SK2352001A3 - New use of taxoid derivatives - Google Patents

Abstract

The present invention relates a new use of taxoid derivatives. It relates more precisely to a method for treating abnormal cell proliferation of different resistant cell lines expressing multidrug resistance P-glycoprotein. This type of cells are representative of colon cancer cells. The products of the present invention are also usable to treat the colon cancer of mammals including men.

Description

The present invention relates to a new use of taxoid derivatives. More specifically, it relates to a method of treating abnormal cell proliferation of various resistant cell strains expressing P-glycoprotein that is resistant to multiple drugs (multidrug resistance by P-glycoprote). These cell types include colon cancer cells.

SUMMARY OF THE INVENTION

The present invention relates to the treatment of abnormal proliferation of various drug resistant P-glycoprotein-expressing cell strains that are resistant to multiple drugs, and also to the treatment of colon tumors in mammals, including humans, by administering a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof:

where

Z-0 .....

HO ococh ₃

OCOC ₆ H _p

Z is hydrogen or a group of formula II:

R ¹ NH 0 (II)

OH: · where · where:

R ¹ is a benzoyl group optionally substituted by one or more identical or different atoms or groups selected from the group consisting of halogen atoms and C 1 -C 4 alkyl groups, C 1 -C 4 alkoxy groups or trifluoromethyl groups;

tenoyl or furoyl or R ² -O-CO-, wherein R ² is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 cycloalkyl C 1 -C 6 cycloalkenyl, C 4 -C 6 cycloalkenyl or C 7 -C 10 bicycloalkyl optionally substituted by one or more substituents selected from the group consisting of halogen and hydroxyl, C 1 -C 4 alkoxy carbon, dialkylamino in which the alkyl moieties contain 1 to 4 carbon atoms, piperidino or morpholino, 1-piperazinyl (optionally substituted in the 4-position with C1-4 alkyl or a phenylalkyl having 1 to 4 carbon atoms) , cycloalkyl groups and containing from 3 to 6 carbon atoms, cycloalkenyl of from 4 to 6 carbon atoms, phenyl (optionally substituted by one or more atoms or groups selected from halogen and C1-C4 alkyl or C1-C4 alkoxy) , a cyano or carboxyl group or an alkoxycarbonyl group in which the alkyl moiety contains 1 to 4 carbon atoms, a phenyl group or an α- or β-naphthyl group optionally substituted by one or more atoms or groups selected from halogen atoms and alkyl groups C 1 -C 4 groups or C 1 -C 4 alkoxy groups or a five-membered aromatic heterocyclic group preferably selected from furyl and thienyl, or a saturated heterocyclic group having 4 to 6 carbon atoms, optionally substituted by one or more C 1-4 alkyl groups

R ³ is a straight or branched (C 1 -C 8) alkyl, a straight or branched (C 2 -C 8) alkenyl, a straight or branched (C 8 -C 8) alkynyl, (C 3 -C 6) cycloalkyl, phenyl or an alkyl group or a β-naphthyl group optionally substituted with one or more atoms or with a group selected from alkenyl, halogen, alkynyl, aryl and alkyl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl group, hydroxyalkyl, mercapto, formyl, acyl, acylamino, amino, amino, aroylamino, alkylamino, alkoxycarbonyldialkylamino, carboxyl, yl, alkoxycarbonyl, carbamoalkylcarbamoy pina, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, or a five-membered aromatic group; a heterocycle containing one or more identical or different heteroatoms selected from the group consisting of nitrogen and optionally substituted with one oxygen atom and an atom or more of the same sulfur or different substituents selected from the group consisting of halogen atoms and alkyl, aryl, amino, an alkyl amino group, a dialkylamino group, an alkoxycarbonylamino group, an acyl group, an arylcarbonyl group, a cyano group, a carboxyl group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group or an alkoxycarbonyl group, aromatic heterocyclic groups include alkyl groups or alkyl moieties of other 1 to 1 carbon atoms and that alkenyl and alkynyl groups contain 2 to 8 carbon atoms and that the aryl groups are or α- or β-naphthyl, phenyl

R ⁴ is a (C 1 -C 6) alkoxy, straight or branched chain, (C 3 -C 6) alkenyloxy, (C 3 -C 6) alkynyloxy, (C 3 -C 6) cycloalkoxy (C 3 -C 6) or a cycloalkenyloxy group containing up to 6 carbon atoms, these groups being optionally substituted by one or more halogen atoms or alkoxy groups having 1 to 4 carbon atoms, alkylthio groups having 1 to 4 carbon atoms or carboxyl groups, alkyloxycarbonyl groups having 1 to 4 atoms in the alkyl moiety carbon, cyano or carbamoyl groups or N-alkyl carbamoyl groups or N, N-dialkylcarbamoyl groups each of which contains from 1 to 4 carbon atoms or together with the nitrogen atom to which they are attached are saturated, 5- or 6-membered heterocyclic moiety optionally containing a second heteroatom selected from oxygen, sulfur or nitrogen, optionally substituted with a C 1-4 alkyl group or a phenyl or phenylalkyl group in which the alkyl moiety contains 1 to 4 atoms alkyl,

R ⁵ is C 1 -C 6 alkoxy in straight or branched chain, C 3 -C 6 alkenyloxy, C 3 -C 6 alkynyloxy, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkenyloxy are optionally substituted with one or more halogen atoms or (C 1 -C 4) alkoxy, (C 2 -C 4) alkylthio or carboxyl groups, (C 1 -C 4) alkyloxycarbonyl groups, cyano (C 1 -C 4) or carbamoyl or N-alkylcarbamoyl; or N, N-dialkylcarbamoyl groups, each alkyl moiety of from 1 to 4 carbon atoms, or together with the nitrogen atom to which they are attached, form a saturated 5- or 6-membered heterocyclic moiety optionally containing a second heteroatom selected from oxygen, sulfur or nitrogen, optionally substituted with a C1-C4 alkyl group or a phenyl or phenylalkyl group wherein the alkyl moiety contains 1 to 4 carbon atoms,

Preferably the aryl groups which may represent a R ³ group are a phenyl group or an α- or β-naphthyl group optionally substituted by one or selected from the group consisting of a chlorine atom, a bromine atom, an alkenyl group, an arylalkyl group,

a plurality of atoms or groups of a halogen atom (fluorine, atom, alkynyl, aryl, alkoxy, alkylthio, aryloxy, s, arylthio, hydroxy, hydroxyalkyl mercapto, formyl, acyl, alkoxy, acylamino, acylamino, acylamino, acylamino, acylamino, acylamino, acylamino) , alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylxarbamoyl, cyano, nitro and trifluoromethyl, it being understood that alkyl groups and alkyl moieties of other groups contain 1 to 4 carbon atoms, that alkenyl and alkynyl groups contain 2 and the aryl groups are phenyl or α- or β-naphthyl.

Preferably, the heterocyclic group which may represent R ³ is a five-membered aromatic heterocyclic group containing one or more of the same or different atoms selected from nitrogen, oxygen and sulfur, optionally substituted with one or more of the same or different substituents selected from the group consisting of halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom) and a (C 1 -C 4) alkyl group, a (C 6 -C 10) aryl group, a (C 1 -C 4) alkoxy group, a (C 6 -C 10) aryloxy group, amino, (C 1 -C 4) alkylamino, (C 1 -C 4) dialkylamino, acylamino (C 1 -C 4), (C 1 -C 4) alkoxycarbonylamino, acyl 1 to 4 carbon atoms, arylcarbonyl of 6 to 10 carbon atoms in the aryl part, cyano, carboxyl group

4

Or a carbamoyl group, an alkylcarbamoyl group having 1 to 4 carbon atoms in the alkyl moiety, a dialkylcarbamoyl group having 1 to 4 carbon atoms in each alkyl moiety, or an alkoxycarbamoyl group containing up to 4 carbon atoms in the alkoxy moiety.

Preferably, the groups R ⁴ and R ⁵ , which may be the same or different, a straight or branched alkoxy group having 1 to 6 carbon atoms, which is optionally substituted by a group selected from the group consisting of ethylthio, carboxyl, methoxy, ethoxy, methoxycarbonyl , ethoxycarbonyl,

N-methylcarbamoyl,

N, N-dimethylcarbamoyl, cyano, carbamoyl

N-ety1karbamoylová

N, N-diethylcarbamoyl, s, group,

N-pyrrolidinocarbonyl or

N-piperidinocarbonyl group.

More specifically, the present invention relates to a compound of formula I wherein Z is a hydrogen atom or a group of formula II wherein R ¹ is a benzoyl group or a group of formula R ² -O-CO- wherein R ² is a tert-butyl group and R ^J is an alkyl group C 1 -C 6 alkenyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, phenyl optionally substituted with one or more identical or different atoms or groups selected from the group consisting of halogen atoms (fluorine, chloro) and alkyl (methyl), alkoxy (methoxy), dialkylamino (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (tert-butoxycarbonylamino) or trifluoromethyl or 2- or 3-furyl, thienyl or 2-, 4- or 5-thiazolyl and R ⁴ and R ⁵ , which may be the same but or different, each is a straight or branched alkoxy group having 1 to 6 carbon atoms.

More particularly, the present invention relates to a compound of formula I wherein Z is a hydrogen atom or a group of formula II wherein R ¹ is a group or a group R ² -O-CO- wherein R ² is tert- butyl

R ³ is isobutyl, isobutenyl, benzoyl and benzoyl, butenyl, cyclohexyl, phenyl,

2-furyl group,

3-furyl, 2-thienyl,

3-thienyl with a group, group or

2-thiazolyl, 4-thiazolyl

5-thiazolyl and R ⁴ a

R ⁵ , which may be the same or different, are each methoxy, ethoxy or propoxy.

Even more preferred are compounds of formula I wherein R ³ is phenyl and R 1 is tert-butoxycarbonyl, R ⁴ and R ⁵ , which may be the same or different, are methoxy, ethoxy or propoxy.

Even more preferably, the present invention relates to 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-β, 10β-dimethoxy-9-oxo-11-taxen-13α-yl- (2R, 3S) - 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate of formula Ia

It is known from the international patent application WO 96/30355 to prepare a derivative according to the present invention by two processes. According to the first, multi-step process, starting from 10-deacetyl baccatin of formula III:

· · · · · · · · · · · · · · · · · · ·

which is selectively protected at positions 7 and 13, for example in the form of silyl ether, followed by reaction with a compound of the formula

IV:

R-X wherein R is a group as defined above and X is a reactive ester group, such as a sulfuric or sulfonic acid ester or a halogen atom, to yield a compound that carries a unit

-OR at position 10 and silyl groups at position a 13.

Then, the silyl protecting groups are replaced with hydrogen atoms to give a compound that still bears the coupon

The -OR position and the hydroxyl groups at the 13 position.

This derivative is etherified selectively at the 7-position by reaction with a derivative of the formula

IV is a hydrogen atom.

The last step involves esterification at the 13-position according to a method known to those skilled in the art, wherein the derivative of formula Ia, wherein Z is hydrogen, is reacted in the presence of β-lactam, for example according to the method described in EP 617,018, or oxazolidine as described, for example, in International Patent Application WO 96/30355, cited above. Removal of the protecting groups from positions 7 and 10 yields a derivative of the formula Ia, in which Z is as hydrogen and R is hydrogen. The next step involves the reaction at the 7 and 10 positions with the action of a reagent prepared m situ from the sulfoxide of formula V and the acid anhydride (Pummer-type reaction),

R-SO-R (V) wherein R has the same meaning as previously described to give the alkylthioalkyloxy group at the 7 and 10 positions.

The final step to give the desired compound Ia is carried out with the intermediate obtained prior to this activated Raney nickel treatment.

Generally, the treatment of an agent prepared m situ from a sulfoxide of formula V, preferably dimethylsulfoxide, and acetic anhydride is carried out in the presence of acetic acid or an acetic acid derivative such as haloacetic acid at a temperature of 0 to 50 ° C.

Generally, the treatment of activated Raney nickel in the presence of an aliphatic alcohol or ether is carried out at a temperature of -10 to 60 ° C.

FR 97-14442 describes the following procedure. The present invention makes it possible, in one step, to directly, selectively simultaneously alkylate two hydroxyl functional groups at the 7-position of 10-deacetylbaccatin

an esterified position derivative thereof

wherein A is a hydrogen atom or a side chain of Formula IIIa below:

(IIa) wherein G is a hydroxyl protecting group, R ¹ and R ³ have the same meaning as in formula II or the oxazolidine unit of formula Id:

• · · · · ·

(IIb) wherein R ¹ and R ³ have the same meaning as in formula II, R ^a and R ^b , which may be the same or different, are a hydrogen atom or an alkyl group, an aryl group, a halogen atom, an alkoxy group, an arylalkyl group, alkoxyaryl, haloalkyl, haloaryl, wherein the substituents may optionally form a four to seven membered ring.

Preferably, 10-deacetylbaccatin is used as the starting material, i. the compound of formula III, which makes the process famous and further avoids the step of protecting and deprotecting the intermediate required in the foregoing procedures.

With respect to the protecting groups G of the hydroxyl functional groups in the formula IIa, it is generally preferred to select all the protecting groups described in the books such as Greene and Wuts, Protective Groups in Organic Synthesis, 1991, John Wiley & Sons, and MacOmie, Protective Groups in Organic Chemistry, 1975, Plenum Press, and which are removed under conditions that do not degrade or otherwise degrade the rest of the molecule, such as ethers and preferably ethers such as methoxymethyl ether, 1-ethoxyethyl ether, benzyloxymethyl ether, p-methoxybenzyloxymethyl ether, benzyl ethers optionally substituted with one or more groups such as methoxy, chloro, nitro, 1-methyl-1-methoxyethyl ether, 2- (trimethylsilyl) ethoxymethyl ether, tetrahydropyranyl ether and silyl ethers such as trialkylsilyl ethers, carbonates such as trichloroethyl carbonates.

More specifically, the groups R ^a and R ^b of formula IIb are selected from those described in International Patent Application WO 94/07878, and more preferred derivatives are those wherein R ^a is an atom

·· ···· ·· • ·

9

9

9999 hydrogen and R ^b is p-methoxyphenyl.

The alkylating agents are selected from the group consisting of:

Alkyl halides and preferably alkyl iodides (RI) alkyl sulfates such as methyl sulfate oxonium salts such as trialkyloxonium boronic acid salts, in particular trimethyloxonium tetrafluoroborate (Me ₃ OBF ₄ ).

Preferably methyl iodide is used.

The alkylating agent is used in the presence of an anionizing agent such as one or more strong bases in an anhydrous medium.

Policies that can be used in anhydrous media include:

• alkali metal hydrides such as sodium or potassium hydride • alkali metal alkoxides such as potassium tert-butoxide • silver oxide Ag ₂ O • 1, S-bis (dimethylamino) naphthalene • mono- or di-alkali mixtures as described for example in publications such as P. Caubere Chem. Rev. 1993, 93, 2317-2334 or M. Schlosser Mod. Synth. Methods (1992)

6, 227-271; particularly preferred are alkyllithium / alkali metal tert-butoxide or alkali metal amide / alkali metal tert-butoxide combinations. One of the two principles can be generated m situ.

Among all possible combinations of the alkylating agent and the anionizing agent, it is preferred to use methyl iodide in the presence of potassium hydride.

The reaction is preferably carried out in an organic medium which is inert under the reaction conditions. Preferably, for example, the following solvents are used:

Ethers, such as tetrahydrofuran or dimethoxyethane, when silver oxide is used, it is preferable to use polar aprotic solvents such as is dimethylformamide or aromatic solvents such as toluene when 1,8-bis (dimethylamino) naphthalene is used, it is preferable to use alkyl esters such as ethyl acetate. For the sake of a better embodiment of the present invention, it is preferable to use a molar ratio between the anionizing agent and the substrate greater than 2 and preferably 2 to 20.

It is also preferred to use a molar ratio between the alkylating agent and the substrate of greater than 2 and preferably 2 to 40.

It is preferred to use a reaction temperature of -30 ° C to 80 ° C.

The reaction is preferably carried out for a few hours to 48 hours, depending on the reagents selected.

The alkylation step, when carried out with 10-deacetylbaccatin, is followed by an esterification step known to those skilled in the art and is described, for example, in the patent

EP 617,018 or in the international patent application

WO 96/30355, which are mentioned above.

Thus, according to the first, three-step process, the process is first initiated by dialkylating 10-deacetylbaccatin using an alkylating agent in the presence of a strong base, in a second step 10-deacetylbaccatin, dieterified at positions 7 and 10, is condensed with a suitably is selected from the group consisting of tertiary amines and metal bases which give rise to the alkoxide at the 13-position. The deprotection of the side chain is then effected by treatment with an inorganic or organic acid.

According to the second, three-step process, the process is first initiated by dialkylating 10-deacetylbaccatin using an alkylating agent using an alkylating agent. 1a in the presence of a strong base, in a second step, 10-deacetylbaccatin, dietherified at positions 7 and 10, is condensed at position 13 with oxazolidine in the presence of a condensing agent such as diimides in the presence of an activating agent such as dialkylaminopyridines. The opening of the oxazolidine is achieved by treatment with an inorganic or organic acid.

According to a third method, the process is initiated by esterification at the 13-position of baccatin, which is suitably protected at the 7 and 10 positions, with β-lactam or oxazolidine in the presence of a condensing agent and / or activating agent as described in the above two procedures.

After deprotection of positions 7 and 10, dietherification at positions 7 and 10 is carried out with an alkylating agent in the presence of a strong base.

Deprotection from the side chain is achieved by treatment with an inorganic or organic acid.

The products of formula I have significant biological properties.

The compounds of formula I have been shown to be active in C51 adenocarcinoma transplanted mice or in vivo.

C38 colon at doses of 1 to 30 mg / kg, as well as against other liquid or solid tumors.

The compounds of formula I have antitumor properties, more specifically they are active against tumors that are resistant to Taxol® and Taxotere®. Such tumors include, for example, colon tumors that have overexpression

P-glycoprotein, which is resistant to multiple drugs.

Multidrug resistance is a common term relating to tumor resistance to various compounds having different actions. In general, taxoids are known to be highly recognized by mechanisms of experimental tumors such as P388 / DOX, a mouse leukemia cell selected for doxorubicin (DOX) resistance that expresses P-glycoprotein. The compounds of the present invention are less recognized by P388 / DOX.

More specifically, the compounds are less recognized than Taxotere®.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

In particular, the compounds of formula I are used for the preparation of a medicament for the treatment of abnormal proliferation of cell strains expressing

P-glycoprotein, which is resistant to multiple drugs.

Compounds of formula

In particular, they are used for the preparation of a medicament for the treatment of colon cancer.

A compound, in particular a compound of the formula

I, where R ⁴ and R ⁵ are both active compared to

Taxotere®, when treated with other known taxoids, is a cancer cell strain expressing P-glycoprotein that is resistant to multiple drugs. It is also tumor cells resistant to Doxorubicin or

Vmcristí nu.

The compound of formula I may be used simultaneously with at least another therapeutic treatment. It is more preferred to use it with a therapeutic treatment comprising antineoplastic agents with one other drug, monoclonal antibodies, immunotherapy, radiotherapy, or with biological response modifiers.

The compound of formula I is preferably administered parenterally, for example intravenously, intraperitoneally, intramuscularly or subcutaneously.

Example 1

1. Introduction

The compound of formula Ia is a potent antitumor agent in preclinical models.

In vitro antiproliferative properties on resistant cell strains

Docetaxel has been found to be cross-resistant to multiple drug-resistant P-glycoprotein strains (Rigel I. and Horwitz S.B.,

Studies with RP 56976 (Taxotere (R): a semisynthetic analogue of

Taxol, J. Natl. Cancer Inst. 83: 288-291 (1991)).

The cytotoxicity of Compound 1a was tested against various resistant, multi-drug resistant P-glycoprotein cell strains, as compared to docetaxel after 4 days of continuous exposure using standard methods.

The resistance factor was calculated by dividing the IC ₅₀ value obtained on resistant cells by the IC ₅₀ value obtained on sensitive cells.

Compound 1a was found to be more active than docetaxel in all resistant tumor cell strains that were tested.

Interestingly, compound la was found to be at least cross-resistant in P388 / TXT cell strains,

P388 / VCR, HL60 / TAX and Calcl8 / TXT, which are moderately cross - resistant to docetaxel (a factor of clinical situation.

and which may better represent compounds of cellular was found strains, a strong decrease in cross resistance: 7.6 which are most resistant to resistance up to 10) for docetaxel for two

KB VI and P388 / DOX

The compound of formula Ia was also tested on a cellular basis

P388 / CPT5 in Camptothecin Resistant Mice Not Expressed

P-glycoprotein.

A strong decrease in cross-resistance was observed for the compound of formula Ia and docetaxel resistance:

10.5) compared to camptothecin resistance:

These results indicate the potential use of a compound of formula Ia for the treatment of tumors having acquired resistance to camptothecin derivatives.

········

Table 0.1: Relative resistance of the compound of formula Ia and docetaxel to resistant cell strains expressing

P-glycoprotein

Resistant cell strain Resistance Factor mdr 1 mRNA level * docetaxel Compound of Formula Ia P388 / DOX 50.7 10,0 + + + P388 / TXT 4.8 1.8 + + P388 / VCR 5.8 1.8 + + HL60 / TAX 8.1 2.5 + + Calc 18 / TXT 23.5 4.3 + + KB VI 59, 0 7.6 + + + +

* Relative expression obtained from Northern blot using human mdrl gene as probe

CaCo2

The antiproliferative properties of the compound of formula Ia and docetaxel were tested in a human CaCo-2 cell line (ATCC HTB37), which was found to include a basal level of expression of the P-glycoprotein encoded by the mdr1 gene. A 96-well plate procedure, drug contact time (96 hours) and neutral red staining of viable cells were used. The results are expressed as IC ₅₀ and are summarized in the following table.

In vitro inhibitory effect of compound of formula Ia and docetaxel on CaCo-2 cell growth

Cells The drug IC ₅ o (pg / ml) * Caco-2 docetaxel compound of formula Ia 108 + 17 22 + 3

* Numbers in brackets: number of attempts

The compound of formula Ia is cytotoxic to CaCo-2 cells at IC ₅₀ in the range described in other human cell strains tested, i. HL60, Calcl8 and KB (see previous paragraph). However, docetaxel exhibits a higher IC ₅₀ on CaCo-2 cells, equivalent to 4.9 times the value observed for the compound of formula Ia. Therefore, the higher antiproliferative activity of the compound of Formula Ia (as compared to docetaxel) on CaCo-2 cells is consistent with the lower recognition of the compound of Formula Ia, as docetaxel, by the β-glycoprotein endogenously expressed by this cell strain.

In vivo anti-tumor activity

In vivo dosing schedules and antitumor efficacy studies were performed using a preclinical standard formulation of the compound of Formula Ia in ethanol: polysorbate 80 (50:50 by volume). After dilution, the final concentration was 5% ethanol, 5% polysorbate, 90% 5% glucose in water.

A composition containing a compound of formula Ia solubilized in polysorbate 80 was then prepared. After dilution, the final polysorbate 80 concentration was 5%. Unless otherwise stated, in the summaries that follow, in vivo studies were conducted using a standard over-the-counter formulation.

The compound of formula Ia was administered by the intravenous route (i.v.). Experiments and data analysis were performed in a standard manner.

the following two result evaluation parameters:

The resulting activities obtained when testing subcutaneously implanted solid tumors were:

inhibition of tumor growth, T / C, where T and C are average tumor weights in mg of treatment and control groups. According to NCI standards, T / C> 42% is inactive, T / C f 42% is the minimum level of activity.

T / C <10%, ++, is considered to be a high level of antitumor activity that justifies further development (DN-2 level).

Tumor growth retardation, TC, where T and C are the average days in days for tumors of the treated and untreated groups to reach a predetermined size (750 to 1500 mg) of log dead cells, were also used in cases of anti-tumor activity. , which is the logarithm of the total number of cells killed by treatment. This value can be converted to any measure of activity by the Southern Research Institute (SRI): log of total dead cells <0.7 = -inactive; 0.7 to 1.2 = +; 1,3 to

1.9 = ++; 2.0 to 2.8 = +++; > 2.8 = ++++ highly active.

In advanced tumor stages, regression may be either partial (greater than 50% reduction in tumor mass) or complete. Full regression is included in partial regression.

The end result obtained when testing activity in intraperitoneally implanted leukemia was the percentage increase in the life span of the host (% ILS), calculated relative to the mean day of death.

The NCI criteria for activity are as follows:

P388: highly active, ++ 2 75% ILS; active, + 27-74% ILS; inactive, <27% ILS.

Toxicity was derived from drug death (2 10%) or weight loss> 20%.

If necessary docetaxel was used in the comparative tests.

Colon tumors

Colon 51

The compound of formula Ia was administered i.v. on day 4, 6, 8. High activity was found in HNTD (9.3 mg / kg / injection) with 0% T / C and 2.6 log dead cells. Lower dosing yielded 2.2 log dead cells. Docetaxel has also been shown to be highly active at 3.1 log dead cells.

Evaluation of the efficacy of the compound of Formula Ia administered i.v. C51 colon adenocarcinoma in female BALB / c mice

agent dose mg / kg per injection Schedule in days T / C in% day 18 T-C in days Log dead cells in total comment Bile. vz. 24.2 4, 6, 8 - - - Toxic (5/5 DD) ia 15, 0 - - - Toxic (1/5 DD) 9, 3 0 25, 8 2, 6 HNTD active 5.8 0 21.9 2, 2 active docetaxel 24, 2 4,6,8 - - - - Toxic 22, 8 ' bwl 0 31, 1 3, 1 HNTD high active 0 22, 4 2.2 active 4 8.9 0.9 active

Mean time at which the tumor reaches a weight of 750 mg at control = 15.1 days

Abbreviations used: HNTD = highest non-toxic dose, bwl = weight loss, DD = drug-related death

Advanced Stage 38

The compound of formula I was administered to i.v. mice having a tumor of 200-400 g. HNTD (20 mg / kg / injection) showed high activity and achieved 5/5 complete regression, all mice were tumor free on day 139. The lower dose (12.4 mg / kg / injection) induced the same number of complete regressions and 80% of the mice survived without tumors. For comparison, docetaxel gave only a 40% partial regression in the same test in HNTD.

Evaluation of i.v. of a compound of formula Ia administered to advanced stage adenocarcinoma C38 colon in female mice

B6D2F1

agent Dose in mg / kg per dose Schedule in days T-C in days Log dead cells in total Full regression comment Merge 'j z. 32, 2 14, 17,20 - - - Toxic (1/5 DD) ia 20, 0 - - 5/5 HNTD highly active (5/5 TRS) 12.4 - - 5/5 highly active (4/5 TFS) 7.7 25.0 2.7 2/5 active docetaxel 32.2 14,17,20 - - - Toxic 20.6% bwl 20, 0 29, 1 3, 1 0/5 HNTD highly active 12.4 6, 1 0.7 0/5 marginal activity 7.7 2.5 0, 3 0/5 inactive

• · · · · ·

Mean time to reach 1000 mg tumor weight at control = 18.5 days

Abbreviations used: HNTD = highest non-toxic dose, bwl = weight loss, DD = drug-induced death, TFS = mice that were tumor free on day 139.

• · · · · ·

Claims (9)

Use of a compound of formula I for the preparation of a medicament for the treatment of abnormal cell proliferation of multi-drug resistant P-glycoprotein-expressing cell strains, said use comprising administering to a mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. ) Z is hydrogen or a group of formula II: R ¹ NH 0 (II) Oh where: R ¹ is a benzoyl group optionally substituted by one or more identical or different atoms or groups selected from the group consisting of halogen atoms and C 1 -C 4 alkyl groups, C 1 -C 4 alkoxy groups or trifluoromethyl groups; tenoyl or furoyl or R ^-O-CO-, wherein R ² is C až-C alkyl alkyl, C až-C alk alkenyl, C až-C alk alkynyl C 8 -C 3 cycloalkyl, C 4 -C 6 cycloalkenyl or C 7 -C 10 bicycloalkyl optionally substituted by one or more substituents selected from the group consisting of halogen and hydroxyl C1-4 alkoxy, dialkylamino in which the alkyl moieties contain 1-4 carbon atoms, piperidino or morpholino, 1-piperazinyl (optionally substituted in the 4-position with C1-4 alkyl or phenylalkyl) alkyl moieties of 1 to 4 carbon atoms ), C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, phenyl (optionally substituted with one or more atoms or groups selected from halogen atom and C 1 -C 4 alkyl or C 1 -C 4 alkoxy groups) carbon atoms), a cyano group or a carboxyl group or an alkoxycarbonyl group in which the alkyl moiety contains 1 to 4 carbon atoms, a phenyl group or an α- or β-naphthyl group optionally substituted by one or more halogen atoms or alkyl groups containing 1 1-4 carbon atoms or 1-4 alkoxy groups or a five-membered aromatic heterocyclic group preferably selected from furyl and thienyl, or a saturated heterocyclic group having 4 to 6 carbon atoms, optionally substituted with one or two or more having a plurality of alkyl groups containing 1 to 4 carbon atoms, R ³ is a straight or branched (C 1 -C 8) alkyl group, a straight or branched (C 1 -C 8) alkenyl group (C 2 -C 8), straight or branched alkynyl C 2 -C 8 -cycloalkyl, C 3 -C 6 -cycloalkyl, phenyl or substituted with one or more β- or naphthyl or more, or optionally with a group selected from halogen, alkenyl, and alkyl alkynyl, aryl, arylalkyl, aryloxy, arylthio, alkoxy, alkylthio, hydroxyl, hydroxyalkyl, mercapto, formyl aroylamino, acylamino, amino, amino, alkoxy, alkylamino, alkylamino, carboxy, alkoxy , a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl nitro group and a trifluoromethyl group, a cyano group, or a five-membered aromatic heterocycle containing one or more of the same or different nitrogen-containing groups, heteroatoms in the and selected from the group consisting of or halogen and alkyl, aryl, alkylamino, dialkylamino, amino, alkoxycarbonylamino, acyl, arylcarbonyl, carbamoyl, carbamoyl, carbamoyl, carbamoyl, carbonyl, carbamoyl, carbonyl, carbamoyl, carbonyl, , a group, a group, a dialkylcarbamoyl or cyano group, an alkylcarbamoyl alkoxycarbonyl group, which is to be understood as being in the substituents of the phenyl group, and a β-naphthyl group and an aromatic heterocyclic group contain alkyl groups or alkyl portions of other groups having 1 to 4 carbon atoms and that alkenyl and alkynyl groups contain 2 to 8 carbon atoms and that the aryl groups are phenyl or α- or β-naphthyl, R ⁴ is • an alkoxy group containing 1 in unbranched or branched -to 6 chain, carbon carbon alkenyloxy containing 3 to 6 carbon carbon in unbranched or branched chain, al kmyloxys group containing 3 to 6 carbon carbon in unbranched or branched chain, cycloalkoxy containing 3 up to 6 carbon atoms or cycloalkenyloxy containing From 4 to 6 carbon atoms r these groups are optionally substituted by one or more halogen atoms or C1-C4 alkoxy, C1-C4 alkylthio or carboxyl, C1-C4alkyloxycarbonyl, cyano or carbamoyl groups in the alkyl moiety; -alkylcarbamoyl groups or N, N-dialkylcarbamoyl groups, each alkyl moiety of from 1 to 4 carbon atoms, or together with the nitrogen atom to which they are attached, form a saturated 5- or 6-membered heterocyclic moiety optionally containing a second heteroatom selected from oxygen, or a nitrogen atom optionally substituted by a C1-C4 alkyl group or a phenyl or phenylalkyl group in which the alkyl moiety contains 1 to 4 carbon atoms, R ⁵ is a (C 1 -C 6) alkoxy in a straight or branched chain, (C 3 -C 6) alkenyloxy, (C 3 -C 6) alkynyloxy, (C 3 -C 6) cycloalkyloxy, (C 3 -C 6) cycloalkenyloxy these groups are optionally substituted by one or more halogen atoms or alkoxy groups having 1 to 4 carbon atoms, alkylthio groups having 2 to 4 carbon atoms or carboxyl groups, alkyloxycarbonyl groups having 1 to 4 carbon atoms in the alkyl moiety, cyano groups or carbamoyl groups or N-alkylcarbamoyl groups or N, N-dialkylcarbamoyl groups, each alkyl moiety having 1 to 4 carbon atoms or, together with the nitrogen atom to which they are attached, form a saturated 5- or 6-membered heterocyclic moiety; optionally containing a second heteroatom selected from oxygen, sulfur or nitrogen, optionally substituted with a C 1 -C 4 alkyl group or a phenyl or phenylalkyl group wherein the alkyl moiety contains 1 to 4 carbon atoms. Use of a compound according to claim 1, wherein Z is a hydrogen atom or a group of formula II, wherein R ¹ is a benzoyl group or a group of formula R ² -O-CO, wherein R ² is a tert-butyl group and R ³ is an alkyl group containing 1 C 1 -C 6 alkenyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, phenyl optionally substituted with one or more identical or different atoms or groups selected from the group consisting of halogen atoms and alkyl, alkoxy, dialkylamino, acylamino, alkoxycarbonylamino or trifluoromethyl or 2- or 3-furyl, 2- or 3-thienyl or 2-, 4- or 5-thiazolyl and R ⁴ and R ⁵ , which may be the same or different, are each unbranched or branched alkoxy group having 1 to 6 carbon atoms. Use of a compound according to claim 2, wherein Z is a hydrogen atom or a group of formula II, wherein R ¹ is a benzoyl group or a group of formula R ² -O-CO-, wherein R ² is a tert-butyl group and R ₃ is an isobutyl group; isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl group, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl and R ⁴ and R ⁵ , which may be the same or different, are each methoxy, ethoxy or propoxy. 4. Use of 4α-acetoxy-2a-benzoyloxy-β, 20-epoxy-1β-hydroxy- -7β, 108-dimethoxy-9-oxo-11-taxen-13a-yl- (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate for the preparation of a medicament for the treatment of abnormal cell proliferation of cell cells a strain expressing a P-glycoprotein that is resistant to multiple drugs. Use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for the treatment of colon cancer. The use of a compound according to claim 5, wherein the use is carried out simultaneously with at least one other therapeutic treatment. The use of a compound according to claim 6, wherein the further therapeutic treatment comprises antmeoplastic drugs, monoclonal antibodies, immunotherapy, radiotherapy, or biological response modifying agents. Use of a compound according to claim 1, wherein the medicament is administered parenterally. • · · · · · Use of a compound according to any one of claims 1 to 8, wherein the compound of formula I is administered intravenously, intraperitoneally, intramuscularly or subcutaneously.