EP1747214A2 - Dihydrobenzothiophenes - Google Patents

Dihydrobenzothiophenes

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Publication number
EP1747214A2
EP1747214A2 EP05751906A EP05751906A EP1747214A2 EP 1747214 A2 EP1747214 A2 EP 1747214A2 EP 05751906 A EP05751906 A EP 05751906A EP 05751906 A EP05751906 A EP 05751906A EP 1747214 A2 EP1747214 A2 EP 1747214A2
Authority
EP
European Patent Office
Prior art keywords
methyl
compounds
formula
phenyl
bis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05751906A
Other languages
German (de)
French (fr)
Inventor
Dirk Finsinger
Soheila Anzali
Matthias Frech
Johannes Gleitz
Nina Heiss
Bjoern Hock
Kai Schiemann
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
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Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1747214A2 publication Critical patent/EP1747214A2/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the present invention further relates to compounds of the formula I for the prophylaxis and treatment of diseases in which the inhibition, regulation and / or modulation of the mitotic motor proteins, in particular the mitotic motor protein Eg5, plays a role
  • the present invention relates to compounds of the formula I which preferably inhibit one or more mitotic motor proteins,
  • compositions containing these compounds regulate and / or modulate, compositions containing these compounds, and methods of their use for the treatment of diseases and conditions such as angiogenesis, cancer, tumor formation, growth and spread, arteriosclerosis, eye
  • -. diseases choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, wound healing or graft rejection.
  • the compounds according to the invention are particularly suitable for the therapy or prophylaxis of cancerous diseases.
  • various kinesins regulate the formation and dynamics of the spindle apparatus, which is 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 a collapse of the spindle fibers. This results, that the chromosomes can no longer be correctly distributed to the daughter cells. This leads to mitotic arrest and can do so
  • Eg5 was e.g. described in tissue from breast, lung and colon tumors. Since Eg5 has a specific function for mitosis, cells that divide quickly and cells that are not fully differentiated are mainly affected by Eg5 inhibition. In addition, Eg5 regulates only the movement of mitotic microtubules (spindle apparatus) and not that of the cytoskeleton. This is crucial for the side effect profile, e.g. Neuropathies, such as those observed with Taxol, do not occur or only weakly. Therefore, the inhibition of Eg5 by organic molecules is a relevant therapy concept for the treatment of malignant tumors.
  • all solid and non-solid tumors can be treated with the compounds of formula I, e.g. monocyte leukemia, brain, urogenital, lymphatic, gastric, larynx and lung carcinoma, including lung adenocarcinoma and small cell lung carcinoma.
  • Other examples include prostate, pancreatic and breast cancer.
  • Compounds cause a specific inhibition of the mitotic motor proteins, especially Eg5.
  • the compounds according to the invention preferably exhibit an advantageous biological activity which is easily detectable in the assays described, for example, herein.
  • the compounds according to the invention preferably show and bring about an inhibitory effect which is usually documented by IC 50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.
  • effects are those of the present invention
  • the compounds according to the invention are useful in the prophylaxis and / or treatment of diseases which are influenced by inhibition of one or more mitotic motor proteins, in particular Eg5.
  • the present invention therefore relates to the invention
  • the compounds according to the invention have an advantageous effect in a xenograft tumor model.
  • the host or patient can belong to any mammalian species, e.g. B. a primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for treating a human disease.
  • mammalian species e.g. B. a primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for treating a human disease.
  • the sensitivity of a particular cell to treatment with the compounds according to the invention can be determined by testing in vitro.
  • a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to enable the active agents to induce cell death or to inhibit migration, usually between about an hour and a week.
  • Cultured cells from a biopsy sample can be used for in vitro testing. The viable cells remaining after treatment are then counted.
  • a therapeutic dose is sufficient to significantly reduce the unwanted cell population in the target tissue while maintaining the patient's viability. Treatment generally continues until there is a substantial reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no unwanted cells can be detected in the body.
  • the invention relates to compounds of the formula I:
  • R 2 , R 3 independently of one another A, Het, H, -OH, -OA, -OAr, Ar, -O-CO-A, -OS0 3 R 5 , -OSO2R 5 , -OAr 2 R 5 , S0 2 R 5 , shark, COOR 5 , CON (R 5 ) 2) NHS0 2 A, COA, CHO or S0 2 N (R 5 ) 2) - (CH 2 ) 0 -Ar, - (CH 2 ) 0 - cycloalkyl, - (CH 2 ) 0 -OH, - (CH 2 ) oN (R 5 ) 2 , N0 2 , CN, - (CH 2 ) 0 -COOR 5 , - (CH 2 ) o-CON (R 5 ) 2 , - (CH 2 ) 0 -NHCOA, NHCON (R 5 ) 2 , - (CH 2 ) 0 -NHCO
  • R 5 is H or A, in the case of geminal radicals R 5 together also - (CH 2 ) s-, (CH 2 ) 4 - or - (CH 2 ) n -Q- (CH 2 ) n ,
  • A has a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, the unsubstituted or mono-, di- or triple by shark, A, - (CH 2 ) 0 -Ar, - (CH 2 ) 0 -cycloalkyl, - (CH 2 ) 0 -OH, - (CH 2 ) 0 -N (R 5 ) 2 , N ( CN, - (CH 2 ) 0 -COOR 5 , - (CH 2 ) o-CON (R 5 ) 2) - (CH 2 ) 0 -NHCOA, NNHHCCOONN ((RR 55 )) 22 ,, - ((CCHH 22 )) 00 --NNHHSS00 22 A, CHO, COA, S0 2 NH 2 and / or S (0) 0 A may be substituted,
  • a unbranched or branched alkyl having 1 -10 C atoms it being possible for one or more H atoms to be replaced by sharks, in particular F or Ar,
  • the invention also relates to the optically active forms
  • Solvates are e.g. Mono- or dihydrates or
  • compositions are e.g. the salts of the compounds according to the invention and also so-called prodrug compounds.
  • Prodrug derivatives are understood with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention.
  • an effective amount means the amount of a drug or active pharmaceutical ingredient that elicits a biological or medical response in a tissue, system, animal or human, e.g. is sought or sought by a researcher or medical professional.
  • therapeutically effective amount means an amount that, compared to a corresponding subject, this
  • terapéuticaally effective amount also includes the amounts that are effective in increasing normal physiological function.
  • the invention also relates to the use of mixtures of the compounds of the formula I, e.g. Mixtures of two diastereomers e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.
  • the invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula according to the patent claims and their pharmaceutically usable derivatives, salts, solvates and stereoisomers, characterized in that a compound of the formula II
  • R 2 , R and R 4 have the meanings given in claim 1 and X 1 can be a leaving group and preferably shark or a reactive modified OH group, in particular tosyl or mesyl, with a compound of the formula
  • R 1 has the meanings given in claim 1,
  • R) 1, ⁇ R-) 2, o R3, D R4 and q have the meanings given in claim 1, is converted into the free acid by hydrolysis and this is then converted into the corresponding formula V by customary methods
  • L shark or a reactive modified OH group such as tiflate, nonaflate, tosylate, mesylate or benzenesulfonate, but especially tosylate or mesylate and R 1 , R 2 , R 3 , R 4 and q have the meanings given in claim 1 ,
  • the compound of formula V is then in the presence of a suitable catalyst, such as. B. a Friedel craft catalyst, in particular AICI 3 to formula IA
  • R 1 , R 2 , R 3 , R 4 and q have the meanings given in Claim 1.
  • the compounds of the formula IA1 are particularly preferred:
  • R 1 , R 2 , X, Y 1 and n have the meaning given above and R 1 is preferably methyl.
  • Alkylation reagents such as e.g. iodoalkane,
  • the corresponding tertiary alcohols which are likewise an object of the invention, are preferably obtained from the reaction of the compounds of the formula I in which R 4 is O with the organometallic reagents mentioned. These are particularly preferably the compounds of the formulas A, B, C and D.
  • the compounds of the formula I, IA, VIA and VIB are also preferably used as starting materials for an oxidation of the sulfur atom. This is preferably done by using H 2 0 2 or others Oxidizing agents (e.g. according to Patai, "Supplement E,” Ref. 42, pt. 1, pp. 539-608; Org. Prep. Proced. Int. 14, 45-89 (1982); "The Chemisti ⁇ of Sulfur , "pp. 385-390, Plenum, New York, 1977; Tetrahedron Lett. 22, 1287 (1981)).
  • the compounds of the formula I in which W is SO or SO 2 are very particularly preferably prepared by starting from corresponding intermediates which are oxidized on the sulfur atom and which can be produced by oxidation of the thio compounds of the formulas II, IV and V.
  • the compounds oxidized to the sulfoxides or sulfones can be reacted like the underlying thio compounds of the formula II, IV and V.
  • R 4 in the compounds of the formulas II, IV and V is preferably O.
  • R 2 and / or R 3 are particularly preferred for R 2 and / or R 3 :
  • Q f stands for F, Cl, Br or A, in particular ethyl or methyl
  • R 1 and W 1 are Cl, Br, A, in particular methyl and ethyl or SA, and in particular SMethyl and SEthyl, and in which R 3 is preferably H or alkyl, in particular methyl.
  • R 2 is preferably p- or m-hydroxyphenyl, and o, m or p-fluorophenyl.
  • all radicals, such as the radicals R 1 , R 2 , R 3 , R 4 , R 5 , X, Q, Q 1 , Y, Y 1 , m, n, y, T, k, p , q, I and s have the meanings given in formula I, unless expressly stated otherwise. If individual residues occur several times within a compound, the residues independently assume the meanings given.
  • Y 1 preferably denotes COCH 2 NMe 2 .
  • Alkyl and is preferably unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1, 2-, 1,3-, 2,2-, 2,3 - or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, more preferred eg Trifluoromethyl.
  • Alkyl very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl , Pentafluoroethyl or 1, 1, 1 trifluoroethyl.
  • Alkyl also means cycloalkyl. Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • R 1 preferably denotes A, SR 5 , OR 5 , shark, CN, N0 2 , N (R 5 ) 2 .
  • R denotes methyl, ethyl, isopropyl, tert-butyl, F, Cl, CN, or OH.
  • R 2 preferably denotes H, A, such as, for example, ethyl, phenyl, methyl, aryl ooddeerr HHeett. IInnssbbeessoonnddeerree bbeeddceutet R 2 A or Ar.
  • W preferably means S.
  • R preferably denotes H, A, Ar or - (C (R 5 ) 2 ) oAr, in particular denotes
  • R 2 denotes Ar
  • Ar preferably denotes 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-
  • 2-amino-6-chlorophenyl 2-nitro-4-N, N-dimethylamino- or 3-nitro-4-N, N-dimethylammophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3, 5-, 2,3,6-, 2,4,6- or
  • Het preferably means a mono- or dinuclear aromatic or saturated heterocycle with one or more N-, O- and / or S-
  • N0 2l NHA, NA 2 , OA, COOA or CN can be substituted.
  • Het groups are preferred.
  • Het means unsubstituted heteroaryl. This is e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2 -, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 -, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazo -, -4- or -5-yl, 1, 2,4-triazol-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-thi
  • 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
  • Shark is preferably F, Cl or Br, but also I, particularly preferably F or Cl.
  • the compounds of formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms.
  • Formula I encompasses all of these forms.
  • 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 indicated above.
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • 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 the solvents mentioned.
  • 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 nitromethan
  • a functionally modified amino and / or hydroxyl group in a compound of the formula I can be obtained by solvolysis or Hydrogenolysis can be set free according to customary methods. This can be done, for example, with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • the compounds according to the invention mentioned can be used in their final non-salt form.
  • the present invention also includes the use of these compounds in the form of them
  • a C pharmaceutically acceptable salts that can be derived from various organic and inorganic acids and bases according to procedures known in the art. Most of the pharmaceutically acceptable salt forms of the compounds of formula I are prepared conventionally. If the compound of formula I is a carboxylic acid
  • Contains 20 group one of their suitable salts can be formed by reacting the compound with a suitable base to the corresponding base addition salt.
  • bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; 5 alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; as well as various organic bases such as piperidine, diethanolamine and N-methylglutamine.
  • bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; 5 alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; as well as various organic bases such as piperidine, diethanolamine and N-methylglutamine.
  • the aluminum salts of the compounds of formula I are, for example, alkal
  • 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 hydrogen iodide, other mineral acids and their corresponding salts 5 such as sulfate, nitrate or phosphate and the like and alkyl and monoaryl sulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, as well as other organic acids and their corresponding salts such as
  • pharmaceutically acceptable organic and inorganic acids for example hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts 5 such as sulfate, nitrate or phosphate and the like and alkyl and monoaryl sulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, as well as other organic acids
  • compositions of the formula I include the following: acetate, adipate, alginate, arginate, aspartate,
  • Cyclopentanepropionate digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, 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, maleate, malonate, mandelate,
  • Metaphosphate methanesulfonate, methyl benzoate, monohydrogen phosphate
  • 2-naphthalene sulfonate nicotinate, nitrate, oxalate, oleate, pamoate, pectinate,
  • Phthalate but this is not a limitation.
  • the base salts of the compounds according to the invention also include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium -, sodium and zinc salts, but this should not be a limitation.
  • Preferred among the salts mentioned above are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium.
  • Salts of the compounds of the formula I which are derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g.
  • Hydrabamine isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procain, purines,
  • Compounds of the present invention which contain basic nitrogen-containing groups can be prepared using agents such as (C 1 -C 4 ) alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide;
  • Di (-C 4 ) alkyl sulfates such as dimethyl, diethyl and diamyl sulfate; (C 10 -
  • Ci 8 alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; as well as aryl (C 1 -C 4 ) alkylhaiogenides, for example
  • compositions which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,
  • Meglumine nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to be a limitation.
  • the acid addition salts of basic compounds of the formula I are prepared by contacting the free base form with a sufficient amount of the desired acid, which is how the salt is prepared in the usual way.
  • the free base can be obtained by contacting the salt form with a base and isolating the free base to conventional ones
  • the free base forms differ in a sense from their corresponding salt forms with regard to certain physical properties such as solubility in polar solvents; in the In the context of the invention, however, the salts otherwise correspond to their respective free base forms.
  • the base addition salts of acidic compounds according to the invention are prepared by bringing the free acid form with a C A sufficient amount of the desired base, causing the formation of the salt in the conventional manner.
  • the free acid can be regenerated in a conventional manner by contacting the salt form with an acid and isolating the free acid.
  • the free acid forms differ in a sense from their corresponding salt forms in
  • a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also includes multiple salts.
  • Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate,
  • 35 is to be understood as an active ingredient which contains a compound of the formula I in the form of one of its salts, especially when this salt form Drug gives improved pharmacokinetic properties compared to the free form of the drug or any other salt form of the drug used previously.
  • the pharmaceutically acceptable salt form of the active ingredient can also give this active ingredient a desired pharmacokinetic property which it did not previously have, and can even have a positive influence on the pharmacodynamics of this active ingredient with regard to its therapeutic effectiveness in the body.
  • the invention further relates to medicaments containing at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in A g in all ratios, and, if appropriate, carriers and / or auxiliaries.
  • compositions can be presented in the form of dose units containing a predetermined amount of active ingredient per dose unit.
  • a unit can, for example, 0.5 mg to 1 g,
  • 20 preferably contain 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the condition of the disease being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be used in
  • Preferred dosage unit formulations are those which contain a daily dose or partial dose, as stated above, or a corresponding fraction thereof of a Q active ingredient. Furthermore, such pharmaceutical formulations can be produced using one of the methods generally known in the pharmaceutical field.
  • compositions can be administered
  • any suitable route for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • oral including buccal or sublingual
  • rectal including buccal or sublingual
  • nasal including buccal, sublingual, or transdermal
  • vaginal including vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • parenteral including subcutaneous, intramuscular, intravenous, or intradermal
  • Formulations can be prepared by any method known in the pharmaceutical art, for example by the
  • Active ingredient is brought together with the carrier (s) or auxiliary (s).
  • compositions adapted for oral administration can be used as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam dishes; 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 administered with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as e.g. Ethanol, glycerin, water etc. combine.
  • an oral, non-toxic and pharmaceutically acceptable inert carrier such as e.g. Ethanol, glycerin, water etc. combine.
  • Powders are made by comminuting the compound to an appropriate fine size and with a similarly comminuted pharmaceutical carrier such as e.g. an edible carbohydrate such as starch or mannitol is mixed.
  • a flavor, preservative, dispersant and color may also be present.
  • Capsules are made by making a powder mixture as described above and filling shaped gelatin shells with it.
  • Lubricants such as e.g. finely divided 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 such as agar-agar, calcium carbonate or sodium carbonate, can also be added to improve the availability of the medication after taking the capsule.
  • Lubricants, disintegrants and 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 such as Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc.
  • the lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and others.
  • Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite,
  • the tablets are formulated by, for example, producing a powder mixture, granulating or dry-pressing, adding a lubricant and a disintegrant and compressing the whole to tablets.
  • a powder mixture is prepared by appropriately comminuting the compound with a diluent or a base as described above, and optionally with a binder such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution retarder such as paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent such as bentonite, kaolin or dicalcium phosphate, is mixed.
  • a binder such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone
  • a solution retarder such as paraffin
  • a resorption accelerator such as a quaternary salt and / or an absorbent
  • bentonite kaolin or dicalcium phosphate
  • the powder mixture can be granulated by wetting it with a binder, such as syrup, starch paste, Acadia mucilage or solutions made of cellulose or polymer materials, and pressing it through a sieve.
  • a binder such as syrup, starch paste, Acadia mucilage or solutions made of cellulose or polymer materials
  • the powder mixture can be run through a tabletting machine, resulting in irregularly shaped lumps which are broken up into granules.
  • the granules can be greased by adding stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased The mixture is then compressed into tablets.
  • the compounds according to the invention can also be combined with a free-flowing inert carrier and then without carrying out the granulation or
  • a transparent or opaque protective layer consisting of a
  • Shellac a layer of sugar or polymeric material and a glossy layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.
  • Oral liquids e.g. Solution, syrups and elixirs can be prepared in unit dosage forms so that a given quantity contains a given amount of the compound.
  • Syrups can be made by dissolving the compound in an aqueous solution with a suitable taste, while elixirs are made 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, flavor additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. can also be added.
  • Dosage unit formulations for oral administration can optionally be enclosed in microcapsules.
  • the formulation can also be prepared in such a way that the release is prolonged or delayed, for example by coating or embedding particulate material in polymers, wax and the like.
  • the compounds of the formula I and salts, solvates and physiologically functional derivatives thereof can also be large in the form of liposome delivery systems, such as small unilamellar vesicles unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • soluble polymers can be coupled as targeted drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethylaspartamide phenol or polyethylene oxide polylysine substituted with palmitoyl residues.
  • the compounds can be linked to a class of biodegradable polymers which are suitable for achieving a controlled release of a pharmaceutical, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and cross-linked or amphipatic block copolymers
  • a pharmaceutical e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and cross-linked or amphipatic block copolymers
  • compositions adapted for transdermal administration can be administered as independent patches for prolonged, close contact with the epidermis of the recipient.
  • the active ingredient can be supplied from the patch by means of iontophoresis, as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
  • Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably used as a topical ointment or cream applied.
  • the active ingredient can be used either with a paraffinic or with a water-miscible cream base.
  • the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base 5.
  • compositions adapted for topical application to the eye include eye drops, the active ingredient being dissolved or suspended in a suitable carrier, in particular an aqueous solvent.
  • compositions adapted for topical application in the mouth include lozenges, lozenges and mouthwashes.
  • compositions adapted for rectal administration can be administered in the form of suppositories or enemas.
  • compositions adapted for nasal administration in which the carrier substance is a solid, contain a coarse powder with a particle size, for example in the range of 20-500 micrometers, which is administered in the manner in which snuff is taken up, i.e. by rapid inhalation via the nasal passages from a container with the powder held close to the nose.
  • Suitable formulations for administration as a nasal spray or nasal drops with a liquid as carrier include
  • Fine particulate dusts or mists which are formed using various types of pressurized dispensers
  • Formulations can be used as pessaries, tampons, creams, gels, pastes,
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions, the antioxidants, buffers, bacteriostatics and solutes, through which the formulation is isotonic with the blood of the person to be treated
  • Recipient is made included; as well as aqueous and non-aqueous sterile suspensions, which can contain suspending agents and thickeners.
  • the formulations can be in single dose or multiple dose containers, e.g. sealed ampoules and vials, presented and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections is required immediately before use.
  • sterile carrier liquid e.g. Water for injections
  • Injection solutions and suspensions prepared according to the recipe can be made from sterile powders, granules and tablets.
  • formulations may contain, in addition to the above-mentioned ingredients, other means common in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.
  • a therapeutically effective amount of a compound of Formula I will depend on a number of factors, including, for example, 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 will ultimately determined by the attending doctor or veterinarian. However, an effective amount is one Compound according to the invention for the treatment of neoplastic materials.
  • 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 particularly typically in the range of 1 to 10 mg / kg body weight per
  • the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more usually in a series of
  • Partial doses (such as two, three, four, five or six) can be given per day 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 perse as a proportion of the effective amount of the compound of the invention. It is believed that similar dosages are suitable for the treatment of the other conditions mentioned above.
  • the invention further relates to medicaments containing at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.
  • the invention also relates to a set (kit) consisting of separate packs of
  • the set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules.
  • the set can contain, for example, separate ampoules, each containing an effective amount of a compound of formula I and / or its pharmaceutically usable Derivatives, solvates and stereoisomers, including their mixtures in all proportions, and an effective amount of another active pharmaceutical ingredient are dissolved or in lyophilized form.
  • the medicaments in Table 1 are combined with the compounds of the formula I.
  • a combination of Formula I and drugs of Table I can also be combined with compounds of Formula VI.
  • Antibiotics D) Azonafid doxorubicin (Adriamycin) anthrapyrazole Deoxyrubicin Oxantrazol Valrubicin losoxantrone daunorubicin bleomycin sulfate (daunomycin) (Blenoxane) epirubicin Bleomycinklare Therarubicin bleomycin A Idarubicin Bleomycin B rubidazone mitomycin C Plicamycinp MEN-10755 (Menarini) porfiromycin GPX-100 (Gem Cyanomorpholinodoxorubi Pharmaceuticals) M l Mitoxantron (Novantron)
  • TNF-alpha virulizine (Lorus Revimid (Celgene)
  • Agent inhibitor Sanofi-BioCryst Synthelabo) Ranpimase Tocladesin (cyclic (ribonuclease stimulant, AMP agonist, Ribapharm) Alfacell) alvocidib (CDK inhibitor, galarubicin (RNA-Aventis) synthesis inhibitor, Dong-CV-247 (COX -2-inhibitor, A) Ivy Medical) Tirapazamine P54 (COX-2 inhibitor, (reducing agent, SRI Phytopharm) International) CapCell TM (CYP450-N-acetylcysteine stimulant, Bavarian (reducing agent, Nordic) zambon) GCS-IOO (gal3 - R-Flurbiprofen (NF-antagonist, kappaB inhibitor, Encore) GlycoGenesys) 3CPA (NF-kappaB- G17DT immunogen inhibitor, Active Biotech) (gastrin inhibitor, aphtone) Seocaicitol (vitamin D
  • PBI-1402 PMN stimulant, (immunotoxin, KS ProMetic LifeSciences) Biomedix) bortezomib (Proteasome-PCK-3145 (apoptosis inhibitor, millennium) promoter, Procyon) SRL-172 (T cell doranidazole (apoptosis stimulant, SR Pharma) Conveyor, Pola) TLK-286 (Glutathione-S-CHS-828 (cytotoxic
  • TNF-alpha virulizine (Lorus Revimid (Celgene)
  • ProMetic promoter ProMetic promoter, Pola) LifeSciences
  • CHS-828 cytotoxic bortezomib (proteasome agent, Leo) inhibitor, millennium
  • trans retinoic acid SRL-172 T cell (differentiator, NIH) stimulant, SR Pharma)
  • MX6 Apoptosis promoter, TLK-286 (Glutathione-S-MAXIA)
  • the compounds of the formula I are preferably combined with those with known anti-cancer agents:
  • estrogen receptor modulators include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxics, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other.
  • the present compounds are particularly suitable for joint use with radiotherapy.
  • the synergistic effects of inhibiting VEGF in combination with radiotherapy have been described in the specialist field (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 is done.
  • the estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifene, 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'-dihydroxybenzo- phenon-2,4-dinitrophenylhydrazone and SH646, which, however, is not intended to be a limitation.
  • Androgen receptor modulators refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this is done.
  • the androgen receptor modulators include, for example, finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, Bicalutamide, liarozole and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this is done.
  • retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis retinoic acid,
  • Cytotoxics refers to compounds that cause cell death primarily through direct action on cell function or that inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis
  • cytotoxics include, for example, tirapazimin, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine,
  • microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S ' ⁇ ' - Dideshydro ⁇ '- deoxy- ⁇ '-norvincaleukoblastin, docetaxol,
  • Rhizoxin Rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,
  • Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4'-0-exo-benzylidene-chartreusin, 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 ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazo-furin, decitabine, nolatrexed, pemetrexed-2'-desfluoro-ethane -2'-deoxycytidine, N- [5- (2,3-
  • antiproliferative agents also contain monoclonal antibodies against growth factors other than those already mentioned under the “angiogenesis inhibitors”, such as trastuzumab, and tumor suppressor genes, such as p53, which can be released via recombinant virus-mediated gene transfer (see, for example, US Pat. No. 6,069,134).
  • the use of the compound according to the invention is particularly preferred for the treatment and prophylaxis of tumor diseases.
  • the tumor is preferably selected from the group of tumors of the squamous epithelium, the bladder, the stomach, the kidneys, the head and neck, the esophagus, the cervix, the thyroid, the intestine, the liver, the brain, the prostate and the urogenital tract , the lymphatic system, the stomach, the larynx and / or the lungs.
  • the tumor is also preferably selected from the group of lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.
  • a tumor of the blood and immune system preferably for the treatment of a tumor selected from the group of acute myelotic leukemia, chronic myelotic leukemia, acute lymphatic leukemia and / or chronic lymphatic leukemia.
  • the invention also encompasses a method for treating a patient who has a neoplasm, such as a cancer, by administering a) one or more of the compounds of the formula I:
  • Y 'and Z' each independently represent O or N
  • R 7 and R 9 each independently represent H, OH, halogen, OCI-10-alkyl, OCF 3 , N0 2 or NH 2
  • n is an integer between 2 and 6, each inclusive
  • R 6 and R 8 are each independently of one another at the meta or para position and from the group:
  • first and second compounds are selected, the first and second compounds being administered simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of the neoplasm.
  • Suitable pentamidine analogs include stilbamidine (G-1) and hydroxystilbamidine (G-2) and their indole analogues (e.g. G-3):
  • Each amidine unit can be replaced independently of one another by one of the other entire units.
  • salts of stilbamidine, hydroxystilbamidine and their indole derivatives are also suitable in the process according to the invention.
  • Preferred salts include, for example, dihydrochloride and methanesulfonate salts.
  • Exemplary analogs include 1, 5-bis (4 '- (N-hydroxyamidino) phenoxy) pentane, 1, 3-bis (4' - (N-hydroxyamidino) phenoxy) propane, 1, 3-bis (2 , -methoxy-4 '- (N-hydroxyamidino) phenoxy) propane, 1,4-bis (4' - (N-hydroxyamidino) phenoxy) butane, 1,5-bis (4 '- (N- hydroxyamidino) phenoxy) pentane, 1,4-bis (4 '- (N-hydroxyamidino) phenoxy) butane, 1,3-bis (4' - (4-hydroxyamidino) phenoxy) propane, 1,3-bis - (2 ' methoxy-4 '- (N-hydroxyamidino) phenoxy) propane, 2,5-bis- [4-amidinophenyljfuran, 2,5-bis- [4-amidinophenyl] furan-bis-amidoxime, 2,5-bis-bis-[4
  • Pentamidine metabolites are also suitable in the antiproliferative combination according to the invention. Pentamidine is rapidly metabolized to at least seven primary metabolites in the body. Some of these metabolites share one or more effects with pentamidine. Some pentamidine metabolites can show antiproliferative effects when combined with a benzimidazole or an analogue thereof.
  • Neoplasms A combination therapy can be carried out alone or in conjunction with another therapy (e.g. surgery, radiation, chemotherapy, biological therapy).
  • another therapy e.g. surgery, radiation, chemotherapy, biological therapy.
  • a person who is at greater risk of developing a neoplasm e.g., someone who is genetically predisposed or someone who has previously had a neoplasm
  • each compound of the combination can be controlled independently. For example, one
  • Compound can be administered intramuscularly once a day.
  • the antiproliferative combinations according to the invention can also be provided as components of a pharmaceutical package.
  • the two drugs can be formulated together or separately and in individual dosage amounts.
  • the invention includes for treating a patient who has a neoplasm such as a cancer by administering a compound of formula (I) and (VI) in combination with an antiproliferative agent.
  • Suitable antiproliferative agents include those provided in Table 1.
  • customary workup means: if necessary, water is added, if necessary, depending on the constitution of the End product to pH values between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, the organic phase dried over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1.
  • 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) +
  • mandelic acid derivatives used below are e.g. accessible from aromatic aldehydes.
  • methyl mandelate 10.0 g (60 mmol) of methyl mandelate are dissolved in 10 mL dichloromethane and, after adding 4.79 mL (66 mmol, 1.1 equiv.) Thionyl chloride, heated to 60 ° C. The mixture is stirred for 18 hours, the reaction solution is cooled to room temperature, a further 20 ml of dichloromethane are added and the mixture is extracted twice with 30 ml of water and saturated NaHC03 solution. The organic Phase is dried over sodium sulfate and the reaction product is obtained after filtration and distillation of the solvent.
  • phenyl-p-tolylsulfanylacetic acid 2.2 g (6.4 mmol) 2 are dissolved in 8 mL methanol and a solution of 1.32g (9.57 mmol, 1.5 equiv.) Potassium carbonate in 1.5 mL water. The mixture is heated under reflux for 15 hours. After the solvent has been distilled off, the residue is dissolved in water and extracted once with diethyl ether. The aqueous phase is mixed with cooling with 18 mL 1N HCl and extracted with ethyl acetate. After drying over sodium sulfate, Filtration and distillation of the solvent gives the product 3.
  • phenyl methyl 10. phenyl methyl H 0 11. phenyl phenyl H 0 12. phenyl methyl methyl 0 13. phenyl phenyl methyl 0 14. phenyl methyl H
  • phenyl methyl 90. phenyl methyl HO 91. phenyl phenyl HO 92. phenyl methyl methyl O 93. phenyl phenyl methyl 0 94. phenyl methyl H
  • the determination of the effectiveness of the compounds of formula I according to the invention can, for. B. on the Eg5-ATPase activity, which is measured via an enzymatic regeneration of the product ADP to ATP using pyruvate kinase (PK) and subsequent coupling to a NADH-dependent lactate dehydrogenase (LDH) reaction.
  • PK pyruvate kinase
  • LDH NADH-dependent lactate dehydrogenase
  • the reaction can be followed by changing the absorbance at 340 nm.
  • regeneration of the ATP ensures that the substrate concentration remains constant.
  • the absorbance changes per unit of time are analyzed graphically and a linear regression is carried out in the vusually linear area of the reaction.
  • 10 3 to 10 4 cells of a defined cell line (HCT116, Colo 205, MDA-MB 231, etc.) are sown per well in a 96-well microtiter plate and cultivated overnight under standard conditions.
  • 10-50 mM stock solutions in DMSO were prepared for the substances of the combination to be tested.
  • 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 and kept under for a further 48 hours Culture conditions incubated. At the end of the cultivation, the cells were crystal violet stained. After extraction of the crystal violet from the fixed cells, the absorption was measured spectrophotometrically at 550 nm. It can be used as a quantitative measure of the adherent cells present.
  • Example C Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, under sterile conditions lyophilized and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • Example D suppositories
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example F ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient ,
  • Example H coated tablets Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Abstract

The invention relates to compounds of formula (I), in which W, R1, R2, R3, R4, and q are defined as cited in claim 1. One application for said compounds is the treatment of tumours.

Description

Dihydrobenzothiophene Dihydrobenzothiophene
HINTERGRUND DER ERFINDUNGBACKGROUND OF THE INVENTION
5 Der Erfindung lag die Aufgabe zugrunde, neue Verbindungen mit wertvollen 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 production of medicaments.
10 Die vorliegende Erfindung betrifft Verbindungen der Formel I zur Prophylaxe und Behandlung von Krankheiten, bei denen die Hemmung, Regulierung und/oder Modulation der mitotische Motor-Proteine, insbesondere des mitotischen Motor-Protein Eg5 eine Rolle spielt, fernerThe present invention further relates to compounds of the formula I for the prophylaxis and treatment of diseases in which the inhibition, regulation and / or modulation of the mitotic motor proteins, in particular the mitotic motor protein Eg5, plays a role
15 pharmazeutische Zusammensetzungen, die diese Verbindungen enthalten.15 pharmaceutical compositions containing these compounds.
Im einzelnen betrifft die vorliegende Erfindung Verbindungen der Formel I, die bevorzugt eines oder mehrere mitotische Motor-Proteine hemmen,In particular, the present invention relates to compounds of the formula I which preferably inhibit 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, Tumorentstehung, -Wachstum und -Verbreitung, Arteriosklerose, Augen-20 regulate and / or modulate, compositions containing these compounds, and methods of their use for the treatment of diseases and conditions such as angiogenesis, cancer, tumor formation, growth and spread, arteriosclerosis, eye
„-. erkrankungen, choroidale Neovaskularisierung und diabetische Retinopathie, Entzündungserkrankungen, Arthritis, Neurodegeneration, Restenose, Wundheilung oder Transplantatabstossung. Insbesondere eignen sich die erfindungsgemäßen Verbindungen zur Therapie oder Prophylaxe von Krebserkrankungen. 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 wurde 35 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"-. diseases, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, wound healing or graft rejection. The compounds according to the invention are particularly suitable for the therapy or prophylaxis of cancerous diseases. 30 During mitosis, various kinesins regulate the formation and dynamics of the spindle apparatus, which is 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 a collapse of the spindle fibers. This results, that the chromosomes can no longer be correctly distributed to the daughter cells. This leads to mitotic arrest and can do so
Absterben der Zelle verursachen. Eine Hochregulierung des MotorproteinsCause cell death. An upregulation of the engine protein
Eg5 wurde z.B. in Gewebe von Brust- Lungen- und Colon- Tumoren beschrieben. Da Eg5 eine für die Mitose spezifische Funktion einnimmt, sind hauptsächlich sich schnell teilende Zellen und nicht vollständig ausdifferenzierte Zellen von einer Eg5 Inhibierung betroffen. Darüber hinaus regelt Eg5 ausschließlich die Bewegung mitotischer Mikrotubuli (Spindelapparat) und nicht die des Cytoskeletts. Dies ist entscheidend für das Nebenwirkungsprofil, da z.B. Neuropathien, wie sie bei Taxol beobachtet werden, nicht oder nur abgeschwächt auftreten. Daher ist die Inhibierung von Eg5 durch organische Moleküle ein relevantes Therapiekonzept für die Behandlung von malignen Tumoren.Eg5 was e.g. described in tissue from breast, lung and colon tumors. Since Eg5 has a specific function for mitosis, cells that divide quickly and cells that are not fully differentiated are mainly affected by Eg5 inhibition. In addition, Eg5 regulates only the movement of mitotic microtubules (spindle apparatus) and not that of the cytoskeleton. This is crucial for the side effect profile, e.g. Neuropathies, such as those observed with Taxol, do not occur or only weakly. Therefore, the inhibition of Eg5 by organic molecules is a relevant therapy concept for the treatment of malignant tumors.
Generell können alle soliden und nicht soliden Tumore mit den Verbindungen der Formel I behandelt werden, wie z.B. die Monozytenleukämie, Hirn-, Urogenital-, Lymphsystem-, Magen-, Kehlkopf- und Lungenkarzinom, darunter Lungenadenokarzinom und kleinzelliges Lungenkarzinom. Zu weiteren Beispielen zählen Prostata-, Bauchspeicheldrüsen- und Brustkarzinom.In general, all solid and non-solid tumors can be treated with the compounds of formula I, e.g. monocyte leukemia, brain, urogenital, lymphatic, gastric, larynx and lung carcinoma, including lung adenocarcinoma and small cell lung carcinoma. Other examples include prostate, pancreatic and breast cancer.
Es wurde überraschend gefunden, daß die erfindungsgemäßenIt has surprisingly been found that the inventive
Verbindungen eine spezifische Inhibierung der mitotischen Motor-Proteine, insbesondere Eg5 bewirken. Die erfindungsgemäßen Verbindungen zeigen bevorzugt eine vorteilhafte biologische Aktivität, die in den, zum Beispiel hierin beschrieben Assays, leicht nachweisbar ist. In derartigen Assays zeigen und bewirken die erfindungsgemäßen Verbindungen bevorzugt einen inhibierenden Effekt, der gewöhnlich durch ICso-Werte in einem geeigneten Bereich, bevorzugt im mikromolaren Bereich und bevorzugter im nanomolaren Bereich dokumentiert wird. Wie hierin besprochen, sind Wirkungen der erfindungsgemäßenCompounds cause a specific inhibition of the mitotic motor proteins, especially Eg5. The compounds according to the invention preferably exhibit an advantageous biological activity which is easily detectable in the assays described, for example, herein. In such assays, the compounds according to the invention preferably show and bring about an inhibitory effect which is usually documented by IC 50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range. As discussed herein, effects are those of the present invention
Verbindung für verschiedene Erkrankungen relevant. Dementsprechend sind die erfindungsgemäßen Verbindungen nützlich bei der Prophylaxe und/oder Behandlung von Erkrankungen, die durch eine Inhibierung eines oder mehrerer mitotischer Motor-Proteine, insbesondere Eg5, beeinflusst werden.Connection relevant for various diseases. Accordingly, the compounds according to the invention are useful in the prophylaxis and / or treatment of diseases which are influenced by inhibition of one or more mitotic motor proteins, in particular Eg5.
Gegenstand der vorliegenden Erfindung sind deshalb erfindungsgemäßeThe present invention therefore relates to the invention
Verbindungen als Arzneimittel und/oder Arzneimittelwirkstoffe bei der Behandlung und/oder Prophylaxe der genannten Erkrankungen und dieCompounds as drugs and / or active pharmaceutical ingredients in the 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 genannten Erkrankungen umfassend die Verabreichung eines oder mehrerer erfindungsgemäßer Verbindungen an einen Patienten mit Bedarf an einer derartigen Verabreichung.Use of compounds according to the invention for the manufacture of a pharmaceutical for the treatment and / or prophylaxis of the diseases mentioned, and also a method for the treatment of the diseases mentioned, comprising the administration of one or more compounds according to the invention to a patient in need of such an administration.
Es kann gezeigt werden, dass die erfindungsgemäßen Verbindungen in einem Xenotransplantat-Tumor-Modell eine vorteilhafte Wirkung aufweisen.It can be shown that the compounds according to the invention have an advantageous effect in a xenograft tumor model.
Der Wirt oder Patient kann jeglicher Säugerspezies angehören, z. B. einer Primatenspezies, besonders Menschen; Nagetieren, einschließlich Mäusen, Ratten und Hamstern; Kaninchen; Pferden, Rindern, Hunden, Katzen usw. Tiermodelle sind für experimentelle Untersuchungen von Interesse, wobei sie ein Modell zur Behandlung einer Krankheit des Menschen zur Verfügung stellen.The host or patient can belong to any mammalian species, e.g. B. a primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are of interest for experimental studies, providing a model for treating a human disease.
Die Sensitivität einer bestimmten Zelle gegenüber der Behandlung mit den erfindungsgemäßen Verbindungen kann durch Testen in vitro bestimmt werden. Typischerweise wird eine Kultur der Zelle mit einer erfindungsgemäßen Verbindung bei verschiedenen Konzentrationen für eine Zeitdauer kombiniert, die ausreicht, um den aktiven Mitteln zu ermöglichen, Zelltod zu induzieren oder Migration zu inhibieren, gewöhnlich zwischen ungefähr einer Stunde und einer Woche. Zum Testen in vitro können kultivierte Zellen aus einer Biopsieprobe verwendet werden. Die nach der Behandlung zurückbleibenden lebensfähigen Zellen werden dann gezählt.The sensitivity of a particular cell to treatment with the compounds according to the invention can be determined by testing in vitro. Typically, a culture of the cell is combined with a compound of the invention at various concentrations for a period of time sufficient to enable the active agents to induce cell death or to inhibit migration, usually between about an hour and a week. Cultured cells from a biopsy sample can be used for in vitro testing. 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 die Lebensfähigkeit des Patienten aufrechterhalten wird. Die Behandlung wird im Allgemeinen fortgesetzt, bis eine erhebliche Reduktion vorliegt, z. B. mindestens ca. 50 % Verminderung der Zelllast und kann fortgesetzt werden, bis im Wesentlichen keine unerwünschten Zellen mehr im Körper nachgewiesen werden können.The dose varies depending on the specific compound used, the specific disease, patient status, etc. Typically, a therapeutic dose is sufficient to significantly reduce the unwanted cell population in the target tissue while maintaining the patient's viability. Treatment generally continues until there is a substantial reduction, e.g. B. at least about 50% reduction in cell load and can be continued until essentially no unwanted cells can be detected in the body.
STAND DER TECHNIKSTATE OF THE ART
Ähnliche Verbindungen sind in US3328411 beschrieben, sind aber nicht im Zusammenhang mit Krebsbehandlungen genannt und/oder enthalten nicht die erfindungswesentlichen Merkmale.Similar compounds are described in US3328411, 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:The invention relates to compounds of the formula I:
wobeiin which
W S, SO oder S02l R1 H, A, Ar, Het, Phenyl, Methyl, OR5, SR5, OAr, SAr, N(R5)2, N R5Ar, Hai, N02, CN, (CH2)mCOOR5, (CH2)mCOOAr, (CH2)mCON(R5)2, (CH2)mCONHAr, COR5, COAr, S(0)mA, S(0)mAr, NHCOA, NHCOAr, NHSO2A, NHS02Ar oder S02N(R5)2, Heteroaryl, Hai, - (CY2)n-SA, -(CY2)n-SCF3, -(CY2)n-SCN, -(CY2)n-CF3, -(CY2)n-OCF3, Cycloalkyl, -SCH3l -SCN, -CF3, -OCF3, -OA, -(CY2)n-OH, -(CY2)n- C02R5, -(CY2)n-CN, -(CY2)n-Hal, -(CY2)n-N(R5)2, (CY2)n-OA, (CY2)n-OCOA, -SCF3, (CY2)n-CON(R5)2, - (CY2)n-NHCOA, -(CY2)n-NHS02A, SF5l Si(CH3)3, CO-(CY2)n-CH3j - (CY2)n-(N-Pyrolidon), und, sofern der R1 doppelt und vicinal am aromatischen Ring auftritt, zusammen auch -N-C(CF3)=N-, -N- CR=N-, -N-N=N-,WS, SO or S0 2l R 1 H, A, Ar, Het, phenyl, methyl, OR 5 , SR 5 , OAr, SAr, N (R 5 ) 2 , NR 5 Ar, Hai, N0 2 , CN, (CH 2 ) m COOR 5 , (CH 2 ) mCOOAr, (CH 2 ) mCON (R 5 ) 2 , (CH 2 ) mCONHAr, COR 5 , COAr, S (0) m A, S (0) m Ar, NHCOA, NHCOAr, NHSO2A, NHS0 2 Ar or S0 2 N (R 5 ) 2 , heteroaryl, shark, - (CY 2 ) n -SA, - (CY 2 ) n -SCF 3 , - (CY 2 ) n-SCN, - (CY 2 ) n- CF 3, - (CY 2) n -OCF 3, cycloalkyl, -SCH 3l -SCN, -CF 3, -OCF 3, -OA, - (CY 2) n -OH, - (CY 2) n - C0 2 R 5 , - (CY 2 ) n -CN, - (CY 2 ) n -Hal, - (CY 2 ) n -N (R 5 ) 2 , (CY 2 ) n -OA, (CY 2 ) n -OCOA , -SCF 3 , (CY 2 ) n -CON (R 5 ) 2 , - (CY 2 ) n-NHCOA, - (CY 2 ) n -NHS0 2 A, SF 5l Si (CH 3 ) 3 , CO- ( CY 2 ) n-CH 3j - (CY 2 ) n - (N-pyrolidone), and, if R 1 occurs twice and vicinally on the aromatic ring, together also -NC (CF 3 ) = N-, -N- CR = N-, -NN = N-,
R2, R3 unabhängig voneinander A, Het, H, -OH, -OA, -OAr, Ar, -O-CO-A, -OS03R5, -OSO2R5, -OAr2R5, S02R5, Hai, COOR5, CON(R5)2) NHS02A,COA, CHO oder S02N(R5)2) -(CH2)0-Ar, -(CH2)0- Cycloalkyl, -(CH2)0-OH, -(CH2)o-N(R5)2, N02, CN, -(CH2)0-COOR5, - (CH2)o-CON(R5)2, -(CH2)0-NHCOA, NHCON(R5)2, -(CH2)0-NHSO2A, -(C(R5)2)o-Ar, oder unsubstituiertes oder einfach oder mehrfach durch Aryl oder Heteroaryl, das durch Hai, N02, CN, A, OR, OCOR, COR, NR2, CF3, OCF3, OCH(CF3)2 substituiert sein kann, Hai, N02, CN, OR, A, -(CY2)n-OR, -OCO R5, -(CY2)n-C02 R5, -(CY2)n-CN, - NGO R5, -CO R5 oder -(CY2)n-N(R5)2 substituiertes Aryl oder Heteroaryl, N[(CH2)nXCOOR5]CO(CH2)nAryl, N[(CH2)nXR5]CO(CH2)nAryl, N[(CH2)nXR5]CO(CH2)nXAryl, N[(CH2)πXR5]S02(CH2)πAryl, N[(CH2)nNR5COOR5]CO(CH2)nAryl, N[(CH2)nN(R5)2]CO(CH2)nAryl, N[(CH2)nN(R5)2]CO(CH2)πNR5Aryl, N[(CH2)nN(R5)2]S02(CH2)πAryl, N[(CH2)nXR5]CO(CH2)nHeteroaryl, N[(CH2)nXR5]CO(CH2)nXHeteroaryl, N[(CH2)nXR5]Sθ2(CH2)nHeteroaryl, N[(CH2)nNR5COOR5]CO(CH2)nHeteroaryl, N[(CH2)nN(R5)2]CO(CH2)nHeteroaryl oder N[(CH2)nN(R5)2]CO(CH2)nNR5Heteroaryl,R 2 , R 3 independently of one another A, Het, H, -OH, -OA, -OAr, Ar, -O-CO-A, -OS0 3 R 5 , -OSO2R 5 , -OAr 2 R 5 , S0 2 R 5 , shark, COOR 5 , CON (R 5 ) 2) NHS0 2 A, COA, CHO or S0 2 N (R 5 ) 2) - (CH 2 ) 0 -Ar, - (CH 2 ) 0 - cycloalkyl, - (CH 2 ) 0 -OH, - (CH 2 ) oN (R 5 ) 2 , N0 2 , CN, - (CH 2 ) 0 -COOR 5 , - (CH 2 ) o-CON (R 5 ) 2 , - (CH 2 ) 0 -NHCOA, NHCON (R 5 ) 2 , - (CH 2 ) 0 -NHSO 2 A, - (C (R 5 ) 2 ) o-Ar, or unsubstituted or singly or multiply by aryl or heteroaryl, which can be substituted by shark, N0 2 , CN, A, OR, OCOR, COR, NR 2 , CF 3 , OCF 3 , OCH (CF 3 ) 2 , shark, N0 2 , CN, OR, A, - (CY 2 ) n -OR, -OCO R 5 , - (CY 2 ) n -C0 2 R 5 , - (CY 2 ) n -CN, - NGO R 5 , -CO R 5 or - (CY 2 ) n -N (R 5 ) 2 substituted aryl or heteroaryl, N [(CH 2 ) nXCOOR 5 ] CO (CH 2 ) nAryl, N [(CH 2 ) nXR 5 ] CO (CH 2 ) nAryl, N [(CH 2 ) n XR 5 ] CO (CH 2 ) nXAryl, N [(CH 2 ) πXR 5 ] S0 2 (CH 2 ) πAryl, N [(CH 2 ) nNR 5 COOR 5 ] CO (CH 2 ) nAryl, N [(CH 2 ) n N (R 5) 2] CO (CH 2) n aryl, N [(CH 2) n N (R 5) 2] CO (CH 2) NR 5 aryl, N [(CH 2) n N (R 5) 2] S0 2 (CH 2) πAryl, N [(CH 2) n XR 5] CO (CH 2) nHeteroaryl, N [(CH 2) n XR 5 ] CO (CH 2 ) nX heteroaryl, N [(CH 2 ) nXR 5 ] Sθ2 (CH 2 ) n heteroaryl, N [(CH 2 ) nNR 5 COOR 5 ] CO (CH 2 ) n heteroaryl, N [(CH 2 ) n N (R 5 ) 2 ] CO (CH 2 ) n heteroaryl or N [(CH 2 ) n N (R 5 ) 2 ] CO (CH 2 ) n NR 5 heteroaryl,
R4 0, =CH-(CH2)nN(R5)2, oder cyclo[C(CH2)κ (NY1)-(CH2)P-] , cyclo[C(CH2)κ (CHY1)-(CH2)P-] oderE oder Z - =CH(CH2)nX(CH2)ιQ(CH2)sTR 4 0, = CH- (CH 2 ) nN (R 5 ) 2 , or cyclo [C (CH 2 ) κ (NY 1 ) - (CH 2 ) P -], cyclo [C (CH 2 ) κ (CHY 1 ) - (CH 2 ) P -] or E or Z - = CH (CH 2 ) nX (CH2) ιQ (CH 2 ) s T
R5 H oder A, bei geminalen Resten R5 zusammen auch -(CH2)s-, (CH2)4- oder -(CH2)n-Q-(CH2)n,R 5 is H or A, in the case of geminal radicals R 5 together also - (CH 2 ) s-, (CH 2 ) 4 - or - (CH 2 ) n -Q- (CH 2 ) n ,
Y H, A, HaiY H, A, shark
Y1 R2, R5, Ar, -(C(R5)2)0-Ar oder -(C(R5)2)0-Het, X(CH2),Q(CH2)ST, XCH2T oderT,Y 1 R 2 , R 5 , Ar, - (C (R 5 ) 2 ) 0 -Ar or - (C (R 5 ) 2 ) 0 -Het, X (CH 2 ), Q (CH 2 ) S T, XCH 2 T or T,
X NR5, CH2) CO oder S02 oder eine EinfachbindungX NR 5 , CH 2) CO or S0 2 or a single bond
Q CH2, NR5, O, S, CO, S02, C(R5)2 oder eine Einfachbindung, CH(CH2)nNR5C00R5, CHNR5COOR5, NGO, CH(CH2)nCOOR5, NCOOR5, CHX(CH2)nOH, N(CH2)nOH, CHNH2) CH(CH2)nN(R5)2, CHX(CH2)nN(R5)2) C(OH)R5, CHNCOR5, CH(CH2)nAryl, CH(CH2)nHeteroaryl, CH(CH2)nR1, N(CH2)nCOOR5, CH(CH2)nX(CH2)nAryl, CH(CH2)nX(CH2)nHeteroaryl, N(CH2)nCON(R5)2, CHCONR5(CH2)nN(R5)2,Q CH 2 , NR 5 , O, S, CO, S0 2 , C (R 5 ) 2 or a single bond, CH (CH 2 ) n NR 5 C00R 5 , CHNR 5 COOR 5 , NGO, CH (CH 2 ) n COOR 5 , NCOOR 5 , CHX (CH 2 ) n OH, N (CH 2 ) n OH, CHNH 2) CH (CH 2 ) nN (R 5 ) 2 , CHX (CH 2 ) n N (R 5 ) 2) C (OH) R 5 , CHNCOR 5 , CH (CH 2 ) n aryl, CH (CH 2 ) n heteroaryl, CH (CH 2 ) nR 1 , N (CH 2 ) nCOOR 5 , CH (CH 2 ) nX (CH 2 ) nAryl, CH (CH 2 ) nX (CH 2 ) n heteroaryl, N (CH 2 ) n CON (R 5 ) 2 , CHCONR 5 (CH 2 ) n N (R 5 ) 2 ,
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S-Atomen, der unsubstituiert oder ein-, zwei- oder dreifach durch Hai, A, -(CH2)0-Ar, -(CH2)0-Cycloalkyl, -(CH2)0-OH, -(CH2)0-N(R5)2, N( CN, -(CH2)0-COOR5, -(CH2)o-CON(R5)2) -(CH2)0-NHCOA, NNHHCCOONN((RR55))22,, --((CCHH22))00--NNHHSS0022A, CHO, COA, S02NH2 und/oder S(0)0A substituiert sein kann,Has a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, the unsubstituted or mono-, di- or triple by shark, A, - (CH 2 ) 0 -Ar, - (CH 2 ) 0 -cycloalkyl, - (CH 2 ) 0 -OH, - (CH 2 ) 0 -N (R 5 ) 2 , N ( CN, - (CH 2 ) 0 -COOR 5 , - (CH 2 ) o-CON (R 5 ) 2) - (CH 2 ) 0 -NHCOA, NNHHCCOONN ((RR 55 )) 22 ,, - ((CCHH 22 )) 00 --NNHHSS00 22 A, CHO, COA, S0 2 NH 2 and / or S (0) 0 A may be substituted,
Ar Aryl, unsubstituiertes oder ein-, zwei- oder dreifach durch Hai, A, OR5, N(R5)2, N02, CN, COOR5, CON(R5)2, NHCOA, NHCON(R5)2) NHS02A, CHO, COA, S02N(R5)2 oder S(0)oA substituiertes Phenyl, Naphthyl oder Biphenyl,Ar aryl, unsubstituted or single, double or triple by shark, A, OR 5 , N (R 5 ) 2 , N0 2 , CN, COOR 5 , CON (R 5 ) 2 , NHCOA, NHCON (R 5 ) 2 ) NHS0 2 A, CHO, COA, S0 2 N (R 5 ) 2 or S (0) oA substituted phenyl, naphthyl or biphenyl,
A unverzweigtes oder verzweigtes Alkyl mit 1 -10 C-Atomen, wobei eines oder mehrere H-Atome durch Hai insbesondere F oder Ar ersetzt sein können,A unbranched or branched alkyl having 1 -10 C atoms, it being possible for one or more H atoms to be replaced by sharks, in particular F or Ar,
Hai F, Cl, Br oder I, o 0, 1 , 2 oder 3, m 0 , 1, 2 oder 3, n 0, 1 , 2 ,3 oder 4, k,p,l,s 1, 2, 3, 4 oder 5,Shark F, Cl, Br or I, o 0, 1, 2 or 3, m 0, 1, 2 or 3, n 0, 1, 2, 3 or 4, k, p, l, s 1, 2, 3 , 4 or 5,
wobeiin which
k + p 2, 3, 4 oder 5k + p 2, 3, 4 or 5
undand
q 1, 2, 3 oder 4q 1, 2, 3 or 4
bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Tautomere, Salze und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.mean, as well as their pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, including their mixtures in all ratios.
Gegenstand der Erfindung sind auch die optisch aktiven FormenThe invention also relates to the optically active forms
(Stereoisomeren), die Enantiomeren, die Racemate, die Diastereomeren sowie die Hydrate und Solvate dieser Verbindungen. Unter Solvate der(Stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate's
Verbindungen werden Anlagerungen von inerten Lösungsmittelmolekülen an die Verbindungen verstanden, die sich aufgrund ihrer gegenseitigenCompounds are understood to mean the addition of inert solvent molecules to the compounds, which are mutually exclusive
Anziehungskraft ausbilden. Solvate sind z.B. Mono- oder Dihydrate oderDevelop attraction. Solvates are e.g. Mono- or dihydrates or
Alkoholate.Alcoholates.
Unter pharmazeutisch verwendbaren Derivaten versteht man z.B. die Salze der erfindungsgemäßen Verbindungen als auch sogenannte Prodrug-Verbindungen.Pharmaceutically usable derivatives are e.g. the salts of the compounds according to the invention and also so-called prodrug compounds.
Unter Prodrug-Derivaten versteht man mit z. B. Alkyl- oder Acylgruppen, Zuckern oder Oligopeptiden abgewandelte Verbindungen der Formel I, die im Organismus rasch zu den wirksamen erfindungsgemäßen Verbindungen gespalten werden.Prodrug derivatives are understood with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention.
Hierzu gehören auch bioabbaubare Polymerderivate der erfindungsgemäßen Verbindungen, wie dies z. B. in Int. J. Pharm. 115, 61-67 (1995) beschrieben ist.This also includes biodegradable polymer derivatives of the compounds according to the invention, as described, for. B. in Int. J. Pharm. 115, 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. Darüberhinaus bedeutet der Ausdruck "therapeutisch wirksame Menge" eine Menge, die, verglichen zu einem entsprechenden Subjekt, das dieseThe term "effective amount" means the amount of a drug or active pharmaceutical ingredient that elicits a biological or medical response in a tissue, system, animal or human, e.g. is sought or sought by a researcher or medical professional. In 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 einer Krankheit, eines Krankheitsbildes, eines Krankheitszustandes, eines Leidens, einer Störung oder von Nebenwirkungen oder auch die Verminderung des Fortschreitens einer Krankheit, eines Leidens oder einer Störung.Has not received the quantity, the following results: Improved treatment, healing, prevention or elimination of a disease, a clinical picture, a disease state, a condition, a disorder or side effects or also the reduction in the progression of a disease, a condition 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 that are effective in increasing 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 stereoisomerer Verbindungen.The invention also relates to the use of mixtures of the compounds of the formula I, e.g. Mixtures of two diastereomers e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.
Gegenstand der Erfindung sind die Verbindungen der Formel I und ihre Salze sowie ein Verfahren zur Herstellung von Verbindungen der Formel nach den Patentansprüchen sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate und Stereoisomeren, dadurch gekennzeichnet, daß man eine Verbindung der Formel IIThe invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula according to the patent claims and their pharmaceutically usable derivatives, salts, solvates and stereoisomers, characterized in that a compound of the formula II
worin R2, R und R4 die in Anspruch 1 angegebenen Bedeutungen haben und X1 eine Abgangsgruppe und bevorzugt Hai oder eine reaktionsfähige abgewandelte OH-Gruppe, insbesondere Tosyl oder Mesyl sein kann, mit einer Verbindung der Formelin which R 2 , R and R 4 have the meanings given in claim 1 and X 1 can be a leaving group and preferably shark or a reactive modified OH group, in particular tosyl or mesyl, with a compound of the formula
worinwherein
R1 die in Anspruch 1 angegebenen Bedeutungen aufweist,R 1 has the meanings given in claim 1,
umgesetzt wird.is implemented.
Die daraus resultierende Verbindung der Formel IVThe resulting compound of formula IV
worinwherein
R )1 , ι R-)2 , o R3 , D R4 und q die in Anspruch 1 angegebene Bedeutungen haben, wird durch Verseifung in die freie Säure umgewandelt und diese anschließend nach üblichen Methoden in die entsprechende Formel VR) 1, ι R-) 2, o R3, D R4 and q have the meanings given in claim 1, is converted into the free acid by hydrolysis and this is then converted into the corresponding formula V by customary methods
worin L Hai oder eine reaktionsfähige abgewandelte OH-Gruppe wie z.B. Tiflat, Nonaflat, Tosylat, Mesylat oder Benzolsulfonat, insbesondere aber Tosylat oder Mesylat bedeutet und R1, R2 , R3, R4 und q die in Anspruch 1 angegebene Bedeutungen haben, überführt. wherein L shark or a reactive modified OH group such as tiflate, nonaflate, tosylate, mesylate or benzenesulfonate, but especially tosylate or mesylate and R 1 , R 2 , R 3 , R 4 and q have the meanings given in claim 1 ,
Die Verbindung der Formel V wird dann in Gegenwart eines geeigneten Katalysators, wie z. B. eines Friedel-Craft-Katalysators, insbesondere AICI3 zu Formel IAThe compound of formula V is then in the presence of a suitable catalyst, such as. B. a Friedel craft catalyst, in particular AICI 3 to formula IA
umgesetzt, worin implemented where
R1, R2, R3 , R4 und q die in Anspruch 1 angegebene Bedeutungen haben.R 1 , R 2 , R 3 , R 4 and q have the meanings given in Claim 1.
Die Verbindungen der Formel IA sind bevorzugt.The compounds of formula IA are preferred.
Insbesondere bevorzugt sind die Verbindungen der Formel IA1 :The compounds of the formula IA1 are particularly preferred:
worin R1, R2, X, Y1 und n die oben angegebene Bedeutung aufweisen und R1 bevorzugt Methyl bedeutet. wherein R 1 , R 2 , X, Y 1 and n have the meaning given above and R 1 is preferably methyl.
Verbindungen der Formel I, worin R2 und/oder R3 H bedeuten, können beispielsweise durch Umsetzung mit einer Base wie zum Beispiel Natriumhydrid und einem Alkylierungsreagenz in die weiteren Verbindungen der Formel I, worin R2 und/oder R3 eine andere Bedeutung als H aufweisen, umgewandelt werden.Compounds of the formula I in which R 2 and / or R 3 are H can, for example, by reaction with a base such as sodium hydride and an alkylating reagent in the others Compounds of the formula I in which R 2 and / or R 3 have a meaning other than H are converted.
Besonders bevorzugt werden Alkylierungsreagenzien wie z.B. lodalkan,Alkylation reagents such as e.g. iodoalkane,
Alkylsulfat, Benzylhalogenide, -sulfate, -mesylate oder -tosylate, insbesondere lodmethan, Methylsulfat oder Benzylchlorid.Alkyl sulfate, benzyl halides, sulfates, mesylates or tosylates, especially iodomethane, methyl sulfate or benzyl chloride.
Verbindungen der Formel I worin R4 0 bedeutet, werden gegebenenfalls durch Umsetzung mit entsprechenden metallorganischen Reagenzien wie zum Beispiel lithiumorganische oder Grignard Verbindungen insbesondere Verbindungen der FormelnCompounds of the formula I in which R 4 is 0 are, if appropriate, in particular compounds of the formulas, by reaction with corresponding organometallic reagents such as organolithium or Grignard compounds
HalMg-CH2(CH2)nX(CH2),Q(CH2)sT oder Li-CH2(CH2)nX(CH2)ιQ(CH2)sT und nachfolgender Eliminierung in die weiteren Verbindungen der Formel I, worin R4 die oben angegebene Bedeutung aufweist, umgewandelt. Gegebenenfalls erhaltene E/Z-Isomerengemische können durch bekannte, vorzugsweise chromatographische Methoden, oder aber durch Kristallisation voneinander getrennt werden.HalMg-CH 2 (CH 2 ) n X (CH 2 ), Q (CH 2 ) s T or Li-CH 2 (CH 2 ) n X (CH 2 ) ιQ (CH 2 ) s T and subsequent elimination into the others Compounds of formula I, wherein R 4 has the meaning given above, converted. Any E / Z isomer mixtures obtained can be separated from one another by known, preferably chromatographic, methods or by crystallization.
Durch wässrige Aufarbeitung werden aus den durch Umsetzung der Verbindungen der Formel I, worin R4 O bedeutet, mit den genannten metallorganischen Reagenzien bevorzugt zunächst die entsprechenden tertiären Alkohle erhalten, die als Zwischenstufen ebenfalls Gegenstand der Erfindung sind. Besonders bevorzugt sind dies die Verbindungen der Formel A, B, C und D. By aqueous work-up, the corresponding tertiary alcohols, which are likewise an object of the invention, are preferably obtained from the reaction of the compounds of the formula I in which R 4 is O with the organometallic reagents mentioned. These are particularly preferably the compounds of the formulas A, B, C and D.
Die Sulfoxide (W=SO) und Sulfone (W=S02) der Verbindungen der Formel I, A, B, C und D lassen sich bevorzugt durch Oxidation der Verbindungen der Formel I, worin W S bzw. SO bedeutet, herstellen. Bevorzugt werden auch die Verbindungen der Formel I, IA, VIA und VIB als Ausgangsmaterialien für eine Oxidation des Schwefelatoms eingesetzt. Dies geschieht bevorzugt durch Anwendung von H202 oder anderen Oxidationsmitteln (z. B. nach Patai, „Supplement E, „ Ref. 42, pt. 1 , pp. 539-608; Org. Prep. Proced. Int. 14, 45-89 (1982); „The Chemistiγ of Sulfur," pp. 385-390, Plenum, New York, 1977; Tetrahedron Lett. 22, 1287 (1981)).The sulfoxides (W = SO) and sulfones (W = S0 2 ) of the compounds of the formula I, A, B, C and D can preferably be prepared by oxidation of the compounds of the formula I, in which WS or SO means. The compounds of the formula I, IA, VIA and VIB are also preferably used as starting materials for an oxidation of the sulfur atom. This is preferably done by using H 2 0 2 or others Oxidizing agents (e.g. according to Patai, "Supplement E," Ref. 42, pt. 1, pp. 539-608; Org. Prep. Proced. Int. 14, 45-89 (1982); "The Chemistiγ of Sulfur , "pp. 385-390, Plenum, New York, 1977; Tetrahedron Lett. 22, 1287 (1981)).
Ganz besonders bevorzugt werden die Verbindungen der Formel I worin W SO oder S02 bedeutet, hergestellt, indem man von entsprechenden am Schwefelatom oxidierten Zwischenstufen ausgeht, die sich durch Oxidation der Thioverbindungen der Formel II, IV und V erzeugen lassen. Die zu den Sulfoxiden oder Sulfonen oxidierten Verbindungen lassen sich wie die zugrundeliegenden Thioverbindungen der Formel II, IV und V umsetzen.The compounds of the formula I in which W is SO or SO 2 are very particularly preferably prepared by starting from corresponding intermediates which are oxidized on the sulfur atom and which can be produced by oxidation of the thio compounds of the formulas II, IV and V. The compounds oxidized to the sulfoxides or sulfones can be reacted like the underlying thio compounds of the formula II, IV and V.
Bevorzugt weist R4 in den Verbindungen der Formel II, IV und V die Bedeutung O auf.R 4 in the compounds of the formulas II, IV and V is preferably O.
Für die Formel III werden bevorzugt die nachfolgenden Formeln 1111- 15 eingesetzt:The following formulas 1111-15 are preferably used for the formula III:
wobei Verbindungen bevorzugt sind, die mit der Ausnahme von F keine Sustituenten an C-5, C-7 oder C-8 aufweisen (bezogen auf Formel I). Weiterhin sind die folgenden Verbindungen bevorzugt:with preference being given to compounds which, with the exception of F, have no substituents on C-5, C-7 or C-8 (based on formula I). The following compounds are also preferred:
sowie , insbesondere as well, in particular
Insbesondere werden für R2 und/oder R3 die nachfolgenden Gruppen bevorzugt: The following groups are particularly preferred for R 2 and / or R 3 :
insbesondere in particular
wobei Q f fü.--.r F, Cl, Br, oder A insbesondere Ethyl oder Methyl steht,where Q f stands for F, Cl, Br or A, in particular ethyl or methyl,
wobei Q1 und W1 für Cl, Br, A, insbesondere Methyl und Ethyl oder SA, und insbesondere SMethyl und SEthyl steht und worin R3 bevorzugt H oder Alkyl insbesondere Methyl bedeuten. R2 ist bevorzugt p- oder m- Hydroxyphenyl, sowie o, m oder p-Fluorphenyl. Vor- und nachstehend haben sämtliche Reste, wie z.B. die Reste R1, R2, R3, R4, R5, X, Q, Q1, Y, Y1, m , n , y, T, k, p, q, I und s die bei der Formel I angegebenen Bedeutungen, sofern nicht ausdrücklich etwas anderes angegeben ist. Bei mehrfachem Auftreten einzelner Reste innerhalb einer Verbindung nehmen die Reste unabhängig voneinander die angegebenen Bedeutungen an.where Q 1 and W 1 are Cl, Br, A, in particular methyl and ethyl or SA, and in particular SMethyl and SEthyl, and in which R 3 is preferably H or alkyl, in particular methyl. R 2 is preferably p- or m-hydroxyphenyl, and o, m or p-fluorophenyl. Above and below, all radicals, such as the radicals R 1 , R 2 , R 3 , R 4 , R 5 , X, Q, Q 1 , Y, Y 1 , m, n, y, T, k, p , q, I and s have the meanings given in formula I, unless expressly stated otherwise. If individual residues occur several times within a compound, the residues independently assume the meanings given.
Y1 bedeutet vorzugsweise COCH2NMe2.Y 1 preferably denotes COCH 2 NMe 2 .
Alkyl und ist bevorzugt unverzweigt (linear) oder verzweigt, und hat 1, 2, 3, 4, 5, 6, 7, 8, 9 oder 10 C-Atome. Alkyl bedeutet vorzugsweise Methyl, weiterhin Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.-Butyl oder tert.-Butyl, ferner auch Pentyl, 1-, 2- oder 3-Methylbutyl, 1 ,1- , 1,2- oder 2,2-Dimethyl- propyl, 1-Ethylpropyl, Hexyl, 1- , 2- , 3- oder 4-Methylpentyl, 1,1- , 1 ,2- , 1,3- , 2,2- , 2,3- oder 3,3-Dimethylbutyl, 1- oder 2-Ethylbutyl, 1-Ethyl-1-methyl- propyl, 1-Ethyl-2-methylpropyl, 1,1,2- oder 1,2, 2-Trimethylpropyl, weiter bevorzugt z.B. Trifluormethyl.Alkyl and is preferably unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1, 2-, 1,3-, 2,2-, 2,3 - or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, more preferred eg Trifluoromethyl.
Alkyl bedeutet ganz besonders bevorzugt Alkyl mit 1 , 2, 3, 4, 5 oder 6 C- Atomen, vorzugsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.- Butyl, tert.-Butyl, Pentyl, Hexyl, Trifluormethyl, Pentafluorethyl oder 1 ,1 ,1- Trifluorethyl. Alkyl bedeutet auch Cycloalkyl. Cycloalkyl bedeutet vorzugsweise Cyclopropyl, Cyclobutyl, Cylopentyl, Cyclohexyl oder Cycloheptyl.Alkyl very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl , Pentafluoroethyl or 1, 1, 1 trifluoroethyl. Alkyl also means cycloalkyl. Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
R1 bedeutet bevorzugt A, SR5, OR5, Hai, CN, N02, N(R5)2. Insbesondere bedeutet R Methyl, Ethyl, iso-Propyl, tert-Butyl, F, Cl, CN, oder OH.R 1 preferably denotes A, SR 5 , OR 5 , shark, CN, N0 2 , N (R 5 ) 2 . In particular, R denotes methyl, ethyl, isopropyl, tert-butyl, F, Cl, CN, or OH.
R2 bedeutet bevorzugt H, A wie zum Beispiel Ethyl, Phenyl, Methyl, Aryl ooddeerr HHeett.. IInnssbbeessoonnddeerree bbeeddceutet R2 A oder Ar. W bedeutet vorzugsweise S. R bedeutet bevorzugt H, A, Ar oder -(C(R5)2)oAr, Insbesondere bedeutetR 2 preferably denotes H, A, such as, for example, ethyl, phenyl, methyl, aryl ooddeerr HHeett. IInnssbbeessoonnddeerree bbeeddceutet R 2 A or Ar. W preferably means S. R preferably denotes H, A, Ar or - (C (R 5 ) 2 ) oAr, in particular denotes
R3 H oder A.R 3 H or A.
In besonders bevorzugten Verbindungen der Formel I bedeutet R2 Ar undIn particularly preferred compounds of the formula I, R 2 denotes Ar and
R3 gleichzeitig A.R 3 at the same time A.
R4 bedeutet bevorzugt cyclo[-C(CH2)k (NY1)-(CH2)P-] , oder E oder Z =CH(CH2)nX(CH2)ιQ(CH2)sT, insbesondere ,R 4 preferably denotes cyclo [-C (CH 2 ) k (NY 1 ) - (CH 2 ) P -], or E or Z = CH (CH 2 ) n X (CH 2 ) ιQ (CH 2 ) s T, in particular ,
sowie die E oder Z-Isomere der folgenden Gruppen R and the E or Z isomers of the following groups R
worin X, n, I, Q, s und T die oben angegebene Bedeutung aufweisen.wherein X, n, I, Q, s and T have the meaning given above.
Im Wesentlichen diastereomerenreine Verbindungen der Formel I d.h. reineSubstantially diastereomerically pure compounds of formula I i.e. pure
E- oder Z-Diasteromere sind bevorzugt.E or Z diasteromers are preferred.
Ar bedeutet bevorzugt Phenyl, o-, m- oder p-Tolyl, o-, m- oder p-Ethyl- phenyl, o-, m- oder p-Propylphenyl, o-, m- oder p-lsopropylphenyl, o-, m- oder p-tert.-Butylphenyl, o-, m- oder p-Hydroxyphenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p-Nitrophenyl, o-, m- oder p-Aminophenyl, o-, m- oder p-(N-Methylamino)-phenyl, o-, m- oder p-(N-Methylaminocarbonyl)- phenyl, o-, m- oder p-Acetamidophenyl, o-, m- oder p-Methoxyphenyl, o-, m- oder p-Ethoxyphenyl, o-, m- oder p-Ethoxycarbonylphenyl, o-, m- oder p-(N,N-Dimethylamino)-phenyl, o-, m- oder p-(N,N-Dimethylaminocarbonyl)- phenyl, o-, m- oder p-(N-Ethylamino)-phenyl, o-, m- oder p-(N,N- Diethylamino)-phenyl, o-, m- oder p-Fluorphenyl, o-, m- oder p-Bromphenyl, o-, m- oder p- Chlorphenyl, o-, m- oder p-(Methylsulfonamido)-phenyl, o-, m- oder p-(Methylsulfonyl)-phenyl, weiter bevorzugt 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Difluorphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dichlor- phenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- oder 3,5-Dibromphenyl, 2,4- oder 2,5-Ar preferably denotes 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-dichloro- phenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-
Dinitrophenyl, 2,5- oder 3,4-Dimethoxyphenyl, 3-Nitro-4-chlorphenyl, 3-Dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-
Amino-4-chlor-, 2-Amino-3-chlor-, 2-Amino-4-chlor-, 2-Amino-5-chlor- oderAmino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or
2-Amino-6-chlorphenyl, 2-Nitro-4-N,N-dimethylamino- oder 3-Nιtro-4-N,N- dimethylammophenyl, 2,3-Diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- oder2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino- or 3-nitro-4-N, N-dimethylammophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3, 5-, 2,3,6-, 2,4,6- or
3,4,5-Trichlorphenyl, 2,4,6-Trimethoxyphenyl, 2-Hydroxy-3,5-dichlorphenyl, p-lodphenyl, 3,6-Dichlor-4-aminophenyl, 4-Fluor-3-chlorphenyl, 2-Fluor-4- bromphenyl, 2,5-Difluor-4-bromphenyl, 3-Brom-6-methoxyphenyl, 3-Chlor- 6-methoxyphenyl, 3-Chlor-4-acetamidophenyl, 3-Fluor-4-methoxyphenyl, 3-3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2- Fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-
Amino-6-methylphenyl, 3-Chlor-4-acetamidophenyl oder 2,5-Dimethyl-4- chlorphenyl.Amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.
Het bedeutet vorzugsweise einen ein- oder zweikernigen aromatischen oder gesättigten Heterocyclus mit einem oder mehreren N-, O- und/oder S-Het preferably means a mono- or dinuclear aromatic or saturated heterocycle with one or more N-, O- and / or S-
Atomen, der unsubstituiert oder ein-, zwei- oder dreifach durch Hai, Methyl,Atoms that are unsubstituted or one, two or three times by shark, methyl,
N02l NHA, NA2, OA, COOA oder CN substituiert sein kann. AromatischeN0 2l NHA, NA 2 , OA, COOA or CN can be substituted. aromatic
Gruppen Het sind bevorzugt.Het groups are preferred.
Ungeachtet weiterer Substitutionen, bedeutet Het unsubstituiertes Heteroaryl. Dies ist z.B. 2- oder 3-Furyl, 2- oder 3-Thienyl, 1-, 2- oder 3- Pyrrolyl, 1-, 2, 4- oder 5-lmidazolyl, 1-, 3-, 4- oder 5-Pyrazolyl, 2-, 4- oder 5- Oxazolyl, 3-, 4- oder 5-lsoxazolyl, 2-, 4- oder 5-Thiazolyl, 3-, 4- oder 5- Isothiazolyl, 2-, 3- oder 4-Pyridyl, 2-, 4-, 5- oder 6-Pyrimidinyl, weiterhin bevorzugt 1 ,2,3-Triazo -, -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-Regardless of other substitutions, Het means unsubstituted heteroaryl. This is e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2 -, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 -, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazo -, -4- or -5-yl, 1, 2,4-triazol-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- oder -5-yl, 3- oder 4-Pyridazinyl, Pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- oder 7-lndolyl, 4- oder 5-lsoindolyi, 1-, 2-, 4- oder 5-Benzimidazolyl, 1-, 3-, 4-, 5-, 6- oder 7-Benzopyrazolyl, 2-, 4-, 5-, 6- oder 7-Benzoxazolyl, 3-, 4-, 5-Thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyi, 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- 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-,, 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- 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 bevorzugt5-, 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- oder -1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-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.Shark is preferably F, Cl or Br, but also I, particularly preferably F or Cl.
Für die gesamte Erfindung gilt, daß sämtliche Reste, die mehrfach auftreten, gleich oder verschieden sein können, d.h. unabhängig voneinander sind.It applies to the entire invention that all residues which occur more than once can be the same or different, i.e. are independent of each other.
Die Verbindungen der Formel I können ein oder mehrere chirale Zentren besitzen und daher in verschiedenen stereoisomeren Formen vorkommen. Die Formel I umschließt alle diese Formen.The compounds of formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms. Formula I encompasses all of these forms.
Dementsprechend sind Gegenstand der Erfindung insbesondere diejenigen Verbindungen der Formel I, in denen mindestens einer der genannten Reste eine der vorstehend angegebenen bevorzugten Bedeutungen hat.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 indicated above.
Einige bevorzugte Gruppen von Verbindungen können durch die folgenden Teilformeln 11 bis I64 ausgedrückt werden:Some preferred groups of compounds can be expressed by the following sub-formulas 11 to I64:
3030
35 35
1010
2020
35 35
1010
115 115
35 35
1010
35 35
131 131
30 30
35 I3735 I37
I40 I40
I43 I43
15 I4615 I46
I47 I47
35 35
35 35
I64 I64
Die Verbindungen der Formel I und auch die Ausgangsstoffe zu ihrer Herstellung werden im übrigen nach an sich bekannten Methoden hergestellt, wie sie in der Literatur (z.B. in den Standardwerken wie Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) beschrieben sind, und zwar unter Reaktionsbedingungen, die für die genannten Umsetzungen bekannt und geeignet sind. Dabei kann man auch von an sich bekannten, hier nicht näher erwähnten Varianten Gebrauch machen.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 (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart). are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.
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 l umsetzt.If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
Als inerte Lösungsmittel eignen sich z.B. Kohlenwasserstoffe wie Hexan, Petrolether, Benzol, Toluol oder Xylol; 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 the solvents mentioned.
Gewünschtenfalls kann in einer Verbindung der Formel I eine funktioneil abgewandelte Amino- und /oder Hydroxygruppe durch Solvolyse oder Hydrogenolyse nach üblichen Methoden in Freiheit gesetzt werden. Dies kann z.B. mit NaOH oder KOH in Wasser, Wasser-THF oder Wasser- Dioxan bei Temperaturen zwischen 0 und 100° erfolgen.If desired, a functionally modified amino and / or hydroxyl group in a compound of the formula I can be obtained by solvolysis or Hydrogenolysis can be set free according to customary methods. This can be done, for example, with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
Die Reduktion eines Esters zum Aldehyd oder zum Alkohol, oder die Reduktion eines Nitrils zum Aldehyd oder Amin erfolgt nach Methoden wie sie dem Fachmann bekannt sind und in Standardwerken der organischen Chemie beschrieben sind.The reduction of an ester to the aldehyde or to the alcohol, or the reduction of a nitrile to the aldehyde or amine, is carried out by methods known to the person skilled in the art and described in standard works in organic chemistry.
10 Die genannten erfindungsgemäßen Verbindungen lassen sich in ihrer endgültigen Nichtsalzform verwenden. Andererseits umfaßt die vorliegende Erfindung auch die Verwendung dieser Verbindungen in Form ihrerThe compounds according to the invention mentioned can be used in their final non-salt form. On the other hand, the present invention also includes the use of these compounds in the form of them
A C pharmazeutisch unbedenklichen Salze, die von verschiedenen organischen und anorganischen Säuren und Basen nach fachbekannten Vorgehensweisen abgeleitet werden können. Pharmazeutisch unbedenkliche Salzformen der Verbindungen der Formel I werden größtenteils konventionell hergestellt. Sofern die Verbindung der Formel I eine Carbonsäure¬A C pharmaceutically acceptable salts that can be derived from various organic and inorganic acids and bases according to procedures known in the art. Most of the pharmaceutically acceptable salt forms of the compounds of formula I are prepared conventionally. If the compound of formula I is a carboxylic acid
20 gruppe 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 Alkalimetall- hydroxide, darunter Kaliumhydroxid, Natriumhydroxid und Lithiumhydroxid; 5 Erdalkalimetallhydroxide wie Bariumhydroxid und Calciumhydroxid; Alkali- metallalkoholate, z.B. Kaliumethanolat und Natriumpropanolat; sowie verschiedene organische Basen wie Piperidin, Diethanolamin und N-Methylglutamin. Die Aluminiumsalze der Verbindungen der Formel IContains 20 group, one of their suitable salts can be formed by reacting the compound with a suitable base to the corresponding base addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; 5 alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; as well as various organic bases such as piperidine, diethanolamine and N-methylglutamine. The aluminum salts of the compounds of formula I.
30 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 5 wie Sulfat, Nitrat oder Phosphat und dergleichen sowie Alkyl- und Monoarylsulfonaten wie Ethansulfonat, Toluolsulfonat und Benzolsulfonat, sowie anderen organischen Säuren und ihren entsprechenden Salzen wie 30 also count. For 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 hydrogen iodide, other mineral acids and their corresponding salts 5 such as sulfate, nitrate or phosphate and the like and alkyl and monoaryl sulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, as well as other organic acids and their corresponding salts such as
Acetat, Trifluoracetat, Tartrat, Maleat, Succinat, Citrat, Benzoat, Salicylat,Acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate,
Ascorbat und dergleichen behandelt. Dementsprechend zählen zu pharmazeutisch unbedenklichen Säureadditionssalzen der Verbindungen der Formel I die folgenden: Acetat, Adipat, Alginat, Arginat, Aspartat,Ascorbate and the like treated. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of the formula I include the following: acetate, adipate, alginate, arginate, aspartate,
Benzoat, Benzolsulfonat (Besylat), Bisulfat, Bisulfit, Bromid, Butyrat,Benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate,
Kampferat, Kampfersulfonat, Caprylat, Chlorid, Chlorbenzoat, Citrat,Camphorate, camphor sulfonate, caprylate, chloride, chlorobenzoate, citrate,
Cyclopentanpropionat, Digluconat, Dihydrogenphosphat, Dinitrobenzoat, Dodecylsulfat, Ethansulfonat, Fumarat, Galacterat (aus Schleimsäure), Galacturonat, Glucoheptanoat, Gluconat, Glutamat, Glycerophosphat, Hemisuccinat, Hemisulfat, Heptanoat, Hexanoat, Hippurat, Hydrochlorid, Hydrobromid, Hydroiodid, 2-Hydroxyethansulfonat, lodid, Isethionat, Isobutyrat, Lactat, Lactobionat, Malat, Maleat, Malonat, Mandelat,Cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, 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, maleate, malonate, mandelate,
Metaphosphat, Methansulfonat, Methylbenzoat, Monohydrogenphosphat,Metaphosphate, methanesulfonate, methyl benzoate, monohydrogen phosphate,
2-Naphthalinsulfonat, Nicotinat, Nitrat, Oxalat, Oleat, Pamoat, Pectinat,2-naphthalene sulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate,
Persulfat, Phenylacetat, 3-Phenylpropionat, Phosphat, Phosphonat,Persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate,
Phthalat, was jedoch keine Einschränkung darstellt.Phthalate, but this is not a limitation.
Weiterhin zählen zu den Basensalzen der erfindungsgemäßen Verbindungen Aluminium-, Ammonium-, Calcium-, Kupfer-, Eisen(lll)-, Eisen(ll)-, Lithium-, Magnesium-, Mangan(lll)-, Mangan(ll), Kalium-, Natrium- und Zinksalze, was jedoch keine Einschränkung darstellen soll. Bevorzugt unter den oben genannten Salzen sind Ammonium; die Alkalimetallsalze Natrium und Kalium,sowie die Erdalkalimetalsalze Calcium und Magnesium. Zu Salzen der Verbindungen der Formel I, die sich von pharmazeutisch unbedenklichen organischen nicht-toxischen Basen ableiten, zählen Salze primärer, sekundärer und tertiärer Amine, substituierter Amine, darunter auch natürlich vorkommender substituierter Amine, cyclischer Amine sowie basischer lonenaustauscherharze, z.B.The base salts of the compounds according to the invention also include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium -, sodium and zinc salts, but this should not be a limitation. Preferred among the salts mentioned above are ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts calcium and magnesium. Salts of the compounds of the formula I which are derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g.
Arginin, Betain, Koffein, Chlorprocain, Cholin, N,N'-DibenzylethylendiaminArginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine
(Benzathin), Dicyclohexylamin, Diethanolamin, Diethylamin, 2-Diethyl- aminoethanol, 2-Dimethylaminoethanol, Ethanolamin, Ethylendiamin, N- Ethylmorpholin, N-Ethylpiperidin, Glucamin, Glucosamin, Histidin,(Benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- Ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,
Hydrabamin, Iso-propylamin, Lidocain, Lysin, Meglumin, N-Methyl-D- glucamin, Morpholin, Piperazin, Piperidin, Polyaminharze, Procain, Purine,Hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procain, purines,
Theobromin, Triethanolamin, Triethylamin, Trimethylamin, Tripropylamin sowie Trιs-(hydroxymethyl)-methylamin (Tromethamin), was jedoch keineTheobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and Trιs- (hydroxymethyl) methylamine (tromethamine), but none
Einschränkung darstellen soll.To represent limitation.
Verbindungen der vorliegenden Erfindung, die basische stickstoffhaltige Gruppen enthalten, lassen sich mit Mitteln wie (C1-C4) Alkylhalogeniden, z.B. Methyl-, Ethyl-, Isopropyl- und tert.-Butylchlorid, -bromid und -iodid;Compounds of the present invention which contain basic nitrogen-containing groups can be prepared using agents such as (C 1 -C 4 ) alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide;
Di(Cι-C4)Alkylsulfaten, z.B. Dimethyl-, Diethyl- und Diamylsulfat; (C10-Di (-C 4 ) alkyl sulfates, such as dimethyl, diethyl and diamyl sulfate; (C 10 -
Ci8)Alkylhalogeniden, z.B. Decyl-, Dodecyl-, Lauryl-, Myristyl- und Stearylchlorid, -bromid und -iodid; sowie Aryl-(Cι-C4)Alkylhaiogeniden, z.B.Ci 8 ) alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; as well as aryl (C 1 -C 4 ) alkylhaiogenides, for example
Benzylchlorid und Phenethylbromid, quartemisieren. Mit solchen Salzen können sowohl wasser- als auch öllösliche erfindungsgemäßeBenzyl chloride and phenethyl bromide, quartemize. With such salts, both water- and oil-soluble according to the invention
Verbindungen hergestellt werden.Connections are made.
Zu den oben genannten pharmazeutischen Salzen, die bevorzugt sind, zählen Acetat, Trifluoracetat, Besylat, Citrat, Fumarat, Gluconat,The above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,
Hemisuccinat, Hippurat, Hydrochlorid, Hydrobromid, Isethionat, Mandelat,Hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate,
Meglumin, Nitrat, Oleat, Phosphonat, Pivalat, Natriumphosphat, Stearat, Sulfat, Sulfosalicylat, Tartrat, Thiomalat, Tosylat und Tromethamin, was jedoch keine Einschränkung darstellen soll.Meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to be a limitation.
Die Säureadditionssalze basischer Verbindungen der Formel l werden dadurch hergestellt, daß man die freie Basenform mit einer ausreichenden Menge der gewünschten Säure in Kontakt bringt, wodurch man auf übliche Weise das Salz darstellt. Die freie Base läßt sich durch In-Kontakt-Bringen der Salzform mit einer Base und Isolieren der freien Base auf üblicheThe acid addition salts of basic compounds of the formula I are prepared by contacting the free base form with a sufficient amount of the desired acid, which is how the salt is prepared in the usual way. The free base can be obtained by contacting the salt form with a base and isolating the free base to conventional ones
Weise regenerieren. Die freien Basenformen unterscheiden sich in gewis- sem 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 Basenformen.Regenerate wisely. The free base forms differ in a sense from their corresponding salt forms with regard to certain physical properties such as solubility in polar solvents; in the In the context of the invention, however, the salts otherwise correspond to their respective free base forms.
Wie erwähnt werden die pharmazeutisch unbedenklichen Basenadditions-As mentioned, the pharmaceutically acceptable base addition
5 salze der Verbindungen der Formel I mit Metallen oder Aminen wie Alkalimetallen und Erdalkalimetallen oder organischen Aminen gebildet. Bevorzugte Metalle sind Natrium, Kalium, Magnesium und Calcium. Bevorzugte organische Amine sind N,N'-Dibenzylethylendiamin, Chlorprocain,5 salts of the compounds of formula I with metals or amines such as alkali metals and alkaline earth metals or organic amines are formed. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine,
10 Cholin, Diethanolamin, Ethylendiamin, N-Methyl-D-glucamin und Procain.10 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 A C ausreichenden Menge der gewünschten Base in Kontakt bringt, wodurch man das Salz auf übliche Weise darstellt. Die freie Säure läßt sich durch In- Kontakt-Bringen der Salzform mit einer Säure und Isolieren der freien Säure auf übliche Weise regenerieren. Die freien Säureformen unterscheiden sich in gewissem Sinn von ihren entsprechenden Salzformen inThe base addition salts of acidic compounds according to the invention are prepared by bringing the free acid form with a C A sufficient amount of the desired base, causing the formation of the salt in the conventional manner. The free acid can be regenerated in a conventional manner by contacting the salt form with an acid and isolating the free acid. The free acid forms differ in a sense from their corresponding salt forms in
20 bezug auf bestimmte physikalische Eigenschaften wie Löslichkeit in polaren Lösungsmitteln; im Rahmen der Erfindung entsprechen die Salze jedoch sonst ihren jeweiligen freien Säureformen.20 related to certain physical properties such as solubility in polar solvents; in the context of the invention, however, the salts otherwise correspond to their respective free acid forms.
25 Enthält eine erfindungsgemäße Verbindung mehr als eine Gruppe, die solche pharmazeutisch unbedenklichen Salze bilden kann, so umfaßt die Erfindung auch mehrfache Salze. Zu typischen mehrfachen Salzformen zählen zum Beispiel Bitartrat, Diacetat, Difumarat, Dimeglumin, Diphosphat,25 If a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, the invention also includes multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate,
30 Dinatrium und Trihydrochlorid, was jedoch keine Einschränkung darstellen soll. 30 disodium and trihydrochloride, but this should not be a limitation.
Im Hinblick auf das oben Gesagte sieht man, daß unter dem Ausdruck "pharmazeutisch unbedenkliches Salz" im vorliegenden ZusammenhangIn view of the above, it can be seen that the term "pharmaceutically acceptable salt" in the present context
35 ein Wirkstoff zu verstehen ist, der eine Verbindung der Formel I in der Form eines ihrer Salze enthält, insbesondere dann, wenn diese Salzform dem Wirkstoff im Vergleich zu der freien Form des Wirkstoffs oder irgendeiner anderen Salzform des Wirkstoffs, die früher verwendet wurde, verbesserte pharmakokinetische Eigenschaften verleiht. Die pharmazeutisch unbedenkliche Salzform des Wirkstoffs kann auch diesem Wirkstoff erst eine gewünschte pharmakokinetische Eigenschaft verleihen, über die er früher nicht verfügt hat, und kann sogar die Pharmakodynamik dieses Wirkstoffs in bezug auf seine therapeutische Wirksamkeit im Körper positiv beeinflussen.35 is to be understood as an active ingredient which contains a compound of the formula I in the form of one of its salts, especially when this salt form Drug gives improved pharmacokinetic properties compared to the free form of the drug or any other salt form of the drug used previously. The pharmaceutically acceptable salt form of the active ingredient can also give this active ingredient a desired pharmacokinetic property which it did not previously have, and can even have a positive influence on the pharmacodynamics of this active ingredient with regard to its therapeutic effectiveness in the body.
10 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 A g allen Verhältnissen, sowie gegebenenfalls Träger- und/oder Hilfsstoffe.The invention further relates to medicaments containing at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in A g in all ratios, and, if appropriate, carriers and / or auxiliaries.
Pharmazeutische Formulierungen können in Form von Dosiseinheiten, die eine vorbestimmte Menge an Wirkstoff pro Dosiseinheit enthalten, dargereicht werden. Eine solche Einheit kann beispielsweise 0,5 mg bis 1 g,Pharmaceutical formulations can be presented in the form of dose units containing a predetermined amount of active ingredient per dose unit. Such a unit can, for example, 0.5 mg to 1 g,
20 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 in20 preferably contain 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the condition of the disease being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be used in
25 Form von Dosiseinheiten, die eine vorbestir imte Menge an Wirkstoff pro Dosiseinheit enthalten, dargereicht werden. Bevorzugte Dosierungs- einheitsformulierungen sind solche, die eine Tagesdosis oder Teildosis, wie oben angegeben, oder einen entsprechenden Bruchteil davon eines Q Wirkstoffs enthalten. Weiterhin lassen sich solche pharmazeutischen Formulierungen mit einem der im pharmazeutischen Fachgebiet allgemein bekannten Verfahren herstellen.25 form of dose units, which contain a predetermined amount of active ingredient per dose unit. Preferred dosage unit formulations are those which contain a daily dose or partial dose, as stated above, or a corresponding fraction thereof of a Q active ingredient. Furthermore, such pharmaceutical formulations can be produced using one of the methods generally known in the pharmaceutical field.
Pharmazeutische Formulierungen lassen sich zur Verabreichung überPharmaceutical formulations can be administered
35 einen beliebigen geeigneten Weg, beispielsweise auf oralem (einschließlich buccalem bzw. sublingualem), rektalem, nasalem, topischem (einschließlich buccalem, sublingualem oder transdermalem), vaginalem oder parenteralem (einschließlich subkutanem, intramuskulärem, intravenösem oder intradermalem) Wege, anpassen. Solche35 any suitable route, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such
Formulierungen können mit allen im pharmazeutischen Fachgebiet bekannten Verfahren hergestellt werden, indem beispielsweise derFormulations can be prepared by any method known in the pharmaceutical art, for example by the
Wirkstoff mit dem bzw. den Trägerstoff(en) oder Hilfsstoff (en) zusammengebracht wird.Active ingredient is brought together with the carrier (s) or auxiliary (s).
An die orale Verabreichung angepaßte pharmazeutische Formulierungen können als separate Einheiten, wie z.B. Kapseln oder Tabletten; Pulver oder Granulate; Lösungen oder Suspensionen in wäßrigen oder nichtwäßrigen Flüssigkeiten; eßbare Schäume oder Schaumspeisen; oder Öl-in- Wasser-Flüssigemulsionen oder Wasser-in-ÖI-FIüssigemulsionen dargereicht werden.Pharmaceutical formulations adapted for oral administration can be used as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam dishes; 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, nichttoxischen und pharmazeutisch unbedenklichen inerten Trägerstoff, wie z.B. Ethanol, Glyzerin, Wasser u.a. kombinieren. Pulver werden hergestellt, indem die Verbindung auf eine geeignete feine Größe zerkleinert und mit einem in ähnlicher Weise zerkleinerten pharmazeutischen Trägerstoff, wie z.B. einem eßbaren Kohlenhydrat wie beispielsweise Stärke oder Mannit vermischt wird. Ein Geschmacksstoff, Konservierungsmittel, Dispersionsmittel und Farbstoff können ebenfalls vorhanden sein.For example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component can be administered with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as e.g. Ethanol, glycerin, water etc. combine. Powders are made by comminuting the compound to an appropriate fine size and with a similarly comminuted pharmaceutical carrier such as e.g. an edible carbohydrate such as starch or mannitol is mixed. A flavor, preservative, dispersant and color may also be present.
Kapseln werden hergestellt, indem ein Pulvergemisch wie oben beschrieben hergestellt und geformte Gelatinehüllen damit gefüllt werden. Gleit- und Schmiermittel wie z.B. hochdisperse Kieselsäure, Talkum, Magnesiumstearat, Kalziumstearat oder Polyethylenglykol in Festform können dem Pulvergemisch vor dem Füllvorgang zugesetzt werden. EinCapsules are made by making a powder mixture as described above and filling shaped gelatin shells with it. Lubricants such as e.g. finely divided silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process. On
Sprengmittel oder Lösungsvermittler, wie z.B. Agar-Agar, Kalziumcarbonat oder Natriumcarbonat, kann ebenfalls zugesetzt werden, um die Verfügbarkeit des Medikaments nach Einnahme der Kapsel zu verbessern.Disintegrants or solubilizers, such as agar-agar, calcium carbonate or sodium carbonate, can also be added to improve the availability of the medication after taking the capsule.
Außerdem können, falls gewünscht oder notwendig, geeignete Bindungs-,In addition, if desired or necessary, suitable binding,
Schmier- und Sprengmittel sowie Farbstoffe ebenfalls in das Gemisch eingearbeitet werden. Zu den geeigneten Bindemitteln gehören Stärke,Lubricants, disintegrants and dyes can also be incorporated into the mixture. Suitable binders include starch,
Gelatine, natürliche Zucker, wie z.B. Glukose oder Beta-Lactose, Süßstoffe aus Mais, natürliche und synthetische Gummi, wie z.B. Akazia, Traganth oder Natriumalginat, Carboxymethylzellulose, Polyethylenglykol, Wachse, u.a. Zu den in diesen Dosierungsformen verwendeten Schmiermitteln gehören Natriumoleat, Natriumstearat, Magnesiumstearat, Natriumbenzoat, Natriumacetat, Natriumchlorid u.a. Zu den Sprengmitteln gehören, ohne darauf beschränkt zu sein, Stärke, Methylzellulose, Agar, Bentonit,Gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and others. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite,
Xanthangummi u.a. Die Tabletten werden formuliert, indem beispielsweise ein Pulvergemisch hergestellt, granuliert oder trockenverpreßt wird, ein Schmiermittel und ein Sprengmittel zugegeben werden und das Ganze zu Tabletten verpreßt wird. Ein Pulvergemisch wird hergestellt, indem die in geeigneter Weise zerkleinerte Verbindung mit einem Verdünnungsmittel oder einer Base, wie oben beschrieben, und gegebenenfalls mit einem Bindemittel, wie z.B. Carboxymethylzellulose, einem Alginat, Gelatine oder Polyvinylpyrrolidon, einem Lösungsverlangsamer, wie z.B. Paraffin, einem Resorptionsbeschleuniger, wie z.B. einem quatemären Salz und/oder einem Absorptionsmittel, wie z.B. Bentonit, Kaolin oder Dikalziumphosphat, vermischt wird. Das Pulvergemisch läßt sich granulieren, indem es mit einem Bindemittel, wie z.B. Sirup, Stärkepaste, Acadia-Schleim oder Lösungen aus Zellulose- oder Polymermaterialen benetzt und durch ein Sieb gepreßt wird. Als Alternative zur Granulierung kann man das Pulvergemisch durch eine Tablettiermaschine laufen lassen, wobei ungleichmäßig geformte Klumpen entstehen, die in Granulate aufgebrochen werden. Die Granulate können mittels Zugabe von Stearinsäure, einem Stearatsalz, Talkum oder Mineralöl gefettet werden, um ein Kleben an den Tablettengußformen zu verhindern. Das gefettete Gemisch wird dann zu Tabletten verpreßt. Die erfindungsgemäßen Verbindungen können auch mit einem freifließenden inerten Trägerstoff kombiniert und dann ohne Durchführung der Granulierungs- oderXanthan gum, etc. The tablets are formulated by, for example, producing a powder mixture, granulating or dry-pressing, adding a lubricant and a disintegrant and compressing the whole to tablets. A powder mixture is prepared by appropriately comminuting the compound with a diluent or a base as described above, and optionally with a binder such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution retarder such as paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent such as bentonite, kaolin or dicalcium phosphate, is mixed. The powder mixture can be granulated by wetting it with a binder, such as syrup, starch paste, Acadia mucilage or solutions made of cellulose or polymer materials, and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine, resulting in irregularly shaped lumps which are broken up into granules. The granules can be greased by adding stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased The mixture is then compressed into tablets. The compounds according to the invention can also be combined with a free-flowing inert carrier and then without carrying out the granulation or
Trockenverpressungssch ritte direkt zu Tabletten verpreßt werden. Eine durchsichtige oder undurchsichtige Schutzschicht, bestehend aus einerDry compression steps can be pressed directly into tablets. A transparent or opaque protective layer consisting of a
Versiegelung aus Schellack, einer Schicht aus Zucker oder Polymermaterial und einer Glanzschicht aus Wachs, kann vorhanden sein. Diesen Beschichtungen können Farbstoffe zugesetzt werden, um zwischen unter- schiedlichen Dosierungseinheiten unterscheiden zu können.Shellac, a layer of sugar or polymeric material and a glossy layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.
Orale Flüssigkeiten, wie z.B. Lösung, Sirupe und Elixiere, können in Form von Dosierungseinheiten hergestellt werden, so daß eine gegebene Quantität eine vorgegebene Menge der Verbindung enthält. Sirupe lassen sich herstellen, indem die Verbindung in einer wäßrigen Lösung mit geeignetem Geschmack gelöst wird, während Elixiere unter Verwendung eines nichttoxischen alkoholischen Vehikels hergestellt werden. Suspensionen können durch Dispersion der Verbindung in einem nichttoxischen 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.ä. können ebenfalls zugegeben werden.Oral liquids, e.g. Solution, syrups and elixirs can be prepared in unit dosage forms so that a given quantity contains a given amount of the compound. Syrups can be made by dissolving the compound in an aqueous solution with a suitable taste, while elixirs are made 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, flavor additives such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. 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.ä.Dosage unit formulations for oral administration can optionally be enclosed in microcapsules. The formulation can also be prepared in such a way that the release is prolonged or delayed, for example by coating or embedding particulate material in polymers, wax and the like.
Die Verbindungen der Formel I sowie Salze, Solvate und physiologisch funktioneile 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 the formula I and salts, solvates and physiologically functional derivatives thereof can also be large in the form of liposome delivery systems, such as small unilamellar vesicles unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
5 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 mit5 The compounds of formula I as well as the salts, solvates and physiologically functional derivatives thereof can also be supplied using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The connections can also be made with
10 löslichen Polymeren als zielgerichtete Arzneistoffträger gekoppelt werden. Solche Polymere können Polyvinylpyrrolidon, Pyran-Copolymer, Poly- hydroxypropylmethacrylamidphenol, Polyhydroxyethylaspartamidphenol oder Polyethylenoxidpolylysin, substituiert mit Palmitoylresten, umfassen.10 soluble polymers can be coupled as targeted drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethylaspartamide phenol or polyethylene oxide polylysine substituted with palmitoyl residues.
Λ C Weiterhin können die Verbindungen an eine Klasse von biologisch abbaubaren Polymeren, die zur Erzielung einer kontrollierten Freisetzung eines Arzneistoffs geeignet sind, z.B. Polymilchsäure, Polyepsilon-Caprolacton, Polyhydroxybuttersäure, Polyorthoester, Polyacetale, Polydihydroxypyrane, Polycyanoacrylate und quervernetzte oder amphipatische BlockcopolymereΛ C Furthermore, the compounds can be linked to a class of biodegradable polymers which are suitable for achieving a controlled release of a pharmaceutical, e.g. Polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and cross-linked or amphipatic block copolymers
20 von Hydrogelen, gekoppelt sein.20 of hydrogels.
An die transdermale Verabreichung angepaßte pharmazeutische Formulierungen können als eigenständige Pflaster für längeren, engen 25 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.Pharmaceutical formulations adapted for transdermal administration can be administered as independent patches for prolonged, close contact with the epidermis of the recipient. For example, the active ingredient can be supplied from the patch by means of iontophoresis, as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
30 An die topische Verabreichung angepaßte pharmazeutische Verbindungen können als Salben, Cremes, Suspensionen, Lotionen, Pulver, Lösungen, Pasten, Gele, Sprays, Aerosole oder Öle formuliert sein.Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
35 Für Behandlungen des Auges oder anderer äußerer Gewebe, z.B. Mund und Haut, werden die Formulierungen vorzugsweise als topische Salbe oder Creme appliziert. Bei Formulierung zu einer Salbe kann der Wirkstoff entweder mit einer paraffinischen oder einer mit Wasser mischbaren Cremebasis eingesetzt werden. Alternativ kann der Wirkstoff zu einer Creme mit einer Öl-in-Wasser-Cremebasis oder einer Wasser-in-ÖI-Basis 5 formuliert werden.35 For treatments of the eye or other external tissues, such as the mouth and skin, the formulations are preferably used as a topical ointment or cream applied. When formulated into an ointment, the active ingredient can be used either with a paraffinic or with a water-miscible cream base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base 5.
Zu den an die topische Applikation am Auge angepaßten pharmazeutischen Formulierungen gehören Augentropfen, wobei der Wirkstoff in 10 einem geeigneten Träger, insbesondere einem wäßrigen Lösungsmittel, gelöst oder suspendiert ist.Pharmaceutical formulations adapted for topical application to the eye include eye drops, the active ingredient being dissolved or suspended in a suitable carrier, in particular an aqueous solvent.
An die topische Applikation im Mund angepaßte pharmazeutische A C Formulierungen umfassen Lutschtabletten, Pastillen und Mundspülmittel.Pharmaceutical A C formulations adapted for topical application in the mouth include lozenges, lozenges and mouthwashes.
An die rektale Verabreichung angepaßte pharmazeutische Formulierungen können in Form von Zäpfchen oder Einlaufen dargereicht werden.Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas.
20 An die nasale Verabreichung angepaßte pharmazeutische Formulierungen, in denen die Trägersubstanz ein Feststoff ist, enthalten ein grobes Pulver mit einer Teilchengröße beispielsweise im Bereich von 20-500 Mikrometern, das in der Art und Weise, wie Schnupftabak aufgenommen 5 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 umfassenPharmaceutical formulations adapted for nasal administration, in which the carrier substance is a solid, contain a coarse powder with a particle size, for example in the range of 20-500 micrometers, which is administered in the manner in which snuff is taken up, i.e. by rapid inhalation via the nasal passages from a container with the powder held close to the nose. Suitable formulations for administration as a nasal spray or nasal drops with a liquid as carrier include
3Q Wirkstofflösungen in Wasser oder Öl. 3 Q active ingredient solutions in water or oil.
An die Verabreichung durch Inhalation angepaßte pharmazeutische Formulierungen umfassen feinpartikuläre Stäube oder Nebel, die mittels verschiedener Arten von unter Druck stehenden Dosierspendern mitPharmaceutical formulations adapted for administration by inhalation include fine particulate dusts or mists, which are formed using various types of pressurized dispensers
35 Aerosolen, Verneblern oder Insufflatoren erzeugt werden können. An die vaginale Verabreichung angepaßte pharmazeutische35 aerosols, nebulizers or insufflators can be generated. Pharmaceutical adapted for vaginal administration
Formulierungen können als Pessare, Tampons, Cremes, Gele, Pasten,Formulations can be used as pessaries, tampons, creams, gels, pastes,
Schäume oder Sprayformulierungen dargereicht werden.Foams or spray formulations are given.
Zu den an die parenterale Verabreichung angepaßten pharmazeutischen Formulierungen gehören wäßrige und nichtwäßrige sterile Injektionslösungen, die Antioxidantien, Puffer, Bakteriostatika und Solute, durch die die Formulierung isotonisch mit dem Blut des zu behandelndenPharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions, the antioxidants, buffers, bacteriostatics and solutes, through which the formulation is isotonic with the blood of the person to be treated
Empfängers gemacht wird, enthalten; sowie wäßrige und nichtwäßrige sterile Suspensionen, die Suspensionsmittel und Verdicker enthalten können. Die Formulierungen können in Einzeldosis- oder Mehrfach- dosisbehältem, z.B. versiegelten Ampullen und Fläschchen, dargereicht und in gefriergetrocknetem (lyophilisiertem) Zustand gelagert werden, so daß nur die Zugabe der sterilen Trägerflüssigkeit, z.B. Wasser für Injektionszwecke, unmittelbar vor Gebrauch erforderlich ist. Rezepturmäßig hergestellte Injektionslösungen und Suspensionen können aus sterilen Pulvern, Granulaten und Tabletten hergestellt werden.Recipient is made included; as well as aqueous and non-aqueous sterile suspensions, which can contain suspending agents and thickeners. The formulations can be in single dose or multiple dose containers, e.g. sealed ampoules and vials, presented and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections is required immediately before use. Injection solutions and suspensions prepared according to the recipe can be made from sterile powders, granules and tablets.
Es versteht sich, daß die Formulierungen neben den obigen besonders erwähnten Bestandteilen andere im Fachgebiet übliche Mittel mit Bezug auf die jeweilige Art der Formulierung enthalten können; so können beispielsweise für die orale Verabreichung geeignete Formulierungen Geschmacksstoffe enthalten.It is understood that the formulations may contain, in addition to the above-mentioned ingredients, other means common in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may 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 behandelnden Arzt bzw. Tierarzt festgelegt. Jedoch liegt eine wirksame Menge einer erfindungsgemäßen Verbindung für die Behandlung von neoplastischemA therapeutically effective amount of a compound of Formula I will depend on a number of factors, including, for example, 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 will ultimately determined by the attending doctor or veterinarian. However, an effective amount is one Compound according to the invention for the treatment of neoplastic
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 proGrowth, 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 particularly typically in the range of 1 to 10 mg / kg body weight per
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 vonDay. Thus, for a 70 kg adult mammal, the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more usually in a series of
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 die Behandlung der anderen, obenerwähnten Krankheitszustände geeignet sind.Partial doses (such as two, three, four, five or six) can be given per day 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 perse as a proportion of the effective amount of the compound of the invention. It is believed that similar dosages are suitable for the treatment of the other conditions mentioned above.
Gegenstand der Erfindung sind ferner Arzneimittel enthaltend mindestens eine Verbindung der Formel I und/oder ihre pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und mindestens einen weiteren Arzneimittelwirkstoff.The invention further relates to medicaments containing at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.
Gegenstand der Erfindung ist auch ein Set (Kit), bestehend aus getrennten Packungen vonThe invention also relates to a set (kit) consisting of separate packs of
(a) einer wirksamen Menge an einer Verbindung der Formel I und/oder ihrer pharmazeutisch verwendbaren Derivate, Solvate und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen, und(a) an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including their mixtures in all proportions, and
(b) einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs.(b) an effective amount of another drug ingredient.
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 set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules. The set can contain, for example, separate ampoules, each containing an effective amount of a compound of formula I and / or its pharmaceutically usable Derivatives, solvates and stereoisomers, including their mixtures in all proportions, and an effective amount of another active pharmaceutical ingredient are 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 I kann auch mit Verbindungen der Formel VI kombiniert werden.Preferably, but not exclusively, the medicaments in Table 1 are combined with the compounds of the formula I. A combination of Formula I and drugs of Table I can also be combined with compounds of Formula VI.
Tabelle 1.Table 1.
Alkylierungsmittel Cyclophosphamid Lomustin Busulfan Procarbazin Ifosfamid Altretamin Melphalan Estramustinphosphat Hexamethylmelamin Mechlorethamin Thiotepa Streptozocin Chlorambucil Temozolomid Dacarbazin Semustin CarmustinAlkylating agent cyclophosphamide lomustine busulfan procarbazine ifosfamide altretamine melphalan estramustine phosphate hexamethylmelamine mechlorethamine thiotepa streptozocin chlorambucil temozolomide dacarbazine semustin carmustine
Platinmittel Cisplatin Carboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 (Hoffmann-La Iproplatin Röche) SM-11355 (Sumitomo) AP-5280 (Access)Platinum agent Cisplatin Carboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 (Hoffmann-La Iproplatin Röche) SM-11355 (Sumitomo) AP-5280 (Access)
Antimetabolite Azacytidin Tomudex Gemcitabin Trimetrexate Capecitabin Deoxycoformycin 5-Fluoruracil Fludarabin Floxuridin Pentostatin 2-Chlordesoxyadenosin Raltitrexed 6-Mercaptopurin Hydroxyhamstoff 6-Thioguanin Decitabin (SuperGen) Cytarabin Clofarabin (Bioenvision) 2-Fluordesoxycytidin Irofulven (MGI Pharrna) Methotrexat DMDC (Hoffmann-La Idatrexate Röche) Ethinylcytidin (Taiho )Antimetabolite Azacytidine Tomudex Gemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-Fluorouracil Fludarabine Floxuridine Pentostatin 2-Chlorodesoxyadenosine Raltitrexed 6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen) Cytarenine Clofionxidirinovitone (BioGen) Fluofarxenxdiridine (BioGen) Fluofluidinex (I) Ethinylcytidine (Taiho)
Topoisomerase- Amsacrin Rubitecan (SuperGen)Topoisomerase- Amsacrine Rubitecan (SuperGen)
Inhibitoren Epirubicin Exatecanmesylat (Daiichi) Etoposid Quinamed (ChemGenex) Teniposid oder Gimatecan (Sigma- Tau) Mitoxantron Diflomotecan (Beaufour- Irinotecan (CPT-11) Ipsen) 7-EthyH O- TAS-103 (Taiho) hyd roxycam ptothecin Elsamitrucin (Spectrum) Topotecan J-107088 (Merck & Co) Dexrazoxanet BNP-1350 (BioNumerik) (TopoTarget) CKD-602 (Chong Kun Pixantron (Novuspharrna) Dang) Rebeccamycin-Analogon KW-2170 (Kyowa Hakko) (Exelixis) BBR-3576 (Novuspharrna)Inhibitors Epirubicin Exatecan Mesylate (Daiichi) Etoposide Quinamed (ChemGenex) Teniposide or Gimatecan (Sigma- Tau) Mitoxantron Diflomotecan (Beaufour- Irinotecan (CPT-11) Ipsen) 7-EthyH O- TAS roxy (103) pod Topotecan J-107088 (Merck & Co) Dexrazoxanet BNP-1350 (BioNumerik) (TopoTarget) CKD-602 (Chong Kun Pixantron (Novuspharrna) Dang) Rebeccamycin analog KW-2170 (Kyowa Hakko) (Exelixis) BBR-3576 (Novuspharrna)
Antitumor- Dactinomycin (Actinomycin AmonafidAntitumor dactinomycin (Actinomycin amonafid
Antibiotika D) Azonafid Doxorubicin (Adriamycin) Anthrapyrazol Deoxyrubicin Oxantrazol Valrubicin Losoxantron Daunorubicin Bleomycinsulfat (Daunomycin) (Blenoxan) Epirubicin Bleomycinsäure Therarubicin Bleomycin A Idarubicin Bleomycin B Rubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini) Porfiromycin GPX-100 (Gem Cyanomorpholinodoxorubi Pharmaceuticals) M l Mitoxantron (Novantron)Antibiotics D) Azonafid doxorubicin (Adriamycin) anthrapyrazole Deoxyrubicin Oxantrazol Valrubicin losoxantrone daunorubicin bleomycin sulfate (daunomycin) (Blenoxane) epirubicin Bleomycinsäure Therarubicin bleomycin A Idarubicin Bleomycin B rubidazone mitomycin C Plicamycinp MEN-10755 (Menarini) porfiromycin GPX-100 (Gem Cyanomorpholinodoxorubi Pharmaceuticals) M l Mitoxantron (Novantron)
Antimitotische Paclitaxel SB 408075Antimitotic paclitaxel SB 408075
Mittel Docetaxel (GlaxoSmithKline) Colchicin E7010 (Abbott) Vinblastin PG-TXL (Cell Vincristin Therapeutics) Vinorelbin IDN 5109 (Bayer) Vindesin A 105972 (Abbott) Dolastatin lO (NCI) A 204197 (Abbott) Rhizoxin (Fujisawa) LU 223651 (BASF) Mivobulin (Warner- D 24851 (ASTA Medica) Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilon B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly) IDN-5109 (Indena) Vinflunin (Fabre) AVLB (Prescient Auristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS 247550 (BMS) BNP- 7787 (BioNumerik) BMS 184476 (BMS) CA-4-Prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga) CA-4 (OXiGENE)Medium Docetaxel (GlaxoSmithKline) Colchicin E7010 (Abbott) Vinblastin PG-TXL (Cell Vincristin Therapeutics) Vinorelbin IDN 5109 (Bayer) Vindesin A 105972 (Abbott) Dolastatin lO (NCI) A 204197 (Abbott) Rhizoxin (Fujisawa) LU 22365 Mivobulin (Warner- D 24851 (ASTA Medica) Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilon B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asycini) Lilly) IDN-5109 (Indena) Vinflunin (Fabre) AVLB (Prescient Auristatin PE (Teikoku NeuroPharma) Hormones) Azaepothilon B (BMS) BMS 247550 (BMS) BNP- 7787 (BioNumerik) BMS 184476 (BMS) CA-4-Prodrug ( OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga) CA-4 (OXiGENE)
Aromatase- Aminoglutethimid ExemestanAromatase aminoglutethimide exemestane
Inhibitoren Letrozol Atamestan (BioMedicines) Anastrazol YM-511 (Yamanouchi) FormestanInhibitors Letrozole Atamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi) Formestan
Thymidylatsyntha Pemetrexed (Eli Lilly) Nolatrexed (Eximias) se-lnhibitoren ZD-9331 (BTG) CoFactor™ (BioKeys)Thymidylate syntha Pemetrexed (Eli Lilly) Nolatrexed (Eximias) se inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys)
DNA- Trabectedin (PharmaMar) Mafosfamid (BaxterDNA trabectedin (PharmaMar) mafosfamide (Baxter
Antagonisten Glufosfamid (Baxter International) International) Apaziquon (Spectrum Albumin + 32P (Isotope Pharmaceuticals) Solutions) 06-Benzylguanin Thymectacin (NewBiotics) (Paligent) Edotreotid (Novartis)Antagonists glufosfamide (Baxter International) International) Apaziquon (Spectrum Albumin + 32P (Isotope Pharmaceuticals) Solutions) 06-Benzylguanin Thymectacin (NewBiotics) (Paligent) Edotreotide (Novartis)
Famesyltransfera Arglabin (NuOncology Tipifarnib (Johnson & se-lnhibitoren Labs) . Johnson) lonafamib (Schering- Perillylalkohol (DOR Plough) BioPharma) BAY-43-9006 (Bayer)Famesyltransfera Arglabin (NuOncology Tipifarnib (Johnson & se-Inhibitoren Labs). Johnson) lonafamib (Schering-Perillylalkohol (DOR Plow) BioPharma) BAY-43-9006 (Bayer)
Pumpen- CBT-1 (CBA Pharma) Zosuquidar-TrihydrochloridPump CBT-1 (CBA Pharma) zosuquidar trihydrochloride
Inhibitoren Tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG) Biricodar-Dicitrat (Vertex)Inhibitors Tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG) Biricodar dicitrate (Vertex)
Histonacetyltransf Tacedinalin (Pfizer) Pivaloyloxymethylbutyrat erase- SAHA (Aton Pharma) (Titan)Histone Acetyltransf Tacedinalin (Pfizer) Pivaloyloxymethylbutyrat erase- SAHA (Aton Pharma) (Titan)
Inhibitoren MS-275 (Schering AG) Depsipeptid (Fujisawa)Inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)
Metalloproteinase- Neovastat (Aeterna CMT -3 (CollaGenex)Metalloproteinase Neovastat (Aeterna CMT -3 (CollaGenex)
Inhibitoren Laboratories) BMS-275291 (Celltech)Inhibitors Laboratories) BMS-275291 (Celltech)
Ribonucleosidred Marimastat (British Tezacitabin (Aventis) uktase- Biotech) Didox (Moiecules forRibonucleosidred Marimastat (British Tezacitabine (Aventis) uktase- Biotech) Didox (Moiecules for
Inhibitoren Galliummaltolat (Titan) Health) Triapin (Vion)Inhibitors Gallium Maltolate (Titan) Health) 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) LGD-1550 (Ligand)Retinoic acid receptor fenretinide (Johnson & alitretinoin (ligand) r agonist Johnson) LGD-1550 (ligand)
Immunmodulatore Interferon Dexosom-Therapie n Oncophage (Antigenics) (Anosys) GMK (Progenics) Pentrix (Australian Cancer Adenokarzinom-Impfstoff Technology) (Biomira) JSF-154 (Tragen) CTP-37 (AVI BioPharma) Krebsimpfstoff (Intercell) JRX-2 (Immuno-Rx) Norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) Sy nch rovax- 1 mpf Stoffe MGV (Progenics) (CTL Immuno) I3-Alethin (Dovetail) Melanom-Impfstoff (CTL CLL-Thera (Vasogen) Immuno) p21-RAS-lmpfstoff (GemVax)Immunomodulators Interferon Dexosome Therapy n Oncophage (Antigenics) (Anosys) GMK (Progenics) Pentrix (Australian Cancer Adenocarcinoma Vaccine Technology) (Biomira) JSF-154 (Wear) CTP-37 (AVI BioPharma) Cancer Vaccine (Intercell) JRX-2 ( Immuno-Rx) Norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) Sy nch rovax- 1 mpf substances MGV (Progenics) (CTL Immuno) I3-Alethin (Dovetail) Melanoma vaccine (CTL CLL-Thera (Vasogen) Immuno) p21 RAS vaccine (GemVax)
Hormonelle und Ostrogene Prednison antihormonelle konjugierte Ostrogene MethylprednisolonHormonal and estrogenic prednisone anti-hormonal conjugated estrogenic methylprednisolone
Mittel Ethinylöstradiol Prednisolon Chlortrianisen Aminoglutethimid Idenestrol Leuprolid Hydroxyprogesteroncaproa Goserelin t Leuporelin Medroxyprogesteron Bicalutamid Testosteron Flutamid Testosteronpropionat Octreotid Fluoxymesteron Nilutamid Methyltestosteron Mitotan Diethylstilbestrol P-04 (Novogen) Megestrol 2-Methoxyöstradiol Tamoxifen (EntreMed) Toremofin Arzoxifen (Eli Lilly) DexamethasonMeans ethinyl estradiol prednisolone chlorotrianisene aminoglutethimide Idenestrol leuprolide Hydroxyprogesteroncaproa goserelin medroxyprogesterone bicalutamide testosterone flutamide t Leuporelin testosterone propionate fluoxymesterone octreotide methyltestosterone nilutamide diethylstilbestrol mitotane P-04 (Novogen) megestrol 2-methoxyestradiol tamoxifen (EntreMed) Toremofin arzoxifene (Eli Lilly) dexamethasone
Photodynamische Talaporfin (Light Sciences) Pd-BacteriopheophorbidPhotodynamic Talaporfin (Light Sciences) Pd bacteriopheophorbid
Mittel Theralux (Yeda) (Theratechnologies) Lutetium-Texaphyrin Motexafin-Gadolinium (Pharmacyclics) (Pharmacyclics) HypericinMedium Theralux (Yeda) (Theratechnologies) Lutetium-Texaphyrin Motexafin-Gadolinium (Pharmacyclics) (Pharmacyclics) Hypericin
Tyrosinkinase- Imatinib (Novartis) Kahalid F (PharmaMar)Tyrosine Kinase- Imatinib (Novartis) Kahalid F (PharmaMar)
Inhibitoren Leflunomid CEP- 701 (Cephalon) (Sugen/Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis) Science) Phenoxodiol O Canertjnib (Pfizer) Trastuzumab (Genentech) Squalamin (Genaera) C225 (ImClone) SU5416 (Pharmacia) rhu-Mab (Genentech) SU6668 (Pharmacia) MDX-H210 (Medarex) ZD4190 (AstraZeneca) 2C4 (Genentech) ZD6474 (AstraZeneca) MDX-447 (Medarex) Vatalanib (Novartis) ABX-EGF (Abgenix) PKI166 (Novartis) IMC-1C11 (ImClone) GW2016 (GlaxoSmithKline) EKB-509 (Wyeth) EKB-569 (Wyeth)Inhibitors Leflunomide CEP-701 (Cephalon) (Sugen / Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis) Science) Phenoxodiol O Canertjnib (Pfizer) Genechuza Abal (Genizer) Genstuza C225 (ImClone) SU5416 (Pharmacia) rhu-Mab (Genentech) SU6668 (Pharmacia) MDX-H210 (Medarex) ZD4190 (AstraZeneca) 2C4 (Genentech) ZD6474 (AstraZeneca) MDX-447 (Medarex) Vatalanib (Novartis) ABX Abgenix) PKI166 (Novartis) IMC-1C11 (ImClone) GW2016 (GlaxoSmithKline) EKB-509 (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) Ranpimase Tocladesin (cyclisches- (Ribonuclease-Stimulans, AMP-Agonist, Ribapharm) Alfacell) Alvocidib (CDK-Inhibitor, Galarubicin (RNA- Aventis) Synthese-Inhibitor, Dong- CV-247 (COX-2-lnhibitor, A) Ivy Medical) Tirapazamin P54 (COX-2-lnhibitor, (Reduktionsmittel, SRI Phytopharm) International) CapCell™ (CYP450- N-Acetylcystein Stimulans, Bavarian (Reduktionsmittel, Nordic) Zambon) GCS-IOO (gal3- R-Flurbiprofen (NF- Antagonist, kappaB-lnhibitor, Encore) GlycoGenesys) 3CPA (NF-kappaB- G17DT-lmmunogen Inhibitor, Active Biotech) (Gastrin-Inhibitor, Aphton) Seocaicitol (Vitamin-D- Efaproxiral (Oxygenator, Rezeptor-Agonist, Leo) Allos Therapeutics) 131-I-TM-601 (DNA- Pi-88 (Heparanase- Antagonist, Inhibitor, Progen) TransMolecular) Tesmilifen (Histamin- Eflomithin (ODC-Inhibitor, Antagonist, YM ILEX Oncology) BioSciences) Minodronsäure Histamin (Histamin-H2- (Osteoclasten-Inhibitor, Rezeptor- Agonist, Maxim) Yamanouchi) Tiazofurin (IMPDH- Indisulam (p53-Stimulans, Inhibitor, Ribapharm) Eisai) Cilengitid (Integrin- Aplidin (PPT-Inhibitor, Antagonist, Merck KGaA) PharmaMar) SR-31747 (IL-1- Rituximab (CD20-Agent inhibitor, Sanofi-BioCryst) Synthelabo) Ranpimase Tocladesin (cyclic (ribonuclease stimulant, AMP agonist, Ribapharm) Alfacell) alvocidib (CDK inhibitor, galarubicin (RNA-Aventis) synthesis inhibitor, Dong-CV-247 (COX -2-inhibitor, A) Ivy Medical) Tirapazamine P54 (COX-2 inhibitor, (reducing agent, SRI Phytopharm) International) CapCell ™ (CYP450-N-acetylcysteine stimulant, Bavarian (reducing agent, Nordic) zambon) GCS-IOO (gal3 - R-Flurbiprofen (NF-antagonist, kappaB inhibitor, Encore) GlycoGenesys) 3CPA (NF-kappaB- G17DT immunogen inhibitor, Active Biotech) (gastrin inhibitor, aphtone) Seocaicitol (vitamin D efroxroxiral (oxygenator, receptor Agonist, Leo) Allos Therapeutics) 131-I-TM-601 (DNA Pi-88 (heparanase antagonist, inhibitor, progen) TransMolecular) Tesmilifen (histamine effomithine (ODC inhibitor, antagonist, YM ILEX Oncology) BioSciences) minodronic acid histamine (histamine H2 (osteoclast inhibitor, receptor agonist, Maxim) Yamanouchi) tiazofurin (IMPDH- indisulam (p53 stimulant, inhibitor, Ribapharm) Eisai) cilengitide (integrin aplidine (PPT inhibitor, antagonist, Merck KGaA) PharmaMar) SR-31747 (IL-1 rituximab (CD20-
10 Antagonist, Sanofi- Antikörper, Genentech) Synthelabo) Gemtuzumab (CD33- CCI-779 (mTOR-Kinase- Antikörper, Wyeth Ayerst) Inhibitor, Wyeth) PG2 (Hämatopoese- Exisulind (PDE-V-Inhibitor, Verstärker, Cell Pathways) Pharmagenesis) CP-461 (PDE-V-Inhibitor, Immunol™ (Triclosan-10 Antagonist, Sanofi antibody, Genentech) Synthelabo) Gemtuzumab (CD33-CCI-779 (mTOR kinase antibody, Wyeth Ayerst) inhibitor, Wyeth) PG2 (hematopoiesis exisulin (PDE-V inhibitor, enhancer, cell pathways) pharmagenesis ) CP-461 (PDE-V inhibitor, Immunol ™ (triclosan
15 Cell Pathways) Oralspülung, Endo) AG-2037 (GART-Inhibitor, Triacetyluridin (Uridin- Pfizer) Prodrug, Wellstat) WX-UK1 SN-4071 (Sarkom-Mittel, (Plasminogenaktivator- Signature BioScience) Inhibitor, Wilex) TransMID-107™15 Cell Pathways) Oral irrigation, Endo) AG-2037 (GART inhibitor, triacetyluridine (Uridin-Pfizer) prodrug, Wellstat) WX-UK1 SN-4071 (sarcoma agent, (plasminogen activator- Signature BioScience) inhibitor, Wilex) TransMID-107 ™
20 PBI-1402 (PMN-Stimulans, (Immunotoxin, KS ProMetic LifeSciences) Biomedix) Bortezomib (Proteasom- PCK-3145 (Apoptose- Inhibitor, Millennium) Förderer, Procyon) SRL-172 (T-Zell- Doranidazol (Apoptose- Stimulans, SR Pharma) Förderer, Pola) TLK-286 (Glutathion-S- CHS-828 (cytotoxisches20 PBI-1402 (PMN stimulant, (immunotoxin, KS ProMetic LifeSciences) Biomedix) bortezomib (Proteasome-PCK-3145 (apoptosis inhibitor, millennium) promoter, Procyon) SRL-172 (T cell doranidazole (apoptosis stimulant, SR Pharma) Conveyor, Pola) TLK-286 (Glutathione-S-CHS-828 (cytotoxic
25 Transferase-Inhibitor, Mittel, Leo) Telik) trans-Retinsäure PT-100 (Wachstumsfaktor- (Differentiator, NIH) Agonist, Point MX6 (Apoptose-Förderer, Therapeutics) MAXIA) Midostaurin (PKC-Inhibitor, Apomin (Apoptose-25 Transferase inhibitor, medium, Leo) Telik) trans retinoic acid PT-100 (growth factor (differentiator, NIH) agonist, point MX6 (apoptosis promoter, therapeutics) MAXIA) midostaurin (PKC inhibitor, apomin (apoptosis)
30 Novartis) Förderer, ILEX Oncology) Bryostatin-1 (PKC- Urocidin (Apoptose- Stimulans, GPC Biotech) Förderer, Bioniche) CDA-II (Apoptose- Ro-31-7453 (Apoptose- Förderer, Everlife) Förderer, La Röche) SDX-101 (Apoptose- Brostallicin (Apoptose- Förderer, Salmedix) Förderer, Pharmacia)30 Novartis) Conveyor, ILEX Oncology) Bryostatin-1 (PKC-Urocidin (Apoptosis Stimulant, GPC Biotech) Conveyor, Bioniche) CDA-II (Apoptosis- Ro-31-7453 (Apoptosis Conveyor, Everlife) Conveyor, La Röche) SDX-101 (Apoptosis- Brostallicin (Apoptosis promoter, Salmedix) promoter, Pharmacia)
35 Ceflatonin (Apoptose- Förderer, ChemGenex) Alkylierungsmittel Cyclophosphamid Lomustin Busulfan Procarbazin Ifosfamid Altretamin Melphalan Estramustinphosphat Hexamethylmelamin Mechlorethamin Thiotepa Streptozocin Chlorambucil Temozolomid Dacarbazin Semustin Carmustin35 Ceflatonin (apoptosis promoter, ChemGenex) Alkylating agent cyclophosphamide lomustine busulfan procarbazine ifosfamide altretamine melphalan estramustine phosphate hexamethylmelamine mechlorethamine thiotepa streptozocin chlorambucil temozolomide dacarbazine semustin carmustine
Platinmittel Cisplatin Carboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aeterna) Carboxyphthalatoplatinum Satraplatin (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 (Hoffrnann-La Iproplatin Röche) SM-11355 (Sumitomo) AP-5280 (Access) ,Platinum agent Cisplatin Carboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aeterna) Carboxyphthalatoplatinum Satraplatin (Johnson Tetraplatin Matthey) Ormiplatin BBR-3464 (Hoffrnann-La Iproplatin Röche) SM-11355 (Sumitomo) AP-5280 (Access
Antimetabolite Azacytidin Tomudex Gemcitabin Trimetrexate Capecitabin Deoxycoformycin 5-Fluoruracil Fludarabin Floxuridin Pentostatin 2-Chlordesoxyadenosin Raltitrexed 6-Mercaptopurin Hydroxyhamstoff 6-Thioguanin Decitabin (SuperGen) Cytarabin Clofarabin (Bioenvision) 2-Fluordesoxycytidin Irofulven (MGI Pharma) Methotrexat DMDC (Hoffmann-La Idatrexate Röche) Ethinylcytidin (Taiho )Antimetabolite Azacytidine Tomudex Gemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-Fluorouracil Fludarabine Floxuridine Pentostatin 2-Chlordesoxyadenosin Raltitrexed 6-Mercaptopurine Hydroxyurea 6-Thioguanin Decitabine (SuperGen) Cytarenine Clofionxididine (BioGen) Fluofaridinexofinxinx (I) Ethinylcytidine (Taiho)
Topoisomerase- Amsacrin Rubitecan (SuperGen)Topoisomerase- Amsacrine Rubitecan (SuperGen)
Inhibitoren Epirubicin Exatecanmesylat (Daiichi) Etoposid Quinamed (ChemGenex) Teniposid oder Gimatecan (Sigma- Tau) Mitoxantron Diflomotecan (Beaufour- lrinotecan (CPT-11) Ipsen) 7-EthyMO- TAS-103 (Taiho) hydroxycamptothecin Elsamitrucin (Spectrum) Topotecan J-107088 (Merck & Co) Dexrazoxanet BNP-1350 (BioNumerik) (TopoTarget) CKD-602 (Chong Kun Pixantron (Novuspharrna) Dang) Rebeccamycin-Analogon KW-2170 (Kyowa Hakko) (Exelixis) BBR-3576 (Novuspharrna)Inhibitors Epirubicin Exatecan Mesylate (Daiichi) Etoposide Quinamed (ChemGenex) Teniposide or Gimatecan (Sigma-Tau) Mitoxantron Diflomotecan (Beaufour-lrinotecan (CPT-11) Ipsen) 7-EthyMO- TAS-103 (Topcinotam) (Taicin) Eliminate 107088 (Merck & Co) Dexrazoxanet BNP-1350 (BioNumerik) (TopoTarget) CKD-602 (Chong Kun Pixantron (Novuspharrna) Dang) Rebeccamycin analog KW-2170 (Kyowa Hakko) (Exelixis) BBR-3576 (Novuspharrna)
Antitumor- Dactinomycin (Actinomycin AmonafidAntitumor dactinomycin (Actinomycin amonafid
Antibiotika D) Azonafid Doxorubicin (Adriamycin) Anthrapyrazol Deoxyrubicin Oxantrazol Valrubicin Losoxantron Daunorubicin Bleomycinsulfat (Daunomycin) (Blenoxan) Epirubicin Bleomycinsäure Therarubicin Bleomycin A Idarubicin Bleomycin B Rubidazon Mitomycin C Plicamycinp MEN-10755 (Menarini) Porfiromycin GPX-100 (Gem Cyanomorpholinodoxorubi Pharmaceuticals) r U*ιlri 1ι Mitoxantron (Novantron)Antibiotics D) Azonafid doxorubicin (Adriamycin) anthrapyrazole Deoxyrubicin Oxantrazol Valrubicin losoxantrone daunorubicin bleomycin sulfate (daunomycin) (Blenoxane) epirubicin Bleomycinsäure Therarubicin bleomycin A Idarubicin Bleomycin B rubidazone mitomycin C Plicamycinp MEN-10755 (Menarini) porfiromycin GPX-100 (Gem Cyanomorpholinodoxorubi Pharmaceuticals) r U * ιlri 1ι Mitoxantron (Novantron)
Antimitotische Paclitaxel SB 408075Antimitotic paclitaxel SB 408075
Mittel Docetaxel (GlaxoSmithKline) Colchicin E7010 (Abbott) Vinblastin PG-TXL (Cell Vincristin Therapeutics) Vinorelbin IDN 5109 (Bayer) Vindesin A 105972 (Abbott) Dolastatin lO (NCI) A 204197 (Abbott) Rhizoxin (Fujisawa) LU 223651 (BASF) Mivobulin (Warner- D 24851 (ASTA Medica) Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilon B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly) IDN-5109 (Indena) Vinflunin (Fabre) AVLB (Prescient Auristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) Metalloproteinase- Neovastat (Aeterna CMT -3 (CollaGenex)Medium Docetaxel (GlaxoSmithKline) Colchicin E7010 (Abbott) Vinblastin PG-TXL (Cell Vincristin Therapeutics) Vinorelbin IDN 5109 (Bayer) Vindesin A 105972 (Abbott) Dolastatin lO (NCI) A 204197 (Abbott) Rhizoxin (Fujisawa) LU 22365 Mivobulin (Warner-D 24851 (ASTA Medica) Lambert) ER-86526 (Eisai) Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilon B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly) IDN-5109 (Indena) Vinflunin (Fabre) AVLB (Prescient Auristatin PE (Teikoku) NeuroPharma Azaepothilon B (BMS) Metalloproteinase Neovastat (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) Triapin (Vion)Inhibitors Gallium Maltolate (Titan) Health) 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) LGD-1550 (Ligand)Retinoic acid receptor fenretinide (Johnson & alitretinoin (ligand) r agonist Johnson) LGD-1550 (ligand)
Immunmodulatore Interferon Dexosom-Therapie n Oncophage (Antigenics) (Anosys) GMK (Progenics) Pentrix (Australian Cancer Adenokarzinom-Impfstoff Technology) (Biomira) JSF-154 (Tragen) CTP-37 (AVI BioPharma) Krebsimpfstoff (Intercell) JRX-2 (Immuno-Rx) Norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) Synchrovax-Impfstoffe MGV (Progenics) (CTL Immuno) !3-Alethin (Dovetail) Melanom-Impfstoff (CTL CLL-Thera (Vasogen) Immuno) p21-RAS-lmpfstoff (GemVax)Immunomodulators Interferon Dexosome Therapy n Oncophage (Antigenics) (Anosys) GMK (Progenics) Pentrix (Australian Cancer Adenocarcinoma Vaccine Technology) (Biomira) JSF-154 (Wear) CTP-37 (AVI BioPharma) Cancer Vaccine (Intercell) JRX-2 ( Immuno-Rx) Norelin (Biostar) PEP-005 (Peplin Biotech) BLP-25 (Biomira) Synchrovax vaccines MGV (Progenics) (CTL Immuno)! 3-Alethin (Dovetail) Melanoma vaccine (CTL CLL-Thera (Vasogen) Immuno) p21 RAS vaccine (GemVax)
Hormonelle und Ostrogene Prednison antihormonelle konjugierte Ostrogene MethylprednisolonHormonal and estrogenic prednisone anti-hormonal conjugated estrogenic methylprednisolone
Mittel Ethinylöstradiol Prednisolon Chlortrianisen Aminoglutethimid Idenestrol Leuprolid Hydroxyprogesteroncaproa Goserelin t Leuporelin Medroxyprogesteron Bicalutamid Testosteron Flutamid Testosteronpropionat Octreotid Fluoxymesteron Nilutamid Methyltestosteron Mitotan Diethylstilbestrol P-04 (Novogen) Megestrol 2-Methoxyöstradiol Tamoxifen (EntreMed) Toremofin Arzoxifen (Eli Lilly) DexamethasonMedium ethinyl estradiol prednisolone chlorotrianisen aminoglutethimide iddenestrol leuprolide hydroxyprogesterone caproa goserelin t leuporelin medroxyprogesterone bicalutamide testosterone flutamide testosterone propionate octreotide fluoxymesterone nilutamide methyltestosterone mitotane diethylstilbestrol P- Megestrol 2-methoxyestradiol tamoxifen (EntreMed) toremofin arzoxifene (Eli Lilly) dexamethasone
Photodynamische Talaporfin (Light Sciences) Pd-BacteriopheophorbidPhotodynamic Talaporfin (Light Sciences) Pd bacteriopheophorbid
Mittel Theralux (Yeda) (Theratechnologies) Lutetium-Texaphyrin Motexafin-Gadolinium (Pharmacyclics) (Pharmacyclics) HypericinMedium Theralux (Yeda) (Theratechnologies) Lutetium-Texaphyrin Motexafin-Gadolinium (Pharmacyclics) (Pharmacyclics) Hypericin
Tyrosinkinase- Imatinib (Novartis) Kahalid F (PharmaMar)Tyrosine Kinase- Imatinib (Novartis) Kahalid F (PharmaMar)
Inhibitoren Leflunomid CEP- 701 (Cephalon) (Sugen/Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis) Science) Phenoxodiol O Canertjnib (Pfizer) Trastuzumab (Genentech) Squalamin (Genaera) C225 (ImClone) SU5416 (Pharmacia) rhu-Mab (Genentech) SU6668 (Pharmacia) MDX-H210 (Medarex) ZD4190 (AstraZeneca) 2C4 (Genentech) ZD6474 (AstraZeneca) MDX-447 (Medarex) Vatalanib (Novartis) ABX-EGF (Abgenix) PK1166 (Novartis) IMC-1C11 (ImClone) GW2016 (GlaxoSmithKline) EKB-509 (Wyeth) EKB-569 (Wyeth)Inhibitors Leflunomide CEP-701 (Cephalon) (Sugen / Pharmacia) CEP-751 (Cephalon) ZDI839 (AstraZeneca) MLN518 (Millenium) Erlotinib (Oncogene PKC412 (Novartis) Science) Phenoxodiol O Canertjnib (Pfizer) Genechuza Abal (Genizer) Genstuza C225 (ImClone) SU5416 (Pharmacia) rhu-Mab (Genentech) SU6668 (Pharmacia) MDX-H210 (Medarex) ZD4190 (AstraZeneca) 2C4 (Genentech) ZD6474 (AstraZeneca) MDX-447 (Medarex) Vatalanib (Novartis) ABX Abgenix) PK1166 (Novartis) IMC-1C11 (ImClone) GW2016 (GlaxoSmithKline) EKB-509 (Wyeth) EKB-569 (Wyeth)
Verschiedene SR-27897 (CCK-A- BCX-1777 (PNP-Inhibitor,Various SR-27897 (CCK-A-BCX-1777 (PNP inhibitor,
Mittel Inhibitor, Sanofi- BioCryst) Synthelabo) Ranpirnase (Ribonuclease- Tocladesin (cyclisches- Stimulans, Alfacell) AMP-Agonist, Ribapharm) Galarubicin (RNA- Alvocidib (CDK-Inhibitor, Synthese-Inhibitor, Dong-A) Aventis) Tirapazamin CV-247 (COX-2-lnhibitor, (Reduktionsmittel, SRI Ivy Medical) International) P54 (COX-2-lnhibitor, N-Acetylcystein Phytopharm) (Reduktionsmittel, Zambon) CapCell™ (CYP450- R-Flurbiprofen (NF- Stimulans, Bavarian kappaB-lnhibitor, Encore) Nordic) 3CPA (NF-kappaB- GCS-IOO (gal3- Inhibitor, Active Biotech) Antagonist, Seocaicitol (Vitamin-D- GlycoGenesys) Rezeptor-Agonist, Leo) G17DT-lmmunogen 131-I-TM-601 (DNA- (Gastrin-Inhibitor, Aphton) Antagonist, Efaproxiral (Oxygenator, TransMolecular) Allos Therapeutics) Eflornithin (ODC-Inhibitor, PI-88 (Heparanase- ILEX Oncology)Agent Inhibitor, Sanofi-BioCryst) Synthelabo) Ranpirnase (Ribonuclease-Tocladesin (cyclic stimulant, Alfacell) AMP agonist, Ribapharm) Galarubicin (RNA-Alvocidib (CDK inhibitor, synthesis inhibitor, Dong-A) Aventis) Tirapazamine CV- 247 (COX-2 inhibitor, (reducing agent, SRI Ivy Medical) International) P54 (COX-2 inhibitor, N-acetylcysteine Phytopharm) (reducing agent, Zambon) CapCell ™ (CYP450-R-Flurbiprofen (NF-Stimulans, Bavarian kappaB-lnhibitor, Encore) Nordic) 3CPA (NF-kappaB-GCS-IOO (gal3-Inhibitor, Active Biotech) antagonist, Seocaicitol ( Vitamin-D-GlycoGenesys) receptor agonist, Leo) G17DT immunogen 131-I-TM-601 (DNA- (gastrin inhibitor, aphton) antagonist, efaproxiral (oxygenator, TransMolecular) Allos Therapeutics) eflornithine (ODC inhibitor, PI -88 (Heparanase- ILEX Oncology)
10 Inhibitor, Progen) Minodronsäure Tesmilifen (Histamin- (Osteoclasten-lnhibitor, Antagonist, YM Yamanouchi) BioSciences) Indisulam (p53-Stimulans, Histamin (Histamin-H2- Eisai) Rezeptor- Agonist, Aplidin (PPT-Inhibitor, Maxim) PharmaMar)10 inhibitor, progen) minodronic acid tesmilifes (histamine (osteoclast inhibitor, antagonist, YM Yamanouchi) BioSciences) indisulam (p53 stimulant, histamine (histamine H2-Eisai) receptor agonist, aplidine (PPT inhibitor, Maxim) PharmaMar)
15 Tiazofurin (IMPDH- Rituximab (CD20- Inhibitor, Ribapharm) Antikörper, Genentech) Cilengitid (Integrin- Gemtuzumab (CD33- Antagonist, Merck KGaA) Antikörper, Wyeth Ayerst) SR-31747 (IL-1- PG2 (Hämatopoese- Antagonist, Sanofi- Verstärker,15 Tiazofurin (IMPDH rituximab (CD20 inhibitor, Ribapharm) antibody, Genentech) cilengitide (integrin gemtuzumab (CD33 antagonist, Merck KGaA) antibody, Wyeth Ayerst) SR-31747 (IL-1-PG2 (hematopoiesis antagonist, Sanofi - amplifier,
20 Synthelabo) Pharmagenesis) CCI-779 (mTOR-Kinase- Immunol™ (Triclosan- Inhibitor, Wyeth) Oralspülung, Endo) Exisulind (PDE-V- Triacetyluridin (Uridin- Inhibitor, Cell Pathways) Prodrug, Wellstat) CP-461 (PDE-V-Inhibitor, SN-4071 (Sarkom-Mittel, Cell Pathways) Signature BioScience)20 Synthelabo) Pharmagenesis) CCI-779 (mTOR-Kinase-Immunol ™ (triclosan inhibitor, Wyeth) oral rinse, Endo) exisulin (PDE-V-triacetyluridine (uridine inhibitor, cell pathways) prodrug, wellstat) CP-461 (PDE -V inhibitor, SN-4071 (sarcoma agent, Cell Pathways) Signature BioScience)
25 AG-2037 (GART-Inhibitor, TransMID-107™ Pfizer) (Immunotoxin, KS WX-UK1 Biomedix) (Plasminogenaktivator- PCK-3145 (Apoptose- Inhibitor, Wilex) Förderer, Procyon) PBI-1402 (PMN- Doranidazol (Apoptose-25 AG-2037 (GART inhibitor, TransMID-107 ™ Pfizer) (immunotoxin, KS WX-UK1 Biomedix) (plasminogen activator-PCK-3145 (apoptosis inhibitor, Wilex) promoter, Procyon) PBI-1402 (PMN-doranidazole (apoptosis -
30 Stimulans, ProMetic Förderer, Pola) LifeSciences) CHS-828 (cytotoxisches Bortezomib (Proteasom- Mittel, Leo) Inhibitor, Millennium) trans-Retinsäure SRL-172 (T-Zell- (Differentiator, NIH) Stimulans, SR Pharma) MX6 (Apoptose-Förderer, TLK-286 (Glutathion-S- MAXIA)30 stimulant, ProMetic promoter, Pola) LifeSciences) CHS-828 (cytotoxic bortezomib (proteasome agent, Leo) inhibitor, millennium) trans retinoic acid SRL-172 (T cell (differentiator, NIH) stimulant, SR Pharma) MX6 ( Apoptosis promoter, TLK-286 (Glutathione-S-MAXIA)
35 Transferase-Inhibitor, Apomin (Apoptose- Telik) Förderer, ILEX Oncology) PT-100 Urocidin (Apoptose- (Wachstumsfaktor- Förderer, Bioniche) Agonist, Point Ro-31-7453 (Apoptose- Therapeutics) Förderer, La Röche) Midostaurin (PKC- Brostallicin (Apoptose- Inhibitor, Novartis) Förderer, Pharmacia) Bryostatin-1 (PKC- Stimulans, GPC Biotech) CDA-II (Apoptose- Förderer, Everlife) SDX-101 (Apoptose- Förderer, Salmedix) Ceflatonin (Apoptose- Förderer, ChemGenex)35 Transferase inhibitor, Apomin (Apoptosis-Telik) promoter, ILEX Oncology) PT-100 Urocidin (Apoptosis (growth factor promoter, Bioniche) agonist, Point Ro-31-7453 (Apoptose Therapeutics) promoter, La Röche) Midostaurin (PKC- Brostallicin (Apoptosis inhibitor, Novartis) promoter, Pharmacia) Bryostatin- 1 (PKC stimulant, GPC Biotech) CDA-II (apoptosis promoter, Everlife) SDX-101 (apoptosis promoter, Salmedix) ceflatonin (apoptosis promoter, ChemGenex)
Bevorzugt werden die Verbindungen der Formel I mit den mit bekannten Antikrebsmitteln kombiniert:The compounds of the formula I are preferably combined with those with known anti-cancer agents:
Zu diesen bekannten Antikrebsmitteln zählen die folgenden: Östrogenrezeptormodulatoren, Androgenrezeptormodulatoren, Retinoid- rezeptormodulatoren, Zytotoxika, antiproliferative Mittel, Prenyl- Proteintransferasehemmer, HMG-CoA-Reduktase-Hemmer, HlV-Protease- Hemmer, Reverse-Transkriptase-Hemmer sowie weitere Angiogenese- hemmer. Die vorliegenden Verbindungen eignen sich insbesondere zur gemeinsamen Anwendung mit Radiotherapie. Die synergistischen Wirkungen der Hemmung des VEGF in Kombination mit Radiotherapie sind in der Fachwelt beschrieben worden (siehe WO 00/61186). „Östrogenrezeptormodulatoren" bezieht sich auf Verbindungen, die die Bindung von Östrogen an den Rezeptor stören oder diese hemmen, und zwar unabhängig davon, wie dies geschieht. Zu den Östrogenrezeptormodulatoren zählen zum Beispiel Tamoxifen, Raloxifen, Idoxifen, LY353381 , LY 117081 , Toremifen, Fulvestrant, 4-[7-(2,2-Dimethyl-1- oxopropoxy-4-methyl-2-[4-[2-(1 - piperidinyl)ethoxy]phenyl]-2H-1 - benzopyran-3-yl]phenyl-2,2-dimethylpropanoat, 4,4'-Dihydroxybenzo- phenon-2,4-dinitrophenylhydrazon und SH646, was jedoch keine Einschränkung darstellen soll. „Androgenrezeptormodulatoren" bezieht sich auf Verbindungen, die die Bindung von Androgenen an den Rezeptor stören oder diese hemmen, und 5 zwar unabhängig davon, wie dies geschieht. Zu den Androgenrezeptormodulatoren zählen zum Beispiel Finasterid und andere 5α-Reduktase-Hemmer, Nilutamid, Flutamid, Bicalutamid, Liarozol und Abirateron-acetat.These known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxics, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other. The present compounds are particularly suitable for joint use with radiotherapy. The synergistic effects of inhibiting VEGF in combination with radiotherapy have been described in the specialist field (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 is done. The estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifene, 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'-dihydroxybenzo- phenon-2,4-dinitrophenylhydrazone and SH646, which, however, is not intended to be a limitation. “Androgen receptor modulators” refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this is done. The androgen receptor modulators include, for example, finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, Bicalutamide, liarozole and abiraterone acetate.
10 „Retinoidrezeptormodulatoren" bezieht sich auf Verbindungen, die die Bindung von Retinoiden an den Rezeptor stören oder diese hemmen, und zwar unabhängig davon, wie dies geschieht. Zu solchen Retinoidrezeptormodulatoren zählen zum Beispiel Bexaroten, Tretinoin, 13-cis-Retinsäure,10 “Retinoid receptor modulators” refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this is done. Such retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis retinoic acid,
A C 9-cis-Retinsäure, α-Difluormethylornithin, ILX23-7553, trans-N-(4'-Hydroxy- phenyl)retinamid und N-4-Carboxyphenylretinamid. „Zytotoxika" bezieht sich auf Verbindungen, die in erster Linie durch direkte Einwirkung auf die Zellfunktion zum Zelltod führen oder die die Zellmyose hemmen oder diese stören, darunter Alkylierungsmittel, Tumomekrose-A C 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) retinamide and N-4-carboxyphenylretinamide. “Cytotoxics” refers to compounds that cause cell death primarily through direct action on cell function or that inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis
20 faktoren, interkaliernde Mittel, Mikrotubulin-Hemmer und Topoisomerase- Hemmer. Zu den Zytotoxika zählen zum Beispiel Tirapazimin, Sertenef, Cachectin, Ifosfamid, Tasonermin, Lonidamin, Carboplatin, Altretamin, Prednimustin,20 factors, intercalating agents, microtubulin inhibitors and topoisomerase inhibitors. The cytotoxics include, for example, tirapazimin, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine,
25 Dibromdulcit, Ranimustin, Fotemustin, Nedaplatin, Oxaliplatin, Temozolomid, Heptaplatin, Estramustin, Improsulfan-tosylat, Trofosfamid, Nimustin, Dibrospidium-chlorid, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulven, Dexifosfamid, cis-Amindichlor(2-25 dibromodulcite, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosylate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profamidine cis, dfiratinifin, iridafinifinomyifin, iridifinifin, cifinatin, dfiratinifin, difiratinifin, iridifin, difiratinifin, dfiratinifin, difiratinin
30 methylpyridin)platin, Benzylguanin, Glufosfamid, GPX100, (trans,trans,trans)-bis-mu-(hexan-1 ,6-diamin)-mu-[diamin-platin(ll)]bis- [diamin(chlor)platin(ll)]-tetrachlorid, Diarizidinylspermin, Arsentrioxid, 1-(11- Dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthin, Zorubicin, Idarubicin, Daunorubicin, Bisantren, Mitoxantron, Pirarubicin, Pinafid, 30 methylpyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans) -bis-mu- (hexane-1, 6-diamine) -mu- [diamine-platinum (II)] bis- [diamine (chlorine) platinum (ll)] - tetrachloride, diarizidinyl spermine, arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafid,
35 Valrubicin, Amrubicin, Antineoplaston, 3'-Desamino-3'-morpholino-13- desoxo-10-hydroxycarminomycin, Annamycin, Galarubicin, Elinafid, MEN10755 und 4-Desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl- daunorubicin (siehe WO 00/50032), was jedoch keine Einschränkung darstellen soll.35 valrubicin, amrubicin, antineoplaston, 3'-desamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafid, MEN10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032), which, however, is not intended to be a restriction.
Zu den Mikrotubulin-Hemmern zählen zum Beispiel Paclitaxel, Vindesin- sulfat, S'^'-Dideshydro^'-desoxy-δ'-norvincaleukoblastin , Docetaxol,The microtubulin inhibitors include, for example, paclitaxel, vindesine sulfate, S '^' - Dideshydro ^ '- deoxy-δ'-norvincaleukoblastin, docetaxol,
Rhizoxin, Dolastatin, Mivobulin-isethionat, Auristatin, Cemadotin,Rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,
RPR109881 , BMS184476, Vinflunin, Cryptophycin, 2,3,4,5,6-pentafluor-N-RPR109881, BMS184476, Vinflunin, Cryptophycin, 2,3,4,5,6-pentafluor-N-
(3-fluor-4-methoxyphenyl)benzolsulfonamid, Anhydrovinblastin, N,N- dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-prolin-t-butylamid, TDX258 und BMS188797.(3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-prolin-t-butylamide, TDX258 and BMS188797 ,
Topoisomerase-Hemmer sind zum Beispiel Topotecan, Hycaptamin, Irinotecan, Rubitecan, 6-Ethoxypropionyl-3',4'-0-exo-benzyliden- chartreusin, 9-Methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridin-2-Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3 ', 4'-0-exo-benzylidene-chartreusin, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4, 5-kl] acridine-2
(δH)propanamin, 1-Amino-9-ethyl-5-fluor-2,3-dihydro-9-hydroxy-4-methyl- 1H,12H-benzo[de]pyrano[3',4,:b,7]indolizino[1 ,2b]chinolin-10!13(9H,15H)- dion, Lurtotecan, 7-[2-(N-lsopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942, Etoposid-phosphat, Teniposid, Sobuzoxan, 2'-Dimethylamino-2'-desoxy-etoposid, GL331, N-[2- (Dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazoi-1- carboxamid, Asulacrin, (5a,5aB,8aa,9b)-9-[2-[N-[2-(Dimethylamino)ethyl]-N- methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9- hexohydrofuro(3',4':6,7)naphtho(2,3-d)-1 ,3-dioxol-6-on, 2,3-(Methylen- dioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium, 6,9-Bis[(2- aminoethyl)amino]benzo[g]isochinolin-5,10-dion, 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.(delta H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3 ', 4,: b, 7 ] indolizino [1, 2b] quinoline-10 ! 13 (9H, 15H) - dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-dimethylamino- 2'-deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl] -9-hydroxy-5,6-dimethyl-6H-pyrido [4,3-b] carbazoi-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, 9-hexohydrofuro (3 ', 4': 6,7) naphtho (2,3-d) -1, 3-dioxol-6-one, 2,3- (methylene-dioxy) -5 -methyl-7-hydroxy-8-methoxybenzo [c] phenanthridinium, 6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline-5,10-dione, 5- (3-aminopropylamino) - 7, 10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1-de] - acridin-6-one, N- [1- [2 (diethylamino) ethylamino] -7-methoxy-9- oxo-9H-thio-xanthene-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, Tiazo- furin, Decitabin, Nolatrexed, Pemetrexed, Nelzarabin, 2'-Desoxy-2'- methylidencytidin, 2'-Fluormethylen-2'-desoxycytidin, N-[5-(2,3-The “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 ocfosfate, fosteabin sodium hydrate, raltitrexed, paltitrexide, emitefur, tiazo-furin, decitabine, nolatrexed, pemetrexed-2'-desfluoro-ethane -2'-deoxycytidine, N- [5- (2,3-
Dihydrobenzofuryl)sulfonyl]-N'-(3,4-dichlorphenyl)hamstoff, N6-[4-Desoxy- 4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-hepto- pyranosyljadenin, Aplidin, Ecteinascidin, Troxacitabine, 4-[2-Amino-4-oxo- 4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1 ,4]thiazin-6-yl-(S)-ethyl]-2,5- thienoyl-L-glutaminsäure, Aminopterin, 5-Flurouracil, Alanosin, 11-Acetyl-8- (carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1 ,11 -diazatetracyclo- (7.4.1.0.0)-tetradeca-2,4,6-trien-9-ylessigsäureester, Swainsonin, Lometrexol, Dexrazoxan, Methioninase, 2'-cyan-2'-desoxy-N4-palmitoyl-1- B-D-Arabinofuranosylcytosin und 3-Aminopyridin-2-carboxaldehyd- thiosemicarbazon. Die „antiproliferativen Mittel" beinhalten auch andere monoklonale Antikörper gegen Wachstumsfaktoren als bereits unter den „Angiogenese-Hemmem" angeführt wurden, wie Trastuzumab, sowie Tumorsuppressorgene, wie p53, die über rekombinanten .virusvermittelten Gentransfer abgegeben werden können (siehe z.B. US-Patent Nr. 6,069,134).Dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy- 4- [N2- [2 (E), 4 (E) -tetradecadienoyl] glycylamino] -L-glycero-BL -manno-hepto-pyranosyljadenine, aplidine, ecteinascidine, troxacitabine, 4- [2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino [5,4-b] [1,4] thiazine -6-yl- (S) -ethyl] -2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14- oxa-1, 11 -diazatetracyclo- (7.4.1.0.0) tetradeca-2,4,6-trien-9-ylacetic acid ester, Swainsonin, lometrexol, dexrazoxane, methioninase, 2'-cyan-2'-deoxy-N4- palmitoyl-1-BD-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative agents" also contain monoclonal antibodies against growth factors other than those already mentioned under the "angiogenesis inhibitors", such as trastuzumab, and tumor suppressor genes, such as p53, which can be released via recombinant virus-mediated gene transfer (see, for example, US Pat. No. 6,069,134).
Insbesondere bevorzugt ist die Verwendung der erfindungsgemäßen Verbindung zur Behandlung und Prophylaxe von Tumorerkrankungen.The use of the compound according to the invention is particularly preferred for the treatment and prophylaxis of tumor diseases.
Der Tumor ist vorzugsweise ausgewählt aus der Gruppe der Tumoren des Plattenepithel, der Blasen, des Magens, der Nieren, von Kopf und Hals, des Ösophagus, des Gebärmutterhals, der Schilddrüse, des Darm, der Leber, des Gehirns, der Prostata, des Urogenitaltrakts, des lymphatischen Systems, des Magens, des Kehlkopft und/oder der Lunge. Der Tumor ist weiterhin vorzugsweise ausgewählt aus der Gruppe Lungenadenokarzinom, kleinzellige Lungenkarzinome, Bauchspeicheldrüsenkrebs, Glioblastome, Kolonkarzinom und Brustkarzinom.The tumor is preferably selected from the group of tumors of the squamous epithelium, the bladder, the stomach, the kidneys, the head and neck, the esophagus, the cervix, the thyroid, the intestine, the liver, the brain, the prostate and the urogenital tract , the lymphatic system, the stomach, the larynx and / or the lungs. The tumor is also preferably selected from the group of 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 eines Tumors ausgewählt aus der Gruppe der akuten myelotischen Leukämie, der chronischen myelotischen Leukämie, akuten lymphatischen Leukämie und/oder chronischen lymphatischen Leukämie.Also preferred is the use for the treatment of a tumor of the blood and immune system, preferably for the treatment of a tumor selected from the group of acute myelotic leukemia, chronic myelotic leukemia, acute lymphatic leukemia and / or chronic lymphatic leukemia.
Die Erfindung umfasst auch ein Verfahren zur Behandlung eines Patienten, der ein Neoplasma, wie einen Krebs, hat, durch Verabreichung a) einer oder mehrerer der Verbindung der Formel I:The invention also encompasses a method for treating a patient who has a neoplasm, such as a cancer, by administering a) one or more of the compounds of the formula I:
b) und mindestens einer Verbindung der Formel VI: b) and at least one compound 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, N02 oder NH2 bedeuten, n 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: wherein Y 'and Z' each independently represent O or N, R 7 and R 9 each independently represent H, OH, halogen, OCI-10-alkyl, OCF 3 , N0 2 or NH 2 , n is an integer between 2 and 6, each inclusive, and R 6 and R 8 are each independently of one another at the meta or para position and 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.are selected, the first and second compounds being administered simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of the neoplasm.
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 analogues (e.g. G-3):
(G-1) (G-2) (G-1) (G-2)
(G-3)(G-3)
Jede Amidineinheit kann unabhängig voneinander durch eine der weiteren gesamten Einheiten ersetzt werden. 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 Beispiel Dihydrochlorid- und Methansulfonatsalze.Each amidine unit can be replaced independently of one another by one of the other entire units. As in the case of benzimidazoles and pentamidines, salts of stilbamidine, hydroxystilbamidine and their indole derivatives are also suitable in the process according to the invention. Preferred salts include, for example, dihydrochloride and methanesulfonate salts.
Noch andere Analoga sind diejenigen, die unter eine Formel fallen, die in einem der U.S.-Patente Nr. 5,428,051 , 5,521 ,189, 5,602,172, 5,643,935, 5,723,495, 5,843,980, 6,172,104 und 6,326,395 oder der U.S.Patentanmeldung mit der Veröffentlichungsnr. US 2002/0019437 A1 bereitgestellt werden, die jeweils in ihrer Gesamtheit durch Bezugname aufgenommen sind. Beispielhafte Analoga umfassen 1 ,5-Bis-(4'-(N- hydroxyamidino)phenoxy)pentan, 1 ,3-Bis-(4'-(N-hydroxyamidino)- phenoxy)propan, 1 ,3-Bis-(2,-methoxy-4'-(N-hydroxyamidino)-phenoxy)- propan, 1 ,4-Bis-(4'-(N-hydroxyamidino)phenoxy)butan, 1 ,5-Bis-(4'-(N- hydroxyamidino)phenoxy)pentan, 1 ,4-Bis-(4'-(N-hydroxyamidino)- phenoxy)butan, 1 ,3-Bis-(4'-(4-hydroxyamidino)phenoxy)propan, 1 ,3-Bis-(2'- methoxy-4'-(N-hydroxyamidino)phenoxy)propan, 2,5-Bis-[4- amidinophenyljfuran, 2,5-Bis-[4-amidinophenyl]furan-bis-amidoxim, 2,5-Bis-Still other analogs are those that fall within a formula set forth in one 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 Publication No. US 2002/0019437 A1 are provided, each of which is included in its entirety by reference name. 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-amidinophenyljfuran, 2,5-bis- [4-amidinophenyl] furan-bis-amidoxime, 2,5-bis-
[4-amidinophenyl]furan-bis-0-methylamidoxim, 2,5-Bis-[4- amidinophenyljfuran-bis-O-ethylamidoxim, 2,8-Diamidinodibenzothiophen,[4-amidinophenyl] furan-bis-0-methylamidoxime, 2,5-bis- [4-amidinophenyljfuran-bis-O-ethylamidoxime, 2,8-diamidinodibenzothiophene,
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-imidazolinyI)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-benzimidazoyl)pyridin, 2,6-Bis-[5-(1 ,4,5,6-tetrahydro-2- pyrimidinyl)-2-benzimidazolyl]pyridin, 2,5-Bis-(5-amidino-2- benzimidazolyl)furan, 2,5-Bis-[5-(2-imidazolinyl)-2-benzimidazolyl]furan, 2,5-Bis-(5-N-isopropylamidino-2-benzimidazolyl)furan, 2,5-Bis-(4- guanylphenyl)furan, 2,5-Bis(4-guanylphenyl)-3,4-dimethylfuran, 2,5-Di-p-[2- (3,4,5,6-tetrahydropyrimidyl)phenyl]furan, 2,5-Bis-[4-(2-imidazolinyl)phenyl]- furan, 2,5-[Bis-{4-(2-tetrahydropyrimidinyl)}phenyl]-p-(tolyloxy)furan, 2,5- [Bis-{4-(2-imidazolinyl)}-phenyl]-3-p-(tolyloxy)furan, 2,5-Bis-{4-[5-(N-2- aminoethylamido)benzimidazol-2-yl]phenyl}furan, 2,5-Bis-[4-(3a,4,5,6,7,7a- hexahydro-1H-benzimidazol-2-yl)phenyl]furan, 2,5-Bis-[4-(4,5,6,7- tetrahydro-1 H-1 ,3-diazepin-2-yl)phenyl]furan, 2,5-Bis-(4-N,N- dimethylcarboxhydrazidphenyl)furan, 2,5-Bis-{4-[2-(N-2- hydroxyethyl)imidazolinyl]phenyl}furan, 2,5-Bis-[4-(N-isopropyl- amidino)phenyl]furan, 2,5-Bis-{4-[3-(dimethylaminopropyl)amidino]phenyl}- furan, 2,5-Bis-{4-[N-(3-aminopropyl)amidino]phenyl}furan, 2,5-Bis-[2- 5 (imidzaolinyl)phenyl]-3,4-bis-(methoxymethyl)furan, 2,5-Bis-[4-N-(dimethyl- aminoethyl)guanyl]-phenylfuran, 2,5-Bis-{4-[(N-2-hydroxyethyl)guanyl]- phenyljfuran, 2,5-Bis-[4-N-(cyclopropylguanyl)phenyl]furan, 2,5-Bis-[4-(N,N- diethylaminopropyl)-guanyl]phenylfuran, 2,5-Bis-{4-[2-(N-ethylimidazolinyl)]-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-imidazolinyI) 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-dicyano-dibenzofuran, 2,5-bis- (5-amidino-2-benzimidazolyl) pyrrole, 2,5-bis- [5- (2-imidazolinyl) -2-benzimidazolyl] pyrrole, 2,6- Bis- [5- (2-imidazolinyl) -2-benzimidazolylpyridine, 1-methyl-2,5-bi s- (5-amidino-2-benzimidazolyl) pyrrole, 1-methyl-2,5-bis- [5- (2-imidazolyl) -2-benzimidazolyl] pyrrole, 1-methyl-2,5-bis- [5 - (1, 4,5,6-tetrahydro-2-pyrimidinyl) -2-benzimidazolyl] pyrrole, 2,6-bis- (5-amidino-2-benzimidazoyl) pyridine, 2,6-bis- [5- ( 1, 4,5,6-tetrahydro-2-pyrimidinyl) -2-benzimidazolyl] pyridine, 2,5-bis (5-amidino-2-benzimidazolyl) furan, 2,5-bis- [5- (2- imidazolinyl) -2-benzimidazolyl] furan, 2,5-bis (5-N-isopropylamidino-2-benzimidazolyl) furan, 2,5-bis (4-guanylphenyl) furan, 2,5-bis (4-guanylphenyl) ) -3,4-dimethylfuran, 2,5-di-p- [2- (3,4,5,6-tetrahydropyrimidyl) phenyl] furan, 2,5-bis- [4- (2-imidazolinyl) phenyl] - furan, 2,5- [bis- {4- (2-tetrahydropyrimidinyl)} phenyl] -p- (tolyloxy) furan, 2,5- [bis- {4- (2-imidazolinyl)} - phenyl] -3 -p- (tolyloxy) furan, 2,5-bis- {4- [5- (N-2-aminoethylamido) benzimidazol-2-yl] phenyl} furan, 2,5-bis- [4- (3a, 4 , 5,6,7,7a-hexahydro-1H-benzimidazol-2-yl) phenyl] furan, 2,5-bis- [4- (4,5,6,7-tetrahydro-1 H-1,3- diazepin-2-yl) phenyl] furan, 2,5-bis- (4-N, N- dimethylcarboxhydrazidphenyl) furan, 2,5-bis- {4- [2- (N-2-hydroxyethyl) imidazolinyl] phenyl} furan, 2,5-bis- [4- (N-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- 5 (imidzaolinyl) 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- (cyclopropylguanyl) phenyl] furan, 2,5-bis- [4- (N, N-diethylaminopropyl) guanyl ] phenylfuran, 2,5-bis- {4- [2- (N-ethylimidazolinyl)] -
10 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- benzimidazolyljmethan, Bis-[5-(2-imidazolyl)-2-benzimidazolyl]methan, 1 ,2-10 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-benzimidazolylmethane, bis- [5- (2-imidazolyl) -2-benzimidazolyl] methane, 1, 2-
A 5 Bis-[5-amidino-2-benzimidazolyl]ethan, 1 ,2-Bis-[5-(2-ιmidazolyl)-2- benzimidazolyljethan, 1 ,3-Bis-[5-amidino-2-benzimidazolyl]propan, 1 ,3-Bis- [5-(2-imidazolyl)-2-benzimidazolyl]propan, 1 ,4-Bis-[5-amidino-2-benzimida- zolyljpropan, 1 ,4-Bis-[5-(2-imidazolyl)-2-benzimidazolyl]butan, 1 ,8-Bis-[5- amidino-2-benzimidazolyl]octan, trans-1 ,2-Bis-[5-amidino-2-A 5 bis- [5-amidino-2-benzimidazolyl] ethane, 1, 2-bis- [5- (2-imidazolyl) -2-benzimidazolylethane, 1, 3-bis [5-amidino-2-benzimidazolyl] propane , 1,3-bis- [5- (2-imidazolyl) -2-benzimidazolyl] propane, 1,4-bis- [5-amidino-2-benzimidazolyljpropane, 1,4-bis- [5- (2nd -imidazolyl) -2-benzimidazolyl] butane, 1,8-bis- [5-amidino-2-benzimidazolyl] octane, trans-1,2-bis- [5-amidino-2-
20 benzimidazolyljethen, 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-benzimidazolyi]-1-methylbutan, 1 ,4-Bis-[5-(2-imidazolyl)-2- benzimidazolyl]-2-ethylbutan, 1 ,4-Bis-[5-(2-imidazolyl)-2-benzimidazolyl]-1-20 benzimidazolyljethen, 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-benzimidazolyi] -1-methylbutane, 1,4-bis- [5- (2-imidazolyl) -2-benzimidazolyl] -2-ethylbutane, 1st , 4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -1-
25 methyl-1-buten, 1 ,4-Bis-[5-(2-imidazolyl)-2-benzimidazolyl]-2,3-diethyl-2- buten, 1 ,4-Bis-[5-(2-imidazolyl)-2-benzimidazolyl]-1 ,3-butadien, 1 ,4-Bis-[5- (2-imidazolyl)-2-benzimidazolyl]-2-methyl-1 ,3-butadien, Bis-[5-(2-pyrimidyl)- 2-benzimidazolyl]methan, 1 ,2-Bis-[5-(2-pyrimidyl)-2-benzimidazolyl]ethan,25 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-butadiene, bis- [5- (2nd -pyrimidyl) -2-benzimidazolyl] methane, 1,2-bis- [5- (2-pyrimidyl) -2-benzimidazolyl] ethane,
3Q 1 ,3-Bis-[5-amidino-2-benzimidazolyl]propan, 1 ,3-Bis-[5-(2-pyrimidyl)-2- benzimidazolyljpropan, 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- 3Q 1,3 -bis- [5-amidino-2-benzimidazolyl] propane, 1,3-bis- [5- (2-pyrimidyl) -2-benzimidazolyljpropane, 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-
35 Bis-[5-(2-pyrimidyl)-2-benzimidazolyl]-1-methyl-1-buten, 1 ,4-Bis-[5-(2- pyrimidyl)-2-benzimidazolyl]-2,3-diethyl-2-buten, ,4-Bis-[5-(2-pyrimidyl)-2- benzimidazolyl]-1 ,3-butadien und 1 ,4-Bis-[5-(2-pyrimidyl)-2-benzimidazoiyl]~ 2-methyl-1 ,3-butadien, 2,4-Bis-(4-guanylphenyl)pyrimidin, 2,4-Bis-(4- imidazolin-2-yl)pyrimidin, 2,4-Bis-[(tetrahydropyrimidinyl-2- yl)phenyl]pyrimidin, 2-(4-[N-i-Propylguanyl]phenyl)-4-(2-methoxy-4-[N-i- 5 propylguanyl]phenyl)pyrimidin, 4-(N-Cyclopentylamidino)-1 ,2- phenylendiamin, 2,5-Bis-[2-(5-amidino)benzimidazoyl]furan, 2,5-Bis-[2-{5- (2-imidazolino)}benzimidazoyl]furan, 2,5-Bis-[2-(5-N-isopropylamidino)- benzimidazoyljfuran, 2,5-Bis-[2-(5-N-cyclopentylamidino)-benzimida-35 bis- [5- (2-pyrimidyl) -2-benzimidazolyl] -1-methyl-1-butene, 1,4-bis- [5- (2-pyrimidyl) -2-benzimidazolyl] -2,3-diethyl -2-butene,, 4-bis- [5- (2-pyrimidyl) -2- benzimidazolyl] -1, 3-butadiene and 1,4-bis- [5- (2-pyrimidyl) -2-benzimidazoiyl] ~ 2-methyl-1,3-butadiene, 2,4-bis (4-guanylphenyl) pyrimidine, 2,4-bis (4-imidazolin-2-yl) pyrimidine, 2,4-bis - [(tetrahydropyrimidinyl-2-yl) phenyl] pyrimidine, 2- (4- [Ni-propylguanyl] phenyl) - 4- (2-methoxy-4- [Ni-5-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) benzimidazoyljfuran, 2,5-bis- [2 - (5-N-cyclopentylamidino) -benzimida-
10 zoyljfuran, 2,5-Bis[2-(5-amidino)benzimidazoyl]pyrrol, 2,5-Bis-[2-{5-(2- imidazolino)}benzimidazoyl]pyrrol, 2,5-Bis-[2-(5-N-isopropylamidino)- benzimidazoyljpyrrol, 2,5-Bis-[2-(5-N-cyclopentylamidino)- benzimidazoyljpyrrol, 1-Methyl-2,5-bis-[2-(5-amidino)benzimidazoyl]pyrrol,10 zoyljfuran, 2,5-bis [2- (5-amidino) benzimidazoyl] pyrrole, 2,5-bis- [2- {5- (2-imidazolino)} benzimidazoyl] pyrrole, 2,5-bis- [2 - (5-N-isopropylamidino) - benzimidazoylpyrrole, 2,5-bis- [2- (5-N-cyclopentylamidino) - benzimidazoylpyrrole, 1-methyl-2,5-bis- [2- (5-amidino) benzimidazoyl] pyrrole,
A 5 2,5-Bis-[2-{5-(2-imidazolino)}benzimidazoyl]-1 -methylpyrrol, 2,5-Bis-[2-(5-N- cyclopentylamidino)benzimidazoyl]-1-methylpyrrol, 2,5-Bis-[2-(5-N- isopropylamidino)benzimidazoyl]thiophen, 2,6-Bis-[2-{5-(2- imidazolino)}benzimidazoyl]pyridin, 2,6-Bis-[2-(5-amidino)benzimidazoyl]- pyridin, 4,4'-Bis-[2-(5-N-isopropylamidino)benzimidazoyl]-1,2-diphenylethan,A 5 2,5-bis- [2- {5- (2-imidazolino)} benzimidazoyl] -1-methylpyrrole, 2,5-bis- [2- (5-N-cyclopentylamidino) benzimidazoyl] -1-methylpyrrole, 2,5-bis- [2- (5-N-isopropylamidino) benzimidazoyl] thiophene, 2,6-bis- [2- {5- (2-imidazolino)} benzimidazoyl] pyridine, 2,6-bis- [2 - (5-amidino) benzimidazoyl] - pyridine, 4,4'-bis- [2- (5-N-isopropylamidino) benzimidazoyl] -1,2-diphenylethane,
20 4,4'-Bis-[2-(5-N-cyclopentylamidino)benzimidazoyl]-2,5-diphenylfuran, 2,5- Bis-[2-(5-amidino)benzimidazoyl]benzo-[b]-furan, 2,5-Bis-[2-(5-N- cyclopentylamidino)benzimidazoyl]benzo-[b]-furan, 2,7-Bis-[2-(5-N- isopropylamidino)benzimidazoyl]fluor, 2,5-Bis-[4-(3-(N-morpholinopropyl)-20 4,4'-bis- [2- (5-N-cyclopentylamidino) benzimidazoyl] -2,5-diphenylfuran, 2,5-bis- [2- (5-amidino) benzimidazoyl] benzo [b] furan , 2,5-bis- [2- (5-N-cyclopentylamidino) benzimidazoyl] benzo- [b] -furan, 2,7-bis- [2- (5-N-isopropylamidino) benzimidazoyl] fluorine, 2.5 bis [4- (3- (N-morpholinopropyl) -
25 carbamoyl)phenyl]furan, 2,5-Bis-[4-(2-N,N- dimethylaminoethylcarbamoyl)phenyl]furan, 2,5-Bis-[4-(3-N,N- dimethylaminopropylcarbamoyl)phenyl]furan, 2,5-Bis-[4-(3-N-methyl-3-N- phenylaminopropylcarbamoyl)phenyl]furan, 2,5-Bis-[4-(3-N,N8,N11-25 carbamoyl) phenyl] furan, 2,5-bis- [4- (2-N, N-dimethylaminoethylcarbamoyl) phenyl] furan, 2,5-bis- [4- (3-N, N-dimethylaminopropylcarbamoyl) phenyl] furan , 2,5-bis- [4- (3-N-methyl-3-N-phenylaminopropylcarbamoyl) phenyl] furan, 2,5-bis- [4- (3-N, N8, N11-
3Q trimethylaminopropylcarbamoyl)phenyl]furan, 2,5-Bis-[3- amidinophenyljfuran, 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- 3Q trimethylaminopropylcarbamoyl) phenyl] furan, 2,5-bis- [3-amidinophenyljfuran, 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-
35 benzyloxycarbonyl)amidinophenyl]furan, 2,5-Bis[4-(N-phenoxycarbonyl)- amidinophenyljfuran, 2,5-Bis-[4-(N-(4-fluor)-phenoxycarbonyl)amidino- phenyljfuran, 2,5-Bis-[4-(N-(4- methoxy)phenoxycarbonyl)amidinophenyl]furan, 2,5-Bis-[4-(1- acetoxyethoxycarbonyl)amidinophenyl]furan und 2,5-Bis-[4-(N-(3- fluor)phenoxycarbonyl)amidinophenyl]furan. Verfahren zur Herstellung einer der vorstehenden Verbindungen sind in den U.S.-Patenten Nr.35 benzyloxycarbonyl) amidinophenyl] furan, 2,5-bis [4- (N-phenoxycarbonyl) amidinophenyljfuran, 2,5-bis- [4- (N- (4-fluoro) phenoxycarbonyl) amidino- phenyljfuran, 2,5-bis- [4- (N- (4-methoxy) phenoxycarbonyl) amidinophenyl] furan, 2,5-bis- [4- (1-acetoxyethoxycarbonyl) amidinophenyl] furan and 2,5-bis- [ 4- (N- (3-fluoro) phenoxycarbonyl) amidinophenyl] furan. Methods for making one of the above compounds are described in U.S. Patent Nos.
5,428,051 , 5,521 ,189, 5,602,172, 5,643,935, 5,723,495, 5,843,980,5,428,051, 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 der6,172,104 and 6,326,395 or US patent application with the
Veröffentlich ungsnr. US 2002/0019437 A1 beschrieben.Publication no. US 2002/0019437 A1.
Pentamidin-Metabolite eignen sich ebenfalls in der erfindungsgemäßen antiproliferativen Kombination. Pentamidin wird im Körper schnell zu mindestens sieben primären Metaboliten metabolisiert. Einige dieser Metabolite haben eine oder mehrere Wirkungen mit Pentamidin gemeinsam. Einige Pentamidin-Metabolite können antiproliferative Wirkung zeigen, wenn sie mit einem Benzimidazol oder einem Analogon davon kombiniert werden. Pentamidine metabolites are also suitable in the antiproliferative combination according to the invention. Pentamidine is rapidly metabolized to at least seven primary metabolites in the body. Some of these metabolites share one or more effects with pentamidine. Some pentamidine metabolites can show antiproliferative effects when combined with a benzimidazole or an 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 und einer Metaboliten eignen sich zur Behandlung vonThe combinations according to the invention of compounds of the formula I and formula VI and a metabolite are suitable for the treatment of
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.Neoplasms. A combination therapy can be carried out alone or in conjunction with another therapy (e.g. surgery, radiation, chemotherapy, biological therapy). In addition, a person who is at greater risk of developing a neoplasm (e.g., someone who is genetically predisposed or someone who has previously had a neoplasm) can receive prophylactic treatment to inhibit or delay neoplasm formation.
Die Dosierung und Häufigkeit der Verabreichung jeder Verbindung der Kombination kann unabhängig gesteuert werden. Zum Beispiel kann eineThe dosage and frequency of administration of each compound of the combination can be controlled independently. For example, one
Verbindung dreimal täglich oral verabreicht werden, während die zweiteCompound to be administered orally three times a day while the second
Verbindung einmal pro Tag intramuskulär verabreicht werden kann. DieCompound can be administered intramuscularly once a day. The
Verbindungen können auch zusammen formuliert werden, so dass eineConnections can also be formulated together, so that a
Verabreichung beiden Verbindungen zuführt.Administration feeds 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 according to the invention can also be provided as components of a pharmaceutical package. The two drugs can be formulated together or separately and in individual 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 for treating a patient who has a neoplasm such as a cancer by administering a compound of formula (I) and (VI) in combination with an antiproliferative agent. Suitable antiproliferative agents include those provided in Table 1.
Vor- und nachstehend sind alle Temperaturen in °C angegeben. In den nachfolgenden Beispielen bedeutet „übliche Aufarbeitung": Man gibt, falls erforderlich, Wasser hinzu, stellt, falls erforderlich, je nach Konstitution des Endprodukts auf pH-Werte zwischen 2 und 10 ein, extrahiert mit Ethylacetet oder Dichlormethan, trennt ab, trocknet die organische Phase über Natriumsulfat, dampft ein und reinigt duch Chromatographie an Kieselgel und/oder durch Kristallisation. Rf-Werte an Kieselgel; Laufmittel: Ethylacetat/Methanol 9:1. Massenspektrometrie (MS): El (Electronenstoß-Ionisation) M+ FAB (Fast Atom Bombardment) (M+H)+ ESI (Electrospray lonization) (M+H)+ APCI-MS (atmospheric pressure chemical ionization - mass spectrometry) (M+H)+ All temperatures above and below are given in ° C. In the examples below, "customary workup" means: if necessary, water is added, if necessary, depending on the constitution of the End product to pH values between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, the organic phase dried over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1. 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) +
Die im Folgenden eingesetzten Mandelsäurederivate sind nach in der Literatur beschriebenen Synthesen z.B. aus aromatischen Aldehyden zugänglich.The mandelic acid derivatives used below are e.g. accessible from aromatic aldehydes.
Beispiel 1example 1
a) Synthese von Chlorphenylessigsäure-methylester 1.a) Synthesis of chlorophenylacetic acid methyl ester 1.
Zur Synthese von Chlorphenylessigsäure-methyleste werden 10,0 g (60 mmol) Mandelsäuremethylester in 10 mL Dichlomethan gelöst und nach Zusatz von 4,79 mL (66 mmol, 1.1 equiv.) Thionylchlorid auf 60°C erwärmt. Es wird 18 Stunden gerührt, die Reaktionslösung auf Raumtemperatur abgekühlt, mit weiteren 20 mL Dichlormethan versetzt und je zweimal mit 30 mL Wasser und gesättigter NaHC03-Lösung extrahiert. Die organische Phase wird über Natriumsulfat getrocknet und das Reaktionsprodukt nach Filtration und Abdestillieren des Lösungsmittels erhalten.To synthesize methyl chlorophenylacetate, 10.0 g (60 mmol) of methyl mandelate are dissolved in 10 mL dichloromethane and, after adding 4.79 mL (66 mmol, 1.1 equiv.) Thionyl chloride, heated to 60 ° C. The mixture is stirred for 18 hours, the reaction solution is cooled to room temperature, a further 20 ml of dichloromethane are added and the mixture is extracted twice with 30 ml of water and saturated NaHC03 solution. The organic Phase is dried over sodium sulfate and the reaction product is obtained after filtration and distillation of the solvent.
b) Synthese von Phenyl-p-tolylsulfanylessigsäure-methylester 2b) Synthesis of phenyl p-tolylsulfanylacetic acid methyl ester 2
Zur Synthese von Phenyl-p-tolylsulfanylessigsäure-methyleste werden 2,0 g (7.9 mmol) 1 in 10 mL Dichlormethan gelöst, mit je 1 equiv. 4- Methylthiophenol (7.9 mmol, 0.98 g) und Natriumhydroxid (7.9 mmol, 0.32 g) versetzt und 2 Stunden unter Rückfluss erhitzt. Das auf Raumtemperatur abgekühlte Reaktionsgemisch wird filtriert und das Lösungsmittel abdestilliert. Der Rückstand wird mit Wasser versetzt und das Reaktionsprodukt mit Essigester extrahiert. Die organische Phase wird mit Natriumsulfat getrocknet und das Lösungsmittel nach Filtration abdestilliert. Wodurch das Produkt 2 erhalten wurde.For the synthesis of methyl phenyl-p-tolylsulfanylacetate, 2.0 g (7.9 mmol) 1 are dissolved in 10 mL dichloromethane, each with 1 equiv. 4-Methylthiophenol (7.9 mmol, 0.98 g) and sodium hydroxide (7.9 mmol, 0.32 g) were added and the mixture was heated under reflux for 2 hours. The reaction mixture, cooled to room temperature, is filtered and the solvent is distilled off. Water is added to the residue and the reaction product is extracted with ethyl acetate. The organic phase is dried with sodium sulfate and the solvent is distilled off after filtration. Whereby product 2 was obtained.
c) Synthese von Phenyl-p-tolylsulfanylessigsäure 3c) Synthesis of phenyl-p-tolylsulfanylacetic acid 3
Zur Synthese von Phenyl-p-tolylsulfanylessigsäure werden 2,2 g (6.4 mmol) 2 in 8 mL Methanol gelöst und mit einer Lösung von 1.32g (9.57 mmol, 1.5 equiv.) Kaliumcarbonat in 1.5 mL Wasser versetzt. Es wird 15 Stunden unter Rückfluss erhitzt. Nach Abdestillieren des Lösungsmittels wird der Rückstand in Wasser gelöst und einmal mit Diethylether extrahiert. Die wässrige Phase wird unter Kühlung mit 18 mL 1N HCI versetzt und mit Essigsäureethylester extrahiert. Nach Trocknung über Natriumsulfat, Filtration und Abdestillieren des Lösungsmittels wird das Produkt 3 erhalten.For the synthesis of phenyl-p-tolylsulfanylacetic acid, 2.2 g (6.4 mmol) 2 are dissolved in 8 mL methanol and a solution of 1.32g (9.57 mmol, 1.5 equiv.) Potassium carbonate in 1.5 mL water. The mixture is heated under reflux for 15 hours. After the solvent has been distilled off, the residue is dissolved in water and extracted once with diethyl ether. The aqueous phase is mixed with cooling with 18 mL 1N HCl and extracted with ethyl acetate. After drying over sodium sulfate, Filtration and distillation of the solvent gives the product 3.
d) Synthese von Phenyl-p-tolylsulfanylessigsäurechlorid 4d) Synthesis of phenyl-p-tolylsulfanylacetic acid chloride 4
Zur Synthese von Phenyl-p-tolylsulfanylessigsäurechlorid werden 1 ,7 g (5.5 mmol) 3 in 10 mL Dichlormethan gelöst und mit 1.4 mL (3.5 equiv.) Thionylchlorid versetzt. Der Rückstand wird mit Wasser versetzt und das Reaktionsprodukt mit Essigester extrahiert. Die organische Phase wird mit Natriumsulfat getrocknet und da Lösungsmittel nach Filtration abdestilliert wodurch das Produkt 4 erhalten wurde.For the synthesis of phenyl-p-tolylsulfanylacetic acid chloride, 1.7 g (5.5 mmol) 3 are dissolved in 10 mL dichloromethane and mixed with 1.4 mL (3.5 equiv.) Thionyl chloride. Water is added to the residue and the reaction product is extracted with ethyl acetate. The organic phase is dried with sodium sulfate and since the solvent is distilled off after filtration, the product 4 being obtained.
e) Synthese von 5-Methyl-2-phenyl-2,3-dihydro-benzothiophen-3-on 5e) Synthesis of 5-methyl-2-phenyl-2,3-dihydro-benzothiophen-3-one 5
Zur Synthese von 5-Methyl-2-phenyl-2,3-dihydro-benzothiophen-3-on werden zu 0,33g (2.44 mmol, 1.3 equiv.) AlCI3 in 2 mL Dichlormethan, vorgekühlt auf -65°C, 0.8 g (1.88 mmol) 4 in 8 mL Dichlormethan langsam zugetropft. Nach 15 stündigem Rühren bei Raumtemperatur wird der Reaktionsansatz auf Eis gegossen, die organische Phase abgetrennt und 2 mal gegen 1N Natronlauge extrahiert. Der pH-Wert wird mit 50%iger Essigsäure auf 6 eingestellt und das ausgefallene Reaktionsprodukt abfiltriert.For the synthesis of 5-methyl-2-phenyl-2,3-dihydro-benzothiophen-3-one, AlCI 3 in 0.3 mL (2.44 mmol, 1.3 equiv.) In 2 mL dichloromethane, precooled to -65 ° C, 0.8 g (1.88 mmol) 4 in 8 mL dichloromethane are slowly added dropwise. After stirring for 15 hours at room temperature, the reaction mixture is poured onto ice, the organic phase is separated off and extracted twice against 1N sodium hydroxide solution. The pH is adjusted to 6 with 50% acetic acid and the precipitated reaction product is filtered off.
f) Synthese von 2,5-Dimethyl-2-phenyl-2,3-dihydrobenzothiophen-3-on _6 f) Synthesis of 2,5-dimethyl-2-phenyl-2,3-dihydrobenzothiophene-3-one _6
Zur Synthese von 2,5-Dimethyl-2-phenyl-2,3-dihydrobenzothiophen-3-on werden 23.8 mg Natriumhydrid (0,59 mmol, 60% in Paraffinöl) in 10 mL Toluol suspendiert. Unter Rühren werden 122 μl (1.27 mmol; 3 equiv.) tert- Butanol zugesetzt. Nach einstündigem Rühren bei Raumtemperatur werden 200 mg (0,42 mmol) 5 zugegeben und eine halbe Stunde auf 60 °C erhitzt und nach Abkühlen auf 40°C mit 90,3 mg (0,63 mmol, 1.5 equiv.) lodmethan versetzt. Es wird 3 Stunden bei 80 °C gerührt. Nach Abkühlen wird mit Eiswasser versetzt und nach Abtrennen der organischen Phase mit Toluol nachextrahiert. Nach Trocknen über Natriumsulfat wird abfiltriert. Das Produkt 6 wird nach Filtration über Kieselgel und Abdestillieren des Lösungsmittels erhalten.To synthesize 2,5-dimethyl-2-phenyl-2,3-dihydrobenzothiophen-3-one, 23.8 mg sodium hydride (0.59 mmol, 60% in paraffin oil) are suspended in 10 mL toluene. 122 μl (1.27 mmol; 3 equiv.) Tert-butanol are added with stirring. After stirring for one hour at room temperature, 200 mg (0.42 mmol) 5 are added and the mixture is heated at 60 ° C. for half an hour and, after cooling to 40 ° C., 90.3 mg (0.63 mmol, 1.5 equiv.) Iodomethane are added. The mixture is stirred at 80 ° C for 3 hours. After cooling, ice water is added and, after the organic phase has been separated off, extracted with toluene. After drying over sodium sulfate is filtered off. The product 6 is obtained after filtration through silica gel and distilling off the solvent.
g) Synthese von 2,5-Dimethyl-3-(1-methyl-piperidin-4-yl)-2-phenyl-2,3- dihydro-benzothiophen-3-ol 7g) Synthesis of 2,5-dimethyl-3- (1-methyl-piperidin-4-yl) -2-phenyl-2,3-dihydro-benzothiophene-3-ol 7
Zur Synthese von 2,5-Dimethyl-3-(1-methyl-piperidin-4-yl)-2-phenyl-2,3- dihydro-benzothiophen-3-o werden 0,42 g Magnesium-Späne in 5 mL getrocknetem THF vorgelegt und die Grignard Reaktion durch Zusatz von lod und Ethylbromid gestartet. Unter Rühren werden 2.3 g (17.2 mmol, 1.5 equiv.) N-Methyl-4-chlorpiperidin (erhalten aus N-Methylpiperidinol durch Umsetzen mit Thionylchlorid) gelöst in 5 mL THF zugesetzt und eine Stunde unter Rückfluss erhitzt. Nach Abkühlen auf 10 °C werden 2.66 g (11.0 mmol) 6 gelöst in 10 mL THF zugetropft und über Nacht gerührt. Nach Zusatz von 2 mL Wasser wird der Niederschlag abfiltriert, die flüssige Phase eingeengt und mit 1 N HCI versetzt und mit Essigsäureethylester extrahiert. Die abgetrennte wässrige Phase wird mit NaOH-Lösung auf pH 12 eingestellt und das ausgefallene Reaktionsprodukt abfiltriert.For the synthesis of 2,5-dimethyl-3- (1-methyl-piperidin-4-yl) -2-phenyl-2,3-dihydro-benzothiophene-3-o, 0.42 g of magnesium shavings are dried in 5 mL THF submitted and the Grignard reaction started by adding iodine and ethyl bromide. With stirring, 2.3 g (17.2 mmol, 1.5 equiv.) Of N-methyl-4-chloropiperidine (obtained from N-methylpiperidinol by reaction with thionyl chloride) dissolved in 5 ml of THF are added and the mixture is heated under reflux for one hour. After cooling to 10 ° C., 2.66 g (11.0 mmol) 6 dissolved in 10 mL THF are added dropwise and the mixture is stirred overnight. After adding 2 mL of water, the precipitate is filtered off, the liquid phase is concentrated and 1N HCl is added and the mixture is extracted with ethyl acetate. The separated aqueous phase is adjusted to pH 12 with NaOH solution and the precipitated reaction product is filtered off.
h) Synthese von 4-(2,5-Dimethyl-2-phenyl-2,3-dihydro-benzothiophen-3- ylidene)-1-methyl-piperidin 8h) Synthesis of 4- (2,5-dimethyl-2-phenyl-2,3-dihydro-benzothiophene-3-ylidenes) -1-methyl-piperidine 8
Zur Synthese von 4-(2,5-Dimethyl-2-phenyl-2,3-dihydro-benzothiophen-3- ylidene)-1-methyl-piperidin werden 1,9 g (5.4 mmol) 7 in 20 mL HCI gesättigtem Isopropanol 3 Stunden bei 60 °C gerührt. Nach Beendigung der Reaktion wird eingeengt und der kristalline Rückstand mit Diethylether verrührt. Das kristalline Produkt 8 wird getrocknet.For the synthesis of 4- (2,5-dimethyl-2-phenyl-2,3-dihydro-benzothiophene-3-ylidenes) -1-methyl-piperidine, 1.9 g (5.4 mmol) 7 in 20 mL HCI saturated isopropanol are used Stirred at 60 ° C for 3 hours. After the reaction has ended, the mixture is concentrated and the crystalline residue is stirred with diethyl ether. The crystalline product 8 is dried.
Analog werden unter Verwendung oder entsprechenden Vorstufen die folgenden erfindungsgemäßen Verbindungen erhalten: The following compounds according to the invention are obtained analogously using or corresponding precursors:
Beispiel 2-41Example 2-41
Nr. R' R^ R R4 2. Methyl Methyl H 0 3. Methyl Phenyl H 0 4. Methyl Methyl Methyl 0 5. Methyl Phenyl Methyl 0 6. Methyl Methyl HNo. R 'R ^ RR 4 2. Methyl Methyl H 0 3. Methyl Phenyl H 0 4. Methyl Methyl Methyl 0 5. Methyl Phenyl Methyl 0 6. Methyl Methyl H
7. Methyl Phenyl H7. Methyl phenyl H
8. Methyl Methyl Methyl8. Methyl methyl methyl
9. Methyl Phenyl Methyl 10. Phenyl Methyl H 0 11. Phenyl Phenyl H 0 12. Phenyl Methyl Methyl 0 13. Phenyl Phenyl Methyl 0 14. Phenyl Methyl H9. methyl phenyl methyl 10. phenyl methyl H 0 11. phenyl phenyl H 0 12. phenyl methyl methyl 0 13. phenyl phenyl methyl 0 14. phenyl methyl H
15. Phenyl Phenyl H 16. Phenyl Methyl Methyl15. Phenyl phenyl H 16. Phenyl methyl methyl
17. Phenyl Phenyl Methyl 17. Phenyl phenyl methyl
18. OH Methyl H O18. OH methyl H O
19. OH Phenyl H O19. OH phenyl HO
20. OH Methyl Methyl O20. OH methyl methyl O
2211.. OOHH Phenyl Methyl O2211 .. OOHH phenyl methyl O
22. OH Methyl H22. OH methyl H
23. OH Phenyl H23. OH phenyl H.
24. OH Methyl Methyl24. OH methyl methyl
25 OH Phenyl Methyl 25 OH phenyl methyl
No. R1 R^ RJ R"No. R 1 R ^ R J R "
26. NH2 Methyl H 026. NH 2 methyl H 0
27. NH2 Phenyl H 027. NH 2 phenyl H 0
28. NH2 Methyl Methyl 028. NH 2 methyl methyl 0
29. NH2 Phenyl Methyl 029. NH 2 phenyl methyl 0
30. NH2 Methyl H30. NH 2 methyl H
31. NH2 Phenyl H31. NH 2 phenyl H
32. NH2 Methyl Methyl32. NH 2 methyl methyl
33. NH2 Phenyl Methyl 33. NH 2 phenyl methyl
34. CN Methyl H O34. CN Methyl H O
3355.. CCNN Phenyl H O3355 .. CCNN phenyl H O
36. CN Methyl Methyl 036. CN methyl methyl 0
37. CN Phenyl Methyl O37. CN Phenyl Methyl O
38. CN Methyl H38. CN Methyl H
39. CN Phenyl H39. CN Phenyl H
40. CN Methyl Methyl40. CN methyl methyl
41. CN Phenyl Methyl Beispiel 42-8141. CN phenyl methyl Example 42-81
Nr. R1 R< RJ R< 42. Methyl Methyl H 0 43. Methyl Phenyl H 0 44. Methyl Methyl Methyl 0 45. Methyl Phenyl Methyl 0 46. Methyl Methyl H No. R 1 R < R J R <42. methyl methyl H 0 43. methyl phenyl H 0 44. methyl methyl methyl 0 45. methyl phenyl methyl 0 46. methyl methyl H
47. Methyl Phenyl H47. Methyl phenyl H
48. Methyl Methyl Methyl48. methyl methyl methyl
49. Methyl Phenyl Methyl 49. methyl phenyl methyl
50. Phenyl Methyl H 0 51. Phenyl Phenyl H 0 52. Phenyl Methyl Methyl 0 53. Phenyl Phenyl Methyl 0 54. Phenyl Methyl H50. phenyl methyl H 0 51. phenyl phenyl H 0 52. phenyl methyl methyl 0 53. phenyl phenyl methyl 0 54. phenyl methyl H
55. Phenyl Phenyl H Nr. R1 R^ R R55. Phenyl phenyl H No. R 1 R ^ RR
56. Phenyl Methyl Methyl56. Phenyl methyl methyl
57. Phenyl Phenyl Methyl 57. Phenyl phenyl methyl
58. OH Methyl H O 59. OH Phenyl H O 60. OH Methyl Methyl O 61. OH Phenyl Methyl O 62. OH Methyl H58.OH methyl H O 59.OH phenyl H O 60.OH methyl methyl O 61.OH phenyl methyl O 62.OH methyl H
63. OH Phenyl H63. OH phenyl H.
64. OH Methyl Methyl64. OH methyl methyl
65. OH Phenyl Methyl 65. OH phenyl methyl
No. R1 R2 R3 R4 No. R 1 R 2 R 3 R 4
66. NH2 Methyl H 066. NH 2 methyl H 0
67. NH2 Phenyl H 067. NH 2 phenyl H 0
68. NH2 Methyl Methyl 068. NH 2 methyl methyl 0
69. NH2 Phenyl Methyl 069. NH 2 phenyl methyl 0
70. NH2 Methyl H70. NH 2 methyl H
71. NH2 Phenyl H71. NH 2 phenyl H
72. NH2 Methyl Methyl72. NH 2 methyl methyl
73. NH2 Phenyl Methyl 73. NH 2 phenyl methyl
74. CN Methyl H 074. CN methyl H 0
75. CN Phenyl H 075. CN phenyl H 0
76. CN Methyl Methyl 076. CN methyl methyl 0
77. CN Phenyl Methyl 077. CN phenyl methyl 0
78. CN Methyl H78. CN Methyl H
79. CN Phenyl H79. CN Phenyl H
80. CN Methyl Methyl80. CN methyl methyl
81. CN Phenyl Methyl Beispiel 82-12181. CN phenyl methyl Example 82-121
Nr. R1 R^ Rά R* 82. Methyl Methyl H 0 83. Methyl Phenyl H 0 84. Methyl Methyl Methyl 0 85. Methyl Phenyl Methyl 0 86. Methyl Methyl H No.R 1 R ^ R ά R * 82. methyl methyl H 0 83. methyl phenyl H 0 84. methyl methyl methyl 0 85. methyl phenyl methyl 0 86. methyl methyl H
87. Methyl Phenyl H87. Methyl Phenyl H
88. Methyl Methyl Methyl88. Methyl Methyl Methyl
89. Methyl Phenyl Methyl 90. Phenyl Methyl H O 91. Phenyl Phenyl H O 92. Phenyl Methyl Methyl O 93. Phenyl Phenyl Methyl 0 94. Phenyl Methyl H89. methyl phenyl methyl 90. phenyl methyl HO 91. phenyl phenyl HO 92. phenyl methyl methyl O 93. phenyl phenyl methyl 0 94. phenyl methyl H
95, Phenyl Phenyl H Nr. R1 R^ RJ R"95, phenyl phenyl H No. R 1 R ^ R J R "
96. Phenyl Methyl Methyl96. phenyl methyl methyl
97. Phenyl Phenyl Methyl 97. phenyl phenyl methyl
98. OH Methyl H 098. OH methyl H 0
99. OH Phenyl H 099. OH phenyl H 0
100. OH Methyl Methyl 0100. OH methyl methyl 0
101. OH Phenyl Methyl 0101. OH phenyl methyl 0
102. OH Methyl H102. OH methyl H
103. OH Phenyl H103. OH phenyl H.
104. OH Methyl Methyl104. OH methyl methyl
105. OH Phenyl Methyl 105. OH phenyl methyl
Nr. R1 R2 R3 R4 No. R 1 R 2 R 3 R 4
106. NH2 Methyl H 0106. NH 2 methyl H 0
107. NH2 Phenyl H 0107. NH 2 phenyl H 0
108. NH2 Methyl Methyl 0108. NH 2 methyl methyl 0
109. NH2 Phenyl Methyl 0109. NH 2 phenyl methyl 0
110. NH2 Methyl H110. NH 2 methyl H
111. NH2 Phenyl H111. NH 2 phenyl H
112. NH2 Methyl Methyl112. NH 2 methyl methyl
113. NH2 Phenyl Methyl 113. NH 2 phenyl methyl
114. CN Methyl H 0114. CN methyl H 0
115. CN Phenyl H 0115. CN phenyl H 0
116. CN Methyl Methyl 0116. CN methyl methyl 0
117. CN Phenyl Methyl 0117. CN phenyl methyl 0
118. CN Methyl H118. CN Methyl H
119. CN Phenyl H119. CN Phenyl H
120. CN Methyl Methyl120. CN methyl methyl
121. CN Phenyl Methyl Beispiel 122 ■ 161121. CN phenyl methyl Example 122 ■ 161
Nr. R1 R2 R3 R4 122. Methyl Methyl H 0 123. Methyl Phenyl H 0 124. Methyl Methyl Methyl 0 125. Methyl Phenyl Methyl 0 126. Methyl Methyl H No. R 1 R 2 R 3 R 4 122. methyl methyl H 0 123. methyl phenyl H 0 124. methyl methyl methyl 0 125. methyl phenyl methyl 0 126. methyl methyl H
127. Methyl Phenyl H127. Methyl phenyl H
128. Methyl Methyl Methyl128. Methyl Methyl Methyl
129. Methyl Phenyl Methyl 130. Phenyl Methyl H O 131. Phenyl Phenyl H O 132. Phenyl Methyl Methyl O 133. Phenyl Phenyl Methyl O 134. Phenyl Methyl H129. methyl phenyl methyl 130. phenyl methyl HO 131. phenyl phenyl HO 132. phenyl methyl methyl O 133. phenyl phenyl methyl O 134. phenyl methyl H
135. Phenyl Phenyl H Nr. R1 R2 R3 R4 135. Phenyl phenyl H No. R 1 R 2 R 3 R 4
136. Phenyl Methyl Methyl136. Phenyl methyl methyl
137. Phenyl Phenyl Methyl 137. Phenyl phenyl methyl
138. OH Methyl H 0138. OH methyl H 0
139. OH Phenyl H 0139. OH phenyl H 0
140. OH Methyl Methyl 0140. OH methyl methyl 0
141. OH Phenyl Methyl 0141. OH phenyl methyl 0
142. OH Methyl H142. OH methyl H
143. OH Phenyl H143. OH phenyl H.
144. OH Methyl Methyl144. OH methyl methyl
145. OH Phenyl Methyl 145. OH phenyl methyl
No. R1 R2 R3 R4 No. R 1 R 2 R 3 R 4
146. NH2 Methyl H 0146. NH 2 methyl H 0
147. NH2 Phenyl H 0147. NH 2 phenyl H 0
148. NH2 Methyl Methyl 0148. NH 2 methyl methyl 0
149. NH2 Phenyl Methyl 0149. NH 2 phenyl methyl 0
150. NH2 Methyl H150. NH 2 methyl H
151. NH2 Phenyl H 151. NH 2 phenyl H
152. NH2 Methyl Methyl "Λ NH • _J152. NH 2 methyl methyl " Λ NH • _J
153. NH2 Phenyl Methyl 153. NH 2 phenyl methyl
154. CN Methyl H 0154. CN methyl H 0
155. CN Phenyl H 0155. CN phenyl H 0
156. CN Methyl Methyl 0156. CN methyl methyl 0
157. CN Phenyl Methyl 0157. CN phenyl methyl 0
158. CN Methyl H158. CN Methyl H
159. CN Phenyl H159. CN Phenyl H
160. CN Methyl Methyl160. CN methyl methyl
161. CN Phenyl Methyl Beispiel 162-254161. CN phenyl methyl Example 162-254
Nr. R1 R^ RJ R4 162. Methyl Methyl H 0 163. Methyl Phenyl H 0 164. Methyl Methyl Methyl 0 165. Methyl Phenyl Methyl 0 166. Methyl Methyl H No. R 1 R ^ R J R 4 162. methyl methyl H 0 163. methyl phenyl H 0 164. methyl methyl methyl 0 165. methyl phenyl methyl 0 166. methyl methyl H
167. Methyl Phenyl H167. Methyl phenyl H
168. Methyl Methyl Methyl168. methyl methyl methyl
169. Methyl Phenyl Methyl 170. Phenyl Methyl H O 171. Phenyl Phenyl H 0 172. Phenyl Methyl Methyl O 173. Phenyl Phenyl Methyl O 174. Phenyl Methyl H 175. Phenyl Phenyl H 169. methyl phenyl methyl 170. phenyl methyl HO 171. phenyl phenyl H 0 172. phenyl methyl methyl O 173. phenyl phenyl methyl O 174. phenyl methyl H 175. phenyl phenyl H
Nr. R1 R' R- R4 No. R 1 R 'R- R 4
176. Phenyl Methyl Methyl176. Phenyl methyl methyl
177. Phenyl Phenyl Methyl 177. phenyl phenyl methyl
178. OH Methyl H 0178. OH methyl H 0
179. OH Phenyl H o179. OH phenyl H o
180. OH Methyl Methyl o180. OH methyl methyl o
181. OH Phenyl Methyl 0181. OH phenyl methyl 0
182. OH Methyl H182. OH methyl H
183. OH Phenyl H183. OH phenyl H.
184. OH Methyl Methyl184. OH methyl methyl
185. OH Phenyl Methyl 185. OH phenyl methyl
No. R1 R2 R3 R4 No. R 1 R 2 R 3 R 4
186. NH2 Methyl H 0186. NH 2 methyl H 0
187. NH2 Phenyl H 0187. NH 2 phenyl H 0
188. NH2 Methyl Methyl O188. NH 2 methyl methyl O
189. NH2 Phenyl Methyl 0189. NH 2 phenyl methyl 0
190. NH2 Methyl H190. NH 2 methyl H
191. NH2 Phenyl H191. NH 2 phenyl H
192. NH2 Methyl Methyl192. NH 2 methyl methyl
193. NH2 Phenyl Methyl 193. NH 2 phenyl methyl
194. CN Methyl H 0 119955.. CCNN Phenyl H 0194. CN methyl H 0 119955 .. CCNN phenyl H 0
196. CN Methyl Methyl 0196. CN methyl methyl 0
197. CN Phenyl Methyl 0197. CN phenyl methyl 0
198. CN Methyl H198. CN Methyl H
199. CN Phenyl H199. CN Phenyl H
200. CN Methyl Methyl200. CN methyl methyl
201. CN Phenyl Methyl 202.201. CN phenyl methyl 202nd
203203
206. 206th
208.208th
211. 211th
212.212th
213.213th
214.214th
215. 215th
216.216th
217.217th
218.218th
219. 219th
220.220th
221.221st
CIH 222.CIH 222.
223. 223rd
224.224th
225.225th
226.226th
227. 227th
228.228th
229.229th
230.230th
231. 231st
232.232nd
233233
234.234th
235. 235th
236.236th
237.237th
238.238th
239. 239th
240.240th
241. 241st
242.242nd
244. 244th
245.245th
246.246th
249. 249th
251.251st
252.252nd
253.253rd
254. 254th
Beispiel A: Assay IExample A: Assay I
Die Bestimmung der Wirksamkeit der erfindungsgemäßen Verbindungen der Formel I 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 die 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 der Reaktion durchgeführt.The determination of the effectiveness of the compounds of formula I according to the invention can, for. B. on the Eg5-ATPase activity, which is measured via an enzymatic regeneration of the product ADP to ATP using pyruvate kinase (PK) and subsequent coupling to a NADH-dependent lactate dehydrogenase (LDH) reaction. By coupling to the NADH-dependent LDH, the reaction can be followed by changing the absorbance at 340 nm. At the same time, regeneration of the ATP ensures that the substrate concentration remains constant. The absorbance changes per unit of time are analyzed graphically and a linear regression is carried out in the vusually linear area of the reaction.
Beispiel B: Assay IIExample B: Assay II
Die Bestimmung der Wirksamkeit der erfindungsgemäßen Verbindungen 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 effectiveness of the compounds of the formula I according to the invention in combination with compounds of the formula VI and / or medicaments from Table I can be shown in combination assays as follows:
103 bis 104 Zellen einer definierten Zeil-Linie (HCT116, Colo 205, MDA-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.10 3 to 10 4 cells of a defined cell line (HCT116, Colo 205, MDA-MB 231, etc.) are sown per well in a 96-well microtiter plate and cultivated overnight under standard conditions. 10-50 mM stock solutions in DMSO were prepared for the substances of the combination to be tested. 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 next morning, the cells were mixed with the substance mixtures and kept under for a further 48 hours Culture conditions incubated. At the end of the cultivation, the cells were crystal violet stained. After extraction of the crystal violet from the fixed cells, the absorption was measured spectrophotometrically at 550 nm. It can be used as a quantitative measure of the adherent cells present.
Schemascheme
Substanz 1 (Eα5)Substance 1 (Eα5)
SubstanSubstan
Die nachfolgenden Beispiele betreffen Arzneimittel:The following examples relate to drugs:
Beispiel C: InjektionsgläserExample C: Injection glasses
Eine Lösung von 100 g eines Wirkstoffes der Formel I und 5 g Dinatrium- hydrogenphosphat wird in 3 l zweifach destilliertem Wasser mit 2 n Salzsäure auf pH 6,5 eingestellt, steril filtriert, in Injektionsgläser abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jedes Injektionsglas enthält 5 mg Wirkstoff.A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, under sterile conditions lyophilized and sealed sterile. Each injection jar contains 5 mg of active ingredient.
Beispiel D: SuppositorienExample D: suppositories
Man schmilzt ein Gemisch von 20 g eines Wirkstoffes der Formel I mit 100 g Sojalecithin und 1400 g Kakaobutter, gießt in Formen und läßt erkalten. Jedes Suppositorium enthält 20 mg Wirkstoff.A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
Beispiel E: LösungExample E: Solution
Man bereitet eine Lösung aus 1 g eines Wirkstoffes der Formel I, 9,38 g NaH2P04 • 2 H20, 28,48 g Na2HP04 • 12 H20 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 of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.
Beispiel F: SalbeExample F: ointment
Man mischt 500 mg eines Wirkstoffes der Formel I mit 99,5 g Vaseline unter aseptischen Bedingungen.500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
Beispiel G: TablettenExample G: tablets
Ein Gemisch von 1 kg Wirkstoff der Formel I, 4 kg Lactose, 1 ,2 kg Kartoffel- stärke, 0,2 kg Talk und 0,1 kg Magnesiumstearat wird in üblicher Weise zu Tabletten verpreßt, derart, daß jede Tablette 10 mg Wirkstoff enthält.A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient ,
Beispiel 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.Example H: coated tablets Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
Beispiel I: KapselnExample I: capsules
2 kg Wirkstoff der Formel I werden in üblicher Weise in Hartgelatinekapseln gefüllt, so daß jede Kapsel 20 mg des Wirkstoffs enthält.2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.
Beispiel J: AmpullenExample J: Ampoules
Eine Lösung von 1 kg Wirkstoff der Formel I in 60 I zweifach destilliertem Wasser wird steril filtriert, in Ampullen abgefüllt, unter sterilen Bedingungen lyophilisiert und steril verschlossen. Jede Ampulle enthält 10 mg Wirkstoff. A solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Claims

Patentansprücheclaims
1. Verbindungen der Formel I:1. Compounds of the formula I:
wobeiin which
W S, SO oder S02,WS, SO or S0 2 ,
R1 H, A, Ar, Het, Phenyl, Methyl, ORb, SR5, OAr, SAr, N(Rό)2, N R5Ar, Hai, N02, CN, (CH2)mCOOR5, (CH2)mCOOAr, (CH2)mCON(R5)2, (CH2)mCONHAr, COR5, COAr, S(0)mA, S(0)mAr, NHCOA, NHCOAr, NHS02A, NHS02Ar oder S02N(R5)2, Heteroaryl, Hai, -(CY2)n-SA, -(CY2)n-SCF3, -(CY2)n- SCN, -(CY2)n-CF3, -(CY2)n-OCF3, Cycloalkyl, -SCH3, -SCN, - CF3, -OCF3, -OA, -(CY2)n-OH, -(CY2)n-C02R5, -(CY2)n-CN, - (CY2)n-Hal, -(CY2)n-N(R5)2, (CY2)n-OA, (CY2)n-OCOA, -SCF3, (CY2)n-CON(R5)2, -(CY2)n-NHCOA, -(CY2)n-NHS02A, SF5, Si(CH3)3, CQ-(CY2)n-CH3, -(CY2)n-(N-Pyrolidon), und, sofern der R1 doppelt und vicinal am aromatischen Ring auftritt, zusammen auch -N-C(CF3)=N-, -N-CR=N-, -N-N=N-,R 1 H, A, Ar, Het, phenyl, methyl, OR b , SR 5 , OAr, SAr, N (R ό ) 2 , NR 5 Ar, Hai, N0 2 , CN, (CH 2 ) mCOOR 5 , ( CH 2 ) mCOOAr, (CH 2 ) mCON (R 5 ) 2 , (CH 2 ) m CONHAr, COR 5 , COAr, S (0) m A, S (0) m Ar, NHCOA, NHCOAr, NHS0 2 A, NHS0 2 Ar or S0 2 N (R 5 ) 2 , heteroaryl, shark, - (CY 2 ) n -SA, - (CY 2 ) n-SCF 3 , - (CY 2 ) n - SCN, - (CY 2 ) n -CF 3 , - (CY 2 ) n -OCF 3 , cycloalkyl, -SCH 3 , -SCN, - CF 3 , -OCF 3 , -OA, - (CY 2 ) n -OH, - (CY 2 ) n -C0 2 R 5 , - (CY 2 ) n -CN, - (CY 2 ) n -Hal, - (CY 2 ) nN (R 5 ) 2 , (CY 2 ) n -OA, (CY 2 ) n - OCOA, -SCF 3 , (CY 2 ) n -CON (R 5 ) 2 , - (CY 2 ) n -NHCOA, - (CY 2 ) n -NHS0 2 A, SF 5 , Si (CH 3 ) 3 , CQ - (CY 2 ) n-CH 3 , - (CY 2 ) n - (N-pyrolidone), and, if R 1 occurs twice and vicinally on the aromatic ring, together also -NC (CF 3 ) = N-, - N-CR = N-, -NN = N-,
R2, R3 unabhängig voneinander A, Het, H, -OH, -OA, -OAr, Ar, -O- CO-A, OS03 sRR55,, --OOSSOO22RR55,, --OOAArr22RR55,, SS0022R5, Hai, COOR5, CON(R5)2l NHS02A,COA, CHO oder S02N(R5)2, -(CH2)0-Ar, -(CH2)0- Cycloalkyl, -(CH2)0-OH, -(CH2)o-N(R5)2, N02, CN, -(CH2)0- COOR5, -(CH2)0-CON(R5)2, -(CH2)0-NHCOA, NHCON(R5)2, (CH2)0-NHS02A, -(C(R5)2)o-Ar, oder unsubstituiertes oder einfach oder mehrfach durch Aryl oder Heteroaryl, das durch Hai, N02, CN, A, OR, OCOR, COR, NR2, CF3) OCF3> OCH(CF3)2 substituiert sein kann, Hai, N02, CN, OR, A, -(CY2)n-OR, -OCO R5, - (CY2)n-C02 R5, -(CY2)n-CN, -NCO R5, -CO R5 oder -(CY2)n- N(R5)2 substituiertes Aryl oder Heteroaryl, N[(CH2)nXCOOR5]CO(CH2)nAryl, N[(CH2)nXR5]CO(CH2)πAryl, N[(CH2)nXR5]CO(CH2)nXAryl, N[(CH2)nXR5]S02(CH2)nAryl, N[(CH2)nNR5COOR5]CO(CH2)nAryl, N[(CH2)nN(R5)2]CO(CH2)nAryl, N[(CH2)nN(R5)2]CO(CH2)nNR5Aryl, N[(CH2)nN(R5)2]S02(CH2)nAryl, N[(CH2)nXR5]CO(CH2)nHet, N[(CH2)nXR5]CO(CH2)nXHet, N[(CH2)nXR5]S02(CH2)nHet, N[(CH2)πNR5COOR5]CO(CH2)nHet, N[(CH2)nN(R5)2]CO(CH2)nHet oder N[(CH2)nN(R5)2]CO(CH2)nNR5Het,R 2 , R 3 independently of one another A, Het, H, -OH, -OA, -OAr, Ar, -O- CO-A, OS0 3 sRR 55 ,, --OOSSOO22RR 55 ,, --OOAArr 22 RR 55 , , SS00 22 R 5 , Hai, COOR 5 , CON (R 5 ) 2l NHS0 2 A, COA, CHO or S0 2 N (R 5 ) 2 , - (CH 2 ) 0 -Ar, - (CH 2 ) 0 - Cycloalkyl, - (CH 2 ) 0 -OH, - (CH 2 ) oN (R 5 ) 2 , N0 2 , CN, - (CH 2 ) 0 - COOR 5 , - (CH 2 ) 0 -CON (R 5 ) 2 , - (CH 2 ) 0 -NHCOA, NHCON (R 5 ) 2 , (CH 2 ) 0 -NHS0 2 A, - (C (R 5 ) 2 ) o-Ar, or unsubstituted or singly or multiply by aryl or heteroaryl, which is represented by shark, N0 2 , CN, A, OR, OCOR, COR , NR 2 , CF 3) OCF 3> OCH (CF 3 ) 2 may be substituted, shark, N0 2 , CN, OR, A, - (CY 2 ) n -OR, -OCO R 5 , - (CY 2 ) n -C0 2 R 5 , - (CY 2 ) n -CN, -NCO R 5 , -CO R 5 or - (CY 2 ) n - N (R 5 ) 2 substituted aryl or heteroaryl, N [(CH 2 ) n XCOOR 5 ] CO (CH 2 ) n aryl, N [(CH 2 ) n XR 5 ] CO (CH 2 ) πAryl, N [(CH 2 ) n XR 5 ] CO (CH 2 ) n XAryl, N [( CH 2 ) n XR 5 ] S0 2 (CH 2 ) nAryl, N [(CH 2 ) n NR 5 COOR 5 ] CO (CH 2 ) nAryl, N [(CH 2 ) n N (R 5 ) 2 ] CO ( CH 2 ) n aryl, N [(CH 2 ) n N (R 5 ) 2 ] CO (CH 2 ) n NR 5 aryl, N [(CH 2 ) n N (R 5 ) 2 ] S0 2 (CH 2 ) n aryl, N [(CH 2 ) n XR 5 ] CO (CH 2 ) n Het, N [(CH 2 ) n XR 5 ] CO (CH 2 ) n XHet, N [(CH 2 ) n XR 5 ] S0 2 (CH 2 ) n Het, N [(CH 2 ) π NR 5 COOR 5 ] CO (CH 2 ) nHet, N [(CH 2 ) nN (R 5 ) 2 ] CO (CH 2 ) n Het or N [ (CH 2 ) n N (R 5 ) 2 ] CO (CH 2 ) n NR 5 Het,
R4 O, =CH-(CH2)nN(R5)2, oder cyclo[C(CH2)k (NY1)-(CH2)P-] , cyclo[C(CH2)k (CHY1)-(CH2)P-] oderE oder Z - =CH(CH2)nX(CH2)ιQ(CH2)sTR 4 O, = CH- (CH 2 ) n N (R 5 ) 2 , or cyclo [C (CH 2 ) k (NY 1 ) - (CH 2 ) P -], cyclo [C (CH 2 ) k ( CHY 1 ) - (CH 2 ) P -] or E or Z - = CH (CH 2 ) n X (CH 2 ) ιQ (CH 2 ) s T
R5 H oder A, bei geminalen Resten R5 zusammen auch -(CH2)5-, -(CH2)4- oder -(CH2)π-Q-(CH2)n,R 5 H or A, in the case of geminal radicals R 5 together also - (CH 2 ) 5 -, - (CH 2 ) 4 - or - (CH 2 ) π -Q- (CH 2 ) n ,
Y H, A, HaiY H, A, shark
Y1 R2, R5, Ar, -(C(R5)2)0-Ar oder -(C(R5)2)0-Het, X(CH2)ιQ(CH2)sT, XCH2T oder T,Y 1 R 2 , R 5 , Ar, - (C (R 5 ) 2 ) 0 -Ar or - (C (R 5 ) 2 ) 0 -Het, X (CH 2 ) ιQ (CH 2 ) s T, XCH 2 T or T,
X NR5, CH2, CO oder S02 oder eine Einfachbindung Q CH2, NR5, O, S, CO, S02, C(R5)2 oder eine Einfachbindung, CH(CH2)nNR5COOR5, CHNR5COOR5, NCO, CH(CH2)nCOOR5, NCOOR5, CHX(CH2)nOH, N(CH2)nOH, CHNH2, CH(CH2)nN(R5)2, CHX(CH2)nN(R5)2, C(OH)R5, CHNCOR5, CH(CH2)πAryl, CH(CH2)πHeteroaryl, CH(CH2)nR1, N(CH2)nCOOR5, CH(CH2)nX(CH2)nAryl, CH(CH2)nX(CH2)nHeteroaryl, N(CH2)nCON(R5)2, CHCONR5(CH2)nN(R5)2,X NR 5 , CH 2 , CO or S0 2 or a single bond Q CH 2 , NR 5 , O, S, CO, S0 2 , C (R 5 ) 2 or a single bond, CH (CH 2 ) n NR 5 COOR 5 , CHNR 5 COOR 5 , NCO, CH (CH 2 ) n COOR 5 , NCOOR 5 , CHX (CH 2 ) n OH, N (CH 2 ) nOH, CHNH 2, CH (CH 2 ) n N (R 5 ) 2 , CHX (CH 2 ) n N (R 5 ) 2 , C (OH) R 5 , CHNCOR 5 , CH (CH 2 ) π aryl, CH (CH 2 ) π heteroaryl, CH (CH 2 ) n R 1 , N (CH 2 ) n COOR 5 , CH (CH 2 ) n X (CH 2 ) n aryl, CH (CH 2 ) n X (CH 2 ) n heteroaryl, N (CH 2 ) n CON (R 5 ) 2 , CHCONR 5 (CH 2 ) n N (R 5 ) 2 ,
Het einen ein- oder zweikernigen gesättigten, ungesättigten oder aromatischen Heterocyclus mit 1 bis 4 N-, O- und/oder S- Atomen, der unsubstituiert oder ein-, zwei- oder dreifach durch Hai, A, -(CH2)0-Ar, -(CH2)0-Cycloalkyl, -(CH2)0-OH, -(CH2)0-N(R5)2, N02, CN, -(CH2)0-COOR5, -(CH2)0-CONR5, -(CH2)0-NHCOA, NHCONR5, -(CH2)0-NHS02A, CHO, COA, S02NH2 und/oder S(O)0A substituiert sein kann,Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by shark, A, - (CH 2 ) 0 - Ar, - (CH 2 ) 0 -cycloalkyl, - (CH 2 ) 0 -OH, - (CH 2 ) 0 -N (R 5 ) 2 , N0 2 , CN, - (CH 2 ) 0 -COOR 5 , - (CH 2 ) 0 -CONR 5 , - (CH 2 ) 0 -NHCOA, NHCONR 5 , - (CH 2 ) 0 -NHS0 2 A, CHO, COA, S0 2 NH 2 and / or S (O) 0 A can be,
Ar Aryl, unsubstituiertes oder ein-, zwei- oder dreifach durch Hai, A, OR5, N(R5)2, N02, CN, COOR5, CON(R5)2, NHCOA, NHCON(R5)2, NHS02A, CHO, COA, S02N(R5)2 oder S(O)0A substituiertes Phenyl, Naphthyl oder Biphenyl,Ar aryl, unsubstituted or single, double or triple by shark, A, OR 5 , N (R 5 ) 2 , N0 2 , CN, COOR 5 , CON (R 5 ) 2 , NHCOA, NHCON (R 5 ) 2 , NHS0 2 A, CHO, COA, S0 2 N (R 5 ) 2 or S (O) 0 A substituted phenyl, naphthyl or biphenyl,
A unverzweigtes oder verzweigtes Alkyl mit 1-10 C-Atomen, wobei eines oder mehrere H-Atome durch Hai oder Ar ersetzt sein können, Hai F, Cl, Br oder I, o 0, 1, 2 oder 3, m 0 , 1, 2 oder 3, n 0, 1, 2 , 3 oder 4, k,p,l,s 1, 2, 3, 4 oder 5, wobei k + p 2, 3, 4 oder 5 und q 1, 2, 3 oder 4 bedeuten, sowie ihre pharmazeutisch verwendbaren Derivate, Solvate.Tautomere, Salze und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.A unbranched or branched alkyl having 1-10 C atoms, where one or more H atoms can be replaced by shark or Ar, Shark F, Cl, Br or I, o 0, 1, 2 or 3, m 0, 1, 2 or 3, n 0, 1, 2, 3 or 4, k, p, l, s 1, 2, 3 , 4 or 5, where k + p is 2, 3, 4 or 5 and q is 1, 2, 3 or 4, and their pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, including their mixtures in all ratios.
2. Verbindungen nach Anspruch 1, worin R1 A, SR5, OR5, Hai, CN, N02, N(R5)2 und q 1 oder 2 bedeutet und R5 die in Anspruch 1 angegebene Bedeutung aufweist.2. Compounds according to claim 1, wherein R 1 A, SR 5 , OR 5 , shark, CN, N0 2 , N (R 5 ) 2 and q is 1 or 2 and R 5 has the meaning given in claim 1.
3. Verbindungen nach Anspruch 1 oder 2, worin R2 H, A, Ar oder Methyl und R3 H, Ar oder -(C(R5)2)0Ar bedeutet. 3. Compounds according to claim 1 or 2, wherein R 2 is H, A, Ar or methyl and R 3 is H, Ar or - (C (R 5 ) 2 ) 0 Ar.
4. Verbindungen nach einem oder mehreren der Ansprüche 1-3, worin W die Bedeutung S für ein Schwefelatom aufweist.4. Compounds according to one or more of claims 1-3, wherein W has the meaning S for a sulfur atom.
5. Verbindungen nach einem oder mehreren der Ansprüche 1-4, worin R4 cyclo[-C(CH2)k (NY)-(CH2)P-] oder -=CH(CH2)nX(CH2)ιQ(CH2)sT, bedeutet.5. Compounds according to one or more of claims 1-4, wherein R 4 cyclo [-C (CH 2 ) k (NY) - (CH 2 ) P -] or - = CH (CH 2 ) n X (CH 2 ) ιQ (CH 2 ) sT means.
6. Verbindungen der Teilformeln 11 bis I64:6. Connections of sub-formulas 11 to I64:
35 35
112112
2020
3030
35 35
2020
35 35
CIH 131CIH 131
I32 I32
I36 I36
I37 I37
I38 I38
I39I39
I40I40
141 141
35 I42 35 I42
I44 I44
147 147
I48 I48
I49 I49
I53I53
I54 I54
35 35 35 35
I64 sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Tautomere, Salze und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen. I64 and its pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, including their mixtures in all ratios.
Verbindungen der Formel IA1:Compounds of the formula IA1:
worin R1, R2, X, Y1 und n die in Anspruch 1 angegebene Bedeutung aufweisen sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Tautomere, Salze und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.. wherein R 1 , R 2 , X, Y 1 and n have the meaning given in claim 1 and their pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, including their mixtures in all ratios.
8. Verfahren zur Herstellung von Verbindungen der Formel I nach den Ansprüchen 1-7 sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomeren und Stereoisomeren, dadurch gekennzeichnet, daß man eine Verbindung der Formel II8. A process for the preparation of compounds of formula I according to claims 1-7 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, thereby characterized in that a compound of formula II
worin R , R und R die in Anspruch 1 angegebenen Bedeutungen haben und X1 eine Abgangsgruppe und bevorzugt Hai oder eine reaktionsfähige abgewandelte OH-Gruppe, insbesondere Tosyl oder Mesyl sein kann,in which R, R and R have the meanings given in claim 1 and X 1 can be a leaving group and preferably shark or a reactive modified OH group, in particular tosyl or mesyl,
mit einer Verbindung der Formel IIIwith a compound of formula III
worinwherein
R ,1 und q die in Anspruch 1 angegebenen Bedeutungen aufweisen,R, 1 and q have the meanings given in Claim 1,
umgesetzt wird und die daraus resultierende Verbindung der Formel IVis implemented and the resulting compound of formula IV
worin wherein
R1, R2, R3, R4 und q die in Anspruch 1 angegebene Bedeutungen haben, wird durch Verseifung in die freie Säure umgewandelt und diese anschließend nach üblichen Methoden in die entsprechende Formel VR 1 , R 2 , R 3 , R 4 and q have the meanings given in claim 1, is converted into the free acid by hydrolysis and this is then converted into the corresponding formula V by customary methods
worin wherein
L Hai oder eine reaktionsfähige abgewandelte OH-Gruppe wie z.B. Tiflat, Nonaflat, Tosylat, Mesylat oder Benzolsulfonat bedeutet und R1, R2 , R3, R4 und q die in Anspruch 1 angegebene Bedeutungen haben, überführt undL means shark or a reactive modified OH group such as, for example, tiflate, nonaflate, tosylate, mesylate or benzenesulfonate and R 1 , R 2 , R 3 , R 4 and q have the meanings given in claim 1, transferred and
die Verbindung der Formel V wird dann in Gegenwart eines geeigneten Katalysators zu Formel IAthe compound of formula V then becomes formula IA in the presence of a suitable catalyst
umgesetzt, worin implemented where
R11, R ι-ι22, R3 , R4 und q die in Anspruch 1 angegebene Bedeutungen haben, und gegebenenfalls Verbindungen der Formel l.worin R2 und/oder R3 H bedeuten, durch Umsetzung in einer Base und einem Alkylierungsreagenz in weitere Verbindungen der Formel I, worin R2 und/oder R eine andere Bedeutung als H aufweisen, umgewandelt werden und gegebenenfalls Verbindungen der Formel I worin R4 O bedeutet, durch Umsetzung mit entsprechenden metallorganischen Reagenzien und nachfolgender Eliminierung in die weiteren Verbindungen der Formel I worin R4 die in Anspruch 1 angegebene Bedeutung aufweist, umgewandelt werden, und gegebenenfalls Verbindungen der Formel I worin W SO oder SO2 bedeutet, durch Umsetzung mit geeigneten Oxidationsmitteln erhalten werden.R1 1 , R ι-ι2 2 , R 3 , R 4 and q have the meanings given in claim 1, and optionally compounds of the formula I.worin R 2 and / or R 3 H, by reaction in a base and an alkylating reagent in further compounds of the formula I in which R 2 and / or R have a meaning other than H, are converted and, if appropriate, compounds of the formula I in which R 4 is O, by reaction with corresponding organometallic reagents and subsequent elimination into the further compounds of the formula I in which R 4 has the meaning given in claim 1 has, converted, and optionally compounds of formula I wherein W is SO or SO 2 , are obtained by reaction with suitable oxidizing agents.
9. Verfahren nach Anspruch 8, dadurch gekennzeichnet, dass als Katalysator ein Friedel-Crafts-Katalysator verwendet wird.9. The method according to claim 8, characterized in that a Friedel-Crafts catalyst is used as the catalyst.
10. Verbindungen der Formeln A, B, C und D:10. Compounds of the formulas A, B, C and D:
2)sT worin R1, R2, R3, Y1, X, Q, T, n, I, p, k, q und s die in Anspruch 1 angegebene Bedeutung aufweisen, sowie die durch Oxidation des Ring-Schwefelatoms der Verbindungen A bis D erhältlichen Sufoxide und Sulfone. 2 ) sT wherein R 1 , R 2 , R 3 , Y 1 , X, Q, T, n, I, p, k, q and s have the meaning given in claim 1, and also by oxidation of the ring sulfur atom of the compounds A to D available sufoxides and sulfones.
11. Arzneimittel, enthaltend mindestens eine Verbindung der Formel I nach Anspruch 1 bis 7 und/oder ihre pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomere und Stereoisomeren, einschließlich deren Mischungen in allen Verhältnissen, sowie gegebenenfalls Träger- und/oder Hilfsstoffe.11. Medicament containing at least one compound of formula I according to claim 1 to 7 and / or its pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including their mixtures in all ratios, and, if appropriate, carriers and / or auxiliaries.
12. Verwendung von Verbindungen nach Anspruch 1 bis 7 sowie ihrer pharmazeutisch verwendbaren Derivate, Salze, Solvate, Tautomeren und Stereoisomeren, einschließlich deren Mischungen in allen Verhältnissen, zur Herstellung eines Arzneimittels zur Behandlung von Krankheiten, bei denen die Hemmung, Regulierung und/oder Modulation der mitotischen Motor-Proteins Eg5 eine Rolle spielt.12. Use of compounds according to claim 1 to 7 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for the treatment of diseases in which the inhibition, regulation and / or modulation the mitotic motor protein Eg5 plays a role.
13. Verwendung von Verbindungen nach Anspruch 1 bis 7, zur Herstellung eines Arzneimittels zur Behandlung und Prophylaxe von Krebskrankheiten. 13. Use of compounds according to claim 1 to 7, for the manufacture of a medicament for the treatment and prophylaxis of cancerous diseases.
14. Verwendung nach Anspruch 13, wobei die Krebskrankheiten mit einem Tumor aus der Gruppe der Tumoren des Plattenepithel, der Blasen, des Magens, der Nieren, von Kopf und Hals, des Ösophagus, 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 erhergehen.14. Use according to claim 13, wherein the cancer diseases with a tumor from the group of tumors of the squamous epithelium, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, of the brain, prostate, urogenital tract, lymphatic system, stomach, larynx and / or lungs.
15. Verwendung nach Anspruch 14, wobei der Tumor aus der Gruppe Monozytenleukämie, Lungenadenokarzinom, kleinzellige Lungenkarzinome, Bauchspeicheldrüsenkrebs, Glioblastome und Brustkarzinom und Kolokarzinom stammt.15. Use according to claim 14, wherein the tumor comes from the group monocyte leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma and colocarcinoma.
16. Verwendung nach Anspruch 15, wobei die zu behandelnde Krankheit ein Tumor des Blut- und Immunsystems ist.16. Use according to claim 15, wherein the disease to be treated is a tumor of the blood and immune system.
17. Verwendung nach Anspruch 16, wobei der Tumor aus der Gruppe der akuten myelotischen Leukämie, der chronischen myelotischen Leukämie, akuten lymphatischen Leukämie und/oder chronischen lymphatischen Leukämie stammt.17. Use according to claim 16, wherein the tumor originates from the group of acute myelotic leukemia, chronic myelotic leukemia, acute lymphatic leukemia and / or chronic lymphatic leukemia.
18. Verwendung von Verbindungen der Formel I gemäß Anspruch 1 bis 7 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) Androgenrezeptormodulator, 3) Retinoidrezeptormodulator, 4) Zytotoxikum, 5) antiproliferatives Mittel, 6) Prenyl-Proteintransferasehemmer, 7) HMG-CoA-Reduktase- Hemmer, 8) HIV-Protease-Hemmer, 9) Reverse-Transkriptase- Hemmer sowie 10) weiterer Angiogenese-Hemmer verabreicht wird. 18. Use of compounds of formula I according to claim 1 to 7 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 transcriptase Inhibitor and 10) other angiogenesis inhibitors.
19. Verwendung von Verbindungen der Formel I gemäß Anspruch 1 bis 7 und/oder ihrer physiologisch unbedenklichen Salze und Solvate zur Herstellung eines Arzneimittels zur Behandlung von Tumoren in Kombination mit einer therapeutisch wirksamen Menge einer oder mehrerer Verbindungen der Formel VI,19. Use of compounds of the formula I according to claims 1 to 7 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of tumors in combination with a therapeutically effective amount of one or more 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, OC1-10-Alkyl, OCF3, N02 oder NH2 bedeuten, n 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:wherein Y 'and Z' are each independently O or N, R 7 and R 9 are each independently H, OH, halogen, OC1-10 alkyl, OCF 3 , N0 2 or NH 2 , n is an integer between 2 and 6, each inclusive, and R 6 and R 8 are each independently at the meta or para position and 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 eines Tumors zu hemmen. are selected, the first and second connections being simultaneous or within 14 Days are administered in amounts sufficient to inhibit the growth of a tumor.
20. Verfahren zur Herstellung der Verbindungen nach Anspruch 8 oder 9, dadurch gekennzeichnet, dass die Verbindungen der Formel I worin R4 O bedeutet, mit geeigneten metallorganischen Reagenzien umgesetzt und wässrig aufgearbeitet werden. 20. A process for the preparation of the compounds according to claim 8 or 9, characterized in that the compounds of the formula I in which R 4 is O are reacted with suitable organometallic reagents and worked up in aqueous form.
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