KR20060127002A - 2-(hetero)-aryl-substituted tetrahydroquinoline derivatives - Google Patents

Abstract

Disclosed are compounds of formula (I), wherein W, R, R1, R2, R3, R4, R 5, R6, and R7have the meanings indicated in claim 1. Said compounds can be used for the treatment of tumors, among other things.

Description

2- (hetero) -aryl-substituted tetrahydroquinoline derivative {2- (HETERO) -ARYL-SUBSTITUTED TETRAHYDROQUINOLINE DERIVATIVES}

The present invention aims to find novel compounds having important properties, in particular that can be used for the manufacture of a medicament.

The present invention provides a compound of formula (I) and its use for the treatment and prevention of diseases in which the inhibition, regulation and / or modulation of mitotic motor protein, in particular mitotic motor protein Eg5, is affected. It relates to the pharmaceutical composition it contains.

In particular, the present invention preferably provides a compound of formula (I) which inhibits, modulates and / or modulates one or more mitogenic promoter proteins, compositions containing such compounds, and angiogenesis, cancer, tumor formation, growth and metastasis, arteriosclerosis , Eye diseases, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, treatment of diseases such as wound healing or transplant rejection, and methods of use thereof. In particular the compounds according to the invention are suitable for the treatment or prevention of cancer diseases.

During mitosis, various kinesins regulate the formation and dynamics of spindles that are responsible for accurate, coordinated arrangement and separation of chromosomes. It has been observed that certain inhibition of mitotic starter protein-Eg5- causes disruption of spindles. As a result, chromosomes can no longer be correctly distributed to daughter cells. This result in mitosis arrest thus leads to cell death. Upregulation of the mobile protein Eg5 has been described, for example, in tissues of breast, lung and colon tumors. Since Eg5 is responsible for mitotic-specific function, mainly rapidly dividing cells and undifferentiated cells are affected by Eg5 inhibition. In addition, Eg5 only regulates the movement of the mitotic microtubules (spindle), not the movement of the cytoskeleton. This is important for the side effect profile of the compounds of the present invention, for example because the neuropathy observed in the case of Taxol does not occur or only occurs to a slight extent. Eg5 inhibition of the compounds according to the invention is therefore an important therapeutic concept for the treatment of malignant tumors.

      In general, lung carcinomas including all solid and non-solid tumors such as, for example, monocytic leukemia, brain, genitourinary system, lymphatic system, stomach, larynx and lung adenocarcinoma and small cell lung carcinoma are of formula (I). It can be treated with a compound.

Surprisingly, the compounds according to the invention influence the specific inhibition of mitotic starting proteins, in particular Eg5. The compounds according to the invention preferably have a beneficial biological activity that can be easily detected with the assays described by way of example herein. In such assays, the compounds according to the invention are preferably IC ₅₀ in a suitable range, preferably in the micromolar range, more preferably in the nanomolar range. Has the inhibitory effect that is recorded numerically and causes.

As described herein, the effects of the compounds according to the invention are associated with various diseases. Thus, the compounds according to the invention are useful for the prophylaxis and / or treatment of diseases affected by the inhibition of one or more mitotic promoter proteins, in particular Eg5.

The present invention therefore contemplates not only the use of a compound according to the invention as a medicament and / or a medicament active ingredient for the treatment and / or prophylaxis of such diseases, but also the use of a compound according to the invention in the preparation of a medicament for the treatment and / or prevention of such diseases. It also relates to a method for treating such a disease comprising administering one or more compounds according to the invention to a patient in need of such administration.

The compounds according to the invention can be shown to have beneficial effects in animal organ transplant tumor models.

The host or patient can be any mammalian species, for example primates, especially humans; Rodents, including mice, rats and hamsters; Rabbit family; Horse, bovine, canine, feline, and the like. Animal models are important in experimental studies because they provide a model for the treatment of human disease.

The ease of treatment of certain cells with the compounds according to the invention can be determined by in-vitro experiments. Typically, the compound according to the invention is combined with the cell culture at various concentrations for a time sufficient for the active agent to induce or inhibit cell death, usually between about 1 hour and 1 week. For in vitro testing, cultured cells from biopsy samples can be used. The viable cells remaining after treatment are then counted.

The dosage will vary depending on the specific compound used, the particular disease, the patient's condition and the like. Typically the therapeutic dosage is sufficient to substantially reduce the undesirable cell population in the target tissue while maintaining patient viability. Treatment generally continues until there is a substantial reduction, for example, a reduction in cell stack of at least about 50% and until no undesirable cells are essentially detected in the body.

Summary of the invention

The present invention relates to compounds of formula (I) and pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers, and mixtures thereof in all ratios:

[In the meal,

W represents CH or N,

R^One, R², R³ Are independently of each other, H, A, aryl, heteroaryl, Hal,-(CY₂)_n-SA,-(CY₂)_n-SCF₃,-(CY₂)_n-SCN,-(CY₂)_n-CF₃,-(CY₂)_n-OCF₃, Cycloalkyl, -SCH₃, -SCN, -CF₃, -OCF₃, -OA,-(CY₂)_n-OH,-(CY₂)_n-CO₂R,-(CY₂)_n-CN,-(CY₂)_n-Hal,-(CY₂)_n-NR₂, (CY₂)_n-OA, (CY₂)_n-OCOA, -SCF₃, (CY₂)_n-CONR₂,-(CY₂)_n-NHCOA,-(CY₂)_n-NHSO₂A, SF₅, Si (CH₃)₃, CO- (CY₂)_n-CH₃,-(CY₂)_n-N-pyrrolidone, CH (CH₂)_nNRCOOR, CHNRCOOR, NCO, CH (CH₂)_nCOOR, NCOOR, CH (CH₂)_nOH, N (CH₂)_nOH, CHNH_{2 ,}CH (CH₂)_nNR₂, CH (CH₂)_nNR₂, C (OH) R, CHNCOR, CH (CH₂)_n-Aryl, CH (CH₂)_nHeteroaryl, CH (CH)₂)_nR^One, N (CH₂)_nCOOR, CH (CH₂)_nX (CH₂)_n-Aryl, CH (CH₂)_nX (CH₂)_nHeteroaryl, N (CH₂)_nCONR₂, XCONR (CH₂)_nNR₂, N [(CH₂)_nXCOOR] CO (CH₂)_n-Aryl, N [(CH₂)_nXR] CO (CH₂)_n-Aryl, N [(CH₂)_nXR] CO (CH₂)_nX-aryl, N [(CH₂)_nXR] SO₂(CH₂)_n-Aryl, N [(CH₂)_nNRCOOR] CO (CH₂)_n-Aryl, N [(CH₂)_nNR₂] CO (CH₂)_n-Aryl, N [(CH₂)_nNR₂] CO (CH₂)_nNR-aryl, N [(CH₂)_nNR₂] SO₂(CH₂)_n-Aryl, N [(CH₂)_nXR] CO (CH₂)_nHeteroaryl, N [(CH₂)_nXR] CO (CH₂)_nX-heteroaryl, N [(CH₂)_nXR] SO₂(CH₂)_nHeteroaryl, N [(CH₂)_nNRCOOR] CO (CH₂)_nHeteroaryl, N [(CH₂)_nNR₂] CO (CH₂)_nHeteroaroyl, N [(CH₂)_nNR₂] CO (CH₂)_nNR-heteroaryl, R^One And R² Together with -N-C (CF₃) = N-, -N-CR = N-, -N-N = N-,

Y represents H, A, Hal,

A represents alkyl or cycloalkyl, wherein one or more H atoms can be replaced with Hal,

Hal represents F, Cl, Br or I,

R represents H or A, and in the case of the chemical radical R is also-(CH ₂ ) ₅ -,-(CH ₂ ) ₄ -,-(CH ₂ ) _n -X- (CH ₂ ) _n , or- (CH ₂ ) _n -Z- (CH ₂ ) _{n represents}

R⁴, R⁵ Independently of one another, represent H, or unsubstituted or mono- or poly-OR-, NO₂-, Hal-, CF₃-, OCF₃-, CN-, NR₂Or SR-, aryl- or heteroaryl-substituted N-pyrrolidone, -X- (CH₂)₂OR, -X-CO (CH₂)_nCH₃, -X- (CH₂)₂NR₂, R^One, S-aryl, O-aryl, CH₂Si (CH₃)₃Or together with -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-, -XCHQ (CR₂)₂-, -XCHQCR₂-, R-N- (C = X) -N-R, -XC [(CH₂) nOR]₂CH₂CH₂Indicating-,

X represents O, S or NR,

Q is CH ₂ Hal, CHO, COR ^a , CH ₂ R ^a , CH ₂ OCOR ^a , CH ₂ NCOR ¹ , CH ₂ N (R ¹ ) ₂ , CH ₂ OR ¹ , CH ₂ OCON (R ¹ ) ₂ , CH ₂ OCOOR ¹ , CH ₂ NHCON (R ¹ ) ₂ , CH ₂ NHCOOR ¹ is represented,

R ^a is

OR, NHR₂, NR_{2 ,}OR, NHR₂, NR₂, NR (CH₂)_n-Aryl, NR (CH₂)_nOR, COOR, N-pyrrolidone radical, OCOR, NR (CH₂)_nNR₂, N [(CH₂)_nNR₂] CO (CH₂)_n-Aryl, N [(CH₂)_nNHCOOR] CO-aryl, R^One, N [CH₂(CH₂)_nOR]₂, NR (CH₂)_nNCOOR, X (CH₂)_nX (CH₂)_nXR, NR (CH₂)_nX (CH₂)_nOH, NR (CH₂)_nO (CH₂)_nOH, (CH₂)_nCOOR, O (CO) NR (CH₂) _nOR, O (CO) (CH₂)_nNR₂, NR (CH₂)_nNR₂, N [(CH₂)_nNR₂] CO (CH₂)_nAryl, N [(CH₂)_nXR] CO (CH₂)_n-Aryl, N [(CH₂)_nXR] CO (CH₂)_nHeteroaryl, N [(CH₂)_nNR₂] CO (CH₂)_nHeteroaryl, N [(CH₂)_nNR₂] CO (CH₂)_nR^One, N (R) (CH₂)_nN (R) COOR, XCOO (CH₂)_nNR₂, OSO₂A, OSO₂CF₃, OSO₂Ar, OCONR₂, OCH₂(CH₂)_nNR₂Indicates,

Z is CH ₂ , X, CHCONH ₂ , CH (CH ₂ ) _n NRCOOR, CHNRCOOR, NCO, CH (CH ₂ ) _n COOR, NCOOR, CH (CH ₂ ) _n OH, N (CH ₂ ) _n OH, CHNH _{2 ,} CH (CH ₂ ) _n NR ₂ , CH (CH ₂ ) _n NR ₂ , C (OH) R, CHNCOR, CH (CH ₂ ) _n -aryl, CH (CH ₂ ) _n -heteroaryl, CH (CH ₂ ) _n R ¹ , N (CH ₂ ) _n COOR, CH (CH ₂ ) _n X (CH ₂ ) _n -aryl, CH (CH ₂ ) _n X (CH ₂ ) _n -heteroaryl, N (CH ₂ ) _n CONR ₂ , XCONR (CH ₂ ) _n NR ₂ , N [(CH ₂ ) _n XCOOR] CO (CH ₂ ) _n -aryl, N [(CH ₂ ) _n XR] CO (CH ₂ ) _n -aryl, N [ (CH ₂ ) _n XR] CO (CH ₂ ) _n X-aryl, N [(CH ₂ ) _n XR] SO ₂ (CH ₂ ) _n -aryl, N [(CH ₂ ) _n NRCOOR] CO (CH ₂ ) _n -aryl, N [(CH ₂ ) _n NR ₂ ] CO (CH ₂ ) _n -aryl, N [(CH ₂ ) _n NR ₂ ] CO (CH ₂ ) _n NR-aryl, N [(CH ₂ ) _n NR ₂ ] SO ₂ (CH ₂ ) _n -aryl, N [(CH ₂ ) _n XR] CO (CH ₂ ) _n -heteroaryl, N [(CH ₂ ) _n XR] CO (CH ₂ ) _n X-hetero Aryl, N [(CH ₂ ) _n XR] SO ₂ (CH ₂ ) _n -heteroaryl, N [(CH ₂ ) _n NRCOOR] CO (CH ₂ ) _n -heteroaryl, N [(CH ₂ ) _n NR ₂ ] CO (CH ₂ ) _n -heteroaryl, N [(CH ₂ ) _n NR ₂ ] CO (CH ₂ ) nNR-heteroaryl, N [(CH ₂ ) _n NR ₂ ] SO ₂ (CH 2) n -heteroaryl, O (CH ₂ ) _n NR ₂ , X (CH ₂ ) _n NR ₂ , NCO (CH ₂ ) _n NR ₂ , and

R ⁶ Silver aryl or heteroaryl, each of which is unsubstituted or substituted with Hal, NO ₂ , CN, A, OR, OCOR, COR, NR ₂ , CF ₃ , OCF ₃ , OCH (CF ₃ ) ₂ , or Hal , NO ₂ , CN, OR, A,-(CY ₂ ) _n -OR, -OCOR,-(CY ₂ ) _n -CO ₂ R,-(CY ₂ ) _n -CN, -NCOR, -COR or-( CY ₂ ) mono- or multiply substituted by aryl or heteroaryl which may be substituted by _n- NR ₂ ,

R⁷ silver (C = O) -R, (C = O) -NR₂, (C = O) -OR, H or A,

m represents 0, 1 or 2,

n represents 0, 1, 2, 3, 4, 5, 6 or 7.

The invention also relates to optically active forms, enantiomers, racemates, diastereomers and hydrates and solvates of such compounds. The term solvate of a compound means that due to its mutual attraction the inert solvent molecules gather into the compound of formula (I). Solvates are, for example, monohydrates or dihydrates or alkoxides.

The term pharmaceutically usable derivative means, for example, salts of the compounds according to the invention and also so-called prodrugs.

The term prodrug derivative means a compound of formula (I) which has been modified, for example, with alkyl or acyl groups, sugars or oligopeptides, and which is rapidly cut in an organism to form the active compounds according to the invention.

This is also the case with Int. J. Pharm. Biodegradable polymer derivatives of the compounds according to the invention described in 115 , 61-67 (1995).

Similar compounds are described, 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, US2003149069A1, which have not been mentioned in connection with the treatment of cancer and / or do not contain information essential to the invention.

The expression "effective amount" means the amount of a medicament or pharmaceutically active ingredient that elicits a biological or medical response in an animal or human, for example in tissues, systems that are explored or required by a researcher or clinician.

In addition, the term “therapeutically effective amount” means an amount that causes one or more of the following effects in humans or mammals (relative to those subjects who have not received this amount): complaints of disease, syndrome, condition, pain , Improved treatment, healing, prevention or elimination of dysfunction or side effects or also reduction of disease, pain or further progress in disease, condition or dysfunction.

The term "therapeutically effective amount" also includes an amount effective to enhance normal physiological action.

The invention also relates to mixtures of compounds of the formula according to the invention, for example two diastereomers, for example 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: It relates to the use of mixtures in ratios of 10, 1: 100 or 1: 1000. This is particularly preferably a mixture of isomeric compounds.

The present invention relates to compounds of formula (I) and salts thereof and to processes for the preparation of compounds of formula (I) and their pharmaceutically usable derivatives, salts, solvates and stereoisomers according to the patent claims, which are preferably protic acids Or in the presence of Lewis acids such as, for example, trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium (III) triflate, scandium (III) triflate or cerium (IV) ammonium nitrate And reacting a compound of formula (II) with a compound of formula (III), a compound of formula (IV), a double bond isomer thereof (E isomer) or a mixture thereof, and for R ⁷ radicals other than H are optionally It is characterized by being incorporated:

,

,

[Wherein, R ¹ , R ² and R ³ have the meanings indicated above],

,

,

[Wherein, R ⁶ has the meaning indicated above],

,

,

[Wherein, R ⁴ and R ⁵ have the meanings indicated above.

The diastereomeric and enantiomeric mixtures of the compounds of formula (I), obtainable by the above-mentioned methods, can preferably be separated via chromatography or crystallization.

If required, the base and the acid of formula (I) obtained by the above process can be converted into their salts.

Above and below, the radicals R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X, Y, Q, R ^a , Z, W, m and n do not indicate otherwise As long as it has the meaning indicated in formula (I). If individual radicals appear multiple times in a compound, the radicals have the meanings indicated independently of each other.

A is alkyl, preferably unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A is preferably methyl, also ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, additionally 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, also preferably means trifluoromethyl, for example.

In particular A is 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 means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, in particular cyclopentyl.

R ¹ is preferably A, CF ₃ , OCF ₃ , SA, SCN, CH ₂ CN, -OCOA, Hal, SCF ₃ , and also preferably t-butyl, -CH (CH ₃ ) CH ₂ CH ₃ , iso Propyl, ethyl or methyl. In particular, R ¹ is t-butyl, isopropyl, ethyl, CF ₃ , methyl, Br, Cl, SCF ₃ , CH (CH ₃ ) CH ₂ CH ₃ , n-propyl, OCH ₃ , SCH ₃ , n-butyl, -Means SCN, CH ₂ CN. R ¹ particularly preferably means t-butyl, isopropyl, ethyl or CF ₃ .

R ² preferably means Hal, A or OA, in particular Br, cyclopropyl, OCH ₃ . Especially preferred are H or F.

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

In particularly preferred compounds of formula (I), R ² and R ³ simultaneously mean H. In a further preferred compound of formula I, one of the radicals R ² and R ³ means H and the other radical means F.

If R ⁵ means H, then R ⁴ Means preferably one of the following groups:

R ⁵ preferably represents H, or R ⁴ With one of the following:

[Wherein X, R and R ^a have the above meaning].

R ⁴ Particularly preferably together with R ⁵ means one of the following:

[Wherein R has the above meaning].

R ^a preferably means 1-piperazinyl, N-morpholinyl, NHR or NR ₂ .

If radicals and indices, for example n, appear more than once, the radicals and indices may have different meanings, independently of one another. N in the radical R ^a preferably means 2 or 0, and m preferably means 0.

R ⁶ preferably means phenyl, 2-, 3- or 4-pyridyl, pyrimidyl, furyl or thienyl, which are unsubstituted or Hal, CN, NO ₂ , OH, fCF ₃ , OCH (CF _{3, respectively)} ) ₂ , mono- or multiple substitutions by OCOCH ₃ or A. R ⁶ is preferably not a heteroaromatic radical. In particular, R ⁶ means one of the following groups:

[In the meal,

X means O, S or NR and in particular O or S, A has the above meaning, preferably methyl and Hal preferably F or Cl].

Also particularly preferred are compounds of formula I, wherein R ⁶ has one of the following meanings:

[Wherein R ⁷ preferably means H or A, in particular H].

Aryl preferably means phenyl, naphthyl or biphenyl, which is unsubstituted or Hal, A, OH, OA, NH ₂ , NO ₂ , CN, COOH, COOA, CONH ₂ , NHCOA, NHCONH ₂ , NHSO ₂ , respectively. Single, double or triple substituted with A, CHO, COA, SO ₂ NH ₂ , SO ₂ A, —CH ₂ —COOH or —OCH ₂ —COOH.

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-chloro Phenyl, 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-methylfe Nyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Heteroaryl is preferably mono- or unsubstituted or mono- or having one or more N, O and / or S atoms mono-, double- or triple substituted with Hal, A, NO ₂ , NHA, NA ₂ , OA, COOA or CN Bicyclic aromatic heterocycles.

Heteroaryls are particularly preferably monocyclic saturated with one N, S or O atom, which may be unsubstituted or mono-, double- or triple substituted with Hal, A, NHA, NA ₂ , NO ₂ , COOA or benzyl. Or aromatic heterocycle.

Regardless of further substitution, unsubstituted heteroaryl is, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5 Imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-triazazolyl, 2-, 4- or 5- Thiazolinyl, 3-, 4- or 5-isothiazolinyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, more preferably 1 , 2,3-triazol-1-,-4- or -5-yl, 1,2,4-triazol-1-,-3- or 5-yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazole-4- or -5-yl, 1,2,4-oxadiazole-3- or -5-yl, 1,3,4-thiadiazole-2- or -5- 1, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1- , 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7- Zoxazolyl, 3-, 4-, 5-, 6- or 7-benzoziazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolinyl, 2-, 4-, 5-, 6- or 7-benzisothiazolinyl, 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-shinoli Neyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H -Benzo-1,4-oxazinyl, and also preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazole -4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

Hal preferably means F, Cl or Br, also I, particularly preferably F or Cl.

Throughout the invention, all radicals which appear more than once may be the same or different, ie independent of each other.

Compounds of formula (I) have one or more chiral centers and therefore exist in various stereoisomeric forms. Formula I includes all such forms.

Particularly preferred compounds of formula I are the compounds of the sub-formulas of IA to ID:

[In the meal,

R, R ¹ , R ² , R ⁶ , R ⁷ and X have the above meanings,

R ⁸ Means H, CH ₂ OR, CH ₂ NR ₂ , CH ₂ R ^a , COR ^a ].

Particularly preferred compounds of formula (IA) are compounds of sub-formulas (IA1) to (IA4):

[Wherein, R, R ^a , R ¹ , R ² , R ³ , R ⁶ and R ⁷ have the above meanings].

In particularly preferred compounds of formula (IB), R ⁸ means H.

The radicals R ⁴ and R ⁵ are particularly preferably in the cis-position relative to each other. The radical R ⁶ is more preferably in the trans-position relative to the radical R ⁵ .

Preference is given here to other mixtures of compounds of the formula A or B and racemates or enantiomers thereof having the structure:

.

.

The present invention therefore relates in particular to compounds of formula (I) having at least one of said radicals having the above-mentioned preferred meanings. Some preferred groups of compounds are represented by the following sub-formulas I1-I45a:

.

.

In addition, the compounds of formula (I) and also starting materials for their preparation are described in, for example, standard operations such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart It is prepared as it is known as described, more particularly suitable for the above reactions, and is made under known reaction conditions. As is known variants may also be used here and are not mentioned in detail here.

If desired, starting materials can also be formed in situ, so that they are not separated from the reaction mixture, but are further converted directly to the compound of formula (I).

The reaction is generally carried out in an inert solvent, preferably a proton acid or a Lewis acid such as TFA, HFIP, bismuth (III) salt, ytterium (III) salt or CAN. Depending on the conditions used, the reaction time is between several minutes and 14 days, and the reaction temperature is between about 0 ° C and 180 ° C, usually between 0 ° C and 100 ° C, particularly preferably between 15 ° C and 35 ° C.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; Chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Nitriles such as acetonitrile; Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene, or mixtures of the above solvents.

Compounds of formula (I) in which R ⁷ has a meaning other than H are preferably prepared by alkylation or acylation from compounds of formula (I) in which R ⁷ is H.

If desired, functionally modified amino and / or hydroxyl groups in the compound of formula I may be isolated via solvolysis and hydrocracking in conventional manner. This can be done at temperatures between 0 and 100 ° C., for example using NaOH or KOH in water, water / THF or water / dioxane.

Reduction of esters to aldehydes or alcohols or reduction of nitriles to aldehydes or amines is carried out by methods known to those skilled in the art and by methods described by standard operations in organic chemistry.

The compounds according to the invention can be used in their final non-salt form. In contrast, the present invention also relates to the use of such compounds in the form of their pharmaceutically suitable salts, which can be derived from various organic and inorganic acids and bases through processes known in the art. Pharmaceutically acceptable salt forms of the compounds of formula (I) are prepared in the most conventional manner. If the compound of formula (I) comprises a carboxyl group, one of the suitable salts may be formed by reacting the compound with a suitable base to obtain 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 alkoxides such as potassium ethoxide and sodium propoxide; And various organic bases such as piperidine, diethanolamine and N-methylglutamine. Aluminum salts of the compounds of formula I are likewise included. In the case of certain compounds of formula (I), acid-addition salts may be used to prepare such compounds 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 such as sulfates, nitrates or phosphates, and alkyl- and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetates, trifluoroacetates, tarts It may be formed by reacting with latex, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Thus, pharmaceutically acceptable acid-addition salts of compounds of formula I include, but are not limited to: acetates, adipates, alginates, arginates, aspartates, benzoates, benzenesulfonates (vesil ), Bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, di Nitrobenzoate, dodecyl sulfate, ethanesulfonate, fumarate, galactate (from mucinic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemi Sulphate, heptanoate, hexanoate, hypoflate, hydrochloride, hydrobromide, Hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, Methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphate Phosphates, phthalates.

Basic 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. However, it is not limited thereto. Among the salts mentioned above, ammonium; Alkali metal salts sodium and potassium, and alkaline earth metal salts calcium and magnesium are preferred. Salts of the compounds of formula I, derived from pharmaceutically acceptable organic non-toxic bases, include primary, secondary and tertiary amines, substituted amines, as well as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzatin), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucoseamine, histidine, hydravamin, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris (hydroxymethyl) methyl Amines (trometamines) Including but not limited to.

Compounds of the present invention comprising basic nitrogen-containing groups include (C ₁ -C ₄ ) -alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C ₁ -C ₄ ) alkyl sulfates such as dimethyl, diethyl and diamyl sulfates; (C ₁₀ -C ₁₈ ) alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; And aryl- (C ₁ -C ₄ ) alkyl halides such as benzyl chloride and phenethyl bromide, and may be quaternized. Water soluble and fat soluble compounds according to the invention can be prepared using such salts.

Preferred pharmaceutical salts mentioned above are preferably acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hypofulate, hydrochloride, hydrobromide, isethionate, mandelate, Including but not limited to meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and trometamine Does not.

Acid-addition salts of basic compounds of formula (I) are prepared by contacting a sufficient amount of the required acid with the free base to form the salt in a conventional manner. The free base can be contacted with the base to form the salt and regenerated by separating the free base in conventional manner. The free base form is somewhat different from the corresponding salt in which certain physical properties, such as solubility in polar solvents, correspond, for the purposes of the invention, otherwise the salt corresponds to the corresponding free base form.

As noted above, pharmaceutically acceptable base-addition salts of compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

Base-addition salts of acidic compounds according to the invention are prepared by contacting the free acid form with a sufficient amount of the required base to form a salt in a conventional manner. The free acid can contact the salt form with the acid and separate and regenerate the free acid in a conventional manner. The free acid form is somewhat different from its corresponding salts in that certain physical properties, such as solubility in polar solvents, are for the purposes of the invention otherwise the salt corresponds to the corresponding free acid form.

If the compounds according to the invention comprise one or more groups capable of forming pharmaceutically acceptable salts of this type, the invention also encompasses multiple salts. Typical multisalt forms include, but are not limited to, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium, and trihydrochloride.

In connection with the foregoing, the term “pharmaceutically acceptable salts” in this context means that the compound of Formula I is in the form of one of its salts, in particular in the free form of the active ingredient or any other salt form of the active ingredient previously used. It can be considered to mean an active ingredient which contains a salt form which imparts improved pharmacokinetic properties to the active ingredient in comparison with. In addition, the pharmaceutically acceptable salt form of the active ingredient, for the first time, has the active pharmacokinetic properties of the active ingredient, which has not previously been used and may have a positive effect on the pharmacodynamics of the active ingredient with respect to therapeutic efficacy in vivo. To provide.

The present invention further relates to a medicament containing at least one compound of formula (I) and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, and mixtures of any proportion thereof and any excipients and / or auxiliaries. have.

The pharmaceutical preparations can be administered in the form of dosage units comprising a predetermined amount of active ingredient per dosage unit. Such units are, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg, depending on the condition to be treated, the method of administration, and the age, weight, and condition of the patient. Or a pharmaceutical formulation may be administered in the form of a dosage unit comprising a predetermined amount of active ingredient per dosage unit. Preferred dosage unit dosage forms are those comprising the daily dosage or partial-dose indicated above, or the active ingredient thereof. In addition, pharmaceutical formulations of this type can be prepared using methods generally known in the pharmaceutical art.

The pharmaceutical formulation may be any, for example, oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, venous or skin layers). It can be adapted to administration through the required method of. Such formulations may be prepared by any method known in the art of pharmacy, for example, by combining the active ingredient with excipient (s) or adjuvant (s).

Pharmaceutical formulations adapted for oral administration include, for example, capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; Edible foams or foam foods; Or in separate units such as a water-in-oil liquid emulsion or an oil-in-water liquid emulsion.

Thus, for oral administration, for example in the form of tablets or capsules, the active ingredient elements can be combined with oral, non-toxic and pharmaceutically suitable inert excipients such as, for example, ethanol, glycerol, water and the like. Powders are prepared by grinding the compound to a suitable fine size and mixing it with a similar excipient such as, for example, edible carbohydrates such as starch or mannitol. Fragrances, preservatives, dispersants and pigments may be similarly present.

Capsules are produced by preparing a powder mixture as described above and filling the molded gelatin sheath. For example, solid forms of fluidizing agents and lubricants such as highly dispersed salicylic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol can be added to the powder mixture prior to the filling process. For example, disintegrants or solubilizers such as agar-agar, calcium carbonate or sodium carbonate may be similarly added to improve the availability of the medicament after taking the capsule.

In addition, suitable binders, lubricants and disintegrants as well as pigments, if desired or necessary, can similarly be incorporated into the mixture. Suitable binders are starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic rubbers such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, wax And the like. Lubricants used in such dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated by, for example, preparing a powder mixture, granulating or drying the mixture by adding presses, lubricants and disintegrants, and pressing the entire mixture to make tablets. The compound ground in a suitable manner as described above is mixed with a diluent or base and optionally a binder such as, for example, carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone, an antidegradant such as, for example, paraffin, Powder mixtures are prepared by mixing absorption accelerators, such as quaternary salts and / or absorbents such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture may be wetted with a binder such as syrup, starch paste, acacia gum paste or a solution of cellulose or polymeric material, and pressed through a sieve to granulate. As an alternative to granulation, the powder mixture may be passed through a tablet which breaks into granules and then breaks into granules. Stearic acid, stearate salts, talc or mineral oils can be added to the granules to lubricate them so that they do not stick to the tablet mold. The lubricated mixture is then pressed to provide tablets. The compounds according to the invention can also be combined with free-flowing inert excipients and then pressed directly without granulation or dry-pressing steps to provide tablets. There may be a transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymeric material and a gloss layer of wax. Pigments may be added to these coatings to distinguish between different dosage units.

Oral liquids such as, for example, solutions, syrups, and elixirs are prepared in the form of dosage units such that a given amount may contain the above amounts of a compound. Syrups can be prepared by dissolving the compound with a suitable fragrance in an aqueous solution, while elixirs can be prepared using non-toxic alcoholic vehicles. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as, for example, ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners, may similarly be added. have.

Dosage unit dosage forms for oral administration may be encapsulated in microcapsules if desired. The formulations may also be prepared by prolonging or delaying the release, for example by coating or embedding particulate material into polymers, waxes and the like.

The compounds of formula (I) and salts, solvates and their physiologically functional derivatives can also be administered in the form of liposome delivery systems such as small single membrane vesicles, large single membrane vesicles and multimembrane vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholine.

The compounds of formula (I) and their salts, solvates and physiologically functional derivatives can also be delivered using the monoclonal antibodies coupled with the compound molecules as individual carriers. The compound may also be coupled with the soluble polymer as the target pharmaceutical carrier. Such polymers may include polyethylene oxide polylysine, polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidophenols or polyhydroxyethylaspartamidophenols substituted with palmitoyl radicals. The compound is also a biodegradable polymer suitable for achieving controlled release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanos It can be coupled with an acrylate and crosslinked hydrogel or an amphiphilic block copolymer of hydrogel.

Pharmaceutical formulations adapted for transdermal administration may be administered in independent plaster for extended, close contact with the epithelium of the patient. Thus, for example, the active ingredient can be delivered from a plaster via iontophoresis, which is described in general terms in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissues, for example mouth and skin, the formulation is preferably applied as a topical ointment or cream. In the case of formulation for ointment, the active ingredient may be used with a paraffinic or water-mixable cream base.

Alternatively, the active ingredient may be formulated to provide a cream with a water-in-oil cream base or an oil-in-water base.

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

Pharmaceutical formulations adapted for topical application to the mouth include lozenge tablets, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration may be administered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in which the carrier material is a solid, including, for example, a coarse powder having a particle size in the range of 20-500 microns, are inhaled, ie, in a container containing the powder. As soon as it is nearby, it is rapidly inhaled through the nasal passages Suitable formulations for nasal sprays or nasal drops with liquids as carrier materials include the active ingredient in water or oils.

Pharmaceutical formulations adapted for inhalation administration include fine particulate dusts or mists, which can be produced by pressurized dispensers with various types of aerosols, nebulizers or blowers.

Pharmaceutical formulations adapted for vaginal administration may be administered in vaginal suppositories, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions comprising antioxidants, buffers, bactericides and solutes achieved by bringing the formulation into isotonic fluid with the blood of the patient to be treated; And aqueous and non-aqueous sterile suspensions which may include suspending media and thickeners. The formulations may be administered in single-dose or multidose containers, for example sealed ampoules and vials, stored in a freeze-dried (lyophilised) state, for example, only for sterile carrier liquids, for injection purposes. It is necessary to add water just before use.

Injection solutions and suspensions prepared according to the preparation can be prepared as sterile powders, granules and tablets.

Naturally, in addition to the above-mentioned constructs, the formulation may also include other agents conventional in the art for a particular type of formulation; Thus, for example, formulations suitable for oral administration may include perfumes.

The therapeutically effective amount of a compound of formula (I) depends on a number of factors including, for example, the age and weight of the animal, the exact condition and severity thereof requiring treatment, the nature of the formulation and the method of administration, and ultimately the treatment It is determined by the doctor or veterinarian. However, the effective amount of a compound according to the invention for the treatment of tumor growth, for example colon or breast carcinoma, is generally in the range of 0.1 to 100 mg per kg of patient (mammal) body weight per day, especially usually body weight per day It is in the range of 1 to 10 mg per kg. Thus, the actual amount per day for adult mammals weighing 70 kg is mainly between 70 and 700 mg, which amount is a single dose per day or a series of partial doses per day (eg 2, 3, 4, 5 or 6). ), The total daily dose may be administered to be the same. The effective amount of the salt or solvate or physiologically functional derivative thereof can be determined essentially by the fraction itself of the effective amount of the compound according to the invention. Similar dosages can be assumed to be suitable for the treatment of other conditions described above.

The present invention additionally contains a medicament containing at least one compound of formula (I) and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, and mixtures thereof in all proportions and containing at least one additional pharmaceutically active ingredient Related to

The invention also relates to a set (kit) of the following separate packs:

(a) an effective amount of a compound of formula (I) and / or pharmaceutically usable derivatives, solvates and stereoisomers, and mixtures thereof in all ratios, and

(b) an effective amount of an additional pharmaceutical active ingredient.

This set includes suitable containers such as boxes, individual bottles, bags or ampoules. This set includes, for example, isolated ampoules and dissolved or frozen, containing an effective amount of a compound of Formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, and mixtures of all proportions thereof, respectively, It may comprise an effective amount of additional pharmaceutical active ingredient in dried form.

Agents from Table 1 are preferably, but not exclusively, combined with compounds of formula (I). Combinations of the agents of Formula I and Table 1 may also be combined with compounds of Formula V.

Compounds of formula (I) are preferably used in combination with known anticancer agents:

The compound is also suitable for use with known anticancer agents. Such known anticancer agents include:

Estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors and other angiogenesis inhibitors . It is particularly suitable that the compound is administered simultaneously with radiation therapy. The synergistic effect of VEGF inhibition in combination with radiation therapy is known by experts (see WO 00/61186).

"Estrogen receptor modulator" refers to a compound that interferes with or inhibits the binding of estrogens to a receptor regardless of the mechanism. Examples of estrogen receptor modulators are 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'-dihydroxybenzo Phenone-2,4-dinitrophenylhydrazone and SH646.

"Androgen receptor modulator" refers to compounds that interfere with or inhibit the binding of androgens to receptors regardless of their mechanism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarosol and abiraterone acetate.

"Retinoid receptor modulator" refers to a compound that prevents or inhibits the binding of a retinoid to a receptor regardless of its mechanism. Examples of such retinoid receptor modulators are bexarotin, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N- (4'-hydroxy Phenyl) retinamide and N-4-carboxyphenylretinamide.

"Cytotoxic agents" mainly act directly on cellular functions or inhibit cell interference by inhibiting or interfering cell death, including alkylating agents, tumor necrosis factors, intercalants, microtubulin inhibitors and topoisomerases. Refers to the compound causing.

Examples of cytotoxic agents include tyrapazin, certene, cactin, ifosfamide, tasornermine, ronidamine, carboplatin, altretamine, prednismustine, dibromodulcitol, lanimustine , Fortemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, esturamustine, impprosulfane tosylate, trophosphamide, nimusstin, dibrospidium chloride, fumitepa, lovaplatin, satrapule Latin, Propyromycin, Cisplatin, Irofulbene, Dexyphosphamide, Cis-aminedichloro (2-methylpyridine) platinum, Benzylguanine, Gluphosphamide, GPX100, (trans, trans, trans) bis-mu- ( Hexane-1,6-diamine) mu- [diamineplatinum (II)] bis [diamine (chloro) platinum (II)] tetrachloride, diazidinylspermine, arsenic trioxide, 1- (11-dodecylamino -10-hydroxyundecyl) -3,7-dimethylxanthine, zorubicin, idaru Bicine, daunorubicin, bisantrene, mitoxantrone, pyrarubicin, pinafide, valerubicin, amrubicin, antineoplaston, 3'-de-amino-3'-morpholino-13-deoxo -10-hydroxycarminomycin, anamycin, galarubicin, elinapide, MEN10755 and 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyldaunorubicin (WO # 00/50032 Note), but is not limited thereto.

Examples of microtubulin inhibitors are paclitaxel, vindesine sulfate, 3 ', 4'-didehydro-4'-deoxy-8'-norvinkalleukoblastin, docetaxol, lioxin, dolastatin, mibobulin isetio Nate, Auristatin, Semadotin, RPR109881, BMS184476, Vinfluin, Cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzene Sulfonamides, vinblastine anhydride, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-prolyl-t-butylamide, TDX258 and BMS188797 do.

Some examples of topoisomerase inhibitors are Topotecan, Hicaptamine, Irinotecan, Rubitane, 6-Ethoxypropionyl-3 ', 4'-0-exobenzylidenecartleucine, 9-methoxy-N, N -Dimethyl-5-nitropyrazolo [3,4,5-kl] acridin-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] indolinino [1,2b] quinoline-10,13 (9H, 15H) dione, ruru Totecan, 7- [2- (N-isopropylamino) ethyl]-(20S) -camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sopoic acid, 2'-dimethyl Amino-2'-deoxyetoposide, 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-hexhydrofuro (3 ', 4': 6,7) Proto (2,3-d) -1,3-dioxol-6-one, 2,3- (methylenedioxy) -5-methyl-7-hydroxy-8-methoxybenzo [c] phenanthridinium , 6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline-5,10-dione, 5- (3-aminopropylamino) -7,10-dihydroxy-2- (2 -Hydroxyethylaminomethyl) -6H-pyrazolo [4,5,1-de] acridin-6-one, N- [1- [2 (diethylamino) ethylamino-7-methoxy-9 -Oxo-9H-thioxazanten-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.

"Anti-proliferative agents" include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 and anti-metabolites such as enositabine, camofur, tegapur, pentostatin, doxyfluidine, tri Metrexate, fludarabine, capexitabine, galoxitabine, cytarabine oxphosphate, postavin sodium hydrate, raltitrexed, paltitrexide, emitepur, thiazopurin, decitabine, nolatrexed, Pemetrexed, nerzarabine, 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] glycidylamino ] -L-glycero-BL-mannoheptopyranosyl] adenine, aplidine, ectocysidine, 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-form Mil-6-methoxy-14-oxa-1,11-diazatetracyclo- (7.4.1.0.0) tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lome Trexol, dexrazoic acid, methionase, 2'-cyano-2'-deoxy-N4-palmitoyl-1-BD-arabinofuranosyl cytosine and 3-aminopyridine-2-carboxaldehyde thiosemi Carbazone. "Anti-proliferative agents" also include monoclonal antibodies to growth factors such as trastuzumab, and tumor suppressor genes, such as p53, other than those listed under "Angiogenesis Inhibitors", which are recombinant virus-mediated genes. It may be delivered via transport (see, eg, US Pat. No. 6,069,134).

Particular preference is given to the use of the compounds according to the invention for the treatment and prevention of tumor diseases.

Tumors are preferably selected from the group of squamous, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, urinary system, lymphatic system, stomach, larynx and / or lung tumors.

In addition, the tumor is preferably selected from the group of lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma, colon carcinoma and breast carcinoma.

Also preferred is the use for the treatment of tumors of the blood and immune system, preferably for the treatment of tumors selected from the group of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and / or chronic lymphocytic leukemia.

The invention also includes a method of treatment wherein the following is administered to a patient having a neotumor such as cancer:

a) at least one compound of formula (I); And

b) at least one compound of formula V or acid-addition salts thereof, in particular hydrochloride:

[Wherein, Y ′ and Z ′ each independently represent O or N, and R ⁶ and R ⁷ each independently of each other, H, OH, halogen, OC 1-10 -alkyl , OCF ₃ , NO ₂ or NH ₂ , n means an integer between 2 and 6, and R ⁸ and R ⁹ are each independently of one another, preferably in a meta- or para-position Selected from the following groups:

],

],

At this time, the first and second compounds are administered in amounts sufficient to inhibit the growth of neoplastic tumors simultaneously or within 14 days relative to each other.

Combination of a compound of formula (I) with a compound of formula (V) and other pentamidine homologues results in synergistic activity in the inhibition of neotumor production. Combinations containing compounds of formula V are mentioned, for example, in WO 02058684.

The mechanism of activity of pentamidine or its derivatives has not been described in detail at present, but as it reduces the synthesis of DNA, RNA and proteins, pentamidine or its derivatives appear to have pleiotropic activity. Recently, pentamidine is a competent inhibitor of PRL1, -2 and 3 phosphatase (Pathak et al., 2002) and tyrosine phosphatase, and its overexpression has been described as being associated with neoplastic tumors in humans. On the other hand, it has been described that pentamidine can bind to the minor groove of DNA (Puckowska et al., 2004) and exert its activity through disruption of gene expression and / or DNA synthesis.

The attached experiment shows:

Pentamidine and also compounds of formula I both maintain cells in G2 / M during the cell cycle.

The combination of pentamidine and the compound of formula (I) has additional to synergistic activity for cell proliferation.

Other suitable pentamidine homologs include stilbamidine (G-1) and hydroxystilbamidine (G-2) and indole homologues thereof (eg G-3):

.

.

Each amidine unit is the R ⁸ and R ¹¹ It may be replaced independently of each other by one of the units defined for. In the case of benzimidazole and pentamidine, stilbamidine, salts of hydroxystilbamidine and indole derivatives are also suitable for the process according to the invention. Preferred salts include, for example, dihydrochloride and methane-sulfonate salts.

However, other homologues belong to the formulas provided in U.S. Pat. will be.

Exemplary homologs include: 1,5-bis (4 '-(N-hydroxyamidino) phenoxy) pentane, 1,3-bis (4'-(N-hydroxyamidino) phenoxy) Propane, 1,3-bis (2'-methoxy-4 '-(N-hydroxyamidino) phenoxy) propane, 1,4-bis (4'-(N-hydroxyamidino) phenoxy) Butane, 1,5-bis (4 '-(N-hydroxyamidino) phenoxy) pentane, 1,4-bis (4'-(N-hydroxyamidino) phenoxy) butane, 1,3- Bis (4 '-(4-hydroxyamidino) phenoxy) propane, 1,3-bis (2'-methoxy-4'-(N-hydroxyamidino) phenoxy) propane, 2,5- Bis [4-amidinophenyl] furan, 2,5-bis [4-amidinophenyl] furan bisamide oxime, 2,5-bis [4-amidinophenyl] furan bis-O-methylamide oxime, 2, 5-bis [4-amidinophenyl] furan bis-O-ethylamide oxime, 2,8-diimidinodibenzothiophene, 2,8-bis (N-isopropylamidino) carbazole, 2,8- Bis (N-hydroxyamidino) carbazole, 2,8-bis (2-di Dazolinyl) dibenzothiophene, 2,8-bis (2-imidazolinyl) -5,5-dioxodibenzothiophene, 3,7-diimidinodibenzothiophene, 3,7-bis (N-isopropylamidino) dibenzothiophene, 3,7-bis (N-hydroxyamidino) dibenzothiophene, 3,7-diaminodibenzothiophene, 3,7-dibromodibenzo Thiophene, 3,7-dicyanodibenzothiophene, 2,8-diimidinodibenzofuran, 2,8-di- (2-imidazolinyl) dibenzofuran, 2,8-di- (N Isopropylamidino) dibenzofuran, 2,8-di- (N-hydroxyamidino) dibenzofuran, 3,7-di- (2-imidazolinyl) dibenzofuran, 3,7- Di- (isopropylamidino) dibenzofuran, 3,7-di- (A-hydroxyamidino) dibenzofuran, 2,8-dicyanodibenzofuran, 4,4'-dibromo-2 , 2'-dinitrobiphenyl, 2-methoxy-2'-nitro-4,4'-dibromobiphenyl, 2-methoxy-2'-amino-4,4'-dibromobiphenyl, 3 , 7-dibromodibenzofuran, 3,7-dicyanodibenzofuran, 2,5-bis (5-amidino-2- Benzimidazolyl) pyrrole, 2,5-bis [5- (2-imidazolinyl) -2-benzimidazolyl] pyrrole, 2,6-bis [5- (2-imidazolinyl)- 2-benzimidazolyl] pyridine, 1-methyl-2,5-bis (5-amidino-2-benzimidazolyl) pyrrole, 1-methyl-2,5-bis [5- (2-imida Zolyl) -2-benzimidazolyl] pyrrole, 1-methyl-2,5-bis [5- (1,4,5,6-tetrahydro-2-pyrimidinyl) -2-benzimidazolyl] Pyrrole, 2,6-bis (5-amidino-2-benzimidazolyl) pyridine, 2,6-bis [5- (1,4,5,6-tetrahydro-2-pyrimidinyl) -2 -Benzimidazolyl] pyridine, 2,5-bis (5-amidino-2-benzimidazolyl) furan, 2,5-bis [5- (2-imidazolinyl) -2-benzimida Zolyl] furan, 2,5-bis (5-N-isopropylamidino-2-benzimidazolyl) furan, 2,5-bis (4-guanylphenyl) furan, 2,5-bis (4- Guanylphenyl) -3,4-dimethylfuran, 2,5-di-p- [2- (3,4,5,6-tetrahydropyrimidyl) phenyl] furan, 2,5-bis [4- ( 2-imidazolinyl) phenyl] furan, 2,5- [bis {4- (2- Tetrahydropyrimidinyl)} phenyl] p- (tolyloxy) furan, 2,5- [bis {4- (2-imidazolinyl)} phenyl] -3-p- (tolyloxy) furan, 2, 5-bis {4- [5- (N-2-aminoethylamido) benzimidazol-2-yl] phenyl} furan, 2,5-bis [4- (3a, 4,5,6,7, 7a-hexahydro-1H-benzimidazol-2-yl) phenyl] furan, 2,5-bis [4- (4,5,6,7-tetrahydro-1H-1,3-diazepine-2- 1) phenyl] furan, 2,5-bis (4-N, N-dimethylcarboxhydrazidophenyl) furan, 2,5-bis {4- [2- (N-2-hydroxyethyl) imida Zolinyl] phenyl} furan, 2,5-bis [4- (N-isopropylamidino) phenyl] furan, 2,5-bis {4- [3- (dimethylaminopropyl) amidino] phenyl} furan, 2,5-bis {4- [N- (3-aminopropyl) amidino] phenyl} furan, 2,5-bis [2- (imidazolinyl) phenyl] -3,4-bis (methoxymethyl ) Furan, 2,5-bis [4-N- (dimethylaminoethyl) guanyl] phenylfuran, 2,5-bis {4-[(N-2-hydroxyethyl) guanyl] phenyl} furan, 2 , 5-bis [4-N- (cyclopropylguanyl ) Phenyl] furan, 2,5-bis [4- (N, N-diethylaminopropyl) guanyl] phenylfuran, 2,5-bis {4- [2- (N-ethylimidazolinyl)] Phenyl} furan, 2,5-bis {4- [N- (3-pentylguanyl)]} phenylfuran, 2,5-bis [4- (2-imidazolinyl) phenyl] -3-methoxy Furan, 2,5-bis [4- (N-isopropylamidino) phenyl] -3-methylfuran, bis [5-amidino-2-benzimidazolyl] methane, bis [5- (2-imi Dazolyl) -2-benzimidazolyl] methane, 1,2-bis [5-amidino-2-benzimidazolyl] ethane, 1,2-bis [5- (2-imidazolyl) -2 -Benzimidazolyl] ethane, 1,3-bis [5-amidino-2-benzimidazolyl] propane, 1,3-bis [5- (2-imidazolyl) -2-benzimidazolyl ] Propane, 1,4-bis [5-amidino-2-benzimidazolyl] propane, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -butane, 1 , 8-bis [5-amidino-2-benzimidazolyl] octane, trans-1,2-bis [5-amidino-2-benzimidazolyl] ethene, 1,4-bis [5- ( 2-imidazolyl) -2-benzimidazole Aryl] -1-butene, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -2-butene, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -1-methylbutane, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -2-ethylbutane, 1,4-bis [5 -(2-imidazolyl) -2-benzimidazolyl] -1-methyl-1-butene, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -2 , 3-diethyl-2-butene, 1,4-bis [5- (2-imidazolyl) -2-benzimidazolyl] -1,3-butadiene, 1,4-bis [5- (2 -Imidazolyl) -2-benzimidazolyl] -2-methyl-1,3-butadiene, bis [5- (2-pyrimidyl) -2-benzimidazolyl] methane, 1,2-bis [ 5- (2-pyrimidyl) -2-benzimidazolyl] ethane, 1,3-bis [5-amidino-2-benzimidazolyl] propane, 1,3-bis [5- (2-pyri Midyl) -2-benzimidazolyl] propane, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] butane, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -1-butene, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -2-butene, 1,4-bis [ 5- (2-pyrimidyl) -2-benzimidazolyl] -1-methylbutane, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -2-ethylbutane, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -1-methyl-1-butene, 1,4-bis [5- (2-pyrimidyl) -2-benzimi Dazolyl] -2,3-diethyl-2-butene, 1,4-bis [5- (2-pyrimidyl) -2-benzimidazolyl] -1,3-butadiene and 1,4-bis [ 5- (2-pyrimidyl) -2-benzimidazolyl] -2-methyl-1,3-butadiene, 2,4-bis (4-guanylphenyl) pyrimidine, 2,4-bis (4- Imidazolin-2-yl) pyrimidine, 2,4-bis [(tetrahydropyrimidinyl-2-yl) phenyl] pyrimidine, 2- (4- [Ni-propylguanyl] phenyl) -4- (2-methoxy-4- [Ni-propylguanyl] phenyl) pyrimidine, 4- (N-cyclopentylamidino) -1,2-phenylenediamine, 2,5-bis [2- (5- Amidino) benzimidazolyl] furan, 2,5-bis [2- {5- (2-imidazolino)} benzimidazolyl] furan, 2,5-bis [2- (5-N- Isopropylamidino) benzimidazolyl] furan, 2,5-bis [2- (5-N-cysteine Lopentylamidino) benzimidazolyl] furan, 2,5-bis [2- (5-amidino) benzimidazolyl] pyrrole, 2,5-bis [2- {5- (2-imidazoli No)} benzimidazolyl] pyrrole, 2,5-bis [2- (5-N-isopropylamidino) benzimidazolyl] pyrrole, 2,5-bis [2- (5-N-cyclopentyl Amidino) benzimidazolyl] pyrrole, 1-methyl-2,5-bis [2- (5-amidino) benzimidazolyl] pyrrole, 2,5-bis [2- {5- (2-imi Dazolino)} benzimidazolyl] -1-methylpyrrole, 2,5-bis [2- (5-N-cyclopentylamidino) benzimidazolyl] -1-methylpyrrole, 2,5-bis [2- (5-N-isopropylamidino) benzimidazolyl] thiophene, 2,6-bis [2- {5- (2-imidazolino)} benzimidazolyl] pyridine, 2, 6-bis [2- (5-amidino) benzimidazolyl] pyridine, 4,4'-bis [2- (5-N-isopropylamidino) benzimidazolyl] -1,2-diphenyl Ethane, 4,4'-bis [2- (5-N-cyclopentylamidino) benzimidazolyl] -2,5-diphenylfuran, 2,5-bis [2- (5-amidino) bene Zimidazolyl] benzo [b] furan, 2,5-bis [2- (5-N-cyclopentylamidino) benzimidazolyl] benzo [b] furan, 2,7-bis [2- (5 -N-isopropylamidino) benzimidazolyl] florin, 2,5-bis [4- (3- (N-morpholinopropyl) carbamoyl) phenyl] furan, 2,5-bis [4- (2-N, N-dimethylaminoethylcarbamoyl) phenyl] furan, 2,5-bis [4- (3-N, N-dimethylaminopropylcarbamoyl) phenyl] furan, 2,5-bis [ 4- (3-N-methyl-3-N-phenylaminopropylcarbamoyl) phenyl] furan, 2,5-bis [4- (3-N, N8, N11-trimethylaminopropylcarbamoyl) phenyl] Furan, 2,5-bis [3-amidinophenyl] furan, 2,5-bis [3- (N-isopropylamidino) amidinophenyl] furan, 2,5-bis [3-[(N- (2-dimethylaminoethyl) amidino] phenylfuran, 2,5-bis [4- (N-2,2,2-trichloroethoxycarbonyl) amidinophenyl] furan, 2,5-bis [4 -(N-thioethylcarbonyl) amidinophenyl] furan, 2,5-bis [4- (N-benzyloxycarbonyl) amidinophenyl] Column, 2,5-bis [4- (N-phenoxycarbonyl) amidinophenyl] furan, 2,5-bis [4- (N- (4-fluoro) phenoxycarbonyl) amidinophenyl] Furan, 2,5-bis [4- (N- (4-methoxy) phenoxycarbonyl) amidinophenyl] furan, 2,5-bis [4- (1-acetoxyethoxycarbonyl) amidino Phenyl] furan and 2,5-bis [4- (N- (3-fluoro) phenoxycarbonyl) amidinophenyl] furan. Methods for the preparation of one of these compounds are described in U.S. Pat.

Pentamidine metabolites are similarly suitable for antiproliferative combinations according to the invention. Pentamidine is rapidly metabolized into seven or more primary metabolites in the body. Some of these metabolites have one or more activities in common with pentamidine. Pentamidine metabolites have antiproliferative activity when combined with benzimidazole or its analogs.

Seven pentamidine homologues are shown below:

The combination according to the invention of the compounds of the formulas (I) and (V) or their analogs and metabolites thereof is suitable for the treatment of neoplastic tumors. Combination therapy may be performed alone or in combination with other therapies (eg, surgery, radiation, chemotherapy, biological therapy). In addition, prophylactic treatment may be performed to suppress or delay the formation of neoplastic tumors in people at greater risk of neoplastic tumor development (eg, those with genetic propensity or previously had neoplastic tumors). Can be.

The present invention similarly relates to the combination of the kinesin ATPase Eg5 / KSP with a compound of formula (V), pentamidine, its analogs and / or metabolites thereof.

The dosage and frequency of administration of each compound in combination can be adjusted independently. For example, one compound may be administered orally three times a day, wherein the second compound may be administered intramuscularly once a day. The compounds may also be formulated together to administer both compounds.

Antiproliferative combinations according to the invention may also be provided as a component of a pharmaceutical package. The two agents can be formulated together or separately in separate dosages.

In another aspect, the invention includes a method of treating a patient with a neoplastic tumor, such as cancer, by administering a compound of Formulas I and V in combination with an antiproliferative agent. Suitable antiproliferatives include those provided in Table 1.

All temperatures above and below are expressed in degrees Celsius. In the examples which follow, "normal finishing" means: if necessary, water is added, if necessary, the pH is adjusted to a value between 2 and 10, depending on the composition of the final product, and the mixture is ethyl acetate or Extract with dichloromethane, separate phases, dry organic phase with sodium sulfate, evaporate and purify product via chromatography on silica gel and / or through crystallization. Rf value on silica gel; Eluent: ethyl acetate / methanol 9: 1.

Mass spectrometry (MS): EI (electron impact ionization) M ⁺

FAB (High-Speed Atomic Impact Method) (M + H) ⁺

ESI (electrospray ionization) (M + H) ⁺

Atmospheric Pressure Chemical Ionization-Mass Spectrometer (APCI-MS) ⁺

Example  One

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

A solution of the TFA salt of 4- tert - butylaniline in acetonitrile (4- tert - butylaniline (0.50 g, 3.35 mmol)) was added to acetonitrile (4 ml), cooled to 0 ° C. and stirred with TFA (0.38 g, 3.35 mmol) was slowly added) 3-hydroxybenzaldehyde (0.41 g, 3.35 mmol) and 3,4-dihydro-2H-pyran (0.28 g) in acetonitrile (2 ml), cooled to 0 ° C. , 3.35 mmol) was added rapidly and the mixture was stirred at this temperature for 60 minutes. The reaction solution was evaporated to dryness and separated by column chromatography to give a colorless solid (620 mg, 1.84 mmol, 55%), which is an isomeric mixture in which the racemic trans / cis compound was 13: 1. Was found to be.

To separate the cis / trans isomer, the solid was placed in 0.1 N HCl in isopropanol (20 ml), 100 ml each of diethyl ether and cyclohexene were added and the mixture was crystallized at 4 ° C. overnight. The colorless solid was filtered off, washed with a small amount of diethyl ether and dried to give 570 mg (1.52 mmol) of the colorless compound rac-1 hydrochloride. The mother liquor was evaporated in a rotary evaporator until dry and the cis isomer was purified by column chromatography and converted to hydrochloride (70 mg mg, colorless solid of 0.19 mmol).

Relatively small amounts of rac-1 and rac-2 were separated into the corresponding enantiomers via chiral HPLC (2 × Chiralpak AD 20 μm, eluent: methanol) and converted back to hydrochloride.

b. Reaction in the presence of hexafluoroisopropanol (HFIP)

In order to obtain higher yields of cis isomers, hexafluoroisopropanol (HFIP) was used instead of TFA.

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) were acetonitrile (1 ml), HFIP (0.56 g, 3.35 mmol) was added dropwise at room temperature and the mixture was stirred for an additional 60 minutes at room temperature and 18 hours at room temperature. The reaction solution was evaporated to dryness and separated by column chromatography to give a colorless solid (485 mg, 1.44 mmol, 43%), which isomer wasomer of the racemic trans / cis compound in a 1: 1.6 ratio. It was found to be a mixture.

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

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

3-hydroxybenzaldehyde (0.41 g, 3.35 mmol) and 4- tert - butylaniline (0.50 g, 3.35 mmol) dissolved in acetonitrile (1 ml), respectively, were dissolved in BiCl ₃ (2 ml) in acetonitrile (2 ml) at room temperature. 0.21 g, 0.67 mmol) and anhydrous sodium sulfate (0.40 g) were added and the mixture was stirred for 10 minutes at room temperature. 3,4-Dihydro-2H-pyran (0.28 g, 3.35 mmol) was then added dropwise at room temperature and the mixture was stirred for an additional 30 minutes. The reaction solution was filtered through celite and evaporated until the filtrate was dried and purified via column chromatography to give a colorless solid (850 mg, 2.51 mmol, 75%), which racemic The trans / cis compound was found to be an isomer mixture in a 1: 1.1 ratio.

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

d. Reaction in the presence of ytterbium (III) triflate

3-hydroxybenzaldehyde (0.41 g, 3.35 mmol) and 4- tert - butylaniline (0.50 g, 3.35 mmol) dissolved in acetonitrile (1 ml), respectively, were added to Yb (OTf) in acetonitrile (2 ml) at room temperature. ) ₃ (0.42 g, 0.67 mmol) and anhydrous sodium sulfate (0.40 g) were added and the mixture was stirred for 10 minutes at room temperature. 3,4-Di hydro-2H-pyran (0.28 g, 3.35 mmol) was then added dropwise at room temperature and the mixture was stirred for an additional 30 minutes. The reaction solution was filtered through celite, evaporated until the filtrate was dried and purified by column chromatography to give a colorless solid (780 mg, 2.31 mmol, 69%), which was the racemic The trans / cis compound was found to be an isomer mixture in a 1: 1.3 ratio.

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

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

3-hydroxybenzaldehyde (0.41 g, 3.35 mmol) and 4- tert - butylaniline (0.50 g, 3.35 mmol) dissolved in acetonitrile (1 ml) respectively, Sc (OTf) in acetonitrile (2 ml) at room temperature ) ₃ (0.33 g, 0.67 mmol) and anhydrous sodium sulfate (0.40 g) were added and the mixture was stirred for 10 minutes at room temperature. 3,4-Dihydro-2H-pyran (0.28 g, 3.35 mmol) was then added dropwise at room temperature and the mixture was stirred for an additional 30 minutes. The reaction solution was filtered through celite and evaporated until the filtrate was dried and purified by column chromatography to give a colorless solid (620 mg, 1.84 mmol, 55%), which was the racemic It was found to be an isomeric mixture of trans / cis compounds.

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

f. Reaction in the presence of cerium (IV) ammonium nitrate (CAN)

CAN (0.37 g, 0.67 mmol) was added at room temperature, 3-hydroxybenzaldehyde (0.41 g, 3.35 mmol), 4- tert - butylaniline (0.50 g, 3.35 mmol) and 3, in acetonitrile (1 ml). To a solution of 4-dihydro-2H-pyran (0.28 g, 3.35 mmol) was added and the mixture was stirred for an additional 30 minutes at room temperature. The reaction mixture was evaporated to dryness and purified via column chromatography to give a colorless solid (237 mg, 0.70 mmol, 21%), which isomer in which the racemic trans / cis compound was 5: 1. It was found to be a mixture.

Example  2

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

A solution of TFA salt of 4-thiocyanatoaniline (thiocyanatoaniline (0.46 g, 3.06 mmol) in acetonitrile was placed in acetonitrile (4 mL), cooled to 0 ° C., and stirred with TFA (0.35 g, 3.06 mmol). ) Was slowly added) 3-hydroxybenzaldehyde (0.37 g, 3.06 mmol) and 1-vinyl-2-pyrrolidone (0.34 g, 3.06 mmol) in acetonitrile (2 mL), cooled to 0 ° C. ) Was added quickly and the mixture was stirred at this temperature for an additional 18 hours. The reaction solution was evaporated, taken up with a small amount of ethyl acetate and crystallized with diethyl ether to give a colorless solid (390 mg, 1.06 mmol, 35%) which was found to be the cis isomer.

To separate the cis / trans isomer, the filtrate was evaporated to dryness and purified by column chromatography to give the trans isomer as a colorless solid (160 mg, 0.44 mmol, 14%).

Relatively small amounts of rac-3 and rac-4 were separated into the corresponding enantiomers via chiral HPLC (2 × Chiralpak AD 20 μm, eluent: methanol) and converted back to hydrochloride.

The following compounds according to the present invention were similarly obtained using the corresponding precursors. The indicated residence time was obtained under the following conditions.

Method A

Merck Hitachi LaChrom

Gradient 9 minutes

Flow rate: from 1.5 μg / min 80:20 to 0: 100 (within 6 minutes), 0: 100 (1 minute),

Return to 80:20 (within 1 minute), water / acetonitrile

Water + TFA (0.1% by volume)

Acetonitrile + TFA (0.1% by volume)

Column: LichroCART 125-4 RP-LiChrospher 60, RP-select-B (5µm / 60µmm)

Wavelength: 220 nm

Method B:

Merck Hitachi LaChrom

Gradient 9 minutes

Flow rate: from 1.5 μg / min 80:20 to 0: 100 (within 6 minutes), 0: 100 (1 minute),

Return to 80:20 (within 0.8 minutes), water / acetonitrile

Water + TFA (0.1% by volume)

Acetonitrile + TFA (0.1% by volume)

Column: Lichrospher RP-select-B (5µm / 125µmm)

Wavelength: 220 nm

Method C:

Agilent 1100 Series

Gradient 3.5 min

Flow rate: from 2 μml / min 80:20 to 0: 100 (within 2.3 min), 0: 100 (0.5 min), back to 80:20, water / acetonitrile

Water + TFA (0.1% by volume)

Acetonitrile + TFA (0.1% by volume)

Column: β test research sample, Chromolith Performance RP-18e

(3 μm / 100 mm)

Wavelength: 220 nm

Example  3-654

98

.

Compounds of formula I from Examples 562 to 654 are particularly preferred because they have increased activity according to the present invention.

Example  A: Assay I

The efficacy of the compounds according to the invention is measured, for example, by Eg5 ATP as measured by enzymatic regeneration of the product from ADP to ATP via coupling to pyruvate kinase (PK) and subsequent NADH-dependent lactate dehydrogenase (LDH). Determination can be made through an aze activity. The reaction can be monitored by a change in absorbance at 340 nm through coupling to NADH-dependent LDH. Regeneration of ATP continually ensures that the substrate concentration is constant. The change in absorbance per unit of time was graphically analyzed and linear regression was performed in the visually linear region of the response.

Example  B: Assay II

The combination of an antiprotozoic pentamidine and inhibitor of the kinesin ATPase Eg5 / KSP results in increased inhibitory effects in cell proliferation tests with colon carcinoma cell line HCT116. Eg5 inhibitors adversely affect ATPase activity and inhibit cell cycle pathways due to errors in spindle pole separation.

Determination of the efficacy of a compound of formula (I) according to the invention in combination with a compound of formula (V) and / or a medicament from Table 1 may appear in the combination assay as follows:

Inoculated with 10 ³ to 10 ⁴ cells of a defined cell line (HCT116, Colo 205, MDA- MB 231 , etc.) to each well of a 96-well microtiter plates and incubated overnight under standard conditions. For the combination material to be tested, 10-50 mM stock solution in DMSO was prepared. Dilution series of individual materials (typically 3-fold dilution series) were combined with each other in the form of a pipette scheme while maintaining a DMSO final concentration of 0.5% (v / v) (see the scheme below). The next morning, the material mixture was added to the cells and incubated for an additional 48 hours under culture conditions. Crystal violet staining of cells was performed at the end of the culture. After extracting the crystal violet from the fixed cells, the absorbance at 550 nm was measured with a spectrophotometer. It can be used to measure the quantity of adherent cells present.

[scheme]

The following results provide by way of example indications of inhibition of the cell cycle by the compound I12 compound according to the invention.

Monasterol and Pentamidine in Individual Experiments:

HCT116 cells were treated with a predetermined concentration of compound for 24 hours, and propidium iodide analysis was performed by BD-FACS scan to determine the DNA content of the treated cell population. Percentages of cells in the G0 / G1 phase (unreplicated DNA), S phase (DNA replication phase) and G2 / M phase (copy DNA before mitosis) are shown. 10,000 counts were made for each concentration. Significant changes in the G2 / M increase were evident.

Ⅰ12 (Eg5 inhibitor according to the present invention)

Monastrol (Eg5 Inhibitor in Previous Technology)

Pentamidine isothionate

The following results provide by way of example indications of inhibition of the cell cycle by monasterol and pentamidine in Compound I12 compounds or combination experiments according to the invention.

Combination Therapies: Ⅰ12 Plus Pentamidine

HCT116 cells were incubated overnight at 37 ° C. at a density of 2500 or 5000 cells / well in 96-well plates. The next day, a concentration matrix of pentamidine and the indicated compound was added and cells were incubated for an additional 48 hours. Cells were then stained with crystal violet, and after dye extraction, absorbance was measured. Absorbance values reflect the number of cells in the wells.

result:

Upper Matrix: OD550 nm background correction

Central Matrix:% of Control (100% value means vehicle treated cell negative background signal)

Lower region: -fold inhibition level (ie 100% / x% level means -fold inhibition of proliferation)

Schematic representation of the data:

The data is shown in FIG. 1 as concentration curves, each line representing one curve at a given pentamidine concentration.

Combination Treatment: Monastrol Plus Pentamidine

result:

Upper Matrix: OD550 nm background correction

Central Matrix:% of Control (100% value means vehicle treated cell negative background signal)

Lower region: -fold inhibition level (ie 100% / x% level means -fold inhibition of proliferation)

TABLE 3

Schematic representation of the data:

The data is shown in FIG. 2 as concentration curves, each line representing one curve at a given pentamidine concentration.

The following examples relate to medicaments:

Example  C: Injection vial

A solution of 100 g of the active ingredient of formula (I) and 5 g of di (di) sodium hydrogenphosphate in 3 L of distilled water twice was adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred to an injection vial, and then frozen under sterile conditions. Dry and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

Example  D: suppository

A mixture of 100 g soy lecithin and 20 g of the active ingredient of formula I and 1400 g of cocoa butter were melted, poured into a mold and left to cool. Each suppository contains 20 mg of active ingredient.

Example  E: solution

A solution of 1 g of the active ingredient of formula I, 9.38 g of NaH ₂ PO ₄ · 2 H ₂ O, 28.48 g of Na ₂ HPO ₄ · 12 H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water Was prepared. The pH was adjusted to 6.8, the solution was brought to 1 L and sterilized by irradiation. This solution can be used in the form of eye drops.

Example  F: Ointment

500 mg of the active ingredient of formula (I) were mixed with 99.5 g of petrolatum under aseptic conditions.

Example  G: refine

1 kg of the active ingredient of formula (I), 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate were compressed in a conventional manner to obtain a tablet such that each tablet contains 10 mg of active ingredient.

Example  H: Party

Similar to Example E, the tablets were compressed and coated in a conventional manner, subsequently coating with fructose, potato starch, talc, tragacanth and pigments.

Example  I: capsule

2 kg of the active ingredient of formula (I) were incorporated into hard gelatin capsules in a conventional manner, with each capsule containing 20 mg of active ingredient.

Example  J: ample

A 1 kg solution of the active ingredient of formula (I) in 60 L of distilled water was sterile filtered, transferred to an ampoule, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

1

Schematic representation of the data from Table 2:

Data is represented by concentration curves of the material of formula (I12). Each line represents one curve at a given pentamidine concentration.

2

Schematic representation of the data from Table 3:

Data is represented by concentration curves of monastrol material. Each line represents one curve at a given pentamidine concentration.

3 To  25

NMR spectrum of representative compound of Formula (I).

Claims (29)

A compound of formula (I) and pharmaceutically usable derivatives, solvates, tautomers, salts and stereoisomers thereof, and mixtures thereof in all ratios:

[In the meal, W represents CH or N, R^One, R², R³ Are independently of each other, H, R, A, aryl, heteroaryl, Hal,-(CY₂)_n-SA,-(CY₂)_n-SCF₃,-(CY₂)_n-SCN,-(CY₂)_n-CF₃,-(CY₂)_n-OCF₃, Cycloalkyl, -SCH₃, -SCN, -CF₃, -OCF₃, -OA,-(CY₂)_n-OH,-(CY₂)_n-CO₂R,-(CY₂)_n-CN,-(CY₂)_n-Hal,-(CY₂)_n-NR₂, (CY₂)_n-OA, (CY₂)_n-OCOA, -SCF₃, (CY₂)_n-CONR₂,-(CY₂)_n-NHCOA,-(CY₂)_n-NHSO₂A, SF₅, Si (CH₃)₃, CO- (CY₂)_n-CH₃,-(CY₂)_n-N-pyrrolidone, CH (CH₂)_nNRCOOR, CHNRCOOR, NCO, CH (CH₂)_nCOOR, NCOOR, CH (CH₂)_nOH, N (CH₂)_nOH, CHNH_{2 ,}CH (CH₂)_nNR₂, CH (CH₂)_nNR₂, C (OH) R, CHNCOR, CH (CH₂)_n-Aryl, CH (CH₂)_nHeteroaryl, CH (CH)₂)_nR^One, N (CH₂)_nCOOR, CH (CH₂)_nX (CH₂)_n-Aryl, CH (CH₂)_nX (CH₂)_nHeteroaryl, N (CH₂)_nCONR₂, XCONR (CH₂)_nNR₂, N [(CH₂)_nXCOOR] CO (CH₂)_n-Aryl, N [(CH₂)_nXR] CO (CH₂)_n-Aryl, N [(CH₂)_nXR] CO (CH₂)_nX-aryl, N [(CH₂)_nXR] SO₂(CH₂)_n-Aryl, N [(CH₂)_nNRCOOR] CO (CH₂)_n-Aryl, N [(CH₂)_nNR₂] CO (CH₂)_n-Aryl, N [(CH₂)_nNR₂] CO (CH₂)_nNR-aryl, N [(CH₂)_nNR₂] SO₂(CH₂)_n-Aryl, N [(CH₂)_nXR] CO (CH₂)_nHeteroaryl, N [(CH₂)_nXR] CO (CH₂)_nX-heteroaryl, N [(CH₂)_nXR] SO₂(CH₂)_nHeteroaryl, N [(CH₂)_nNRCOOR] CO (CH₂)_nHeteroaryl, N [(CH₂)_nNR₂] CO (CH₂)_nHeteroaroyl, N [(CH₂)_nNR₂] CO (CH₂)_nNR-heteroaryl, N [(CH₂)_nNR₂] SO₂(CH₂)_nHeteroaryl, O (CH)₂)_nNR₂, X (CH₂)_nNR₂, NCO (CH₂)_nNR₂ Represents R^One And R² Together with -N-C (CF₃) = N-, -N-CR = N-, -N-N = N-, Y represents H, A, Hal, A represents alkyl or cycloalkyl, wherein one or more H atoms can be replaced with Hal, Hal represents F, Cl, Br or I, R represents H or A, and in the case of the chemical radical R is also-(CH ₂ ) ₅ -,-(CH ₂ ) ₄ -,-(CH ₂ ) ₂ -X- (CH ₂ ) ₂ , or- (CH ₂ ) ₂ -Z- (CH ₂ ) _n R⁴, R⁵ Are independently of each other, H, or unsubstituted or mono- or poly- OR-, NO₂-, Hal-, CF₃-, OCF₃-, CN-, NR₂Or an SR-, aryl- or heteroaryl-substituted N-pyrrolidone radical, -X- (CH₂)₂OR, -X-CO (CH₂)_nCH₃, -X- (CH₂)₂NR₂, R^One, S-aryl, O-aryl, CH₂Si (CH₃)₃Or together with -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-, -XCHQ (CR₂)₂-, -XCHQCR _2- , RN- (C = X) -NR, -XC [(CH ₂ ) nOR] ₂ CH ₂ CH _2- ; X represents O, S or NR, Q is CH ₂ Hal, CHO, COR ^a , CH ₂ R ^a , CH ₂ OCOR ^a , CH ₂ NCOR ¹ , CH ₂ N (R ¹ ) ₂ , CH ₂ OR ¹ , CH ₂ OCON (R ¹ ) ₂ , CH ₂ OCOOR ¹ , CH ₂ NHCON (R ¹ ) ₂ , CH ₂ NHCOOR ¹ is represented, R ^a is

OR, NHR₂, NR_{2 ,}NR (CH₂)_n-Aryl, NR (CH₂)_nOR, COOR, N-pyrrolidone radical, OCOR, NR (CH₂)_nNR₂, N [(CH₂)_nNR₂] CO (CH₂)_n-Aryl, N [(CH₂)_nNHCOOR] CO- aryl, R^One, N [CH₂(CH₂)_nOR]₂, NR (CH₂)_nNCOOR, X (CH₂)_nX (CH₂)_nXR, NR (CH₂)_nX (CH₂)_nOH, NR (CH₂)_nO (CH₂)_nOH, (CH₂)_nCOOR, O (CO) NR (CH₂)_nOR, O (CO) (CH₂)_nNR₂, NR (CH₂)_nNR₂, N [(CH₂)_nNR₂] CO (CH₂)_nAryl, N [(CH₂)_nXR] CO (CH₂)_n-Aryl, N [(CH₂)_nXR] CO (CH₂)_nHeteroaryl, N [(CH₂)_nNR₂] CO (CH₂)_nHeteroaryl, N [(CH₂)_nNR₂] CO (CH₂)_nR^One, N (R) (CH₂)_nN (R) COOR, XCOO (CH₂)_nNR₂, OSO₂A, OSO₂CF₃, OSO₂Ar, OCONR₂, OCH₂(CH₂)_nNR₂Indicates, Z is CH ₂ , X, CHCONH ₂ , CH (CH ₂ ) _n NRCOOR, CHNRCOOR, NCO, CH (CH ₂ ) _n COOR, NCOOR, CH (CH ₂ ) _n OH, N (CH ₂ ) _n OH, CHNH _{2 ,} CH (CH ₂ ) _n NR ₂ , CH (CH ₂ ) _n NR ₂ , C (OH) R, CHNCOR, CH (CH ₂ ) _n -aryl, CH (CH ₂ ) _n -heteroaryl, CH (CH ₂ ) _n R ¹ , N (CH ₂ ) _n COOR, CH (CH ₂ ) _n X (CH ₂ ) _n -aryl, CH (CH ₂ ) _n X (CH ₂ ) _n -heteroaryl, N (CH ₂ ) _n CONR ₂ , XCONR (CH ₂ ) _n NR ₂ , N [(CH ₂ ) _n XCOOR] CO (CH ₂ ) _n -aryl, N [(CH ₂ ) _n XR] CO (CH ₂ ) _n -aryl, N [ (CH ₂ ) _n XR] CO (CH ₂ ) _n X-aryl, N [(CH ₂ ) _n XR] SO ₂ (CH ₂ ) _n -aryl, N [(CH ₂ ) _n NRCOOR] CO (CH ₂ ) _n -aryl, N [(CH ₂ ) _n NR ₂ ] CO (CH ₂ ) _n -aryl, N [(CH ₂ ) _n NR ₂ ] CO (CH ₂ ) _n NR-aryl, N [(CH ₂ ) _n NR ₂ ] SO ₂ (CH ₂ ) _n -aryl, N [(CH ₂ ) _n XR] CO (CH ₂ ) _n -heteroaryl, N [(CH ₂ ) _n XR] CO (CH ₂ ) _n X-hetero Aryl, N [(CH ₂ ) _n XR] SO ₂ (CH ₂ ) _n -heteroaryl, N [(CH ₂ ) _n NRCOOR] CO (CH ₂ ) _n -heteroaryl, N [(CH ₂ ) _n NR ₂ ] CO (CH _{2) n} - O heteroatom _{reel, n [(CH 2) n} NR 2] CO (CH 2) n NR- _{heteroaryl, n [(CH 2) n} NR 2] SO ₂ (CH ₂ ) _n -heteroaryl, O (CH ₂ ) _n NR ₂ , X (CH ₂ ) _n NR ₂ , NCO (CH ₂ ) _n NR ₂ , and R ⁶ Silver aryl or heteroaryl, each of which is unsubstituted or substituted with Hal, NO ₂ , CN, A, OR, OCOR, COR, NR ₂ , CF ₃ , OCF ₃ , OCH (CF ₃ ) ₂ , or Hal , NO ₂ , CN, OR, A,-(CY ₂ ) _n -OR, -OCOR,-(CY ₂ ) _n -CO ₂ R,-(CY ₂ ) _n -CN, -NCOR, -COR or-( CY ₂ ) mono- or multiply substituted by aryl or heteroaryl which may be substituted by _n- NR ₂ , R⁷ silver (C = O) -R, (C = O) -NR₂, (C = O) -OR, H or A, m represents 0, 1 or 2, n represents 0, 1, 2, 3, 4, 5, 6 or 7. The compound of claim 1, wherein R ¹ Yi A, CF _3, OCF _3, SA, SCN, CH ₂ CN, -OCOA, Hal, SCF _3, t- _{butyl, -CH (CH 3) CH 2} CH 3, a compound represented isopropyl, ethyl or methyl. The compound of claim 1 or 2, wherein R ² The compound which shows this F or H. The compound of claim 1, wherein R ³ Is a compound represented by F or H. The compound of claim 1, wherein R ⁵ When H represents H, R ⁴ preferably represents one of the following groups:

Wherein X and R have the meanings indicated in claim 1. A compound according to any one of claims 1 to 5, wherein R ^5. Is H. A compound according to any one of claims 1 to 6, wherein R ⁵ R ⁴ With compounds which adopt one of the following meanings:

Wherein X, R and R ^a have the meanings indicated in claim 1. 8. The compound of claim 1, wherein R ⁶ Phenyl, 2-, 3- or 4-pyridyl, pyri, unsubstituted or mono- or multiply substituted with Hal, CN, NO ₂ , OH, CF ₃ , OCH (CF ₃ ) ₂ , OCOCH ₃ or A, respectively Compounds representing midyl, furyl or thienyl. The method according to any one of claims 1 to 8, R ⁶ Is a compound represented by one of the following groups:

. 10. A compound according to claim 1, wherein R ⁷ represents H. ¹¹ . Sub-Formulas IA-ID Compounds:

[Wherein R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and X have the meanings indicated in claim 1, and R ⁸ is H, CH ₂ OR or CH ₂ NR ₂ ]. Other compounds of the compounds of formulas (A) and (B) below and racemates or enantiomers thereof:

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ Has the meaning indicated in paragraph 1]. Compounds of lower formulas I1 to I45a:

14. A process for the preparation of the compounds of formula (I) and pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers according to claims 1 to 13, wherein the compounds of formula (II) are A radical R ⁷ which reacts with a compound, a double bond isomer thereof (E isomer) or a mixture thereof and, if required, H Is converted to a radical R ⁷ having a meaning other than H and / or if required, the base or acid of formula I is converted to one of its salts:

, [Wherein R ¹ , R ² and R ³ have the meaning indicated in claim 1],

, [Wherein R ⁶ has the meaning indicated in claim 1],

[Wherein R ⁴ and R ⁵ have the meaning indicated in claim 1]. The method according to claim 14, wherein the reaction is carried out in the presence of a protic acid or a Lewis acid. 16. The reaction of claim 14 or 15 wherein the reaction is carried out of trifluoroacetic acid, hexafluoroisopropanol, bismuth (III) chloride, ytterbium (III) triflate, scandium (III) triflate or cerium (IV) ammonium nitrate. Characterized in that it is carried out in the presence. At least one compound of formula (I) according to claims 1 to 13 and / or pharmaceutically usable derivatives, salts, solvates, tautomers and stereoisomers, and mixtures of all proportions thereof, and any excipients and A medicament comprising an adjuvant. Mixtures containing amounts of at least one compound of formula (I) and at least one compound of formula (V), homologues thereof and / or metabolites thereof:

[Wherein, Y ′ and Z ′ independently represent O or N with respect to each other, R ⁹ and R ¹⁰ independently from each other, H, OH, halogen, OC 1-10 -alkyl, OCF ₃ , NO ₂ or NH ₂ , n represents an integer between 2 and 6, and R ⁸ and R ¹¹ are, independently of each other, in the meta- or para-position and are selected from the following groups:

]. Use according to claim 18, wherein the compound of formula V used is pentamidine or a salt thereof. 14. A compound according to claims 1 to 13, and a pharmaceutically usable derivative thereof, for the manufacture of a medicament for the treatment of a disease that may be affected by the inhibition, regulation and / or modulation of mitotic triggering protein Eg5, Use of salts, solvates, tautomers and stereoisomers, and mixtures thereof in all proportions or in accordance with claim 18. Use of a compound according to claims 1 to 13 or a mixture according to claim 18 for the manufacture of a medicament for the treatment and prevention of cancer diseases. The method of claim 21, wherein the cancer disease is squamous epithelium, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate, urinary system, lymphatic system, stomach, larynx and / Or use associated with a tumor from a group of lung tumors. Use according to claim 22, wherein the tumor is from a group of monocytic leukemia, lung adenocarcinoma, small cell lung carcinoma, pancreatic cancer, glioblastoma and breast carcinoma and colon carcinoma. Use according to claim 21, wherein the cancer disease to be treated is a tumor of the blood and immune system. The use according to claim 24, wherein the tumor is from a group of acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and / or chronic lymphocytic leukemia. 14. A compound of formula (I) and / or a physiology thereof according to claims 1 to 13, in combination with a therapeutically effective amount of at least one compound of formula (V), its analogs and / or metabolites thereof for the preparation of a medicament for the treatment of a tumor As the use of academically suitable salts and solvates:

[Wherein, Y ′ and Z ′ independently represent O or N with respect to each other, R ⁹ and R ¹⁰ independently from each other, H, OH, halogen, OC 1-10 -alkyl, OCF ₃ , NO ₂ or NH ₂ , n is an integer between 2 and 6, and R ⁸ and R ¹¹ are, independently of each other, in the meta- or para-position and are selected from the group:

], A method of administering a compound of Formula I and a compound of Formula V, a homologue thereof and / or a metabolite thereof, simultaneously or within 14 days with respect to each other, sufficient amount to inhibit growth of tumors or other hyperproliferative cells. Use according to claim 26, wherein the compound of formula V used is pentamidine or a salt thereof. Therapeutic effective amount of the compound of formula (I) is determined by radiotherapy and 1) estrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) prenyl-protein transfer Enzyme preparations, 7) HMG-CoA reductase inhibitors, 8) HIV protease inhibitors, 9) reverse transcriptase inhibitors, and 10) in combination with compounds from the group of other angiogenesis inhibitors. Use of the compounds of formula (I) according to claims 1 to 13 and / or physiologically suitable salts and solvates thereof. Q represents CH2R ^a , and R ^a has one of the following meanings: NHR ₂ , NR ₂ , NR (CH ₂ ) _n aryl, NR (CH ₂ ) _n OR, COOR, N-pyrroli Don radical, OCOR, NR (CH ₂ ) _n NR ₂ , N [(CH ₂ ) _n NR ₂ ] CO (CH ₂ ) _n aryl, N [(CH ₂ ) _n NHCOOR] CO aryl, R ¹ , N [CH ₂ (CH ₂ ) _n OR] ₂ , NR (CH ₂ ) _n NCOOR, X (CH ₂ ) _n X (CH ₂ ) _n XR, NR (CH ₂ ) _n X (CH ₂ ) _n OH, NR (CH ₂ ) _n O (CH ₂ ) _n OH, (CH ₂ ) _n COOR, O (CO) NR (CH ₂ ) _n OR, O (CO) (CH ₂ ) _n NR ₂ , NR (CH ₂ ) _n NR ₂ , N [(CH ₂ ) _n NR ₂ ] CO (CH ₂ ) _n aryl, N [(CH ₂ ) _n XR] CO (CH ₂ ) _n aryl, N [(CH ₂ ) _n XR] CO (CH ₂ ) _n Heteroaryl, N [(CH ₂ ) _n NR ₂ ] CO (CH ₂ ) _n heteroaryl, N [(CH ₂ ) _n NR ₂ ] CO (CH ₂ ) _n R ¹ , N (R) (CH ₂ ) _n N (R) COOR, XCOO (CH ₂ ) _n NR ₂ , OSO ₂ A, OSO ₂ CF ₃ , OSO ₂ Ar, OCONR ₂ or OCH ₂ (CH ₂ ) _n NR.

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