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EP1778694A1 - Tetrahydroquinolines - Google Patents

Tetrahydroquinolines

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Publication number
EP1778694A1
EP1778694A1 EP05750999A EP05750999A EP1778694A1 EP 1778694 A1 EP1778694 A1 EP 1778694A1 EP 05750999 A EP05750999 A EP 05750999A EP 05750999 A EP05750999 A EP 05750999A EP 1778694 A1 EP1778694 A1 EP 1778694A1
Authority
EP
European Patent Office
Prior art keywords
compounds
formula
aryl
bis
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05750999A
Other languages
German (de)
French (fr)
Inventor
Kai Schiemann
David Bruge
Hans-Peter Buchstaller
Dirk Finsinger
Wolfgang Staehle
Christiane Amendt
Ulrich Emde
Frank Zenke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1778694A1 publication Critical patent/EP1778694A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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
    • A61K31/4355—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 five-membered ring having oxygen as a ring hetero atom
    • 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

Definitions

  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.
  • the present invention relates to compounds and the use of
  • the present invention relates to compounds of the formula I which inhibit preferably one or more mitotic motor proteins,
  • compositions containing these compounds regulate and / or modulate compositions containing these compounds, as well as methods for their use in the treatment of diseases and conditions such as angiogenesis, cancer, tumor development, growth and spread, arteriosclerosis, ocular
  • the compounds according to the invention are suitable for therapy or
  • Motor protein Eg5 was e.g. in tissues of the thoracic-lung and colon 5
  • 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 mitotic
  • old solid and non-solid tumors are treated with the compounds of formula I, such as e.g. the
  • lung carcinoma including lung adenocarcinoma and small cell
  • Lung cancer Other examples include prostate, pancreatic and breast carcinoma.
  • connections cause a specific inhibition of mitotic motor proteins, in particular Eg5.
  • the compounds of the invention preferably exhibit a beneficial biological activity which
  • the compounds of the invention preferably exhibit and effect an inhibiting 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. 35
  • 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 host or patient may be of any mammalian species, e.g. A primate species, especially humans; Including rodents
  • mice Mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental investigations, where they provide a model of treating a disease 30 people available.
  • 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 time sufficient to provide the active agents allow to induce cell death or to inhibit migration, usually between about one hour and one week.
  • 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 undesired cell population in the target tissue, while the
  • 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.
  • the invention relates to compounds of the formula I. wherein
  • R 1 , R 2 , R 3 independently of one another are H, A, aryl, heteroaryl, Hal, - (CY 2 ) n -
  • A is alkyl or cycloalkyl
  • R 4 , R 5 together are -X (CH 2 ) 2 X-, -X (CR 2 ) X-, -X CH (CH 2 OR) X-, -XCH (CH 2 OR) CR 2 X -, - X CR 2 CH (CH 2 OR) X-, -XCH (CH 2 NR 2 ) X-, -XCH (CH 2 NR 2 ) CR 2 X-, -X CR 2 CH (CH 2 NR 2 ) X-, - OCH 2 CH 2 O-, -X (CH 2 ) 2 X-, -XCHQCR 2 X, -XCR 2 CHQX-, Q
  • NR (CH 2 ) n NCOOR X (CH 2 ) n X (CH 2 ) n XR, NR (CH 2 ) n X (CH 2 ) ⁇ OH, NR (CH 2 ) n O (CH 2 ) n OH, (CH 2 ) n COOR, O (CO) NR (CH 2 ) n OR, O (CO) (CH 2 ) n NR 2 , NR (CH 2 ) n NR 2 , N [(CH 2 ) n NR 2 ] CO (CH 2 ) n aryl, N [(CH 2 ) n XR] CO (CH 2 ) n aryl, N [(CH 2 ) n XR] CO (CH 2 ) n heteroaryl,
  • CH (CHz) n COOR NCOOR, CH (CHz) n OH, N (CH 2) n OH, CHNH 2, CH (CHZ) n NR 2, CH (CH 2) n NR 2, C (OH) R, CHNCOR, CH (CH 2 ) n aryl, CH (CH 2 ) n heteroaryl, CH (CH 2 ) n R 1 , N (CH 2 ) n COOR, CH (CH 2 ) n X (CH 2 ) n aryl,
  • R 6 unsubstituted or singly or multiply by aryl or
  • Heteroaryl which may be substituted by Hal 1 NO 2 , CN, A, OR, OCOR, NR 2 , CF 3 , OCF 3 , OCH (CF 3 ) 2 , Hal, NO 2 , CN, OR 1 A, - (CY 2 ) n -OR, -OCOR, - (CY 2 ) n -CO 2 R, - (CY 2 ) n -CN or
  • n, m are independently 0, 1, 2, 3, 4, 5, 6 or 7
  • the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate the optically active forms (stereoisomers),
  • Solvates are e.g. Mono- or dihydrate or
  • Alcoholates By pharmaceutically acceptable derivatives are meant, for example, the salts of the compounds of the invention as well as so-called prodrug compounds.
  • biodegradable polymer derivatives of the inventive compounds include biodegradable polymer derivatives of the inventive compounds, as z. In Int. J. Pharm. 1J_5, 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, compared to a corresponding subject, this
  • Quantity has not resulted in: improved treatment, cure, prevention or elimination of a
  • Reduction of the progression of a disease, a disease or a disorder Reduction of the progression of a disease, a disease or a disorder.
  • terapéuticaally effective amount also includes the amounts effective to increase normal physiological function.
  • the invention also provides the use of mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereo ⁇ isomeric compounds.
  • the invention relates to the compounds of the formula I and their
  • R 1 , R 2 and R 3 have the meanings given above,
  • R 6 has the abovementioned meaning
  • R 4 and R 5 have the abovementioned meanings, preferably in the presence of a protic acid or Lewis acid, for example trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium (III) triflate, scandium (III) triflate or cerammonium (IV) nitrate
  • a protic acid or Lewis acid for example trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium (III) triflate, scandium (III) triflate or cerammonium (IV) nitrate
  • the bases and acids of formula I obtained by the process described above are converted into their salts.
  • A is alkyl, is preferably unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms.
  • A 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-,
  • A also denotes cycloalkyl.
  • Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • R 1 is preferably A, CF 3 , OCF 3 , SA, SCN 1 CH 2 CN, -OCOA, Hal,
  • SCF 3 preferably also t-butyl, -CH (CH 3 ) CH 2 CH 3 , isopropyl, ethyl or methyl.
  • R 1 is t-butyl, isopropyl, ethyl, CF 3 , methyl,
  • R 1 is t-butyl, isopropyl, ethyl or
  • R 2 is preferably Hal, A or OA, in particular Br, cyclopropyl, OCH 3 . Furthermore, particularly preferably H or F.
  • R 3 is preferably H or A, in particular H.
  • R 3 is preferably in the 5-position.
  • R 3 is H or F.
  • R 2 and R 3 simultaneously have the meaning H.
  • one of the radicals R 2 and R 3 has the meaning H and the other radical has the meaning F.
  • R preferably together with R has one of the following meanings:
  • R 4 together with R 5 takes one of the following
  • R 6 is preferably unsubstituted or mono- or polysubstituted by Hal, CN, NO 2 , OH, CF 3 , OCH (CF 3 ) 2 , OCOCH 3 or A substituted phenyl, 2-, 3- or 4-pyridyl, pyrimidyl, furyl or thienyl.
  • R 6 is one of the following groups:
  • A has the meaning indicated above, but preferably is methyl and Hal preferably denotes F or Cl.
  • R 7 is preferably H or A, in particular H.
  • Aryl is preferably unsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NH 2 , NO 2 , CN, COOH, COOA, CONH 2 , NHCOA, NHCONH 2 , NHSO 2 A, CHO, 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
  • 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 an N, S or O atom which is unsubstituted or mono-, di- or trisubstituted by Hal, A, NHA, NA 2 , NO 2 ,
  • 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
  • Hal preferably denotes F, Cl or Br, but also I, particularly preferably F or Cl.
  • R 1 , R 2 , R 3 independently of one another are H, A, aryl, heteroaryl, Hal, - (CY 2 ) n-SA, - (CY 2 ) n-SCF 3 , - (CYs) n -SCN 1 - (CY 2 J n -CF 3 , -
  • A is alkyl or cycloalkyl
  • R 4 , R 5 together are -X (CH 2 ) 2 X-, -X CR 2 ) X-, -X CH (CH 2 OR) X-,
  • XO, S or NR R 6 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, - (CY 2 Jn-OR, -OCOR, -
  • n 0, 1, 2, 3, 4, 5, 6 or 7
  • W is preferably CH.
  • 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
  • R 1 R 1 , R 2 , R 6 , R 7 and X have the meanings given above
  • Particularly preferred compounds of the formula IA are those of the subformulae IA1 to IA3:
  • R, R 1 , R 2 , R 3 , R 6 and R 7 have the meanings given above.
  • R 8 has the meaning H.
  • radicals R 4 and R 5 are particularly preferably in the cis-position relative to one another. Further preferably, the radical R 6 is in the trans position to
  • the invention relates, in particular, to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings given above.
  • Some preferred groups of compounds can be expressed by the following partial formulas II to I43:
  • 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.
  • reaction is generally carried out in an inert solvent, preferably in the presence of a protic acid or Lewis acid such as TFA,
  • Reaction time is between a few minutes and 14 days, depending on the conditions used, the reaction temperature between about 0 ° and 180 °, normally between 0 ° and 100 °, particularly preferably between 15 ° and 35 ° 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; Nitriles such as acetonitrile; Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene 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
  • Nitriles such as acetonitrile
  • Carbon disulphide Carboxylic acids
  • Nitro compounds such as nitromethane
  • Hydrogenolysis be set free by conventional methods. This can e.g. with NaOH or KOH in water, water-THF or water
  • Dioxane be carried out at temperatures between 0 and 100 °.
  • compositions of the 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.
  • bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and
  • acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides, such as hydrogen chloride, Hydrogen bromide or hydriodic acid, other mineral acids and their corresponding salts, such as sulfate, nitrate or phosphate and the like, and also alkyl and monoaryl sulfonates, such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts, such as acetate, trifluoroacetate, tartrate, maleate, succinate,
  • organic and inorganic acids for example hydrogen halides, such as hydrogen chloride, Hydrogen bromide or hydriodic acid, other mineral acids and their corresponding salts, such as sulfate, nitrate or phosphate and the like, and also alkyl and monoaryl sulfonates, such as ethanesulfonate, to
  • compositions of the formula I include the following: acetate, adipate,
  • the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium -
  • Derive bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted ones Amines, cyclic amines and basic ion exchange resins, eg arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N -
  • Tromethamine Hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl) -methylamine ( Tromethamine), but this is not intended to be limiting.
  • Compounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C 4 ) alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C 1 -C 4 ) alkyl sulfates, eg dimethyl, diethyl and diamylsulfate; (Ci 0 - Ci ⁇ ) alkyl halides, eg decyl, dodecyl, lauryl, myristyl and
  • Salts can be prepared both water-soluble and oil-soluble compounds of the invention.
  • Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, Sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, which is not intended to be limiting.
  • the amount of the desired acid brings into contact, which is the salt in a conventional manner.
  • the free base can be prepared by contacting Bring the salt form with a base and isolate the free base in the usual way regenerate.
  • the free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar
  • the pharmaceutically acceptable base addition salts of the compounds of the 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, chloro-procain, 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 regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
  • the free acid forms differ, in a sense, from their corresponding salt forms with respect to 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,
  • the term "pharmaceutically acceptable salt” in the present context means an active ingredient which contains a compound of the formula I in the form of one of its salts, especially if this salt form is the active ingredient in the Imparts improved pharmacokinetic properties to the free form of the active ingredient or any other salt form of the active ingredient which has previously been used.
  • the pharmaceutically acceptable salt form of the active ingredient can also be this
  • the active ingredient first conferred a desired pharmacokinetic property that it did not previously possess, and may even positively affect the pharmacodynamics of that agent in terms of its therapeutic efficacy in the body.
  • the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including the same
  • compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per dosage unit.
  • a moiety 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 of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
  • Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of an active ingredient.
  • such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
  • compositions may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intravenous) intradermal) routes.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, intramuscular, intravenous or intravenous) intradermal
  • parenteral including subcutaneous, intramuscular, intravenous or intravenous) intradermal routes.
  • 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 administered as separate units, e.g. 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 in the case of oral administration in the form of a tablet or capsule, can be combined with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as, for example, ethanol, glycerol, water and the like.
  • 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 and lubricants such as 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.
  • 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, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like.
  • the lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate,
  • the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing, adding a lubricant and a disintegrating agent and pressing the whole into tablets.
  • a powder mixture is prepared by dissolving the appropriately comminuted compound with a diluent or a base as described above, and optionally with a binder, e.g. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution reducer, such as e.g. Paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent, e.g. bentonite,
  • a binder e.g. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone
  • a dissolution reducer such as
  • the powder mixture can be granulated by mixing it with a binder such as, for example, syrup, starch paste, acadia slime or solutions of cellulose or polymer. wetted material and pressed through a sieve.
  • a binder such as, for example, syrup, starch paste, acadia slime or solutions of cellulose or polymer. wetted material 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 polymer 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 e.g. Solution, syrups and elixirs
  • Oral fluids e.g. Solution, syrups and elixirs
  • Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, i.a. can also be added.
  • the unit dosage formulations for oral administration may optionally be encapsulated in microcapsules.
  • the formulation can also be prepared so that the release is prolonged or retarded For example, by coating or embedding particulate material in polymers, wax, etc.
  • 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 polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol,
  • Polyhydroxyethylaspartamidphenol or polyethylene oxide polylysine substituted with Palmitoylresten include.
  • the compounds can be attached to a class of biodegradable polymers suitable for the controlled release of a drug, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyano-acrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • Formulations may be presented as discrete plasters for prolonged, intimate contact with the epidermis of the recipient.
  • the drug may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration may be used as ointments, creams, suspensions, lotions,
  • the formulations are preferably as a topical ointment
  • the active ingredient can be used with either a paraffinic or water miscible cream base.
  • the active ingredient may be 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, the active substance being suspended in a suitable carrier, in particular an aqueous solvent,
  • compositions adapted for topical application in the mouth include lozenges, troches and mouthwashes. 25
  • compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
  • compositions adapted for nasal administration in which the carrier is a solid, contain a coarse powder having a particle size, for example, in the range of 20-500
  • Fine particulate dusts or mists which may be generated by various types of pressurized dosing dispensers with 10 aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations A c.
  • the pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes, by the
  • Recipient is included; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
  • the formulations may be administered in single dose or multiple
  • 25 dose containers e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use.
  • the sterile carrier liquid e.g. Water for injections
  • O0 Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
  • formulations suitable for oral administration may contain other conventional means in the art with respect to the particular type of formulation; so can For example, formulations suitable for oral administration contain flavorings.
  • 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, 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 for the
  • Treatment of the other, above-mentioned disease states are suitable.
  • 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 other
  • 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 may also be combined with compounds of Formula VI.
  • TNF-alpha-virulizine (Lorus Revimid (Celgene)
  • CapCell TM CYP450-N-acetylcysteine
  • Antagonist kappaB inhibitor, Encore
  • Efaproxiral oxygenator, receptor agonist, Leo
  • PI-88 heparanase antagonist
  • SRL-172 T-cell doranidazole (apoptosis
  • 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)
  • Mitoxantrone diflomotecan (Beaufourrinotecan (CPT-11) Ipsen)
  • Rhizoxin (Fujisawa) LU 223651 (BASF)
  • Epothilone B Novartis
  • ZD 6126 AstraZeneca
  • Auristatin PE (Teikoku NeuroPharma)
  • Taxoprexin (Protarga) CA-4 (OXiGENE)
  • TNF-alpha-virulizine (Lorus Revimid (Celgene)
  • RNA cyclic stimulant, Alfacell
  • AMP AMP agonist
  • ribapharm galarubicin
  • CapCell TM CYP450-R flurbiprofen (NF-1)
  • GCS-IOO gal3 inhibitor, Active Biotech
  • SR-31747 (IL-1 PG2 (hematopoietic)
  • SRL-172 T-cell (differentiator, NIH)
  • TLK-286 (glutathione-S-MAXIA)
  • PLC-brostallicin apoptosis
  • the compounds of the formula I are combined with those 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.
  • 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
  • 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 containing the Bin ⁇ dung of retinoids to the receptor, interfere with or inhibit, regardless of how this is done.
  • Retinoidrezeptor ⁇ modulators include, for example, bexarotene, tretinoin, 13-cis retinoic acid,
  • Cytotoxic agents refers to compounds that cause cell death, primarily by direct action on cell function, or that inhibit or interfere with cell myosis, including alkylating agents, tumor cells,
  • the cytotoxic agents include, for example, tirapazimine, sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine,
  • Temozolomide Heptaplatin, Estramustine, Improsulfan-tosylate, Trofosfamide, Nimustin, Dibrospidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulvene, Dexifosfamide, cis-Amine dichloro (2-methylpyridine) platinum, Benzylguanine, Glufosfamide, GPX100,
  • MEN 10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin see WO 00/50032, but this is not intended to be limiting.
  • microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S '''-dideshidroxydeoxy- ⁇ '-norvincaleukoblastin, docetaxol, 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.
  • paclitaxel vindesine sulfate
  • Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecane, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4; 5-kl] acridine-2
  • Antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine.
  • ocfosfat Fosteabin Sodium Hydrate, Raltitrexed, Paltitrexide, Emitefur, Tiazofurin, Decitabine, Nolatrexed, Pemetrexed, Nelzarabine, 2'-Deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- (2, 3-dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy-4- [N 2 - [2 (E), 4 (E) -tetra-decadienoylglycylamino] -L-glycero BL-manno-heptopyranosyl-jadenine, aplidine, ecteinascidin, troxacitabine, 4- [2-amino-4-oxo-4,6,7
  • antiproliferative agents also include other monoclonal antibodies against growth factors than those already mentioned among 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, e.g., U.S. Patent No. 6,069,134).
  • the tumor is preferably selected from the group of tumors of the
  • the tumor is furthermore preferably selected from the group
  • Lung adenocarcinoma small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.
  • Tumors selected from the group of acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.
  • the invention also includes a method for treating a
  • Y 'and Z' are each independently O or N
  • R 7 and R 9 are each independently H, OH, halogen, OCI-10-alkyl, OCF 3 , NO 2 or NH 2
  • p is an integer between 2 and 6 each including
  • R 6 and R 8 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. It has recently been described that pentamidine is a potent inhibitor of PRL1, -2 and 3 phosphatases (Pathak et al., 2002) and tyrosine phosphatases, and their Overexpression is associated with neoplastic malignant tumors in humans. 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.
  • Suitable pentamidine analogs include stilbamidine (G-1) and hydroxystilbamidine (G-2) and their indole analogs (e.g., G-3):
  • Each amidine moiety may be independently replaced by one of the moieties defined above for R 8 and R 9 .
  • salts of stilbamidine, hydroxystilbamidine and their indole derivatives are also useful in the process of the present invention.
  • Preferred salts include, for example
  • 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 -
  • 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 analogue thereof.
  • the combinations of compounds of the formula I and formula VI 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 the kinesin ATPase Eg5 / KSP with the compounds of the formula VI, pentamidine, its analogues and / or its metabolites is likewise provided by 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 method for treating a patient having a neoplasm such as a cancer by administering a compound of the formula (I) and (VI) in combination with an antiproliferative agent.
  • Suitable antiproliferative agents include those provided in Table 1.
  • “usual workup” means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracted with ethyl acetate or dichloromethane, separating, drying organic phase over sodium sulfate, evaporated and purified by chromatography
  • Mass spectrometry (MS): El (electron impact ionization) M + FAB (Fast Atom Bombardment) (M + H) + ESI (Electrospray Ionization) (M + H) +

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Abstract

Disclosed are compounds of formula (I), wherein W, R, R1, R2, R3, R4, R5, R6, and R7 have the meanings indicated in claim 1. Said compounds can be used for the treatment of tumors, among other things.

Description

Tetrahydrochinoline Tetrahydroquinolines
HINTERGRUND DER ERFINDUNGBACKGROUND OF THE INVENTION
55
Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvol¬ len Eigenschaften aufzufinden, insbesondere solche, die zur Herstellung von Arzneimitteln verwendet werden können.The object of the invention was to find new compounds with valuable properties, in particular those which can be used for the preparation of medicaments.
1010
Die vorliegende Erfindung betrifft Verbindungen und die Verwendung vonThe present invention relates to compounds and the use of
Verbindungen von Krankheiten, bei denen die Hemmung, Regulierung und/oder Modulation der mitotische Motor-Proteine, insbesondere des mitotischen Motor-Protein Eg5 eine Rolle spielt, ferner pharmazeutischeCompounds 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, also pharmaceutical
15 Zusammensetzungen, die diese Verbindungen enthalten.15 compositions containing these compounds.
Im einzelnen betrifft die vorliegende Erfindung Verbindungen der Formel I, die die bevorzugt eines oder mehrere mitotische Motor-Proteine hemmen,In particular, the present invention relates to compounds of the formula I which inhibit preferably one or more mitotic motor proteins,
20 regulieren und/oder modulieren, Zusammensetzungen, die diese Verbindungen enthalten, sowie Verfahren zu ihrer Verwendung zur Behandlung von Krankheiten und Leiden wie Angiogenese, Krebs, Tumor¬ entstehung, -Wachstum und -Verbreitung, Arteriosklerose, Augen-20 regulate and / or modulate compositions containing these compounds, as well as methods for their use in the treatment of diseases and conditions such as angiogenesis, cancer, tumor development, growth and spread, arteriosclerosis, ocular
?(- erkrankungen, choroidale Neovaskularisierung und diabetische ? (- diseases, choroidal neovascularisation and diabetic
Retinopathie, Entzündungserkrankungen, Arthritis, Neurodegeneration, Restenose, Wundheilung oder Transplantatabstossung. Insbesondere eignen sich die erfindungsgemäßen Verbindungen zur Therapie oderRetinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, wound healing or graft rejection. In particular, the compounds according to the invention are suitable for therapy or
Prophylaxe von Krebserkrankungen. 30Prophylaxis of cancer. 30
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 35 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 desDuring 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. from that The result is that the chromosomes can no longer be correctly distributed to the daughter cells. This leads to mitotic arrest and can thus cause cell death. An upregulation of the
Motorproteins Eg5 wurde z.B. in Gewebe von Brust- Lungen- und Colon- 5Motor protein Eg5 was e.g. in tissues of the thoracic-lung and colon 5
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 mitotischerTumors described. 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 mitotic
10 Mikrotubuli (Spindelapparat) und nicht die des Cytoskeletts. Dies ist entscheidend für das Nebenwirkungsprofil, da z.B. Neuropathien, wie sie bei Taxol beobachtet werden, nicht oder nur abgeschwächt auftreten. Daher ist die Inhibierung von Eg5 durch organische Moleküle ein10 microtubules (spindle apparatus) and not those of the cytoskeleton. This is crucial for the adverse event profile, e.g. Neuropathies, as observed in Taxol, do not occur or only weakened. Therefore, the inhibition of Eg5 by organic molecules is a
.. C relevantes Therapiekonzept für die Behandlung von malignen Tumoren... C relevant therapy concept for the treatment of malignant tumors.
Generell kommen alte solide und nicht solide Tumore mit den Verbindungen der Formel I behandelt werden, wie z.B. dieGenerally, old solid and non-solid tumors are treated with the compounds of formula I, such as e.g. the
Monozytenleukämie, Hirn-, Urogenital-, Lymphsystem-, Magen-, Kehlkopf-Monocytic leukemia, brain, urogenital, lymphatic, gastric, laryngeal
20 und Lungenkarzinom, darunter Lungenadenokarzinom und kleinzelliges20 and lung carcinoma, including lung adenocarcinoma and small cell
Lungenkarzinom. Zu weiteren Beispielen zählen Prostata-, Bauchspeicheldrüsen- und Brustkarzinom.Lung cancer. Other examples include prostate, pancreatic and breast carcinoma.
25 Es wurde überraschend gefunden, daß die erfindungsgemäßenIt has surprisingly been found that the inventive
Verbindungen einen spezifische Inhibierung der mitotischen Moter- Proteine, insbesondere Eg5 bewirken. Die erfindungsgemäßen Verbindungen zeigen bevorzugt eine vorteilhafte biologische Aktivität, dieConnections cause a specific inhibition of mitotic motor proteins, in particular Eg5. The compounds of the invention preferably exhibit a beneficial biological activity which
O0 in den, zum Beispiel hierin beschrieben Assays, leicht nachweisbar ist. In derartigen zeigen und bewirken die erfindungsgemäßen Verbindungen bevorzugt einen inhibierenden Effekt, der gewöhnlich durch IC50-Werte in einem geeigneten Bereich, bevorzugt im mikromolaren Bereich und bevorzugter im nanomolaren Bereich dokumentiert wird. 35 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 5 oder mehreren mitoischer Motor-Proteine, insbesondere Eg5, beeinflusst werden. O0 in the assays described, for example, herein. In such compounds, the compounds of the invention preferably exhibit and effect an inhibiting 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. 35 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 erfindungsgemäßeThe subject of the present invention is therefore inventive
Verbindungen als Arzneimittel und/oder Arzneimittelwirkstoffe bei derCompounds as drugs and / or active pharmaceutical ingredients in the
10 Behandlung und/oder Prophylaxe der genannten Erkrankungen und die10 Treatment and / or prophylaxis of the diseases mentioned and the
Verwendung von erfindungsgemäßen Verbindungen zur Herstellung eines Pharmazeutikums für die Behandlung und/oder Prophylaxe der genannten Erkrankungen wie auch ein Verfahren zur Behandlung der genanntenUse of compounds of the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis of said diseases as well as a method for the treatment of said
^ c Erkrankungen umfassend die Verabreichung eines oder mehrerer erfindungsgemäßer Verbindungen an einen Patienten mit Bedarf an einer derartigen Verabreichung.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 inIt can be shown that the compounds of the invention in
20 einem Xenotransplantat-Tumor-Modell eine vorteilhafte Wirkung aufweisen.20 have a beneficial effect on a xenograft tumor model.
Der Wirt oder Patient kann jeglicher Säugerspezies angehören, z. B. einer 5 Primatenspezies, besonders Menschen; Nagetieren, einschließlichThe host or patient may be of any mammalian species, e.g. A primate species, especially humans; Including rodents
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 30 Menschen zur Verfügung stellen.Mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental investigations, where they provide a model of treating a disease 30 people available.
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 5 erfindungsgemäßen Verbindung bei verschiedenen Konzentrationen für eine Zeitdauer kombiniert, die ausreicht, um den aktiven Mitteln zu ermöglichen, Zelltod zu induzieren oder Migration zu inhibieren, gewöhn¬ lich zwischen ungefähr einer Stunde und einer Woche. Zum Testen in vitro können kultivierte Zellen aus einer Biopsieprobe verwendet 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 time sufficient to provide the active agents allow to induce cell death or to inhibit migration, usually between about one hour and one week. For testing in vitro, cultured cells from a biopsy sample can be used.
Die nach der Behandlung zurückbleibenden lebensfähigen Zellen werden dann gezählt.The viable cells remaining after treatment are then counted.
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 dieThe 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 undesired cell population in the target tissue, while the
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.Viability of the patient is maintained. 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.
STAND DER TECHNIKSTATE OF THE ART
Ähnliche Verbindungen sind z.B. in Tetrahedron Lett. 1988, 29, 5855-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 beschrieben, sind aber nicht im Zusammenhang mit Krebsbehandlungen genannt und/oder enthalten nicht die erfindungswesentlichen Merkmale.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.
ZUSAMMENFASSUNG DER ERFINDUNGSUMMARY OF THE INVENTION
Die Erfindung betrifft Verbindungen der Formel I worinThe invention relates to compounds of the formula I. wherein
W CH oder N,W CH or N,
R1, R2, R3 unabhängig voneinander H, A, Aryl, Heteroaryl, HaI, -(CY2)n-R 1 , R 2 , R 3 independently of one another are H, A, aryl, heteroaryl, Hal, - (CY 2 ) n -
Y H, A, HaIY H, A, HaI
A Alkyl oder CycloalkylA is alkyl or cycloalkyl
HaI F, Cl, Br oder IHaI F, Cl, Br or I
R H oder A, bei gemimalen Resten R zusammen auch -(CH2)5-RH or A, together with geminal residues R together also - (CH 2 ) 5 -
R4, R5 zusammen -X (CH2)2X-, -X (CR2)X-, -X CH(CH2OR)X-, -XCH(CH2OR)CR2X-,-X CR2CH(CH2OR) X-, - XCH(CH2NR2)X-, -XCH(CH2NR2)CR2X-, -X CR2CH(CH2NR2)X-, -OCH2CH2O-, -X(CH2)2X-, -XCHQCR2X, -XCR2CHQX-, QR 4 , R 5 together are -X (CH 2 ) 2 X-, -X (CR 2 ) X-, -X CH (CH 2 OR) X-, -XCH (CH 2 OR) CR 2 X -, - X CR 2 CH (CH 2 OR) X-, -XCH (CH 2 NR 2 ) X-, -XCH (CH 2 NR 2 ) CR 2 X-, -X CR 2 CH (CH 2 NR 2 ) X-, - OCH 2 CH 2 O-, -X (CH 2 ) 2 X-, -XCHQCR 2 X, -XCR 2 CHQX-, Q
Ra R a
OR1 NHR2, NR2 OR, NHR2, NR2, NR(CH2)nAryl, NR(CHz)nOR, COOR, N-Pyrrolidon-Rest, OCOR, NR(CH2)nNR2, N[(CH2)nNR2]CO(CH2)nAryl, N[(CH2)nNHCOOR]COAryl, R1, N[CH2(CH2)nOR]2,OR 1 NHR 2 , NR 2 OR, NHR 2 , NR 2 , NR (CH 2 ) n aryl, NR (CHz) n OR, COOR, N-pyrrolidone radical, OCOR, NR (CH 2 ) n NR 2 , N [ (CH 2 ) n NR 2 ] CO (CH 2 ) n aryl, N [(CH 2 ) n NHCOOR] COAryl, R 1 , N [CH 2 (CH 2 ) n OR] 2 ,
NR(CH2)nNCOOR, X(CH2)nX(CH2)nXR, NR(CH2)nX(CH2)πOH, NR(CH2)nO(CH2)nOH, (CH2)nCOOR, 0(CO)NR(CH2) nOR, O(CO)(CH2)nNR2, NR(CH2)nNR2, N[(CH2)nNR2]CO(CH2)nAryl, N[(CH2)nXR]CO(CH2)nAryl, N[(CH2)nXR]CO(CH2)nHeteroaryl,NR (CH 2 ) n NCOOR, X (CH 2 ) n X (CH 2 ) n XR, NR (CH 2 ) n X (CH 2 ) π OH, NR (CH 2 ) n O (CH 2 ) n OH, (CH 2 ) n COOR, O (CO) NR (CH 2 ) n OR, O (CO) (CH 2 ) n NR 2 , NR (CH 2 ) n NR 2 , N [(CH 2 ) n NR 2 ] CO (CH 2 ) n aryl, N [(CH 2 ) n XR] CO (CH 2 ) n aryl, N [(CH 2 ) n XR] CO (CH 2 ) n heteroaryl,
N[(CH2)nNR2]CO(CH2)nHeteroaryl, N[(CH2)nNR2]CO(CH2)nR1, N(R)(CH2)nN(R)COOR, XCOO(CH2)nNR2, OSO2A, OSO2CF3, OSO2Ar, OCONR2, OCH2(CH2)nNR2 N [(CH 2 ) n NR 2 ] CO (CH 2 ) n heteroaryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n R 1 , N (R) (CH 2 ) n N (R) COOR, XCOO (CH 2 ) n NR 2 , OSO 2 A, OSO 2 CF 3 , OSO 2 Ar, OCONR 2 , OCH 2 (CH 2 ) n NR 2
CH2, X, CHCONH2, CH(CHz)nNRCOOR, CHNRCOOR, NCO,CH 2 , X, CHCONH 2 , CH (CHz) n NRCOOR, CHNRCOOR, NCO,
CH(CHz)nCOOR, NCOOR, CH(CHz)nOH, N(CH2)nOH, CHNH2, CH(CHz)nNR2, CH(CH2)nNR2, C(OH)R, CHNCOR, CH(CH2)nAryl, CH(CH2)nHeteroaryl, CH(CH2)nR1, N(CH2)nCOOR, CH(CH2)nX(CH2)nAryl,CH (CHz) n COOR, NCOOR, CH (CHz) n OH, N (CH 2) n OH, CHNH 2, CH (CHZ) n NR 2, CH (CH 2) n NR 2, C (OH) R, CHNCOR, CH (CH 2 ) n aryl, CH (CH 2 ) n heteroaryl, CH (CH 2 ) n R 1 , N (CH 2 ) n COOR, CH (CH 2 ) n X (CH 2 ) n aryl,
CH(CH2)nX(CH2)nHeteroaryl, N(CH2JnCONR2, XCONR(CH2)nNR2, N[(CHz)nXCOOR]CO(CH2)nAryl, N[(CH2)nXR]CO(CH2)nAryl, N[(CH2)nXR]CO(CH2)nXAryl, N[(CH2)nXR]SO2(CH2)nAryl,CH (CH 2 ) n X (CH 2 ) n heteroaryl, N (CH 2 J n CONR 2 , XCONR (CH 2 ) n NR 2 , N [(CHz) n X COOR] CO (CH 2 ) n aryl, N [( CH 2 ) n XR] CO (CH 2 ) n aryl, N [(CH 2 ) n XR] CO (CH 2 ) n XAryl, N [(CH 2 ) n XR] SO 2 (CH 2 ) n aryl,
N[(CH2)nNRCOOR]CO(CH2)nAryl,N [(CH 2 ) n NRCOOR] CO (CH 2 ) n aryl,
N[(CH2)nNR2]CO(CH2)nAryl, N[(CH2)nNR2]CO(CH2)nNRAryl,N [(CH 2 ) n NR 2 ] CO (CH 2 ) n aryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n NRAryl,
N[(CH2)nNR2]SO2(CH2)nAryl,N [(CH 2 ) n NR 2 ] SO 2 (CH 2 ) n aryl,
N[(CH2)nXR]CO(CH2)nHeteroaryl,N [(CH 2 ) n XR] CO (CH 2 ) n heteroaryl,
N[(CH2)nXR]CO(CH2)nXHeteroaryl,N [(CH 2 ) n XR] CO (CH 2 ) n X heteroaryl,
N[(CH2)nXR]SO2(CH2)nHeteroaryl,N [(CH 2 ) n XR] SO 2 (CH 2 ) n heteroaryl,
N[(CH2)nNRCOOR]CO(CH2)nHeteroaryl,N [(CH 2 ) n NRCOOR] CO (CH 2 ) n heteroaryl,
N[(CH2)nNR2]CO(CH2)nHeteroaryl, N[(CH2)nNR2]CO(CH2)nNRHeteroaryl, N[(CH2)nNR2]S02(CH2)nHeteroaryl, O(CH2)nNR2, X(CH2)nNR2, NCO(CH2)nNR2) N [(CH 2 ) n NR 2 ] CO (CH 2 ) n heteroaryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n NR heteroaryl, N [(CH 2 ) n NR 2 ] SO 2 (CH 2 ) n heteroaryl, O (CH 2 ) n NR 2 , X (CH 2 ) n NR 2 , NCO (CH 2 ) n NR 2)
X O, S oder NRX O, S or NR
R6 unsubstituiertes oder einfach oder mehrfach durch Aryl oderR 6 unsubstituted or singly or multiply by aryl or
Heteroaryl, das durch HaI1 NO2, CN, A, OR, OCOR, NR2, CF3, OCF3, OCH(CF3)2 substituiert sein kann, HaI, NO2, CN, OR1 A, -(CY2)n-OR, -OCOR, -(CY2)n-CO2R, -(CY2)n-CN oderHeteroaryl, which may be substituted by Hal 1 NO 2 , CN, A, OR, OCOR, NR 2 , CF 3 , OCF 3 , OCH (CF 3 ) 2 , Hal, NO 2 , CN, OR 1 A, - (CY 2 ) n -OR, -OCOR, - (CY 2 ) n -CO 2 R, - (CY 2 ) n -CN or
-(CY2)n-NR2 substituiertes Aryl oder Heteroaryl,- (CY 2 ) n -NR 2 substituted aryl or heteroaryl,
R7 (C=O)-R, (C=O)-NR2, (C=O)-OR, H oder AR 7 (C = O) -R, (C = O) -NR 2, (C = O) -OR, H or A
undand
n, m unabhängig voneinander 0, 1 , 2, 3, 4, 5, 6 oder 7n, m are independently 0, 1, 2, 3, 4, 5, 6 or 7
. . . bedeuten,, , , mean,
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.
Gegenstand der Erfindung sind auch die optisch aktiven Formen (Stereoisomeren), die Enantiomeren, die Racemate, die Diastereomeren sowie die Hydrate und Solvate dieser Verbindungen. Unter Solvate derThe invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate the
Verbindungen werden Anlagerungen von inerten Lösungsmittelmolekülen an die Verbindungen verstanden, die sich aufgrund ihrer gegenseitigen Anziehungskraft ausbilden. Solvate sind z.B. Mono- oder Dihydrate oderCompounds are understood to be attachments of inert solvent molecules to the compounds that form due to their mutual attraction. Solvates are e.g. Mono- or dihydrate or
Alkoholate. Unter pharmazeutisch verwendbaren Derivaten versteht man z.B. die Salze der erfindungsgemäßen Verbindungen als auch sogenannte Prodrug-Verbindungen.Alcoholates. By pharmaceutically acceptable derivatives are meant, for example, 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,Under prodrug derivatives is understood with z. B. alkyl or acyl groups,
Zuckern oder Oligopeptiden abgewandelte Verbindungen der Formel I, die im Organismus rasch zu den wirksamen erfindungsgemäßen Verbindungen gespalten werden.Sugars or oligopeptides modified compounds of formula I, which are rapidly cleaved in the organism to the active compounds of the invention.
Hierzu gehören auch bioabbaubare Polymerderivate der erfindungs- gemäßen Verbindungen, wie dies z. B. in Int. J. Pharm. 1J_5, 61-67 (1995) beschrieben ist.These include biodegradable polymer derivatives of the inventive compounds, as z. In Int. J. Pharm. 1J_5, 61-67 (1995).
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, verglichen zu einem entsprechenden Subjekt, das dieseIn addition, the term "therapeutically effective amount" means an amount that, compared to a corresponding subject, this
Menge nicht erhalten hat, folgendes zur Folge hat: verbesserte Heilbehandlung, Heilung, Prävention oder Beseitigung einerQuantity has not resulted in: improved treatment, cure, prevention or elimination of a
Krankheit, eines Krankheitsbildes, eines Krankheitszustandes, eines Leidens, einer Störung oder von Nebenwirkungen oder auch dieIllness, a medical condition, a medical condition, a disease, a disorder or side effects or even those
Verminderung des Fortschreitens einer Krankheit, eines Leidens oder einer Störung.Reduction of the progression of a disease, a disease or a disorder.
Die Bezeichnung "therapeutisch wirksame Menge" umfaßt auch die Mengen, die wirkungsvoll sind, die normale physiologische Funktion zu erhöhen.The term "therapeutically effective amount" also includes the amounts effective to increase 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. Besonders bevorzugt handelt es sich dabei um Mischungen stereo¬ isomerer Verbindungen.The invention also provides the use of mixtures of the compounds of the formula I, for example mixtures of two diastereomers, for example in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereo¬ isomeric compounds.
Gegenstand der Erfindung sind die Verbindungen der Formel I und ihreThe invention relates to the compounds of the formula I and their
Salze sowie 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 IlSalts and 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 II
worin R1, R2 und R3 die oben angegebenen Bedeutungen haben,wherein R 1 , R 2 and R 3 have the meanings given above,
mit einer Verbindung der Formel IIIwith a compound of formula III
worinwherein
R6 die oben angegebene Bedeutung aufweist,R 6 has the abovementioned meaning,
undand
mit einer Verbindung der Formel III, dessen Doppelbindungsisomer (E- Isomer) oder deren Mischungen with a compound of formula III, its double bond isomer (E isomer) or mixtures thereof
5 worin R4 und R5 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)nitratIn which R 4 and R 5 have the abovementioned meanings, preferably in the presence of a protic acid or Lewis acid, for example trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium (III) triflate, scandium (III) triflate or cerammonium (IV) nitrate
<J Q umsetzt,<J Q converts,
und gegebenenfalls nach üblichen Methoden für R7 einen anderen Rest als H einführt.and, if appropriate, introduction of a residue other than H by customary methods for R 7 .
Vorzugsweise werden die nach dem oben beschriebenen VerfahrenPreferably, those according to the method described above
15 gegebenenfalls erhaltenen Gemische von Diastereomeren und15 optionally obtained mixtures of diastereomers and
Enantiomeren der Verbindungen der Formel I durch Chromatographie oder Kristallisation aufgetrennt. Sofern W nicht CH bedeutet werden für das Herstellungsverfahren entsprechende Verbindungen der Formel Il 20 eingesetzt.Enantiomers of the compounds of formula I separated by chromatography or crystallization. If W is not CH, corresponding compounds of the formula II are used for the preparation process.
Gegebenenfalls werden die nach dem oben beschriebenen Verfahren erhaltenen Basen und Säuren der Formel I in ihre Salze umwandelt.Optionally, the bases and acids of formula I obtained by the process described above are converted into their salts.
2525
Vor- und nachstehend haben die Reste W1 R, R1, R2, R3, R4, R5, R6, R7,Above and below, the radicals W 1 R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 ,
X, Y und n die bei der Formel I angegebenen Bedeutungen, sofern nicht ausdrücklich etwas anderes angegeben ist. Bei mehrfachem Auftreten einzelner Reste innerhalb einer Verbindung nehmen die ResteX, Y and n are the meanings given for the formula I, unless expressly stated otherwise. When multiple occurrences of individual radicals within a compound take the remainders
30 unabhängig voneinander die angegebenen Bedeutungen an.30 independently of one another the specified meanings.
A bedeutet Alkyl, ist bevorzugt unverzweigt (linear) oder verzweigt, und hat 1 , 2, 3, 4, 5, 6, 7, 8, 9 oder 10 C-Atome. A bedeutet vorzugsweise 35 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-,A is alkyl, is preferably unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C-atoms. A 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- 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.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.
A 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. A bedeutet auch Cycloalkyl.A 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. A also denotes cycloalkyl.
Cycloalkyl bedeutet vorzugsweise Cyclopropyl, Cyclobutyl, Cylopentyl, Cyclohexyl oder Cycloheptyl.Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
R1 bedeutet vorzugsweise A, CF3, OCF3, SA, SCN1 CH2CN, -OCOA, HaI,R 1 is preferably A, CF 3 , OCF 3 , SA, SCN 1 CH 2 CN, -OCOA, Hal,
SCF3, bevorzugt auch t-Butyl, -CH(CH3)CH2CH3, Isopropyl, Ethyl oder Methyl. Insbesondere bedeutet R1 t-Butyl, Isopropyl, Ethyl, CF3, Methyl,SCF 3 , preferably also t-butyl, -CH (CH 3 ) CH 2 CH 3 , isopropyl, ethyl or methyl. In particular, R 1 is t-butyl, isopropyl, ethyl, CF 3 , methyl,
Br, Cl, SCF3, CH(CH3)CH2CH3, n-Propyl, OCH3, SCH3, n-Butyl, -SCN,Br, Cl, SCF 3 , CH (CH 3 ) CH 2 CH 3 , n-propyl, OCH 3 , SCH 3 , n-butyl, -SCN,
CH2CN. Besonders bevorzugt bedeutet R1 t-Butyl, Isopropyl, Ethyl oderCH 2 CN. Particularly preferably, R 1 is t-butyl, isopropyl, ethyl or
CF3.CF 3 .
R2 bedeutet bevorzugt HaI, A oder OA, insbesondere Br, Cyclopropyl, OCH3. Weiterhin sind insbesondere bevorzugt H oder F.R 2 is preferably Hal, A or OA, in particular Br, cyclopropyl, OCH 3 . Furthermore, particularly preferably H or F.
R3 bedeutet vorzugsweise H oder A, insbesondere H. R3 steht bevorzugt in 5-Position. Insbesondere bedeutet R3 H oder F.R 3 is preferably H or A, in particular H. R 3 is preferably in the 5-position. In particular, R 3 is H or F.
In besonders bevorzugten Verbindungen der Formel I weisen R2 und R3 gleichzeitig die Bedeutung H auf. In weiteren bevorzugten Verbindungen der Formel I weist einer der Reste R2 und R3 die Bedeutung H und der andere Rest die Bedeutung F auf. R nimmt bevorzugt zusammen mit R eine der folgenden Bedeutungen an:In particularly preferred compounds of the formula I, R 2 and R 3 simultaneously have the meaning H. In further preferred compounds of the formula I, one of the radicals R 2 and R 3 has the meaning H and the other radical has the meaning F. R preferably together with R has one of the following meanings:
worin X und R die oben angegebene Bedeutung aufweisen und X insbesondere O bedeutet. wherein X and R have the meaning given above and X is in particular O means.
Besonders bevorzugt nimmt R4 zusammen mit R5 eine der folgendenParticularly preferably, R 4 together with R 5 takes one of the following
Bedeutungen an:Meanings of:
worin R die oben angegeben Bedeutung aufweist. wherein R has the meaning given above.
R6 bedeutet vorzugsweise unsubstituiertes oder einfach oder mehrfach durch HaI, CN, NO2, OH, CF3, OCH(CF3)2, OCOCH3 oder A substituiertes Phenyl, 2-, 3- oder 4-Pyridyl, Pyrimidyl, Furyl oder Thienyl. Insbesondere bedeutet R6 eine der folgenden Gruppen: R 6 is preferably unsubstituted or mono- or polysubstituted by Hal, CN, NO 2 , OH, CF 3 , OCH (CF 3 ) 2 , OCOCH 3 or A substituted phenyl, 2-, 3- or 4-pyridyl, pyrimidyl, furyl or thienyl. In particular, R 6 is one of the following groups:
worin wherein
O oder S bedeutet, A die oben angegebene Bedeutung aufweist, bevorzugt aber Methyl bedeutet und HaI bevorzugt F oder Cl bedeutet.O or S, A has the meaning indicated above, but preferably is methyl and Hal preferably denotes F or Cl.
Weiterhin sind insbesondere Verbindungen der Formel I bevorzugt, worin R6 eine der folgenden Bedeutungen aufweist: Particular preference is furthermore given to compounds of the formula I in which R 6 has one of the following meanings:
R7 bedeutet bevorzugt H oder A, insbesondere H.R 7 is preferably H or A, in particular H.
Aryl bedeutet vorzugsweise unsubstituiertes oder ein-, zwei- oder dreifach durch HaI, A, OH, OA, NH2, NO2, CN, COOH, COOA, CONH2, NHCOA, NHCONH2, NHSO2A, CHO, 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-Methylamino- carbonyl)-phenyl, o-, m- oder p-Acetamidophenyl, o-, m- oder p-Methoxy- phenyl, o-, m- oder p-Ethoxyphenyl, o-, m- oder p-Ethoxycarbonylphenyl, o-, m- oder p-(N,N-Dimethylamino)-phenyl, o-, m- oder p-(N,N-Dimethyl- aminocarbonyl)-phenyl, o-, m- oder p-(N-Ethylamiπo)-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-(Methylsulfon- amido)-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-,Aryl is preferably unsubstituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NH 2 , NO 2 , CN, COOH, COOA, CONH 2 , NHCOA, NHCONH 2 , NHSO 2 A, CHO, 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-dimethylamino or 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,2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,
2-Hydroxy-3,5-dichlorphenyl, p-lodphenyl, 3,6-Dichlor-4-aminophenyl, 4-2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-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-acetamido- phenyl, 3-Fluor-4-methoxyphenyl, 3-Amino-6-methylphenyl, 3-Chlor-4- acetamidophenyl oder 2,5-Dimethyl-4-chlorphenyl.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,Heteroaryl particularly preferably denotes a monocyclic saturated or aromatic heterocycle having an N, S or O atom which is unsubstituted or mono-, di- or trisubstituted by Hal, A, NHA, NA 2 , NO 2 ,
COOA oder Benzyl substituiert sein kann. U ngeachtet weiterer Substitutionen, bedeutet unsubstituiertes Heteroaryl z.B. 2- oder 3-Furyl, 2- oder 3-Thienyl, 1-, 2- oder 3-Pyrrolyl, 1-, 2, 4- oderCOOA or benzyl may be substituted. Notwithstanding 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-lmidazolyl, 1-, 3-, 4- oder 5-Pyrazolyl, 2-, 4- oder 5-Oxazolyl, 3-, 4- oder5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or
5-lsoxazolyl, 2-, 4- oder 5-Thiazolyl, 3-, 4- oder 5-lsothiazolyl, 2-, 3- oder5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or
4-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- 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-Chin- oxalinyl, 2-, 3-, 5-, 6-, 7- oder 8-2H-Benzo[1 ,4]oxazinyl, weiter bevorzugt4-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- 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 preferred
1 ,3-Benzodioxol-5-yl, 1 ,4-Benzodioxan-6-yl, 2,1,3-Benzothiadiazol-4- oder1, 3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazole-4 or
-5-yl oder 2,1 ,3-Benzoxadiazol-5-yl.-5-yl or 2,1,3-benzoxadiazol-5-yl.
HaI bedeutet vorzugsweise F, Cl oder Br, aber auch I, besonders bevorzugt F oder Cl.Hal preferably denotes F, Cl or Br, but also I, particularly preferably F or Cl.
Für die gesamte Erfindung gilt, daß sämtliche Reste, die mehrfach auf¬ treten, gleich oder verschieden sein können, d.h. unabhängig voneinander Sind-It applies to the entire invention that all radicals which occur several times auf¬ may be the same or different, are independently ie -
Verbindungen der Formel A worinCompounds of the formula A wherein
R1, R2, R3 unabhängig voneinander H, A, Aryl, Heteroaryl, HaI, - (CY2)n-SA, -(CY2)n-SCF3, -(CYs)n-SCN1 -(CY2Jn-CF3, -R 1 , R 2 , R 3 independently of one another are H, A, aryl, heteroaryl, Hal, - (CY 2 ) n-SA, - (CY 2 ) n-SCF 3 , - (CYs) n -SCN 1 - (CY 2 J n -CF 3 , -
(CY2)n-OCF3, Cycloalkyl, -SCH3, -SCN, -CF3, -OCF3, - OA, -(CY2)n-OH, -(CY2)H-CO2R, -(CY2)n-CN, -(CY2)n-Hal, -(CY2)π-NR2, (CY2)H-OA, (CY2)H-OCOA, -SCF3, (CY2)n- CONR2, -(CY2)H-NHCOA, -(CY2)n-NHSO2A(CY 2 ) n -OCF 3 , cycloalkyl, -SCH 3 , -SCN, -CF 3 , -OCF 3 , - OA, - (CY 2 ) n -OH, - (CY 2 ) H -CO 2 R, - (CY 2 ) n -CN, - (CY 2 ) n -Hal, - (CY 2 ) π -NR 2 , (CY 2 ) H -OA, (CY 2 ) H -OCOA, -SCF 3 , (CY 2 ) n - CONR 2 , - (CY 2 ) H -NHCOA, - (CY 2 ) n -NHSO 2 A
Y H, A, HaIY H, A, HaI
A Alkyl oder CycloalkylA is alkyl or cycloalkyl
HaI F, Cl, Br oder IHaI F, Cl, Br or I
R H oder A, bei gemimalen Resten R zusammen auch - (CH2)S-, -(CH2)4- oder -(CH2)2-NR-(CH2)2,RH or A, when Gemimalen R together also - (CH 2 ) S -, - (CH 2 ) 4 - or - (CH 2 ) 2 -NR- (CH 2 ) 2 ,
R4, R5 zusammen -X (CH2)2X-, -X CR2)X-, -X CH(CH2OR)X-,R 4 , R 5 together are -X (CH 2 ) 2 X-, -X CR 2 ) X-, -X CH (CH 2 OR) X-,
-X CH(CH2OR)CR2X-, -X CR2CH(CH2OR) X-, -X CH(CH2NR2)X-, -X CH(CH2NR2)CR2X-, -X-XCH (CH 2 OR) CR 2 X-, -X CR 2 CH (CH 2 OR) X-, -X CH (CH 2 NR 2 ) X-, -X CH (CH 2 NR 2 ) CR 2 X -, -X
CR2CH(CH2NR2) X-, -OCH2CH2O-, -X (CH2)2X-, CR 2 CH (CH 2 NR 2 ) X-, -OCH 2 CH 2 O-, -X (CH 2 ) 2 X- ,
-X CR2)X-, -X CH(CH2OR)X-, -X CH(CH2OR)CR2X-,-XCR 2 ) X-, -X CH (CH 2 OR) X-, -X CH (CH 2 OR) CR 2 X-,
-X CH(CH2NR2)X-, -X CH(CH2NR2)CR2X-, -OCH2CH2O-, -X-C-X-,-X CH (CH 2 NR 2 ) X-, -X CH (CH 2 NR 2 ) CR 2 X-, -OCH 2 CH 2 O-, -XCX-,
""
X O, S oder NR R6 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, -(CY2Jn-OR, -OCOR, -XO, S or NR R 6 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, - (CY 2 Jn-OR, -OCOR, -
(CYz)n-CO2R, -(CY2)n-CN oder -(CYz)n-NR2 substituiertes Aryl oder Heteroaryl,(CYz) n -CO 2 R, - (CY 2 ) n -CN or - (CYz) n -NR 2 substituted aryl or heteroaryl,
R7 (C=O)-R, (C=O)-NR2, (C=O)-OR, H oder AR 7 (C = O) -R, (C = O) -NR 2, (C = O) -OR, H or A
undand
n O, 1 , 2, 3, 4, 5, 6 oder 7n is 0, 1, 2, 3, 4, 5, 6 or 7
bedeuten,mean,
sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Tautomere,and their pharmaceutically usable derivatives, solvates, tautomers,
Salze und Stereoisomere, einschließlich deren Mischungen in allenSalts and stereoisomers, including mixtures thereof in all
Verhältnissen.Conditions.
W bedeutet bevorzugt CH.W is preferably CH.
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 derParticularly preferred compounds of the formula I are those of
Teilformeln IA bis IB: Part formulas IA to IB:
worinwherein
R1 R1, R2, R6, R7 und X die oben angegebenen Bedeutungen aufweisenR 1 R 1 , R 2 , R 6 , R 7 and X have the meanings given above
undand
Re H, CH2OR oder CH2NR2 R e H, CH 2 OR or CH 2 NR 2
bedeutet.means.
Besonders bevorzugte Verbindungen der Formel IA simd die der Teilformeln IA1 bis IA3:Particularly preferred compounds of the formula IA are those of the subformulae IA1 to IA3:
worin R, R1, R2, R3, R6 und R7 die oben angegebenen Bedeutungen aufweisen. wherein R, R 1 , R 2 , R 3 , R 6 and R 7 have the meanings given above.
In besonders bevorzugten Verbindungen der Formel IB weist R8 die Bedeutung H auf.In particularly preferred compounds of the formula IB, R 8 has the meaning H.
Besonders bevorzugt stehen die Reste R4 und R5 in cis-Stellung zueinander. Weiterhin bevorzugt steht der Rest R6 in trans-Stellung zumThe radicals R 4 and R 5 are particularly preferably in the cis-position relative to one another. Further preferably, the radical R 6 is in the trans position to
Rest R-Rest of R
Bevorzugt ist dabei eine Verbindung der Formel A oder B mit folgender Struktur: sowie deren Racemat oder andere Gemische der Enantiomeren.Preference is given to a compound of the formula A or B having the following structure: and their racemate or other mixtures of the enantiomers.
Dementsprechend sind Gegenstand der Erfindung insbesondere diejeni¬ gen Verbindungen der Formel I, in denen mindestens einer der genannten Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat. Einige bevorzugte Gruppen von Verbindungen können durch die folgen¬ den Teilformeln 11 bis I43 ausgedrückt werden:Accordingly, the invention relates, in particular, to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings given above. Some preferred groups of compounds can be expressed by the following partial formulas II to I43:
12 12
Iδ Iδ
Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrer Her¬ stellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wie Houben-Weyl, The compounds of the 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,
Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) beschrieben sind, und zwar unter Reaktionsbedingungen, die für die ge¬ nannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.Methods of organic chemistry, Georg Thieme Verlag, Stuttgart) are described, under reaction conditions which are known and suitable for the ge called reactions. One can also make use of known per se, not mentioned here variants.
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 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 Umsetzung erfolgt in der Regel in einem inerten Lösungsmittel, bevorzugt in Gegenwart einer Protonensäure oder Lewis-Säure wie TFA,The reaction is generally carried out in an inert solvent, preferably in the presence of a protic acid or Lewis acid such as TFA,
HFIP, Bismut(lll)-Salzen, Ytterhium(lll)-Salzen oder CAN. DieHFIP, bismuth (III) salts, ytterhium (III) salts or CAN. The
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 15° und 35°C.Reaction time is between a few minutes and 14 days, depending on the conditions used, the reaction temperature between about 0 ° and 180 °, normally between 0 ° and 100 °, particularly preferably between 15 ° and 35 ° 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; Nitrile wie Acetonitril; Schwefelkohlenstoff; Carbonsäuren wie Ameisensäure oder Essigsäure; Nitroverbindungen wie Nitromethan oder Nitrobenzol 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; Nitriles such as acetonitrile; Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene or mixtures of said solvents.
Verbindungen der Formel I worin R7 eine andere Bedeutung als H aufweist, werden vorzugsweise durch Alkylherung oder Azylierung aus den Verbindungen der Formel I hergestellt, worin R7 H bedeutet. Gewünschtenfalls kann in einer Verbindung der Formel I eine funktionell abgewandelte Amino- und /oder Hydroxygruppe durch Solvolyse oderCompounds of the formula I in which R 7 has a meaning other than H are preferably prepared by alkylation or acylation from the compounds of the formula I in which R 7 is H. If desired, in a compound of formula I, a functionally modified amino and / or hydroxy group by solvolysis or
Hydrogenolyse nach üblichen Methoden in Freiheit gesetzt werden. Dies kann z.B. mit NaOH oder KOH in Wasser, Wasser-THF oder Wasser-Hydrogenolysis be set free by conventional methods. This can e.g. with NaOH or KOH in water, water-THF or water
Dioxan bei Temperaturen zwischen 0 und 100° erfolgen.Dioxane be carried out 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 vor¬ liegende Erfindung auch die Verwendung dieser Verbindungen in Form ihrer pharmazeutisch unbedenklichen Salze, die von verschiedenen organischen und anorganischen Säuren und Basen nach fachbekanntenThe 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, which are known in the art from various organic and inorganic acids and bases
Vorgehensweisen abgeleitet werden können. Pharmazeutisch unbedenk¬ liche 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 undProcedures can be derived. Pharmaceutically acceptable salt forms of the compounds of the 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, e.g. Potassium ethanolate and
Natriumpropanolat; sowie verschiedene organische Basen wie Piperidin, Diethanolamin und N-Methylglutamin. Die Aluminiumsalze der Verbindun¬ gen 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 oder 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 ent- 5 sprechenden Salzen wie Acetat, Trifluoracetat, Tartrat, Maleat, Succinat,Natriumpropanolat; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. The aluminum salts of the compounds of the formula I are also included. In certain compounds of the formula I, acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides, such as hydrogen chloride, Hydrogen bromide or hydriodic acid, other mineral acids and their corresponding salts, such as sulfate, nitrate or phosphate and the like, and also alkyl and monoaryl sulfonates, such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts, such as acetate, trifluoroacetate, tartrate, maleate, succinate,
Citrat, Benzoat, Salicylat, Ascorbat und dergleichen behandelt. Dement¬ sprechend zählen zu pharmazeutisch unbedenklichen Säureadditions¬ salzen der Verbindungen der Formel I die folgenden: Acetat, Adipat,Citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of the formula I include the following: acetate, adipate,
10 Alginat, Arginat, Aspartat, Benzoat, Benzolsulfonat (Besylat), Bisulfat, Bisulfit, Bromid, Butyrat, Kampferat, Kampfersulfonat, Caprylat, Chlorid, Chlorbenzoat, Citrat, Cyclopentanpropionat, Digluconat, Dihydrogen- phosphat, Dinitrobenzoat, Dodecylsulfat, Ethansulfonat, Fumarat,10 alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate,
^ c Galacterat (aus Schleimsäure), Galacturonat, Glucoheptanoat, Gluconat, Glutamat, Glycerophosphat, Hemisuccinat, Hemisulfat, Heptanoat, Hexanoat, Hippurat, Hydrochlorid, Hydrobromid, Hydroiodid, 2-Hydroxy- ethansulfonat, lodid, Isethionat, Isobutyrat, Lactat, Lactobionat, Malat,^ c Galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate,
Maleat, Malonat, Mandelat, Metaphosphat, Methansulfonat,Maleate, malonate, mandelate, metaphosphate, methanesulfonate,
2020
Methylbenzoat, Monohydrogenphosphat, 2-Naphthalinsulfonat, Nicotinat,Methyl benzoate, monohydrogen phosphate, 2-naphthalenesulfonate, nicotinate,
Nitrat, Oxalat, Oleat, Pamoat, Pectinat, Persulfat, Phenylacetat, 3- Phenylpropionat, Phosphat, Phosphonat, Phthalat, was jedoch keine Einschränkung darstellt.Nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenyl acetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not limiting.
2525
Weiterhin zählen zu den Basensalzen der erfindungsgemäßen Verbindungen Aluminium-, Ammonium-, Calcium-, Kupfer-, Eisen(lll)-, Eisen(ll)-, Lithium-, Magnesium-, Mangan(lll)-, Mangan(ll), Kalium-,Furthermore, the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium -
O0 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 O0 sodium and zinc salts, but this is not intended to be limiting. Preferred among the above salts are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium. To salts of the compounds of the formula I, which differ from pharmaceutically acceptable organic non-toxic
3535
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-Diethyl- aminoethanol, 2-Dimethylaminoethanol, Ethanolamin, Ethylendiamin, N-Derive bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted ones Amines, cyclic amines and basic ion exchange resins, eg arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N -
Ethylmorpholin, N-Ethylpiperidin, Glucamin, Glucosamin, Histidin,Ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,
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 soll.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), but this is not intended to be limiting.
Verbindungen der vorliegenden Erfindung, die basische stickstoffhaltige Gruppen enthalten, lassen sich mit Mitteln wie (Ci-C4) Alkylhalogeniden, z.B. Methyl-, Ethyl-, Isopropyl- und tert.-Butylchlorid, -bromid und -iodid; Di(CrC4)Alkylsulfaten, z.B. Dimethyl-, Diethyl- und Diamylsulfat; (Ci0- Ciβ)Alkylhalogeniden, z.B. Decyl-, Dodecyl-, Lauryl-, Myristyl- undCompounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C 4 ) alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C 1 -C 4 ) alkyl sulfates, eg dimethyl, diethyl and diamylsulfate; (Ci 0 - Ciβ) alkyl halides, eg decyl, dodecyl, lauryl, myristyl and
Stearylchlorid, -bromid und -iodid; sowie Aryl-(CrC4)Alkylhalogeniden, z.B. Benzylchlorid und Phenethylbromid, quarternisieren. Mit solchenStearyl chloride, bromide and iodide; and aryl (C 1 -C 4 ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize. With such
Salzen können sowohl wasser- als auch öllösliche erfindungsgemäße Verbindungen hergestellt werden.Salts can be prepared both water-soluble and oil-soluble compounds of the invention.
Zu den oben genannten pharmazeutischen Salzen, die bevorzugt sind, zählen Acetat, Trifluoracetat, Besylat, Citrat, Fumarat, Gluconat, 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.Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, Sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, which is not intended to be limiting.
Die Säureadditionssalze basischer Verbindungen der Formel I werden dadurch hergestellt, daß man die freie Basenform mit einer ausreichendenThe acid addition salts of basic compounds of the formula I are prepared by reacting the free base form with a sufficient
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 polarenThe amount of the desired acid brings into contact, which is the salt in a conventional manner. The free base can be prepared by contacting Bring the salt form with a base and isolate the free base in the usual way regenerate. The free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar
Lösungsmitteln; im Rahmen der Erfindung entsprechen die Salze jedoch sonst ihren jeweiligen freien Basenformen.solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.
Wie erwähnt werden die pharmazeutisch unbedenklichen Basenadditions- salze der Verbindungen der Formel I mit Metallen oder Aminen wie Alkali¬ metallen und Erdalkalimetallen oder organischen Aminen gebildet. Bevorzugte Metalle sind Natrium, Kalium, Magnesium und Calcium. Bevorzugte organische Amine sind N,N'-Dibenzylethylendiamin, Chlor- procain, Cholin, Diethanolamin, Ethylendiamin, N-Methyl-D-glucamin und Procain.As mentioned, the pharmaceutically acceptable base addition salts of the compounds of the 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, chloro-procain, 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 unter- scheiden 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 regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ, in a sense, from their corresponding salt forms with respect to 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,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,
Diphosphat, Dinatrium und Trihydrochlorid, was jedoch keine Ein¬ schränkung darstellen soll. Im Hinblick auf das oben Gesagte sieht man, daß unter dem Ausdruck "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 pharma- zeutisch unbedenkliche Salzform des Wirkstoffs kann auch diesemDiphosphate, disodium and trihydrochloride, but this is not intended to represent a restriction Ein¬. In view of the above, it can be seen that the term "pharmaceutically acceptable salt" in the present context means an active ingredient which contains a compound of the formula I in the form of one of its salts, especially if this salt form is the active ingredient in the Imparts improved pharmacokinetic properties to the free form of the active ingredient or any other salt form of the active ingredient which has previously been used. The pharmaceutically acceptable salt form of the active ingredient can also be this
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.It is believed that the active ingredient first conferred a desired pharmacokinetic property that it did not previously possess, and may even positively affect the pharmacodynamics of that agent in terms of its therapeutic efficacy 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 derenThe invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including the same
Mischungen in allen Verhältnissen, sowie gegebenenfalls Träger- und/oder Hilfsstoffe.Mixtures in all ratios, and optionally excipients and / or adjuvants.
Pharmazeutische Formulierungen können in Form von Dosiseinheiten, die eine vorbestimmte Menge an Wirkstoff pro Dosiseinheit enthalten, darge¬ reicht 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 behandelten 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 Dosierungseinheitsformulierungen 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.Pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per dosage unit. Such a moiety 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 of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of an active ingredient. Farther For example, 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, intramus- kulärem, 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 intravenous) intradermal) routes. 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 nicht- wäßrigen Flüssigkeiten; eßbare Schäume oder Schaumspeisen; oder Öl- in-Wasser-Flüssigemulsionen oder Wasser-in-ÖI-Flüssigemulsionen dargereicht werden.Pharmaceutical formulations adapted for oral administration may be administered as separate units, e.g. 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.
So läßt sich beispielsweise bei der oralen Verabreichung in Form einer Tablette oder Kapsel die Wirkstoffkomponente mit einem oralen, nicht¬ toxischen und pharmazeutisch unbedenklichen inerten Trägerstoff, wie z.B. Ethanol, Glyzerin, Wasser u.a. kombinieren. Pulver werden herge- stellt, 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, Konservierungs¬ mittel, Dispersionsmittel und Farbstoff können ebenfalls vorhanden sein. 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,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. Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith. Lubricants and lubricants such as highly disperse silica, talc,
Magnesiumstearat, Kalziumstearat oder Polyethylenglykol in Festform können dem Pulvergemisch vor dem Füllvorgang zugesetzt werden. EinMagnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process. One
Sprengmittel oder Lösungsvermittler, wie z.B. Agar-Agar, Kalziumcarbonat oder Natriumcarbonat, kann ebenfalls zugesetzt werden, um die Verfüg¬ barkeit des Medikaments nach Einnahme der Kapsel zu verbessern.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, Sü߬ stoffe aus Mais, natürliche und synthetische Gummi, wie z.B. Akazia, Traganth oder Natriumalginat, Carboxymethylzellulose, Polyethylenglykol, Wachse, u.a. Zu den in diesen Dosierungsformen verwendeten Schmier¬ mitteln gehören Natriumoleat, Natriumstearat, Magnesiumstearat,In 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, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate,
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 trocken- verpreßt 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 Lösungsverlang- samer, wie z.B. Paraffin, einem Resorptionsbeschleuniger, wie z.B. einem quaternären Salz und/oder einem Absorptionsmittel, wie z.B. Bentonit,Sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing, adding a lubricant and a disintegrating agent and pressing the whole into tablets. A powder mixture is prepared by dissolving the appropriately comminuted compound with a diluent or a base as described above, and optionally with a binder, e.g. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution reducer, such as e.g. Paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent, e.g. bentonite,
Kaolin oder Dikalziumphosphat, vermischt wird. Das Pulvergemisch läßt sich granulieren, indem es mit einem Bindemittel, wie z.B. Sirup, Stärke¬ paste, Acadia-Schleim oder Lösungen aus Zellulose- oder Polymer- materialen 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 erfindungs¬ gemäßen 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 einer Versiegelung aus Schellack, einer Schicht aus Zucker oder Polymer- material und einer Glanzschicht aus Wachs, kann vorhanden sein. Diesen Beschichtungen können Farbstoffe zugesetzt werden, um zwischen unter¬ schiedlichen Dosierungseinheiten unterscheiden zu können.Kaolin or dicalcium phosphate. The powder mixture can be granulated by mixing it with a binder such as, for example, syrup, starch paste, acadia slime or solutions of cellulose or polymer. wetted material 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 shellac sealant, a layer of sugar or polymer 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 gegebeneOral fluids, e.g. Solution, syrups and elixirs, can be prepared in the form of dosage units, so that a given
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.Quantity contains a given 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.
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.Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, i.a. can 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 can also be prepared so that the release is prolonged or retarded For example, by coating or embedding particulate material in polymers, wax, etc.
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 Polyvinyl- pyrrolidon, Pyran-Copolymer, Polyhydroxypropylmethacrylamidphenol,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 polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol,
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, Polyhydroxybutter- säure, Polyorthoester, Polyacetale, Polydihydroxypyrane, Polycyano- acrylate und quervernetzte oder amphipatische Blockcopolymere von Hydrogelen, gekoppelt sein.Polyhydroxyethylaspartamidphenol or polyethylene oxide polylysine substituted with Palmitoylresten include. Furthermore, the compounds can be attached to a class of biodegradable polymers suitable for the controlled release of a drug, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyano-acrylates, and cross-linked or amphipathic block copolymers of hydrogels.
An die transdermale Verabreichung angepaßte pharmazeutischePharmaceutical adapted to transdermal administration
Formulierungen können als eigenständige Pflaster für längeren, engen 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. An die topische Verabreichung angepaßte pharmazeutische Verbindungen können als Salben, Cremes, Suspensionen, Lotionen,Formulations may be presented as discrete plasters for prolonged, intimate 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). Pharmaceutical compounds adapted for topical administration may be used as ointments, creams, suspensions, lotions,
Pulver, Lösungen, Pasten, Gele, Sprays, Aerosole oder Öle formuliert sein.Be formulated 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 SalbeFor treatments of the eye or other external tissues, e.g. Mouth and skin, the formulations are preferably as a topical ointment
10 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-Basis10 or cream applied. When formulated into an ointment, the active ingredient can be used with either a paraffinic or water miscible cream base. Alternatively, the active ingredient may be a cream with an oil-in-water cream base or a water-in-oil base
At- formuliert werden.A t - be formulated.
Zu den an die topische Applikation am Auge angepaßten pharma¬ zeutischen Formulierungen gehören Augentropfen, wobei der Wirkstoff in einem geeigneten Träger, insbesondere einem wäßrigen Lösungsmittel,The pharmaceutical formulations adapted for topical application to the eye include eye drops, the active substance being suspended in a suitable carrier, in particular an aqueous solvent,
20 gelöst oder suspendiert ist.20 is dissolved or suspended.
An die topische Applikation im Mund angepaßte pharmazeutische Formulierungen umfassen Lutschtabletten, Pastillen und Mundspülmittel. 25Pharmaceutical formulations adapted for topical application in the mouth include lozenges, troches and mouthwashes. 25
An die rektale Verabreichung angepaßte pharmazeutische Formulierungen können in Form von Zäpfchen oder Einlaufen dargereicht werden.Pharmaceutical formulations adapted for rectal administration may be presented in the form of suppositories or enemas.
3030
An die nasale Verabreichung angepaßte pharmazeutische Formulier¬ ungen, in denen die Trägersubstanz ein Feststoff ist, enthalten ein grobes Pulver mit einer Teilchengröße beispielsweise im Bereich von 20-500Pharmaceutical formulations adapted for nasal administration, in which the carrier is a solid, contain a coarse powder having a particle size, for example, in the range of 20-500
Mikrometern, das in der Art und Weise, wie Schnupftabak aufgenommenMicrometre, recorded in the manner of snuff
35 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 umfassen35, 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
Wirkstofflösungen in Wasser oder Öl. 5Active substance solutions in water or oil. 5
An die Verabreichung durch Inhalation angepaßte pharmazeutische Formulierungen umfassen feinpartikuläre Stäube oder Nebel, die mittels verschiedener Arten von unter Druck stehenden Dosierspendern mit 10 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 10 aerosols, nebulizers or insufflators.
An die vaginale Verabreichung angepaßte pharmazeutische Formulierungen können als Pessare, Tampons, Cremes, Gele, Pasten, A c Schäume oder Sprayformulierungen dargereicht werden.Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations A c.
Zu den an die parenterale Verabreichung angepaßten pharmazeutischen Formulierungen gehören wäßrige und nichtwäßrige sterile Injektions¬ lösungen, die Antioxidantien, Puffer, Bakteriostatika und Solute, durch dieThe pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes, by the
20 die Formulierung isotonisch mit dem Blut des zu behandelnden20 the formulation is isotonic with the blood of the treated
Empfängers gemacht wird, enthalten; sowie wäßrige und nichtwäßrige sterile Suspensionen, die Suspensionsmittel und Verdicker enthalten können. Die Formulierungen können in Einzeldosis- oder Mehrfach-Recipient is included; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners. The formulations may be administered in single dose or multiple
25 dosisbehältern, 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.25 dose containers, e.g. sealed vials and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use.
O0 Rezepturmäßig hergestellte Injektionslösungen und Suspensionen können aus sterilen Pulvern, Granulaten und Tabletten hergestellt werden. O0 Injection solutions and suspensions prepared by formulation can be prepared from sterile powders, granules and tablets.
Es versteht sich, daß die Formulierungen neben den obigen besondersIt is understood that the formulations in addition to the above particular
35 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 Formulierungen Geschmacksstoffe enthalten.35 may contain other conventional means in the art with respect to the particular type of formulation; so can For example, formulations suitable for oral administration contain flavorings.
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 behandeln- den 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 erfindungsgemäßen Verbindung perse bestimmt werden. Es läßt sich annehmen, daß ähnliche Dosierungen für dieA 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, 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 for the
Behandlung der anderen, obenerwähnten Krankheitszustände geeignet sind.Treatment of the other, above-mentioned disease states are suitable.
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 weiterenThe 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 other
Arzneimittelwirkstoff. Gegenstand der Erfindung ist auch ein Set (Kit), bestehend aus getrennten Packungen vonDrug 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 Stereo- isomere, 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 VI 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 may also be combined with compounds of Formula VI.
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)Oxaliplatin ZD-0473 (AnorMED)
Spiroplatin Lobaplatin (Aetema) Carboxyphthalatoplatinum Satraplatin (JohnsonSpiroplatin Lobaplatin (Aetema) Carboxyphthalatoplatinum 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-Mitoxantrone diflomotecan (Beaufour
Irinotecan (CPT-11) Ipsen)Irinotecan (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 (Novuspharma) Dang)Pixantron (Novuspharma) Dang)
Rebeccamycin-Analogon KW-2170 (Kyowa Hakko)Rebeccamycin analog KW-2170 (Kyowa Hakko)
(Exelixis)(Exelixis)
BBR-3576 (Novuspharma)BBR-3576 (Novuspharma)
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 (Ligand)LGD-1550 (ligand)
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 (PhamnaMar)Tyrosine kinase imatinib (Novartis) Kahalid F (PhamnaMar)
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-Inhibitor, 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)
10 GCS-IOO (gal3- R-Flurbiprofen (NF-10 GCS-IOO (gal3-R flurbiprofen (NF-
Antagonist, kappaB-lnhibitor, Encore)Antagonist, kappaB inhibitor, Encore)
GlycoGenesys) 3CPA (NF-kappaB-GlycoGenesys) 3CPA (NF-kappaB-
G17DT-Immunogen Inhibitor, Active Biotech)G17DT immunogen 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)
15 Allos Therapeutics) 131-I-TM-601 (DNA-15 Allos Therapeutics) 131-I-TM-601 (DNA
PI-88 (Heparanase- Antagonist,PI-88 (heparanase antagonist,
Inhibitor, Progen) TransMolecular)Inhibitor, progene) TransMolecular)
Tesmilifen (Histamin- Eflomithin (ODC-Inhibitor,Tesmilifen (histamine eflomithine (ODC inhibitor,
Antagonist, YM ILEX Oncology)Antagonist, YM ILEX Oncology)
BioSciences) MinodronsäureBioSciences) Minodronic acid
Histamin (Histamin-H2- (Osteoclasten-Inhibitor,Histamine (histamine H2 (osteoclast inhibitor,
20 Rezeptor- Agonist, Maxim) Yamanouchi)20 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,
Antagonist, Merck KGaA) PharmaMar)Antagonist, Merck KGaA) PharmaMar)
SR-31747 (IL-1- Rituximab (CD20-SR-31747 (IL-1 rituximab (CD20-
Antagonist, Sanofi- Antikörper, Geneπtech)Antagonist, Sanofi antibody, Geneπtech)
2525
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,
Cell Pathways) Pharmagenesis)Cell Pathways) Pharmagenesis)
CP-461 (PDE-V-Inhibitor, Immunol™ (Triclosan-CP-461 (PDE-V inhibitor, Immunol ™ (triclosan)
30 Cell Pathways) Oralspülung, Endo)30 Cell Pathways) Oral Irrigation, Endo)
AG-2037 (GART-Inhibitor, Triacetyluridin (Uridin-AG-2037 (GART inhibitor, triacetyluridine (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 ™
PBI-1402 (PMN-Stimulans, (Immunotoxin, KSPBI-1402 (PMN stimulant, (immunotoxin, KS
35 ProMetic LifeSciences) Biomedix)35 ProMetic LifeSciences) Biomedix)
Bortezomib (Proteasom- PCK-3145 (Apoptose- Inhibitor, Millennium) Förderer, Procyon)Bortezomib (proteasome PCK-3145 (apoptosis) Inhibitor, Millennium) promoter, Procyon)
SRL-172 (T-ZeII- Doranidazol (Apoptose-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)
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)Oxaliplatin ZD-0473 (AnorMED)
Spiroplatin Lobaplatin (Aetema)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) Antimetabolite Azacytidin TomudexAP-5280 (Access) Antimetabolite azacytidine Tomudex
Gemcitabin TrimetrexateGemcitabine trimetrexate
Capecitabin DeoxycoformycinCapecitabine deoxycoformycin
5-Fluoruracil Fludarabin5-fluorouracil fludarabine
Floxuridin PentostatinFloxuridine pentostatin
2-Chlordesoxyadenosin Raltitrexed2-chlorodeoxyadenosine Raltitrexed
6-Mercaptopurin Hydroxyhamstoff6-mercaptopurine hydroxyurea
6-Thioguanin Decitabin (SuperGen)6-thioguanine decitabine (SuperGen)
Cyta rabin Clofarabin (Bioenvision)Cyta rabin 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 BIdarubicin bleomycin B
Rubidazon Mitomycin CRubidazone mitomycin C
Plicamycinp MEN-10755 (Menarini)Plicamycin p MEN-10755 (Menarini)
Porfiromycin GPX-100 (GemPorfiromycin GPX-100 (gem
Cyanomorpholinodoxorubi Pharmaceuticals) einCyanomorpholinodoxorubi Pharmaceuticals)
Mitoxantron (Novantron) Antimitotische Paclitaxel SB 408075Mitoxantrone (Novantrone) Antimitotic Paclitaxel SB 408075
Mittel Docetaxel (GlaxoSmithKline)Agent Docetaxel (GlaxoSmithKline)
Colchicin E7010 (Abbott)Colchicine E7010 (Abbott)
Vinblastin PG-TXL (CellVinblastine PG-TXL (Cell
Vincristin Therapeutics)Vincristin Therapeutics)
Vinorelbin IDN 5109 (Bayer)Vinorelbine IDN 5109 (Bayer)
Vindesin A 105972 (Abbott)Vindesin A 105972 (Abbott)
Dolastatin 10 (NCI) A 204197 (Abbott)Dolastatin 10 (NCI) A 204197 (Abbott)
Rhizoxin (Fujisawa) LU 223651 (BASF)Rhizoxin (Fujisawa) LU 223651 (BASF)
Mivobulin (Warner- D 24851 (ASTA Medica)Mivobulin (Warner-D 24851 (ASTA Medica)
Lambert) ER-86526 (Eisai)Lambert) ER-86526 (Eisai)
Cemadotin (BASF) Combretastatin A4 (BMS)Cemadotin (BASF) Combretastatin A4 (BMS)
RPR 109881A (Aventis) Isohomohalichondrin-BRPR 109881A (Aventis) isohomohalichondrin-B
TXD 258 (Aventis) (PharmaMar)TXD 258 (Aventis) (PharmaMar)
Epothilon B (Novartis) ZD 6126 (AstraZeneca)Epothilone B (Novartis) ZD 6126 (AstraZeneca)
T 900607 (Tularik) PEG-Paclitaxel (Enzon)T 900607 (Tularik) PEG paclitaxel (Enzon)
T 138067 (Tularik) AZ10992 (Asahi)T 138067 (Tularik) AZ10992 (Asahi)
Cryptophycin 52 (EIi Lilly) !DN-5109 (lndena)Cryptophycin 52 (Eli Lilly)! DN-5109 (lndena)
Vinflunin (Fabre) AVLB (PrescientVinflunin (Fabre) AVLB (Prescient
Auristatin PE (Teikoku NeuroPharma)Auristatin PE (Teikoku NeuroPharma)
Hormone) Azaepothilon B (BMS)Hormones) azaepothilone B (BMS)
BMS 247550 (BMS) BNP- 7787 (BioNumerik)BMS 247550 (BMS) BNP-7787 (BioNumerik)
BMS 184476 (BMS) CA-4-Prodrug (OXiGENE)BMS 184476 (BMS) CA-4 prodrug (OXiGENE)
BMS 188797 (BMS) Dolastatin-10 (NrH)BMS 188797 (BMS) Dolastatin-10 (NrH)
Taxoprexin (Protarga) CA-4 (OXiGENE)Taxoprexin (Protarga) CA-4 (OXiGENE)
Aromatase- Aminoglutethimid ExemestanAromatase-aminoglutethimide exemestane
Inhibitoren Letrozol Atamestan (BioMedicines)Inhibitors Letrozole Atamestane (BioMedicines)
Anastrazol YM-511 (Yamanouchi)Anastrazole YM-511 (Yamanouchi)
Formestanformestane
Thymidylatsyntha Pemetrexed (EIi Lilly) Nolatrexed (Eximias) se-lnhibitoren ZD-9331 (BTG) CoFactor™ (BioKeys)Thymidylate Syntha Pemetrexed (EIi Lilly) Nolatrexed (Eximias) se Inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys)
DNA- Trabectedin (PharmaMar) Mafosfamid (BaxterDNA Trabectedin (PharmaMar) Mafosfamide (Baxter
Antagonisten Glufosfamid (Baxter International)Antagonists glufosfamide (Baxter International)
International) Apaziquon (SpectrumInternational) Apaziquon (Spectrum
Albumin + 32P (Isotope Pharmaceuticals)Albumin + 32P (Isotope Pharmaceuticals)
Solutions) O6-BenzylguaninSolutions) O6-Benzylguanine
Thymectacin (NewBiotics) (Paligent)Thymectacin (NewBiotics) (Paligent)
Edotreotid (Novartis)Edotreotide (Novartis)
Farnesyltransfera Arglabin (NuOncology Tipifarnib (Johnson & se-lnhibitoren Labs) Johnson) lonafarnib (Schering- Perillylalkohol (DORFarnesyltransfera Arglabin (NuOncology Tipifarnib (Johnson & se Inhibitors Labs) Johnson) lonafarnib (Schering-Perillyl Alcohol (DOR
Plough) BioPharma)Plow) BioPharma)
BAY-43-9006 (Bayer) Pumpen- CBT-1 (CBA Pharma) Zosuquidar-TrihydrochloridBAY-43-9006 (Bayer) Pump 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 (Ligand)LGD-1550 (ligand)
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-I mpfstoffImmuno) p21 RAS vaccine
(GemVax) Hormonelle und Östrogene Prednison antihormonelle konjugierte Östrogene Methylprednisolon(GemVax) Hormonal and estrogenic prednisone antihormonal conjugated estrogens methylprednisolone
Mittel Ethinylestradiol 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)Medium Inhibitor, Sanofi-BioCryst)
Synthelabo) Ranpirnase (Ribonuclease-Synthelabo) Ranpirnase (Ribonuclease
Tocladesin (cyclisches- Stimulans, Alfacell) AMP-Agonist, Ribapharm) Galarubicin (RNA-Tocladesin (cyclic stimulant, Alfacell) AMP agonist, ribapharm) galarubicin (RNA
Alvocidib (CDK-Inhibitor, Synthese-Inhibitor, Dong-A)Alvocidib (CDK inhibitor, synthesis inhibitor, Dong-A)
Aventis) TirapazaminAventis) Tirapazamine
CV-247 (COX-2-lnhibitor, (Reduktionsmittel, SRICV-247 (COX-2 inhibitor, (reducing agent, SRI
Ivy Medical) International)Ivy Medical) International)
P54 (COX-2-lnhibitor, N-AcetylcysteinP54 (COX-2 inhibitor, N-acetylcysteine
Phytopharm) (Reduktionsmittel, Zambon)Phytopharm) (reducing agent, Zambon)
CapCell™ (CYP450- R-Flurbiprofen (NF-CapCell ™ (CYP450-R flurbiprofen (NF-
Stimulans, Bavarian kappaB-lnhibitor, Encore)Stimulant, Bavarian kappaB inhibitor, Encore)
Nordic) 3CPA (NF-kappaB-Nordic) 3CPA (NF-kappaB-
GCS-IOO (gal3- Inhibitor, Active Biotech)GCS-IOO (gal3 inhibitor, Active Biotech)
Antagonist, Seocalcitol (Vitamin-D-Antagonist, seocalcitol (vitamin D
10 GlycoGenesys) Rezeptor-Agonist, Leo)10 GlycoGenesys) receptor agonist, Leo)
G17DT-lmmunogen 131-I-TM-601 (DNA-G17DT immunogen 131-I-TM-601 (DNA
(Gastrin-Inhibitor, Aphton) Antagonist,(Gastrin inhibitor, Aphton) antagonist,
Efaproxiral (Oxygenator, TransMolecular)Efaproxiral (Oxygenator, TransMolecular)
Allos Therapeutics) Eflornithin (ODC-Inhibitor,Allos Therapeutics) Eflornithine (ODC inhibitor,
PI-88 (Heparanase- ILEX Oncology)PI-88 (Heparanase ILEX Oncology)
15 Inhibitor, Progen) Minodronsäure15 inhibitor, progene) minodronic acid
Tesmilifen (Histamin- (Osteoclasten-Inhibitor,Tesmilifen (histamine (osteoclast inhibitor,
Antagonist, YM Yamanouchi)Antagonist, YM Yamanouchi)
BioSciences) Indisulam (p53-Stimulans,BioSciences) indisulam (p53 stimulant,
Histamin (Histamin-H2- Eisai)Histamine (histamine H2-eisai)
Rezeptor- Agonist, Aplidin (PPT-Inhibitor,Receptor agonist, aplidine (PPT inhibitor,
Maxim) PharmaMar)Maxim) PharmaMar)
20 Tiazofurin (IMPDH- Rituximab (CD20-20 tiazofurin (IMPDH-rituximab (CD20-
Inhibitor, Ribapharm) Antikörper, Genentech)Inhibitor, ribapharm) antibody, Genentech)
Cilengitid (Integrin- Gemtuzumab (CD33-Cilengitide (integrin-gemtuzumab (CD33-
Antagonist, Merck KGaA) Antikörper, Wyeth Ayerst)Antagonist, Merck KGaA) antibodies, Wyeth Ayerst)
SR-31747 (IL-1- PG2 (Hämatopoese-SR-31747 (IL-1 PG2 (hematopoietic)
Antagonist, Sanofi- Verstärker,Antagonist, Sanofi amplifier,
Synthelabo) Pharmagenesis)Synthelabo) Pharmagenesis)
2525
CCI-779 (mTOR-Kinase- Immunol™ (Triclosan-CCI-779 (mTOR kinase Immunol ™ (triclosan)
Inhibitor, Wyeth) Oralspülung, Endo)Inhibitor, Wyeth) Oral Irrigation, Endo)
Exisulind (PDE-V- Triacetyluridin (Uridin-Exisulind (PDE-V-triacetyluridine (uridine)
Inhibitor, Cell Pathways) Prodrug, Wellstat)Inhibitor, cell pathways) prodrug, Wellstat)
CP-461 (PDE-V-Inhibitor, SN-4071 (Sarkom-Mittel,CP-461 (PDE-V inhibitor, SN-4071 (sarcoma agent,
Cell Pathways) Signature BioScience)Cell Pathways) Signature BioScience)
30 AG-2037 (GART-Inhibitor, TransMID-107™30 AG-2037 (GART inhibitor, TransMID-107 ™
Pfizer) (Immunotoxin, KSPfizer) (immunotoxin, KS
WX-U K1 Biomedix)WX-U K1 Biomedix)
(Plasminogenaktivator- PCK-3145 (Apoptose-(Plasminogen activator PCK-3145 (apoptosis
Inhibitor, Wilex) Förderer, Procyon)Inhibitor, Wilex) promoter, Procyon)
PBI-1402 (PMN- Doranidazol (Apoptose-PBI-1402 (PMN-doranidazole (apoptosis)
Stimulans, ProMetic Förderer, PoIa)Stimulant, ProMetic promoter, PoIa)
35 LifeSciences) CHS-828 (cytotoxisches35 LifeSciences) CHS-828 (cytotoxic
Bortezomib (Proteasom- Mittel, Leo) Inhibitor, Millennium) trans-RetinsäureBortezomib (proteasome agent, Leo) Inhibitor, millennium) trans -retinoic acid
SRL-172 (T-ZeII- (Differentiator, NIH)SRL-172 (T-cell (differentiator, NIH)
Stimulans, SR Pharma) MX6 (Apoptose-Förderer,Stimulant, SR Pharma) MX6 (apoptosis promoter,
TLK-286 (Glutathion-S- MAXIA)TLK-286 (glutathione-S-MAXIA)
Transferase-Inhibitor, Apomin (Apoptose-Transferase inhibitor, apomin (apoptosis
Telik) Förderer, ILEX Oncology)Telik) Sponsors, ILEX Oncology)
PT-100 Urocidin (Apoptose-PT-100 urocidin (apoptosis
(Wachstumsfaktor- Förderer, Bioniche)(Growth factor promoter, Bioniche)
Agonist, Point Ro-31-7453 (Apoptose-Agonist, Point Ro-31-7453 (apoptosis
Therapeutics) Förderer, La Roche)Therapeutics) Sponsors, La Roche)
Midostaurin (PKC- Brostallicin (Apoptose-Midostaurin (PKC-brostallicin (apoptosis
Inhibitor, Novartis) Förderer, Pharmacia)Inhibitor, Novartis) promoter, Pharmacia)
Bryostatin-1 (PKC-Bryostatin-1 (PKC
Stimulans, GPC Biotech)Stimulant, GPC Biotech)
CDA-II (Apoptose-CDA-II (apoptosis
Förderer, Everlife)Conveyor, Everlife)
SDX-101 (Apoptose-SDX-101 (apoptosis
Förderer, Salmedix)Conveyor, Salmedix)
Ceflatonin (Apoptose-Ceflatonin (apoptosis
Förderer, ChemGenex)Conveyor, ChemGenex)
Bevorzugt werden die Verbindungen der Formel I mit den mit bekannten Antikrebsmitteln kombiniert:Preferably, the compounds of the formula I are combined with those with known anticancer agents:
Zu diesen bekannten Antikrebsmitteln zählen die folgenden: östrogenrezeptormodulatoren, Androgenrezeptormodulatoren, Retinoid- rezeptormodulatoren, Zytotoxika, antiproliferative Mittel, Prenyl- Proteintransferasehemmer, HMG-CoA-Reduktase-Hemmer, HIV- Protease-Hemmer, Reverse-Transkriptase-Hemmer sowie weitere Angiogenesehemmer. 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).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).
„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 Östrogenrezeptor- modulatoren 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'-Dihydroxybenzo- phenon-2,4-dinitrophenylhydrazon und SH646, was jedoch keine Einschränkung darstellen soll."Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how this occurs. 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,"Androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor,
10 und zwar unabhängig davon, wie dies geschieht. Zu den10 regardless of how this happens. To the
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.
A c „Retinoidrezeptormodulatoren" bezieht sich auf Verbindungen, die die Bin¬ dung von Retinoiden an den Rezeptor stören oder diese hemmen, und zwar unabhängig davon, wie dies geschieht. Zu solchen Retinoidrezeptor¬ modulatoren zählen zum Beispiel Bexaroten, Tretinoin, 13-cis-Retinsäure,A c "Retinoid receptor modulators" refers to compounds containing the Bin¬ dung of retinoids to the receptor, interfere with or inhibit, regardless of how this is done. Such Retinoidrezeptor¬ modulators include, for example, bexarotene, tretinoin, 13-cis retinoic acid,
9-cis-Retinsäure, α-Difluormethylornithin, ILX23-7553, trans-N-(4'-9-cis retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N- (4'-
2020
Hydroxyphenyl)retinamid und N-4-Carboxyphenylretinamid.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 Alkylieruπgsmittel, Tumor-"Cytotoxic agents" refers to compounds that cause cell death, primarily by direct action on cell function, or that inhibit or interfere with cell myosis, including alkylating agents, tumor cells,
25 nekrosefaktoren, interkaliernde Mittel, Mikrotubulin-Hemmer und Topoisomerase-Hemmer.25 necrosis factors, intercalators, microtubulin inhibitors and topoisomerase inhibitors.
Zu den Zytotoxika zählen zum Beispiel Tirapazimin, Sertenef, Cachectin, Ifosfamid, Tasonermin, Lonidamin, Carboplatin, Altretamin, Prednimustin,The cytotoxic agents include, for example, tirapazimine, sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine,
30 Dibromdulcit, Ranimustin, Fotemustin, Nedaplatin, Oxaliplatin, 30 Dibromodulcite, Ranimustin, Fotemustin, Nedaplatin, Oxaliplatin,
Temozolomid, Heptaplatin, Estramustin, Improsulfan-tosylat, Trofosfamid, Nimustin, Dibrospidium-chlorid, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulven, Dexifosfamid, cis-Amindichlor(2- methylpyridin)platin, Benzylguanin, Glufosfamid, GPX100,Temozolomide, Heptaplatin, Estramustine, Improsulfan-tosylate, Trofosfamide, Nimustin, Dibrospidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulvene, Dexifosfamide, cis-Amine dichloro (2-methylpyridine) platinum, Benzylguanine, Glufosfamide, GPX100,
3535
(trans,trans,trans)-bis-mu-(hexan-1 ,6-diamin)-mu-[diamin-platin(ll)]bis-(trans, trans, trans) -bis-mu (hexane-1,6-diamine) -mu- [diamine-platinum (II)] bis-
[diamin(chlor)platin(ll)]-tetrachlorid, Diarizidinylspermin, Arsentrioxid, 1- (11-Dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthin, Zorubicin, Idarubicin, Daunorubicin, Bisantren, Mitoxantron, Pirarubicin, Pinafid, Valrubicin, Amrubicin, Antineoplaston, 3'-Desamino-3'-morpholino-13- desoxo-10-hydroxycarminomycin, Annamycin, Galarubicin, Elinafid,[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-deoxo 10-hydroxycarminomycin, annamycin, galarubicin, elinafide,
MEN 10755 und 4-Desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl- daunorubicin (siehe WO 00/50032), was jedoch keine Einschränkung darstellen soll.MEN 10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032), but this is not intended to be limiting.
Zu den Mikrotubulin-Hemmern zählen zum Beispiel Paclitaxel, Vindesin- sulfat, S'^'-Dideshydro-^-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.The microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S '''-dideshidroxydeoxy-δ'-norvincaleukoblastin, docetaxol, 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, 6-Ethoxypropionyl-3',4'-O-exo-benzyliden- chartreusin, 9-Methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridin-2-Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecane, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4; 5-kl] acridine-2
(6H)propanamin, 1-Amino-9-ethyl-5-fluor-2,3-dihydro-9-hydroxy-4-methyl-(6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl
I H.^H-benzoIdeJpyranoIS'^'ibJJindolizinofi ^blchinolin-IO.ISCΘH.I δH)- dion, Lurtotecan, 7-[2-(N-lsopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPM 100, BN80915, BN80942, Etoposid-phosphat, Teniposid, Sobuzoxan, 2I-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-3,5-dimethoxy- phenyl]-5,5a,6,8,8aI9-hexohydrofuro(3',4l:6,7)naphtho(2,3-d)-1 ,3-dioxol-6- on, 2,3-(Methylendioxy)-5-methyl-7-hydroxy-8- methoxybenzo[c]phenanthridinium, 6,9-Bis[(2- aminoethyl)amino]benzo[g]isochinolin-5,10-dion, 5-(3-Aminopropylamino)-I H. ^ H-benzoIdeJpyranoIS '^' ibJJindolizinofi ^ quinoline-IO.ISCΘH.I δH) -dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin, BNP1350, BNPM 100, BN80915 , BN80942, etoposide phosphate, teniposide, sobuzoxane, 2 I-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-3,5-dimethoxyphenyl] -5,5a, 6,8,8a I 9-hexohydrofuro (3 ', 4 l : 6,7) naphtho (2,3-d) -1,3 -dioxol-6-one, 2,3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [c] -phenanthridinium, 6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline 5,10-dione, 5- (3-aminopropylamino) -
7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]- acridin-6-on, N-[1-[2(Diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thio- xanthen-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.7,10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1-de] acridin-6-one, N- [1- [2 (diethylamino) ethylamino] -7-methoxy 9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4- carboxamide, 6 - [[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2, 1-c] quinolin-7-one and dimesna.
Zu den „antiproliferativen Mitteln" zählen Antisense-RNA- und -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, Tiazofurin, Decitabin, Nolatrexed, Pemetrexed, Nelzarabin, 2'-Desoxy-2'-methylidencytidin, 2'-Fluormethylen-2'- desoxycytidin, N-[5-(2,3-Dihydrobenzofuryl)sulfonyl]-N'-(3,4- dichlorphenyl)harnstoff, N6-[4-Desoxy-4-[N2-[2(E),4(E)-tetra- decadienoyllglycylaminoJ-L-glycero-B-L-manno-heptopyranosylJadenin, Aplidin, Ecteinascidin, Troxacitabine, 4-[2-Amino-4-oxo-4,6,7,8-tetrahydro- SH-pyrimidinotδ^-bJti ^Jthiazin-β-yKSJ-ethylJ^.δ-thienoyl-L- glutaminsäure, Aminopterin, 5-Flurouracil, Alanosin, 11-Acetyl-8- (carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1 ,11 -diazatetracyclo-Antiproliferative agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine. ocfosfat, Fosteabin Sodium Hydrate, Raltitrexed, Paltitrexide, Emitefur, Tiazofurin, Decitabine, Nolatrexed, Pemetrexed, Nelzarabine, 2'-Deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- (2, 3-dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy-4- [N 2 - [2 (E), 4 (E) -tetra-decadienoylglycylamino] -L-glycero BL-manno-heptopyranosyl-jadenine, aplidine, ecteinascidin, troxacitabine, 4- [2-amino-4-oxo-4,6,7,8-tetrahydro-SH-pyrimidinotδ-bJti] -hthiazine-β-yKSJ-ethyl-1-yl thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14-oxa-1,11-diazatetracyc
(7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylessigsäureester, Swainsonin,(7.4.1.0.0) -tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine,
Lometrexol, Dexrazoxan, Methioninase, 2'-cyan-2'-desoxy-N4-palmitoyl-1-Lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1
B-D-Arabinofuranosylcytosin und 3-Aminopyridin-2-carboxaldehyd- thiosemicarbazon. Die „antiproliferativen Mittel" beinhalten auch andere monoklonale Antikörper gegen Wachstumsfaktoren als bereits unter den „Angiogenese-Hemmem" angeführt wurden, wie Trastuzumab, sowieB-D-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative agents" also include other monoclonal antibodies against growth factors than those already mentioned among the "angiogenesis inhibitors", such as trastuzumab, as well as
Tumorsuppressorgene, wie p53, die über rekombinanten virusvermittelten Gentransfer abgegeben werden können (siehe z.B. US-Patent Nr. 6,069,134).Tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, e.g., U.S. Patent No. 6,069,134).
Insbesondere bevorzugt ist die Verwendung der erfindungsgemäßenEspecially preferred is the use of the invention
Verbindung zur Behandlung und Prophylaxe von Tumorerkrankungen.Compound for the treatment and prophylaxis of tumor diseases.
Der Tumor ist vorzugsweise ausgewählt aus der Gruppe der Tumoren desThe tumor is preferably selected from the group of tumors of the
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.Squamous epithelium, bladder, stomach, kidneys, head and neck, esophagus, cervix, thyroid gland, intestine, Liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx and / or lungs.
Der Tumor ist weiterhin vorzugsweise ausgewählt aus der GruppeThe tumor is furthermore preferably selected from the group
Lungenadenokarzinom, kleinzellige Lungenkarzinome, Bauchspeichel¬ drüsenkrebs, Glioblastome, Kolonkarzinom und Brustkarzinom.Lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.
Weiterhin bevorzugt ist die Verwendung zur Behandlung eines Tumors des Blut- und Immunsystems, vorzugsweise zur Behandlung einesFurther preferred is the use for the treatment of a tumor of the blood and immune system, preferably for the treatment of a
Tumors ausgewählt aus der Gruppe der akuten myelotischen Leukämie, der chronischen myelotischen Leukämie, akuten lymphatischen Leukämie und/oder chronischen lymphatischen Leukämie.Tumors selected from the group of acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia and / or chronic lymphocytic leukemia.
Die Erfindung umfasst auch ein Verfahren zur Behandlung einesThe invention also includes a method for treating a
Patienten, der ein Neoplasma, wie einen Krebs, hat, durch VerabreichungPatients who have a neoplasm, such as a cancer, by administration
a) einer oder mehrerer der Verbindung der Formela) one or more of the compound of the formula
b) und einer oder mehrerer der Verbindungen der Formel VI:b) and one or more of the compounds of the formula VI:
worin Y' und Z' jeweils unabhängig voneinander O oder N bedeuten, R7 und R9 jeweils unabhängig voneinander H, OH, Halogen, OCI-10-Alkyl, OCF3, NO2 oder NH2 bedeuten, p eine ganze Zahl zwischen 2 und 6, jeweils einschließlich, bedeutet und R6 und R8 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 7 and R 9 are each independently H, OH, halogen, OCI-10-alkyl, OCF 3 , NO 2 or NH 2 , p is an integer between 2 and 6 each including, and R 6 and R 8 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 VI und anderer Pentamedin-Analoga führt zu einer synergistischen Wirkung bei der Hemmung von Neoplasien.The combination of the compounds of the formula I with the compounds of the formula VI and other pentamedin analogs leads to a synergistic effect in the inhibition of neoplasms.
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. It has recently been described that pentamidine is a potent inhibitor of PRL1, -2 and 3 phosphatases (Pathak et al., 2002) and tyrosine phosphatases, and their Overexpression is associated with neoplastic malignant tumors in humans. 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.
Unsere beigefügten Experimente zeigen, dass:Our attached experiments show that:
- sowohl Pentamidin als auch die Verbindungen der Formel I Zellen im G2/M-Zellzyklus aufhalten.- Both pentamidine and the compounds of the formula I cells in the G2 / M cell cycle stop.
- die Kombination von Pentamidin und Verbindungen der Formel I additive bis synergistische Wirkungen auf die Zeilproliferation haben.the combination of pentamidine and compounds of formula I have additive to synergistic effects on cell proliferation.
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 (e.g., G-3):
(G-1)(G-1)
(G-3)(G-3)
Jede Amidineinheit kann unabhängig voneineander durch eine der Einheiten ersetzt werden, die vorstehend für R8 und R9 definiert sind. Wie im Fall der Benzimidazole und Pentamidine, eignen sich auch Salze von Stilbamidin, Hydroxystilbamidin und ihren Indolderivaten in dem erfindungsgemäßen Verfahren. Bevorzugte Salze umfassen zum BeispielEach amidine moiety may be independently replaced by one of the moieties defined above for R 8 and R 9 . As in the case of benzimidazoles and pentamidines, salts of stilbamidine, hydroxystilbamidine and their indole derivatives are also useful in the process of the present invention. Preferred salts include, for example
Dihydrochlorid- und Methansulfonatsalze.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- amidinophenyljfuran, 2,5-Bis-[4-amidinophenyl]furan-bis-amidoxim, 2,5-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 U.S. Patent Application Publ. US 2002/0019437 A1, each of which is incorporated by reference in its entirety. 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-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)-dibenzo- thiophen, 3,7-Diaminodibenzothiophen, 3,7-Dibromdibenzothiophen, 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, 4,4'-Dibrom-2,2'- dinitrobiphenyl, 2-Methoxy-2'-nitro-4,4'-dibrombiphenyl, 2-Methoxy-2'- amino-4,4'-dibrombiphenyl, 3,7-Dibromdibenzofuran, 3,7-Dicyano- dibenzofuran, 2,5-Bis-(5-amidino-2-benzimidazolyl)pyrrol, 2,5-Bis-[5-(2- imidazolinyl)-2-benzimidazolyl]pyrrol, 2,6-Bis-[5-(2-imidazolinyl)-2- benzimidazolyljpyridin, 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-benzimida- zoyl)pyridin, 2,6-Bis-[5-(1 ,4,5,6-tetrahydro-2-pyrimidinyl)-2- benzimidazolyljpyridin, 2,5-Bis-(5-amidino-2-benzimidazolyl)furan, 2,5-Bis-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-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'-dibromo-2,2'-dinitrobiphenyl, 2-methoxy-2'-nitro-4 , 4'-dibromobiphenyl, 2-methoxy-2'-amino-4,4'-dibromobiphenyl, 3,7-dibromodibenzofuran, 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-benzimi dzoyl) pyridine, 2,6-bis [5- (1, 4,5,6-tetrahydro-2-pyrimidinyl) -2-benzimidazolyl] pyridine, 2,5-bis (5-amidino-2-benzimidazolyl) furan, 2,5-bis-
[5-(2-imidazolinyl)-2-benzimidazolyl]furan, 2,5-Bis-(5-N-isopropylamidino-[5- (2-imidazolinyl) -2-benzimidazolyl] furan, 2,5-bis (5-N-isopropylamido)
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-1 H-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-[2-2-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-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-
(imidzaolinyl)phenyl]-3,4-bis-(methoxymethy!)furan, 2,5-Bis-[4-N-(dimethyl- aminoethyl)guanyl]-phenylfuran, 2,5-Bis-{4-[(N-2-hydroxyethyl)guanyl]- phenyljfuran, 2,5-Bis-[4-N-(cyclopropy!guanyl)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-(imidazolinyl) phenyl] -3,4-bis (methoxymethyl) furan, 2,5-bis [4-N- (dimethylaminoethyl) guanyl] phenylfuran, 2,5-bis- {4 - [( N-2-hydroxyethyl) guanyl] - phenyljfuran, 2,5-bis- [4-N- (cyclopropyl guanyl) 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-benzimida- zolyl]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]-[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-butadiene, 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-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-butene, 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,
2l4-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)- benzimidazoyl]furan, 2,5-Bis-[2-(5-N-cyclopentylamidino)-benzimida- zoyl]furan, 2,5-Bis[2-(5-amidino)benzimidazoyl]pyrrol, 2,5-Bis-[2-{5-(2- 5 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-(5-2 l of 4-bis (4-imidazolin-2-yl) pyrimidine, 2,4-bis - [(tetrahydropyrimidinyl-2-yl) phenyl] pyrimidine, 2- (4- [Ni-propylguanyl] phenyl) -4- (2-methoxy-4- [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- (2-5-imidazolino)} benzimidazoyl] pyrrole, 2,5-bis [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-
10 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, 4,4'-Bis-[2-(5-N-isopropylamidino)benzimidazoyl]-1 ,2-diphenyl-10 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, 4,4'-bis [2- (5-N-isopropylamidino) benzimidazoyl] -1,2-diphenyl-
* c ethan, 4,4'-Bis-[2-(5-N-cyclopentylamidino)benzimidazoyl]-2,5-diphenyl- furan, 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]fluor, 2,5-Bis-[4-(3-(N-morpholinopropyl)- carbamoyl)phenyl]furan, 2,5-Bis-[4-(2-N,N- * c ethane, 4,4'-bis [2- (5-N-cyclopentylamidino) benzimidazoyl] -2,5-diphenyl-furan, 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- (3- (N-morpholinopropyl) -carbamoyl) phenyl] furan, 2,5-bis- [4- (2-N, N-
20 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-[3-20 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-
25 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-25 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-
OQ 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- OQ 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-
35 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.35 fluoro) phenoxycarbonyl) amidinophenyl] furan. Methods for preparing any of the above compounds are described in US Pat. 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 Publ. 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 analogue thereof.
Sieben Pentamidin-Analoga sind nachstehend gezeigt.Seven pentamidine analogs are shown below.
Die erfindungsgemäßen Kombinationen von Verbindungen der Formel I und Formel VI 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 VI, Pentamidin, seine Analoga und /der seiner Metaboliten ist ebenfalls Gegenstand der Erfindung.The combinations of compounds of the formula I and formula VI 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 the kinesin ATPase Eg5 / KSP with the compounds of the formula VI, pentamidine, its analogues and / or its metabolites is likewise provided by 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 (VI) in Kombination mit einem antiproliferativen Mittel. Geeignete antiproliferative Mittel umfassen die in Tabelle 1 bereitgestellten.In another aspect, the invention includes a method for treating a patient having a neoplasm such as a cancer by administering a compound of the formula (I) and (VI) 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 anAbove 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
Kieselgel und/oder durch Kristallisation. Rf-Werte an Kieselgel; Laufmittel:Silica gel and / or by crystallization. Rf values on silica gel; Eluent:
Ethylacetat/Methanol 9:1.Ethyl acetate / methanol 9: 1.
Massenspektrometrie (MS): El (Eletronenstoß-Ionisation) M+ FAB (Fast Atom Bombardment) (M+H)+ ESI (Electrospray lonization) (M+H)+ Mass spectrometry (MS): El (electron impact ionization) M + FAB (Fast Atom Bombardment) (M + H) + ESI (Electrospray Ionization) (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
a. Umsetzung in Gegenwart von Trifluoressigsäure (TFA)a. Reaction in the presence of trifluoroacetic acid (TFA)
Beispiel 2Example 2
4-Trifluormethylanilin (145 mg, 0.9 mmol) wird in 1 ,5 ml Acetonitril gelöst und mit TFA versetzt. 1 ,4-Dioxen (76.1 mg, 0.9 mmol) und Benzaldehyd (0.09 ml_, 0.9 mmol) werden in 1 ,5ml ACN vorgelegt, dann das 4- Trifluormethylanilin-TFA-Salz in Acetonitril schnell bei Raumtemperatur zugegeben. Das Reaktionsgemisch wird über Nacht bei RT gerührt. Das Lösungsmittel wird entfernt. Die Aufreinigung erfolgt durch Chromatographie. Die beiden enthaltenen Isomere können getrennt werden.Dissolve 4-trifluoromethylaniline (145 mg, 0.9 mmol) in 1.5 ml of acetonitrile and add TFA. 1,4-dioxene (76.1 mg, 0.9 mmol) and benzaldehyde (0.09 ml, 0.9 mmol) are initially charged in 1.5 ml ACN, then the 4-trifluoromethylaniline TFA salt in acetonitrile is added rapidly at room temperature. The reaction mixture is stirred overnight at RT. The solvent is removed. The purification is carried out by Chromatography. The two isomers contained can be separated.
Die beiden racemischen Gemische können durch chirale HPLC in die entsprechenden Enantiomere aufgetrennt werden. [M++1] = 336The two racemic mixtures can be separated by chiral HPLC into the corresponding enantiomers. [M + 1] = 336
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:
Chiralchiral
I32I32
Chiralchiral
1195 1195
Chiralchiral
Chiralchiral
Chiralchiral
Chiral chiral
Chiralchiral
I226 I226
Chiral chiral
Chiralchiral
I232I232
Beispeil A: Assay I Example A: Assay I
Die Bestimmung der Wirksamkeit der erfindungsgemäßen Verbindungen kann z. B. über die Eg5-ATPase Aktivität, die über eine enzymatische Regeneration des Produkts ADP zur ATP mittels Pyruvatkinase (PK) und anschließender Kopplung an eine NADH-abhängige Laktat- Dehydrogenase (LDH) Reaktion gemessen wird, erfolgen. Durch die Kopplung an die NADH-abhängige LDH kann die Reaktion über dieThe determination of the effectiveness of the compounds of the invention may, for. B. via the Eg5-ATPase activity, which is measured via an enzymatic regeneration of the product ADP to ATP by pyruvate kinase (PK) and subsequent coupling to an NADH-dependent lactate dehydrogenase (LDH) reaction, take place. By coupling to the NADH-dependent LDH, the reaction across the
10 Änderung der Extinktion bei 340 nm verfolgt werden. Die Regeneration des ATP gewhärleistet gleichzeitig, dass die Substratkonzentration konstant bleibt. Die Extinktionsänderung pro Zeiteinheit werden graphisch analysiert und eine lineare Regression im vusuell linearen Bereich der10 change in absorbance at 340 nm are tracked. The regeneration of the ATP simultaneously ensures that the substrate concentration remains constant. The absorbance change per unit time is graphically analyzed and a linear regression in the vusually linear region of the
^ c Reaktion durchgeführt.^ c reaction performed.
Beispiel B: Assay IlExample B: Assay II
Die Kombination aus dem Antiprotozoikum Pentamidin und denThe combination of the antiprotozoic pentamidine and the
2020
Inhibitoren der Kinesin-ATPase Eg5/KSP führt zu verstärkter hemmenderInhibitors of kinesin ATPase Eg5 / KSP leads to increased inhibitory
Wirkungen bei Zellproliferationstests mit der Kolon-Karzinom-Zelllinie HCT116.Effects on cell proliferation assays with the colon carcinoma cell line HCT116.
Eg5-Inhibitoren stören die ATPase-Aktivität und hemmen den Verlauf des 25 Zellzyklus aufgrund eines Fehlers bei der Trennung der Spindelpole.Eg5 inhibitors interfere with ATPase activity and inhibit the progression of the cell cycle due to a spindle pole separation error.
Die Bestimmung der Wirksamkeit der erfindungsgemäßen Verbindungen 30 der Formel I in Kombination mit Verbindungen der Formel VI und/oder Arzneimitteln der Tabelle I kann in Kombinations-Assays wie folgt gezeigt werden:The determination of the activity of the compounds 30 of the formula I according to the invention in combination with compounds of the formula VI and / or medicaments of the table I can be shown in combination assays as follows:
103 bis 104 Zellen einer definierten Zeil-Linie (HCT116, CoIo 205, MDA- 3510 3 to 10 4 cells of a defined cell line (HCT116, CoIo 205, MDA-35
MB 231 , etc.) werden pro Vertiefung in einer 96-well Mikrotiterplatte ausgesät und über Nacht unter Standardbedingungen kultiviert. Für die Substanzen der zu testenden Kombination wurden 10-50 mM Stocklösungen in DMSO vorbereitet. Verdünnungsreihen (i.d.R. 3-fach Verdünnungsschritte) der einzelnen Substanzen wurden in Form einer Pipettierschemas (s. Schema unten), unter Konstanthaltung einer DMSO Endkonzentration von 0,5 % (v/v) miteinander kombiniert. Die Zellen wurden am nächsten Morgen mit den Substanzgemischen versetzt und für weitere 48 Stunden unter Kulturbedingungen inkubiert. Am Ende der Kultivierung erfolgte eine Kristallviolett-Färbung der Zellen. Nach Extraktion des Kristallviolett aus den fixierten Zellen wurde die Absorption bei 550 nm spektralphotometrisch gemessen. Sie kann als quantitatives Maß für die vorhandenen adhärenten Zellen herangezogen werden. MB 231, etc.) are per well in a 96-well microtiter plate seeded and cultured overnight under standard conditions. For the substances of the combination to be tested, 10-50 mM stock solutions in DMSO were prepared. Dilution series (usually 3-fold dilution steps) of the individual substances were combined in the form of a pipetting scheme (see scheme below) while maintaining a final DMSO concentration of 0.5% (v / v). The cells were mixed with the substance mixtures the next morning and incubated for a further 48 hours under culture conditions. At the end of the cultivation, a crystal violet staining of the cells was performed. After extracting the crystal violet from the fixed cells, absorbance at 550 nm was measured spectrophotometrically. It can be used as a quantitative measure of the existing adherent cells.
Schemascheme
Verbindunαen der Formel ICompounds of the formula I
4 5 6 7 8 9 10 11 124 5 6 7 8 9 10 11 12
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 Salz¬ säure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes In¬ jektionsglas 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 3 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and closed under sterile conditions , Each injection glass 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. Beispiel E: LösungA 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. Example E: Solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I1 9,38 g NaH2PO4 • 2 H2O1 28,48 g Na2HPO4 • 12 H2O und 0,1 g Benzalkonium- chlorid 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 is prepared from 1 g of an active compound of the formula I 1 9.38 g of NaH 2 PO 4 .2H 2 O 1 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.
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 Kar- toffelstärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicherA mixture of 1 kg of active compound 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 customary
Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.Way pressed 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 Hartgelatine- kapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält. Beispiel J: Ampullen2 kg of active ingredient 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. Example 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 Bedingun¬ gen 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
1. Verbindungen der Formel I1. Compounds of the formula I
worin wherein
W CH oder N,W CH or N,
R1, R2, R3 unabhängig voneinander H, A, Aryl, Heteroaryl, HaI, - (CY2)n-SA, -(CY2)n-SCF3) -(CY2)n-SCN, -(CY2)n-CF3, - (CY2)π-OCF3, Cycloalkyl, -SCH3, -SCN, -CF3, -OCF3, - OA, -(CY2)π-OH, -(CY2)H-CO2R, -(CY2)n-CN, -(CY2)π-Hal, -(CY2)H-NR2, (CY2)H-OA, (CY2)n-OCOA, -SCF3, (CY2)n- CONR2, -(CY2)H-NHCOA, -(CY2)n-NHSO2AR 1 , R 2 , R 3 independently of one another are H, A, aryl, heteroaryl, Hal, - (CY 2 ) n -SA, - (CY 2 ) n-SCF 3) - (CY 2 ) n-SCN, - ( CY 2 ) n -CF 3 , - (CY 2 ) π -OCF 3 , cycloalkyl, -SCH 3 , -SCN, -CF 3 , -OCF 3 , - OA, - (CY 2 ) π-OH, - (CY 2 ) H- CO 2 R, - (CY 2 ) n -CN, - (CY 2 ) π -Hal, - (CY 2 ) H -NR 2 , (CY 2 ) H -OA, (CY 2 ) n- OCOA, -SCF 3 , (CY 2 ) n -CONR 2 , - (CY 2 ) H -NHCOA, - (CY 2 ) n -NHSO 2 A
H, A, HaIH, A, HaI
A Alkyl oder CycloalkylA is alkyl or cycloalkyl
HaI F, Cl, Br oder IHaI F, Cl, Br or I
R H oder A, bei gemimalen Resten R zusammen auch -R H or A, together with gem residues R -
(CH2)5-, -(CH2)4- oder -(CH2)2-NR-(CH2)2,(CH 2 ) 5 -, - (CH 2 ) 4 - or - (CH 2 ) 2 -NR- (CH 2 ) 2 ,
R4, R5 zusammen -X (CH2)2X-, -X (CR2)X-, -X CH(CH2OR)X-,R 4 , R 5 together are -X (CH 2 ) 2 X- , -X (CR 2 ) X-, -X CH (CH 2 OR) X-,
-XCH(CH2OR)CR2X-,-X CR2CH(CH2OR) X-, - XCH(CH2NR2)X-, -XCH(CH2NR2)CR2X-, -X CR2CH(CH2NR2)X-, -OCH2CH2O-, -X(CH2)2X-, --XCH (CH 2 OR) CR 2 X-, -X CR 2 CH (CH 2 OR) X-, -XCH (CH 2 NR 2 ) X-, -XCH (CH 2 NR 2 ) CR 2 X-, X CR 2 CH (CH 2 NR 2 ) X-, -OCH 2 CH 2 O-, -X (CH 2 ) 2 X-, -
XCHQCR2X, -XCR2CHQX-,XCHQCR 2 X, -XCR 2 CHQX-,
-X CR2)X-, -X CH(CH2OR)X-, -X CH(CH2OR)CR2X-,-XCR 2 ) X-, -X CH (CH 2 OR) X-, -X CH (CH 2 OR) CR 2 X-,
-X CH(CH2NR2)X-, -X CH(CH2NR2)CR2X-, -OCH2CH2O-, -X-C-X-,-X CH (CH 2 NR 2 ) X-, -X CH (CH 2 NR 2 ) CR 2 X-, -OCH 2 CH 2 O-, -XCX-,
XX
Q CH2HaI, CHO, COR3, CH2Ra , CH2OCOR3, CH2NCOR1, CH2N(R1)2, CH2OR1, CH2OCON(R1)2, CH2OCOOR1, CH2NHCON(R1)2, CH2NHCOOR1,Q CH 2 Hal, CHO, COR 3 , CH 2 R a , CH 2 OCOR 3 , CH 2 NCOR 1 , CH 2 N (R 1 ) 2 , CH 2 OR 1 , CH 2 OCON (R 1 ) 2 , CH 2 OCOOR 1 , CH 2 NHCON (R 1 ) 2 , CH 2 NHCOOR 1 ,
OR, NHR2, NR2 OR, NHR2, NR2, NR(CH2)nAryl, NR(CH2)nOR, COOR, N-Pyrrolidon-Rest, OCOR, NR(CH2)nNR2, N[(CH2)nNR2]CO(CH2)nAryl, OR, NHR 2 , NR 2 OR, NHR 2 , NR 2 , NR (CH 2 ) n aryl, NR (CH 2 ) n OR, COOR, N-pyrrolidone radical, OCOR, NR (CH 2 ) n NR 2 , N [(CH 2 ) n NR 2 ] CO (CH 2 ) n aryl,
NR(CHz)nNCOOR, X(CH2)nX(CH2)nXR, NR(CH2)nX(CH2)nOH, NR(CH2)nO(CH2)nOH, (CH2JnCOOR, 0(CO)NR(CH2) OR, O(CO)(CH2)nNR2, NR(CHz)nNR2, N[(CH2)nNR2]CO(CH2)nAryl,NR (CHz) n NCOOR, X (CH 2 ) n X (CH 2 ) n XR, NR (CH 2 ) n X (CH 2 ) n OH, NR (CH 2 ) n O (CH 2 ) n OH, ( CH 2 J n COOR, O (CO) NR (CH 2 ) OR, O (CO) (CH 2 ) n NR 2 , NR (CHz) n NR 2 , N [(CH 2 ) n NR 2 ] CO (CH 2 ) n aryl,
N[(CHz)nXR]CO(CH2)nAryl, N[(CH2)nXR]CO(CH2)nHeteroaryl, N[(CH2)nNR2]CO(CH2)nHeteroaryl, N[(CH2)nNR2]CO(CH2)nR1, N(R)(CH2)nN(R)COOR, XCOO(CH2)nNR2, OSO2A, OSO2CF3, OSO2Ar,N [(CHz) n XR] CO (CH 2 ) n aryl, N [(CH 2 ) n XR] CO (CH 2 ) n heteroaryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n heteroaryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n R 1 , N (R) (CH 2 ) n N (R) COOR, XCOO (CH 2 ) n NR 2 , OSO 2 A, OSO 2 CF 3 , OSO 2 Ar,
OCONR2, OCH2(CHz)nNR2 OCONR 2 , OCH 2 (CHz) n NR 2
Z CH2, X, CHCONH2, CH(CHz)nNRCOOR, CHNRCOOR, NCO, CH(CH2)nCOOR, NCOOR, CH(CH2)nOH,Z is CH 2 , X, CHCONH 2 , CH (CHz) n NRCOOR, CHNRCOOR, NCO, CH (CH 2 ) n COOR, NCOOR, CH (CH 2 ) n OH,
N(CHz)nOH, CHNH2, CH(CHz)nNR2, CH(CH2)nNR2,N (CHz) n OH, CHNH 2, CH (CHZ) n NR 2, CH (CH 2) n NR 2,
C(OH)R, CHNCOR, CH(CH2)nAryl,C (OH) R, CHNCOR, CH (CH 2 ) n aryl,
CH(CH2)nHeteroaryl, CH(CHz)nR1, N(CHz)nCOOR, CH(CH2)nX(CH2)nAryl, CH(CH2)nX(CH2)nHeteroaryl,CH (CH 2 ) n heteroaryl, CH (CHz) n R 1 , N (CHz) n COOR, CH (CH 2 ) n X (CH 2 ) n aryl, CH (CH 2 ) n X (CH 2 ) n heteroaryl .
N(CHz)nCONR2, XCONR(CHz)nNR2,N (CHz) n CONR 2 , XCONR (CHz) n NR 2 ,
N[(CH2)nXCOOR]CO(CH2)nAryl,N [(CH 2 ) n XCOOR] CO (CH 2 ) n aryl,
N[(CHz)nXR]CO(CH2)nAryl, N[(CH2)nXR]CO(CH2)nXAryl,N [(CHz) n XR] CO (CH 2) n aryl, N [(CH 2) n XR] CO (CH 2) n XAryl,
N[(CH2)nXR]Sθ2(CH2)nAryl, N[(CH2)nNRCOOR]CO(CH2)nAryl,N [(CH 2 ) n XR] SO 2 (CH 2 ) n aryl, N [(CH 2 ) n NRCOOR] CO (CH 2 ) n aryl,
N[(CH2)nNR2]CO(CH2)nAryl,N [(CH 2 ) n NR 2 ] CO (CH 2 ) n aryl,
N[(CH2)nNR2]CO(CH2)nNRAryl,N [(CH 2 ) n NR 2 ] CO (CH 2 ) n NRAryl,
N[(CH2)nNR2]SOz(CH2)nAryl, N[(CH2)nXR]CO(CH2)nHeteroaryl,N [(CH 2 ) n NR 2 ] SO z (CH 2 ) n aryl, N [(CH 2 ) n XR] CO (CH 2 ) n heteroaryl,
N[(CH2)nXR]CO(CH2)nXHeteroaryl, N[(CH2)nXR]Sθ2(CH2)nHeteroaryl, N[(CH2)nNRCOOR]CO(CH2)nHeteroaryl, N[(CH2)nNR2]CO(CH2)nHeteroaryl, N[(CH2)nNR2]CO(CH2)nNRHeteroaryl, N[(CH2)nNR2]SO2(CH2)nHeteroaryl, O(CH2)nNR2, X(CH2)nNR2, NCO(CH2)nNR2,N [(CH 2 ) n XR] CO (CH 2 ) n X heteroaryl, N [(CH 2 ) n XR] SO 2 (CH 2 ) n heteroaryl, N [(CH 2 ) n NRCOOR] CO (CH 2 ) n heteroaryl, N [(CH 2 ) n NR 2 ] CO (CH 2 ) n heteroaryl, N [(CH 2 ) n NR 2] CO (CH 2) n NRHeteroaryl, N [(CH 2) n NR 2] SO 2 (CH 2) n heteroaryl, O (CH 2) n NR 2, X (CH 2) n NR 2, NCO (CH 2 ) n NR 2 ,
X O, S oder NRX O, S or NR
R6 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, - (CY2VCO2R, -(CY2)n-CN oder -(CY2VNR2 substituiertes Aryl oder Heteroaryl,R 6 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, - (CY 2 ) n -OR, -OCOR, - (CY 2 VCO 2 R, - (CY 2 ) n -CN or - (CY 2 VNR 2 substituted aryl or heteroaryl,
R7 (C=O)-R, (C=O)-NR21 (C=O)-OR, H oder AR 7 (C = O) -R, (C = O) -NR 21 (C = O) -OR, H or A
undand
n,m unabhängig voneinander O, 1 , 2, 3, 4, 5, 6 oder 7n, m are independently 0, 1, 2, 3, 4, 5, 6 or 7
bedeuten,mean,
sowie ihre pharmazeutisch verwendbaren Derivate, Solvate,and their pharmaceutically usable derivatives, solvates,
Tautomere, Salze und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.Tautomers, salts and stereoisomers, including mixtures thereof in all ratios.
2. Verbindungen nach Anspruch 1 , worin R1 A, CF3, OCF3, SA, SCN, CH2CN1 -OCOA, HaI, SCF3, t-2. Compounds according to claim 1, wherein R 1 A, CF 3 , OCF 3 , SA, SCN, CH 2 CN 1 -OCOA, Hal, SCF 3 , t-
Butyl, -CH(CH3)CH2CH3, Isopropyl, Ethyl oder MethylButyl, -CH (CH 3 ) CH 2 CH 3 , isopropyl, ethyl or methyl
bedeutet.means.
3. Verbindungen nach Anspruch 1 oder 2, worin R2 F oder H bedeutet3. Compounds according to claim 1 or 2, wherein R 2 is F or H.
bedeutet.means.
4. Verbindungen nach einem oder mehreren der Ansprüche 1-3, worin R3 F oder H4. Compounds according to one or more of claims 1-3, wherein R 3 is F or H
bedeutet.means.
5. Verbindungen nach einem oder mehreren der Ansprüche 1-4, worin5. Compounds according to one or more of claims 1-4, wherein
R4 und R5 zusammen eine der folgenden Gruppen bedeutet:R 4 and R 5 together represent one of the following groups:
-X(CR2)2X- oder -XCR2X- und-X (CR 2 ) 2 X- or -XCR 2 X- and
X und R die in Anspruch 1 angegebene Bedeutung aufweisen.X and R have the meaning given in claim 1.
6. Verbindungen nach einem oder mehreren der Ansprüche 1-5, worin X O bedeutet.6. Compounds according to one or more of claims 1-5, wherein X is O.
7. Verbindungen nach einem oder mehreren der Ansprüche 1-6, worin R5 zusammen mit R4 eine der folgenden Bedeutungen annimmt: worin7. Compounds according to one or more of claims 1-6, wherein R 5 together with R 4 assumes one of the following meanings: wherein
X und R die in Anspruch 1 angegebene Bedeutung aufweisen.X and R have the meaning given in claim 1.
8. Verbindungen nach einem oder mehreren der Ansprüche 1-7, worin8. Compounds according to one or more of claims 1-7, wherein
R6 unsubstituiertes oder einfach oder mehrfach durch HaI, CN, NO2, OH, CF3, OCH(CF3)2, OCOCH3 oder A substituiertes Phenyl, 2-, 3- oder 4-Pyridyl, Pyrimidyl, Furyl oder ThienylR 6 is phenyl which is unsubstituted or mono- or polysubstituted by Hal, CN, NO 2 , OH, CF 3 , OCH (CF 3 ) 2 , OCOCH 3 or A, 2-, 3- or 4-pyridyl, pyrimidyl, furyl or thienyl
bedeutet.means.
9. Verbindungen nach einem oder mehreren der Ansprüche 1-8, worin R6 eine der folgenden Gruppen bedeutet: 9. Compounds according to one or more of claims 1-8, wherein R 6 represents one of the following groups:
10. Verbindungen nach einem oder mehreren der Ansprüche 1-9, worin R7 H bedeutet.10. Compounds according to one or more of claims 1-9, wherein R 7 is H.
11. Verbindungen der Teilformeln IA bis IB: 11. Compounds of sub-formulas IA to IB:
worin R, R1, R2, R3, R6, R7 und X die in Anspruch 1 angegebene Bedeutung aufweisenwherein R, R 1 , R 2 , R 3 , R 6 , R 7 and X have the meaning given in claim 1
undand
RE H, CH2OR oder CH2NR2 R E H, CH 2 OR or CH 2 NR 2
bedeutet.means.
12. Verbindungen der Teilformeln A und B:12. Compounds of Part Formulas A and B:
worin R1, R2, R3, R4, R5, R6, R7 die in Anspruch 1 angegebene Bedeutung aufweisen, sowie deren Racemat oder andere Gemische der Enantiomeren. wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 have the meaning given in claim 1, as well as their racemate or other mixtures of the enantiomers.
13. Verbindungen der Teilformeln 11 bis I43:13. Compounds of sub-formulas 11 to I43:
16 16
Iδa Iδa
137a 137a
14. Verfahren zur Herstellung von Verbindungen der Formel I nach den Ansprüchen 1-13 sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomeren und Stereoisomeren, dadurch gekennzeichnet, daß man eine Verbindung der Formel Il 14. A process for the preparation of compounds of the formula I according to claims 1-13 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, characterized in that a compound of the formula II
worin R1, R2 und R3 die in Anspruch 1 angegebenen Bedeutungen haben,wherein R 1 , R 2 and R 3 have the meanings given in claim 1,
mit einer Verbindung der Formelwith a compound of the formula
worinwherein
R6 die in Anspruch 1 angegebene Bedeutung aufweist,R 6 has the meaning given in claim 1,
undand
mit einer Verbindung der Formel IM, dessen Doppelbindungsisomer (E-Isomer) oder deren Mischungenwith a compound of formula IM, its double bond isomer (E-isomer) or mixtures thereof
worin R4 und R5 die in Anspruch 1 angegebenen Bedeutungen haben,wherein R 4 and R 5 have the meanings given in claim 1,
umsetzt und gegebenenfalls einen Rest R7 der H bedeutet in einen Rest R7 der eine andere Bedeutung als H aufweist, umwandeltimplements and optionally a radical R 7, the H is in a radical R 7 which has a meaning other than H converted
und/oder gegebenenfalls eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.and / or optionally converts a base or acid of the formula I into one of its salts.
15. Verfahren nach Anspruch 14, dadurch gekennzeichnet, dass die Umsetzung in Gegenwart einer Protonensäure oder Lewis-Säure stattfindet.15. The method according to claim 14, characterized in that the reaction takes place in the presence of a protic acid or Lewis acid.
16. Verfahren nach Anspruch 14 oder 15, dadurch gekennzeichnet, dass die Umsetzung in Gegenwart von Trifluoressgsäure, Hexafluorisopropanol, Bismut (III) Chlorid, Ytterbium(lll)triflat,16. The method according to claim 14 or 15, characterized in that the reaction in the presence of trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium (III) triflate,
Scandium (III) triflat oder Cerammonium (IV)nitrat stattfindet.Scandium (III) triflate or cerium ammonium (IV) nitrate.
17. Arzneimittel, enthaltend mindestens eine Verbindung der Formel I nach Anspruch 1 bis 13 und/oder ihre pharmazeutisch verwendbaren17. A pharmaceutical composition containing at least one compound of the formula I according to claim 1 to 13 and / or their pharmaceutically acceptable
Derivate, Salze, Solvate, Tautomere und Stereoisomeren, einschließlich deren Mischungen in allen Verhältnissen, sowie gegebenenfalls Träger- und/oder Hilfsstoffe.Derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
18. Mischung enthalten eine oder mehrere Verbindungen der Formel I sowie Menge einer oder mehrerer Verbindungen der Formel VI, deren Analoga und/oder seiner Metaboliten ,18. Mixture comprise one or more compounds of the formula I and also one or more compounds of the formula VI, their analogues and / or their metabolites,
woπn embedded image in which
Y' und Z' jeweils unabhängig voneinander O oder N bedeuten, R7 und R9 jeweils unabhängig voneinander H, OH, Halogen, OC1-10- Alkyl, OCF3, NO2 oder NH2 bedeuten, p eine ganze Zahl zwischen 2 und 6, jeweils einschließlich, bedeutet und R6 und R8 jeweils unabhängig voneinander an der meta- oder para-Position stehen und aus der Gruppe:Y 'and Z' are each independently of the other O or N, R 7 and R 9 are each independently H, OH, halogen, OC 1-10 alkyl, OCF 3 , NO 2 or NH 2 , p is an integer between 2 and 6 each including, and R 6 and R 8 are each independently at the meta or para position and from the group:
0 /; NH NOH0 /; NH NOH
//%//%
NH2 NH2 NTNH 2 NH 2 NT
HH
ausgewählt sind. 0are selected. 0
19. Verwendung nach Anspruch 18, wobei als Verbindung der Formel VI Pentamidin oder seine Salze verwendet werden.19. Use according to claim 18, wherein pentamidine or its salts are used as the compound of formula VI.
5 20. Verwendung von Verbindungen nach Anspruch 1 bis 13 sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomeren und Stereoisomeren, einschließlich deren Mischungen in allen Verhältnissen oder der Mischung nach Anspruch 18, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, die durch die 05 20. Use of compounds according to claim 1 to 13 and their pharmaceutically acceptable derivatives, salts, solvates, tautomers and stereoisomers, including mixtures thereof in all proportions or the mixture according to claim 18, for the manufacture of a medicament for the treatment of diseases by the 0
Hemmung, Regulierung und/oder Modulation der mitotischen Motor- Proteins Eg5 beeinflusst werden können.Inhibition, regulation and / or modulation of the mitotic motor protein Eg5 can be influenced.
21. Verwendung von Verbindung nach Anspruch 1 bis 13 oder der ^ Mischung nach Anspruch 18, zur Herstellung eines Arzneimittels zur21. Use of compound according to claim 1 to 13 or the mixture according to claim 18, for the preparation of a medicament for
Behandlung und Prophylaxe von Krebskrankheiten. Treatment and prophylaxis of cancer diseases.
22. Verwendung nach Anspruch 21 , wobei die Krebskrankheiten mit einem Tumor aus der Gruppe der Tumoren des Plattenepithel, der22. Use according to claim 21, wherein the cancerous diseases with a tumor from the group of tumors of the squamous epithelium, the
Blasen, des Magens, der Nieren, von Kopf und Hals, desBlisters, stomach, kidneys, head and neck,
55
Ösophagus, des Gebärmutterhals, der Schilddrüse, des Darm, derEsophagus, cervix, thyroid, intestine, the
Leber, des Gehirns, der Prostata, des Urogenitaltrakts, des lymphatischen Systems, des Magens, des Kehlkopf und/oder der Lunge einhergehen. 10Liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx and / or lungs. 10
23. Verwendung nach Anspruch 22, wobei der Tumor aus der Gruppe Monozytenleukämie, Lungenadenokarzinom, kleinzellige Lungenkarzinome, Bauchspeicheldrüsenkrebs, Glioblastome und23. Use according to claim 22, wherein the tumor is selected from the group of monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and
15 Brustkarzinom und Kolokarzinom stammt. 15 breast carcinoma and colon cancer originated.
24. Verwendung nach Anspruch 21 , wobei die zu behandelnde Krebs- Krankheit ein Tumor des Blut- und Immunsystems ist.24. Use according to claim 21, wherein the cancer disease to be treated is a tumor of the blood and immune system.
2020
25. Verwendung nach Anspruch 24, wobei der Tumor aus der Gruppe der akuten myeloischen Leukämie, der chronischen myelotischen Leukämie, akuten lymphatischen Leukämie und/oder chronischen lymphatischen Leukämie stammt. 25Use according to claim 24 wherein the tumor is from the group of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and / or chronic lymphocytic leukemia. 25
26. Verwendung von Verbindungen der Formel I gemäß Anspruch 1 bis 13 und/oder ihrer physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zur Behandlung von Tumoren in26. Use of compounds of the formula I according to claim 1 to 13 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of tumors in
O0 Kombination mit einer therapeutisch wirksamen Menge einer oder mehrerer Verbindungen der Formel VI, deren Analoga und/oder seiner Metaboliten, O0 combination with a therapeutically effective amount of one or more compounds of formula VI, their analogues and / or their metabolites,
35 35
worinwherein
Y' und Z1 jeweils unabhängig voneinander O oder N bedeuten, R7' und R9' jeweils unabhängig voneinander H, OH, Halogen, OC1-10- Alkyl, OCF3, NO2 oder NH2 bedeuten, p eine ganze Zahl zwischen 2 und 6, jeweils einschließlich, bedeutet und R6' und R8 jeweils unabhängig voneinander an der meta- oder para-Position stehen und aus der Gruppe:Y 'and Z 1 are each independently of one another O or N, R 7' and R 9 'are each independently H, OH, halogen, OC 1-10 alkyl, OCF 3 , NO 2 or NH 2 , p is an integer between 2 and 6, inclusive, and R 6 ' and R 8 are each independently at the meta or para position and from the group:
ausgewählt sind, wobei die Verbindungen der Formel I und die Verbindungen der Formel VI, ihre Analoga und/oder ihre Metaboliten gleichzeitig oder innerhalb von 14 Tagen voneinander in Mengen verabreicht werden, die aus¬ reichen, um das Wachstum eines Tumors oder von anderen hyperproliferativen Zellen zu hemmen.wherein the compounds of formula I and the compounds of formula VI, their analogs and / or their metabolites are administered simultaneously or within 14 days of each other in amounts sufficient to promote the growth of a tumor or of other hyperproliferative cells to inhibit.
27. Verwendung nach Anspruch 26, wobei als Verbindung der Formel VI Pentamidin oder seine Salze verwendet werden. 27. Use according to claim 26, wherein pentamidine or its salts are used as the compound of formula VI.
28. Verwendung von Verbindungen der Formel I gemäß Anspruch 1 bis 13 und/oder ihrer physiologisch unbedenklichen Salze und Solvate zur 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) Androgenrezeptor- modulator, 3) Retinoidrezeptormodulator, 4) Zytotoxikum, 5) antiproliferatives Mittel, 6) Prenyl-Proteintransferasehemmer, 7) HMG-CoA-Reduktase-Hemmer, 8) HIV-Protease-Hemmer, 9)28. Use of compounds of formula I according to claim 1 to 13 and / or their physiologically acceptable salts and solvates for the manufacture 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 protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9)
Reverse-Transkriptase-Hemmer sowie 10) weiterer Angiogenese- Hemmer verabreicht wird. Reverse transcriptase inhibitors and 10) other angiogenesis inhibitors is administered.
EP05750999A 2004-06-30 2005-06-03 Tetrahydroquinolines Withdrawn EP1778694A1 (en)

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