EP1747214A2 - Dihydrobenzothiophene - Google Patents

Dihydrobenzothiophene

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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Withdrawn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)
English (en)
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/fr
Withdrawn legal-status Critical Current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.

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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne des composés de formule (I) dans laquelle W, R1, R2, R3, R4, et q ont les significations indiquées dans la revendication 1, lesdits composés pouvant être employés entre autres pour le traitement de tumeurs.
EP05751906A 2004-05-03 2005-04-28 Dihydrobenzothiophene Withdrawn EP1747214A2 (fr)

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DE102004021637A DE102004021637A1 (de) 2004-05-03 2004-05-03 Dihydrobenzothiophene
PCT/EP2005/004554 WO2005108355A2 (fr) 2004-05-03 2005-04-28 Dihydrobenzothiophene

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EP1747214A2 true EP1747214A2 (fr) 2007-01-31

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US (1) US20070219246A1 (fr)
EP (1) EP1747214A2 (fr)
JP (1) JP2007536306A (fr)
AR (1) AR049086A1 (fr)
AU (1) AU2005240308A1 (fr)
CA (1) CA2565367A1 (fr)
DE (1) DE102004021637A1 (fr)
WO (1) WO2005108355A2 (fr)

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CA2702922C (fr) 2007-10-19 2018-01-16 Schering Corporation Derives de 1,3,4-thiadiazole spiro-condenses pour inhiber l'activite de la kinesine ksp

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DE1470055A1 (de) * 1963-12-07 1969-07-17 Merck Ag E Verfahren zur Herstellung von Piperidinderivaten
JP3702320B2 (ja) * 1994-11-15 2005-10-05 味の素株式会社 ２，３−ジヒドロベンゾ［ｂ］チオフェン誘導体
WO2002066468A2 (fr) * 2001-02-16 2002-08-29 Aventis Pharmaceuticals Inc. Nouveaux derives d'uree heterocycliques et leur utilisation en tant que ligands des recepteurs de la dopamine d3
AU2002233698B2 (en) * 2001-02-22 2007-11-08 Teijin Limited Benzo(b)thiophene derivative and process for producing the same
EP1373240B1 (fr) * 2001-03-14 2005-06-15 Eli Lilly And Company Modulateurs des recepteurs x de retinoides
WO2002078639A2 (fr) * 2001-03-29 2002-10-10 Bristol-Myers Squibb Company Traitement de maladies proliferatives au moyen d'inhibiteurs de eg5
BRPI0406883A (pt) * 2003-01-22 2006-01-03 Lilly Co Eli Composto, composição farmacêutica, método de tratar um distúrbio, e, uso de um composto

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Title
See references of WO2005108355A2 *

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Publication number Publication date
DE102004021637A1 (de) 2005-12-01
WO2005108355A3 (fr) 2006-03-23
WO2005108355A2 (fr) 2005-11-17
US20070219246A1 (en) 2007-09-20
JP2007536306A (ja) 2007-12-13
AR049086A1 (es) 2006-06-28
CA2565367A1 (fr) 2005-11-17
AU2005240308A1 (en) 2005-11-17

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