EP2121706A1 - Tetrahydroquinoline derivatives and use of same for treating cancer - Google Patents

Tetrahydroquinoline derivatives and use of same for treating cancer

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Publication number
EP2121706A1
EP2121706A1 EP08715973A EP08715973A EP2121706A1 EP 2121706 A1 EP2121706 A1 EP 2121706A1 EP 08715973 A EP08715973 A EP 08715973A EP 08715973 A EP08715973 A EP 08715973A EP 2121706 A1 EP2121706 A1 EP 2121706A1
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Prior art keywords
compounds
formula
bis
compound
salts
Prior art date
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EP08715973A
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German (de)
French (fr)
Inventor
Kai Schiemann
Dirk Finsinger
Christiane Amendt
Frank Zenke
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Merck Patent GmbH
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Merck Patent GmbH
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Publication of EP2121706A1 publication Critical patent/EP2121706A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the invention was based on the object, new compounds with valuable
  • the present invention relates to compounds of the formula I and their use for the treatment and prophylaxis of diseases in which the inhibition, regulation and / or modulation of mitotic motor proteins, in particular of the mitotic motor protein Eg5 plays a role, and also pharmaceutical compositions which contain these compounds.
  • the present invention relates to compounds of the formula I which inhibit, regulate and / or modulate, preferably, 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.
  • 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 graf
  • Eg5 regulates exclusively the movement of mitotic microtubules (spindle apparatus) and not those of the cytoskeleton. This is crucial for the side effect profile of the compounds according to the invention, since, for example, neuropathies, as are observed in taxol, do not occur or only weakened. Therefore, the inhibition of Eg5 by the compounds according to the invention is a relevant therapeutic concept for the treatment of malignant tumors.
  • all solid and non-solid tumors can be treated with the compounds of formula I, e.g. monocytic leukemia, brain, urogenital, lymphatic, gastric, laryngeal and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma.
  • Other examples include prostate, pancreatic and breast carcinoma.
  • the compounds according to the invention bring about a specific inhibition of the mitotic Moter proteins, in particular Eg5.
  • the compounds of the invention preferably exhibit a beneficial biological activity which is readily detectable in the assays described herein, for example.
  • the compounds of the invention preferably exhibit and effect an inhibitory effect, which is usually documented by IC 50 values in a suitable range, preferably in the micromolar range, and more preferably in the nanomolar range.
  • effects of the compound of the invention are relevant to various diseases. Accordingly, the compounds of the invention are useful in the prophylaxis and / or treatment of diseases that are affected by inhibition of one or more mitotic motor proteins, particularly Eg5.
  • the present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases and the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method of treatment said diseases comprising administering one or more of the compounds of the invention to a patient in need of such administration.
  • the compounds according to the invention have a beneficial effect in a xenograft tumor model.
  • the host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for the treatment of human disease.
  • the susceptibility of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro.
  • a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to allow the drugs to induce cell death or inhibit migration, usually between about one hour and one week.
  • For testing in vitro cultured cells from a biopsy sample can be used.
  • the viable cells remaining after treatment are then counted.
  • the dose will vary depending on the specific compound used, the specific disease, the patient status, etc.
  • a therapeutic dose will be sufficient to substantially reduce the unwanted cell population in the target tissue while maintaining patient viability. Treatment is generally continued until there is a significant reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells are detected in the body.
  • R 1 , R 2 independently of one another are H, A, Hal, SA, (CH 2 ) p CN, SCN, (CF 2 ) p CF 3) SF 5 , OA, O (CF 2 ) p CF 3 , S (CF 2 ) P CF 3 , NR 2 , NRCOR, NRSO 2 R,
  • aryl or heteroaryl which may be substituted by Hal, NO 2 , CN, A, OR, OCOR, NR 2 , CF 3 , OCF 3 , OCH (CF 3 ) 2 , Hal, NO 2 , CN , OR, A, - (CY 2 ) n -OR, -OCOR, - (CY 2 ) n -CO 2 R, - (CY 2 ) n -CN or - (CY 2 ) n -NR 2 substituted aryl or heteroaryl .
  • p 0, 1, 2, 3, 4, 5, 6, 7 or 8
  • s is 0, 1 or 2
  • their pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, including mixtures thereof in all ratios are 0, 1 or 2, and their pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, including mixtures thereof in all ratios.
  • Preferred herbsstad the present application are the compounds of formula 11:
  • the invention also relates to the optically active forms, the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds of the formula I which form on account of their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.
  • compositions of the invention are understood, for example, as the salts of the compounds of the invention as well as so-called prodrug compounds.
  • biodegradable polymer derivatives of the compounds of the invention include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995).
  • the term "effective amount” means the amount of a drug or pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.
  • terapéuticaally effective amount means an amount that produces at least one of the following effects in a human or other mammal (as compared to a subject who has not received that amount):
  • terapéuticaally effective amount also includes those amounts effective to increase or enhance normal physiological function.
  • the invention also provides the use of mixtures of the compounds of formula I, e.g. Mixtures of two diastereomers, e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000.
  • the invention also provides a process for the preparation of compounds of the formula I according to the claims and their pharmaceutically usable derivatives, salts, solvates and stereoisomers, characterized in that a compound of the formula selected from the following group:
  • R 4 has the meaning indicated above
  • X and s have the meanings given above, preferably in the presence of a protic acid or Lewis acid, e.g. Trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium (III) triflate, scandium (III) triflate or ceric ammonium (IV) nitrate,
  • a protic acid or Lewis acid e.g. Trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium (III) triflate, scandium (III) triflate or ceric ammonium (IV) nitrate,
  • R 3 introduces a radical other than H and / or optionally converts a base or acid of the formula I into one of its salts.
  • the mixtures of diastereomers optionally obtained by the process described above and
  • Alkyl is preferably unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms.
  • Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1, 1, 2 or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methylpropyl, 1, 1, 2 or 1, 2,2-trimethylpropyl, more preferably, for example Trifluoromethyl.
  • Alkyl very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl , Pentafluoroethyl or 1,1,1-trifluoroethyl.
  • Alkyl also means cycloalkyl.
  • Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but especially cyclopentyl.
  • X is preferably O or NR, in particular O.
  • R 1 is preferably alkyl, CF 3 , OCF 3 , SCN, COOR, CH 2 CN, OH, S, alkyl, O, alkyl, Hal, SCF 3 .
  • R 1 is t-butyl, CF 3 , Br, Cl, CF 3 or COOR.
  • R 2 is preferably H or Br, in particular H.
  • R 3 is preferably H or methyl, ethyl, n-propyl or n-butyl, in particular H.
  • R 4 is preferably aryl which may be substituted by F, Cl, OR or aryl.
  • R 4 is phenyl, hydroxyphenyl or alkylphenyl.
  • R is preferably H, or A or (CH 2 ) p NA (CH 2 ) p, R 3
  • W is preferably CH 2 or a single bond, in particular CH 2 .
  • Q 1 is preferably NR, a single bond or O, especially NR. Most preferably, Q 1 is NH.
  • Z is preferably SO 2 , CO, CS or a single bond.
  • Q 2 is preferably NR, O or a single bond.
  • R 5 is preferably H, (CY 2 ) P NR 2 or (CY 2 ) P OR, in particular (CY 2 ) P NR, or H.
  • Y is preferably H, A or F, in particular H.
  • n is preferably 0, 1, 2 or 3.
  • m is preferably 0 or 1, in particular 0.
  • p is preferably 0 or 2.
  • s is preferably 0 or 1.
  • Aryl is preferably unsubstituted or substituted once, twice or three times by Hal, A, OH, OA, NH 2 , NO 2 , CN, COOH, COOA, CONH 2 , NHCOA, NHCONH 2 , NHSO 2 A, CHO 1 COA , SO 2 NH 2 , SO 2 A, -CH 2 -COOH or -OCH 2 -COOH substituted phenyl, naphthyl or biphenyl.
  • Aryl is preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N -Methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m-
  • Heteroaryl preferably denotes a mono- or binuclear unsubstituted or mono-, di- or trisubstituted by Hal, A, NO 2 , NHA, NA 2 , OA, COOA or CN substituted aromatic heterocycle having one or more N-, O- and / or S atoms.
  • Heteroaryl particularly preferably denotes a monocyclic saturated or aromatic heterocycle having one N, S or O atom which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, NHA, NA 2 , NO 2 , COOA or benzyl.
  • unsubstituted heteroaryl means, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or A-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1, 2,3-triazoM-, -4- or -5-yl, 1, 2,4-triazole-1 , -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or -5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazol-2 or -5-yl, 1, 2,4-thiadiazol-3 or -5-yl, 1,
  • Benzopyrazolyl 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7- benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6 -, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1, 4 ] oxazinyl, more preferably 1, 3-benzodioxol-5-yl, 1,4-benzodioxan-6-y
  • Hal preferably denotes F, Cl or Br, in particular F or Cl.
  • the compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms.
  • Formula I encompasses all these forms.
  • Particularly preferred compounds of the formula I are those of the subformulae IA to IF:
  • Y, W, Q 1 , Q 2 , Z 1 R, R 1 , R 2 R 4 , R 5 and n have the meanings given above.
  • the compounds of formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart) are described, under reaction conditions which are known and suitable for the said reactions.
  • the starting materials are preferably prepared according to WO 2005/063735. One can also make use of known per se, not mentioned here variants.
  • the starting materials may, 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 formula I.
  • the reactions of the compounds of the formula III with the compounds of the formula II are generally carried out in an inert solvent.
  • the reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about 0 ° and 180 °, usually between 0 ° and 100 °, more preferably between 0 ° C and 70 ° C.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane or mixtures of said solvents.
  • Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene
  • chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane or mixtures of said solvents.
  • a functionally modified amino and / or hydroxyl group can be liberated by solvolysis or hydrogenolysis by customary methods. This can e.g. with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • the abovementioned compounds according to the invention can be used in their final non-salt form.
  • the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acids and bases according to procedures known in the art can be derived.
  • Pharmaceutically acceptable salt forms of the compounds of formula I are for the most part prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt.
  • 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, eg, potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and N-methylglutamine.
  • 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 eg, potassium ethanolate and sodium propanolate
  • various organic bases such as piperidine, diethanolamine and N-methylglutamine.
  • Aluminum salts of the compounds of formula I are also included.
  • acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, e.g. 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, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate , Salicylate, ascorbate and the like.
  • pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate .
  • Cyclopentane propionate digluconate, dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galactate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate, 2- Naphthalene sulfonate, nicotinate, nitrate, oxalate, oleate, pamo
  • base salts of the invention include
  • 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, 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 should not be limiting.
  • Groups can be, with agents such as (Ci-C 4 ) alkyl halides, such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C 1 -C 4 ) alkyl sulfates, eg dimethyl, diethyl and diamyl sulfate; (Ci 0 - C 18 ) 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. With such salts Both water-soluble and oil-soluble compounds according to the invention can be prepared.
  • (Ci-C 4 ) alkyl halides such as methyl, ethyl, is
  • compositions which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,
  • the acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner.
  • the free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner.
  • the free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free base forms.
  • the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines.
  • metals are sodium, potassium, magnesium and calcium.
  • Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
  • the base addition salts of acidic compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner.
  • the free acid can be determined by Contact the salt form with an acid and isolate the free acid in the usual way.
  • the free acid forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms.
  • a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts.
  • Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
  • pharmaceutically acceptable salt as used herein means an active ingredient containing a compound of formula I in the form of one of its salts, particularly when that salt form is the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient that has been used earlier confers improved pharmacokinetic properties.
  • 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 activity 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. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound according to the invention, depending on the treatment
  • dosage units containing a predetermined amount of active ingredient per unit dose.
  • Preferred unit dosage formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of an active ingredient.
  • 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 ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as, for example, ethanol, glycerol, water and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as 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.
  • Lubricants such as e.g. highly disperse 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 or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
  • suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc.
  • Lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.
  • the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.
  • the tablets are formulated by, for example, preparing a powder mixture, granulating or dry pressing Add a lubricant and a disintegrant and add the whole Tablets is pressed.
  • a powder mix is prepared by mixing the appropriately 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 reducer such as paraffin
  • Absorption enhancer e.g. a quaternary salt and / or an absorbent, e.g. Bentonite, kaolin or dicalcium phosphate is mixed.
  • the powder mixture can be granulated by mixing it with a binder, e.g. Syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials wetted and pressed through a sieve.
  • a binder e.g. Syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials wetted and pressed through a sieve.
  • the powder mixture can be run through a tabletting machine to produce non-uniformly shaped lumps which are broken up into granules.
  • the granules may be greased by the addition of 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 may be prepared by dispersing the compound in a non-aqueous solution. be formulated 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 formula I as well as salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, such as 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 formula I as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds can also be coupled with soluble polymers as targeted drug carriers.
  • Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals.
  • the compounds can be attached to a class of biodegradable polymers suitable for obtaining a controlled release of a drug, eg polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, Polycyanoacrylate and cross-linked or amphipatic block copolymers of hydrogels, be coupled.
  • a drug eg polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, Polycyanoacrylate and cross-linked or amphipatic block copolymers of hydrogels, be coupled.
  • compositions adapted for transdermal administration may be used as stand-alone patches for longer, narrower patches
  • 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 can be used with either a paraffinic or water miscible cream base.
  • the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.
  • 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.
  • compositions adapted for topical application in the mouth include lozenges, troches and mouthwashes.
  • compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
  • Pharmaceutical formulations adapted for nasal administration in which the vehicle is a solid contain 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, ie by rapid inhalation via the nasal passages from a container held close to the nose with the powder.
  • 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 aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • 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 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. It will be understood that in addition to the above particularly mentioned ingredients, the formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration
  • a therapeutically effective amount of a compound of formula I depends on a number of factors, including e.g. the age and weight of the animal, the exact condition of the disease requiring treatment, as well as its severity, the nature of the formulation and the route of administration, and is ultimately determined by the attending physician or veterinarian.
  • an effective amount of a compound of the invention is useful for the treatment of neoplastic growth, e.g. Colon or breast carcinoma, generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and more typically in the range of 1 to 10 mg / kg body weight per day.
  • the actual amount per day would usually be between 70 and 700 mg, this amount being given as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same.
  • An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
  • 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 at least one further active pharmaceutical ingredient.
  • the invention is also a set (kit), consisting of separate packages of
  • 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 formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance is dissolved or in lyophilized form.
  • the medicaments of Table 1 are combined with the compounds of the formula I.
  • a combination of formula I and drugs of Table 1 can also be combined with compounds of formula V.
  • Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema)
  • Mitoxantrone diflomotecan (Beaufourrinotecan (CPT-11) Ipsen)
  • TNF-alpha-virulizine (Lorus Revimid (Celgene)
  • CapCell TM CYP450-N-acetylcysteine
  • Antagonist kappaB inhibitor, Encore
  • Efaproxiral oxygenator, receptor agonist, Leo
  • PI-88 heparanase antagonist
  • TLK-286 glutthione-S-CHS-828 (cytotoxic)
  • PT-100 growth factor (differentiator, NIH)
  • Point MX6 apoptosis promoter
  • CDA-II apoptosis-Ro-31-7453 (apoptosis
  • SDX-101 apoptosis-brostallicin (apoptosis)
  • the compounds of the formula I are combined with known anticancer agents.
  • anticancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors.
  • the present compounds are particularly suitable for co-administration with radiotherapy.
  • the synergistic effects of inhibiting VEGF in combination with radiotherapy have been described in the art (see WO 00/61186).
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how this occurs: Estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifen, LY353381, LY 117081, toremifene, fulvestrant , 4- [7- (2,2-Dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl] phenyl 2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4- dinitrophenylhydrazone and SH646, but this is not intended to be limiting.
  • “Androgen receptor modulators” refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this occurs
  • Androgen receptor modulators include, for example, finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this occurs
  • retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis Retinoic acid, ⁇ -difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) -retinamide and N-4-carboxyphenylretinamide.
  • Cytotoxic agents refers to compounds that cause cell death primarily through direct action on cell function or that inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.
  • the cytotoxic agents include, for example, tirapazimine, Sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improvisulfan-tosylate, trofosfamide, nimustine, dibrosylamine.
  • microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S''-didehydro-desoxy- ⁇ '-norvincaleukoblastin, docetaxol,
  • Rhizoxin Rhizoxin, dolastatin, mivobulinisethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N 1 N - dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline t-butylamide, TDX258 and BMS188797.
  • Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecane, ⁇ -ethoxypropionyl-S '-' - O-exo-benzylidene-chartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4,5 -kl] acridine-2- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] -pyrano [ 3 ⁇ 4 ⁇ b, 7] indolizino [1,2b] quinoline-10,13 (9H, 15H) -dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin, BNP1350, BNPH 100, BN80915, BN80
  • Oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, Doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene -2'-deoxycytidine > N- [5- (2,3-dihydrobenzofuyl) sulfonyl] -N ⁇ 3,4-dichlorophenyl) urea, N6- [4-deoxy-4-
  • antiproliferative agents also include other monoclonal antibodies to growth factors than those already listed under the “angiogenesis inhibitors”, such as trastuzumab, as well as tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, eg, US Patent No. 6,069,134 ).
  • Particularly preferred is the use of the compound according to the invention for the treatment and prophylaxis of tumor diseases.
  • the tumor is preferably selected from the group of squamous cell tumors, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract , the lymphatic system, the stomach, the larynx and / or the lungs.
  • the tumor is furthermore preferably selected from the group
  • Lung adenocarcinoma small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.
  • a tumor of the blood and immune system preferably for the treatment of a tumor selected from the group of acute myelotic leukemia, chronic myelotic leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.
  • the invention also includes a method of treating a patient having a neoplasm, such as a cancer, by administration
  • Y 'and Z' are each independently O or N
  • R and R 7 are each independently H, OH, halogen, OC 1-10 alkyl, OCF 3 , NO 2 or NH 2
  • s' is an integer between 2 and 6, each inclusive
  • R 8 and R 9 are each independently preferably at the meta or para position and selected from the group:
  • first and second compounds are administered simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of the neoplasm.
  • pentamidine or its derivatives appear to have pleiotropic effects as it leads to a decrease in DNA, RNA and protein synthesis.
  • Pentamidine has recently been described as a potent inhibitor of PRL1, -2 and 3 phosphatases (Pathak et al., 2002) and tyrosine phosphatases, and its overexpression is associated with human neoplastic malignant tumors.
  • pentamidine is a drug that binds to the small DNA groove (Puckowska et al., 2004) and that can exert its effect via the disruption of gene expression and / or DNA synthesis.
  • Suitable pentamidine analogs include stilbamidine (G-1) and hydroxystilbamidine (G-2) and their indole analogs (eg G-3):
  • Each amidine unit can be independently replaced by one of the units defined above for R 8 and R 11 .
  • salts of stilbamidine, hydroxystilbamidine and their indole derivatives are also suitable for the process according to the 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 '-methoxy-4' - (N-hydroxyamidino) phenoxy) propane, 1,4-bis (4 '- (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-
  • Pentamidine metabolites are also useful in the antiproliferative combination of this invention. Pentamidine is rapidly metabolized in the body to at least seven primary metabolites. Some of these metabolites have one or more effects in common with pentamidine. Pentamidine metabolites exhibit antiproliferative activity when combined with a benzimidazole or an analog thereof.
  • the combinations of compounds of the formula I and formula V or their analogues and their metabolites according to the invention are suitable for the treatment of neoplasms.
  • 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 combination of kinesin ATPase Eg5 / KSP with the compounds of formula V, pentamidine, its analogues and / or its metabolites is also an object of the invention.
  • each compound of the combination can be independently controlled. For example, a compound may be administered orally three times a day while the second compound may be administered intramuscularly once a day.
  • the compounds may also be formulated together so that administration will deliver to both compounds.
  • the antiproliferative combinations of the invention may also be provided as components of a pharmaceutical package.
  • the two drugs may be formulated together or separately and in single dosage amounts.
  • the invention includes a treatment of a patient having a neoplasm such as a cancer by administering a compound of the formula (I) and (V) 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 on silica gel and / or by crystallization Rf values on silica gel, mobile phase: ethyl acetate / methanol 9: 1.
  • 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 sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active compound of the formula I 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.
  • a solution of 1 g of an active ingredient of the formula I 1 9.38 g of NaH 2 PO 4 • 2H 2 O, 28.48 g Na 2 HPO 4 • 12 H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double-one prepares distilled water. Adjust to pH 6.8, make up to 1 liter on and sterilized 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.
  • 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 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.

Abstract

The invention relates to compounds of formula (I) wherein E, R3, R4, R5, X, Y, W, Q1, Q2, Z, s and m have the designations cited in claim 1. Said compounds can be used, inter alia, for the treatment of tumours.

Description

TETRAHYDROCHINOLINEDERIVATE UND IHRE VERWENDUNG ZUR BEHANDLUNG VON KREBS TETRAHYDROCHINOLINE DERIVATIVES AND THEIR USE FOR THE TREATMENT OF CANCER
HINTERGRUND DER ERFINDUNGBACKGROUND OF THE INVENTION
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvollenThe invention was based on the object, new compounds with valuable
Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können.Find properties, especially those that can be used for the production of medicines.
Die vorliegende Erfindung betrifft Verbindungen der Formel I und deren Verwendung zur Behandlung und Prophylaxe von Krankheiten, bei denen die Hemmung, Regulierung und/oder Modulation der mitotische Motor- Proteine, insbesondere des mitotischen Motor-Protein Eg5 eine Rolle spielt, ferner pharmazeutische Zusammensetzungen, die diese Verbindungen enthalten.The present invention relates to compounds of the formula I and their use for the treatment and prophylaxis of diseases in which the inhibition, regulation and / or modulation of mitotic motor proteins, in particular of the mitotic motor protein Eg5 plays a role, and also pharmaceutical compositions which contain these compounds.
Im einzelnen betrifft die vorliegende Erfindung Verbindungen der Formel I, die die bevorzugt eines oder mehrere mitotische Motor-Proteine hemmen, regulieren und/oder modulieren, Zusammensetzungen, die diese Verbindungen enthalten, sowie Verfahren zu ihrer Verwendung zur Behandlung von Krankheiten und Leiden wie Angiogenese, Krebs, Tumorentstehung, -Wachstum und -Verbreitung, Arteriosklerose, Augenerkrankungen, choroidale Neovaskularisierung und diabetische Retinopathie, Entzündungserkrankungen, Arthritis, Neurodegeneration, Restenose, Wundheilung oder Transplantatabstossung. Insbesondere eignen sich die erfindungsgemäßen Verbindungen zur Therapie oder Prophylaxe vonIn particular, the present invention relates to compounds of the formula I which inhibit, regulate and / or modulate, preferably, 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. In particular, the compounds according to the invention are suitable for the therapy or prophylaxis of
Krebserkrankungen.Cancers.
Während der Mitose regulieren verschiedenen Kinesine die Ausbildung und Dynamik des Spindelapparates, der für eine korrekte und koordinierte Ausrichtung und Separation der Chromosomen verantwortlich ist. Es wurde beobachtet, dass eine spezifische Inhibierung eines mitotischen Motor- Proteins - Eg5 - zu einem Kollaps der Spindelfasern führt. Daraus resultiert, dass die Chromosomen nicht mehr korrekt auf die Tochterzellen aufgeteilt werden können. Dies führt zu mitotischem Arrest und kann damit das Absterben der Zelle verursachen. Eine Hochregulierung des Motorproteins Eg5 wurde z.B. in Gewebe von Brust- Lungen- und Colon- Tumoren beschrieben. Da Eg5 eine für die Mitose spezifische Funktion einnimmt, sind hauptsächlich sich schnell teilende Zellen und nicht vollständig ausdifferenzierte Zellen von einer Eg5 Inhibierung betroffen. Darüber hinaus regelt Eg5 ausschließlich die Bewegung mitotischer Mikrotubuli (Spindelapparat) und nicht die des Cytoskeletts. Dies ist entscheidend für das Nebenwirkungsprofil der erfindungsgemäßen Verbindungen, da z.B. Neuropathien, wie sie bei Taxol beobachtet werden, nicht oder nur abgeschwächt auftreten. Daher ist die Inhibierung von Eg5 durch die erfindungsgemäßen Verbindungen ein relevantes Therapiekonzept für die Behandlung von malignen Tumoren.During mitosis, various kinesins regulate the formation and dynamics of the spindle apparatus responsible for correct and coordinated alignment and separation of the chromosomes. It has been observed that specific inhibition of a mitotic motor protein - Eg5 - leads to collapse of the spindle fibers. This results, that the chromosomes can no longer be correctly distributed to the daughter cells. This leads to mitotic arrest and can thus cause cell death. Upregulation of the motor protein Eg5 has been described, for example, in tissues of breast, lung and colon tumors. Since Eg5 occupies a function specific to mitosis, mainly rapidly dividing cells and not fully differentiated cells are affected by Eg5 inhibition. In addition, Eg5 regulates exclusively the movement of mitotic microtubules (spindle apparatus) and not those of the cytoskeleton. This is crucial for the side effect profile of the compounds according to the invention, since, for example, neuropathies, as are observed in taxol, do not occur or only weakened. Therefore, the inhibition of Eg5 by the compounds according to the invention is a relevant therapeutic concept for the treatment of malignant tumors.
Generell können alle soliden und nicht soliden Tumore mit den Verbindungen der Formel I behandelt werden, wie z.B. die Monozytenleukämie, Hirn-, Urogenital-, Lymphsystem-, Magen-, Kehlkopf- und Lungenkarzinom, darunter Lungenadenokarzinom und kleinzelliges Lungenkarzinom. Zu weiteren Beispielen zählen Prostata-, Bauchspeicheldrüsen- und Brustkarzinom.In general, all solid and non-solid tumors can be treated with the compounds of formula I, e.g. monocytic leukemia, brain, urogenital, lymphatic, gastric, laryngeal and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma. Other examples include prostate, pancreatic and breast carcinoma.
Es wurde überraschend gefunden, daß die erfindungsgemäßen Verbindungen eine spezifische Inhibierung der mitotischen Moter-Proteine, insbesondere Eg5 bewirken. Die erfindungsgemäßen Verbindungen zeigen bevorzugt eine vorteilhafte biologische Aktivität, die in den zum Beispiel hierin beschrieben Assays leicht nachweisbar ist. In derartigen Assays zeigen und bewirken die erfindungsgemäßen Verbindungen bevorzugt einen inhibierenden Effekt, der gewöhnlich durch IC50-WeIIe in einem geeigneten Bereich, bevorzugt im mikromolaren Bereich und bevorzugter im nanomolaren Bereich dokumentiert wird. Wie hierin besprochen, sind Wirkungen der erfindungsgemäßen Verbindung für verschiedene Erkrankungen relevant. Dementsprechend sind die erfindungsgemäßen Verbindungen nützlich bei der Prophylaxe und/oder Behandlung von Erkrankungen, die durch eine Inhibierung eines oder mehreren mitotischer Motor-Proteine, insbesondere Eg5, beeinflusst werden.It has surprisingly been found that the compounds according to the invention bring about a specific inhibition of the mitotic Moter proteins, in particular Eg5. The compounds of the invention preferably exhibit a beneficial biological activity which is readily detectable in the assays described herein, for example. In such assays, the compounds of the invention preferably exhibit and effect an inhibitory effect, which is usually documented by IC 50 values in a suitable range, preferably in the micromolar range, and more preferably in the nanomolar range. As discussed herein, effects of the compound of the invention are relevant to various diseases. Accordingly, the compounds of the invention are useful in the prophylaxis and / or treatment of diseases that are affected by inhibition of one or more mitotic motor proteins, particularly Eg5.
Gegenstand der vorliegenden Erfindung sind deshalb erfindungsgemäße Verbindungen als Arzneimittel und/oder Arzneimittelwirkstoffe bei der Behandlung und/oder Prophylaxe der genannten Erkrankungen und die Verwendung von erfindungsgemäßen Verbindungen zur Herstellung eines Pharmazeutikums für die Behandlung und/oder Prophylaxe der genannten Erkrankungen wie auch ein Verfahren zur Behandlung der genannten Erkrankungen umfassend die Verabreichung eines oder mehrerer erfindungsgemäßer Verbindungen an einen Patienten mit Bedarf an einer derartigen Verabreichung.The present invention therefore relates to compounds according to the invention as medicaments and / or active pharmaceutical ingredients in the treatment and / or prophylaxis of said diseases and the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method of treatment said diseases comprising administering one or more of the compounds of the invention to a patient in need of such administration.
Es kann gezeigt werden, dass die erfindungsgemäßen Verbindungen in einem Xenotransplantat-Tumor-Modell eine vorteilhafte Wirkung aufweisen.It can be shown that the compounds according to the invention have a beneficial effect in a xenograft tumor model.
Der Wirt oder Patient kann jeglicher Säugerspezies angehören, z. B. einer Primatenspezies, besonders Menschen; Nagetieren, einschließlich Mäusen, Ratten und Hamstern; Kaninchen; Pferden, Rindern, Hunden, Katzen usw. Tiermodelle sind für experimentelle Untersuchungen von Interesse, wobei sie ein Modell zur Behandlung einer Krankheit des Menschen zur Verfügung stellen.The host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for the treatment of human disease.
Die Suszeptibilität einer bestimmten Zelle gegenüber der Behandlung mit den erfindungsgemäßen Verbindungen kann durch Testen in vitro bestimmt werden. Typischerweise wird eine Kultur der Zelle mit einer erfindungsgemäßen Verbindung bei verschiedenen Konzentrationen für eine Zeitdauer kombiniert, die ausreicht, um den Wirkstoffen zu ermöglichen, Zelltod zu induzieren oder Migration zu inhibieren, gewöhnlich zwischen ungefähr einer Stunde und einer Woche. Zum Testen in vitro können kultivierte Zellen aus einer Biopsieprobe verwendet werden. Die nach der Behandlung zurückbleibenden lebensfähigen Zellen werden dann gezählt. Die Dosis variiert abhängig von der verwendeten spezifischen Verbindung, der spezifischen Erkrankung, dem Patientenstatus usw.. Typischerweise ist eine therapeutische Dosis ausreichend, um die unerwünschte Zellpopulation im Zielgewebe erheblich zu vermindern, während die Lebensfähigkeit des Patienten aufrechterhalten wird. Die Behandlung wird im Allgemeinen fortgesetzt, bis eine erhebliche Reduktion vorliegt, z. B. mindestens ca. 50 % Verminderung der Zelllast und kann fortgesetzt werden, bis im Wesentlichen keine unerwünschten Zellen mehr im Körper nachgewiesen werden.The susceptibility of a particular cell to treatment with the compounds of the invention can be determined by testing in vitro. Typically, a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to allow the drugs to induce cell death or inhibit migration, usually between about one hour and one week. For testing in vitro cultured cells from a biopsy sample can be used. The viable cells remaining after treatment are then counted. The dose will vary depending on the specific compound used, the specific disease, the patient status, etc. Typically, a therapeutic dose will be sufficient to substantially reduce the unwanted cell population in the target tissue while maintaining patient viability. Treatment is generally continued until there is a significant reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no more unwanted cells are detected in the body.
ZUSAMMENFASSUNG DER ERFINDUNGSUMMARY OF THE INVENTION
Verbindungen der Formel ICompounds of the formula I
worin wherein
X O, NR oder S,X O, NR or S,
R1 , R2 unabhängig voneinander H, A, HaI, SA, (CH2)PCN, SCN, (CF2)PCF3) SF5, OA, O (CF2)PCF3, S(CF2)PCF3, NR2, NRCOR, NRSO2R,R 1 , R 2 independently of one another are H, A, Hal, SA, (CH 2 ) p CN, SCN, (CF 2 ) p CF 3) SF 5 , OA, O (CF 2 ) p CF 3 , S (CF 2 ) P CF 3 , NR 2 , NRCOR, NRSO 2 R,
NR(CH2)PNR2) CONR(CH2)PNR2, SO2NR(CH2)PNR2, CONR2, SO2NR2, COOR,NR (CH 2 ) P NR 2) CONR (CH 2 ) P NR 2 , SO 2 NR (CH 2 ) P NR 2 , CONR 2 , SO 2 NR 2 , COOR,
H1 AH 1 A
lineares oder verzweigtes Alkyl mit 1 bis 10 C-Atomen oder Cycloalkyl mit 3 bis 7 C-Atomen,linear or branched alkyl having 1 to 10 C atoms or cycloalkyl having 3 to 7 C atoms,
unsubstituiertes oder einfach oder mehrfach durch Aryl oder Heteroaryl, das durch HaI, NO2, CN, A, OR, OCOR, NR2, CF3, OCF3, OCH(CF3)2 substituiert sein kann, HaI, NO2, CN, OR, A, -(CY2)n-OR, -OCOR, -(CY2)n-CO2R, -(CY2)n-CN oder -(CY2)n-NR2 substituiertes Aryl oder Heteroaryl,unsubstituted or mono- or polysubstituted by aryl or heteroaryl which may be substituted by Hal, NO 2 , CN, A, OR, OCOR, NR 2 , CF 3 , OCF 3 , OCH (CF 3 ) 2 , Hal, NO 2 , CN , OR, A, - (CY 2 ) n -OR, -OCOR, - (CY 2 ) n -CO 2 R, - (CY 2 ) n -CN or - (CY 2 ) n -NR 2 substituted aryl or heteroaryl .
H, A, HaI, ORH, A, HaI, OR
H, A, (CH2)pO(CH2)pR3, (CH2)pNA(CH2)pR3, W CH2, C=O, C=S oder eine EinfachbindungH, A, (CH 2 ) p O (CH 2 ) p R 3 , (CH 2 ) p NA (CH 2 ) p R 3 , W is CH 2 , C = O, C = S or a single bond
Q1 NR, O, S oder eine EinfachbindungQ 1 NR, O, S or a single bond
oder eine Einfachbindung, or a single bond,
Q2 NR, S, O oder eine Einfachbindung,Q 2 NR, S, O or a single bond,
R5 H, (CY2)PNR2, (CY2)POR, (CY2)PSR, R 5 H, (CY 2 ) P NR 2 , (CY 2 ) P OR, (CY 2 ) P SR,
(CY2)PQ1COQ1R, (CY2)PCOOR und, sofern Q2 eine Einfachbindung bedeutet, auch HaI,(CY 2 ) P Q 1 COQ 1 R, (CY 2 ) P COOR and, if Q 2 is a single bond, also Hal,
HaI F, Br oder ClHaI F, Br or Cl
n 1 , 2, 3 oder 4,n 1, 2, 3 or 4,
m 0, 1 oder 2m 0, 1 or 2
p 0, 1 , 2, 3, 4, 5, 6, 7 oder 8p is 0, 1, 2, 3, 4, 5, 6, 7 or 8
undand
s 0, 1 oder 2 bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Tautomere, Salze und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.s is 0, 1 or 2, and their pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, including mixtures thereof in all ratios.
Bevorzugter Gegenstad der vorliegenden Anmeldung sind die Verbindungen der Formel 11 :Preferred Gegenstad the present application are the compounds of formula 11:
worin E, R3, R4, R5, Y, W, Q1, Q2, Z, X, m und s die oben angegebene Bedeutung aufweisen.wherein E, R 3 , R 4 , R 5 , Y, W, Q 1 , Q 2 , Z, X, m and s have the abovementioned meaning.
Gegenstand der Erfindung sind auch die optisch aktiven Formen, die Enantiomere, die Racemate, die Diastereomere sowie die Hydrate und Solvate dieser Verbindungen. Unter Solvaten der Verbindungen werden Anlagerungen von inerten Lösungsmittelmolekülen an die Verbindungen der Formel I verstanden, die sich aufgrund ihrer gegenseitigen Anziehungskraft ausbilden. Solvate sind z.B. Mono- oder Dihydrate oder Alkoholate.The invention also relates to the optically active forms, the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Solvates of the compounds are understood to mean additions of inert solvent molecules to the compounds of the formula I which form on account of their mutual attraction. Solvates are e.g. Mono or dihydrate or alcoholates.
Unter pharmazeutisch verwendbaren Derivaten versteht man z.B. die Salze der erfindungsgemäßen Verbindungen als auch sogenannte Prodrug- Verbindungen.Pharmaceutically usable derivatives are understood, for example, as the salts of the compounds of the invention as well as so-called prodrug compounds.
Unter Prodrug-Derivaten versteht man mit z. B. Alkyl- oder Acylgruppen, Zuckern oder Oligopeptiden abgewandelte Verbindungen der Formel I, die im Organismus rasch zu den wirksamen erfindungsgemäßen Verbindungen gespalten werden.Under prodrug derivatives is understood with z. As alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, the be rapidly cleaved in the organism to the active compounds of the invention.
Hierzu gehören auch bioabbaubare Polymerderivate der erfindungsgemäßen Verbindungen, wie dies z. B. in Int. J. Pharm. 115, 61-67 (1995) beschrieben ist.These include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995).
Ähnliche Verbindungen sind z.B. in Tetrahedron Lett. 1988, 29, 5855-5858, Tetrahedron Lett. 2003, 44, 217-219, J. Org. Chem. 1997, 62, 4880-4882, J. Org. Chem. 1999, 64, 6462-6467, Chem. Lett. 1995, 423-424, J. Org. Chem. 2000, 65, 5009-5013, Chem. Lett. 2003, 32, 222-223, US2003149069A1 beschrieben, sind aber nicht im Zusammenhang mit Krebsbehandlungen genannt und/oder enthalten nicht die erfindungswesentlichen Merkmale.Similar compounds are e.g. in Tetrahedron Lett. 1988, 29, 5855-5858, Tetrahedron Lett. 2003, 44, 217-219, J. Org. Chem. 1997, 62, 4880-4882, J. Org. Chem. 1999, 64, 6462-6467, Chem. Lett. 1995, 423-424, J. Org. Chem. 2000, 65, 5009-5013, Chem. Lett. 2003, 32, 222-223, US2003149069A1, but are not mentioned in connection with cancer treatments and / or do not contain the features essential to the invention.
Der Ausdruck "wirksame Menge" bedeutet die Menge eines Arzneimittels oder eines pharmazeutischen Wirkstoffes, die eine biologische oder medizinische Antwort in einem Gewebe, System, Tier oder Menschen hervorruft, die z.B. von einem Forscher oder Mediziner gesucht oder erstrebt wird.The term "effective amount" means the amount of a drug or pharmaceutical agent which elicits a biological or medical response in a tissue, system, animal or human, e.g. sought or desired by a researcher or physician.
Darüberhinaus bedeutet der Ausdruck "therapeutisch wirksame Menge" eine Menge, die in einem Menschen oder einem anderen Säuger mindestens eine der folgenden Wirkungen hervorruft (im Vergleich zu einem Subjekt, das diese Menge nicht erhalten hat):In addition, the term "therapeutically effective amount" means an amount that produces at least one of the following effects in a human or other mammal (as compared to a subject who has not received that amount):
Verbesserung der Heilbehandlung, Heilung, Prävention oder Beseitigung einer Krankheit, eines Krankheitsbildes, eines Krankheitszustandes, eines Leidens, einer Störung oder von Nebenwirkungen oder auch die Verminderung des Fortschreitens einer Krankheit, eines Leidens oder einer Störung. Die Bezeichnung "therapeutisch wirksame Menge" umfaßt auch die Mengen, die wirkungsvoll sind, die normale physiologische Funktion zu erhöhen oder zu verstärken.Improvement of the curative treatment, cure, prevention or elimination of a disease, a clinical picture, a disease state, a disease, a disorder or side effects or even the reduction of the progression of a disease, a disease or a disorder. The term "therapeutically effective amount" also includes those amounts effective to increase or enhance normal physiological function.
Gegenstand der Erfindung ist auch die Verwendung von Mischungen der Verbindungen der Formel I, z.B. Gemische zweier Diastereomerer z.B. im Verhältnis 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 1 :100 oder 1 :1000.The invention also provides the use of mixtures of the compounds of formula I, e.g. Mixtures of two diastereomers, e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000.
Besonders bevorzugt handelt es sich dabei um Mischungen stereoisomerer Verbindungen.These are particularly preferably mixtures of stereoisomeric compounds.
Gegenstand der Erfindung ist auch ein Verfahren zur Herstellung von Verbindungen der Formel I nach den Patentansprüchen sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomeren, dadurch gekennzeichnet, daß man eine Verbindung der Formel ausgewählt aus der folgenden Gruppe:The invention also provides a process for the preparation of compounds of the formula I according to the claims and their pharmaceutically usable derivatives, salts, solvates and stereoisomers, characterized in that a compound of the formula selected from the following group:
worin R >1 , π R2 und R die oben angegebenen Bedeutungen haben,wherein R> 1, π R 2 and R have the meanings given above,
mit einer Verbindung der Formel with a compound of the formula
worinwherein
R4 die oben angegebene Bedeutung autweist,R 4 has the meaning indicated above,
undand
mit einer Verbindung der Formel IV,with a compound of the formula IV,
worin X und s die oben angegebenen Bedeutungen haben, bevorzugt in Gegenwart einer Protonensäure oder Lewis-Säure wie z.B. Trifluoressgsäure, Hexafluorisopropanol, Bismut (lll)chlorid, Ytterbium(lll)triflat, Scandium (III) triflat oder Cerammonium (IV)nitrat umsetzt,wherein X and s have the meanings given above, preferably in the presence of a protic acid or Lewis acid, e.g. Trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium (III) triflate, scandium (III) triflate or ceric ammonium (IV) nitrate,
und gegebenenfalls nach üblichen Methoden für R3 einen anderen Rest als H einführt und/oder gegebenenfalls eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.and, if appropriate, by conventional methods for R 3 introduces a radical other than H and / or optionally converts a base or acid of the formula I into one of its salts.
Vorzugsweise werden die nach dem oben beschriebenen Verfahren gegebenenfalls erhaltenen Gemische von Diastereomeren undPreferably, the mixtures of diastereomers optionally obtained by the process described above and
Enantiomeren der Verbindungen der Formel I durch Chromatographie oderEnantiomers of the compounds of formula I by chromatography or
Kristallisation aufgetrennt. Gegebenenfalls werden die nach dem oben beschriebenen Verfahren erhaltenen Basen und Säuren der Formel I in ihre Salze umgewandelt. Vor- und nachstehend haben die Reste HaI, R, R1, R2, R3, R4, R5, W, Q1, Q2, Z, m, n, s und p die bei der Formel I angegebenen Bedeutungen, sofern nicht ausdrücklich etwas anderes angegeben ist. Bei mehrfachem Auftreten einzelner Reste innerhalb einer Verbindung nehmen die Reste unabhängig voneinander die angegebenen Bedeutungen an.Crystallization separated. Optionally, the bases and acids of formula I obtained by the process described above are converted into their salts. Above and below, the radicals Hal, R, R 1 , R 2 , R 3 , R 4 , R 5 , W, Q 1 , Q 2 , Z, m, n, s and p have the meanings given for the formula I. unless expressly stated otherwise. When multiple occurrences of individual radicals within a compound, the radicals independently of one another assume the meanings indicated.
Alkyl ist bevorzugt unverzweigt (linear) oder verzweigt, und hat 1 , 2, 3, 4, 5, 6, 7, 8, 9 oder 10 C-Atome. Alkyl bedeutet vorzugsweise Methyl, weiterhin Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.-Butyl oder tert.-Butyl, ferner auch Pentyl, 1-, 2- oder 3-Methylbutyl, 1 ,1- , 1 ,2- oder 2,2-Dimethylpropyl, 1- Ethylpropyl, Hexyl, 1-, 2-, 3- oder 4-Methylpentyl, 1 ,1-, 1 ,2-, 1 ,3-, 2,2- , 2,3- oder 3,3-Dimethylbutyl, 1- oder 2-Ethylbutyl, 1-Ethyl-1-methyl- propyl, 1-Ethyl-2-methylpropyl, 1 ,1 ,2- oder 1 ,2,2-Trimethylpropyl, weiter bevorzugt z.B. Trifluormethyl.Alkyl is preferably unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1, 1, 2 or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methyl-propyl, 1-ethyl-2-methylpropyl, 1, 1, 2 or 1, 2,2-trimethylpropyl, more preferably, for example Trifluoromethyl.
Alkyl bedeutet ganz besonders bevorzugt Alkyl mit 1 , 2, 3, 4, 5 oder 6 C- Atomen, vorzugsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.- Butyl, tert.-Butyl, Pentyl, Hexyl, Trifluormethyl, Pentafluorethyl oder 1 ,1 ,1 - Trifluorethyl. Alkyl bedeutet auch Cycloalkyl.Alkyl very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl , Pentafluoroethyl or 1,1,1-trifluoroethyl. Alkyl also means cycloalkyl.
Cycloalkyl bedeutet vorzugsweise Cyclopropyl, Cyclobutyl, Cylopentyl, Cyclohexyl oder Cycloheptyl, insbesondere aber Cyclopentyl.Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but especially cyclopentyl.
X ist bevorzugt O oder NR, insbesondere O.X is preferably O or NR, in particular O.
R1, bedeutet vorzugsweise, Alkyl, CF3, OCF3, SCN, COOR, CH2CN, OH, S Alkyl, O Alkyl, HaI, SCF3. Insbesondere bedeutet R1 t-Butyl, CF3, Br, Cl, CF3 oder COOR.R 1 is preferably alkyl, CF 3 , OCF 3 , SCN, COOR, CH 2 CN, OH, S, alkyl, O, alkyl, Hal, SCF 3 . In particular, R 1 is t-butyl, CF 3 , Br, Cl, CF 3 or COOR.
R2 ist bevorzugt H oder Br, insbesondere H. R3 ist bevorzugt H oder Methyl, Ethyl, n-Propyl oder n-Butyl, insbesondere H.R 2 is preferably H or Br, in particular H. R 3 is preferably H or methyl, ethyl, n-propyl or n-butyl, in particular H.
R4 ist vorzugsweise Aryl, das durch F, Cl, OR oder Aryl substituiert sein kann. Insbesondere bedeutet R4 Phenyl, Hydroxyphenyl oder Alkylphenyl.R 4 is preferably aryl which may be substituted by F, Cl, OR or aryl. In particular, R 4 is phenyl, hydroxyphenyl or alkylphenyl.
R ist bevorzugt H, oder A oder (CH2)pNA(CH2)p, R3 R is preferably H, or A or (CH 2 ) p NA (CH 2 ) p, R 3
W ist vorzugsweise CH2 oder eine Einfachbindung, insbesondere CH2.W is preferably CH 2 or a single bond, in particular CH 2 .
Q1 ist vorzugsweise NR, eine Einfachbindung oder O, insbesondere NR. Ganz besonders bevorzugt bedeutet Q1 NH.Q 1 is preferably NR, a single bond or O, especially NR. Most preferably, Q 1 is NH.
Z bedeutet vorzugsweise SO2, CO, CS oder eine Einfachbindung.Z is preferably SO 2 , CO, CS or a single bond.
Q2 ist bevorzugt NR, O oder eine Einfachbindung.Q 2 is preferably NR, O or a single bond.
R5 ist vorzugsweise H, (CY2)PNR2 oder (CY2)POR, insbesondere (CY2)PNR, oder H.R 5 is preferably H, (CY 2 ) P NR 2 or (CY 2 ) P OR, in particular (CY 2 ) P NR, or H.
Y bedeutet vorzugsweise H, A oder F, insbesondere H. n bedeutet vorzugsweise 0, 1 , 2, oder 3. m bedeutet vorzugsweise 0 oder 1 , insbesondere 0. p bedeutet vorzugsweise 0 oder 2. s bedeutet vorzugsweise 0 oder 1.Y is preferably H, A or F, in particular H. n is preferably 0, 1, 2 or 3. m is preferably 0 or 1, in particular 0. p is preferably 0 or 2. s is preferably 0 or 1.
Aryl bedeutet vorzugsweise unsubstituiert.es oder ein-, zwei- oder dreifach durch HaI, A, OH, OA, NH2, NO2, CN, COOH, COOA, CONH2, NHCOA, NHCONH2, NHSO2A, CHO1 COA, SO2NH2, SO2A, -CH2-COOH oder -OCH2-COOH substituiertes Phenyl, Naphthyl oder Biphenyl. Aryl bedeutet bevorzugt Phenyl, o-, m- oder p-Tolyl, o-, m- oder p-Ethyl- phenyl, o-, m- oder p-Propylphenyl, o-, m- oder p-lsopropylphenyl, o-, m- oder p-tert.-Butylphenyl, o-, m- oder p-Hydroxyphenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p-Nitrophenyl, o-, m- oder p-Aminophenyl, o-, m- oder p-(N-Methylamino)-phenyl, o-, m- oder p-(N-Methylaminocarbonyl)- phenyl, o-, m- oder p-Acetamidophenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p-Ethoxyphenyl, o-, m- oder p-Ethoxycarbonylphenyl, o-, m- oder p- (N,N-Dimethylamino)-phenyl, o-, m- oder p-(N,N-Dimethylaminocarbonyl)- phenyl, o-, m- oder p-(N-Ethylamino)-phenyl, o-, m- oder p-(N,N- Diethylamino)-phenyl, o-, m- oder p-Fluorphenyl, o-, m- oder p-Bromphenyl, o-, m- oder p- Chlorphenyl, o-, m- oder p-(Methylsulfonamido)-phenyl, o-, m- oder p-(Methylsulfonyl)-phenyl, weiter bevorzugt 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Difluorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dichlorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dibromphenyl, 2,4- oder 2,5-Dinitrophenyl, 2,5- oder 3,4-Dimethoxyphenyl, 3-Nitro-4-chlorphenyl, 3-Amino-4-chlor-, 2-Amino- 3-chlor-, 2-Amino-4-chlor-, 2-Amino-5-chlor- oder 2-Amino-6-chlorphenyl, 2- Nitro-4-N,N-dimethylamino- oder 3-Nitro-4-N,N-dimethylaminophenyl, 2,3- Diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- oder 3,4,5-Trichlorphenyl, 2,4,6- Trimethoxyphenyl, 2-Hydroxy-3,5-dichlorphenyl, p-lodphenyl, 3,6-Dichlor-4- aminophenyl, 4-Fluor-3-chlorphenyl, 2-Fluor-4-bromphenyl, 2,5-Difluor-4- bromphenyl, 3-Brom-6-methoxyphenyl, 3-Chlor-6-methoxyphenyl, 3-Chlor-4- acetamidophenyl, 3-Fluor-4-methoxyphenyl, 3-Amino-6-methylphenyl, 3- Chlor-4-acetamidophenyl oder 2,5-Dimethyl-4-chlorphenyl.Aryl is preferably unsubstituted or substituted once, twice or three times by Hal, A, OH, OA, NH 2 , NO 2 , CN, COOH, COOA, CONH 2 , NHCOA, NHCONH 2 , NHSO 2 A, CHO 1 COA , SO 2 NH 2 , SO 2 A, -CH 2 -COOH or -OCH 2 -COOH substituted phenyl, naphthyl or biphenyl. Aryl is preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N -Methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m - or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N, N-dimethylaminocarbonyl) -phenyl, o-, m- or p- (N-ethylamino) -phenyl, o- , m- or p- (N, N-diethylamino) -phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m or p- (methylsulfonamido) -phenyl, o-, m- or p- (methylsulfonyl) -phenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2, 5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3 -Amino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N , N-dimethyl amine o- or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3 , 4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro 4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino 6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.
Heteroaryl bedeutet vorzugsweise einen ein- oder zweikernigen unsubstituierten oder ein-, zwei- oder dreifach durch HaI, A, NO2, NHA, NA2, OA, COOA oder CN substituierten aromatischen Heterocyclus mit einem oder mehreren N-, O- und/oder S-Atomen.Heteroaryl preferably denotes a mono- or binuclear unsubstituted or mono-, di- or trisubstituted by Hal, A, NO 2 , NHA, NA 2 , OA, COOA or CN substituted aromatic heterocycle having one or more N-, O- and / or S atoms.
Heteroaryl bedeutet besonders bevorzugt einen einkernigen gesättigten oder aromatischen Heterocyclus mit einem N, S oder O-Atom, der unsubstituiert oder ein-, zwei- oder dreifach durch HaI, A, NHA, NA2, NO2, COOA oder Benzyl substituiert sein kann. Ungeachtet weiterer Substitutionen, bedeutet unsubstituiertes Heteroaryl z.B. 2- oder 3-Furyl, 2- oder 3-Thienyl, 1-, 2- oder 3-Pyrrolyl, 1-, 2, 4- oder 5- Imidazolyl, 1-, 3-, 4- oder 5-Pyrazolyl, 2-, 4- oder 5-Oxazolyl, 3-, 4- oder 5- Isoxazolyl, 2-, 4- oder 5-Thiazolyl, 3-, 4- oder 5-lsothiazolyl, 2-, 3- oder A- Pyridyl, 2-, 4-, 5- oder 6-Pyrimidinyl, weiterhin bevorzugt 1 ,2,3-TriazoM-, -4- oder -5-yl, 1 ,2,4-Triazol-1-, -3- oder 5-yl, 1- oder 5-Tetrazolyl, 1 ,2,3- Oxadiazol-4- oder -5-yl, 1 ,2,4-Oxadiazol-3- oder -5-yl, 1 ,3,4-Thiadiazol-2- oder -5-yl, 1 ,2,4-Thiadiazol-3- oder -5-yl, 1 ,2,3-Thiadiazol-4- oder -5-yl, 3- oder 4-Pyridazinyl, Pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- oder 7-lndolyl, 4- oder 5- Isoindolyl, 1-, 2-, 4- oder 5-Benzimidazolyl, 1-, 3-, 4-, 5-, 6- oder 7-Heteroaryl particularly preferably denotes a monocyclic saturated or aromatic heterocycle having one N, S or O atom which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, NHA, NA 2 , NO 2 , COOA or benzyl. Regardless of further substitutions, unsubstituted heteroaryl means, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or A-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1, 2,3-triazoM-, -4- or -5-yl, 1, 2,4-triazole-1 , -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4 or -5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazol-2 or -5-yl, 1, 2,4-thiadiazol-3 or -5-yl, 1, 2,3-thiadiazol-4 or -5-yl, 3 or 4 Pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3, 4, 5, 6 or 7
Benzopyrazolyl, 2-, 4-, 5-, 6- oder 7-Benzoxazolyl, 3-, 4-, 5-, 6- oder 7- Benzisoxazolyl, 2-, 4-, 5-, 6- oder 7-Benzothiazolyl, 2-, 4-, 5-, 6- oder 7- Benzisothiazolyl, 4-, 5-, 6- oder 7-Benz-2,1 ,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- oder 8-Chinolyl, 1-, 3-, 4-, 5-, 6-, 7- oder 8-lsochinolyl, 3-, 4-, 5-, 6-, 7- oder 8-Cinnolinyl, 2-, 4-, 5-, 6-, 7- oder 8-Chinazolinyl, 5- oder 6-Chinoxalinyl, 2-, 3-, 5-, 6-, 7- oder 8-2H-Benzo[1 ,4]oxazinyl, weiter bevorzugt 1 ,3-Benzo- dioxol-5-yl, 1 ,4-Benzodioxan-6-yl, 2,1 ,3-Benzothiadiazol-4- oder -5-yl oder 2,1 ,3-Benzoxadiazol-5-yl.Benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7- benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6 -, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1, 4 ] oxazinyl, more preferably 1, 3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4 or 5-yl or 2,1,3-benzoxadiazole -5-yl.
HaI bedeutet vorzugsweise F, Cl oder Br insbesondere F oder Cl.Hal preferably denotes F, Cl or Br, in particular F or Cl.
Für die gesamte Erfindung gilt, daß sämtliche Reste, die mehrfach auftreten, gleich oder verschieden sein können, d.h. unabhängig voneinander sind.For the entire invention, all residues that occur multiple times may be the same or different, i. are independent of each other.
Die Verbindungen der Formel I können ein oder mehrere chirale Zentren besitzen und daher in verschiedenen stereoisomeren Formen vorkommen. Die Formel I umschließt alle diese Formen.The compounds of the formula I can possess one or more chiral centers and therefore occur in different stereoisomeric forms. Formula I encompasses all these forms.
Besonders bevorzugte Verbindungen der Formel I sind die der Teilformeln IA bis IF: Particularly preferred compounds of the formula I are those of the subformulae IA to IF:
worinwherein
Y, W, Q1, Q2, Z1R, R1, R2 R4, R5 und n die oben angegebenen Bedeutungen aufweisen.Y, W, Q 1 , Q 2 , Z 1 R, R 1 , R 2 R 4 , R 5 and n have the meanings given above.
Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrer Herstellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wie Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) beschrieben sind, und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Bevorzugt werden die Ausgangsstoffe hergestellt nach WO 2005/063735. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen. Die Ausgangsstoffe können, falls erwünscht, auch in situ gebildet werden, so daß man sie aus dem Reaktionsgemisch nicht isoliert, sondern sofort weiter zu den Verbindungen der Formel I umsetzt.The compounds of formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart) are described, under reaction conditions which are known and suitable for the said reactions. The starting materials are preferably prepared according to WO 2005/063735. One can also make use of known per se, not mentioned here variants. The starting materials may, 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 formula I.
Die Umsetzungen der Verbindungen der Formel III mit den Verbindungen der Formel Il erfolgen in der Regel in einem inerten Lösungsmittel. Die Reaktionszeit liegt je nach den angewendeten Bedingungen zwischen einigen Minuten und 14 Tagen, die Reaktionstemperatur zwischen etwa 0° und 180°, normalerweise zwischen 0° und 100°, besonders bevorzugt zwischen 0°C und 70°C.The reactions of the compounds of the formula III with the compounds of the formula II are generally carried out in an inert solvent. The reaction time is between a few minutes and 14 days depending on the conditions used, the reaction temperature between about 0 ° and 180 °, usually between 0 ° and 100 °, more preferably between 0 ° C and 70 ° C.
Als inerte Lösungsmittel eignen sich z.B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder XyIoI; chlorierte Kohlenwasserstoffe wie Trichlorethylen, 1 ,2-Dichlorethan,Tetrachlorkohlenstoff, Chloroform oder Dichlormethan oder Gemische der genannten Lösungsmittel.Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane or mixtures of said solvents.
Gewϋnschtenfalls kann in einer Verbindung der Formel I eine funktionell abgewandelte Amino- und /oder Hydroxygruppe durch Solvolyse oder Hydrogenolyse nach üblichen Methoden in Freiheit gesetzt werden. Dies kann z.B. mit NaOH oder KOH in Wasser, Wasser-THF oder Wasser-Dioxan bei Temperaturen zwischen 0 und 100° erfolgen.If desired, in a compound of the formula I, a functionally modified amino and / or hydroxyl group can be liberated by solvolysis or hydrogenolysis by customary methods. This can e.g. with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
Die Reduktion eines Esters zum Aldehyd oder zum Alkohol, oder die Reduktion eines Nitrils zum Aldehyd oder Amin erfolgt nach Methoden wie sie dem Fachmann bekannt sind und in Standardwerken der organischen Chemie beschrieben sind.The reduction of an ester to the aldehyde or to the alcohol, or the reduction of a nitrile to the aldehyde or amine by methods known in the art and are described in standard works of organic chemistry.
Die genannten erfindungsgemäßen Verbindungen lassen sich in ihrer endgültigen Nichtsalzform verwenden. Andererseits umfaßt die vorliegende Erfindung auch die Verwendung dieser Verbindungen in Form ihrer pharmazeutisch unbedenklichen Salze, die von verschiedenen organischen und anorganischen Säuren und Basen nach fachbekannten Vorgehensweisen abgeleitet werden können. Pharmazeutisch unbedenkliche Salzformen der Verbindungen der Formel I werden größtenteils konventionell hergestellt. Sofern die Verbindung der Formel I eine Carbonsäuregruppe enthält, läßt sich eines ihrer geeigneten Salze dadurch bilden, daß man die Verbindung mit einer geeigneten Base zum entsprechenden Basenadditionssalz umsetzt. Solche Basen sind zum Beispiel Alkalimetallhydroxide, darunter Kaliumhydroxid, Natriumhydroxid und Lithiumhydroxid; Erdalkalimetallhydroxide wie Bariumhydroxid und Calciumhydroxid; Alkalimetallalkoholate, z.B. Kaliumethanolat und Natriumpropanolat; sowie verschiedene organische Basen wie Piperidin, Diethanolamin und N-Methylglutamin. DieThe abovementioned compounds according to the invention can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts derived from various organic and inorganic acids and bases according to procedures known in the art can be derived. Pharmaceutically acceptable salt forms of the compounds of formula I are for the most part prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt. 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, eg, potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. The
Aluminiumsalze der Verbindungen der Formel I zählen ebenfalls dazu. Bei bestimmten Verbindungen der Formel I lassen sich Säureadditionssalze dadurch bilden, daß man diese Verbindungen mit pharmazeutisch unbedenklichen organischen und anorganischen Säuren, z.B. Halogenwasserstoffen wie Chlorwasserstoff, Bromwasserstoff oderAluminum salts of the compounds of formula I are also included. For certain compounds of formula I, acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, e.g. Hydrogen halides such as hydrogen chloride, hydrogen bromide or
Jodwasserstoff, anderen Mineralsäuren und ihren entsprechenden Salzen wie Sulfat, Nitrat oder Phosphat und dergleichen sowie Alkyl- und Monoarylsulfonaten wie Ethansulfonat, Toluolsulfonat und Benzolsulfonat, sowie anderen organischen Säuren und ihren entsprechenden Salzen wie Acetat, Trifluoracetat, Tartrat, Maleat, Succinat, Citrat, Benzoat, Salicylat, Ascorbat und dergleichen behandelt. Dementsprechend zählen zu pharmazeutisch unbedenklichen Säureadditionssalzen der Verbindungen der Formel I die folgenden: Acetat, Adipat, Alginat, Arginat, Aspartat, Benzoat, Benzolsulfonat (Besylat), Bisulfat, Bisulfit, Bromid, Butyrat, Kampferat, Kampfersulfonat, Caprylat, Chlorid, Chlorbenzoat, Citrat,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, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate , Salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate .
Cyclopentanpropionat, Digluconat, Dihydrogenphosphat, Dinitrobenzoat, Dodecylsulfat, Ethansulfonat, Fumarat, Galacterat (aus Schleimsäure), Galacturonat, Glucoheptanoat, Gluconat, Glutamat, Glycerophosphat, Hemisuccinat, Hemisulfat, Heptanoat, Hexanoat, Hippurat, Hydrochlorid, Hydrobromid, Hydroiodid, 2-Hydroxyethansulfonat, lodid, Isethionat, Isobutyrat, Lactat, Lactobionat, Malat, Maleat, Malonat, Mandelat, Metaphosphat, Methansulfonat, Methylbenzoat, Monohydrogenphosphat, 2- Naphthalinsulfonat, Nicotinat, Nitrat, Oxalat, Oleat, Pamoat, Pectinat, Persulfat, Phenylacetat, 3-Phenylpropionat, Phosphat, Phosphonat, Phthalat, was jedoch keine Einschränkung darstellt.Cyclopentane propionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galactate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate, 2- Naphthalene sulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.
Weiterhin zählen zu den Basensalzen der erfindungsgemäßenFurthermore, the base salts of the invention include
Verbindungen Aluminium-, Ammonium-, Calcium-, Kupfer-, Eisen(lll)-, Eisen(ll)-, Lithium-, Magnesium-, Mangan(lll)-, Mangan(ll), Kalium-, Natrium- und Zinksalze, was jedoch keine Einschränkung darstellen soll. Bevorzugt unter den oben genannten Salzen sind Ammonium; die Alkalimetallsalze Natrium und Kalium, sowie die Erdalkalimetalsalze Calcium und Magnesium. Zu Salzen der Verbindungen der Formel I, die sich von pharmazeutisch unbedenklichen organischen nicht-toxischen Basen ableiten, zählen Salze primärer, sekundärer und tertiärer Amine, substituierter Amine, darunter auch natürlich vorkommender substituierter Amine, cyclischer Amine sowie basischer lonenaustauscherharze, z.B. Arginin, Betain, Koffein, Chlorprocain, Cholin, N.N'-Dibenzylethylendiamin (Benzathin), Dicyclohexylamin, Diethanolamin, Diethylamin, 2-Diethylaminoethanol, 2- Dimethylaminoethanol, Ethanolamin, Ethylendiamin, N-Ethylmorpholin, N- Ethylpiperidin, Glucamin, Glucosamin, Histidin, Hydrabamin, Iso-propylamin, Lidocain, Lysin, Meglumin, N-Methyl-D-glucamin, Morpholin, Piperazin, Piperidin, Polyaminharze, Procain, Purine, Theobromin, Triethanolamin, Triethylamin, Trimethylamin, Tripropylamin sowie Tris-(hydroxymethyl)- methylamin (Tromethamin), was jedoch keine Einschränkung darstellen soil.Compounds aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc salts, but this should not be a limitation. Preferred among the above salts are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium. 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, 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 should not be limiting.
Verbindungen der vorliegenden Erfindung, die basische stickstoffhaltigeCompounds of the present invention containing basic nitrogen-containing
Gruppen enthalten, lassen sich mit Mitteln wie (Ci-C4) Alkylhalogeniden, z.B. Methyl-, Ethyl-, Isopropyl- und tert.-Butylchlorid, -bromid und -iodid; Di(d- C-4)Alkylsulfaten, z.B. Dimethyl-, Diethyl- und Diamylsulfat; (Ci0- C18)Alkylhalogeniden, z.B. Decyl-, Dodecyl-, Lauryl-, Myristyl- und Stearylchlorid, -bromid und -iodid; sowie Aryl-(CrC4)Alkylhalogeniden, z.B. Benzylchlorid und Phenethylbromid, quarternisieren. Mit solchen Salzen können sowohl wasser- als auch öllösliche erfindungsgemäße Verbindungen hergestellt werden.Groups can be, with agents such as (Ci-C 4 ) alkyl halides, such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C 1 -C 4 ) alkyl sulfates, eg dimethyl, diethyl and diamyl sulfate; (Ci 0 - C 18 ) 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. With such salts Both water-soluble and oil-soluble compounds according to the invention can be prepared.
Zu den oben genannten pharmazeutischen Salzen, die bevorzugt sind, zählen Acetat, Trifluoracetat, Besylat, Citrat, Fumarat, Gluconat,The above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,
Hemisuccinat, Hippurat, Hydrochlorid, Hydrobromid, Isethionat, Mandelat, Meglumin, Nitrat, Oleat, Phosphonat, Pivalat, Natriumphosphat, Stearat, Sulfat, Sulfosalicylat, Tartrat, Thiomalat, Tosylat und Tromethamin, was jedoch keine Einschränkung darstellen soll.Hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to be limiting.
Die Säureadditionssalze basischer Verbindungen der Formel I werden dadurch hergestellt, daß man die freie Basenform mit einer ausreichenden Menge der gewünschten Säure in Kontakt bringt, wodurch man auf übliche Weise das Salz darstellt. Die freie Base läßt sich durch In-Kontakt-Bringen der Salzform mit einer Base und Isolieren der freien Base auf übliche Weise regenerieren. Die freien Basenformen unterscheiden sich in gewissem Sinn von ihren entsprechenden Salzformen in bezug auf bestimmte physikalische Eigenschaften wie Löslichkeit in polaren Lösungsmitteln; im Rahmen der Erfindung entsprechen die Salze jedoch sonst ihren jeweiligen freien Basen- formen.The acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free base forms.
Wie erwähnt werden die pharmazeutisch unbedenklichen Basenadditionssalze der Verbindungen der Formel I mit Metallen oder Aminen wie Alkalimetallen und Erdalkalimetallen oder organischen Aminen gebildet. Bevorzugte Metalle sind Natrium, Kalium, Magnesium und Calcium. Bevorzugte organische Amine sind N,N'-Dibenzylethylendiamin, Chlorprocain, Cholin, Diethanolamin, Ethylendiamin, N-Methyl-D-glucamin und Procain.As mentioned, the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
Die Basenadditionssalze von erfindungsgemäßen sauren Verbindungen werden dadurch hergestellt, daß man die freie Säureform mit einer ausreichenden Menge der gewünschten Base in Kontakt bringt, wodurch man das Salz auf übliche Weise darstellt. Die freie Säure läßt sich durch In- Kontakt-Bringen der Salzform mit einer Säure und Isolieren der freien Säure auf übliche Weise regenerieren. Die freien Säureformen unterscheiden sich in gewissem Sinn von ihren entsprechenden Salzformen in bezug auf bestimmte physikalische Eigenschaften wie Löslichkeit in polaren Lösungsmitteln; im Rahmen der Erfindung entsprechen die Salze jedoch sonst ihren jeweiligen freien Säureformen.The base addition salts of acidic compounds of the invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid can be determined by Contact the salt form with an acid and isolate the free acid in the usual way. The free acid forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms.
Enthält eine erfindungsgemäße Verbindung mehr als eine Gruppe, die solche pharmazeutisch unbedenklichen Salze bilden kann, so umfaßt die Erfindung auch mehrfache Salze. Zu typischen mehrfachen Salzformen zählen zum Beispiel Bitartrat, Diacetat, Difumarat, Dimeglumin, Diphosphat, Dinatrium und Trihydrochlorid, was jedoch keine Einschränkung darstellen soll.If a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
Im Hinblick auf das oben Gesagte sieht man, daß unter dem AusdruckIn view of the above, one sees that under the expression
"pharmazeutisch unbedenkliches Salz" im vorliegenden Zusammenhang ein Wirkstoff zu verstehen ist, der eine Verbindung der Formel I in der Form eines ihrer Salze enthält, insbesondere dann, wenn diese Salzform dem Wirkstoff im Vergleich zu der freien Form des Wirkstoffs oder irgendeiner anderen Salzform des Wirkstoffs, die früher verwendet wurde, verbesserte pharmakokinetische Eigenschaften verleiht. Die pharmazeutisch unbedenkliche Salzform des Wirkstoffs kann auch diesem Wirkstoff erst eine gewünschte pharmakokinetische Eigenschaft verleihen, über die er früher nicht verfügt hat, und kann sogar die Pharmakodynamik dieses Wirkstoffs in bezug auf seine therapeutische Wirksamkeit im Körper positiv beeinflussen."pharmaceutically acceptable salt" as used herein means an active ingredient containing a compound of formula I in the form of one of its salts, particularly when that salt form is the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient that has been used earlier confers improved pharmacokinetic properties. 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 activity in the body.
Gegenstand der Erfindung sind ferner Arzneimittel, enthaltend mindestens eine Verbindung der Formel I und/oder ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, sowie gegebenenfalls Träger- und/oder Hilfsstoffe. Pharmazeutische Formulierungen können in Form von Dosiseinheiten, die eine vorbestimmte Menge an Wirkstoff pro Dosiseinheit enthalten, dargereicht werden. Eine solche Einheit kann beispielsweise 0,5 mg bis 1 g, vorzugsweise 1 mg bis 700 mg, besonders bevorzugt 5 mg bis 100 mg einer erfindungsgemäßen Verbindung enthalten, je nach dem behandeltenThe 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. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound according to the invention, depending on the treatment
Krankheitszustand, dem Verabreichungsweg und dem Alter, Gewicht und Zustand des Patienten, oder pharmazeutische Formulierungen können in Form von Dosiseinheiten, die eine vorbestimmte Menge an Wirkstoff pro Dosiseinheit enthalten, dargereicht werden. Bevorzugte Dosierungseinheits- formulierungen sind solche, die eine Tagesdosis oder Teildosis, wie oben angegeben, oder einen entsprechenden Bruchteil davon eines Wirkstoffs enthalten. Weiterhin lassen sich solche pharmazeutischen Formulierungen mit einem der im pharmazeutischen Fachgebiet allgemein bekannten Verfahren herstellen.Disease condition, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of an active ingredient. Furthermore, such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
Pharmazeutische Formulierungen lassen sich zur Verabreichung über einen beliebigen geeigneten Weg, beispielsweise auf oralem (einschließlich buccalem bzw. sublingualem), rektalem, nasalem, topischem (einschließlich buccalem, sublingualem oder transdermalem), vaginalem oder parenteralem (einschließlich subkutanem, intramuskulärem, intravenösem oder intradermalem) Wege, anpassen. Solche Formulierungen können mit allen im pharmazeutischen Fachgebiet bekannten Verfahren hergestellt werden, indem beispielsweise der Wirkstoff mit dem bzw. den Trägerstoff(en) oder Hilfsstoff(en) zusammengebracht wird.Pharmaceutical formulations 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).
An die orale Verabreichung angepaßte pharmazeutische Formulierungen können als separate Einheiten, wie z.B. Kapseln oder Tabletten; Pulver oder Granulate; Lösungen oder Suspensionen in wäßrigen oder nichtwäßrigen Flüssigkeiten; eßbare Schäume oder Schaumspeisen; oder Öl-in-Wasser- Flüssigemulsionen oder Wasser-in-ÖI-Flüssigemulsionen dargereicht werden. So läßt sich beispielsweise bei der oralen Verabreichung in Form einer Tablette oder Kapsel die Wirkstoffkomponente mit einem oralen, nichttoxischen und pharmazeutisch unbedenklichen inerten Trägerstoff, wie z.B. Ethanol, Glyzerin, Wasser u.a. kombinieren. Pulver werden hergestellt, indem die Verbindung auf eine geeignete feine Größe zerkleinert und mit einem in ähnlicher Weise zerkleinerten pharmazeutischen Trägerstoff, wie z.B. einem eßbaren Kohlenhydrat wie beispielsweise Stärke oder Mannit vermischt wird. Ein Geschmacksstoff, Konservierungsmittel, Dispersionsmittel und Farbstoff können ebenfalls vorhanden sein.Pharmaceutical formulations 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. Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and dye may also be present.
Kapseln werden hergestellt, indem ein Pulvergemisch wie oben beschrieben hergestellt und geformte Gelatinehüllen damit gefüllt werden. Gleit- und Schmiermittel wie z.B. hochdisperse Kieselsäure, Talkum, Magnesium- stearat, Kalziumstearat oder Polyethylenglykol in Festform können dem Pulvergemisch vor dem Füllvorgang zugesetzt werden. Ein Sprengmittel oder Lösungsvermittler, wie z.B. Agar-Agar, Kalziumcarbonat oder Natriumcarbonat, kann ebenfalls zugesetzt werden, um die Verfügbarkeit des Medikaments nach Einnahme der Kapsel zu verbessern.Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith. Lubricants such as e.g. highly disperse 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 or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
Außerdem können, falls gewünscht oder notwendig, geeignete Bindungs-, Schmier- und Sprengmittel sowie Farbstoffe ebenfalls in das Gemisch eingearbeitet werden. Zu den geeigneten Bindemitteln gehören Stärke, Gelatine, natürliche Zucker, wie z.B. Glukose oder Beta-Lactose, Süßstoffe aus Mais, natürliche und synthetische Gummi, wie z.B. Akazia, Traganth oder Natriumalginat, Carboxymethylzellulose, Polyethylenglykol, Wachse, u.a. Zu den in diesen Dosierungsformen verwendeten Schmiermitteln gehören Natriumoleat, Natriumstearat, Magnesiumstearat, Natriumbenzoat, Natriumacetat, Natriumchlorid u.a. Zu den Sprengmitteln gehören, ohne darauf beschränkt zu sein, Stärke, Methylzellulose, Agar, Bentonit, Xanthangummi u.a. Die Tabletten werden formuliert, indem beispielsweise ein Pulvergemisch hergestellt, granuliert oder trockenverpreßt wird, ein Schmiermittel und ein Sprengmittel zugegeben werden und das Ganze zu Tabletten verpreßt wird. Ein Pulvergemisch wird hergestellt, indem die in geeigneter Weise zerkleinerte Verbindung mit einem Verdünnungsmittel oder einer Base, wie oben beschrieben, und gegebenenfalls mit einem Bindemittel, wie z.B. Carboxymethylzellulose, einem Alginat, Gelatine oder Polyvinylpyrrolidon, einem Lösungsverlangsamer, wie z.B. Paraffin, einemIn addition, if desired or necessary, suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Among those used in these dosage forms Lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. The disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry pressing Add a lubricant and a disintegrant and add the whole Tablets is pressed. A powder mix is prepared by mixing the appropriately 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 reducer such as paraffin
Resorptionsbeschleuniger, wie z.B. einem quatemären Salz und/oder einem Absorptionsmittel, wie z.B. Bentonit, Kaolin oder Dikalziumphosphat, vermischt wird. Das Pulvergemisch läßt sich granulieren, indem es mit einem Bindemittel, wie z.B. Sirup, Stärkepaste, Acadia-Schleim oder Lösungen aus Zellulose- oder Polymermaterialen benetzt und durch ein Sieb gepreßt wird. Als Alternative zur Granulierung kann man das Pulvergemisch durch eine Tablettiermaschine laufen lassen, wobei ungleichmäßig geformte Klumpen entstehen, die in Granulate aufgebrochen werden. Die Granulate können mittels Zugabe von Stearinsäure, einem Stearatsalz, Talkum oder Mineralöl gefettet werden, um ein Kleben an den Tablettengußformen zu verhindern. Das gefettete Gemisch wird dann zu Tabletten verpreßt. Die erfindungsgemäßen Verbindungen können auch mit einem freifließenden inerten Trägerstoff kombiniert und dann ohne Durchführung der Granulierungs- oder Trockenverpressungsschritte direkt zu Tabletten verpreßt werden. Eine durchsichtige oder undurchsichtige Schutzschicht, bestehend aus einerAbsorption enhancer, e.g. a quaternary salt and / or an absorbent, e.g. Bentonite, kaolin or dicalcium phosphate is mixed. The powder mixture can be granulated by mixing it with a binder, e.g. Syrup, starch paste, Acadia slime or solutions of cellulose or polymer materials wetted and pressed through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine to produce non-uniformly shaped lumps which are broken up into granules. The granules may be greased by the addition of 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
Versiegelung aus Schellack, einer Schicht aus Zucker oder Polymermaterial und einer Glanzschicht aus Wachs, kann vorhanden sein. Diesen Beschichtungen können Farbstoffe zugesetzt werden, um zwischen unterschiedlichen Dosierungseinheiten unterscheiden zu können.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.
Orale Flüssigkeiten, wie z.B. Lösung, Sirupe und Elixiere, können in Form von Dosierungseinheiten hergestellt werden, so daß eine gegebene Quantität eine vorgegebene Menge der Verbindung enthält. Sirupe lassen sich herstellen, indem die Verbindung in einer wäßrigen Lösung mit geeignetem Geschmack gelöst wird, während Elixiere unter Verwendung eines nichttoxischen alkoholischen Vehikels hergestellt werden. Suspensionen können durch Dispersion der Verbindung in einem nicht- toxischen Vehikel formuliert werden. Lösungsvermittler und Emulgiermittel, wie z.B. ethoxylierte Isostearylalkohole und Polyoxyethylensorbitolether, Konservierungsmittel, Geschmackszusätze, wie z.B. Pfefferminzöl oder natürliche Süßstoffe oder Saccharin oder andere künstliche Süßstoffe, u.a. können ebenfalls zugegeben werden.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 may be prepared by dispersing the compound in a non-aqueous solution. be formulated 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.
Die Dosierungseinheitsformulierungen für die orale Verabreichung können gegebenenfalls in Mikrokapseln eingeschlossen werden. Die Formulierung läßt sich auch so herstellen, daß die Freisetzung verlängert oder retardiert wird, wie beispielsweise durch Beschichtung oder Einbettung von partikulärem Material in Polymere, Wachs u.a.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.
Die Verbindungen der Formel I sowie Salze, Solvate und physiologisch funktionelle Derivate davon lassen sich auch in Form von Liposomen- zuführsystemen, wie z.B. kleinen unilamellaren Vesikeln, großen unilamellaren Vesikeln und multilamellaren Vesikeln, verabreichen. Liposomen können aus verschiedenen Phospholipiden, wie z.B. Cholesterin, Stearylamin oder Phosphatidylcholinen, gebildet werden.The compounds of formula I as well as salts, solvates and physiologically functional derivatives thereof can also be administered in the form of liposome delivery systems, such as 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.
Die Verbindungen der Formel I sowie die Salze, Solvate und physiologisch funktionellen Derivate davon können auch unter Verwendung monoklonaler Antikörper als individuelle Träger, an die die Verbindungsmoleküle gekoppelt werden, zugeführt werden. Die Verbindungen können auch mit löslichen Polymeren als zielgerichtete Arzneistoffträger gekoppelt werden. Solche Polymere können Polyvinylpyrrolidon, Pyran-Copolymer, Polyhydroxypropyl- methacrylamidphenol, Polyhydroxyethylaspartamidphenol oder Polyethylenoxidpolylysin, substituiert mit Palmitoylresten, umfassen. Weiterhin können die Verbindungen an eine Klasse von biologisch abbaubaren Polymeren, die zur Erzielung einer kontrollierten Freisetzung eines Arzneistoffs geeignet sind, z.B. Polymilchsäure, Polyepsilon-Caprolacton, Polyhydroxybuttersäure, Polyorthoester, Polyacetale, Polydihydroxypyrane, Polycyanoacrylate und quervernetzte oder amphipatische Blockcopolymere von Hydrogelen, gekoppelt sein.The compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals. Furthermore, the compounds can be attached to a class of biodegradable polymers suitable for obtaining a controlled release of a drug, eg polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, Polycyanoacrylate and cross-linked or amphipatic block copolymers of hydrogels, be coupled.
An die transdermale Verabreichung angepaßte pharmazeutische Formulierungen können als eigenständige Pflaster für längeren, engenPharmaceutical formulations adapted for transdermal administration may be used as stand-alone patches for longer, narrower patches
Kontakt mit der Epidermis des Empfängers dargereicht werden. So kann beispielsweise der Wirkstoff aus dem Pflaster mittels lontophorese zugeführt werden, wie in Pharmaceutical Research, 3(6), 318 (1986) allgemein beschrieben.Be presented with contact with the epidermis of the recipient. For example, the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
An die topische Verabreichung angepaßte pharmazeutische Verbindungen können als Salben, Cremes, Suspensionen, Lotionen, Pulver, Lösungen, Pasten, Gele, Sprays, Aerosole oder Öle formuliert sein.Pharmaceutical compounds adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
Für Behandlungen des Auges oder anderer äußerer Gewebe, z.B. Mund und Haut, werden die Formulierungen vorzugsweise als topische Salbe oder Creme appliziert. Bei Formulierung zu einer Salbe kann der Wirkstoff entweder mit einer paraffinischen oder einer mit Wasser mischbaren Cremebasis eingesetzt werden. Alternativ kann der Wirkstoff zu einer Creme mit einer Öl-in-Wasser-Cremebasis oder einer Wasser-in-ÖI-Basis formuliert werden.For treatments of the eye or other external tissues, e.g. Mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated into an ointment, the active ingredient can be used with either a paraffinic or water miscible cream base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.
Zu den an die topische Applikation am Auge angepaßten pharmazeutischen Formulierungen gehören Augentropfen, wobei der Wirkstoff in einem geeigneten Träger, insbesondere einem wäßrigen Lösungsmittel, gelöst oder suspendiert ist.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.
An die topische Applikation im Mund angepaßte pharmazeutische Formulierungen umfassen Lutschtabletten, Pastillen und Mundspülmittel.Pharmaceutical formulations adapted for topical application in the mouth include lozenges, troches and mouthwashes.
An die rektale Verabreichung angepaßte pharmazeutische Formulierungen können in Form von Zäpfchen oder Einlaufen dargereicht werden. An die nasale Verabreichung angepaßte pharmazeutische Formulierungen, in denen die Trägersubstanz ein Feststoff ist, enthalten ein grobes Pulver mit einer Teilchengröße beispielsweise im Bereich von 20-500 Mikrometern, das in der Art und Weise, wie Schnupftabak aufgenommen wird, verabreicht wird, d.h. durch Schnellinhalation über die Nasenwege aus einem dicht an die Nase gehaltenen Behälter mit dem Pulver. Geeignete Formulierungen zur Verabreichung als Nasenspray oder Nasentropfen mit einer Flüssigkeit als Trägersubstanz umfassen Wirkstofflösungen in Wasser oder Öl.Pharmaceutical formulations adapted for rectal administration may be presented in the form of suppositories or enemas. Pharmaceutical formulations adapted for nasal administration in which the vehicle is a solid contain 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, ie by rapid inhalation via the nasal passages from a container held close to the nose with the powder. Suitable formulations for administration as a nasal spray or nasal drops with a liquid carrier include drug solutions in water or oil.
An die Verabreichung durch Inhalation angepaßte pharmazeutische Formulierungen umfassen feinpartikuläre Stäube oder Nebel, die mittels verschiedener Arten von unter Druck stehenden Dosierspendern mit Aerosolen, Verneblern oder Insufflatoren erzeugt werden können.Pharmaceutical formulations adapted for administration by inhalation include fine particulate dusts or mists which may be generated by various types of pressurized dosing dispensers with aerosols, nebulizers or insufflators.
An die vaginale Verabreichung angepaßte pharmazeutische Formulierungen können als Pessare, Tampons, Cremes, Gele, Pasten, Schäume oder Sprayformulierungen dargereicht werden.Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Zu den an die parenterale Verabreichung angepaßten pharmazeutischen Formulierungen gehören wäßrige und nichtwäßrige sterile Injektionslösungen, die Antioxidantien, Puffer, Bakteriostatika und Solute, durch die die Formulierung isotonisch mit dem Blut des zu behandelnden Empfängers gemacht wird, enthalten; sowie wäßrige und nichtwäßrige sterile Suspensionen, die Suspensionsmittel und Verdicker enthalten können. Die Formulierungen können in Einzeldosis- oder Mehrfachdosisbehältern, z.B. versiegelten Ampullen und Fläschchen, dargereicht und in gefriergetrocknetem (lyophilisiertem) Zustand gelagert werden, so daß nur die Zugabe der sterilen Trägerflüssigkeit, z.B. Wasser für Injektionszwecke, unmittelbar vor Gebrauch erforderlich ist. Rezepturmäßig hergestellte Injektionslösungen und Suspensionen können aus sterilen Pulvern, Granulaten und Tabletten hergestellt werden. Es versteht sich, daß die Formulierungen neben den obigen besonders erwähnten Bestandteilen andere im Fachgebiet übliche Mittel mit Bezug auf die jeweilige Art der Formulierung enthalten können; so können beispielsweise für die orale Verabreichung geeignete FormulierungenPharmaceutical formulations 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 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. It will be understood that in addition to the above particularly mentioned ingredients, the formulations may include other means conventional in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration
Geschmacksstoffe enthalten.Flavors contain.
Eine therapeutisch wirksame Menge einer Verbindung der Formel I hängt von einer Reihe von Faktoren ab, einschließlich z.B. dem Alter und Gewicht des Tiers, dem exakten Krankheitszustand, der der Behandlung bedarf, sowie seines Schweregrads, der Beschaffenheit der Formulierung sowie dem Verabreichungsweg, und wird letztendlich von dem behandelnden Arzt bzw. Tierarzt festgelegt. Jedoch liegt eine wirksame Menge einer erfindungsgemäßen Verbindung für die Behandlung von neoplastischem Wachstum, z.B. Dickdarm- oder Brustkarzinom, im allgemeinen im Bereich von 0,1 bis 100 mg/kg Körpergewicht des Empfängers (Säugers) pro Tag und besonders typisch im Bereich von 1 bis 10 mg/kg Körpergewicht pro Tag. Somit läge für einen 70 kg schweren erwachsenen Säuger die tatsächliche Menge pro Tag für gewöhnlich zwischen 70 und 700 mg, wobei diese Menge als Einzeldosis pro Tag oder üblicher in einer Reihe von Teildosen (wie z.B. zwei, drei, vier, fünf oder sechs) pro Tag gegeben werden kann, so daß die Gesamttagesdosis die gleiche ist. Eine wirksame Menge eines Salzes oder Solvats oder eines physiologisch funktionellen Derivats davon kann als Anteil der wirksamen Menge der erfindungs- gemäßen Verbindung per se bestimmt werden. Es läßt sich annehmen, daß ähnliche Dosierungen für die Behandlung der anderen, obenerwähnten Krankheitszustände geeignet sind.A therapeutically effective amount of a compound of formula I depends on a number of factors, including e.g. the age and weight of the animal, the exact condition of the disease requiring treatment, as well as its severity, the nature of the formulation and the route of administration, and is ultimately determined by the attending physician or veterinarian. However, an effective amount of a compound of the invention is useful for the treatment of neoplastic growth, e.g. Colon or breast carcinoma, generally in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and more typically in the range of 1 to 10 mg / kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be between 70 and 700 mg, this amount being given as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se. It can be assumed that similar dosages are suitable for the treatment of the other, above-mentioned disease states.
Gegenstand der Erfindung sind ferner Arzneimittel enthaltend mindestens eine Verbindung der Formel I und/oder ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und mindestens einen weiteren Arzneimittelwirkstoff. Gegenstand der Erfindung ist auch ein Set (Kit), bestehend aus getrennten Packungen vonThe 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 at least one further active pharmaceutical ingredient. The invention is also a set (kit), consisting of separate packages of
(a) einer wirksamen Menge an einer Verbindung der Formel I und/oder ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und(A) an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and
(b) einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs.(b) an effective amount of another drug.
Das Set enthält geeignete Behälter, wie Schachteln oder Kartons, individuelle Flaschen, Beutel oder Ampullen. Das Set kann z.B. separate Ampullen enthalten, in denen jeweils eine wirksame Menge an einer Verbindung der Formel I und/oder ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs gelöst oder in lyophilisierter Form vorliegt.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 formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance is dissolved or in lyophilized form.
Bevorzugt aber nicht ausschliesslich werden die Arzneimittel der Tabelle 1 mit den Verbindungen der Formel I kombiniert. Eine Kombination der Formel I und Arzneimitteln der Tabelle 1 kann auch mit Verbindungen der Formel V kombiniert werden.Preferably, but not exclusively, the medicaments of Table 1 are combined with the compounds of the formula I. A combination of formula I and drugs of Table 1 can also be combined with compounds of formula V.
Tabelle 1.Table 1.
Alkylierungsmittel Cyclophosphamid LomustinAlkylating agent Cyclophosphamide Lomustine
Busulfan ProcarbazinBusulfan procarbazine
Ifosfamid AltretaminIfosfamide altretamine
Melphalan EstramustinphosphatMelphalan estramustin phosphate
Hexamethylmelamin MechlorethaminHexamethylmelamine mechlorethamine
Thiotepa StreptozocinThiotepa streptozocin
Chlorambucil TemozolomidChlorambucil Temozolomide
Dacarbazin SemustinDacarbazine Semustin
Carmustincarmustine
Platinmittel Cisplatin CarboplatinPlatinum agent cisplatin carboplatin
Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema)Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema)
Carboxyphthalatoplatinum Satraplatin (JohnsonCarboxyphthalatoplatinum Satraplatin (Johnson
Tetraplatin Matthey)Tetraplatinum Matthey)
Ormiplatin BBR-3464 (Hoffrnann-LaOrmiplatin BBR-3464 (Hoffrnann-La
Iproplatin Roche)Iproplatin Roche)
SM-11355 (Sumitomo)SM-11355 (Sumitomo)
AP-5280 (Access)AP-5280 (Access)
Antimetabolite Azacytidin TomudexAntimetabolite azacytidine Tomudex
Gemcitabin TrimetrexateGemcitabine trimetrexate
Capecitabin DeoxycoformycinCapecitabine deoxycoformycin
5-Fluoruracil Fludarabin5-fluorouracil fludarabine
Floxuridin PentostatinFloxuridine pentostatin
2-Chlordesoxyadenosin Raltitrexed2-chlorodeoxyadenosine Raltitrexed
6-Mercaptopurin Hydroxyharnstoff6-mercaptopurine hydroxyurea
6-Thioguanin Decitabin (SuperGen)6-thioguanine decitabine (SuperGen)
Cytarabin Clofarabin (Bioenvision)Cytarabine Clofarabine (Bioenvision)
2-Fluordesoxycytidin Irofulven (MGI Pharma)2-Fluorodeoxycytidine Irofulvene (MGI Pharma)
Methotrexat DMDC (Hoffmann-LaMethotrexate DMDC (Hoffmann-La
Idatrexate Roche)Idatrexate Roche)
Ethinylcytidin (Taiho )Ethinylcytidine (Taiho)
Topoisomerase- Amsacrin Rubitecan (SuperGen)Topoisomerase Amsacrine Rubitecane (SuperGen)
Inhibitoren Epirubicin Exatecanmesylat (Daiichi)Inhibitors Epirubicin Exatecan Mesylate (Daiichi)
Etoposid Quinamed (ChemGenex)Etoposide Quinamed (ChemGenex)
Teniposid oder Gimatecan (Sigma- Tau)Teniposide or Gimatecan (Sigma-Tau)
Mitoxantron Diflomotecan (Beaufour- lrinotecan (CPT-11 ) Ipsen)Mitoxantrone diflomotecan (Beaufourrinotecan (CPT-11) Ipsen)
7-Ethyl-10- TAS-103 (Taiho) hydroxycamptothecin Elsamitrucin (Spectrum)7-Ethyl-10-TAS-103 (Taiho) hydroxycamptothecin Elsamitrucine (Spectrum)
Topotecan J- 107088 (Merck & Co)Topotecan J-107088 (Merck & Co)
Dexrazoxanet BNP-1350 (BioNumerik)Dexrazoxanet BNP-1350 (BioNumerik)
(TopoTarget) CKD-602 (Chong Kun(TopoTarget) CKD-602 (Chong Kun
Pixantron (Novuspharrna) Dang)Pixantron (Novuspharrna) Dang)
Rebeccamycin-Analogon KW-2170 (Kyowa Hakko)Rebeccamycin analog KW-2170 (Kyowa Hakko)
(Exelixis)(Exelixis)
BBR-3576 (Novuspharrna)BBR-3576 (Novuspharrna)
Antitumor- Dactinomycin (Actinomycin AmonafidAntitumor Dactinomycin (Actinomycin Amonafide
Antibiotika D) AzonafidAntibiotics D) Azonafide
Doxorubicin (Adriamycin) AnthrapyrazolDoxorubicin (adriamycin) anthrapyrazole
Deoxyrubicin OxantrazolDeoxyrubicin Oxantrazole
Valrubicin LosoxantronValrubicin losoxantrone
Daunorubicin BleomycinsulfatDaunorubicin bleomycin sulfate
(Daunomycin) (Blenoxan)(Daunomycin) (Blenoxan)
Epirubicin BleomycinsäureEpirubicin bleomycinic acid
Therarubicin Bleomycin ATherarubicin Bleomycin A
Idarubicin Bleomycin B Edotreotid (Novartis)Idarubicin bleomycin B Edotreotide (Novartis)
Farnesyltransfera Arglabin (NuOncology Tipifarnib (Johnson & se-lnhibitoren Labs) Johnson) lonafamib (Schering- Perillylalkohol (DORFarnesyltransfera Arglabin (NuOncology Tipifarnib (Johnson & se Inhibitors Labs) Johnson) lonafamib (Schering-Perillyl Alcohol (DOR
Plough) BioPharma)Plow) BioPharma)
BAY-43-9006 (Bayer)BAY-43-9006 (Bayer)
Pumpen- CBT-1 (CBA Pharma) Zosuquidar-TrihydrochloridPump CBT-1 (CBA Pharma) Zosuquidar trihydrochloride
Inhibitoren Tariquidar (Xenova) (EIi Lilly)Inhibitors Tariquidar (Xenova) (EIi Lilly)
MS-209 (Schering AG) Biricodar-Dicitrat (Vertex)MS-209 (Schering AG) Biricodar dicitrate (vertex)
Histonacetyltransf Tacedinalin (Pfizer) Pivaloyloxymethylbutyrat erase- SAHA (Aton Pharma) (Titan)Histone acetyl trans Tacedinalin (Pfizer) pivaloyloxymethyl butyrate erase SAHA (Aton Pharma) (titanium)
Inhibitoren MS-275 (Schering AG) Depsipeptid (Fujisawa)Inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)
Metalloproteinase- Neovastat (Aeterna CMT -3 (CollaGenex)Metalloproteinase neovastate (Aeterna CMT -3 (CollaGenex)
Inhibitoren Laboratories) BMS-275291 (Celltech)Inhibitors Laboratories) BMS-275291 (Celltech)
Ribonucleosidred Marimastat (British Tezacitabin (Aventis) uktase- Biotech) Didox (Molecules forRibonucleosidred Marimastat (British Tezacitabine (Aventis) uktase-Biotech) Didox (Molecules for
Inhibitoren Galliummaltolat (Titan) Health)Inhibitors gallium maltolate (titanium) Health)
Triapin (Vion)Triapin (Vion)
TNF-alpha- Virulizin (Lorus Revimid (Celgene)TNF-alpha-virulizine (Lorus Revimid (Celgene)
Agonisten/Antago Therapeutics) nisten CDC-394 (Celgene)Agonists / Antago Therapeutics) nest CDC-394 (Celgene)
Endothelin-A- Atrasentan (Abbot) YM-598 (Yamanouchi)Endothelin A Atrasentan (Abbot) YM-598 (Yamanouchi)
Rezeptor- ZD-4054 (AstraZeneca)Receptor ZD-4054 (AstraZeneca)
Antagonistenantagonists
Retinsäurerezepto Fenretinid (Johnson & Alitretinoin (Ligand) r-Agonisten Johnson)Retinoic Acid Fenretinide (Johnson & Alitretinoin (Ligand) R-agonist Johnson)
LGD-1550 (ügand)LGD-1550 (ügand)
Immunmodulatore Interferon Dexosom-Therapie n Oncophage (Antigenics) (Anosys)Immunomodulators Interferon Dexosome Therapy n Oncophage (Antigenics) (Anosys)
GMK (Progenics) Pentrix (Australian CancerGMK (Progenics) Pentrix (Australian Cancer
Adenokarzinom-Impfstoff Technology)Adenocarcinoma Vaccine Technology)
(Biomira) JSF-154 (Tragen)(Biomira) JSF-154 (Carrying)
CTP-37 (AVI BioPharma) Krebsimpfstoff (Intercell)CTP-37 (AVI BioPharma) cancer vaccine (Intercell)
JRX-2 (Immuno-Rx) Norelin (Biostar)JRX-2 (Immuno-Rx) Norelin (Biostar)
PEP-005 (Peplin Biotech) BLP-25 (Biomira)PEP-005 (Peplin Biotech) BLP-25 (Biomira)
Synchrovax-Impfstoffe MGV (Progenics)Synchrovax vaccines MGV (Progenics)
(CTL Immuno) !3-Alethin (Dovetail)(CTL Immuno)! 3-Alethine (Dovetail)
Melanom-Impfstoff (CTL CLL-Thera (Vasogen)Melanoma vaccine (CTL CLL-Thera (Vasogen)
Immuno) p21-RAS-lmpfstoffImmuno) p21 RAS vaccine
(GemVax)(GemVax)
Hormonelle und Östrogene Prednison antihormonelle konjugierte Östrogene MethylprednisolonHormonal and estrogenic prednisone antihormonal conjugated estrogens methylprednisolone
Mittel Ethinylöstradiol PrednisolonAgent ethinyl estradiol prednisolone
Chlortrianisen AminoglutethimidChlorotrienes Aminoglutethimide
Idenestrol LeuprolidIdenestrol Leuprolide
Hydroxyprogesteroncaproa Goserelin t LeuporelinHydroxyprogesterone caproa Goserelin t Leuporelin
Medroxyprogesteron BicalutamidMedroxyprogesterone Bicalutamide
Testosteron FlutamidTestosterone Flutamide
Testosteronpropionat OctreotidTestosterone Propionate Octreotide
Fluoxymesteron NilutamidFluoxymesterone nilutamide
Methyltestosteron MitotanMethyltestosterone mitotane
Diethylstilbestrol P-04 (Novogen)Diethylstilbestrol P-04 (Novogen)
Megestrol 2-MethoxyöstradiolMegestrol 2-Methoxyestradiol
Tamoxifen (EntreMed)Tamoxifen (EntreMed)
Toremofin Arzoxifen (EIi Lilly)Toremofin Arzoxifen (EIi Lilly)
Dexamethasondexamethasone
Photodynamische Talaporfin (Light Sciences) Pd-BacteriopheophorbidPhotodynamic Talaporfin (Light Sciences) Pd-Bacteriopheophorbide
Mittel Theralux (Yeda)Central Theralux (Yeda)
(Theratechnologies) Lutetium-Texaphyrin(Theratechnologies) Lutetium Texaphyrin
Motexafin-Gadolinium (Pharmacyclics)Motexafin Gadolinium (Pharmacyclics)
(Pharmacyclics) Hypericin(Pharmacyclics) Hypericin
Tyrosinkinase- Imatinib (Novartis) Kahalid F (PharmaMar)Tyrosine kinase imatinib (Novartis) Kahalid F (PharmaMar)
Inhibitoren Leflunomid CEP- 701 (Cephalon)Inhibitors Leflunomide CEP-701 (Cephalon)
(Sugen/Pharmacia) CEP-751 (Cephalon)(Sugen / Pharmacia) CEP-751 (Cephalon)
ZDI839 (AstraZeneca) MLN518 (Millenium)ZDI839 (AstraZeneca) MLN518 (Millenium)
Erlotinib (Oncogene PKC412 (Novartis)Erlotinib (Oncogene PKC412 (Novartis)
Science) Phenoxodiol OScience) phenoxodiol O
Canertjnib (Pfizer) Trastuzumab (Genentech)Canertjnib (Pfizer) Trastuzumab (Genentech)
Squalamin (Genaera) C225 (ImCIone)Squalamine (Genaera) C225 (ImCIone)
SU5416 (Pharmacia) rhu-Mab (Genentech)SU5416 (Pharmacia) rhu-Mab (Genentech)
SU6668 (Pharmacia) MDX-H210 (Medarex)SU6668 (Pharmacia) MDX-H210 (Medarex)
ZD4190 (AstraZeneca) 2C4 (Genentech)ZD4190 (AstraZeneca) 2C4 (Genentech)
ZD6474 (AstraZeneca) MDX-447 (Medarex)ZD6474 (AstraZeneca) MDX-447 (Medarex)
Vatalanib (Novartis) ABX-EGF (Abgenix)Vatalanib (Novartis) ABX-EGF (Abgenix)
PK1166 (Novartis) IMC-1C11 (ImCIone)PK1166 (Novartis) IMC-1C11 (ImCIone)
GW2016GW2016
(GlaxoSmithKline)(GlaxoSmithKline)
EKB-509 (Wyeth)EKB-509 (Wyeth)
EKB-569 (Wyeth)EKB-569 (Wyeth)
Verschiedene SR-27897 (CCK-A- BCX-1777 (PNP-lnhibitor,Various SR-27897 (CCK-A-BCX-1777 (PNP inhibitor,
Mittel Inhibitor, Sanofi- BioCryst) Synthelabo) RanpirnaseMedium Inhibitor, Sanofi-BioCryst) Synthelabo) Ranpirnase
Tocladesin (cyclisches- (Ribonuclease-Stimulans,Tocladesin (cyclic (ribonuclease stimulant,
AMP-Agonist, Ribapharm) Alfacell)AMP agonist, Ribapharm) Alfacell)
Alvocidib (CDK-Inhibitor, Galarubicin (RNA-Alvocidib (CDK inhibitor, galarubicin (RNA
Aventis) Synthese-lnhibitor, Dong-Aventis) Synthesis Inhibitor, Dong-
CV-247 (COX-2-lnhibitor, A)CV-247 (COX-2 inhibitor, A)
Ivy Medical) TirapazaminIvy Medical) Tirapazamine
P54 (COX-2-lnhibitor, (Reduktionsmittel, SRIP54 (COX-2 inhibitor, (reducing agent, SRI
Phytopharm) International)Phytopharm) International)
CapCell™ (CYP450- N-AcetylcysteinCapCell ™ (CYP450-N-acetylcysteine
Stimulans, Bavarian (Reduktionsmittel,Stimulant, Bavarian (reducing agent,
Nordic) Zambon)Nordic) Zambon)
GCS-IOO (gal3- R-Flurbiprofen (NF-GCS-IOO (gal3-R-flurbiprofen (NF-
Antagonist, kappaB-l nhibitor, Encore)Antagonist, kappaB inhibitor, Encore)
10 GlycoGenesys) 3CPA (NF-kappaB-10 GlycoGenesys) 3CPA (NF-kappaB-
G17DT-lmmunogen Inhibitor, Active Biotech)G17DT immunogenic inhibitor, Active Biotech)
(Gastrin-Inhibitor, Aphton) Seocalcitol (Vitamin-D-(Gastrin inhibitor, Aphton) seocalcitol (vitamin D
Efaproxiral (Oxygenator, Rezeptor-Agonist, Leo)Efaproxiral (oxygenator, receptor agonist, Leo)
Allos Therapeutics) 131-I-TM-601 (DNA-Allos Therapeutics) 131-I-TM-601 (DNA
PI-88 (Heparanase- Antagonist,PI-88 (heparanase antagonist,
Inhibitor, Progen) TransMolecular)Inhibitor, progene) TransMolecular)
15 Tesmilifen (Histamin- Eflornithin (ODC-Inhibitor,15 tesmilifen (histamine eflornithine (ODC inhibitor,
Antagonist, YM ILEX Oncology)Antagonist, YM ILEX Oncology)
BioSciences) MinodronsäureBioSciences) Minodronic acid
Histamin (Histamin-H2- (Osteoclasten-Inhibitor,Histamine (histamine H2 (osteoclast inhibitor,
Rezeptor- Agonist, Maxim) Yamanouchi)Receptor agonist, Maxim) Yamanouchi)
Tiazofurin (IMPDH- Indisulam (p53-Stimulans,Tiazofurin (IMPDH-indisulam (p53 stimulant,
Inhibitor, Ribapharm) Eisai)Inhibitor, Ribapharm) Eisai)
Cilengitid (Integrin- Aplidin (PPT-Inhibitor,Cilengitide (Integrin Aplidine (PPT inhibitor,
20 Antagonist, Merck KGaA) PharmaMar)20 antagonist, Merck KGaA) PharmaMar)
SR-31747 (IL-1- Rituximab (CD20-SR-31747 (IL-1 rituximab (CD20-
Antagonist, Sanofi- Antikörper, Genentech)Antagonist, Sanofi antibody, Genentech)
Synthelabo) Gemtuzumab (CD33-Synthelabo) gemtuzumab (CD33-
CCI-779 (mTOR-Kinase- Antikörper, Wyeth Ayerst)CCI-779 (mTOR kinase antibody, Wyeth Ayerst)
Inhibitor, Wyeth) PG2 (Hämatopoese-Inhibitor, Wyeth) PG2 (hematopoietic
Exisulind (PDE-V-Inhibitor, Verstärker,Exisulind (PDE-V inhibitor, enhancer,
25 Cell Pathways) Pharmagenesis)25 Cell Pathways) Pharmagenesis)
CP-461 (PDE-V-Inhibitor, Immunol™ (Triclosan-CP-461 (PDE-V inhibitor, Immunol ™ (triclosan)
Cell Pathways) Oralspülung, Endo)Cell Pathways) Oral Irrigation, Endo)
AG-2037 (GART-I nhibitor, Triacetyluridin (Uridin-AG-2037 (GART inhibitor, triacetyl uridine (uridine)
Pfizer) Prodrug, Wellstat)Pfizer) prodrug, Wellstat)
WX-UK1 SN-4071 (Sarkom-Mittel,WX-UK1 SN-4071 (sarcoma agent,
(Plasminogenaktivator- Signature BioScience)(Plasminogen activator Signature BioScience)
Inhibitor, Wilex) TransMID-107™Inhibitor, Wilex) TransMID-107 ™
30 PBI-1402 (PMN-Stimulans, (Immunotoxin, KS30 PBI-1402 (PMN stimulant, (immunotoxin, KS
ProMetic LifeSciences) Biomedix)ProMetic LifeSciences) Biomedix)
Bortezomib (Proteasom- PCK-3145 (Apoptose-Bortezomib (proteasome PCK-3145 (apoptosis)
Inhibitor, Millennium) Förderer, Procyon) SRL-172 (T-ZeII- Doranidazol (Apoptose-Inhibitor, Millennium) promoter, Procyon) SRL-172 (T-cell doranidazole (apoptosis
Stimulans, SR Pharma) Förderer, PoIa)Stimulant, SR Pharma) promoter, PoIa)
TLK-286 (Glutathion-S- CHS-828 (cytotoxischesTLK-286 (glutathione-S-CHS-828 (cytotoxic
Transferase-Inhibitor, Mittel, Leo)Transferase inhibitor, agent, Leo)
Telik) trans-RetinsäureTelik) trans-retinoic acid
PT-100 (Wachstumsfaktor- (Differentiator, NIH)PT-100 (growth factor (differentiator, NIH)
Agonist, Point MX6 (Apoptose-Förderer,Agonist, Point MX6 (apoptosis promoter,
Therapeutics) MAXIA)Therapeutics) MAXIA)
Midostaurin (PKC-Inhibitor, Apomin (Apoptose-Midostaurin (PKC inhibitor, apomin (apoptosis
Novartis) Förderer, ILEX Oncology)Novartis) Sponsors, ILEX Oncology)
Bryostatin-1 (PKC- Urocidin (Apoptose-Bryostatin-1 (PKC-urocidin (apoptosis)
Stimulans, GPC Biotech) Förderer, Bioniche)Stimulant, GPC Biotech) promoter, Bioniche)
CDA-II (Apoptose- Ro-31-7453 (Apoptose-CDA-II (apoptosis-Ro-31-7453 (apoptosis
Förderer, Everlife) Förderer, La Roche)Conveyor, Everlife) conveyor, La Roche)
SDX-101 (Apoptose- Brostallicin (Apoptose-SDX-101 (apoptosis-brostallicin (apoptosis)
Förderer, Salmedix) Förderer, Pharmacia)Promoter, Salmedix) promoter, Pharmacia)
Ceflatonin (Apoptose-Ceflatonin (apoptosis
Förderer, ChemGenex)Conveyor, ChemGenex)
Bevorzugt werden die Verbindungen der Formel I mit bekannten Antikrebsmitteln kombiniert.Preferably, the compounds of the formula I are combined with known anticancer agents.
Zu diesen bekannten Antikrebsmitteln zählen die folgenden: Östrogenrezeptormodulatoren, Androgenrezeptormodulatoren, Retinoid- rezeptormodulatoren, Zytotoxika, antiproliferative Mittel, Prenyl- Proteintransferasehemmer, HMG-CoA-Reduktase-Hemmer, HlV-Protease- Hemmer, Reverse-Transkriptase-Hemmer sowie weitere Angiogenese- hemmer. Die vorliegenden Verbindungen eignen sich insbesondere zur gemeinsamen Anwendung mit Radiotherapie. Die synergistischen Wirkungen der Hemmung des VEGF in Kombination mit Radiotherapie sind in der Fachwelt beschrieben worden (siehe WO 00/61186). „Östrogenrezeptormodulatoren" bezieht sich auf Verbindungen, die die Bindung von Östrogen an den Rezeptor stören oder diese hemmen, und zwar unabhängig davon, wie dies geschieht. Zu den Östrogenrezeptormodulatoren zählen zum Beispiel Tamoxifen, Raloxifen, Idoxifen, LY353381 , LY 117081 , Toremifen, Fulvestrant, 4-[7-(2,2-Dimethyl-1-oxopropoxy-4- methyl-2-[4-[2-(1 - piperidinyl)ethoxy]phenyl]-2H-1 -benzopyran-3-yl]phenyl- 2,2-dimethylpropanoat, 4,4'-Dihydroxybenzophenon-2,4- dinitrophenylhydrazon und SH646, was jedoch keine Einschränkung darstellen soll.These known anticancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors. The present compounds are particularly suitable for co-administration with radiotherapy. The synergistic effects of inhibiting VEGF in combination with radiotherapy have been described in the art (see WO 00/61186). "Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how this occurs: Estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifen, LY353381, LY 117081, toremifene, fulvestrant , 4- [7- (2,2-Dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl] phenyl 2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4- dinitrophenylhydrazone and SH646, but this is not intended to be limiting.
„Androgenrezeptormodulatoren" bezieht sich auf Verbindungen, die die Bindung von Androgenen an den Rezeptor stören oder diese hemmen, und zwar unabhängig davon, wie dies geschieht. Zu den"Androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this occurs
Androgenrezeptormodulatoren zählen zum Beispiel Finasterid und andere 5α-Reduktase-Hemmer, Nilutamid, Flutamid, Bicalutamid, Liarozol und Abirateron-acetat.Androgen receptor modulators include, for example, finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
„Retinoidrezeptormodulatoren" bezieht sich auf Verbindungen, die die Bindung von Retinoiden an den Rezeptor stören oder diese hemmen, und zwar unabhängig davon, wie dies geschieht. Zu solchen Retinoidrezeptormodulatoren zählen zum Beispiel Bexaroten, Tretinoin, 13-cis-Retinsäure, 9-cis- Retinsäure, α-Difluormethylornithin, ILX23-7553, trans-N-(4'-Hydroxy- phenyl)retinamid und N-4-Carboxyphenylretinamid."Retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this occurs Such retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis Retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) -retinamide and N-4-carboxyphenylretinamide.
„Zytotoxika" bezieht sich auf Verbindungen, die in erster Linie durch direkte Einwirkung auf die Zellfunktion zum Zelltod führen oder die die Zellmyose hemmen oder diese stören, darunter Alkylierungsmittel, Tumornekrosefaktoren, interkaliemde Mittel, Mikrotubulin-Hemmer und Topoisomerase- Hemmer."Cytotoxic agents" refers to compounds that cause cell death primarily through direct action on cell function or that inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.
Zu den Zytotoxika zählen zum Beispiel Tirapazimin, Sertenef, Cachectin, Ifosfamid, Tasonermin, Lonidamin, Carboplatin, Altretamin, Prednimustin, Dibromdulcit, Ranimustin, Fotemustin, Nedaplatin, Oxaliplatin, Temozolomid, Heptaplatin, Estramustin, Improsulfan-tosylat, Trofosfamid, Nimustin, Dibros- pidium-chlorid, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Iro- fulven, Dexifosfamid, cis-Amindichlor(2-methylpyridin)platin, Benzylguanin, Glufosfamid, GPX100, (trans,trans,trans)-bis-mu-(hexan-1 ,6-diamin)-mu- [diamin-platin(ll)]bis[diamin(chlor)platin(ll)]-tetrachlorid, Diarizidinylspermin, Arsentrioxid, 1-(11-Dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthin, Zorubicin, Idarubicin, Daunorubicin, Bisantren, Mitoxantron, Pirarubicin,The cytotoxic agents include, for example, tirapazimine, Sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improvisulfan-tosylate, trofosfamide, nimustine, dibrosylamine. pidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulvene, Dexifosfamide, cis-Amine dichloro (2-methylpyridine) platinum, Benzylguanine, Glufosfamide, GPX100, (trans, trans, trans) -bis-mu (hexane -1, 6-diamine) -mu- [diamine-platinum (II)] bis [diamine (chloro) -platinum (II)] - tetrachloride, diarizidinylspermine, arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3, 7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,
Pinafid, Valrubicin, Amrubicin, Antineoplaston, 3'-Desamino-3'-morpholino- 13-desoxo-10-hydroxycarminomycin, Annamycin, Galarubicin, Elinafid, MEN10755 und 4-Desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl- daunorubicin (siehe WO 00/50032), was jedoch keine Einschränkung darstellen soll. Zu den Mikrotubulin-Hemmern zählen zum Beispiel Paclitaxel, Vindesin- sulfat, S'^'-Dideshydro-^-desoxy-δ'-norvincaleukoblastin, Docetaxol,Pinafid, valrubicin, amrubicin, antineoplaston, 3'-desamino-3'-morpholino-13-desoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032), but this is not intended to be limiting. The microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S''-didehydro-desoxy-δ'-norvincaleukoblastin, docetaxol,
Rhizoxin, Dolastatin, Mivobulin-isethionat, Auristatin, Cemadotin, RPR109881 , BMS184476, Vinflunin, Cryptophycin, 2,3,4,5,6-pentafluor-N- (3-fluor-4-methoxyphenyl)benzolsulfonamid, Anhydrovinblastin, N1N- dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-prolin-t-butylamid, TDX258 und BMS188797.Rhizoxin, dolastatin, mivobulinisethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N 1 N - dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline t-butylamide, TDX258 and BMS188797.
Topoisomerase-Hemmer sind zum Beispiel Topotecan, Hycaptamin, Irinotecan, Rubitecan, β-Ethoxypropionyl-S'^'-O-exo-benzyliden-chartreusin, 9-Methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridin-2-(6H)propanamin, 1-Amino-9-ethyl-5-fluor-2,3-dihydro-9-hydroxy-4-methyl-1 H,12H-benzo[de]- pyrano[3\4^b,7]indolizino[1 ,2b]chinolin-10,13(9H,15H)-dion, Lurtotecan, 7-[2- (N-lsopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPH 100, BN80915, BN80942, Etoposid-phosphat, Teniposid, Sobuzoxan, 21- Dimethylamino-2'-desoxy-etoposid, GL331 , N-[2-(Dimethylamino)ethyl]-9- hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazol-1-carboxamid, Asulacrin, (5a,5aB,8aa,9b)-9-[2-[N-[2-(Dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4- hydroxy-S.S-dimethoxyphenylj-δ.δa.θ.δ.δa.θ- hexohydrofuro(3\4':6,7)naphtho(2,3-d)-1 ,3-dioxol-6-on, 2,3-(Methylendioxy)- 5-methyl-7-hydroxy-8-methoxybenzo[c3phenanthridinium, 6,9-Bis[(2- aminoethyl)amino]benzo[g]isochinolin-5,10-dion, 5-(3-Aminopropylamino)- 7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4I5,1-de]acridin- 6-on, N-[1-[2(Diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4- ylmethyl]formamid, N-(2-(Dimethyl-amino)-ethyl)acridin-4-carboxamid, 6-[[2- (Dimethylamino)-ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]chinolin-7-on und Dimesna. Zu den „antiproliferativen Mitteln" zählen Antisense-RNA- und -DNA-Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecane, β-ethoxypropionyl-S '-' - O-exo-benzylidene-chartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4,5 -kl] acridine-2- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] -pyrano [ 3 \ 4 ^ b, 7] indolizino [1,2b] quinoline-10,13 (9H, 15H) -dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin, BNP1350, BNPH 100, BN80915, BN80942, etoposide-phosphate, teniposide, sobuzoxan, 2 1 -dimethylamino-2'-deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl] -9-hydroxy-5,6-dimethyl-6H -pyrido [4,3-b] carbazole-1-carboxamide, asulacrine, (5a, 5aB, 8aa, 9b) -9- [2- [N- [2- (dimethylamino) ethyl] -N-methylamino] ethyl] -5- [4-hydroxy-SS-dimethoxyphenylj-δ.δa.θ.δ.δa.θ-hexohydrofuro (3 \ 4 ': 6.7) naphtho (2,3-d) -1,3-dioxol 6-one, 2,3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [c3phenanthridinium, 6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline-5,10-dione , 5- (3-aminopropylamino) -7,10-dihydroxy-2- (2-hyd roxyethylaminomethyl) -6H-pyrazolo [4 I 5,1-de] acridine-6-one, N- [1- [2 (diethylamino) ethylamino] -7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6 - [[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2,1-c] quinolin-7-one and dimesna. Antiproliferative agents include antisense RNA and DNA
Oligonucleotide wie G3139, ODN698, RVASKRAS, GEM231 und INX3001 , sowie Antimetaboliten wie Enocitabin, Carmofur, Tegafur, Pentostatin, Doxifluridin, Trimetrexat, Fludarabin, Capecitabin, Galocitabin, Cytarabin- ocfosfat, Fosteabin-Natriumhydrat, Raltitrexed, Paltitrexid, Emitefur, Tiazo- furin, Decitabin, Nolatrexed, Pemetrexed, Nelzarabin, 2'-Desoxy-2'- methylidencytidin, 2'-Fluormethylen-2'-desoxycytidin> N-[5-(2,3- Dihydrobenzofuιyl)sulfonyl]-Nχ3,4-dichlorphenyl)hamstoff, N6-[4-Desoxy-4-Oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, Doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene -2'-deoxycytidine > N- [5- (2,3-dihydrobenzofuyl) sulfonyl] -Nχ3,4-dichlorophenyl) urea, N6- [4-deoxy-4-
[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-hepto- pyranosyl]adenin, Aplidin, Ecteinascidin, Troxacitabine, 4-[2-Amino-4-oxo- 4l6,7)8-tetrahydro-3H-pyrimidino[5,4-b][1 ,4]thiazin-6-yl-(S)-ethyl]-2,5- thienoyl-L-glutaminsäure, Aminopterin, 5-Flurouracil, Alanosin, 11-Acetyl-8- (carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1 ,11 -diazatetracyclo- (7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylessigsäureester, Swainsonin, Lometrexol, Dexrazoxan, Methioninase, 2'-cyan-2'-desoxy-N4-palmitoyl-1-B- D-Arabinofuranosylcytosin und 3-Aminopyridin-2-carboxaldehyd-thiosemi- carbazon. Die „antiproliferativen Mittel" beinhalten auch andere monoklonale Antikörper gegen Wachstumsfaktoren als bereits unter den „Angiogenese- Hemmern" angeführt wurden, wie Trastuzumab, sowie Tumorsuppressorgene, wie p53, die über rekombinanten virusvermittelten Gentransfer abgegeben werden können (siehe z.B. US-Patent Nr. 6,069,134).[N2- [2 (E), 4 (E) -tetradecadienoyl] glycylamino] -L-glycero-BL-manno-heptopyranosyl] adenine, aplidine, ecteinascidin, troxacitabine, 4- [2-amino-4-oxo] 4 l 6,7 ) 8-tetrahydro-3H-pyrimidino [5,4-b] [1,4] thiazin-6-yl (S) -ethyl] -2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo- (7.4.1.0.0) -tetradeca-2,4,6- trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-B-D-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative agents" also include other monoclonal antibodies to growth factors than those already listed under the "angiogenesis inhibitors", such as trastuzumab, as well as tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, eg, US Patent No. 6,069,134 ).
Insbesondere bevorzugt ist die Verwendung der erfindungsgemäßen Verbindung zur Behandlung und Prophylaxe von Tumorerkrankungen.Particularly preferred is the use of the compound according to the invention for the treatment and prophylaxis of tumor diseases.
Der Tumor ist vorzugsweise ausgewählt aus der Gruppe der Tumoren des Plattenepithel, der Blasen, des Magens, der Nieren, von Kopf und Hals, des Ösophagus, des Gebärmutterhals, der Schilddrüse, des Darm, der Leber, des Gehirns, der Prostata, des Urogenitaltrakts, des lymphatischen Systems, des Magens, des Kehlkopft und/oder der Lunge.The tumor is preferably selected from the group of squamous cell tumors, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract , the lymphatic system, the stomach, the larynx and / or the lungs.
Der Tumor ist weiterhin vorzugsweise ausgewählt aus der GruppeThe tumor is furthermore preferably selected from the group
Lungenadenokarzinom, kleinzellige Lungenkarzinome, Bauchspeicheldrüsenkrebs, Glioblastome, Kolonkarzinom und Brustkarzinom. Weiterhin bevorzugt ist die Verwendung zur Behandlung eines Tumors des Blut- und Immunsystems, vorzugsweise zur Behandlung eines Tumors ausgewählt aus der Gruppe der akuten myelotischen Leukämie, der chronischen myelotischen Leukämie, akuten lymphatischen Leukämie und/oder chronischen lymphatischen Leukämie.Lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma. Further preferred is the use for the treatment of a tumor of the blood and immune system, preferably for the treatment of a tumor selected from the group of acute myelotic leukemia, chronic myelotic leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.
Die Erfindung umfasst auch ein Verfahren zur Behandlung eines Patienten, der ein Neoplasma, wie einen Krebs, hat, durch VerabreichungThe invention also includes a method of treating a patient having a neoplasm, such as a cancer, by administration
a) einer oder mehrerer der Verbindungen der Formel I:a) one or more of the compounds of the formula I:
b) und einer oder mehrerer der Verbindungen der Formel V oder deren Säure-Additionssalze, insbesondere Hydrochloride:b) and one or more of the compounds of the formula V or their acid addition salts, in particular hydrochlorides:
worin Y' und Z' jeweils unabhängig voneinander O oder N bedeuten, R und R7 jeweils unabhängig voneinander H, OH, Halogen, OC1-10-Alkyl, OCF3, NO2 oder NH2 bedeuten, s' eine ganze Zahl zwischen 2 und 6, jeweils einschließlich, bedeutet und R8 und R9 jeweils unabhängig voneinander vorzugsweise an der meta- oder para-Position stehen und aus der Gruppe: wherein Y 'and Z' are each independently O or N, R and R 7 are each independently H, OH, halogen, OC 1-10 alkyl, OCF 3 , NO 2 or NH 2 , s' is an integer between 2 and 6, each inclusive, and R 8 and R 9 are each independently preferably at the meta or para position and selected from the group:
ausgewählt sind, wobei die erste und die zweite Verbindung gleichzeitig oder innerhalb von 14 Tagen voneinander in Mengen verabreicht werden, die ausreichen, um das Wachstum des Neoplasmas zu hemmen.wherein the first and second compounds are administered simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of the neoplasm.
Die Kombination der Verbindungen der Formel I mit den Verbindungen der Formeis V und anderer Pentamedin-Analoga führt zu einer synergistischen Wirkung bei der Hemmung von Neoplasien. Kombinationen enthaltend die Verbindungen der Formel V sind z.B. in WO 02058684 erwähnt.The combination of the compounds of the formula I with the compounds of the formula V and other pentamedin analogues leads to a synergistic effect in the inhibition of neoplasms. Combinations containing the compounds of formula V are e.g. mentioned in WO 02058684.
Der Wirkungsmechanismus von Pentamidin oder seiner Derivate ist derzeit nicht eindeutig geklärt: Pentamidin oder seine Derivate hat offenbar pleiotrope Wirkungen, da es zu einer Abnahme von DNA-, RNA- und Protein-Synthese führt. Vor kurzem wurde beschrieben, dass Pentamidin ein leistungsfähiger Hemmstoff von PRL1-, -2- und 3-Phosphatasen (Pathak et al., 2002) und Tyrosinphosphatasen ist, und ihre Überexpression geht mit neoplastischen bösartigen Tumoren beim Menschen einher. Andererseits wurde beschrieben, dass Pentamidin ein Arzneimittel ist, das an die kleine DNA-Furche bindet (Puckowska et al., 2004) und das seine Wirkung über die Störung der Genexpression und/oder DNA-Synthese ausüben kann.The mechanism of action of pentamidine or its derivatives is currently unclear: pentamidine or its derivatives appear to have pleiotropic effects as it leads to a decrease in DNA, RNA and protein synthesis. Pentamidine has recently been described as a potent inhibitor of PRL1, -2 and 3 phosphatases (Pathak et al., 2002) and tyrosine phosphatases, and its overexpression is associated with human neoplastic malignant tumors. On the other hand, it has been described that pentamidine is a drug that binds to the small DNA groove (Puckowska et al., 2004) and that can exert its effect via the disruption of gene expression and / or DNA synthesis.
Andere geeignete Pentamidin-Analoga umfassen Stilbamidin (G-1) und Hydroxystilbamidin (G-2) und ihre Indolanaloga (z.B. G-3): Other suitable pentamidine analogs include stilbamidine (G-1) and hydroxystilbamidine (G-2) and their indole analogs (eg G-3):
(G-1 )(G-1)
(G-3)(G-3)
Jede Amidineinheit kann unabhängig voneinander durch eine der Einheiten ersetzt werden, die vorstehend für R8 und R11 definiert sind. Wie im Fall der Benzimidazole und Pentamidine, eignen sich auch Salze von Stilbamidin, Hydroxystilbamidin und ihren Indolderivaten für das erfindungsgemäße Verfahren. Bevorzugte Salze umfassen zum Beispiel Dihydrochlorid- und Methansulfonatsalze.Each amidine unit can be independently replaced by one of the units defined above for R 8 and R 11 . As in the case of benzimidazoles and pentamidines, salts of stilbamidine, hydroxystilbamidine and their indole derivatives are also suitable for the process according to the invention. Preferred salts include, for example, dihydrochloride and methanesulfonate salts.
Noch andere Analoga sind diejenigen, die unter eine Formel fallen, die in einem der U.S.-Patente Nr. 5,428,051 , 5,521 ,189, 5,602,172, 5,643,935, 5,723,495, 5,843,980, 6,172,104 und 6,326,395 oder der U.S.Patentanmeldung mit der Veröffentlichungsnr. US 2002/0019437 A1 bereitgestellt werden, die jeweils in ihrer Gesamtheit durch Bezugname aufgenommen sind. Beispielhafte Analoga umfassen 1 ,5-Bis-(4'-(N- hydroxyamidino)phenoxy)pentan, 1 ,3-Bis-(4'-(N-hydroxyamidino)- phenoxy)propan, 1 ,3-Bis-(2'-methoxy-4'-(N-hydroxyamidino)-phenoxy)- propan, 1 ,4-Bis-(4'-(N-hydroxyamidino)phenoxy)butan, 1 ,5-Bis-(4'-(N- hydroxyamidino)phenoxy)pentan, 1 ,4-Bis-(4'-(N-hydroxyamidino)- phenoxy)butan, 1 ,3-Bis-(4'-(4-hydroxyamidino)phenoxy)propan, 1 ,3-Bis-(2'- methoxy-4'-(N-hydroxyamidino)phenoxy)propan, 2,5-Bis-[4- amidinophenyl]furan, 2,5-Bis-[4-amidinophenyl]furan-bis-amidoxim, 2,5-Bis- [4-amidinophenyl]furan-bis-O-methylamidoxim, 2,5-Bis-[4- amidinophenyl]furan-bis-O-ethylamidoxim, 2,8-Diamidinodibenzothiophen, 2,8-Bis-(N-isopropylamidino)carbazol, 2,8-Bis-(N-hydroxyamidino)carbazol, 2,8-Bis-(2-imidazolinyl)dibenzothiophen, 2,8-Bis-(2-imidazolinyl)-5,5- dioxodibenzothiophen, 3,7-Diamidinodibenzothiophen, 3,7-BiS-(N- isopropylamidino)dibenzothiophen, 3,7-Bis-(N-hydroxyamidino)-dibenzothio- phen, 3,7-Diaminodibenzothiophen, 3,7-Dibromdibenzothiophen, 3,7-Still other analogs are those falling within a formula disclosed in any of U.S. Patent Nos. 5,428,051, 5,521,189, 5,602,172, 5,643,935, 5,723,495, 5,843,980, 6,172,104 and 6,326,395, or US Patent Application Publ. US 2002/0019437 A1, each of which is incorporated herein by reference are included. Exemplary analogs include 1, 5-bis (4 '- (N-hydroxyamidino) phenoxy) pentane, 1, 3-bis (4' - (N-hydroxyamidino) phenoxy) propane, 1, 3-bis (2 '-methoxy-4' - (N-hydroxyamidino) phenoxy) propane, 1,4-bis (4 '- (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-amidinophenyl] furan-bis-O-methylamidoxime, 2,5-bis [4-amidinophenyl] furan-bis-O-ethylamidoxime, 2,8-diamidinodibenzothiophene, 2,8-bis ( N-isopropylamidino) carbazole, 2,8-bis (N-hydroxyamidino) carbazole, 2,8-bis (2-imidazolinyl) dibenzothiophene, 2,8-bis (2-imidazolinyl) -5,5-dioxodibenzothiophene, 3,7-diamidinodibenzothiophene, 3,7-BiS- (N-isopropylamidino) dibenzothiophene, 3,7-bis- (N-hydroxyamidino) -dibenzothiophene, 3,7-diaminodibenzothiophene, 3,7-dibromodibenzothiophene, 3,7 -
Dicyanodibenzothiophen, 2,8-Diamidinodibenzofuran, 2,8-Di-(2-imidazolinyl)- dibenzofuran, 2,8-Di-(N-isopropylamidino)dibenzofuran, 2, 8-Di-(N- hydroxylamidino)dibenzofuran, 3,7-Di-(2-imidazolinyl)dibenzofuran, 3,7-Di- (isopropylamidino)dibenzofuran, 3,7-Di-(A-hydroxylamidino)dibenzofuran, 2,8-Dicyanodibenzofuran, 4,4I-Dibrom-2,2'-dinitrobiphenyl, 2-Methoxy-2'- nitro-4,4'-dibrombiphenyl, 2-Methoxy-2'-amino-4,41-dibrombiphenylJ 3,7- Dibromdibenzofuran, 3,7-Dicyanodibenzofuran, 2,5-Bis-(5-amidino-2- benzimidazolyl)pyrrol, 2,5-Bis-[5-(2-imidazolinyl)-2-benzimidazolyl]pyrrol, 2,6- Bis-[5-(2-imidazolinyl)-2-benzimidazolyl]pyridin, 1-Methyl-2,5-bis-(5-amidino- 2-benzimidazolyl)pyrrol, 1 -Methyl-2,5-bis-[5-(2-imidazolyl)-2- benzimidazolyl]pyrrol, 1 -Methyl-2,5-bis-[5-(1 ,4,5,6-tetrahydro-2-pyrimidinyl)- 2-benzimidazolyl]pyrrol, 2,6-Bis-(5-amidino-2-benzimidazoyl)pyridin, 2,6-Bis- [5-(1 ,4,5,6-tetrahydro-2-pyrimidinyl)-2-benzimidazolyl]pyridin, 2,5-Bis-(5- amidino-2-benzimidazolyl)furan, 2,5-Bis-[5-(2-imidazolinyl)-2- benzimidazolyl]furan, 2,5-Bis-(5-N-isopropylamidino-2-benzimidazolyl)furan, 2,5-Bis-(4-guanylphenyl)furan, 2,5-Bis(4-guanylphenyl)-3,4-dimethylfuran, 2,5-Di-p-[2-(3,4,5,6-tetrahydropyrimidyl)phenyl]furan, 2,5-Bis-[4-(2- imidazolinyl)phenyl]furan, 2,5-[Bis-{4-(2-tetrahydropyrimidinyl)}phenyl]-p- (tolyloxy)furan, 2,5-[Bis-{4-(2-imidazolinyl)}-phenyl]-3-p-(tolyloxy)furan, 2,5- Bis-{4-[5-(N-2-aminoethylamido)benzimidazol-2-yl]phenyl}furan, 2,5-Bis-[4- (3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)phenyl]furan, 2,5-Bis-[4- (4,5,6,7-tetrahydro-1 H-1 ,3-diazepin-2-yl)phenyl]furan, 2,5-Bis-(4-N,N- dimethylcarboxhydrazidphenyl)furan, 2,5-Bis-{4-[2-(N-2- hydroxyethyl)imidazolinyl]phenyl}furan, 2,5-Bis-[4-(N-isopropyl- amidino)phenyl]furan, 2,5-Bis-{4-[3-(dimethylaminopropyl)amidino]phenyl}- furan, 2,5-Bis-{4-[N-(3-aminopropyl)amidino]phenyl}furan, 2,5-Bis-[2- (imidzaolinyl)phenyl]-3,4-bis-(methoxymethyl)furan, 2,5-Bis-[4-N-(dimethyl- aminoethyl)guanyl]-phenylfuran, 2,5-Bis-{4-[(N-2-hydroxyethyl)guanyl]- phenyl}furan, 2,5-Bis-[4-N-(cyclopropylguanyl)phenyl]furan, 2,5-Bis-[4-(N,N- diethylaminopropyl)-guanyl]phenylfuran, 2,5-Bis-{4-[2-(N-ethylimidazolinyl)]- phenyl}furan, 2,5-Bis-{4-[N-(3-pentylguanyl)]}phenylfuran, 2,5-Bis-[4-(2- imidazolinyl)phenyl]-3-methoxyfuran, 2,5-Bis-[4-(N-isopropylamidino)phenyl]- 3-methylfuran, Bis-[5-amidino-2-benzimidazolyl]methan, Bis-[5-(2-imidazolyl)- 2-benzimidazolyl]methan, 1 ,2-Bis-[5-amidino-2-benzimidazolyl]ethan, 1 ,2- Bis-[5-(2-imidazolyl)-2-benzimidazolyl]ethan, 1 ,3-Bis-[5-amidino-2- benzimidazolyl]propan, 1 ,3-Bis-[5-(2-imidazolyl)-2-benzimidazolyl]propan, 1 ,4-Bis-[5-amidino-2-benzimidazolyl]propan, 1 ,4-Bis-[5-(2-imidazolyl)-2- benzimidazolyl]butan, 1 ,8-Bis-[5-amidino-2-benzimidazolyl]octan, trans-1 ,2- Bis-[5-amidino-2-benzimidazolyl]ethen, 1 ,4-Bis-[5-(2-imidazolyl)-2- benzimidazolyl]-1 -buten, 1 ,4-Bis-[5-(2-imidazolyl)-2-benzimidazolyl]-2-buten, 1 ,4-Bis-[5-(2-imidazolyl)-2-benzimidazolyl]-1 -methylbutan, 1 ,4-Bis-[5-(2- imidazolyl)-2-benzimidazolyl]-2-ethylbutan, 1 ,4-Bis-[5-(2-imidazolyl)-2- benzimidazolyl]-1 -methyl-1 -buten, 1 ,4-Bis-[5-(2-imidazolyl)-2-benzimidazolyl]- 2,3-diethyl-2-buten, 1 ,4-Bis-[5-(2-imidazolyl)-2-benzimidazolyl]-1 ,3-butadien, 1 ,4-Bis-[5-(2-imidazolyl)-2-benzimidazolyl]-2-methyl-1 ,3-butadien, Bis-[5-(2- pyrimidyl)-2-benzimidazolyl]methan, 1 ,2-Bis-[5-(2-pyrimidyl)-2- benzimidazolyl]ethan, 1 ,3-Bis-[5-amidino-2-benzimidazolyl]propan, 1 ,3-Bis- [5-(2-pyrimidyl)-2-benzimidazolyl]propan, 1 ,4-Bis-[5-(2-pyrimidyl)-2- benzimidazolyl]butan, 1 )4-Bis-[5-(2-pyrimidyl)-2-benzimidazolyl]-1 -buten, 1 ,4- Bis-[5-(2-pyrimidyl)-2-benzimidazolyl]-2-buten, 1 ,4-Bis-[5-(2-pyrimidyl)-2- benzimidazolyl]-1 -methylbutan, 1 ,4-Bis-[5-(2-pyrimidyl)-2-benzimidazolyl]-2- ethylbutan, 1 ,4-Bis-[5-(2-pyrimidyl)-2-benzimidazolyl]-1-methyl-1-buten, 1 ,4- Bis-[5-(2-pyrimidyl)-2-benzimidazolyl]-2,3-diethyl-2-buten, 1 ,4-Bis-[5-(2- pyrimidyl)-2-benzimidazolyl]-1 ,3-butadien und 1 ,4-Bis-[5-(2-pyrimidyl)-2- benzimidazolyl]-2-methyl-1 ,3-butadien, 2,4-Bis-(4-guanylphenyl)pyrimidin, 2,4-Bis-(4-imidazolin-2-yl)pyrimidin, 2,4-Bis-[(tetrahydropyrimidinyl-2- yl)phenyl]pyrimidin, 2-(4-[N-i-Propylguanyl]phenyl)-4-(2-methoxy-4-[N-i- propylguanyl]phenyl)pyrimidin, 4-(N-Cyclopentylamidino)-1 ,2- phenylendiamin, 2,5-Bis-[2-(5-amidino)benzimidazoyl]furan, 2,5-Bis-[2-{5-(2- imidazolino)}benzimidazoyl]furan, 2,5-Bis-[2-(5-N-isopropylamidino)- benzimidazoyljfuran, 2,5-Bis-[2-(5-N-cyclopentylamidino)-benzimida- zoyl]furan, 2,5-Bis[2-(5-amidino)benzimidazoyl]pyrrol, 2,5-Bis-[2-{5-(2- imidazolino)}benzimidazoyl]pyrrol, 2,5-Bis-[2-(5-N-isopropylamidino)- benzimidazoyl]pyrrol, 2,5-Bis-[2-(5-N-cyclopentylamidino)- benzimidazoyl]pyrrol, 1-Methyl-2,5-bis-[2-(5-amidino)benzimidazoyl]pyrrol, 2,5-Bis-[2-{5-(2-imidazolino)}benzimidazoyl]-1-methylpyrrol, 2,5-Bis-[2-(5-N- cyclopentylamidino)benzimidazoyl]-1-methylpyrrol, 2,5-Bis-[2-(5-N- isopropylamidino)benzimidazoyl]thiophen, 2,6-Bis-[2-{5-(2- imidazolino)}benzimidazoyl]pyridin, 2,6-Bis-[2-(5-amidino)benzimidazoyl]- pyridin, 4I4'-Bis-[2-(5-N-isopropylamidino)benzimidazoyl]-1 ,2-diphenylethan, 4,4'-Bis-[2-(5-N-cyclopentylamidino)benzimidazoyl]-2,5-diphenylfuran, 2,5- Bis-[2-(5-amidino)benzimidazoyl]benzo-[b]-furan, 2,5-Bis-[2-(5-N- cyclopentylamidino)benzimidazoyl]benzo-[b]-furan, 2,7-Bis-[2-(5-N-isopropyl- amidino)benzimidazoyl]fluor, 2,5-Bis-[4-(3-(N-morpholinopropyl)carbamoyl)- phenyl]furan, 2,5-Bis-[4-(2-N,N-dimethylaminoethylcarbamoyl)phenyl]furan, 2,5-Bis-[4-(3-N,N-dimethylaminopropylcarbamoyl)phenyl]furan, 2,5-Bis-[4-(3- N-methyl-3-N-phenylaminopropylcarbamoyl)phenyl]furan, 2,5-Bis-[4-(3- N,N8,N11-trimethylaminopropylcarbamoyl)phenyl]furan, 2,5-Bis-[3- amidinophenyl]furan, 2,5-Bis-[3-(N-isopropylamidino)amidinophenyl]furan, 2,5-Bis-[3-[(N-(2-dimethylaminoethyl)amidino]phenylfuran, 2,5-Bis-[4-(N- 2,2,2-trichlorethoxycarbonyl)amidinophenyl]furan, 2,5-Bis-[4-(N- thioethylcarbonyl)amidinophenyl]furan, 2,5-Bis-[4-(N- benzyloxycarbonyl)amidinophenyl]furan, 2,5-Bis[4-(N-phenoxycarbonyl)- amidinophenyl]furan, 2,5-Bis-[4-(N-(4-fluor)-phenoxycarbonyl)amidino- phenyl]furan, 2,5-Bis-[4-(N-(4- methoxy)phenoxycarbonyl)amidinophenyl]furan, 2,5-Bis-[4-(1- acetoxyethoxycarbonyl)amidinophenyl]furan und 2,5-Bis-[4-(N-(3- fluor)phenoxycarbonyl)amidinophenyl]furan. Verfahren zur Herstellung einer der vorstehenden Verbindungen sind in den U.S.-Patenten Nr. 5,428,051 , 5,521 ,189, 5,602,172, 5,643,935, 5,723,495, 5,843,980, 6,172,104 und 6,326,395 oder der US-Patentanmeldung mit der Veröffentlichungsnr. US 2002/0019437 A1 beschrieben.Dicyanodibenzothiophene, 2,8-diamidinodibenzofuran, 2,8-di- (2-imidazolinyl) -dibenzofuran, 2,8-di (N-isopropylamidino) dibenzofuran, 2, 8-di (N-hydroxylamidino) dibenzofuran, 3, 7-di- (2-imidazolinyl) dibenzofuran, 3,7-di- (isopropylamidino) dibenzofuran, 3,7-di- (A-hydroxylamidino) dibenzofuran, 2,8-Dicyanodibenzofuran, 4.4 I dibromo-2, 2'-dinitrobiphenyl, 2-methoxy-2'-nitro-4,4'-dibromobiphenyl, 2-methoxy-2'-amino-4,4 1 -dibrombiphenyl J Dibromdibenzofuran 3,7-, 3,7-Dicyanodibenzofuran, 2 , 5-Bis (5-amidino-2-benzimidazolyl) pyrrole, 2,5-bis [5- (2-imidazolinyl) -2-benzimidazolyl] pyrrole, 2,6-bis [5- (2-imidazolinyl ) -2-benzimidazolyl] pyridine, 1-methyl-2,5-bis (5-amidino-2-benzimidazolyl) pyrrole, 1-methyl-2,5-bis [5- (2-imidazolyl) -2- benzimidazolyl] pyrrole, 1-methyl-2,5-bis [5- (1, 4,5,6-tetrahydro-2-pyrimidinyl) -2-benzimidazolyl] pyrrole, 2,6-bis (5-amidino) 2-benzimidazoyl) pyridine, 2,6-bis [5- (1, 4,5,6-tetrahydro-2-pyrimidinyl) -2-benzimidazolyl] pyridine, 2,5-bis (5-amidino-2-yl) benzimidazolyl) furan, 2 , 5-Bis- [5- (2-imidazolinyl) -2-benzimidazolyl] furan, 2,5-bis (5-N-isopropylamidino-2-benzimidazolyl) furan, 2,5-bis (4-guanylphenyl) furan, 2,5-bis (4-guanylphenyl) -3,4-dimethylfuran, 2,5-di-p- [2- (3,4,5,6-tetrahydropyrimidyl) phenyl] furan, 2,5-bis - [4- (2- imidazolinyl) phenyl] furan, 2,5- [bis {4- (2-tetrahydropyrimidinyl)} phenyl] -p- (tolyloxy) furan, 2,5- [bis (4- (2-imidazolinyl)} - phenyl ] -3-p- (tolyloxy) furan, 2,5-bis {4- [5- (N-2-aminoethylamido) benzimidazol-2-yl] phenyl} furan, 2,5-bis- [4- (2-bis) 3a, 4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl) -phenyl] furan, 2,5-bis- [4- (4,5,6,7-tetrahydro-1H-1 , 3-diazepin-2-yl) phenyl] furan, 2,5-bis (4-N, N-dimethylcarboxhydrazidophenyl) furan, 2,5-bis {4- [2- (N-2-hydroxyethyl) imidazolinyl ] phenyl} furan, 2,5-bis [4- (N-isopropylamidino) phenyl] furan, 2,5-bis {4- [3- (dimethylaminopropyl) amidino] phenyl} furan, 2.5 Bis (4- [N- (3-aminopropyl) amidino] phenyl} furan, 2,5-bis [2- (imidazolinyl) phenyl] -3,4-bis (methoxymethyl) furan, 2.5- Bis- [4-N- (dimethylaminoethyl) guanyl] phenylfuran, 2,5-bis {4 - [(N-2-hydroxyethyl) guanyl] phenyl} furan, 2,5-bis- [4- N- (cyclopropylguanyl) phenyl] furan, 2,5-bis [4- (N, N-diethylaminopropyl) guanyl] phenylfuran, 2,5-bis {4- [2- (N-ethylimidazolinyl)] phenyl } furan, 2,5-bis- {4- [N- (3-pentylguanyl)] phenylfura n, 2,5-bis [4- (2-imidazolinyl) phenyl] -3-methoxyfuran, 2,5-bis [4- (N-isopropylamidino) phenyl] -3-methylfuran, bis [5-amidino 2-benzimidazolyl] methane, bis [5- (2-imidazolyl) -2-benzimidazolyl] methane, 1, 2-bis [5-amidino-2-benzimidazolyl] ethane, 1, 2-bis- [5- (2-imidazolyl) -2-benzimidazolyl] ethane, 1, 3-bis [5-amidino-2-benzimidazolyl] propane, 1, 3-bis [5- (2-imidazolyl) -2-benzimidazolyl] propane, 1,4-Bis- [5-amidino-2-benzimidazolyl] propane, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] butane, 1, 8-bis- [5-amidino-2 benzimidazolyl] octane, trans-1,2-bis [5-amidino-2-benzimidazolyl] ethene, 1,4-bis- [5- (2-imidazolyl) -2-benzimidazolyl] -1-butene, 1, 4-Bis- [5- (2-imidazolyl) -2-benzimidazolyl] -2-butene, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -1-methylbutane, 1, 4- Bis- [5- (2-imidazolyl) -2-benzimidazolyl] -2-ethylbutane, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -1-methyl-1-butene, 1, 4-bis- [5- (2-imidazolyl) -2-benzimidazolyl] -2,3-diethyl-2-butene, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -1, 3-bu tadiene, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -2-methyl-1,3-butadiene, bis [5- (2-pyrimidyl) -2-benzimidazolyl] methane, 1 , 2-Bis- [5- (2-pyrimidyl) -2-benzimidazolyl] ethane, 1, 3-bis [5-amidino-2-benzimidazolyl] propane, 1, 3-bis- [5- (2-pyrimidyl ) -2-benzimidazolyl] propane, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] butane, 1 ) 4-bis- [5- (2-pyrimidyl) -2-benzimidazolyl] -1 -but, 1, 4- Bis- [5- (2-pyrimidyl) -2-benzimidazolyl] -2-butene, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -1-methylbutane, 1,4-bis- [5- (2-pyrimidyl) -2-benzimidazolyl] -2-ethylbutane, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -1-methyl-1-butene, 1, 4- Bis [5- (2-pyrimidyl) -2-benzimidazolyl] -2,3-diethyl-2-butene, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -1,3 butadiene and 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -2-methyl-1,3-butadiene, 2,4-bis (4-guanylphenyl) pyrimidine, 2,4-bis - (4-imidazolin-2-yl) pyrimidine, 2,4-bis - [(tetrahydropyrimidinyl-2-yl) phenyl] pyrimidine, 2- (4- [Ni-propylguanyl] phenyl) -4- (2-methoxy- 4- [N-propylguanyl] phenyl) pyrimidine, 4- (N-cyclopentylamidino) -1, 2-phenylenediamine, 2,5-bis- [2- (5-amidino) benzimidazoyl] furan, 2,5-bis- [ 2- {5- (2-imidazolino)} benzimidazoyl] furan, 2,5-bis [2- (5-N-isopropylamidino) benzimidazoyl] furan, 2,5-bis [2- (5-N-cyclopentylamidino) benzimidazoyl] furan, 2,5-bis [2- (5-amidino) benzimidazoyl] pyrrole, 2,5-bis [2- {5- (2-imidazolino)} benzimidazoyl] pyrrole, 2.5- To-[ 2- (5-N-isopropylamidino) benzimidazoyl] pyrrole, 2,5-bis [2- (5-N-cyclopentylamidino) benzimidazoyl] pyrrole, 1-methyl-2,5-bis- [2- (5 -amidino) benzimidazoyl] pyrrole, 2,5-bis [2- {5- (2-imidazolino)} benzimidazoyl] -1-methylpyrrole, 2,5-bis [2- (5-N-cyclopentylamidino) benzimidazoyl] 1-methylpyrrole, 2,5-bis [2- (5-N-isopropylamidino) benzimidazoyl] thiophene, 2,6-bis [2- {5- (2-imidazolino)} benzimidazoyl] pyridine, 2.6 bis [2- (5-amidino) benzimidazoyl] - pyridine, 4 I 4'-bis [2- (5-N-isopropylamidino) benzimidazoyl] -1, 2-diphenylethane, 4,4'-bis [ 2- (5-N-cyclopentylamidino) benzimidazoyl] -2,5-diphenylfuran, 2,5-bis [2- (5-amidino) benzimidazoyl] benzo [b] furan, 2,5-bis [2 - (5-N-cyclopentylamidino) benzimidazoyl] benzo [b] furan, 2,7-bis [2- (5-N-isopropylamidino) benzimidazoyl] fluoro, 2,5-bis- [4- (2-bis) 3- (N-morpholinopropyl) carbamoyl) phenyl] furan, 2,5-bis [4- (2-N, N-dimethylaminoethylcarbamoyl) phenyl] furan, 2,5-bis- [4- (3-N, N-dimethylaminopropylcarbamoyl) phenyl] furan, 2,5-bis [4- (3-N-methyl-3-N-phenylaminopropylcarbamoyl ) phenyl] furan, 2,5-bis- [4- (3-N, N8, N11-trimethylaminopropylcarbamoyl) phenyl] furan, 2,5-bis [3-amidinophenyl] furan, 2,5-bis- [3 - (N-isopropylamidino) amidinophenyl] furan, 2,5-bis [3 - [(N- (2-dimethylaminoethyl) amidino] phenylfuran, 2,5-bis- [4- (N-2,2,2-) trichloroethoxycarbonyl) amidinophenyl] furan, 2,5-bis- [4- (N- thioethylcarbonyl) amidinophenyl] furan, 2,5-bis [4- (N-benzyloxycarbonyl) amidinophenyl] furan, 2,5-bis [4- (N-phenoxycarbonyl) amidinophenyl] furan, 2,5-bis- [4 - (N- (4-fluoro) phenoxycarbonyl) amidinophenyl] furan, 2,5-bis- [4- (N- (4-methoxy) phenoxycarbonyl) amidinophenyl] furan, 2,5-bis- [4- (1-acetoxyethoxycarbonyl) amidinophenyl] furan and 2,5-bis [4- (N- (3-fluoro) phenoxycarbonyl) amidinophenyl] furan. Methods for preparing any of the above compounds are described in U.S. Patent Nos. 5,428,051, 5,521,189, 5,602,172, 5,643,935, 5,723,495, 5,843,980, 6,172,104 and 6,326,395, or U.S. Patent Application Publication no. US 2002/0019437 A1.
Pentamidin-Metabolite eignen sich ebenfalls in der erfindungsgemäßen antiproliferativen Kombination. Pentamidin wird im Körper schnell zu mindestens sieben primären Metaboliten metabolisiert. Einige dieser Metabolite haben eine oder mehrere Wirkungen mit Pentamidin gemeinsam Pentamidin- Metabolite weisenh antiproliferative Wirkung auf, wenn sie mit einem Benzimidazol oder einem Analogon davon kombiniert werden. Pentamidine metabolites are also useful in the antiproliferative combination of this invention. Pentamidine is rapidly metabolized in the body to at least seven primary metabolites. Some of these metabolites have one or more effects in common with pentamidine. Pentamidine metabolites exhibit antiproliferative activity when combined with a benzimidazole or an analog thereof.
Sieben Pentamidin-Analoga sind nachstehend gezeigt.Seven pentamidine analogs are shown below.
Die erfindungsgemäßen Kombinationen von Verbindungen der Formel I und Formel V oder deren Analoga und seiner Metaboliten eignen sich zur Behandlung von Neoplasmen. Eine Kombinationstherapie kann allein oder in Verbindung mit einer anderen Therapie (z.B. Operation, Bestrahlung, Chemotherapie, biologische Therapie) durchgeführt werden. Zusätzlich kann eine Person, deren Risiko, ein Neoplasma zu entwickeln, größer ist, (z.B. jemand, der genetisch prädisponiert ist, oder jemand, der zuvor ein Neoplasma hatte) eine prophylaktische Behandlung erhalten, um die Neoplasmabildung zu hemmen oder zu verzögern. Die Kombination der kinesin-ATPase Eg5/KSP mit den Verbindungen der Formel V, Pentamidin, seine Analoga und /der seiner Metaboliten ist ebenfalls Gegenstand der Erfindung.The combinations of compounds of the formula I and formula V or their analogues and their metabolites according to the invention are suitable for the treatment of neoplasms. Combination therapy may be performed alone or in conjunction with another therapy (eg surgery, radiation, chemotherapy, biological therapy). In addition, a person whose risk of developing a neoplasm is greater (eg, someone who is genetically predisposed or someone who previously had a neoplasm) may be given prophylactic treatment to inhibit or delay neoplasm formation. The combination of kinesin ATPase Eg5 / KSP with the compounds of formula V, pentamidine, its analogues and / or its metabolites is also an object of the invention.
Die Dosierung und Häufigkeit der Verabreichung jeder Verbindung der Kombination kann unabhängig gesteuert werden. Zum Beispiel kann eine Verbindung dreimal täglich oral verabreicht werden, während die zweite Verbindung einmal pro Tag intramuskulär verabreicht werden kann. Die Verbindungen können auch zusammen formuliert werden, so dass eine Verabreichung beiden Verbindungen zuführt.The dosage and frequency of administration of each compound of the combination can be independently controlled. For example, a compound may be administered orally three times a day while the second compound may be administered intramuscularly once a day. The compounds may also be formulated together so that administration will deliver to both compounds.
Die erfindungsgemäßen antiproliferativen Kombinationen können auch als Komponenten eines pharmazeutischen Pakets bereitgestellt werden. Die zwei Arzneimittel können zusammen oder getrennt und in einzelnen Dosierungsmengen formuliert werden.The antiproliferative combinations of the invention may also be provided as components of a pharmaceutical package. The two drugs may be formulated together or separately and in single dosage amounts.
Unter einem anderen Aspekt umfasst die Erfindung ein zur Behandlung eines Patienten, der ein Neoplasma, wie einen Krebs, hat, durch Verabreichung einer Verbindung der Formel (I) und (V) in Kombination mit einem antiproliferativen Mittel. Geeignete antiproliferative Mittel umfassen die in Tabelle 1 bereitgestellten.In another aspect, the invention includes a treatment of a patient having a neoplasm such as a cancer by administering a compound of the formula (I) and (V) in combination with an antiproliferative agent. Suitable antiproliferative agents include those provided in Table 1.
Vor- und nachstehend sina alle Temperaturen in 0C angegeben. In den nachfolgenden Beispielen bedeutet „übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethylacetet oder Dichlormethan, trennt ab, trocknet die organische Phase über Natriumsulfat, dampft ein und reinigt duch Chromatographie an Kieselgel und/oder durch Kristallisation. Rf-Werte an Kieselgel; Laufmittel: Ethylacetat/Methanol 9:1.Above and below all temperatures are given in 0 C. In the following examples, "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 on silica gel and / or by crystallization Rf values on silica gel, mobile phase: ethyl acetate / methanol 9: 1.
Massenspektrometrie (MS): El (Eletronenstoß-Ionisation) M+ Mass spectrometry (MS): El (electron impact ionization) M +
FAB (Fast Atom Bombardment) (M+H)+ ESI (Electrospray lonization) (M+H)+ FAB (Fast Atom Bombardment) (M + H) + ESI (electrospray ionisation) (M + H) +
APCI-MS (atmospheric pressure chemical ionization - mass spectrometry) (M+H)+ APCI-MS (atmospheric pressure chemical ionization - mass spectrometry) (M + H) +
Beispiel 1example 1
Synthese von 1-Methyl-5-phenyl-1 ,4,5,5a,6,7,8,9a-octahydro-9-oxa-1 ,4- diaza-cyclopenta[a]naphthalene-2-carboxylic acid methyl ester 2Synthesis of 1-methyl-5-phenyl-1, 4,5,5a, 6,7,8,9a-octahydro-9-oxa-1,4-diaza-cyclopenta [a] naphthalenes-2-carboxylic acid methyl ester 2
1 2 a. Die Lösung des TFA/HCI-Salzes von Amin 1 in Acetonitril (Amin 11 2 a. The solution of the TFA / HCl salt of amine 1 in acetonitrile (amine 1
(320 mg, 1.68 mmol) wurde in Acetonitril (2 mL) aufgenommen, auf 00C abgekühlt und TFA (0.13 mL, 1.68 mmol) langsam unter Rühren zugefügt) wurde schnell zu einer auf 00C gekühltem Lösung aus Benzaldehyd (178 mg, 1.68 mmol) und 3,4-Dihydro-2H-pyran (141 mg, 1.68 mmol) in Acetonitril (1 mL) gegeben und weitere 18 h bei dieser Temperatur gerührt. Der Rohansatz wurde mit tert.-Butylmethylether (5 mL) versetzt, woraufhin das gewünschte Produkt ausfiel. Dieses wurde abfiltriert, mit tert.- Butylmethylether gewaschen und getrocknet. Man erhielt einen farblosen Feststoff (232 mg, 0.71 mmol, 42 %), der sich als cis/trans-Gemisch der Verbindung 2 herausstellte.(320 mg, 1.68 mmol) was dissolved in acetonitrile (2 mL), cooled to 0 0 C and TFA (0:13 mL, 1.68 mmol) was slowly added with stirring) was added rapidly (to a chilled to 0 0 C solution of benzaldehyde 178 mg , 1.68 mmol) and 3,4-dihydro-2H-pyran (141 mg, 1.68 mmol) in acetonitrile (1 mL) and stirred for a further 18 h at this temperature. Tert-butyl methyl ether (5 mL) was added to the crude batch, whereupon the desired product precipitated. This was filtered off, washed with tert-butyl methyl ether and dried. A colorless solid (232 mg, 0.71 mmol, 42%) was obtained, which turned out to be the cis / trans mixture of compound 2.
Beispiel 2Example 2
Synthese von (4aS,1 OR, 10aS)-10-Phenyl-6-trifluoromethyl-2,3,4a,9,10,10a- hexahydro-1 H-4-oxa-5,9-diaza-phenanthrene 3 Synthesis of (4aS, 1R, 10aS) -10-phenyl-6-trifluoromethyl-2,3,4a, 9,10,10a-hexahydro-1H-4-oxa-5,9-diaza-phenanthrenes 3
b. Die Lösung des TFA/HCI-Salzes von 5-Amino-2-Trifluormethylpyridin in Acetonitril (5-Amino-2-Trifluormethylpyridin (120 mg, 0.74 mmol) wurde in Acetonitril (1 mL) aufgenommen, auf 0°C abgekühlt und TFA (60 μl_, 0.74 mmol) langsam unter Rühren zugefügt) wurde schnell zu einer auf 00C gekühltem Lösung aus Benzaldehyd (80 μL, 0.79 mmol) und 3,4-Dihydro- 2H-pyran (70 μL, 0.77 mmol) in Acetonitril (1 mL) gegeben und weitere 18 h im Druckkolben bei 800C gerührt. Der Rohansatz wurde im Vakuum zur Trockne eingedampft und säulenchromatographisch aufgereinigt (Ethylacetat/Cyclohexan). Man erhielt einen farblosen Feststoff (80 mg, 0.24 mmol, 32 %), der sich als trans-lsomer der Verbindung 3 herausstellte.b. The solution of the TFA / HCl salt of 5-amino-2-trifluoromethylpyridine in acetonitrile (5-amino-2-trifluoromethylpyridine (120 mg, 0.74 mmol) was taken up in acetonitrile (1 mL), cooled to 0 ° C and TFA ( 60 μl_, 0.74 mmol) was slowly added with stirring) was added rapidly (to a chilled to 0 0 C solution of benzaldehyde 80 uL, 0.79 mmol) and 3,4-dihydro-2H-pyran (70 uL, 0.77 mmol) in acetonitrile ( 1 mL) and stirred for a further 18 h in a pressure flask at 80 ° C. The crude batch was evaporated to dryness in vacuo and purified by column chromatography (ethyl acetate / cyclohexane). A colorless solid (80 mg, 0.24 mmol, 32%) was obtained, which turned out to be the trans isomer of compound 3.
Beispiel 3Example 3
Synthese von 2-Ethyl-5-phenyl-2,4,5,5a,6,7,8,9a-octahydro-9-oxa-2,4-diaza- cyclopenta[a]naphthalene 6 Synthesis of 2-ethyl-5-phenyl-2,4,5,5a, 6,7,8,9a-octahydro-9-oxa-2,4-diazacyclopenta [a] naphthalenes 6
c. 1-Ethylpyrrol (1.00 g, 10.5 mmol) wurde in 2 ml Eisessig bei 0°C mitc. 1-Ethylpyrrole (1.00 g, 10.5 mmol) was stirred in 2 ml of glacial acetic acid at 0 ° C
HNO3 rauchend (0.5 ml) versetzt, Acetanhydrid (10 ml_) zugetropft und beiHNO3 fuming (0.5 ml), acetic anhydride (10 ml_) was added dropwise and at
RT 15 h gerührt. Die Lösung wurde auf Eis gegossen und mit Ethylacetat extrahiert. Die organische Phase wurde mit Wasser gewaschen, getrocknet und im Vakuum zur Trockne eingedampft. Das zurückgebliebende dunkle Öl (0.8 g, vorwiegend Verbindung 4) wurde ohne weitere Aufreinigung weiter umgesetzt.RT stirred for 15 h. The solution was poured onto ice and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness in vacuo. The zurückgebliebende dark oil (0.8 g, mainly compound 4) was reacted further without further purification.
d. Die Rohverbindung 4 (0.4 g, ca. 2.85 mmol) wurde in 30 ml_ MeOH aufgenommen, mit Pd/C (5%, 54% H2O feucht, 200 mg) versetzt und 15 unter Wasserstoffatmosphäre gerührt. Die Reaktionsmischung wurde filtriert und im zur Trockne eingedampft. Das zurückgebliebende dunkle Ol (0.33 g, vorwiegend Verbindung 5) wurde ohne weitere Aufreinigung sofort weiter umgesetzt.d. The crude compound 4 (0.4 g, ca. 2.85 mmol) was taken up in 30 ml of MeOH, treated with Pd / C (5%, 54% H 2 O moist, 200 mg) and stirred under a hydrogen atmosphere. The reaction mixture was filtered and evaporated to dryness. The zurückgebliebende dark oil (0.33 g, predominantly compound 5) was reacted immediately without further purification.
e. Analog Beispiel 1 wurde das TFA-SaIz von 5 (330 mg, 3.00 mmol) mit Benzaldehyd (0.32 g, 3.01 mmol) und 3,4-Dihydro-2H-pyran (0.27 ml_,e. Analogously to Example 1, the TFA salt of 5 (330 mg, 3.00 mmol) with benzaldehyde (0.32 g, 3.01 mmol) and 3,4-dihydro-2H-pyran (0.27 ml,
2.99 mmol) in Acetonitril (5 ml_) umgesetzt. Der Rohansatz zur Trockne eingedampft und säulenchromatographisch aufgereinigt (Ethylacetat/ Cyclohexan). Man erhielt einen farblosen Feststoff (26 mg, 0.09 mmol, 3 %), der sich als cis/trans-Gemisch der Verbindung 6 herausstellte.2.99 mmol) in acetonitrile (5 ml_). The crude batch is evaporated to dryness and purified by column chromatography (ethyl acetate / Cyclohexane). This gave a colorless solid (26 mg, 0.09 mmol, 3%), which turned out to be a cis / trans mixture of compound 6.
Beispiel 4Example 4
Synthese von 2-lsobutyl-5-phenyl-2,4,5,5a,6,7,8,9a-octahydro-9-oxa-1 ,2,4- triaza-cyclopenta[a]naphthalene 9Synthesis of 2-isobutyl-5-phenyl-2,4,5,5a, 6,7,8,9a-octahydro-9-oxa-1, 2,4-triaza-cyclopenta [a] naphthalenes 9
The synthesis of 4-Nitropyrazol was described in J.Med.Chem. 2005, 48, 5780-5793.The synthesis of 4-nitropyrazole, described in J. Med. 2005, 48, 5780-5793.
f. 4-Nitropyrazol (610 mg, 5.40 mmol) wurde in 90 ml MeOH gelöst, 1- lod-2-methylpropan (3.8 mL, 32.9 mmol) und KOH-Plätzchen (0.91 g, 16.2 mmol) zugefügt und 3 h unter Rückfluss erhitzt. Die Reaktionslösung wurde mit Wasser versetzt, mehrfach mit DCM extrahiert, die vereinigten organischen Phasen getrocknet, filtriert und im Vakuum zur Trockne eingedampft. Das zurückgebliebende dunkle Öl (0.67 g, vorwiegend Verbindung 7) wurde ohne weitere Aufreinigung weiter umgesetzt. d. Die Rohverbindung 7 (0.3 g, ca. 1.77 mmol) wurde in 10 mL MeOH aufgenommen, mit Pd/C (5%, 54% H2O feucht, 300 mg) versetzt und 15 unter Wasserstoffatmosphäre gerührt. Die Reaktionsmischung wurde filtriert und im zur Trockne eingedampft. Das zurückgebliebende dunkle Öl wurde säulenchromatographisch aufgereinigt (Ethylacetat/MeOH). Man erhieltf. 4-Nitropyrazole (610 mg, 5.40 mmol) was dissolved in 90 mL MeOH, 1-iodo-2-methylpropane (3.8 mL, 32.9 mmol) and KOH pellets (0.91 g, 16.2 mmol) added and heated at reflux for 3 h. The reaction solution was mixed with water, extracted several times with DCM, the combined organic phases dried, filtered and evaporated to dryness in vacuo. The zurückgebliebende dark oil (0.67 g, mainly Compound 7) was reacted further without further purification. d. The crude compound 7 (0.3 g, ca. 1.77 mmol) was taken up in 10 mL MeOH, mixed with Pd / C (5%, 54% H 2 O moist, 300 mg) and stirred under a hydrogen atmosphere. The reaction mixture was filtered and evaporated to dryness. The residual dark oil was purified by column chromatography (ethyl acetate / MeOH). One received
Verbindung 8 als dunkles Öl (190 mg, 77%).Compound 8 as a dark oil (190 mg, 77%).
e. Analog Beispiel 1 wurde das TFA-SaIz von 8 (170 mg, 1.22 mmol) mit Benzaldehyd (0.13 g, 1.29 mmol) und 3,4-Dihydro-2H-pyran (0.11 mL, 1.229 mmol) in Acetonitril (2 mL) umgesetzt. Der Rohansatz zur Trockne eingedampft und säulenchromatographisch aufgereinigt (Ethylacetat/Cyclohexan). Man erhielt einen farblosen Feststoff (42 mg, 0.13 mmol, 11 %), der sich als cis/trans-Gemisch der Verbindung 9 herausstellte.e. Analogously to Example 1, the TFA salt of 8 (170 mg, 1.22 mmol) was reacted with benzaldehyde (0.13 g, 1.29 mmol) and 3,4-dihydro-2H-pyran (0.11 mL, 1.229 mmol) in acetonitrile (2 mL) , The crude batch is evaporated to dryness and purified by column chromatography (ethyl acetate / cyclohexane). A colorless solid (42 mg, 0.13 mmol, 11%) was obtained, which turned out to be a cis / trans mixture of compound 9.
Analog werden unter Verwendung oder entsprechenden Vorstufen die folgenden erfindungsgemäßen Verbindungen erhalten:Analogously, the following compounds according to the invention are obtained using or corresponding precursors:
Beispiel: [M+1]+ Example: [M + 1] +
(5) RAC(5) RAC
(8)(8th)
RACRAC
(14) (14)
RAC RAC
Die nachfolgenden Beispiele betreffen Arzneimittel:The following examples relate to drugs:
Beispiel C: InjektionsgläserExample C: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium- hydrogenphosphat wird in 3 I zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.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 sealed sterile. Each injection jar contains 5 mg of active ingredient.
Beispiel D: SuppositorienExample D: Suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.A mixture of 20 g of an active compound of the formula I 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.
Beispiel E: LösungExample E: Solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I1 9,38 g NaH2PO4 • 2 H2O, 28,48 g Na2HPO4 • 12 H2O und 0,1 g Benzalkoniumchlorid in 940 ml zweifach destilliertem Wasser. Man stellt auf pH 6,8 ein, füllt auf 1 I auf und sterilisiert durch Bestrahlung. Diese Lösung kann in Form von Augentropfen verwendet werden.A solution of 1 g of an active ingredient of the formula I 1 9.38 g of NaH 2 PO 4 • 2H 2 O, 28.48 g Na 2 HPO 4 • 12 H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double-one prepares distilled water. Adjust to pH 6.8, make up to 1 liter on and sterilized by irradiation. This solution can be used in the form of eye drops.
Beispiel F: SalbeExample F: ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of an active compound of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.
Beispiel G: TablettenExample G: Tablets
Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Lactose, 1 ,2 kg Kartoffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.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.
Beispiel H: DrageesExample H: dragees
Analog Beispiel E werden Tabletten gepreßt, die anschließend in üblicher Weise mit einem Überzug aus Saccharose, Kartoffelstärke, Talk, Tragant und Farbstoff überzogen werden.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.
Beispiel I: KapselnExample I: Capsules
2 kg Wirkstoff der Formel I werden in üblicher Weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active compound of the formula I are filled in the usual way in hard gelatin capsules, so that each capsule contains 20 mg of the active ingredient.
Beispiel J: AmpullenExample J: Ampoules
Eine Lösung von 1 kg Wirkstoff der Formel I in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff. 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.

Claims

Patentansprüche claims
Verbindungen der Formel ICompounds of the formula I
worin wherein
X O, NR oder S,X O, NR or S,
R1, R2, unabhängig voneinander H, A, HaI, SA, (CH2)PCN, SCN,R 1 , R 2 , independently of one another H, A, Hal, SA, (CH 2 ) P CN, SCN,
(CF2)PCF3, SF5, OA, O (CF2)pCF3, S(CF2)pCF3, NR2, NRCOR, NRSO2R, NR(CH2)pNR2, CONR(CH2)PNR2, SO2NR(CH2)PNR2, CONR2, SO2NR2, COOR,(CF 2 ) P CF 3 , SF 5 , OA, O (CF 2 ) p CF 3 , S (CF 2 ) p CF 3 , NR 2 , NRCOR, NRSO 2 R, NR (CH 2 ) p NR 2 , CONR (CH 2 ) P NR 2 , SO 2 NR (CH 2 ) P NR 2 , CONR 2 , SO 2 NR 2 , COOR,
H1 AH 1 A
A lineares oder verzweigtes Alkyl mit 1 bis 10 C-Atomen oderA linear or branched alkyl having 1 to 10 carbon atoms or
Cycloalkyl mit 3 bis 7 C-Atomen, R4 unsubstituiertes oder einfach oder mehrfach durch Aryl oder Heteroaryl, das durch HaI, NO2, CN, A, OR, OCOR, NR2, CF3, OCF3, OCH(CF3)2 substituiert sein kann, HaI, NO2, CN, OR, A, -(CYz)n-OR, -OCOR1 -(CY2VCO2R, -(CY2)n-CN oder -(CY2)n- NR2 substituiertes Aryl oder Heteroaryl,Cycloalkyl having 3 to 7 C atoms, R 4 is unsubstituted or mono- or polysubstituted by aryl or heteroaryl which may be substituted by Hal, NO 2 , CN, A, OR, OCOR, NR 2 , CF 3 , OCF 3 , OCH (CF 3 ) 2 , Hal, NO 2 , CN, OR, A, - (CYz) n -OR, -OCOR 1 - (CY 2 VCO 2 R, - (CY 2 ) n -CN or - (CY 2 ) n -NR 2 substituted aryl or heteroaryl,
Y H, A1 HaI, ORYH, A 1 Hal, OR
R H, A, (CH2)pO(CH2)pR3, (CH2)pNA(CH2)pR3,RH, A, (CH 2 ) p O (CH 2 ) pR 3 , (CH 2 ) pNA (CH 2 ) p R 3 ,
W CH2, C=O, C=S oder eine Einfachbindung,W is CH 2 , C = O, C = S or a single bond,
Q1 NR, O, S oder eine Einfachbindung,Q 1 is NR, O, S or a single bond,
oder eine Einfachbindung, or a single bond,
Q2 NR, S, O oder eine Einfachbindung,Q 2 NR, S, O or a single bond,
R5 H, (CY2)pNR2) (CY2)POR, (CY2)PSR, R 5 H, (CY 2 ) pNR 2) (CY 2 ) P OR, (CY 2 ) P SR,
((CCYY22))PPQQ11CCOOQQ11RR,, ((CCY2)PCOOR und, sofern Q2 eine Einfachbindung bedeutet, auch HaI,((CCYY 22 )) PP QQ 11 CCOOQQ 11 RR ,, ((CCY 2 ) P COOR and, if Q 2 is a single bond, also HaI,
HaI F, Br oder ClHaI F, Br or Cl
n 1 , 2, 3 oder 4, m 0, 1 oder 2n 1, 2, 3 or 4, m 0, 1 or 2
p 0, 1 , 2, 3, 4, 5, 6, 7 oder 8p is 0, 1, 2, 3, 4, 5, 6, 7 or 8
undand
s 0, 1 oder 2 bedeuten,s is 0, 1 or 2,
sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Tautomere, Salze und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.and their pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, including mixtures thereof in all ratios.
2. Verbindungen nach Anspruch 1 , worin R1 Alkyl, CF3, OCF3, SCN, COOR, CH2CN, OH, S Alkyl, O Alkyl, HaI oder SCF3 bedeutet.2. Compounds according to claim 1, wherein R 1 is alkyl, CF 3 , OCF 3 , SCN, COOR, CH 2 CN, OH, S is alkyl, O is alkyl, Hal or SCF 3 .
3. Verbindungen nach Anspruch 1 oder 2, worin R2, H oder Br bedeutet.3. Compounds according to claim 1 or 2, wherein R is 2 , H or Br.
4. Verbindungen nach einem oder mehreren der Ansprüche 1-3, worin R3, H, Methyl, Ethyl, n-Propyl oder n-Butyl bedeutet.4. Compounds according to one or more of claims 1-3, wherein R 3 signifies H, methyl, ethyl, n-propyl or n-butyl.
5. Verbindungen nach einem oder mehreren der Ansprüche 1-4, worin R4, Aryl, das durch F, Cl, OR oder Aryl substituiert sein kann, bedeutet.5. Compounds according to one or more of claims 1-4, wherein R 4 , aryl, which may be substituted by F, Cl, OR or aryl means.
6. Verbindungen nach einem oder mehreren der Ansprüche 1-5, worin W1 CH2 oder eine Einfachbindung bedeutet.6. Compounds according to one or more of claims 1-5, wherein W 1 is CH 2 or a single bond.
7. Verbindungen nach einem oder mehreren der Ansprüche 1-6, worin 2 -SO2-, -SO-, -CO-, -CS oder eine Einfachbindung bedeutet. 7. Compounds according to one or more of claims 1-6, wherein 2 is -SO 2 -, -SO-, -CO-, -CS or a single bond.
8. Verbindungen nach einem oder mehreren der Ansprüche 1-7, worin Q1 und Q2 unabhängig voneinander eine Einfachbindung, NR oder O bedeutet.8. Compounds according to one or more of claims 1-7, wherein Q 1 and Q 2 independently of one another is a single bond, NR or O.
9. Verbindungen nach einem oder mehreren der Ansprüche 1-8, worin R5 H, (CY2)pNR2,oder (CY2)POR bedeutet.9. Compounds according to one or more of claims 1-8, wherein R 5 is H, (CY 2 ) p NR 2 , or (CY 2 ) P OR.
10. Verbindungen nach einem oder mehreren der Ansprüche 1-9, worin R10. Compounds according to one or more of claims 1-9, wherein R
H, A oder (CH2)pNA(CH2)pR3 bedeutet.H, A or (CH 2 ) pNA (CH 2 ) pR 3 .
11. Verbindungen der Teilformeln IA bis ID:11. Compounds of sub-formulas IA to ID:
Y, W, Q1, Q2, Z1R, R1, R2 R4, R5 und n die oben angegebenen Bedeutungen aufweisen.Y, W, Q 1 , Q 2 , Z 1 R, R 1 , R 2 R 4 , R 5 and n are those given above Have meanings.
12. Verfahren zur Herstellung von Verbindungen der Formel I sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomeren und Stereoisomeren, dadurch gekennzeichnet, daß man Verbindungen der Formel Il ausgewählt aus der folgenden Gruppe:12. A process for preparing compounds of the formula I and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, characterized in that compounds of the formula II are selected from the following group:
1 2 worin R , R und R die oben angegebenen Bedeutungen haben,1 2 wherein R, R and R have the meanings given above,
mit einer Verbindung der Formelwith a compound of the formula
worinwherein
R4 die oben angegebene Bedeutung aufweist,R 4 has the abovementioned meaning,
und mit einer Verbindung der Formel IV,and with a compound of the formula IV,
worin X und s die oben angegebenen Bedeutungen haben, bevorzugt in Gegenwart einer Protonensäure oder Lewis-Säure wie z.B. Trifluoressgsäure, Hexafluorisopropanol, Bismut (lll)chlorid,0 Ytterbium(lll)triflat, Scandium (IM) triflat oder Cerammonium (IV)nitrat umsetzt,wherein X and s have the meanings given above, preferably in the presence of a protonic acid or Lewis acid such as trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, triflate 0 ytterbium (III), scandium (III) triflate or Cerammonium (IV) nitrate is reacted .
und gegebenenfalls nach üblichen Methoden für R3 einen anderen Rest als H einführt und/oder gegebenenfalls eine Base oder Säure5 der Formel I in eines ihrer Salze umwandelt.and, if appropriate, by conventional methods for R 3 introduces a radical other than H and / or optionally converts a base or acid 5 of the formula I into one of its salts.
o 13. Arzneimittel, enthaltend mindestens eine Verbindung der Formel I nach Anspruch 1 bis 11 und/oder ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomere und Stereoisomeren, einschließlich deren Mischungen in allen Verhältnissen, sowie gegebenenfalls Träger- und/oder Hilfsstoffe. 513. Pharmaceutical compositions containing at least one compound of the formula I according to claim 1 to 11 and / or pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants. 5
14. Mischung enthalten eine oder mehrere Verbindungen der Formel I sowie Menge einer oder mehrerer Verbindungen der Formel V, deren Analoga und/oder seiner Metaboliten, 0 14. Mixture contain one or more compounds of the formula I and the amount of one or more compounds of the formula V, their analogues and / or its metabolites, 0
worinwherein
Y' und Z' jeweils unabhängig voneinander O oder N bedeuten, R9 und R10 jeweils unabhängig voneineander H, OH, Halogen, OCI-10-Alkyl, OCF3, NO2 oder NH2 bedeuten, s' eine ganze Zahl zwischen 2 und 6, jeweils einschließlich, bedeutet und R8 und R11 jeweils unabhängig voneinander an der meta- oder para-Position stehen und aus der Gruppe:Y 'and Z' are each independently O or N, R 9 and R 10 are each independently of another, H, OH, halogen, OCI-10 alkyl, OCF 3 , NO 2 or NH 2 , s' is an integer between 2 and 3 6, each inclusive, and R 8 and R 11 are each independently at the meta or para position and from the group:
ausgewählt sind.are selected.
15. Verwendung nach Anspruch 14, wobei als Verbindung der Formel V Pentamidin oder seine Salze verwendet werden.15. Use according to claim 14, wherein as the compound of formula V pentamidine or its salts are used.
16. Verwendung von Verbindungen nach Anspruch 1 bis 11 sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomeren und Stereoisomeren, einschließlich deren Mischungen in allen Verhältnissen oder der Mischung nach Anspruch 14, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die durch die Hemmung, Regulierung und/oder Modulation der mitotischen Motor- Proteins Eg5 beeinflusst werden können.16. Use of compounds according to claim 1 to 11 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all proportions or the mixture according to claim 14, for the manufacture of a medicament for the treatment of diseases by the Inhibition, regulation and / or modulation of the mitotic motor protein Eg5 can be influenced.
17. Verwendung von Verbindung nach Anspruch 1 bis 11 oder der Mischung nach Anspruch 14, zur Herstellung eines Arzneimittels zur17. Use of compound according to claim 1 to 11 or the mixture according to claim 14, for the preparation of a medicament for
Behandlung und Prophylaxe von Krebskrankheiten.Treatment and prophylaxis of cancer diseases.
18. Verwendung nach Anspruch 17, wobei die Krebskrankheiten mit einem Tumor aus der Gruppe der Tumoren des Plattenepithel, der Blasen, des Magens, der Nieren, von Kopf und Hals, des Ösophagus, des18. Use according to claim 17, wherein the cancerous diseases with a tumor from the group of tumors of the squamous epithelium, the bladder, the stomach, the kidneys, the head and neck, the esophagus, the
Gebärmutterhals, der Schilddrüse, des Darm, der Leber, des Gehirns, der Prostata, des Urogenitaltrakts, des lymphatischen Systems, des Magens, des Kehlkopf und/oder der Lunge einhergehen.Cervix, thyroid, intestine, liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx and / or lungs.
19. Verwendung nach Anspruch 18, wobei der Tumor aus der Gruppe Monozytenleukämie, Lungenadenokarzinom, kleinzellige Lungenkarzinome, Bauchspeicheldrüsenkrebs, Glioblastome und Brustkarzinom und Kolokarzinom stammt.The use of claim 18, wherein the tumor is from the group of monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma, and colon carcinoma.
20. Verwendung nach Anspruch 19, wobei die zu behandelnde Krebs- Krankheit ein Tumor des Blut- und Immunsystems ist.20. Use according to claim 19, wherein the cancer to be treated is a tumor of the blood and immune system.
21. Verwendung nach Anspruch 20, wobei der Tumor aus der Gruppe der akuten myelotischen Leukämie, der chronischen myelotischen Leukämie, akuten lymphatischen Leukämie und/oder chronischen lymphatischen Leukämie stammt.The use of claim 20, wherein the tumor is from the group of acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia and / or chronic lymphocytic leukemia.
22. Verwendung von Verbindungen der Formel I gemäß Anspruch 1 bis 11 und/oder ihrer physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zur Behandlung von Tumoren in22. Use of compounds of the formula I according to claim 1 to 11 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of tumors in
Kombination mit einer therapeutisch wirksamen Menge einer oder mehrerer Verbindungen der Formel V, deren Analoga und/oder seiner Metaboliten,Combination with a therapeutically effective amount of one or several compounds of formula V, their analogues and / or their metabolites,
worinwherein
.j Q Y' und Z' jeweils unabhängig voneinander O oder N bedeuten, R9 und, j Q Y 'and Z' are each independently O or N, R 9 and
R10 jeweils unabhängig voneineander H, OH, Halogen, OC1-10-Alkyl, OCF3, NO2 oder NH2 bedeuten, s' eine ganze Zahl zwischen 2 und 6, jeweils einschließlich, bedeutet und R8 und R11 jeweils unabhängig voneinander an der meta- oder para-Position stehen und aus derR 10 each independently is H, OH, halo, OC 1-10 alkyl, OCF 3 , NO 2 or NH 2 , s' is an integer between 2 and 6 inclusive, and R 8 and R 11 are each independently stand at the meta or para position and from the
15 Gruppe:15 group:
2J. ausgewählt sind, wobei die Verbindungen der Formel I und die Verbindungen der Formel V, ihre Analoga und/oder ihre Metaboliten gleichzeitig oder innerhalb von 14 Tagen voneinander in Mengen verabreicht werden, die ausreichen, um das Wachstum eines Tumors oder von anderen hyperproliferativen2 y . wherein the compounds of formula I and the compounds of formula V, their analogs and / or their metabolites are administered simultaneously or within 14 days of each other in amounts sufficient to prevent the growth of a tumor or other hyperproliferative
Qn Zellen zu hemmen. Inhibit Qn cells.
23. Verwendung nach Anspruch 22, wobei als Verbindung der Formel V Pentamidin oder seine Salze verwendet werden.23. Use according to claim 22, wherein as the compound of formula V pentamidine or its salts are used.
24. Verwendung von Verbindungen der Formel I gemäß Anspruch 1 bis 11 und/oder ihrer physiologisch unbedenklichen Salze und Solvate zur24. Use of compounds of the formula I according to claim 1 to 11 and / or their physiologically acceptable salts and solvates
Herstellung eines Arzneimittels zur Behandlung von Tumoren wobei eine therapeutisch wirksame Menge einer Verbindung der Formel I in Kombination mit Radiotherapie und einer Verbindung aus der Gruppe 1 ) Östrogenrezeptormodulator, 2) Androgenrezeptormodulator, 3) Retinoidrezeptormodulator, 4) Zytotoxikum, 5) antiproliferatives Mittel,Preparation of a medicament for the treatment of tumors wherein a therapeutically effective amount of a compound of formula I in combination with radiotherapy and a compound from the group 1) estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent,
6) Prenyl-Proteintransferasehemmer, 7) HMG-CoA-Reduktase- Hemmer, 8) HIV-Protease-Hemmer, 9) Reverse-Transkriptase-Hemmer sowie 10) weiterer Angiogenese-Hemmer verabreicht wird. 6) prenyl protein transferase inhibitors, 7) HMG-CoA reductase inhibitors, 8) HIV protease inhibitors, 9) reverse transcriptase inhibitors, and 10) other angiogenesis inhibitors.
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