ES2567785T3 - Tubulin Inhibiting Agents - Google Patents

Abstract

A compound of formula (I):**Formula** wherein R is H or an alkyl, alkenyl, alkynyl, CO-alkyl or heteroalkyl group, all of which may be optionally substituted; R' is H or an alkyl, alkenyl, alkynyl, CO-alkyl or heteroalkyl group, all of which may be optionally substituted;**Formula** R'' is a group of the formula CH2OH or n is 0, 1, 2, 3, 4 or 5; the Y's are, independently, optionally substituted alkyl, heteroalkyl, halogen, CN, NO2 or OH; or a pharmacologically acceptable salt, solvate, hydrate or pharmacologically acceptable formulation thereof.

Description

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DESCRIPTION

Tubulin Inhibiting Agents

The present invention relates to new molecules that inhibit the polymerization of the tubulin skeleton of cancer cells.

The aim of the present invention is to provide new cytotoxic molecules that preferably show a very potent activity against cancer cell lineages and strong affinities for tubulin fixation, therefore being preferably capable of annihilating cancer cells.

The present invention provides one or more compounds of the formula (I):

image 1

in which

R is H or an alkyl, alkenyl, alkynyl, CO-alkyl or heteroalkyl group, all of which may be optionally substituted;

R 'is H or an alkyl, alkenyl, alkynyl, CO-alkyl or heteroalkyl group, all of which may be optionally substituted;

R '' is a group of the formula CH2OH or n is 0, 1,2, 3, 4 or 5;

the Y are independently alkyl (eg methyl), heteroalkyl (eg MeO), halogen, CN, NO2 or OH, optionally substituted;

or a pharmacologically acceptable salt, a solvate, a hydrate or a pharmacologically acceptable formulation thereof.

The term "alkyl" refers to a saturated, straight or branched chain hydrocarbyl group containing from 1 to 20 carbon atoms, preferably from 1 to 12 carbon atoms, especially from 1 to 6 (eg. 1,2, 3 or 4) carbon atoms, for example methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec.-butyl, tert-butyl, n-pentyl, 2,2-dimethyl-propyl, 2-methyl-butyl, n-hexyl, 2,2-dimethyl-butyl or 2,3-dimethyl-butyl.

The terms "alkenyl" and "alkynyl" refer to at least partially unsaturated, straight chain or branched hydrocarbyl groups, containing 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, so especially from 2 to 6 (eg 2, 3 or 4) carbon atoms, for example an ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Preferably, the alkenyl groups have one or two

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(especially preferably a) double bond (s), and the alkynyl groups have one or two (especially preferably a) triple bond (s).

Otherwise, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms (eg 1, 2 or 3 hydrogen atoms) has been replaced by a halogen atom (preferably F or Cl), such as, for example, a 2,2,2-trichloro-ethyl or trifluoromethyl group.

The term "heteroalkyl" refers to an alkyl, alkenyl or alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms has been replaced by an atom of oxygen, nitrogen, phosphorus , boron, selenium, silicon or sulfur (preferably by an atom of oxygen, sulfur or nitrogen). The term "heteroalkyl" also refers to a carboxylic acid to a group that is derived from a carboxylic acid, such as, for example, acyl (alkyl-CO-), acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamido or alkoxycarbonyloxy.

Preferably, a heteroalkyl group contains 1 to 12 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). Particularly preferably, a heteroalkyl group contains from 1 to 6 (eg 1,2, 3 or 4) carbon atoms and 1, 2 or 3 (especially 1 or 2) heteroatoms selected from oxygen, nitrogen and sulfur ( especially oxygen and nitrogen).

Examples of heteroalkyl groups are the groups of the formulas:

Ra-O-Ya-, Ra-S-Ya-, Ra-N (Rb) -Ya-, Ra-CO-Ya-, Ra-O-CO-Ya-, Ra-CO-O-Ya-, Ra -CO-N (Rb) -Ya-, Ra-N (Rb) -CO-Ya-, Ra-O-CO-N (Rb) -Ya-, Ra-N (Rb) -CO-O-Ya- , Ra-N (Rb) -CO-N (Rc) -Ya-, Ra-O-CO-O-Ya-, Ra-N (Rb) -C (= NRd) -N (Rc) -Ya-, Ra-CS-Ya-, Ra-O-CS-Ya-, Ra-CS-O-Ya-, Ra-CS-N (Rb) -Ya-, Ra-N (Rb) -CS-Ya-, Ra -O-CS-N (Rb) -Ya-, Ra-N (Rb) -CS-O-Ya-, Ra-N (Rb) -CS-N (Rc) -Ya-, Ra-O-CS- O-Ya-, Ra-S-CO-Ya-, Ra-CO-S-Ya-, Ra-S-CO-N (Rb) -Ya-, Ra-N (Rb) -CO-S-Ya- , Ra-SC-CO- O-Ya-, Ra-O-CO-S-Ya-, Ra-S-CO-S-Ya-, Ra-S-CS-Ya-, Ra-CS-S-Ya -, Ra-S-CS-N (Rb) -Ya-, Ra "N (Rb) -CS-S-Ya-, Ra-S-CS-O-Ya-, Ra-O-CS-S-Ya -, in which Ra is a hydrogen atom, a C1-C6 alkyl group, C2-C6 alkenyl or C2-C6 alkynyl; Rb is a hydrogen atom, a C1-C6 alkyl group, C2 alkenyl C6 or C2-C6 alkynyl; Rc is a hydrogen atom, a C1-C6 alkyl group, C2-C6 alkenyl or C2-C6 alkynyl; Rd is a hydrogen atom, a C1-C6 alkyl group, C2-C6 alkenyl or C2-C6 alkynyl and is already a direct bond, an alkyl group C 1 -C 6, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene, wherein each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms can be replaced by halogen atoms (eg. of fluorine or chlorine).

Specific examples of heteroalkyl groups are the methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy, methoxymethyl, ethoxymethyl, -CH2CH2OH, -CH2OH, methoxyethyl, methylamino, ethylamino, dimethylamino, diethylamino-isopropyl-ethylamino groups methylamino methyl, ethylamino methyl, diisopropylamino ethyl, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl,

N ethyl-N-methyl-carbamono or N-methyl-carbamoMo. Other examples of heteroalkyl groups are nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkyl nitrile groups.

The term "optionally substituted" refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH groups, = O, SH, = S, NH2, = NH or NO2. This term also refers to groups that may be exclusively or additionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or unsubstituted C1-C6 heteroalkyl groups.

Protective groups are known by a professional expert in the field and are described, for example, in the work of PJ Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994 and in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1999. A few common amino protecting groups are eg t-butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBS), benzyloxycarbonyl ( Cbz, Z), benzyl (Bn), benzoflo (Bz), fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), triethylsilyl (TES), trichlorethyloxycarbonyl (Troc), acetyl or trifluoroacetyl.

The compounds of the formula (I) may comprise several chiral centers depending on their substitution model. The present invention relates to all enantiomers and diastereoisomers defined as well as their mixtures in all relationships. Moreover, the present invention relates to all cis / trans isomers of compounds of the general formula (I) as well as their mixtures. Moreover, the present invention relates to all tautomeric forms of compounds of the general formula (I).

Preferably, R is H or C1-C6 alkyl, especially a methyl or propyl group.

Preferably R 'is -CO-alkyl, alkyl or heteroarylalkyl, especially acetyl (Ac) or -CH2CH3.

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Preferably, R "is more preferably R" is -CH 2 OH Preferably, n is 0.

Especially preferred are compounds of the formula (I) in which:

R is C1-C6 alkyl, especially -CH3, ethyl, propyl, butyl, isopropyl, isobutyl, n-pentyl, n-hexyl; R 'is -CO-alkyl 0 heteroalkyl, especially -CO-CH3 0 -CH2OCH3

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R "is -CH2OH 0 (especially -CH2OH) and

n is 0.

Examples of pharmacologically acceptable salts of the compounds of the formula (I) are salts of physiologically acceptable inorganic acids such as chlortndric acid, sulfuric acid and phosphoric acid or salts of organic acids, such as methanesulfonic acid, acid p-toluenesulfonic acid, lactic acid, formic acid, acetic acid, trifluoroacetic acid, citric acid, succmic acid, smoking acid, maleic acid and salidic acid. Other examples of pharmacologically acceptable salts of the compounds of the formula (I) are alkali metal and alkaline earth metal salts such as, for example, sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic bases such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine. The compounds of the formula (I) may be solvated, especially hydrated. Hydration can take place, for example, during the preparation process or as a consequence of the hygroscopic nature of the initially anhydrous compounds of the formula (I). Solvates and / or hydrates may, for example, be present in a solid or liquid form.

The compounds of the formula (I), their pharmacologically acceptable salts, solvates and hydrates, respectively, as well as pharmaceutical formulations and compositions intended for use in therapy are also within the scope of the present invention.

The pharmaceutical compositions according to the present invention comprise at least one compound of the formula (I) as an active ingredient and, optionally, vehicle substances and / or adjuvants.

The use of compounds of the formula (I) for the preparation of medicaments intended for the treatment and / or prevention of cancer is also a subject of the present invention. For the rest, the present compounds are of interest for the prevention and / or treatment of tumor diseases.

Cancers that can be treated or prevented by means of the compositions and methods of the present invention include, but are not limited to, human sarcomas and carcinomas, such as eg fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, an osteogenic sarcoma, a chordoma, an angiosarcoma, endotheliosarcoma, a lymphangiosarcoma, a lymphangioendotheliosarcoma, a synovioma, a mesothelioma, an Ewing's tumor, a leiomyosarcoma, a rhabdomyosarcoma, a colon carcinoma, a pancreatic cancer, a breast cancer, a ovarian cancer, a prostate cancer, a squamous cell carcinoma, a basal cell carcinoma, an adenocarcinoma, a carcinoma of sudonpary glands, a sebaceous gland carcinoma, a papillary carcinoma, a papillary adenocarcinomas, a cystoadenocarcinoma, a medullary carcinoma , a bronchogenic carcinoma, a renal cell carcinoma, a hepatoma, a bile duct carcinoma, a choriocarcinoma, a seminoma, an embryo carcinoma nario, a Wilms tumor, a cervical cancer, a testicular tumor, a lung carcinoma, a small cell lung carcinoma, a vesicle carcinoma, an epithelial carcinoma, a glioma, an astrocytoma, a medulloblastoma, a craniopharyngioma, an ependioma, a pinealoma, a hemangioblastoma, an acoustic neuroma, an oligodendroglioma, a meningioma, a neuroblastoma, a retinoblastoma; leukemias, eg acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelodetic, myelomedotic or monodic leukemia and erythroleukemia); a chronic leukemia (a chronic myelocytic (granulocytic) leukemia and a chronic lymphocytic leukemia and a polycythemia vera, a lymphoma (Hodgkin's disease and non-Hodgkin's disease), a multiple myeloma, Waldenstrohm's macroglobulinemia, and a disease of the heavy chains

Other examples of leukemia include acute and / or chronic leukemias, eg lymphocytic leukemia (eg as illustrated by the p388 (murine) cell lineage), a large granular lymphocytic leukemia and a leukemia

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lymphoblastic; T cell leukemias eg a T cell leukemia (eg as illustrated by the CEM, Jurkat and HSB-2 cell lines (acute), YAC 1 (murine), a T lymphocytic leukemia and a lymphoblastic T leukemia; a B-cell leukemia (eg as illustrated by the SB (acute) cell lineage and a B-lymphocytic leukemia; mixed cell leukemias (eg a B and T cell leukemia) and lymphocytic leukemias By T: myeloid leukemias, eg a granulocytic leukemia, a myelocytic leukemia (eg as illustrated by the HL-60 cell line (promyelocytes), and a myelogenous leukemia (eg As illustrated by the K562 (chronic) cell lineage; a neutrophilic leukemia; an eosinofflic leukemia; a monocytic leukemia (eg as illustrated by the THP-1 cell lineage (acute); a myelomonophic leukemia ; a myeloid leukemia of the Naegeli type; and a non-lymphocytic leukemia.Other examples of leukemia have been described in chapter 60 of the work The Chemotherapy Sourcebook, Michael C. Perry edition coordinator, Williams & Williams (1992) and in section 36 of the work Holland Frie Cancer Medicine 5th edition, Bast et al., coordinators of edition, B.C. Decker Inc. (2000).

In general, the compounds of the formula (I) can be administered as a single treatment or as multiple treatments, either alone or in combination with an arbitrary therapeutic substance, according to known and accepted ways or as a continuous treatment, according to which the active ingredient can be embedded in a matrix such as eg an implantable hydrogel. The compositions according to the invention can be administered in one of the following ways: orally including dragees, coated tablets, pffdoras, semi-solid materials, hard or soft capsules, solutions, emulsions or suspensions; parenterally, including injectable solutions, rectally in the form of suppositories; by inhalation, including a powder formulation or as a spray formulation, and transdermally or intranasally. For the production of such tablets, pills, semi-solid materials, coated tablets, dragees and hard gelatin capsules, the therapeutically used product is mixed with inorganic or organic pharmacologically inert vegetables, eg lactose, sucrose, glucose, gelatin, malt , silica gel, a starch, or derivatives thereof, talc, stearic acid or its salts, dried skim milk and the like. For the production of soft capsules, vehicles such as vegetable oils, petroleum oils, animals or synthetics, a wax, a grease and polyols can be used. For the production of liquid and syrup solutions, vehicles, for example water, alcohols, an aqueous saline solution, an aqueous dextrose, polyols, glycerol, vegetable oils, petroleum oils, animals or synthetics can be used. For the production of suppositories, vehicles such as eg vegetable, petroleum, animal or synthetic oils, a wax, a grease and polyols can be used. For aerosol formulations, compressed gases that are appropriate for this purpose, such as oxygen, nitrogen, a noble gas and carbon dioxide, may be used. Pharmaceutically useful agents may also contain additives for preservation or stabilization, eg UV stabilizing agents, emulsifying agents, sweeteners, flavorings, salts for changing osmotic pressure, buffers, coating additives and antioxidant agents.

Combinations with other therapeutic agents may include additional agents that are commonly used to treat the above-mentioned diseases, especially tumor diseases.

It has been surprisingly found that the compounds of the present invention in which R '' is -CH2OH show the same biological activity or one very similar to that of the known tubulisins (see eg international patent application document WO 9813375; and quotes from F. Sasse, H. Steinmetz, G. Hofle, H. Reichenbach, J. Antibiot. 2000, 53, 879-885; and from AW Patterson et al., Chem. Eur. J. 2007, 13 , 9534-9541), although the "Tup" unit has been replaced by a phenylalanine derivative, a much simpler structural unit that is much less complicated to synthesize. The replacement of the "Tup" unit with a derivative of a natural amino acid makes all the compounds more similar to peptides, which improves the biodegradability of the compounds in the body. In addition, this replacement leads to a reduction in the total weight of the resulting compounds, which leads to increased bioavailability. By addition, the new compounds show an increased fixation to tubulin.

Examples

In accordance with the synthesis procedures of the building blocks described herein, compounds of the formula (I) were synthesized using common methods of coupling peptides that are known to a person skilled in the art.

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Compounds of the formula (I) were prepared which fear the following residues: R: H, methyl, propyl;

R .: acetyl, -CH2OCH3;

R '':

-CH2OH;

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Y

n: 0.

Y

Synthesis Procedures

The syntheses of the respective carbonic acid derivatives, compounds MSRD334, MSRD345 and SDRD28 were performed according to procedures described in PCT / EP2008 / 003762 (WO 2008/138561). All the compounds described in this patent were characterized by a 1 H-NMR, a 13 C-NMR and a mass spectroscopy. Purity was identified by HPLC.

Synthesis of MSRD368:

MSRD356

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To a solution of a dipeptide (200 mg, 0.44 mmol) in a 1: 1 mixture of chloroform and dimethyl acetal of formaldehyde (2 ml) P2O5 (626 mg, 4.4 mmol) was added in portions. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (25 ml) and extracted with AcOEt (1x10 ml). The solvent was removed in vacuo and the crude product was purified by flash evaporation chromatography (a 7: 3 mixture of hexane and AcOEt) to give 154 mg of MSRD356 (with a yield of 70%) as a colorless oil.

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To a solution of MSRD356 (144 mg, 0.29 mmol) in a 4: 1 mixture of THF and H2O (5 ml), LiOH was added. H2O (19 mg, 0.43 mmol). The reaction was stirred for 5 h, then H2O (10 ml) and AcOEt (10 ml) were added. The layers were separated and a 1 M HCl solution was added to the aqueous phase until a pH value of 1-2 was reached. The resulting mixture was extracted with AcOEt. The organic phase was dried over anhydrous Na2SO4, filtered and the solvent removed in vacuo to give 119 mg of pure MSRD357 (with a yield of 87%) as a white solid material.

MSRD360

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To a solution of MSRD357 (109 mg, 0.23 mmol) in DMF (5 ml), HOAt (38 mg, 0.28 mmol), HATU (105 mg, 0.28 mmol) and Et3N (70 pl) were added , 0.51 mmol.) After stirring for 5 min, Tup (55 mg, 0.25 mmol) was added. The reaction mixture was stirred for 2 h. The reaction mixture was diluted with H2O (10 ml) and extracted with Et2O (1x10 ml). The organic phase was washed with a 1 N aqueous solution of HCl (1 x 15 ml), with a saturated aqueous solution of NaHCO3 (1 x 15 ml) and with brine (2 x 15 ml). After drying over anhydrous Na2SO4 and filtering, the solvent was removed in vat to give 159 mg of pure MSRD360 (with a quantitative yield) as a white foam.

MSRD362

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To a solution of the MSRD360 (149 mg, 0.22 mmol) in MeOH (5 ml), Pd / C was added. The reaction mixture was stirred for 18 h under a hydrogen atmosphere. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure to give 142 mg of pure MSRD362 as a white foam, with a quantitative yield.

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To a suspension of N-methyl-pipecolirnco acid (34 mg, 0.24 mmol) in DCM (5 ml), HOAt (35 mg, 0.26 mmol), HATU (99 mg, 0.26 mmol) were added, Et3N (67 jl 0.48 mmol) and MSRD362 (142 mg, 0.22 mmol). The reaction mixture was stirred for 4 h. The reaction was washed with H2O (10 ml), with a saturated aqueous solution of NaHCO3 (1 x 15 ml) and with brine (1 x 15 ml). After drying over anhydrous Na2SO4 and having filtered the solvent, it was removed in vacuo. The crude material was purified by subita evaporation chromatography FC (with a 97: 3 mixture of DCM and MeOH) to give 107 mg of MSRD364 (in a 63% yield) as a white foam.

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MSRD365

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To a solution of MSRD364 (102 mg, 0.13 mmol) in THF (5 ml) was added a 1 N aqueous solution of LiOH (400 mL, 0.40 mmol). The reaction was stirred for 2 days and then acidified with TFA until a pH of 1-2 was reached. The resulting mixture was washed with H2O (5 ml) and extracted with AcOEt (10 ml). The organic phase was based

15 with Et3N until a pH of 8 was reached, washed with H2O (5 ml), dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (with a 9: 1 mixture of DCM and MeOH), providing 52 mg of MSRD365 (52% yield) as a white foam. The reduction of MSRD365 to form the MSRD368 was carried out in accordance with the general procedure described below.

20 MSRD390 Synthesis:

MSRD371

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To a solution of phenylalaninol (300 mg, 1.98 mmol) in DCM (10 ml), cooled to 0 ° C, Et3N (414 pl, 2.97 mmol), imidazole (269 mg, 3.96 mmol) were added ) and TBDPCl (516 pl, 1.98 mmol). The reaction mixture was heated to t.a, (room temperature), stirred overnight and quenched with water (5 ml). The layers were separated and the organic phase was dried over anhydrous Na2SO4, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (in a 97: 3 mixture of DCM and MeOH and in a 95: 5 mixture of DCM and MeOH) to provide 647 mg of MSRD371 (84% yield) as a colorless oil.

MSRD379

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To a solution of a dipeptide (85 mg, 0.20 mmol) in DMF (5 ml) were added HOAt (33 mg, 0.24 mmol), HATU (91 mg, 0.24 mmol), EtsN (61 pl , 0.44 mmol) and MSRD371 (93 mg, 0.24 mmol). The reaction mixture was stirred for 4 h and 20 ml of Et20 was added. The reaction was washed with H20 (10 ml), with a saturated aqueous solution of NaHCO3 (1 x 15 ml) and with brine (1 x 15 ml). After drying over anhydrous Na2SO4 and having filtered, the solvent was removed in vat to give 157 mg of pure MSRD379 (with a quantitative yield) as a white foam.

MSRD380

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To a solution of MSRD379 (149 mg, 0.19 mmol) in DCM (10 ml) were added Ac2O (76 pl, 0.93 mmol), pyridine (45 pl, 0.47 mmol) and a catalytic amount of DMAP . The reaction mixture was stirred for 3 h and the solvent removed in vacuo. The residue was purified by sudden evaporation chromatography (in a 7: 3 mixture of Hex and AcOEt) to give 143 mg of MSRD380 (89% yield) as a white foam.

MSRD388

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To a solution of MSRD380 (133 mg, 0.16 mmol) in MeOH (5 ml) was added Pd / C. The reaction mixture was stirred for 18 h under a hydrogen atmosphere. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure to give 124 mg of pure MSRD388 (95% yield) as a white foam.

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To a suspension of N-methyl-pipecoffnic acid (33 mg, 0.23 mmol) in DCM (5 mL) HOAt (33 mg, 0.24 mmol), HATU (91 mg 10.24 mmol), EtsN were added (54 pl, 0.39 mmol) and MSRD388 (124 mg, 0.15 mmol). The reaction mixture was stirred for 4 h. The reaction was washed with H2O (10 ml), with a saturated aqueous solution of NaHCO3 (1 x 15 ml) and with brine (1 x 15 rnl). After drying over anhydrous Na2SO4 and having filtered, the solvent was removed in vain. The crude product was purified by flash evaporation chromatography (in a 97: 3 mixture of DCM and MeOH) to give 100 mg of MSRD389 (71% yield) as a white foam.

10 MSRD390

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To a solution of MSRD389 (89 mg, 0.09 mmol) in THF (3 ml) was added a 1 M solution of Bu4NF in THF (189 pl, 0.189 mmol). The reaction mixture was stirred for 4 min and washed with water (5 ml). The aqueous phase was extracted with AcOEt (1X10 ml). The collected organic phases were dried over anhydrous Na2SO4, filtered and the solvent removed in vacuo. The crude product was purified by sudden evaporation chromatography (in some

mixtures 97: 3 and 93: 7 of DCM and MeOH) to give 59 mg of MSRD390 (94% yield) as a colored foam

White. All anaphytic data (HnMr, CNMR, MS) correspond to the structure of MSRD390.

General procedure for the reduction of carbonic acid derivatives MSRD334, MSRD345, MSRD368 and SDRD28:

To a solution of the corresponding derivative of carbonic acid (0.04 mmol) in THF (2 ml), Et3N (7 pl, 0.05 mmol). After cooling the reaction mixture to 0 ° C, EtOCOCl (5 pl, 0.05 mmol) was added. The reaction mixture was stirred at the same temperature for 30 min and filtered through celite. Then the solution was added to a solution of NaBH4 (3.0 mg, 0.08 mmol) in water (1 ml) and cooled to 0 ° C. The reaction mixture was stirred at the same temperature for 30 min, quenched with H2O (5 ml) and extracted with EtOAc (1x5 ml). The solvent was removed in

25 ford and the crude product was purified by flash evaporation chromatography (in a 94: 6 mixture of DCM and MeOH)

to give 24 mg of the corresponding alcohol (81% yield) as a white foam.

Determination of the 50% CI-50 inhibitor concentration against various lineages of cancer cells

The activity of some representative examples compounds of the present invention has been determined with the BrdU assay as described in: Porstmann T., Ternynck T., Avrameas S. (1985) “Quantification of incorporation

of 5-bromo-2-deoxyuridine a DNA: an enzymatic immunological assay for the determination of the proliferative response of lymphoid cells ”J. Immunol. Methods 82: 169-179.

The results are shown in Table 1.

Table 1

 Compound

 IC50 of cell lineage [nM]

 HCT- 116

 ■> or CO CO MCF- 7 MCF-7 MX100 MCF-7 TX200 MCF-7 VP

 1.06 1.05 0.57 0.62 15.55 0.88

 MSRD334

 1.35 1.18 0.40 0.28 50.56 1.20

 MSRD354

 a -ax / i x ° 1 2 ^ I-J M JL ^ oh

 41.0 29.91 3.91 4.01 322.3 6.38

 MSRD368

 CV / XW.X0

 1.10 1.06 0.27 0.20 24.41 0.54

 MSRD390

 4.31 3.35 0.55 1.41 370.2 3.04

 SDRD28

In general, the new molecules of the present invention show an activity against various lineages of cancer cells that are comprised between 0.1 and 400 nM

Determination of the destabilization effect against microtubules (Figure 1)

Figure 1 shows the effect of destabilization against microtubules. To verify that the new compounds 10 according to formula (I) are showing a destabilizing effect against microtubules, in vitro activity was measured in a tubulin polymerization test. As controls, a tubulin stabilizing agent (taxol) and strong destabilizing agents (vinblastine and tubulisin A) were used. The new compounds show a remarkable destabilizing effect against microtubules such as, for example, vinblastine.

Determination of the concentration dependence of the microtubule polymerization

Figures 2a-e show the dependence with respect to the concentration in the microtubule polymerization test. A clear, concentration-dependent effect against microtubule polymerization was determined.

5 Determination of in vitro activity in the tubulin polymerization test

Figures 3a - e shows that the CI-50 concentration against tubulin polymerization. The IC-50 concentration of the activity against polymerization was determined and compared with strong inhibitors of microtubule skeletons such as eg vinblastine, tubulisin A.

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Claims (9)

1. A compound of the formula (I): image 1 R is H or an alkyl, alkenyl, alkynyl, CO-alkyl or heteroalkyl group, all of which may be optionally substituted; R 'is H or an alkyl, alkenyl, alkynyl, CO-alkyl or heteroalkyl group, all of which may be optionally substituted; R '' is a group of the formula CH2OH or 10 n is 0,1,2, 3, 4 or 5; the Y are, independently, alkyl, heteroalkyl, halogen, CN, NO2 or OH, optionally substituted; or a pharmacologically acceptable salt, a solvate, a hydrate or a pharmacologically acceptable formulation thereof. 2. A compound according to claim 1, wherein R is H or C1-C6 alkyl. 3. A compound according to claim 1 or 2, wherein R 'is -CO-alkyl, alkyl or heteroalkyl. 4. A compound according to any one of claims 1 to 3, wherein R "is image2 image3 5. A compound according to any one of claims 1 to 3, wherein R "is CH2OH. 6. A compound according to any one of claims 1 to 5, wherein n is 0. A compound according to claim 1, wherein R is C1-C6 alkyl, R 'is -CO-alkyl or heteroalkyl, n is 0 and R '' is -CH2OH or image4 8. A compound according to claim 1, wherein R is methyl, R 'is acetyl, n is 0 and R' 'is image5 9. A pharmaceutical composition containing a compound according to any one of the claims 5 1 to 8 and optionally one or more vehicles and / or adjuvants. 10. A compound or pharmaceutical composition according to any one of claims 1 to 9 for use as a medicament for the treatment and / or prevention of cancerous diseases. 11. The use of a compound or a pharmaceutical composition according to any one of claims 1 to 9, for the preparation of a medicament for the treatment of diseases 10 cancerous