DE10360154A1 - New 2-(hetero)aryl-tetrahydroquinoline derivatives and 1,2,3,4-tetrahydro-1,5-naphthyridine derivatives are mitotic motor protein Eg5 inhibitors used as anticancer agents for treating carcinoma or leukemia - Google Patents

Abstract

2-(Hetero)aryl-substituted 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydro-1,5-naphthyridine derivatives (I) (including tricyclic analogs, e.g. pyrano-quinolines), are new. 2-(Hetero)aryl-substituted 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydro-1,5-naphthyridine derivatives of formula (I) and their derivatives, solvates, tautomers, salts and stereoisomers (including mixtures in all proportions) are new. W = CH or N; R 1> - R 3> = H, R, A, Ar, halo, (CY 2) n-Q 1>, cycloalkyl, SMe, SCN, CF 3, OCF 3, OA, SCF 3, SF 5, SiMe 3, CO-(CY 2) n-Me, CH(CH 2) n-Q 2>, NCO, NCOOR, N(CH 2) nOH, CHNH 2, C(OH)R, CHNCOR, N(CH 2) nCOOR, N(CH 2) nCONR 2, XCONR(CH 2) nNR 2, N((CH 2) nXCOOR)-CO(CH 2) nAr, N((CH 2) nXR)-Q 3>, N((CH 2) nNRCOOR)CO(CH 2) nAr, N((CH 2) nNR 2)-Q 4>, O(CH 2) nNR 2, X(CH 2) nNR 2 or NCO(CH 2) nNR 2, or R 1> + R 2> = -N-C(CF 3)=N-, -N-CR=N- or -N-N=N-; Q 1> = SA, SCF 3, SCN, CF 3, OCF 3, OH, COOR, CN, halo, NR 2, OA, OCOA, CONR 2, NHCOA, NHSO 2A or N-pyrrolidone; Q 2> = NRCOOR, COOR, OH, NR 2, Ar, R 1> or X(CH 2) nAr; Q 3> = CO(CH 2) nAr, CO(CH 2) nXAr or SO 2(CH 2) nAr; Q 4> = CO(CH 2) nAr, CO(CH 2) nNRAr or SO 2(CH 2) nAr; Ar = aryl or heteroaryl; Y = H, A or halo; A = alkyl or cycloalkyl (both os by one or more halo); R = H or A, or geminal groups R = (CH 2) 5, (CH 2) 4, (CH 2) 2X(CH 2) 2 or (CH 2) 2Z(CH 2) 2; (MK#12) R 4>, R 5> = H, N-pyrrolidone residue (optionally substituted by one or more of OR, NO 2, halo, CF 3, OCF 3, CN, NR 2, SR or Ar), -X(CH 2) 2OR, -XCO(CH 2) nMe, -X(CH 2) 2NR 2, R 1>, arylthio, aryloxy or CH 2SiMe 3, or R 4> + R 5> = X(CR 2) 2, X(CR 2) 3, X(CHCH 2OR)(CH 2) 2, X(CHCH 2NR 2)(CH 2) 2, X(CH 2) 2NR 2, (CR 2) 3, X(CR 2) 4, CR=CR-CR=CR, XCHQ(CR 2) 2, XCHQCR 2, R-N-(C=X)-N-R or XC((CH 2) nOR) 2CH 2CH 2; X = O, S or NR; Q = halomethyl, CHO, COR a>, CH 2R a>, CH 2OCOR a>, CH 2NCOR 1>, CH 2N(R 1>) 2, CH 2OR 1>, CH 2OCON(R 1>) 2, CH 2OCOOR 1>, CH 2NHCON(R 1>) 2 or -CH 2NHCOOR 1>; R a> = -(CH 2) n-(X(CH 2) n) m-Q 5>, 4-(CH 2CH(CONH 2)-COO-(CH 2) nQ 6>)-1H-imidazol-1-yl, 2-oxa-3-oxo-4,7,7-tri-(R)-bicyclo-(2,2,1)-heptan-ylcarbonyloxy, OR, NHR 2, NR 2, NR(CH 2) n-aryl, NR(CH 2) n-OR, COOR, N-pyrrolidone, OCOR, NR(CH 2) n-NR 2, N((CH 2) nNR 2)CO(CH 2) nQ 7>, N((CH 2) nNHCOOR)-CO-aryl, R 1>, N(CH 2(CH 2) nOR) 2, NR(CH 2) nNCOOR, X(CH 2) nX(CH 2) nXR, X(CH 2) nX(CH 2) nOH, NR(CH 2) nO(CH 2) nOH, (CH 2) nCOOR, OCONR(CH 2) nOR, OCONR(CH 2) nNR 2, NR(CH 2) nNR 2, N((CH 2) nXR)CO(CH 2) nAr, N(R)(CH2) nN(R)COOR, XCOO(CH 2) nNR 2, OSO 2A, OSO 2CF 3, OSO 2-aryl, OCONR 2 or OCH 2(CH 2) nNR 2; Q 5> = 2- or 3-oxo-piperidino, 3,3,5,5- or 2,2,6,6-tetra-(R)-cyclohexyl or 3,3,5,5-tetra-(R)-piperidino, all having CH 2 in the 4-position replaced by Z, or R 1>-substituted 2-oxo-pyrrolidino, cyclopentyl, pyrrolidino (optionally substituted by NR 2 or in the 3-position by NA 2), R 1>-substituted 2-thienyl, 1H-imidazol-1-yl or 1H-1,2,4-tetrazol-1-yl; Q 6> = Ar or R 1>; Q 7> = CO(CH 2) nAr; Z = CH 2, X, CHCONH 2, CH(CH 2) n-Q 2>, NCO, NCOOR, N(CH 2) nOH, CHNH 2, C(OH)R, CHNCOR, N(CH 2) nCOOR, N(CH 2) nCONR 2, XCONR(CH 2) nNR 2, N((CH 2)XCOOR)-CO(CH 2) nAr, N((CH 2) nXR)-Q 3>, N((CH 2) nNRCOOR)CO(CH 2) nAr, N((CH 2) nNR 2)-Q 4>, O(CH 2) nNR 2, X(CH 2) nNR 2 or NCO(CH 2) nNR 2; R 6> = Ar (optionally substituted by one or more of Ar (optionally substituted by halo, NO 2, CN, A, OR, OCOR, COR, NR 2, CF 3 , OCF 3 or OCH(CF 3) 2), halo, NO 2, CN, OR, A, (CY 2) nOR, OCOR, (CY 2) n-COOR, (CY 2) n-CN, NCOR, COR or (CY 2) n-NR 2)); R 7> = COR, CONR 2, COOR, H or A; m = 0-2, and n = 0-7. Independent claims are also included for: (1) the preparation of (I); and (2) mixtures of compounds (I) with each other or with bis-aromatic compounds of formula (V) (specifically pentamidine or its salt) or their analogs or metabolites. Y', Z' = O or N; R 9>, R 10> = H, OH, halo, 1-10C alkoxy, OCF 3, NO 2 or NH 2; n = 2-6, and R 8>, R 11> (in m- or p-position) = -C(NH 2)=NH, -C(NH 2)=NOH, imidazolin-2-yl, 1-methyl-imidazolin-2-yl or tetrazol-5-yl. [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Mitotic motor protein inhibitor; Mitotic motor protein regulator; Mitotic motor protein modulator. In a test, 3,4-tetrahydropyrano-fused 6-tert. butyl-2-(3-thienyl)-1,2,3,4-tetrahydroquinoline derivative (Ia) inhibited the cell cycle of HCT cells, typically in presence of 0.4 mu M the cells were in 7% G1, 7% S and 86% G2/M phase, compared with 36% G1, 43% S and 21% G2/M in the absence of (Ia).

Description

BACKGROUND THE INVENTION

Of the Invention was based on the object, new compounds with valuable Find properties, especially those for the production of medicines can be used.

The The present invention relates to compounds and the use of Compounds of diseases involving inhibition, regulation and / or modulation of mitotic motor proteins, in particular of the mitotic motor protein Eg5 plays a role, further pharmaceutical Compositions containing these compounds.

in the In particular, the present invention relates to compounds of the formula I, which prefers one or more mitotic motor proteins inhibit, regulate and / or modulate compositions containing these compounds and methods for their use in the treatment of Diseases and conditions such as angiogenesis, cancer, tumor development, growth and spread, arteriosclerosis, eye diseases, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, Arthritis, neurodegeneration, restenosis, wound healing or graft rejection. In particular, the compounds of the invention are suitable for therapy or prophylaxis of cancer.

During the Mitosis regulate the training and dynamics of various kinesins of the spindle apparatus used for a correct and coordinated alignment and separation of the chromosomes responsible for. It was observed that a specific inhibition of a mitotic motor protein - Eg5 - to a collapse the spindle fibers leads. As a result, the chromosomes are no longer correctly on the Daughter cells can be split. This leads to mitotic Arrest and thus can cause the death of the cell. A Upregulation of the motor protein Eg5 has been described e.g. in tissue of breast Lung and colon tumors described. Eg5 is one for mitosis specific function are mainly fast dividing Cells and not completely differentiated cells affected by Eg5 inhibition. Furthermore regulates Eg5 exclusively the movement of mitotic microtubules (spindle apparatus) and not those of the cytoskeleton. This is crucial for the side effect profile, since e.g. Neuropathies as observed with taxol or only toned down occur. Therefore, the inhibition of Eg5 by organic molecules is a relevant one Therapy concept for the treatment of malignant tumors.

As a general rule come old solid and not solid tumors with the connections of the formula I are treated, e.g. monocytic leukemia, brain, Urogenital, lymphatic, gastric, laryngeal and lung carcinomas, including lung adenocarcinoma and small cell lung carcinoma. Other examples include prostate, pancreatic and breast carcinoma.

It has surprisingly been found that the compounds according to the invention bring about a specific inhibition of the mitotic Moter proteins, in particular Eg5. The compounds of the invention preferably exhibit a beneficial biological activity that is readily detectable in the assays described, for example, herein. In such compounds, the compounds of the invention preferably exhibit and effect an inhibiting effect, which is usually documented by IC ₅₀ values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.

As discussed herein are effects of the compound of the invention for different Diseases relevant. Accordingly, the compounds of the invention useful in the prophylaxis and / or treatment of diseases caused by an inhibition of one or more mitogenic motor proteins, especially Eg5.

object The present invention therefore compounds of the invention as drugs and / or drugs in the treatment and / or prophylaxis of said diseases and use of compounds of the invention for the preparation of a pharmaceutical for the treatment and / or prophylaxis the said diseases as well as a method of treatment the said diseases comprising the administration of one or several inventive compounds a patient in need of such administration.

It can be shown that the compounds of the invention in a xenograft Tu Mor model have a beneficial effect.

Of the The host or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including mice, rats and hamsters; Rabbits; Horses, cattle, dogs, cats, etc. Animal models are for experimental studies of interest, where they are a model to treat a human disease.

The susceptibility to a particular cell the treatment with the compounds of the invention can by Testing can be determined in vitro. Typically, a culture becomes the cell with a compound of the invention at various Concentrations for combined a period of time sufficient to the active resources to enable Induce cell death or inhibit migration, usually between approximately an hour and a week. For testing in vitro cultured Cells from a biopsy sample can be used. The after treatment remaining viable Cells are then counted.

The Dose varies depending of the specific compound used, the specific disease, the patient status, etc. Typically, a therapeutic Dose sufficient to the unwanted Significantly reduce cell population in the target tissue, while the viability of the patient is maintained. The treatment is generally continued until a significant reduction is present, for. At least about 50% reduction in cell load and can be continued until essentially no unwanted Cells more in the body be detected.

Similar compounds are, for example, in Tetrahedron Lett. 1988, 29, 5855-5858, Tetrahedron Lett. 2003, 44, 217-219, J. Org. Chem. 1997, 62, 4880-4882, J. Org. Chem. 1999, 64, 6462-6467, Chem. Lett. 1995, 423-424, J. Org. Chem. 2000, 65, 5009-5013, Chem. Lett. 2003, 32, 222-223, US 2003149069 A1 but are not mentioned in connection with cancer treatments and / or do not contain the essential features of the invention.

SUMMARY THE INVENTION

worin
R¹, R² unabhängig voneinander H, A, Aryl, Heteroaryl, Hal, Cycloalkyl, -SCH₃, -SCN, -CF₃, -OCF₃, -OA, -(CY₂)_n-OH, -(CY₂)_n-CO₂R, -(CY₂)_n-CN, -(CY₂)_n-NR₂, (CY₂)_n-OA, (CY₂)_n-OCOA, -SCF₃, (CY₂)_n-CONR₂
Y H, A, Hal
A Alkyl oder Cycloalkyl
Hal F, Cl, Br oder I
R H oder A, bei gemimalen Resten R zusammen auch -(CH₂)₅-, -(CH₂)₄- oder -(CH₂)₂-NR-(CH₂)₂,
R⁴, R⁵ unabhängig voneinander H oder unsubstituiertes oder einfach oder mehrfach durch OR, NO₂, Hal, CF₃, OCF₃, CN, NR₂ oder SR, Aryl oder Heteroaryl substituiertes N-Pyrolidon, -X-(CH₂)₂OR, -X-(CH₂)₂NR₂ oder zusammen -X(CR₂)₂-, -X-(CR₂)₃-, -X-(CHCH₂OR)(CH₂)₂-, -X-(CHCH₂NR₂)(CH₂)₂-, -X(CH₂)₂NR₂, -(CR₂)₃-, -(CR₂)₄-, -CR=CR-CR=CR-
X O, S oder NR
R⁶ unsubstituiertes oder einfach oder mehrfach durch Aryl oder Heteroaryl, das durch Hal, NO₂, CN, A, OR, OCOR, NR₂, CF₃, OCF₃, OCH(CF₃)₂ substituiert sein kann, Hal, NO₂, CN, OR, A, -(CY₂)_n-OR, -OCOR, -(CY₂)_n-CO₂R, -(CY₂)_n-CN oder -(CY₂)_n-NR₂ substituiertes Aryl oder Heteroaryl,
R⁷ (C=O)-R, (C=O)-NR₂, (C=O)-OR, H oder A
und
n 0, 1, 2, 3 oder 4
bedeuten,
sowie ihre pharmazeutisch verwendbaren Derivate, Solvate, Tautomere, Salze und Stereoisomere, einschließlich deren Mischungen in allen Verhältnissen.The invention relates to compounds of the formula I.

wherein
R ¹ , R ² independently of one another are H, A, aryl, heteroaryl, Hal, cycloalkyl, -SCH ₃ , -SCN, -CF ₃ , -OCF ₃ , -OA, - (CY ₂ ) _n -OH, - (CY ₂ ) _n -CO ₂ R, - (CY ₂ ) _n -CN, - (CY ₂ ) _n -NR ₂ , (CY ₂ ) _n -OA, (CY ₂ ) _n -OCOA, -SCF ₃ , (CY ₂ ) _n -CONR ₂
YH, A, Hal
A is alkyl or cycloalkyl
Hal F, Cl, Br or I
RH or A, when Gemimalen R together also - (CH ₂ ) ₅ -, - (CH ₂ ) ₄ - or - (CH ₂ ) ₂ -NR- (CH ₂ ) ₂ ,
R ⁴ , R ⁵ independently of one another denote N or N-pyrrolidone which is unsubstituted or monosubstituted or polysubstituted by OR, NO ₂ , Hal, CF ₃ , OCF ₃ , CN, NR ₂ or SR, aryl or heteroaryl, -X- (CH ₂ ) ₂ OR, -X- (CH ₂ ) ₂ NR ₂ or together -X (CR ₂ ) ₂ -, -X- (CR ₂ ) ₃ -, -X- (CHCH ₂ OR) (CH ₂ ) ₂ -, - X- (CHCH ₂ NR ₂ ) (CH ₂ ) ₂ -, -X (CH ₂ ) ₂ NR ₂ , - (CR ₂ ) ₃ -, - (CR ₂ ) ₄ -, -CR = CR-CR = CR-
X O, S or NR
R ^{6 is} unsubstituted or mono- or polysubstituted by aryl or heteroaryl which may be substituted by Hal, NO ₂ , CN, A, OR, OCOR, NR ₂ , CF ₃ , OCF ₃ , OCH (CF ₃ ) ₂ , Hal, NO ₂ , CN, OR, A, - (CY ₂ ) _n -OR, -OCOR, - (CY ₂ ) _n -CO ₂ R, - (CY ₂ ) _n -CN or - (CY ₂ ) _n -NR ₂ substituted aryl or heteroaryl,
R ⁷ (C = O) -R, (C = O) -NR _2, (C = O) -OR, H or A
and
n 0, 1, 2, 3 or 4
mean,
and their pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, including mixtures thereof in all ratios.

object The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Among solvates of the compounds are deposits of inert solvent molecules to the Compounds understood because of their mutual attraction form. Solvates are e.g. Mono or dihydrate or alcoholates.

Under pharmaceutically usable derivatives are understood e.g. the salts the compounds of the invention as well as so-called prodrug compounds.

Under Prodrug derivatives are understood with z. B. alkyl or acyl groups, Sugars or oligopeptides modified compounds of the formula I, which in the organism rapidly to the effective compounds of the invention be split.

For this belong also biodegradable polymer derivatives of the compounds according to the invention, as this z. In Int. J. Pharm. 115, 61-67 (1995).

Of the Expression "effective Quantity "means the amount of a drug or pharmaceutical agent, the one biological or medical answer in a tissue, System, animal or human, e.g. from a researcher or doctors are sought or desired.

Moreover, the term "therapeutically effective amount" means an amount that, as compared to a corresponding subject who has not received that amount, results in:
improved curative treatment, cure, prevention or elimination of a disease, a clinical picture, a disease state, a condition, a disorder or side effects or even a reduction in the progression of a disease, a condition or a disorder.

The Term "therapeutic effective amount "also includes the amounts being effective, the normal physiological function to increase.

object 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.

Especially These are preferably mixtures of stereoisomeric compounds.

worin R¹, R² und R³ die in Anspruch 1 angegebenen Bedeutungen haben,
mit einer Verbindung der Formel III

worin
R⁶ die oben angegebene Bedeutung aufweist,
und
mit einer Verbindung der Formel III, dessen Doppelbindungsisomer (E-Isomer) oder deren Mischungen

worin R⁴ und R⁵ die oben angegebenen Bedeutungen haben,
bevorzugt in Gegenwart einer Säure wie z.B. Trifluoressgsäure, Hexafluorisopropanol, Bismu(III)chlorid, Ytterbium(III)triflat, Scandium(III)triflat oder Cerammonium(IV)nitrat
umsetzt,
und/oder
eine Base oder Säure der Formel I in eines ihrer Salze umwandelt.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 I according to the claims and their pharmaceutically usable derivatives, salts, solvates and stereoisomers, characterized in that
a compound of formula II

wherein R ¹ , R ² and R ^{3 have} the meanings given in claim 1,
with a compound of formula III

wherein
R ^{6 has} the abovementioned meaning,
and
with a compound of formula III, its double bond isomer (E-isomer) or mixtures thereof

wherein R ⁴ and R ^{5 have} the meanings given above,
preferably in the presence of an acid such as trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium (III) triflate, scandium (III) triflate or cerium ammonium (IV) nitrate
implements,
and or
converts a base or acid of the formula I into one of its salts.

Above and below, the radicals R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, Y and n have the meanings given for the formula I, unless expressly stated otherwise , When multiple occurrences of individual radicals within a compound, the radicals independently of one another assume the meanings indicated.

A is alkyl, is preferably unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A is preferably Methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and 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 preferably e.g. Trifluoromethyl.

A is very particularly preferably alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoroethyl. A also means cycloalkyl.

cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

R ¹ is preferably A, CF ₃ , OCF ₃ , SA, SCN, CH ₂ CN, -OCOA, Hal, SCF ₃ , preferably also t-butyl, -CH (CH ₃ ) CH ₂ CH ₃ , isopropyl, ethyl or methyl ,

R ² is preferably Hal, A or OA, in particular Br, cyclopropyl, OCH ₃ .

R ³ is preferably H or A, in particular H. R ³ is preferably in the 5-position.

R⁵ bedeutet vorzugsweise H oder nimmt zusammen mit R⁴ eine der folgenden Bedeutungen an:

worin X und R die oben angegebene Bedeutung aufweisen.R ⁴ preferably denotes one of the following groups, provided that R ⁵ denotes H:

R ⁵ is preferably H or taken together with R ^{4 has} one of the following meanings:

wherein X and R have the meaning given above.

worin
Q O oder S bedeutet, A die oben angegebene Bedeutung aufweist, bevorzugt aber Methyl bedeutet und Hal bevorzugt F oder Cl bedeutet.R ⁶ is preferably unsubstituted or mono- or polysubstituted by Hal, CN, NO ₂ , OH, CF ₃ , OCH (CF ₃ ) ₂ , OCOCH ₃ or A substituted phenyl, 2-, 3- or 4-pyridyl, pyrimidyl, furyl or thienyl. In particular, R ^{6 is} one of the following groups:

wherein
Q is O or S, A has the abovementioned meaning, but preferably is methyl and Hal is preferably F or Cl.

R ⁷ is preferably H or A, in particular H.

Aryl is preferably unsubstituted or mono-, di- or tri-halo by Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, -CH ₂ -COOH or -OCH ₂ -COOH substituted phenyl, naphthyl or biphenyl.

aryl is preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylaminocarbonyl) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m- or p- (N-ethylamino) -phenyl, o-, m- or p- (N, N-diethylamino) -phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o-, m- or p- (methylsulfonyl) -phenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Heteroaryl preferably denotes a mono- or binuclear aromatic heterocycle having one or more N, O and / or S atoms which is unsubstituted or mono-, di- or trisubstituted by Hal, A, NO ₂ , NHA, NA ₂ , OA , COOA or CN.

Heteroaryl particularly preferably denotes a monocyclic saturated or aromatic heterocycle having an N, S or O atom which may be unsubstituted or mono-, di- or trisubstituted by Hal, A, NHA, NA ₂ , NO ₂ , COOA or benzyl.

regardless further substitutions, unsubstituted heteroaryl, 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, furthermore preferably 1,2,3-triazole-1, -4- or -5-yl, 1,2,4-triazole-1, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4 or -5-yl, 1,2,4-oxadiazole-3 or -5-yl, 1,3,4-thiadiazole-2-or -5-yl, 1,2,4-thiadiazol-3 or -5-yl, 1,2,3-thiadiazole-4 or -5-yl, 3- or 4-pyridazinyl, Pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferred 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4 or 5-yl or 2,1,3-benzoxadiazol-5-yl.

Hal is preferably F, Cl or Br, but also I, more preferably F or Cl.

For the whole Invention applies that all Radicals that are multiple, may be the same or different, i. independently from each other.

The Compounds of the formula I can possess one or more chiral centers and therefore in different stereoisomeric forms occur. Formula I encloses everyone these forms.

worin
R, R¹, R², R⁶, R⁷ und X die oben angegebenen Bedeutungen aufweisen
und
R⁸ H, CH₂OR oder CH₂NR₂
bedeutet.Particularly preferred compounds of the formula I are those of the subformulae IA to ID:

wherein
R, R ¹ , R ² , R ⁶ , R ⁷ and X have the meanings given above
and
R ^{8 is} H, CH ₂ OR or CH ₂ NR ₂
means.

The radicals R ⁴ and R ⁵ are particularly preferably in the cis-position relative to one another. Further preferably, the radical R ^{6 is} trans to the radical R ⁵ .

dessen Enantiomer, Racemat oder andere Gemische der Enantiomeren. 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. Einige bevorzugte Gruppen von Verbindungen können durch die folgenden Teilformeln I1 bis I45 ausgedrückt werden:

Preference is given to a compound of the formula A having the following structure:

its enantiomer, racemate or other mixtures of the enantiomers. Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings given above. Some preferred groups of compounds can be expressed by the following partial formulas I1 to I45:

The Compounds of the formula I and also the starting materials for their preparation the rest are after methods known per se, as described in the literature (e.g., in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart) are described, under Reaction conditions for the said reactions are known and suitable. It can we also make use of known per se, not mentioned here variants.

The Starting materials can, if desired, also be formed in situ so that they can be removed from the reaction mixture not isolated, but immediately further to the compounds of the formula I implements.

The reaction is generally carried out in an inert solvent, preferably in the presence of an acid such as TFA, HFIP, bismuth (III) salts, YHerham (III) salts or CAN. The reaction time is depending on the ange conditions between a few minutes and 14 days, the reaction temperature between about 0 ° and 180 °, normally between 0 ° and 100 °, more preferably between 15 ° and 35 ° C.

When inert solvent are suitable 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 like formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene or mixtures the said solvent.

If desired, can be a functionally modified in a compound of formula I. Amino and / or hydroxy group by solvolysis or hydrogenolysis according to usual Methods are set at liberty. This can e.g. with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.

The Reduction of an ester to aldehyde or alcohol, or reduction a nitrile to the aldehyde or amine is carried out by methods such as these are known in the art and in standard works of organic Chemistry are described.

The said compounds of the invention settle in their final Use non-salt form. On the other hand, the present invention also the use of these compounds. in the form of its pharmaceutical harmless salts of various organic and inorganic Acids and Bases can be derived by methods known in the art. pharmaceutical harmless salt forms of the compounds of formula I are largely conventionally made. If the compound of formula I a Carboxylic acid group contains let yourself form one of their suitable salts by reacting the compound with a suitable base to give the corresponding base addition salt. Such Bases include, for example, alkali metal hydroxides, including potassium hydroxide, Sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as Barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; as well as various organic Bases such as piperidine, diethanolamine and N-methylglutamine. The aluminum salts of the compounds of formula I count also to. For certain compounds of formula I leave acid addition salts by forming one these compounds with pharmaceutically acceptable organic and inorganic acids, e.g. Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding Salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, as well as other organic acids and their corresponding salts, such as acetate, trifluoroacetate, tartrate, Maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like treated. Accordingly count to pharmaceutically acceptable acid addition salts of the compounds of the formula I the following: acetate, adipate, alginate, arginate, aspartate, Benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, Camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, Cyclopentane propionate, digluconate, dihydrogen phosphate, dinitrobenzoate, Dodecylsulfate, ethanesulfonate, fumarate, 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-naphthalenesulfonate, Nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulphate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but no restriction represents.

Farther counting to the base salts of the compounds of the invention aluminum, Ammonium, calcium, copper, iron (III), iron (II), lithium, Magnesium, manganese (III), manganese (II), potassium, sodium and zinc salts, but no restriction should represent. Preferred among the above-mentioned salts Ammonium; the alkali metal salts sodium and potassium, and the alkaline earth metal salts Calcium and magnesium. To salts of the compounds of the formula I, derived from pharmaceutically acceptable non-toxic organic Derive bases, count Salts primary, secondary and tertiary Amines, substituted amines, including naturally occurring substituted Amines, cyclic amines and basic ion exchange resins, e.g. Arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (Benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, Glucamine, glucosamine, histidine, hydrabamine, iso-propylamine, lidocaine, Lysine, meglumine, N-methyl-D-glucamine, Morpholine, piperazine, piperidine, polyamine resins, procaine, purines, Theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl) -methylamine (tromethamine), but what no restriction should represent.

Compounds of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C ₁ -C ₄ ) alkyl halides, eg, methyl, ethyl, isopropyl, and tert-butyl chloride, bromide, and iodide; Di (C ₁ -C ₄ ) alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C ₁₀ -C ₁₈ ) alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl (C ₁ -C ₄ ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize. With such salts, both water- and oil-soluble compounds of the invention can be prepared.

To the abovementioned pharmaceutical salts, which are preferred counting Acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, Hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, Nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulphate, Sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, which but no limitation should represent.

The Acid addition salts basic compounds of the formula I are prepared by that one the free base form with a sufficient amount of the desired Acid in Contact brings you on usual Way the salt represents. The free base can be brought into contact salt form with a base and isolating the free base in the usual way regenerate. The free base forms differ in some way Sense of their corresponding salt forms in relation to certain physical properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.

As mentioned the pharmaceutically acceptable base addition salts of Compounds of formula I with metals or amines such as alkali metals and alkaline earth metals or organic amines. preferred Metals are sodium, potassium, magnesium and calcium. preferred organic amines are N, N'-dibenzylethylenediamine, Chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The Base addition salts of acidic compounds of the invention produced by the free acid form with a sufficient amount of the desired base in contact, causing the salt to usual Way. The free acid let yourself by contacting the salt form with an acid and isolating the free acid on usual Regenerate way. The free acid forms differ In a sense, they are related to their corresponding salt forms to certain physical properties such as solubility in polar solvents; in the context of the invention, however, the salts otherwise correspond to theirs respective free acid forms.

Contains one inventive compound more than one group containing such pharmaceutically acceptable salts can form so includes the invention also multiple salts. To typical multiple salt forms counting for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, Disodium and trihydrochloride, but this is not limiting should.

in the In view of the above, it can be seen that the term "pharmaceutically acceptable Salt "in the present In the context of understanding an active ingredient that is a compound of the formula I in the form of one of its salts, especially if this salt form the active ingredient compared to the free form of Active ingredient or any other salt form of the active substance, the earlier used, imparts improved pharmacokinetic properties. The pharmaceutically acceptable salt form of the active ingredient may also this drug only a desired confer pharmacokinetic properties on which he did not previously has and even the pharmacodynamics of this drug to positively influence its therapeutic efficacy in the body.

object The invention furthermore relates to medicaments containing at least one Compound of formula I and / or its pharmaceutically acceptable Derivatives, solvates and stereoisomers, including mixtures thereof in all conditions and, where appropriate, carrier and / or auxiliaries.

Pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Such a moiety may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction thereof of an active ingredient. Furthermore, such pharmaceutical Make formulations by any of the methods well known in the pharmaceutical art.

pharmaceutical Formulations may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. Such formulations can with all methods known in the pharmaceutical art by, for example, the active ingredient with the carrier (s)) or excipients) is brought together.

At adapted for oral administration pharmaceutical formulations can as separate units, e.g. Capsules or tablets; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; Eatable foams or foam foods; or oil-in-water liquid emulsions or Water-in-oil liquid emulsions be presented.

So let yourself for example, in oral administration in the form of a tablet or capsule the drug component with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as e.g. ethanol, Glycerin, water and the like combine. Powders are made by adding the compound crushed a suitable fine size and with a similar one Way crushed pharmaceutical carrier, such. an edible carbohydrate such as starch or mannitol is mixed. A flavoring, preservative, Dispersant and dye may also be present.

capsules are prepared by mixing a powder mixture as described above prepared and shaped gelatin shells are filled with it. Lubricants such as e.g. fumed silica, talc, Magnesium stearate, calcium stearate or polyethylene glycol in solid form can the powder mixture before the filling process be added. A disintegrants or solubilizers, e.g. Agar Agar, Calcium carbonate or sodium carbonate, may also be added for availability improve the drug after taking the capsule.

In addition, if required or necessary, suitable binding, lubricating and disintegrating agents as well Dyes are also incorporated into the mixture. To the suitable binders include starch, gelatin, natural Sugars, e.g. Glucose or beta-lactose, sweeteners from corn, natural and synthetic Gum, e.g. Acacia, tragacanth or sodium alginate, carboxymethylcellulose, 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 the like Belonging to the explosives without limitation to be, strength, Methyl cellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated for example, by preparing a powder mixture, granulated or is pressed dry, a lubricant and a disintegrant are added and the Whole compressed into tablets becomes. A powder mixture is prepared by the in suitable Way crushed compound with a diluent or a base, as described above, and optionally with a binder, such as. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution slower, such as. Paraffin, a resorption accelerator, such as one quaternary Salt and / or an absorbent, e.g. Bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by mixing with a binder, e.g. Syrup, starch paste, Acadia mucus or solutions made of cellulose or polymer materials wetted and through a sieve pressed becomes. As an alternative to granulation, the powder mixture can be used run through a tabletting machine, wherein unevenly shaped Lumps are formed, which are broken up into granules. The granules can by adding stearic acid, a stearate salt, talc or mineral oil are greased to stick at the tablet casting molds to prevent. The greased mixture is then compressed into tablets. The Compounds of the invention can also with a free-flowing inert carrier combined and then without implementation the granulation or dry compression steps directly to tablets pressed become. A transparent or opaque protective layer, consisting from a shellac sealant, a layer of sugar or Polymer material and a gloss layer of wax, may be present be. These coatings can Dyes are added to between different dosage units to be able to distinguish.

Oral fluids such as solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an appropriate taste aqueous solution while preparing elixirs using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, Preservatives, flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. can also be added.

The Dosage unit formulations for oral administration may optionally enclosed in microcapsules. The formulation can be also produce so that the Release prolonged or is retarded, such as by coating or embedding of particulate Material in polymers, wax, etc.

The Compounds of formula I and salts, solvates and physiological functional derivatives thereof can also be in the form of liposome delivery systems, such as. small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can various phospholipids, e.g. Cholesterol, stearylamine or phosphatidylcholines.

The Compounds of the formula I and the salts, solvates and physiological functional derivatives thereof also using monoclonal antibodies as individual carriers the the connecting molecules coupled, fed become. The connections can also with soluble Polymers are coupled as targeted drug carrier. Such Polymers can Polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, Polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine, substituted with palmitoyl radicals. Furthermore, the Compounds to a class of biodegradable polymers, for the controlled release of a drug are suitable, e.g. polylactic acid, Polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, Polydihydroxypyrans, polycyanoacrylates and cross-linked or amphipathic Block copolymers of hydrogels to be coupled.

At the transdermal administration adapted pharmaceutical formulations can as independent Plaster for longer, close contact with the epidermis of the recipient be presented. So For example, the drug from the patch by iontophoresis supplied as described in Pharmaceutical Research, 3 (6), 318 (1986) described.

At the topical administration adapted pharmaceutical compounds can as ointments, creams, suspensions, lotions, powders, solutions, Be formulated pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissue, e.g. Mouth and skin, the formulations are preferably as topical Ointment or cream applied. When formulated into an ointment can the active ingredient either with a paraffinic or one with water Miscible cream base can be used. Alternatively, the active ingredient to a cream with an oil-in-water cream base or a water-in-oil basis be formulated.

To the adapted to the topical application to the eye pharmaceutical formulations include eye drops, wherein the active ingredient in a suitable carrier, in particular an aqueous solvent, dissolved or is suspended.

At the topical application in the mouth adapted pharmaceutical formulations include lozenges, lozenges and mouthwashes.

At rectal administration adapted pharmaceutical formulations can in the form of suppositories or enemas be presented.

At adapted the nasal administration pharmaceutical formulations in which the vehicle is a solid, contain a coarse powder with a particle size, for example in the range from 20-500 microns, in the way snuff is administered, i. by rapid inhalation over the Nasal passages from a container held close to the nose the powder. Suitable formulations for administration as a nasal spray or nose drops with a liquid as a carrier include drug solutions in water or oil.

At administration by inhalation adapted pharmaceutical formulations include fine particulate dusts or nebulae, which are pressurized by means of various types Dosing dispensers with aerosols, nebulizers or insufflators produced can be.

Pharmaceutical formulations adapted for vaginal administration may be used as pessaries, Tampons, creams, gels, pastes, foams or spray formulations are presented.

To the pharmaceutical formulations adapted for parenteral administration belong to watery and non-aqueous sterile Injection solutions, the antioxidants, buffers, bacteriostats and solutes, by the the formulation is made isotonic with the blood of the recipient to be treated will contain; as well as aqueous and non-aqueous sterile Suspensions which may contain suspending agents and thickeners. The Formulations can in single or multiple dose containers, e.g. sealed ampoules and vials, presented and in freeze-dried (lyophilized) state be stored so that only the addition of the sterile carrier liquid, e.g. Water for Injections, needed immediately before use. Prescribed injection solutions and suspensions can from sterile powders, granules and tablets.

It understands that the Formulations in addition to the above-mentioned components especially others usual in the field Means with respect to the respective type of formulation included can; so can for example the oral administration suitable formulations flavorings contain.

A therapeutically effective amount of a compound of formula I depends on a number of factors, including e.g. the age and weight of the animal, the exact state of the disease requiring treatment, and its severity, the nature of the formulation as well as the route of administration, and will eventually be treated by the patient Doctor or veterinarian set. However, there is an effective amount a compound of the invention for the Treatment of neoplastic growth, e.g. Colon or breast carcinoma, generally in the range of 0.1 to 100 mg / kg of body weight of the recipient (mammal) per Day and more typically in the range of 1 to 10 mg / kg body weight per day. Thus would be for one 70 kg adult mammal the actual Amount per day for usually between 70 and 700 mg, taking this amount as a single dose per day or more usual in a series of sub-doses (such as two, three, four, five, or six) can be given per day, so that the total daily dose the same is. An effective amount of a salt or solvate or a physiologically functional derivative thereof may be used as a proportion the effective amount of the compound of the invention determined per se become. It can be assume that similar Dosages for the treatment of the other, above-mentioned disease states suitable are.

object The invention further comprises medicaments containing at least one Compound of formula I and / or its pharmaceutically acceptable Derivatives, solvates and stereoisomers, including mixtures thereof in all conditions and at least one other drug.

• (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
• (b) einer wirksamen Menge eines weiteren Arzneimittelwirkstoffs:

The invention is also a set (kit), consisting of separate packages of

• (A) an effective amount of a compound of formula I and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and
• (b) an effective amount of another active pharmaceutical ingredient:

The Set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set may e.g. contain separate ampoules, in each case 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 drug solved or in lyophilized form.

Especially the use of the compound according to the invention for treatment is preferred and prophylaxis of tumor diseases.

Of the Tumor is preferably selected from the group of tumors of the squamous epithelium, the bladder, the stomach, of the kidneys, of the head and neck, of the esophagus, of the cervix, the thyroid, intestine, liver, brain, prostate, genitourinary tract, of the lymphatic system, the stomach, the larynx and / or the Lung.

Of the Tumor is furthermore preferably selected from the group lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.

Further preferred is the use for the treatment of a tumor of the blood and immune system, preferably for the treatment of a tumor selected from the group of acute myelotic leukemia, chronic myelotic leukemia, acute lymphoblastic leukemia and / or chronic lymphatic leukemia.

The Present compounds are also suitable for combination with known Anticancer agents. These known anticancer agents include the following: estrogen receptor modulators, Androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-proteintransferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors. The present compounds are particularly suitable for common Application with radiotherapy. The synergistic effects of inhibition of VEGF in combination with radiotherapy are described in the art have been (see WO 00/61186).

"Estrogen receptor modulators" refers to Compounds that interfere with the binding of estrogen to the receptor or these inhibit, independently of how this happens. To the estrogen receptor modulators counting for example tamoxifen, raloxifene, idoxifen, LY353381, LY 117081, Toremifene, fulvestrant, 4- [7- (2,2-dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3 yl] -phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl hydrazone and SH646, which is not intended to be limiting.

"Androgen receptor modulators" refers to Compounds that interfere with the binding of androgens to the receptor or these inhibit, independently of how this happens. The androgen receptor modulators include Example, finasteride and other 5α-reductase inhibitors, Nilutamide, flutamide, bicalutamide, liarozole and abiraterone acetate.

"Retinoid receptor modulators" refers to Compounds that interfere with the binding of retinoids to the receptor or these inhibit, independently of how this happens. To such retinoid receptor modulators counting for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxyphenyl) retinamide and N-4-carboxyphenylretinamide.

"Cytotoxic agents" refers to Compounds primarily by direct action on the Cell function lead to cell death or inhibit or interfere with cell myosis, including alkylating agents, Tumor necrosis factors, intercalators, microtubulin inhibitors and topoisomerase inhibitors.

To counting the cytotoxic agents for example, tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, Lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, Ranimustin, Fotemustin, Nedaplatin, Oxaliplatin, Temozolomide, Heptaplatin, Estramustine, improvisulfan-tosylate, trofosfamide, nimustine, dibrospidium chloride, Pumitepa, Lobaplatin, Satraplatin, Profiromycin, Cisplatin, Irofulven, Dexifosfamide, cis-amine dichloro (2-methylpyridine) platinum, Benzylguanine, glufosfamide, GPX100, (trans, trans, trans) -bis-mu (hexane-1,6-diamine) -mu- [diamine-platinum (II)] bis- [diamine (chloro) -platinum (II)] tetrachloride, Diarizidinylspermine, arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3,7-dimethylxanthine, Zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, Pinafid, valrubicin, amrubicin, antineoplaston, 3'-desamino-3'-morpholino-13-desoxo-10-hydroxycarminomycin, Annamycin, galarubicin, elinafide, MEN10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl daunorubicin (see WO 00/50032), but this is not intended to be limiting.

To include the microtubulin inhibitors for example, paclitaxel, vindesine sulfate, 3 ', 4'-didehydro-4'-deoxy-8'-norvincaleukoblastin, Docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, Cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, Anhydrovinblastine, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258 and BMS188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecane, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidenchartreusine, 9-methoxy-N, N-dimethyl-5-nitropyrazolo [3,4,5- k1] acridine-2- (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3 ', 4 ': b, 7] indolizino [1,2bjquinoline-10,13 (9H, 15H) dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin, BNP1350, BNPI1100, BN80915, BN80942 , Etoposide-phosphate, teniposide, sobuzoxan, 2'-dimethylamino-2'-deoxy-etoposide, GL331, N- [2- (dimethylamino) ethyl] -9-hydroxy-5,6-dimethyl-6H-pyrido [4, 3-b] carbazole-1-carboxamide, asulacrine, (5a, 5aB, 8aa, 9b) -9- [2- [N- [2- (dimethylamino) ethyl] -N-methylamino] ethyl] -5- [4 hydroxy-3,5-dimethoxyphenyl] -5,5a, 6,8,8a, 9-hexohydrofuro (3 ', 4': 6,7) naphtho (2,3-d) -1,3-dioxol-6 -on, 2,3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [c] phenanthridinium, 6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline-5,10 dione, 5- (3-aminopropylamino) -7,10-dihydroxy-2- (2-hydroxyethylaminomethyl l) -6H-pyrazolo [4,5,1-d e] acridin-6-one, N- [1- [2 (diethylamino) ethylamino] -7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N- (2- (dimethylamino) ethyl) acridine-4-carboxamide, 6 - [[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2,1-c] quinolin-7-one and dimesna.

To the "antiproliferative Means "include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, as well as antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, Fludarabine, capecitabine, galocitabine, cytarabinocfosfate, fosteabic sodium hydrate, Raltitrexed, Paltitrexide, Emitefur, Tiazofurin, Decitabine, Nolatrexed, Pemetrexed, furarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- (2,3-dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea . N6- [4-deoxy-4- [N2- [2 (E), 4 (E) -tetradecadienoyl] glycylamino] -L-glycero-B-L-manno-heptopyranosyl] adenine, Aplidine, ecteinascidin, 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-ylessigsäureester, Swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-B-D-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative Means " also other monoclonal antibodies against growth factors as already mentioned among the "angiogenesis inhibitors", such as trastuzumab, as well as tumor suppressor genes, such as p53, via recombinant virus-mediated gene transfer (see, e.g., U.S. Patent No. 6,069,134).

Above and below, all temperatures are given in ° C. In the following examples, "usual workup" means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracted with ethyl acetate or dichloromethane, separating, drying organic phase over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rf values on silica gel;
Ethyl acetate / methanol 9: 1.
Mass Spectrometry (MS): EI (Eletron Impact Ionization) M ⁺
FAB (Fast Atom Bombardment) (M + H) ⁺
ESI (Electrospray Ionization) (M + H) ⁺
APCI-MS (atmospheric pressure chemical ionization - mass spectrometry) (M + H) ⁺

example 1

a. Implementation in the presence of trifluoroacetic acid (TFA)

The solution of the TFA salt of 4-tert-butylaniline in acetonitrile (4-tert-butylaniline (0.50 g, 3.35 mmol) was taken up in acetonitrile (4 mL), cooled to 0 ° C and TFA (0.38 g, 3.35 mmol) added slowly with stirring) quickly became a at 0 ° C chilled solution from 3-hydroxybenzaldehyde (0.41 g, 3.35 mmol) and 3,4-dihydro-2N-pyran (0.28 g, 3.35 mmol) in acetonitrile (2 mL) and a further 60 min at this temperature touched. The reaction solution was evaporated to dryness and separated by column chromatography. A colorless solid (620 mg, 1.84 mmol, 55%) was obtained, which is a mixture of isomers of each racemic trans / cis compound in relation to 13: 1 turned out.

to Separation of the cis / frans isomers became the solid in 0.1 N HCl in isopropanol (20 mL), each 100 mL diethyl ether and cyclohexane added and over Night at 4 ° C crystallized. The colorless solid was filtered off, with little Washed diethyl ether and dried. 570 mg (1.52 mmol) of the colorless Compound rac-1 hydrochloride could be recovered. The mother liquor was evaporated to dryness and the cis-isomer by column chromatography and converted into the hydrochloride (70 mg, 0.19 mmol of a colorless solid).

smaller Levels of rac-1 and rac-2 were determined by chiral HPLC (2 × Chiralpak AD 20μm, Eluent: methanol) into the corresponding enantiomers and again transferred to the hydrochlorides.

b. Implementation in the presence of hexafluoroisopropanol (HFIP)

Around higher Yields of the cis isomer was replaced by TFA hexafluoroisopropanol (HFIP). used.

4-tert-butylaniline (0.50 g, 3.35 mmol), 3-hydroxybenzaldehyde (0.41 g, 3.35 mmol) and 3,4-Dihydro-2H-pyran (0.28 g, 3.35 mmol) was dissolved in acetonitrile (1 mL), at RT HFIP (0.56 g, 3.35 mmol) was added dropwise and a further 18 h at RT stirred. The reaction solution was evaporated to dryness and separated by column chromatography. A colorless solid (485 mg, 1.44 mmol, 43%) was obtained, which is a mixture of isomers of each racemic trans / cis compound in relation to 1: 1.6 turned out.

A Separation of the isomers was carried out as described under a.).

c. Implementation in the presence of bismuth (III) chloride

To a suspension of BiCl ₃ (0.21g, 0.67 mmol) and anhydrous sodium sulfate (0.40 g) in acetonitrile (2 mL) was added at RT 3-hydroxybenzaldehyde (0:41 g, 3:35 mmol) and 4-tert-butylaniline (0.50 g, 3.35 mmol) each dissolved in acetonitrile (1 mL) was added and stirred at RT for 10 min. Then, 3,4-dihydro-2N-pyran (0.28 g, 3.35 mmol) was added dropwise at RT and stirred at RT for a further 30 min. The reaction solution was filtered through Celite, the filtrate was evaporated to dryness and purified by column chromatography. This gave a colorless solid (850 mg, 2.51 mmol, 75%), which turned out to be a mixture of isomers of each racemic trans / cis compound in the ratio 1: 1.1. A separation of the isomers was carried out as described under a.).

d. Implementation in the presence of Ytterbium (III) triflate

To a suspension of Yb (OTf) ₃ (0.42 g, 0.67 mmol) and anhydrous sodium sulfate (0.40 g) in acetonitrile (2 mL) at RT 3-hydroxybenzaldehyde (0.41 g, 3.35 mmol) and 4-tert-butylaniline ( 0.50 g, 3.35 mmol) each dissolved in acetonitrile (1 mL) was added and stirred at RT for 10 min. Then, 3,4-dihydro-2H-pyran (0.28 g, 3.35 mmol) was added dropwise at RT and stirred at RT for a further 30 min. The reaction solution was filtered through Celite, the filtrate was evaporated to dryness and purified by column chromatography. This gave a colorless solid (780 mg, 2.31 mmol, 69%), which turned out to be an isomer mixture of the respective racemic trans / cis compound in a ratio of 1: 1.3. A separation of the isomers was carried out as described under a.).

e. Implementation in the presence of scandium (III) triflate

To a suspension of Sc (OTf) ₃ (0.33 g, 0.67 mmol) and anhydrous sodium sulfate (0.40 g) in acetonitrile (2 mL) at RT 3-hydroxybenzaldehyde (0.41 g, 3.35 mmol) and 4-tert-butylaniline ( 0.50 g, 3.35 mmol) each dissolved in acetonitrile (1 mL) was added and stirred at RT for 10 min. Then, 3,4-dihydro-2H-pyran (0.28 g, 3.35 mmol) was added dropwise at RT and stirred at RT for a further 30 min. The reaction solution was filtered through Celite, the filtrate was evaporated to dryness and purified by column chromatography. This gave a colorless solid (620 mg, 1.84 mmol, 55%), which turned out to be a mixture of isomers of each racemic trans / cis compound in relation.

A Separation of the isomers was carried out as described under a.).

f. Implementation in the presence of ammonium cerium (IV) nitrates (CAN)

To a solution of 3-hydroxybenzaldehyde (0.41 g, 3.35 mmol), 4-tert-butylaniline (0.50 g, 3.35 mmol) and 3,4-dihydro-2H-pyran (0.28 g, 3.35 mmol) in acetonitrile (10 mL) was added at RT CAN (0.37 g, 0.67 mmol) and stirred at RT for a further 30 min. The reaction mixture was evaporated to dryness and purified by column chromatography. This gave a colorless solid (237 mg, 0.70 mmol, 21%), which turned out to be a mixture of isomers of each racemic trans / cis compound in the ratio 5: 1.

A Separation of the isomers was carried out as described under a.).

Example 2

a. Implementation in the presence of trifluoroacetic acid (TFA)

The solution of the TFA salt of 4-thiocyanatoaniline in acetonitrile (thiocyanatoaniline (0.46 g, 3.06 mmol) was taken up in acetonitrile (4 mL), on Cooled to 0 ° C and TFA (0.35 g, 3.06 mmol) added slowly with stirring) quickly became a at 0 ° C chilled solution from 3-hydroxybenzaldehyde (0.37 g, 3.06 mmol) and 1-vinyl-2-pyrrolidinone (0.34 g, 3.06 mmol) in acetonitrile (2 mL) and a further 60 min at this Temperature and stirred for 18 h at RT. The reaction solution was concentrated, taken up with a little ethyl acetate and diethyl ether crystallized. A colorless solid was obtained (390 mg, 1.06 mmol, 35%), which turned out to be a cis isomer.

to Separation of the cis / trans isomers, the filtrate to dryness concentrated and purified by column chromatography purified. The trans isomer was obtained as a colorless solid (160 mg, 0.44 mmol, 14%), Smaller amounts of rac-3 and rac-4 were via chiral HPLC (2 × Chiralpak AD 20μm, Eluent: methanol) into the corresponding enantiomers and converted into the hydrochlorides.

Analogous using or precursors are the following Compounds of the invention receive:

assay

The Determination of the effectiveness of the compounds of the invention may, for. B. over the Eg5 ATPase activity, the above an enzymatic regeneration of the product ADP to ATP by means of Pyruvate kinase (PK) and subsequent Coupling to an NADH-dependent Lactate dehydrogenase (LDH) reaction is measured. By the coupling to the NADH-dependent LDH can change the reaction the change of Absorbance can be followed at 340 nm. The regeneration of the ATP guaranteed at the same time that the substrate concentration remains constant. The extinction per time unit are analyzed graphically and a linear regression performed in the visually linear region of the reaction.

The The following examples refer to drugs:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogen phosphate is dissolved in 3 l of double-distilled water with 2N hydrochloric acid adjusted pH 6.5, sterile filtered, filled into injection jars, under sterile conditions and lyophilized sterile. each Contains injection glass 5 mg of active ingredient.

Example B: Suppositories

you melts a mixture of 20 g of an active ingredient of the formula I with 100 g soy lecithin and 1400 g cocoa butter, pour into molds and allow to cool. Each suppository contains 20 mg of active ingredient.

Example C: Solution

A solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH ₂ PO ₄ · 2 H ₂ O, 28.48 g Na ₂ HPO ₄ · 12 H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of double- distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment

you mixes 500 mg of an active ingredient of the formula I with 99.5 g Vaseline under aseptic conditions.

Example E: Tablets

One 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 in the usual way to tablets pressed, such that each Tablet contains 10 mg of active ingredient.

Example F: dragees

Analogous Example E tablets are pressed, which are then in the usual Way with a plating Sucrose, potato starch, Talc, tragacanth and dyestuff coated become.

Example G: Capsules

2 kg of active ingredient of the formula I are in the usual way in hard gelatin capsules filled, so that everyone Capsule contains 20 mg of the active ingredient.

Example H: Ampoules

A solution of 1 kg of active compound of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, under sterile conditions lyophilized and sealed sterile. Each ampoule contains 10 mg Active ingredient.

Claims (24)

Compounds of the formula I

wherein R ¹ , R ^{2 are} independently H, A, aryl, heteroaryl, Hal, cycloalkyl, -SCH ₃ , -SCN, -CF ₃ , -OCF ₃ , -OA, - (CY ₂ ) _n -OH, - (CY ₂ ) _n -CO ₂ R, - (CY ₂ ) _n -CN, - (CY ₂ ) _n -NR ₂ , (CY ₂ ) _n -OA, (CY ₂ ) _n -OCOA, -SCF ₃ , (CY ₂ ) _n -CONR ₂ YH, A, Hal A is alkyl or cycloalkyl Hal is F, Cl, Br or IRH or A; in the case of geminal radicals R together also - (CH ₂ ) ₅ -, - (CH ₂ ) ₄ - or - (CH ₂ ) ₂ -NR- (CH ₂ ) ₂ , R ⁴ , R ⁵ independently of one another are H or unsubstituted or mono- or polysubstituted by OR, NO ₂ , Hal, CF ₃ , OCF ₃ , CN, NR ₂ or SR, aryl or heteroaryl substituted N-pyrolidone, -X- (CH ₂ ) ₂ OR, -X- (CH ₂ ) ₂ NR ₂ or together -X (CR ₂ ) ₂ -, -X- (CR ₂ ) ₃ -, -X- ( CHCH ₂ OR) (CH ₂ ) ₂ -, -X- (CHCH ₂ NR ₂ ) (CH ₂ ) ₂ -, -X (CH ₂ ) ₂ NR ₂ , - (CR ₂ ) ₃ -, - (CR ₂ ) ₄ -, -CR = CR-CR = CR-X O, S or NR R ⁶ unsubstituted or mono- or polysubstituted by aryl or heteroaryl represented by Hal, NO ₂ , CN, A, OR, OCOR, NR ₂ , CF ₃ , OCF ₃ , OCH (CF ₃ ) ₂ , Hal, NO ₂ , CN, OR, A, - (CY ₂ ) _n -OR, -OCOR, - (CY ₂ ) _n -CO ₂ R, - (CY ₂ ) _n -CN or - (CY ₂ ) _n -NR ₂ substituted aryl or heteroaryl, R ⁷ (C = O) -R, (C = O) -NR ₂ , (C = O) - OR, H or A and n is 0, 1, 2, 3 or 4, and their pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, including mixtures thereof in all ratios. Compounds according to claim 1, wherein R ^{1 is} A, CF ₃ , OCF ₃ , SA, SCN, CH ₂ CN, -OCOA, Hal, SCF ₃ , t -butyl, -CH (CH ₃ ) CH ₂ CH ₃ , isopropyl, ethyl or methyl. Compounds according to claim 1 or 2, wherein R ^{2 is} preferably Hal, A or OA. Compounds according to one or more of claims 1-3, wherein R ^{3 is} preferably H or A. Compounds according to one or more of claims 1-4, in which R ⁴ preferably represents one of the following groups, provided that R ⁵ denotes H:

X and R have the meaning given in claim 1. Compounds according to one or more of claims 1-5, wherein R ^{5 is} H. Compounds according to one or more of Claims 1-6, in which R ^{5 is} preferably H or together with R ^{4 has} one of the following meanings:

wherein X and R have the meaning given in claim 1. Compounds according to one or more of claims 1-7, wherein R ^{6 is} phenyl which is unsubstituted or monosubstituted or polysubstituted by Hal, CN, NO ₂ , OH, CF ₃ , OCH (CF ₃ ) ₂ , OCOCH ₃ or A, - or 4-pyridyl, pyrimidyl, furyl or thienyl. Compounds according to one or more of claims 1-8, wherein R ^{6 represents} one of the following groups:

wherein Q is O or S and A has the meaning indicated above, but preferably methyl. Compounds according to one or more of claims 1-9, wherein R ^{7 is} H or A. Compounds of sub-formulas IA to ID:

wherein R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X have the meaning given in claim 1 and R ^{8 is} H, CH ₂ OR or CH ₂ NR ₂ . Compounds of Partial Formula A:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^{7 have} the meaning given in claim 1. Compounds of sub-formulas I1 to I45:

Process for the preparation of compounds of the formula I according to Claims 1-13 and their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, characterized in that a compound of the formula II

wherein R ¹ , R ² and R ^{3 have} the meanings given in claim 1, with a compound of formula III

wherein R ^{6 has} the meaning given in claim 1, and with a compound of formula III, its double bond isomer (E-isomer) or mixtures thereof

wherein R ⁴ and R ^{5 have} the meanings given in claim 1, and / or converts a base or acid of the formula I into one of its salts. Method according to claim 14, characterized in that that the reaction takes place in the presence of an acid. Method according to claim 14 or 15, characterized that the reaction in the presence of (trifluoroacetic acid, hexafluoroisopropanol, Bismuth (III) chloride, ytterbium (III) triflate, scandium (III) triflate or Cerammonium (IV) nitrate takes place. Medicament containing at least one compound of the formula I according to claim 1 to 13 and / or their pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, including theirs Mixtures in all proportions, and, where appropriate, carrier and / or auxiliaries. Use of compounds according to claim 1 to 13 and their pharmaceutically usable derivatives, salts, solvates, Tautomers and stereoisomers, including mixtures thereof in all conditions for the manufacture of a medicament for the treatment of diseases, in which the inhibition, regulation and / or modulation of the mitotic Motor protein Eg5 plays a role. Use of compound according to claims 1 to 13, for the manufacture of a medicament for the treatment and prophylaxis of cancer diseases. Use according to claim 19, wherein the cancerous diseases with a tumor from the group of tumors of the squamous epithelium, the Blisters, stomach, kidneys, head and neck, esophagus, of the cervix, the thyroid, intestine, liver, brain, prostate, genitourinary tract, of the lymphatic system, the stomach, the larynx and / or the Lung develop. Use according to claim 20, wherein the tumor is the group monocytic leukemia, Lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, Glioblastoma and breast carcinoma and colon cancer originated. Use according to claim 19, wherein the to be treated Illness is a tumor of the blood and immune system. Use according to claim 22, wherein the tumor is the group of acute myeloid leukemia, chronic myeloid Leukemia, acute lymphocytic leukemia and / or chronic lymphocytic leukemia. Use of compounds of the formula I according to Claims 1 to 13 and / or their physiologically acceptable salts and solvates for the preparation of a medicament for the treatment of tumors wherein a therapeutically effective amount of a compound of the formula I in combination with radiotherapy and a Compound from 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 inhibitors and 10) other angiogenesis inhibitors is administered.