｄ蛋白—蛋白相互作用抑制劑之聯芳基衍生物
WO2023155927A1 (fr) * 2022-02-21 2023-08-24 上海奕拓医药科技有限责任公司 Inhibiteur de l'interaction entre yap/taz et tead, sa préparation, composition pharmaceutique associée et son utilisation

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2820817A (en) * 1954-02-04 1958-01-21 Mcneilab Inc Oxygenated indan compounds and method of making the same
DE1470055A1 (de) * 1963-12-07 1969-07-17 Merck Ag E Verfahren zur Herstellung von Piperidinderivaten
US3328441A (en) * 1963-12-10 1967-06-27 Stauffer Chemical Co Preparing organotin mercaptides by reacting diorganotin oxides with esters of thiocarboxylic acids
US3553093A (en) * 1965-03-19 1971-01-05 Xerox Corp Color photoelectrophoretic imaging process
NL7309425A (fr) * 1972-07-21 1974-01-23
CH647235A5 (de) * 1980-02-13 1985-01-15 Sandoz Ag 4-(2,2-dialkylindan-1-yliden)piperidin derivate, ihre herstellung und verwendung.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006094602A1 *

Also Published As

Publication number Publication date
US20120130147A1 (en) 2012-05-24
JP2008531612A (ja) 2008-08-14
AR053156A1 (es) 2007-04-25
DE102005010000A1 (de) 2006-09-07
CA2600606A1 (fr) 2006-09-14
WO2006094602A1 (fr) 2006-09-14
CA2600606C (fr) 2013-12-24
US20090118267A1 (en) 2009-05-07
AU2006222341A1 (en) 2006-09-14
AU2006222341B2 (en) 2012-08-02

Similar Documents

Publication Publication Date Title
EP2193118B1 (fr) Dérivés de pipéridine et de pipérazine pour le traitement de tumeurs
WO2008080455A1 (fr) Tétrahydrobenzo-isoxazole et dérivé de tétrahydro-indazole comme modulateurs de la protéine moteur mitotique
EP2033959B1 (fr) Tétrahydropyranochinolines
WO2006125555A2 (fr) Chinazolinones
WO2010060532A1 (fr) Composés de benzonaphtyridine en tant qu&#39;inhibiteurs de l&#39;autotaxine
WO2009046804A1 (fr) Dérivés d&#39;imidazole
DE102007047735A1 (de) Thiazolderivate
EP1891011B1 (fr) Tetrahydroquinoleines comme modulateurs de la proteine moteur mitotique eg5
EP1891076B1 (fr) Tetrahydrochinoline substituee
EP2121700B1 (fr) Tétrahydroquinoline substituée
EP1891013B1 (fr) Dérivés de tétrahydroquinoléine
DE102007013854A1 (de) Tetrahydrochinoline
WO2006002726A1 (fr) Tetrahydroquinoline
EP1853550A1 (fr) Indanes
EP1858860A1 (fr) Phtalazinones
WO2008113452A1 (fr) Tétrahydropyrroloquinoléines substituées
WO2005108355A2 (fr) Dihydrobenzothiophene

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070707

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

RIN1 Information on inventor provided before grant (corrected)

Inventor name: EMDE, ULRICH

Inventor name: SCHIEMANN, KAI

Inventor name: AMENDT, CHRISTIANE

Inventor name: HEISS, NINA

Inventor name: STAEHLE, WOLFGANG

Inventor name: BRUGE, DAVID

Inventor name: BUCHSTALLER, HANS-PETER

Inventor name: FINSINGER, DIRK

Inventor name: ZENKE, FRANK

RIN1 Information on inventor provided before grant (corrected)

Inventor name: BRUGE, DAVID

Inventor name: FINSINGER, DIRK

Inventor name: HEISS, NINA

Inventor name: EMDE, ULRICH

Inventor name: ZENKE, FRANK

Inventor name: SCHIEMANN, KAI

Inventor name: BUCHSTALLER, HANS-PETER

Inventor name: STAEHLE, WOLFGANG

Inventor name: AMENDT, CHRISTIANE

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20130410

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20130710